Conditions: Acute Kidney Injury Peritonitis Necrotizing Soft Tissue Infection
Keywords: Abdominal sepsis AKI NSTI
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 58
Healthy volunteers: no

Brief summary:
Phase 3 multicenter study to be conducted in up to 90 qualified participating sites globally to assess the efficacy and safety of Reltecimod vs placebo in patients with sepsis-associated Stage 2/3 AKI.

Detailed description:
Phase 3 randomized, placebo controlled study assessing the efficacy (complete recovery from AKI) and safety of Reltecimod in patients with suspected or confirmed abdominal sepsis (planned or completed surgical (laparotomy or laparoscopy) or interventional radiologic procedures for control of underlying abdominal infection within 24 hours of evaluation by medical personnel) or patients with surgically confirmed necrotizing soft tissue infection (NSTI), requiring intensive care unit (ICU) or step down unit admission and in whom the diagnosis of Stage 2/3 acute kidney injury (AKI; as defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria) is established at initial presentation for medical evaluation or up to 48 hours from the suspected diagnosis of abdominal sepsis or from surgically confirmed diagnosis of NSTI.

Arms:
arm 1: Single IV infusion of Reltecimod 0.5 mg/kg arm 2: Single IV infusion of 0.9% Sodium Chloride Injection (Normal Saline)

Interventions: intervention 1: Reltecimod 0.5 mg/kg intervention 2: Placebo
Intervention descriptions: intervention 1: Single IV infusion of 0.5 mg/kg Reltecimod (at a concentration of 1 mg/mL) over approximately 10 minutes intervention 2: Single IV infusion of 0.5 mL/kg of 0.9% saline (volume equivalent to Reltecimod dosing schema) over approximately 10 minutes

Protocol document:
Prot_000.pdf: 
Final Protocol ATB-203 v6.0 
31 July 2019 
 
Page 1 of 131 
 
 
PHASE 3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, PARALLEL-GROUP STUDY TO EVALUATE THE 
SAFETY AND EFFICACY OF RELTECIMOD AS COMPARED TO 
PLACEBO IN ADDITION TO STANDARD OF CARE IN PATIENTS 
WITH SEPSIS-ASSOCIATED ACUTE KIDNEY INJURY (SA-AKI)  
Product: Reltecimod 
 
Protocol Number: ATB-203 
Development Phase: Phase 3 
IND Number: 128927 
EudraCT Number: 2018-002547-29 
SPONSOR:  
Atox Bio Ltd. 
8 Pinhas Sapir St. 
Weizmann Science Park 
Ness Ziona, 7403631 
Israel 
Version 1.0 Protocol (USA) / Approval Date 22 January 2016 
Version 2.0 Protocol (USA) / Approval Date 10 December 2017 
Version 3.0 Protocol (USA) / Approval Date 11 June 2018 
Version 4.0 Protocol (France) / Approval Date 27 September 2018 
Version 5.0 Protocol (Global) / Approval Date 03 January 2019 
Version 6.0 Protocol (Global) / Approval Date 31 July 2019 
 
 


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This clinical study will be conducted in accordance with current Good Clinical Practice 
(GCP) as directed by the provisions of the International Conference on Harmonization 
(ICH); United States (US) Code of Federal Regulations (CFR) and European Union (EU) 
Directives (as applicable in the region of the study); local country regulations; and the 
Sponsor’s Standard Operating Procedures (SOPs). 
This document contains confidential and proprietary information (including confidential 
commercial information pursuant to 21CFR§20.61) and is a confidential communication 
of Atox Bio Ltd. (the “Sponsor”). The recipient agrees that no information contained herein 
may be published or disclosed without written approval from the Sponsor. 
 




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1. TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ..................................................................................................... 4 
INVESTIGATOR AGREEMENT ................................................................................................. 9 
2. 
PROTOCOL SYNOPSIS ................................................................................................... 14 
3. 
ABBREVIATIONS ............................................................................................................ 30 
4. 
INTRODUCTION .............................................................................................................. 35 
4.1 
Background Information ........................................................................................... 35 
4.1.1 
Acute Kidney Injury ................................................................................... 35 
4.1.2 
Indication .................................................................................................... 36 
4.1.3 
Investigational Medicinal Product .............................................................. 36 
4.1.3.1 
Mechanism of Action ................................................................. 36 
4.1.3.2 
Non-clinical Safety Studies ........................................................ 41 
4.1.3.3 
Clinical Studies ........................................................................... 47 
4.2 
Risks and Benefit ...................................................................................................... 54 
4.3 
Study Treatment ........................................................................................................ 56 
4.3.1 
Investigational Medicinal Product (IMP) ................................................... 56 
4.3.2 
Comparator Product ................................................................................... 56 
4.4 
Compliance Statement .............................................................................................. 56 
4.5 
Study Population ....................................................................................................... 57 
5. 
STUDY OBJECTIVES ...................................................................................................... 57 
5.1 
Primary Objective ..................................................................................................... 57 
5.2 
Secondary Objectives ................................................................................................ 57 
5.3 
Exploratory Objectives .............................................................................................. 58 
5.4 
Study Hypothesis ...................................................................................................... 59 
6. 
SELECTION OF STUDY POPULATION ...................................................................... 59 
6.1 
Inclusion Criteria ....................................................................................................... 59 
6.2 
Exclusion Criteria...................................................................................................... 62 
6.3 
Withdrawal ................................................................................................................ 64 
6.3.1 
Criteria for Premature Discontinuation from Study ................................... 64 
7. 
INVESTIGATIONAL PLAN ............................................................................................ 65 
7.1 
Dose Selection Rationale .......................................................................................... 65 
7.2 
Allocation of Treatment, Randomization and Study Drug Administration ............... 65 
7.3 
Schedule of Procedures/Visits ................................................................................... 66 
Visit 1: Screening ...................................................................................................... 66 
Visit 2 (Day 1) ........................................................................................................... 67 
Visit 3 (Day 2) ........................................................................................................... 69 
Visit 4 (Day 3) ........................................................................................................... 70 
(Days 4 to 6) .............................................................................................................. 70 
Visit 5 (Day 7 [±1 day]) ............................................................................................ 71 
Visit 6 (Day 10 [±1 day]; perform only if patient is still hospitalized) ..................... 72 
Visit 7 (Day 14 [±1 day]) .......................................................................................... 72 
Visit 8 (Day 21 [±1 day]) .......................................................................................... 73 
Visit 9 (Day 29 [+3 days]) ........................................................................................ 73 
Visit 10 (3 to 21 Days after Visit 9) .......................................................................... 74 
Visit 11 (Day 90 [+5 days])....................................................................................... 74 
Follow-up of Patients ................................................................................................ 74 
8. 
TREATMENT OF PATIENTS ......................................................................................... 75 


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8.1 
Investigational Medicinal Product............................................................................. 75 
8.1.1 
Presentation and Formulation ..................................................................... 75 
8.1.2 
Storage ........................................................................................................ 76 
8.1.3 
Administration ............................................................................................ 76 
8.1.4 
Accountability and Destruction of Surplus Investigational Product ........... 76 
8.1.5 
Disallowed Medications ............................................................................. 77 
8.1.6 
Allowed Medications ................................................................................. 77 
8.1.6.1 
Antimicrobial Agents ................................................................. 77 
8.1.6.2 
Non-antimicrobial Medications .................................................. 78 
8.2 
Study Medication Compliance .................................................................................. 78 
8.3 
Precautions and Overdose ......................................................................................... 78 
8.3.1 
Study Drug - Reltecimod ............................................................................ 78 
8.3.1.1 
Precautions ................................................................................. 78 
8.3.1.2 
Over Dosage ............................................................................... 78 
8.3.2 
Placebo Comparator ................................................................................... 78 
8.3.2.1 
Precautions ................................................................................. 78 
9. 
STUDY PROCEDURES .................................................................................................... 79 
9.1 
Informed Consent ...................................................................................................... 79 
9.2 
Clinical and Laboratory Procedures .......................................................................... 79 
9.2.1 
Start of Drug Administration Clock ........................................................... 79 
9.2.2 
Inclusion/Exclusion Criteria ....................................................................... 79 
9.2.3 
Medical and Surgical History ..................................................................... 79 
9.2.4 
Physical Examinations ............................................................................... 79 
9.2.4.1 
Interim Physical Examinations (Symptom-driven) .................... 80 
9.2.5 
Concomitant Medications ........................................................................... 80 
9.2.6 
Abdominal Infection Type ......................................................................... 80 
9.2.7 
NSTI Infection Site .................................................................................... 80 
9.2.8 
Acute Kidney Injury ................................................................................... 81 
9.2.9 
Vital Signs .................................................................................................. 81 
9.2.10 
Clinical Scores ............................................................................................ 81 
9.2.10.1 
SOFA Score Definition .............................................................. 81 
9.2.11 
Clinical Laboratory Assessments ............................................................... 82 
9.2.11.1 
Immunogenicity .......................................................................... 82 
9.2.11.2 
AKI Biomarker – Optional Sub-study ........................................ 82 
9.2.11.3 
Systemic Inflammatory Biomarkers – Optional Sub-study ........ 83 
9.2.11.4 
Total Blood Volume Collected ................................................... 83 
9.2.11.5 
Microbiology .............................................................................. 85 
9.2.11.6 
Renal Replacement Therapy Guidelines .................................... 85 
10. 
EVALUATION MEASURES FOR EFFICACY ............................................................. 86 
10.1 
Primary Efficacy Measure ......................................................................................... 86 
10.2 
Secondary Efficacy Measures ................................................................................... 86 
10.3 
Exploratory Efficacy Measures ................................................................................. 87 
10.4 
Adjudication Committee for Evaluation of AKI Stage and Recovery ...................... 87 
11. 
EVALUATION CRITERIA FOR SAFETY .................................................................... 88 
11.1 
Safety Measures ........................................................................................................ 88 
11.1.1 
Adverse Event Definitions and Classifications .......................................... 88 


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11.1.1.1 
Adverse Event ............................................................................ 88 
11.1.1.2 
Serious Adverse Event ............................................................... 89 
11.1.1.3 
Adverse Reaction........................................................................ 89 
11.1.1.4 
Expectedness of the Adverse Event ............................................ 89 
11.1.2 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ..................... 89 
11.1.3 
Adverse Events Based on Examinations and Tests .................................... 90 
11.1.4 
Pregnancies................................................................................................. 90 
11.1.5 
Relationship to Investigational Medicinal Product ..................................... 90 
11.1.6 
Severity ...................................................................................................... 91 
11.2 
Reporting of Adverse Events .................................................................................... 91 
11.3 
Reporting of Serious Adverse Events ....................................................................... 92 
11.3.1 
Initial Report .............................................................................................. 92 
11.3.1.1 
Electronic SAE Reporting System Back-up ............................... 92 
11.3.2 
Follow-up and Final Reports ...................................................................... 92 
11.4 
Disease Related Adverse Events ............................................................................... 93 
11.4.1 
List of Adverse Events that may be Associated with Abdominal Infection, 
NSTI, and Sepsis ........................................................................................ 93 
11.5 
Safety Monitoring ..................................................................................................... 94 
11.6 
Independent Data Monitoring Committee (iDMC) ................................................... 94 
12. 
STATISTICS ...................................................................................................................... 94 
12.1 
Primary Effectiveness Endpoint ................................................................................ 94 
12.2 
Secondary Effectiveness Endpoints .......................................................................... 94 
12.3 
Exploratory Measures ............................................................................................... 95 
12.4 
Safety Endpoints ....................................................................................................... 95 
12.5 
Synopsis of Key Statistical Approaches .................................................................... 95 
12.5.1 
Primary Efficacy Comparison .................................................................... 95 
12.5.2 
Sample Size Justification ............................................................................ 96 
12.5.3 
Sample Size Re-Estimation ........................................................................ 96 
12.5.4 
Futility Analysis ......................................................................................... 98 
12.5.5 
Control of Blinding and iDMC................................................................... 98 
12.6 
Summary of Other Elements of Analysis Plan .......................................................... 99 
12.6.1 
Randomization ........................................................................................... 99 
12.6.2 
Patient Populations ..................................................................................... 99 
12.6.3 
Preliminary and Descriptive Analyses ..................................................... 100 
12.6.4 
Secondary Endpoints ................................................................................ 100 
12.7 
Sub-group Analysis ................................................................................................. 100 
12.8 
Assessment of Poolability Among Sites ................................................................. 101 
12.9 
Analysis of Other Covariate Effects ........................................................................ 101 
12.10 Multiplicity .............................................................................................................. 101 
12.10.1 Longitudinal Data ..................................................................................... 102 
12.10.2 Analysis of Event-time and Overall Survival ........................................... 102 
12.11 Handling of Missing Data ....................................................................................... 102 
12.11.1 Intent-to-Treat .......................................................................................... 102 
12.11.2 LOCF of Day 28 Creatinine ..................................................................... 103 
12.11.3 SOFA Scores ............................................................................................ 103 
12.11.4 Mixed Model Repeated Measures ............................................................ 103 
12.12 Safety Analysis........................................................................................................ 103 


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13. 
SOURCE DATA ACCESS, DATA MANAGEMENT AND DATA HANDLING ..... 104 
13.1 
Data Quality Assurance ........................................................................................... 104 
13.2 
Database Management ............................................................................................ 104 
13.3 
Case Report Forms and Source Documentation ...................................................... 105 
13.4 
Data Collection........................................................................................................ 105 
13.5 
Access to Source Data ............................................................................................. 106 
13.6 
Archiving Study Records ........................................................................................ 106 
14. 
QUALITY ASSURANCE ................................................................................................ 106 
15. 
GENERAL STUDY ADMINISTRATION .................................................................... 107 
15.1 
Ethical Aspects ........................................................................................................ 107 
Good Clinical Practices / Local Regulations ........................................................... 107 
15.2 
Informed Consent .................................................................................................... 107 
15.3 
Institutional Review Board / Ethics Committee ...................................................... 108 
15.3.1 
Conditions for Modifying the Protocol .................................................... 108 
15.4 
Patient Confidentiality ............................................................................................ 109 
15.5 
Investigator Responsibilities ................................................................................... 109 
15.6 
Laboratory Accreditation ........................................................................................ 109 
15.7 
Study Initiation ........................................................................................................ 109 
15.7.1 
Study Completion ..................................................................................... 109 
15.7.2 
Study Termination .................................................................................... 109 
16. 
CONFIDENTIAL INFORMATION .............................................................................. 110 
16.1 
Confidential Information ......................................................................................... 110 
16.2 
ClinicalTrials.gov Study Registration ..................................................................... 110 
16.3 
Publication Policy ................................................................................................... 110 
17. 
REFERENCES ................................................................................................................. 111 
18. 
APPENDICES .................................................................................................................. 116 
18.1 
Appendix A - Study Visits and Procedures ............................................................. 116 
18.2 
Appendix B – APACHE II Score ............................................................................ 121 
18.3 
Appendix C – SOFA Score ..................................................................................... 123 
18.4 
Appendix D – Glasgow Coma Scale ....................................................................... 125 
18.5 
Appendix E – AKI Staging (KDIGO Criteria) ........................................................ 126 
18.6 
Appendix F – Twice the Serum Creatinine for Age, Race, and Gender .................. 127 
18.7 
Appendix G - Immunosuppressive Agents.............................................................. 128 
 
 
 


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List of Tables 
Table 1: Summary of Reltecimod pharmacokinetic parameters in healthy volunteers ....................... 48 
Table 2: Reltecimod pharmacokinetic parameters in NSTI patients .................................................. 50 
Table 3: Recovery from AKI through Day 14 by patient (Study ATX1002K) .................................. 52 
Table 4: NGAL levels (ng/mL) by patient (Study ATX1002K) ......................................................... 53 
Table 5: Maximal blood draw by visit ................................................................................................ 83 
Table 6: Examples of power for fixed sample design (1-sided α=0.025) ........................................... 98 
 
List of Figures 
Figure 1: Th1 induction ...................................................................................................................... 38 
Figure 2: Reltecimod function ............................................................................................................ 39 
Figure 3: Potential role for Reltecimod in AKI .................................................................................. 41 
Figure 4: AKI recovery rates through Day 14 by treatment group (Study ATX1002K) .................... 51 
 


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INVESTIGATOR AGREEMENT 
Version 6.0 Approval Date 31 July 2019 
I have read this protocol and agree that it contains all necessary details for carrying out this 
study. I will conduct the study as outlined herein, in compliance with current Good Clinical 
Practice (GCP) and the applicable regulatory requirements and will make every reasonable 
effort to complete the study within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals under 
my responsibility who assist in the conduct of this study. I will discuss this material with 
them to ensure they are fully informed regarding the IMP and the conduct of the study. 
I will use only the informed consent form (ICF) approved by Atox Bio Ltd. (“Atox Bio”) 
and/or its representative and the Institutional Review Board/Independent Ethics Committee 
(“IRB/IEC”) and will fulfill all responsibilities for submitting pertinent information to the 
IRB/IEC responsible for this study. 
I agree that Atox Bio, its representatives, or regulatory authorities shall have access to any 
source documents from which case report form information may have been generated. I 
agree to maintain in a safe and secure location all required study documents and primary 
source documents until notified by Atox Bio that such documents may by discarded or 
transferred. 
I further agree not to originate or use the name of Atox Bio, or any of its employees, and/or 
Reltecimod in any scientific publication, marketing or publicity material, news release or 
other public announcement, written or oral, whether to the public, press or otherwise, 
relating to this protocol, to any amendment hereto, or to the performance here under, 
without the prior written consent of Atox Bio. I further agree to keep in confidence and not 
disclose any confidential information provided by Atox Bio and/or related to the study or 
Reltecimod. 
 
 
Investigator’s Signature 
 
Date 
 
 
 
Name of Investigator 
 
 
 
 
 
Investigator Title 
 
 


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31 July 2019 
 
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Institution, Address* 
 
 
 
 
 
Institution, Phone Number* 
 
 
* If the address or phone number is changed during the course of the study, the Investigator 
will complete and provide a Form FDA 1572 to Atox Bio or its representatives but will not 
require a protocol amendment(s). Should the Investigator plan to retire or transfer to 
another institution, he/she shall notify the Sponsor and arrange for the transfer of 
responsibility for all retained study materials and source records. 
 
 


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Contact Information 
Medical Monitor 
Name 
David A. Wilfret, MD 
Company 
Atox Bio, Ltd 
Office Phone Number 
+1 919 636 7260 
Mobile Phone Number 
+1 919 805 1632 
Office Fax Number 
+1 919 765 6693 
E-mail Contact Information 
davidw@atoxbio.com  
 
Clinical Trial Managers 
Name 
Peter Vue (USA) 
Company 
Atox Bio, Ltd 
Office Phone Number 
+1 919 636 7260 
Mobile Phone Number 
+1 336 269 5340 
Office Fax Number 
+1 919 765 6693 
E-mail Contact 
peterv@atoxbio.com  
Name 
Pamela Downing (Europe) 
Company 
Atox Bio, Ltd 
Office Phone Number 
+1 919 636 7260 
Office Fax Number 
+1 919 765 6693 
E-mail Contact 
pamelad@atoxbio.com  


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Clinical Project Manager (France) 
Name 
Marie Leveque 
Company 
Centre d’Investigation Clinique / CHU de Limoges 
Office Phone Number 
+33 (0)5 55 05 88 49 (direct) 
Mobile Phone Number 
+33 (0)6 18 33 13 93 
Office Fax Number 
+33 (0)5 55 05 80 57 
E-mail Contact 
marie.leveque@chu-limoges.fr  
 
SAE Reporting Phone Number 
Atox Bio, Ltd 
+1 919 636 7260 
AnticipSante (France) 
+33 (0)1 80 83 52 72 
 
Data Management  
Name 
Ashley Lee 
Company 
PharPoint Research, Inc 
Office Phone Number 
+1 910 386 4282 
Email 
ashley.lee@pharpoint.com 
 


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Data Protection Officer 
Company 
MyData-TRUST 
Office Phone Number 
+32 65 55 41 20 
E-mail Contact 
n.l.rensonnet@mydata-trust.com 
 
 
Central Laboratory 
 
Name 
Molly Griebel 
Company 
LabConnect, LLC 
Office Phone Number 
+1 423 794 3766 
E-mail Contact 
mgriebel@labconnectllc.com  
 
Home Visiting Nurse Service (USA) 
Company 
Symphony Clinical Research 
Office Phone Number 
+1 866 333 1550 


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2. PROTOCOL SYNOPSIS 
Protocol Number 
ATB-203 
Protocol Title 
Phase 3 randomized, double-blind, placebo-controlled, parallel-group study to 
evaluate the safety and efficacy of Reltecimod as compared to placebo in addition to 
standard of care in patients with sepsis-associated acute kidney injury (SA-AKI) 
Location(s) 
A multicenter study to be conducted in up to 90 qualified participating sites globally 
Phase of 
Development 
Phase 3 
Study Population 
Patients with  
• 
Suspected or confirmed abdominal infection (planned or completed surgical 
(laparotomy or laparoscopy) or interventional radiologic procedures for control 
of underlying abdominal infection within 24 hours of evaluation by medical 
personnel); or surgically confirmed necrotizing soft tissue infection (NSTI), 
• 
Requiring hospital admission to an intensive care unit (ICU) or step-down unit 
(or equivalent), 
• 
Total Sequential Organ Failure Assessment (SOFA) score >2, and  
• 
In whom the diagnosis of Stage 2 or 3 acute kidney injury (AKI; as defined by 
Kidney Disease Improving Global Outcomes (KDIGO) criteria) is established at 
initial presentation for medical evaluation; or up to 48 hours from the suspected 
or confirmed diagnosis of abdominal infection or surgical confirmation of NSTI. 


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Study Objectives 
Primary Objective 
• 
To compare the rates of achieving the primary endpoint of freedom from durable 
loss of renal function (defined as alive, free of dialysis, and less than a 37% loss 
of estimated Glomerular Filtration Rate (eGFR; measured with the Modification 
of Diet in Renal Disease (MDRD) formula from the patient’s reference eGFR)) 
at Day 28 between the Reltecimod- and placebo-treated patients 
• 
To demonstrate the safety and tolerance of Reltecimod when administered as a 
single dose of 0.50 mg/kg to patients diagnosed with SA-AKI 
Secondary Objectives 
• 
To compare the rates of the primary endpoint at Day 14 between the 
Reltecimod- and placebo-treated patients 
• 
To compare time to the primary endpoint between the Reltecimod- and placebo-
treated patients 
• 
To compare AKI-free days over 14 and 28 days between the Reltecimod- and 
placebo-treated patients 
• 
To compare the resolution of organ dysfunction (organ resolution is defined as 
having a SOFA score of ≤1 at Day 14, for individual organs and for the total 
SOFA score) between the Reltecimod- and placebo-treated patients over time 
and at Day 14 
• 
To evaluate the effect of Reltecimod (compared to placebo) in relation to the 
critical care and hospital stay parameters in patients with sepsis and AKI 
o Hospital length of stay 
o ICU length of stay 
o ICU free days in 28 days 
o Ventilator days 
o Ventilator free days in 28 days 
o Vasopressor days 
o Vasopressor free days in 28 days 
o Renal Replacement Therapy free days (days alive and free of RRT) in 28 
days 
 
• 
To compare survival status at Days 14 and 28 between the Reltecimod- and 
placebo-treated patients 
• 
To tabulate the incidence of Stages 1, 2 and 3 AKI  (using the KDIGO criteria) 
in patients with abdominal sepsis or NSTI 
• 
To demonstrate the safety of Reltecimod in regard to susceptibility to secondary 
infections 
Exploratory Objectives 
• 
To compare the primary endpoint at Day 90 between the Reltecimod- and 
placebo-treated patients 
• 
To compare the rates of improvement in durable loss of renal function (defined 
as alive, free of dialysis, and improvement leading to a lower AKI stage but no 
better than Stage 1 AKI) at Days 14, 28 and 90, between the Reltecimod- and 
placebo-treated patients 


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• 
To compare the distributions of acute kidney disease (AKD) stages (AKD 0, 1, 
2, 3, and 3F) at Days 14 and 28 between the Reltecimod- and placebo-treated 
patients 
• 
To conduct an exploratory evaluation of the incidence of chronic kidney disease 
(CKD) at Day 90 
• 
To conduct an exploratory evaluation of survival status at Day 90 in the 
Reltecimod- and placebo-treated patients 
• 
To conduct an exploratory evaluation of the primary endpoint by baseline 
pathogen 
• 
To conduct an exploratory evaluation of RRT use (i.e., type of RRT) 
• 
To evaluate the immunogenicity of Reltecimod 
• 
To conduct an exploratory evaluation of plasma and urinary biomarkers in 
patients with AKI 
• 
To conduct an exploratory evaluation of blood leukocyte transcriptome (RNA 
expression) profiling in patients with SA-AKI and compare genomic profile in 
patients treated with Reltecimod versus placebo 
• 
To define potential surrogate biomarkers (systemic) that exhibit change from 
baseline due to treatment with Reltecimod 
Study Hypothesis 
The primary hypothesis of this study is that in addition to standard of care (SoC), the 
probability of meeting the primary endpoint of freedom from durable loss of kidney 
function (defined as alive, free of dialysis, and less than a 37% loss of eGFR 
(measured with the MDRD formula from the patient’s reference eGFR)) at Day 28 
will be higher among Reltecimod-treated patients compared to placebo-treated 
patients. 
Number of 
Patients: 
120 patients with SA-AKI, due to an abdominal infection or NSTI, will be recruited 
into the study and randomized to receive either 0.50 mg/kg Reltecimod or placebo in 
a 1:1 ratio. Randomization will be performed within site and stratified according to 
acuity of AKI (i.e., whether or not AKI is diagnosed at time of presentation of 
abdominal infection or surgically confirmed NSTI; or during the 48 hours post-
diagnosis of  abdominal infection or surgical confirmation of NSTI) and subject age 
at time of enrolling in the study (>18 to <75 or >75 to <85 years old). 
Overall, the study is expected to last approximately 36 months (from first patient in 
to last patient out).    The study design includes plans for an interim analysis for the 
purpose of sample size re-estimation based on conditional power. The enrollment 
period may be longer than 36 months if a sample size expansion occurs. 


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Inclusion Criteria: 
1. Age: 18 up to and including 85 years. 
 
2. Has either suspected or confirmed diagnosis of abdominal infection with 
planned or completed surgical (laparotomy or laparoscopy) or interventional 
radiologic procedures within 24 hours of evaluation by medical personnel, or 
surgically confirmed NSTI, requiring treatment with parenteral antibiotics.  
Recommended surgical or interventional radiologic procedures for 
abdominal infection be performed with 12 hours of evaluation by medical 
personnel. 
 
A. Abdominal Infection 
• 
Suspected clinical diagnosis of abdominal infection as evaluated 
by the attending surgeon including any of the following clinical 
criteria 
- Abdominal pain and/or tenderness 
- Localized or diffuse abdominal wall rigidity 
- Mass 
- Ileus 
AND 
- Any of the following radiologic findings 
 
Free air (plain film, CT or MRI scans) 
 
Intraabdominal abscess (ultrasound, CT or MRI scans) 
 
Free peritoneal fluid (ultrasound, CT or MRI scans) 
OR 
• 
Confirmed diagnosis of abdominal infection by any of the of the 
following criteria 
- Perforation and/or necrotic bowel with surgical confirmation of 
peritonitis 
- Presence of intraabdominal abscess by surgical confirmation or 
drainage of purulent fluid from interventional radiologic 
procedure 
OR 
B. Necrotizing Soft Tissue Infection 
• 
Surgical confirmation of NSTI by attending surgeon (e.g., 
presence of necrotic tissue, thrombosed vessels in the 
subcutaneous tissue, lack of bleeding and “dishwater” (cloudy, 
thin, gray) fluid due to presumed bacterial infection (necrotizing 
cellulitis (most commonly group A strep), necrotizing fasciitis, 
necrotizing myositis and myonecrosis, NSTI of the perineum, 
bacterial synergistic gangrene, Clostridial gas gangrene) that may 
be supported by specific signs and symptoms (e.g., tense edema 
outside area of compromised skin, pain disproportionate to 
appearance, skin discoloration, ecchymosis, blisters/bullae, 
necrosis, crepitus, and or subcutaneous gas). 
 
3. SOFA score >2 (in any one or combination of the 6 major components of the 
SOFA score), measured as close as possible to study drug administration (but 
before study drug is administered). 
 
4. Planned or current admission to an ICU or step down unit (or equivalent). 
 


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5. Initial diagnosis of AKI established either upon presentation to medical care 
at the study site in those patients with suspected or confirmed abdominal 
infection or surgically confirmed NSTI; or in those patients in whom the 
initial diagnosis of AKI is established during the 48-hour period from the 
suspected or confirmed diagnosis of abdominal infection or surgical 
confirmation of NSTI. 
AKI Stage 2 or 3 according to the following KDIGO AKI criteria 
• 
Stage 2 AKI 
- Increase in serum creatinine to > 200% (≥ 2.0–fold) from a reference 
creatinine value (see below) in the absence of primary underlying 
renal disease (eGFR >30 mL/min) 
OR  
- Urine output < 0.5 mL/kg/hr x 12 hours following adequate fluid 
resuscitation [the aggregate over any 12-hour period can be used 
with hourly rate being relatively persistent over the 12-hour period] 
Note: Urine output should be calculated using Ideal Body Weight 
(IBW; using the Miller Formula52) 
• 
Stage 3 AKI 
- Increase in serum creatinine to > 300% (≥ 3.0–fold) from a reference 
creatinine value in the absence of primary underlying renal disease 
(eGFR >30 mL/min) 
OR  
- Serum creatinine ≥4 mg/dL 
OR  
- Planned or initiation of RRT for acute AKI 
 Order for RRT must be in place 
 RRT may be started prior to study drug administration as long as 
the patient is off RRT during study drug administration and at least 
one hour post study drug administration 
OR 
- Urine output < 0.3 ml/kg/hr x 24 hours or anuria x 12 hours 
following adequate fluid resuscitation 
 Urine output should be calculated using IBW (using the Miller 
Formula) 
The reference creatinine value is the serum creatinine value according to the 
following order 
- Value within 3 months of the hospital admission 
- If single value available, then use the single value for reference 
- If two values available, then use the average of two values for 
reference 
- If three or more values available, then use the median of the three 
most recent values for reference 
- Value between 3 and 12 months prior to hospital admission 


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- If single value available, then use the single value for reference 
- If two values available, then use the average of two values for 
reference 
- If three or more values available, then use the median of the three 
most recent values for reference 
- At hospital admission (if the patient is admitted without an acute 
illness) 
• 
Patients without a reference creatinine value would also be considered 
to have Stage 2 or 3 AKI if they have a serum creatinine > 200% (≥ 2.0-
fold) the normal creatinine value for age, race, and gender (Appendix 
F) and a renal ultrasound (US) or computed tomography (CT) showing 
normal kidney size within the past 90 days.  Normal kidney size is 
defined as 
- Computed Tomographic Scan  
- If either kidney is >9 cm length  
- Renal Ultrasound54 
- <60 years if either kidney is >10 cm length 
- >60 years if either kidney is >9.5 cm length 
6. Study medication must be administered within 6 hours of confirmation of 
onset of Stage 2 or 3 AKI as established at the study site, under the following 
criteria 
• 
After the decision is made by the attending surgeon at the study site for 
a surgical or interventional radiology procedure for the abdominal 
infection 
OR 
• 
After confirmed diagnosis of abdominal infection has been established 
by a surgical or interventional radiology procedure 
OR 
• 
After surgical confirmation of NSTI 
7. Females of childbearing potential must consistently use an acceptable 
method of contraception from baseline through Day 28. Females of 
childbearing potential must have a negative β-subunit hCG pregnancy test 
(urine or blood whichever is faster; blood only in France) immediately prior 
to study entry. 
• 
Non-childbearing potential is defined as current tubal ligation, 
hysterectomy, or ovariectomy or post-menopause (1 year without menses 
with an appropriate clinical profile at the appropriate age e.g. >45 years). 
• 
Acceptable methods of contraception for this study is defined as 
abstinence, hormonal therapy (e.g., oral contraceptives, hormone 
implants), intra-uterine (IUD) device, diaphragm with spermicide, 
condom with spermicide. 
 
8. If a male patient’s sexual partner is of childbearing potential, the male patient 
must acknowledge that they will consistently use an acceptable method of 
contraception (defined above) from baseline through Day 28. 


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9. Signed and dated informed consent form (ICF) as defined by the institutional 
review board (IRB) or Ethics Committee (EC) and, if applicable, California 
Bill of Rights. By signing the ICF, the patient agrees to release any medical 
records pursuant to current Health Insurance Portability and Accountability 
Act (HIPAA) Guidelines or to local country privacy regulations. If patient is 
unable to comprehend or sign the ICF, patient’s legally acceptable 
representative (or an independent physician if allowed by local rules and 
regulations) may sign the ICF.  


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Exclusion 
Criteria: 
1. Has known prior history of CKD with a documented eGFR < 30 mL/min by 
a commonly used formula such as MDRD or Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI), or known GFR < 30 mL/min. 
• 
Exception: Patients with history of CKD but no available prior eGFR 
who have documented normal kidney size on ultrasound or computed 
tomography (normal size defined above) evaluation (performed within 
90 days of screening) will be eligible 
 
2. Patients receiving RRT for chronic kidney disease: either hemodialysis, 
peritoneal dialysis, hemofiltration such as Continuous Veno-Venous 
Hemofiltration (CVVH) or hemodiafiltration. 
 
3. Previously diagnosed with documented AKI in the last 30 days. 
 
4. Documented primary glomerular disease or toxic tubulo-interstitial nephritis 
or other underlying renal diseases significantly effecting renal function (e.g., 
renal amyloidosis, polycystic kidney disease, renal cancer, renal abscess) at 
the time of AKI diagnosis. 
 
5. Patients with overt peripheral vascular disease in the involved NSTI area - 
associated with ischemic wounds/ulcers or gangrene, and/or other significant 
symptoms of inadequate vascular supply or where limb amputation is 
considered likely within 7 days due to the peripheral vascular disease. 
 
6. Diabetic patients with peripheral vascular disease who present with below 
the ankle NSTI. 
 
7. Current condition of 
(a) Inability to maintain a mean arterial pressure > 50 mmHg and/or systolic 
blood pressure > 70 mmHg for at least 1 hour prior to dosing despite the 
presence of vasopressors and IV fluids or, 
(b) a patient with respiratory failure such that an SaO2 of 80% for at least 1 
hour prior to dosing cannot be achieved, or 
(c) a patient with refractory coagulopathy (INR >5) or thrombocytopenia 
(platelet count <20,000) that does not partially correct for at least 1 hour prior 
to dosing with administration of appropriate factors or blood products. 
 
8. Severe neurological impairment due to cerebrovascular accident or cardiac 
arrest. 
 
9. Recent cerebrovascular accident in the last 3 months. 
 
10. Patients with cardiac arrest requiring cardiopulmonary resuscitation within 
the past 30 days. 
 
11. Patient is not expected to survive throughout 28 days of study due to 
underlying medical condition, such as poorly controlled neoplasm (e.g. Stage 
III or IV cancer). 
 
12. Classified as “Do Not Resuscitate”, or “Do Not Treat”, or the patient’s family 
is not committed to aggressive management of the patient’s condition. A “no 


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cardiopulmonary resuscitation (CPR)” order is acceptable if the patient 
and/or the family are still committed to aggressive care short of CPR. 
 
13. Any concurrent medical condition, which in the opinion of the Investigator, 
may compromise the safety of the patient or the objectives of the study or the 
patient will not benefit from treatment such as 
• 
Congestive heart failure (CHF) {New York Heart Association (NYHA) 
class III-IV} 
• 
Very severe chronic obstructive pulmonary disease (COPD) {GOLD 
Stage IV or use of continuous home oxygen prior to hospital admission 
(sleep apnoea treated with continuous positive airway pressure or 
biphasic positive airway pressure oxygen during sleep is acceptable)} 
• 
Liver dysfunction {Childs-Pugh class C} 
• 
Primary or acquired immunodeficiency or immunosuppression due to 
treatment with immunosuppressive medications (see Appendix G for 
list of excluded immunosuppressive medications) 
• 
Known HIV infection with CD4 count < 200 cells/mm3 or < 14% of all 
lymphocytes 
• 
Neutropenia < 1,000 cells/mm3 not due to the underlying infection 
• 
Receiving or about to receive chemotherapy or biologic anti-cancer 
treatment, although hormonal manipulation therapies for breast and 
prostate malignancies are permitted 
• 
Hematological and lymphatic malignancies in the last 5 years 
 
14. Patient with >20% body surface area burn wounds. 
 
15. Patient has acute pancreatitis with no established source of infection, 
uncomplicated appendicitis, or cholangitis or cholecystitis without 
peritonitis. Note - necrotic or gangrenous gallbladder or appendix with 
peritonitis is allowed. 
 
16. Pregnant or breastfeeding women (lactating women must not breastfeed and 
must discard breastmilk for at least 28 days after receiving study drug); 
Women of childbearing potential must have a negative β-subunit hCG 
pregnancy test immediately prior to study entry. 
 
17. Previous enrollment in a clinical trial involving investigational drug or a 
medical device within 30 days before provision of written informed consent 
for the study or within five half-lives of the investigational drug, whichever 
is longer. 
 
18. Previous enrollment in any Reltecimod protocol (ATB-001, ATB-201, ATB-
202 or ATB-203). 
 
19. Patients under guardianship or trusteeship (France only). 
 
20. Absence of social insurance (France only). 


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Investigational 
Product: Type, 
Dose and Mode of 
Administration 
Reltecimod is the sodium acetate salt of a 10-amino acids synthetic peptide that is 
homologous to specific amino acid residues of the T-lymphocyte receptor CD28. 
Reltecimod is packaged in glass vials as a lyophilized powder to be reconstituted with 
10.5 mL of sterile water for injection (WFI) to a concentration of 1 mg/mL. Each vial 
contains 10.5 mg of Reltecimod with an excipient to protect the peptide during the 
lyophilization process. Sterile WFI should be obtained by the site pharmacy. 
The dose of Reltecimod will be 0.50 mg/kg, administered as a one-time dose, with 
drug administration initiated within the 6-hour time-window from the diagnosis of 
SA-AKI, only after the decision is made by the attending surgeon at the study site for 
a surgical or interventional radiology procedure for the abdominal infection or after 
confirmed diagnosis of abdominal infection has been established by a surgical or 
interventional radiology procedure; or after surgical confirmation of NSTI as 
described in the inclusion criteria.   
Drug will be reconstituted on the day of its administration, in close proximity to 
infusion time, and several vials will be pooled together to compose the requested 
dose. Drug will be administered as an intravenous infusion, separate from other 
medications, over 10 minutes using a syringe pump (may be manually pushed if 
approved by the medical monitor). Volume of administration will be dependent on 
the patients’ actual weight plus adequate priming volume of the IV line. 
Placebo for Reltecimod is pyrogen-free and preservative-free sterile 0.9% sodium 
chloride solution, USP. This should be obtained by the local pharmacy. The volume 
of blinded placebo should be calculated similarly as for the active group according to 
the patient’s actual body weight (0.50 mL/kg), plus adequate priming volume of the 
IV line. 


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Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study design from clinical presentation to study drug administration for patients 
with abdominal infection or necrotizing soft tissue infection and confirmed Stage 
2 or 3 AKI. 
 


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Study Visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 
Study Day 
1 
Screening 
2 
Day 1 
Begins with study drug administration and ends with 
the same calendar day 
3 
Day 2  
4 
Day 3  
5 
Day 7 (±1 day) 
6 
Day 10 (±1 day) 
Perform only if patient is still hospitalized 
7 
Day 14 (±1 day) 
8 
Day 21 (±1 day) 
9 
Day 29 (+3 days) 
10 
3 to 21 Days after Visit 9 
11 
Day 90 (+5 days) Follow up & Termination 
 


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SOFA Score Definition: 
Screening SOFA 
Screening SOFA score components are to be captured and the total score to be 
calculated prospectively and must be performed prior to study drug 
administration.  The SOFA score should be evaluated any time after arrival at the 
hospital (may include referring hospital evaluations), although should be no more 
than 6 hours prior to study drug administration. Total screening SOFA score must 
be ≥2 to be considered eligible for enrollment.  
Sites are encouraged to re-evaluate the SOFA score as close to study drug 
administration as feasible for patients not meeting SOFA ≥2 inclusion criteria 
during initial screening.  
Screening SOFA will include measurements of the components in the following 
organ/systems: respiratory (to include evaluation of oxygenation either directly by 
arterial blood gas or by calculation of PaO2 from SpO2), cardiovascular, renal, 
coagulation, GI/hepatic, and CNS. 
SOFA Score 
Measurements of 6 organ systems, including CNS. To be measured on Days 1, 3, 
7, and 14 and calculated retrospectively. 
SOFA Respiratory Parameter 
In case it is not possible to take arterial blood gases to determine the SOFA 
respiratory parameter, SpO2/FiO2 ratio can be imputed for PaO2/FiO2 ratio. 


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Statistical Analysis 
Randomization: 120 patients will be recruited into the study and randomized to 
either 0.50 mg/kg Reltecimod or placebo in a 1:1 ratio. Randomization will be 
performed within site and according to two stratification variables. 
•
Acuity of AKI: whether or not AKI is diagnosed at time of presentation
of abdominal infection or surgical confirmation of NSTI; or during the 48
hours following the suspected diagnosis of abdominal infection or
surgical confirmation of NSTI.
•
Subject Age: >18 to <75 or >75 to ≤85 years old.
Four computer generated, blocked randomization lists will be provided for each 
site, one for each of four strata defined on the basis of the 2 by 2 cross-tabulation 
of the two stratification variables. Within each block, half of the assignments will 
be to active drug and half to placebo, in random order. Block sizes will be varied. 
Blinding: The study will remain blinded as to treatment allocation. The actual 
randomized treatment allocations will be kept by a contracted third-party 
responsible only for managing the randomization process. A variable indicating 
the blinded treatment allocations will not be part of the clinical study data to be 
managed by the data management clinical research organization (CRO). 
Therefore, only blinded study data will be available to the primary study 
statistician and responsible primary programming staff. 
Analysis Sets: 
•
The intent-to-treat (ITT) analysis set will include all randomized patients.
•
The As-Treated (AT) analysis set will include all randomized patients
who were exposed to study medication (active or placebo). The AT
analysis set will be used in the primary safety analyses with patients
assigned to actual treatment received.
•
The modified intent-to-treat (mITT) analysis will include all randomized
patients who were exposed to study medication (active or placebo) and
had a definitive diagnosis of abdominal sepsis or NSTI with patients
assigned to their intended randomized assignment.  The mITT set will be
used in primary effectiveness comparisons.
•
Supporting effectiveness analyses may be performed using a Per Protocol
(PP) analysis set.
Primary Analysis: The primary efficacy comparison involves testing the 
following superiority hypotheses: Ho: π0.50 − πPlacebo ≤ 0 vs Ha: π0.50 − πPlacebo > 0; 
where π0.50 and πPlacebo represent the true probability of freedom from durable loss 
of eGFR (alive, free of dialysis, and less than a 37% loss of eGFR (measured with 
the MDRD formula from the patient’s reference eGFR)) at Day 28. Each 
probability represents the proportion of subjects on each arm expected to achieve 
freedom from durable loss of renal function. These hypotheses will be tested using 
an unadjusted chi-square test at a one-sided type 1 error rate of α=0.025. The null 
hypothesis will only be rejected if the proportion of responders is larger in the 
active drug group compared to placebo. 
Sample Size Justification: This trial will enroll 120 subjects that will be 
randomized in a ratio of 1:1 to either Reltecimod 0.50 mg/kg (n=60) or placebo 
(n=60), each in addition to SoC. Sample size analysis was performed assuming 
that all patients will be evaluable for the primary endpoint using last observation 
carried forward (LOCF) for patients missing a serum creatinine value on Day 28. 


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The primary efficacy hypothesis will be tested using an unadjusted χ2 statistic with 
a one-sided α=0.025 significance level. The null hypothesis will only be rejected 
if the investigational drug demonstrates superiority. Statistical power was 
computed for a range of expected treatment group differences supported by the 
results of preliminary studies. Based on preliminary data, a total of 120 patients 
will be enrolled. This sample size results in 89% power if the true success rates 
are 75% and 50% for the investigational drug and placebo, respectively. 
Sample Size Re-Estimation: A “Promising Zone” sample size re-estimation 
interim analysis is planned for when between 50% and 67% of the initial sample 
size is evaluable for the primary efficacy endpoint53).  The purpose of the sample 
size re-estimation is to maintain (conditional) power when the treatment group 
difference is smaller than 0.25, but still clinically meaningful.  
A pre-specified maximum sample size expansion will be specified prior to 
providing unblinded results to the independent data monitoring committee 
(iDMC) but in no case will the sample size expansion exceed an additional 200 
subjects. With this restriction, only clinically meaningful treatment effects are 
detectable with good statistical power at the maximum sample size. The specific 
rules for determining if sample size expansion is permittable and if so, by how 
much, will ensure control of type 1 error. 
Specifically, the sample size will be increased up to the maximum to maintain 
conditional power to as close to 80% as possible, but only if conditional power at 
the interim analysis is above a pre-specified threshold that results in control of 
type 1 error to the desired nominal value. If conditional power falls within the 
Promising Zone, increasing the sample size up to the pre-specified maximum is at 
the discretion of the Sponsor.  
Futility Analysis: In addition to sample size re-estimation, a non-binding futility 
analysis will be conducted at the time of the interim analysis.  If conditional power 
is below a pre-specified futility threshold, enrollment may be immediately stopped 
at the discretion of the Sponsor.  
Independent Data Monitoring Committee (iDMC): A detailed iDMC charter 
will be provided to clarify all relevant issues relating to the conduct of the sample 
size re-estimation and futility analysis, including specific details regarding the 
operational procedures with fire-walls to protect against potential operational 
biases, decision rules, composition of the iDMC members and their conflict of 
interest statements. 
Adjudication Committee for Evaluation of AKI Stage and Recovery: Experts 
chosen for the AKI Adjudication Committee will be independent of the Sponsor 
and neither they nor their institutions participated in the sample collection or 
sample measurement studies. Each adjudicator will be provided a form for each 
patient containing all relevant clinical information. Adjudicators will be blinded 
to group assignment and clinical data will be identified only by anonymized 
identification number. Adjudicators will indicate their assessment of AKI staging 
and recovery independently without consultation with each other. The basis for 
the adjudication will be the KDIGO consensus criteria corresponding to Stages 1-
3 (mild to severe). A two thirds majority was predefined for use as the final 
adjudication. 
Secondary Endpoints: Secondary endpoints have been specified from several 
domains including a similar endpoint but defined at Day 14. Additional secondary 
endpoints include time to the primary endpoint, AKI free days, SOFA over time, 
and critical care and hospital stay parameters (hospital length of stay (LOS), ICU 
and ICU-free days, ventilator days and –free days, vasopressor days and –free 


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days). Analyses for these endpoints will generally be descriptive, with emphasis 
on characterizing clinical effect sizes. Nominal p-values will be presented. 
Categorical outcomes will be described using counts and percentages with 
nominal p-values determined through chi-square or exact methods. Critical care 
and hospital stay endpoints will be described using non-parametric approaches 
including using concordance statistics to characterize clinical effect sizes and 
Wilcoxon rank sum tests to determine nominal statistical significance. Methods 
appropriate for time-to-event endpoints including survival and life-table methods 
will be used for time-to-recovery endpoints. 
 
Safety Analysis: The primary safety measures are Adverse Events (AEs) 
(including serious adverse events [SAEs]), clinical safety laboratory, physical 
exam, vital signs through Day 28 and determination of survival through Day 28. 
The safety profiles will be compared between active and placebo groups using 
descriptive statistics as appropriate for continuous and categorical safety variables. 
Changes in continuous safety measures such as laboratory values will be 
summarized by mean changes over time using descriptive statistics (mean, SD, 
median, minimum and maximum). The presence of clinically significant safety 
findings will be summarized by shift tables separately for each group using counts 
and percentages. AEs will be classified according to system organ class and 
preferred term and summarized by counts and percentages. AEs will also be 
summarized by relationship to study drug, severity, and whether they are serious. 
Specific summaries will involve AEs and SAEs in the Infection/Infestation system 
organ class. Results from physical exams will be tabulated for Screening, Day 7, 
and Day 14. For each test, the number of patients evaluated, and the numbers and 
percentages of patients with Normal and Abnormal results will be tabulated. Vital 
signs including weight, temperature, systolic blood pressure, diastolic blood 
pressure, respiration rate, and heart rate will be summarized across time 
(Screening, Day 1, Day 2, Day 3, Day 7, and Day 14 separately by treatment group 
by N, Mean, and SD.  
 


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3. ABBREVIATIONS 
Abbreviation  
Description 
AE 
 
Adverse Event 
AKD 
 
Acute kidney disease 
AKI 
 
Acute kidney injury 
ALP 
 
Alkaline phosphatase  
ALT 
 
Alanine transaminase  
APC 
 
Antigen-resenting Cell 
ARDS 
 
Acute respiratory distress syndrome 
AST 
 
Aspartate transaminase 
AT 
 
As-Treated 
AUC 
 
Area under the curve 
CBC 
 
Complete blood count 
CFR 
 
Code of Federal Regulations 
CHF 
 
Congestive heart failure 
CI 
 
Confidence Interval 
CKD 
 
Chronic kidney disease  
CL 
 
Clearance (plasma) 
CLSI 
 
Clinical and Laboratory Standards Institute 
CNS 
 
Central Nervous System 
COPD 
 
Chronic obstructive pulmonary disease 
CPR 
 
Cardiopulmonary resuscitation 
CRO 
 
Contract Research Organization 
CRP 
 
C-Reactive Protein 
CRRT 
 
Chronic renal replacement therapy 
CT 
 
Computed tomography 
CVVH 
 
Continuous Veno-Venous Hemofiltration 


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Abbreviation  
Description 
DLT 
 
Dose limiting toxicities 
DPO 
 
Data Protection Officer 
EC 
 
Ethics Committee 
ECC 
 
Endogenous creatinine clearance 
ECG 
 
Electrocardiogram 
eCRF 
 
Electronic Case Report Form 
EDC 
 
Electronic data capture  
eGFR 
 
Estimated glomerular filtration rate 
FDA 
 
US Food and Drug Administration 
FiO2 
 
Fraction of Inspired Oxygen 
GFR 
 
Glomerular filtration rate 
GCP 
 
Good Clinical Practice 
hCG 
 
Human Chorionic Gonadotropin 
hERG 
 
Human Ether-a-go-go Related Gene 
HIPAA 
 
Health Insurance Portability and 
Accountability Act 
IBW 
 
Ideal Body Weight 
ICF 
 
Informed Consent Form 
ICH 
 
International Conference on Harmonization 
ICU 
 
Intensive Care Unit 
iDMC 
 
Independent Data Monitoring Committee 
IEC 
 
Independent Ethics Committee 
IgG 
 
Immunoglobulin G 
IgM 
 
Immunoglobulin M 
IHD 
 
Intermittent hemodialysis  
IMP 
 
Investigational Medicinal Product 


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Abbreviation  
Description 
IND 
 
Investigational New Drug 
IA 
 
Interim analysis 
IRB 
 
Institutional Review Board 
ITT 
 
Intent-to-Treat 
IUD 
 
Intra-uterine device 
IV 
 
Intravenous 
KDIGO 
 
Kidney Disease Improving Global Outcomes 
KLH 
 
Keyhole Limpet Hemocyanin 
LAR 
 
Legally acceptable representative 
LOCF 
 
Last observation carried forward 
LOS 
 
Length of stay 
LPS 
 
Lipopolysaccharide 
MAR 
 
Missing at random 
MCAR 
 
Missing completely at random 
MDRD 
 
Modification of Diet in Renal Disease 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
MHC 
 
Major Histocompatibility Complex 
mITT 
 
modified Intent-to-Treat 
MMRM 
 
Mixed Model Repeated Measures 
MTD 
 
Maximum Tolerated Dose 
NGAL 
 
Neutrophil gelatinase-associated lipocalin 
NOAEL 
 
No Observed Adverse Event Level 
NSAIDS 
 
Non-steroidal anti-inflammatory drugs 
NSTI 
 
Necrotizing Soft Tissue Infection 
NYHA 
 
New York Heart Association 
PAMP 
 
Pathogen associated molecular patterns 


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Abbreviation  
Description 
PaO2 
 
Partial pressure oxygen in arterial blood 
PBMC 
 
Peripheral Blood Mononuclear Cell 
PE 
 
Physical examination 
PK 
 
Pharmacokinetics 
PP 
 
Per Protocol 
QTc 
 
QT interval corrected 
QTcF 
 
QT interval corrected Fridericia 
RRT 
 
Renal replacement therapy 
SAE 
 
Serious Adverse Event 
SA-AKI 
 
Sepsis-Associated Acute Kidney Injury 
SaO2 
 
Arterial oxygen saturation 
SAP 
 
Statistical analysis plan 
SD 
 
Standard Deviation 
SoC 
 
Standard of Care 
SOFA 
 
Sequential Organ Failure Assessment 
SOP 
 
Standard Operating Procedure 
SpO2 
 
Peripheral capillary oxygen saturation 
SSR 
 
Sample size re-estimation 
SUSAR 
 
Suspected Unexpected Serious Adverse 
Reaction 
TCR 
 
T-cell Receptor 
TEAE 
 
Treatment Emergent Adverse Event 
Th1 
 
T-Helper 1 Cell (CD4) subset 
Th2 
 
T-Helper 2 Cell (CD4) subset 
TNF 
 
Tumor Necrosis Factor 
US 
 
Ultrasound 


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Abbreviation  
Description 
WBC 
 
White Blood Cell 
WFI 
 
Water for Injection 
WHO 
 
World Health Organization 


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4. INTRODUCTION 
4.1 
Background Information 
4.1.1 Acute Kidney Injury 
AKI is a common medical condition and results in hospital complications in critically ill 
patients. Its incidence among intensive care unit (ICU) patients has been reported to range 
between 16-67%1, and in the US it occurs in approximately 20% of hospital admissions2, 
and according to an Australian intensive care study, it is increasing every year by 2.8%3. 
AKI results in an abrupt decrease in kidney function and is associated with poor prognosis, 
extensive morbidity, increased short term and long term mortality and significant health 
care expenditures4–78. AKI is one of the most serious and common health complications, in 
the critical care setting (ICU), AKI is associated with a mortality rate of 60%9, and despite 
advances in supportive care, mortality rates associated with AKI remain high. Depending 
on AKI severity, patients spend a long time in the ICU and hospital, may require long term 
dialysis treatment or kidney transplantation, may develop chronic kidney disease (CKD) or 
end stage kidney failure and represents an important burden in clinical practice. 
Any stage of AKI has implications on both short term and long term outcomes10. As was 
reported by Lassnigg et al. 2004, even subtle increases in serum creatinine in surgical 
patients were found to be associated with an augmented mortality. Even patients with 
transient AKI experience worse long term outcomes11. 
A primary driver of AKI is sepsis, especially in critically ill patients, which account for 
26% of cases in developed countries1. Clinical and basic science data indicate that sepsis-
associated AKI (SA-AKI) is distinct from AKI without sepsis, based on characteristic 
pathophysiological mechanisms, unique profile of timing (onset and duration), and 
association with different short-term and long-term outcomes. Sepsis triggers a systemic 
cytokine-chemokine response, leading to end organ injury (which is manifested by cellular 
and subcellular injury: acute tubular necrosis, tubular and mesenchymal apoptosis, injury 
to the glomerulus, and inflammation of the nephron). Organ dysfunction secondary to 
sepsis is a significant contributor to mortality in critical care patients, regardless of the 
underlying septic cause. Furthermore, AKI can lead to inflammation and apoptosis in other 
organs besides the kidney, such as the lungs, heart and brain via organ cross talk12. 
With the lack of specific therapy for AKI that can either prevent AKI, hasten recovery of 
kidney function or abrogate the deleterious systemic effects of AKI, early detection of 
injury, coupled with initiation of appropriate supportive care and harm avoidance remain 
the mainstay of therapy. 
Several components have been associated with development of AKI: inflammation, 
oxidative stress, apoptosis, and epithelial dysfunction. Among them inflammation has an 
important role, supported by evidence from both experimental models and clinical 
studies13. Following tissue injury at the site of sepsis, cells release damage associated 
molecular patterns (DAMPS), molecules that result in a further pro-inflammatory response 


Page 36 of 131 
Final Protocol ATB-203 v6.0 
31 July 2019 
in distant organs, including the kidney through activation of immune cells (T cells and 
dendritic cells)14. 
4.1.2 Indication 
The treatment indication is SA-AKI. The Investigational Medicinal Product (IMP) 
Reltecimod acts as an immunomodulator to attenuate CD28 activation of T-Helper 1 Cell 
1 (CD4) subset (Th1) lymphocytes. Reltecimod is being developed for the treatment of SA-
AKI in conjunction with standard of care (SoC), antibiotic therapy and supportive care. 
The current study, ATB-203, is a Phase 3 clinical trial that will compare efficacy and safety 
of Reltecimod versus placebo (both in conjunction with SoC) for the treatment of SA-AKI. 
4.1.3 Investigational Medicinal Product 
Reltecimod (also known as AB103 or p2TA) is the acetate salt of the synthetic peptide that 
consists of 10 amino acids. Reltecimod has homology to amino acid residues 8-15 of the 
co-stimulatory receptor CD28 and has D-Ala residues abutted to N- and C-termini to render 
them more protease resistant. Binding of Reltecimod to CD28 is postulated to prevent 
activation of CD28 by B7 on the antigen-presenting cell (APC). Reltecimod has broad 
spectrum activity in animal models and was shown to inhibit pro-inflammatory cytokine 
induction without any evidence of agonist activity (up-regulation of cytokines) in response 
to bacterial toxins. 
Reltecimod is a lyophilized powder, formulated to contain 1 mg/mL of the Reltecimod 
peptide, 30 mg/mL mannitol, and 3.6 mg/mL sodium chloride after reconstitution with 
sterile water for injection (WFI). The drug product to be used in clinical trials will be 
supplied in 20 mL vials. Each vial contains nominal amounts of the API and excipients as 
follows: 10.5 mg of Reltecimod, 315 mg of mannitol, and 37.8 mg of sodium chloride.   
Prior to use, each vial of drug (10.5 mg) is solubilized in 10.5 mL of WFI to generate a 
drug concentration of 1 mg/mL. 10 mL (10 mg Reltecimod) will be withdrawn from each 
vial and pooled together with 10 mL from additional vials, to constitute the final amount 
(volume) of drug needed for each patient (based on individual patient’s actual body 
weight). 
The reconstituted drug product is administered directly and is not diluted prior to 
administration. It will be administered at a dose of 0.50 mg/kg as an intravenous infusion 
given over 10 minutes. 
Encouraging results from non-clinical (See Section 4.1.3.2) and clinical studies (Phase 1 
and 2; see Section 4.1.3.3) indicate a good safety profile with no reported toxicities in 
animals or humans as well as potential efficacy in this patient population. 
4.1.3.1 Mechanism of Action 
CD28 is a co-stimulatory receptor, which is a critical regulator of the immune response. 
Expressed constitutively on naïve T cells (mostly CD4+ and CD8+), CD28 is a homodimer. 
Its signal is mediated by dimerization and binding to its ligands on the APC, delivering a 
strong activation signal to the effector cell. This signal is required to avoid an apoptotic or 
anergic response by the lymphocyte. CD28 interacts with its B7 co-ligands (B7.1 (CD80) 


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and B7.2 (CD86), residing on APCs). This interaction transduces the signal that is essential 
for an immediate T-cell response and regulates early antigen signaling. A major component 
of such interaction is the induction of an inflammatory response, mediated by multiple pro-
inflammatory cytokine and chemokine production and release. There is growing 
appreciation that T-cell and APC interactions play a critical role in inflammatory response 
of severe infections and link the adaptive and innate immune systems. Inflammation is a 
protective response that is intended to eliminate the initial cause of cell injury, as well as 
any necrotic cells and tissues resulting from the original insult, and to initiate the process 
of repair. Acute or chronic inflammation might lead to a multitude of diseases and is 
therefore normally closely regulated. Amplified and dysregulated inflammatory response 
is triggered by various insults causing cellular injury (pathogen- and non-pathogen 
induced), eliciting exaggerated response and overexpression of pro-inflammatory 
cytokines and chemokines (cytokine storm), that are harmful to the host. 
Major inducers of the inflammatory response include bacterial exotoxins and endotoxins, 
as well as external stimuli. During Gram-positive bacterial infection exotoxins such as 
superantigens, stable proteins that stimulate virtually all T cells, without a need for 
processing by APC are secreted15–17. Bypassing the restricted presentation of conventional 
antigens, superantigens can activate 30-50% of T cells to divide and produce cytokines. In 
contrast to conventional immune response, during which 0.01% of T cells react with 
antigens to orchestrate immune attack without harming healthy tissue, superantigens 
activate the cellular immune response at least 5,000-fold more strongly than do ordinary 
antigens. Toxic shock results from a sudden and massive induction of Th1 cytokines 
including interleukin-2 (IL-2), interferon gamma (IFN-γ), and tumor necrosis factors 
(TNF)18–20. 
Induction of these Th1 cytokines can occur through the binding of a superantigen (produced 
by Gram-positive bacteria) to the major histocompatibility class II (MHC II) complex 
(located on the surface of an APC), and the T-cell receptor (TCR, located on the surface of 
a Th1 cell). However, this interaction is insufficient for activation. Superantigens must also 
bind to CD28. By engaging all 3 receptors simultaneously, the superantigen overcomes its 
inherently limited affinity for each, allowing it to deliver a strong activation signal (Figure 
1).


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Figure 1: Th1 induction 
 
 
Binding sites of superantigen (blue) in the immunological synapse. Direct binding of superantigen to CD28 
is triggering activation of CD28 
In addition to this superantigen-mediated mechanism, the inflammatory response can be 
triggered by endotoxin-producing bacteria (e.g. Gram-negative bacteria or mixed 
infections). The prototypical example of a bacterial endotoxin is lipopolysaccharide (LPS), 
found in the outer membrane of various Gram-negative bacteria. LPS toxicity (in addition 
to TLR4 signaling) involves the co-stimulatory molecule CD28 and its B7 ligand, which 
upregulates the co-receptors for CD28 co-activating signals, CD80/86, and thereby 
amplifies CD28-CD80/86 signaling21,22. In addition, CD28 is an important mediator in 
LPS-induced septic shock23, and in cases of Gram-negative infections24 or polymicrobial 
infections25,26. 
Inflammatory response in AKI: AKI is a major complication of sepsis, and SA-AKI is 
regarded as the foremost precipitant of AKI. Sepsis-associated AKI portends a high burden 
of morbidity and mortality in patients with critical illness, and represents a distinct subset 
of AKI, contributing to a unique constellation of hemodynamic, inflammatory and immune 
mechanisms1. 
The precise mechanisms that lead to AKI during sepsis remain unknown. It is recognized 
that the pathogenesis of SA-AKI is a multifactorial process involving an interplay between 
inflammation, apoptosis and oxidative stress. Novel therapies directed at these pathways 
are now being considered as potential therapies. 
It has been accepted that the inflammatory component, especially innate immunity, has an 
important contribution to the development of renal injury, and therefore, the immune 
pathway has been acknowledged as a target for developing therapies for AKI. The 
inflammatory response involves the inflammasome which integrates danger signals into 
caspase activation and secretion of pro-inflammatory cytokines27. Depletion of T cells to 
very low levels leads to protection against renal injury28. In particular the co-stimulatory 
pathway of T cells activation via CD28 and CTLA4 has been shown to have a substantial 
role in experimental SA-AKI29. In several models, it has been demonstrated that blocking 
the co-stimulation can be beneficial and protects the kidney: Using CD28 knock-out mice, 


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animals were protected from LPS-induced acute renal failure24. CTLA4-Ig (a competitive 
inhibitor of CD28-B7 interaction) protected mice from renal injury30. Our own data 
indicated that in a model of SA-AKI, Reltecimod conferred improved outcome (both 
survival benefit and renal function). In accordance, therapies modulating the immune 
response (such as alkaline phosphatase), were shown to improve outcome in experimental 
and clinical SA-AKI31. 
In view of the significant role of CD28 in triggering inflammatory response, it was defined 
as a therapeutic target. 
Reltecimod effect: Reltecimod is the sodium salt of a synthetic peptide that consists of 10 
amino acids and has homology to amino acid residues 8-15 of the T-lymphocyte molecule 
CD28, residues that are part of its homodimer interface. Reltecimod is postulated to bind 
to the opposing monomer of CD28 and as such, to prevent activation of CD28 by B7 on 
the APC and modulate the interaction between host T cells (host factors) and pathogen 
associated molecular patterns (PAMPs) such as superantigens and endotoxins. As a result, 
Reltecimod attenuates the excessive inflammatory response mediated by co-stimulation 
(Figure 2) by modulating CD28 signaling, but not blocking it completely, thus maintaining 
the normal immune response. 
Figure 2: Reltecimod function 
 
CD28 signaling can be blocked by peptide mimetics of the contact region in each ligand: the two rims (red 
and green) of the dimer interface predicted for CD28. 
Reltecimod was originally designed and developed towards creating a broad-spectrum 
countermeasure directed against the superantigen toxin family, for the treatment of Gram-
positive bacterial superantigen toxicity. Reltecimod prevents the binding of superantigens 
to CD28 and subsequent activation of the downstream cellular cascade. As superantigens 
play a critical role in the pathogenesis caused by Gram-positive bacteria, Reltecimod could 
modulate the interaction between the host and pathogen factors, inhibiting their harmful 
effects and providing a clinical benefit. Nevertheless, binding of Reltecimod to CD28 was 
found to also intervene with the downstream signaling of CD28 independently of 
superantigens: as Reltecimod binds directly to CD28 on the opposing monomer, it can 
therefore intervene with the downstream signaling of CD28 in cases that are not mediated 


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by superantigens. As such, Reltecimod was found to be a potent attenuator of lethal 
inflammatory signaling induced by multiple pathogens, including Gram-positive and 
Gram-negative bacteria as well as viral pathogens. The role of the co-stimulatory pathway 
in the interaction of bacterial endotoxins with host cells has not been fully characterized, 
however, evidence exists that it has a role in LPS-mediated effects in endotoxin-induced 
Gram-negative infections32–35. Further support for the role of the co-stimulatory pathway 
in Gram-negative infection in animals and in sepsis patients was demonstrated using CD28 
knock out mice25,26. 
The mechanism of Reltecimod is unique as it does not involve down-regulation of the 
normal humoral immune response, is not affecting anti-inflammatory T-Helper 2 Cell 
(CD4) subset (Th2) response and does not block the protective B cell immune response36. 
Further, Reltecimod does not function as a CD28 agonist as it does not stimulate cytokine 
production in vitro, nor have detrimental effects on intoxicated (superantigen-treated) 
animals or animals infected with live bacteria. In addition, Reltecimod does not induce 
intracellular cytokine production ex vivo (tested in a large set of T-cell subsets that were 
isolated from healthy volunteers in a Phase 1 study following Reltecimod administration). 
Thus, Reltecimod is both a superantigen and a CD28 antagonist (acting to modulate their 
biological activity), its activity is not pathogen specific, and it is a host-oriented, broad 
spectrum attenuator of cytokine storm. Reltecimod can therefore be employed to treat 
infections from various sources having a substantial inflammatory component, such as SA-
AKI. Indeed, Reltecimod has been shown to have broad spectrum activity in animal models 
and inhibit pro-inflammatory cytokine induction in several conditions involving 
inflammatory response without any evidence of agonist activity (up-regulation of 
cytokines) in response to bacterial toxins. 
As Reltecimod has been shown to modulate the inflammatory response via attenuation of 
the CD28 co-stimulatory pathway36,37 and to be associated with decrease in apoptosis in 
kidney, it is postulated to have protective therapeutic effect in patients suffering from SA-
AKI by intervening with key important processes (inflammation and apoptosis) that 
contributes to both sepsis and AKI development (Figure 3).


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Figure 3: Potential role for Reltecimod in AKI 
 
 
Adjusted from Alobaidi et al., 2015. Reltecimod can modulate with pathophysiological processes that 
contributes to both sepsis and AKI 
4.1.3.2 Non-clinical Safety Studies 
The non-clinical toxicology and safety pharmacology of Reltecimod has been tested in vitro 
and in in a single-dose toxicology study in mice, repeat-dose toxicology studies in mice, 
pigs and minipigs, and fertility and embryo-fetal developmental studies in mice, and 
embryo-fetal developmental study in rabbits. the central nervous system (CNS) safety 
pharmacology study was performed in mice, and cardiovascular safety study performed in 
pigs and minipigs. Data from these studies are summarized below. 
In Vitro Toxicology Studies 
• Reltecimod was not toxic to human or pig peripheral blood mononuclear cells 
(PBMCs) in vitro at concentrations from 0.01 to 10 μg/mL (study GCF0007).  
• Reltecimod at concentrations of 4, 20 and 100 μg/mL, mixed with human blood 
at a volume ratio of 0.4 (2:5) test material:blood, did not cause hemolysis. In 
the human, this ratio corresponds to an administration of 3.2 mL/min 
intravenous infusion rate (study GCF0009).  
• Reltecimod, when mixed with human plasma at concentrations of 4, 20, and 100 
μg/mL at a ratio of 0.4 (2:5) test material:plasma, showed no adverse reactions 
such as flocculation, precipitation, or coagulation (study GCF0009). 
In Vivo Toxicology Studies 
• In an acute maximum tolerated dose (MTD) toxicology study in male and 
female mice (Study GCF0012), Reltecimod given IV at 2, 4, 8, or 16 mg/kg was 
well tolerated with no toxicologically important clinical signs, no dose-related 
Reltecimod 
Reltecimod 


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effects on body weight or food consumption during the observation period and 
no abnormalities observed at macroscopic examination. Based on the general 
good clinical condition of the animals and the absence of any clear indicators of 
toxicity, the MTD for Reltecimod was not determined within the context of this 
study. 
• In a pharmacokinetic (PK) study in male mice (Study MPS00022) with single 
dose Reltecimod (5 mg/kg), no clinically relevant abnormalities were noted 
throughout dosing and sample collection. 
• In a repeat dose toxicology GLP study in male and female CD-1 mice (Study 
MPS0025), Reltecimod was administered IV for 14 consecutive days at doses 
of 0.3, 1.25, and 5 mg/kg/day. There were no Reltecimod-related changes seen 
in clinical observations, body weights, food consumption, or serum chemistry 
parameters. A non-adverse increase in absolute white blood cells (2.0 × control) 
and absolute neutrophil count (3.0 × control) was noted in male animals dosed 
at 5 mg/kg/day on Day 15, but all recovered after a 2-week recovery period. The 
no-observable-adverse-effect-level (NOAEL) for this study was considered to 
be greater than 5 mg/kg/day. 
• In a repeat dose toxicology GLP study in male and female Yorkshire pigs (Study 
MPS00012), Reltecimod was administered to 7 to 15 kg pigs by slow bolus IV 
injection (10 mL/kg volume) once daily for 14 consecutive days at doses of 0.6, 
2.5, and 5.0 mg/kg/day. In the main study, pigs were sacrificed the day after 
dosing and another group after a 14-day recovery period. No toxicologically-
relevant effects were seen in this study. It was concluded that the apparent 
NOAEL is greater than 5.0 mg/kg. 
• In a repeat dose toxicology GLP study in male and female Gottingen minipigs 
(Study 20156690), Reltecimod Sodium was administered once weekly by 
intravenous 10-min infusion for a minimum of 14 days (i.e., dosing on Days 1, 
7, and 14) at doses of 5, 15 and 50 mg/kg/dose.  There were no early deaths, test 
article-related clinical signs, gross necropsy findings, or microscopic pathology 
findings.  There were no changes in body weights, body weight gains, food 
consumption, respiratory assessments, ophthalmology, electrocardiography, 
clinical pathology parameters (hematology, coagulation, clinical chemistry, and 
urinalysis), or organ weights.  Based on these results, the no-observed-adverse-
effect level (NOAEL) was considered to be 50 mg/kg/dose, the highest dose 
tested.  This corresponded to males and females mean Cmax = 90,100 ng/mL 
(males), 141,000 ng/mL (females) and mean AUC(0-t) = 783,000 ng*min/mL 
(males), 1,100,000 ng*min/mL (females) on Day 14. The exposures of 
Reltecimod in this study were at least 100-fold above the exposure in healthy 
human volunteers, and at least 50-fold above the exposure in NSTI patient. 
• In a fertility toxicology GLP study in male CD-1 mice (study 01136002), 
Reltecimod sodium was administered via intravenous injection (bolus) via 


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vascular access buttons (VAB) once daily for 28 days prior to mating and 
continuing through 1 day prior to euthanasia for a total of 56 to 57 doses at dose 
levels of 5, 15, and 50 mg/kg/day. There were no test article-related effects on 
survival.  One male in the 15 mg/kg/day group was found dead on Study Day 
51 in the absence of clinical observations, effects on body weight or food 
consumption, and gross necropsy observations.  In the absence of mortality 
noted at the highest dosage level of 50 mg/kg/day, this death was not considered 
test article-related.  One male in the control group was sent to necropsy in 
extremis on Study Day 48.  All other males survived to the scheduled necropsy.  
There were no test article-related clinical observations at the daily examinations 
or 5–15 minutes following dose administration at all dosage levels. Mean 
absolute body weights, body weight gains, and food consumption for males in 
the 5, 15, and 50 mg/kg/day groups were unaffected by test article 
administration throughout the treatment period (pre- and post-mating period). 
There were no test article-related effects on male reproductive performance 
(mating, fertility, and copulation indices), spermatogenic parameters (motility, 
concentration, sperm production rate, and morphology), or pre-coital intervals 
at any dosage level. There were no test article-related macroscopic findings or 
effects on organ weights in the 5, 15, and 50 mg/kg/day group males. The mean 
numbers of implantation sites and intrauterine survival of the embryos were 
unaffected by test article administration to the males at 5, 15, and 50 mg/kg/day. 
In conclusion, there were no effects on survival, clinical observations, body 
weights, body weight gains, food consumption, reproductive endpoints, gross 
necropsy findings, organ weights, or intrauterine survival.  Therefore, a dosage 
level of 50 mg/kg/day, the highest dosage level tested, was considered to be the 
no-observed-adverse-effect level (NOAEL) for male systemic and reproductive 
toxicity and early embryonic toxicity of Reltecimod sodium administered by 
intravenous injection (bolus) to Crl:CD1(ICR) mice. 
• In a fertility and embryonic developmental toxicity GLP study in female CD-1 
mice (study 01136006), Reltecimod sodium was administered via intravenous 
injection (bolus) via vascular access buttons (VAB) once daily for 14 days prior 
to mating and continuing through Gestation Day 7 for a total of 24-30 doses at 
dose levels of 5, 15, and 50 mg/kg/day. There were no test article-related effects 
on survival. One female each in the control, 5, 15, and 50 mg/kg/day groups 
were found dead or euthanized in extremis during the study. In the absence of 
other signs of toxicity at any dosage level, the single deaths or moribundity 
noted in the test article-treated groups were not considered test article-related. 
All other females survived to the scheduled necropsy. There were no test article-
related clinical observations at the daily examinations or 5–15 minutes 
following dose administration at all dosage levels. Mean absolute body weights, 
body weight gains, and food consumption for females in the 5, 15, and 50 
mg/kg/day groups were unaffected by test article administration throughout the 
treatment period. There were no test article-related effects on female 


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reproductive performance (female mating, fertility, and conception indices, 
estrous cyclicity, and numbers of days between pairing and mating). There were 
no test article-related macroscopic findings or effects on organ weights in the 5, 
15, and 50 mg/kg/day group females. The mean numbers of corpora lutea and 
implantation sites and intrauterine survival of the embryos were unaffected by 
test article administration at 5, 15, and 50 mg/kg/day. In conclusion, the dosage 
level of 50 mg/kg/day, the highest dosage level tested, was considered to be the 
no-observed-adverse-effect level (NOAEL) for female systemic and 
reproductive toxicity and early embryonic toxicity of Reltecimod sodium 
administered by intravenous injection (bolus) to female Crl:CD1(ICR) mice. 
• In an embryo-fetal developmental toxicity GLP study in female CD-1 mice 
(Study 01136003), Reltecimod sodium was administered via tail intravenous 
injection (bolus) once daily during Gestation Days 6–15 at dose levels of 5, 15, 
and 50 mg/kg/day.  All animals survived to the scheduled necropsy on Gestation 
Day 18, including 1, 2, and 1 females in the control, 5, and 15 mg/kg/day groups, 
respectively, that delivered on the day of scheduled necropsy (Gestation Day 
18). No test article-related clinical observations were noted at the daily 
examinations or 5–15 minutes following dose administration at any dosage 
level. Mean maternal body weights, body weight gains, net body weights, net 
body weight gains, gravid uterine weights, and food consumption were 
unaffected by test article administration. There were no test article-related 
macroscopic findings noted at any dosage level at the scheduled necropsy on 
Gestation Day 18. Intrauterine growth and survival were unaffected by test 
article administration at all dosage levels. There were no test article-related fetal 
malformations or developmental variations observed in all groups. Based on the 
absence of any maternal or embryo/fetal developmental effects at any dosage 
level, a dosage level of 50 mg/kg/day, the highest dosage level evaluated, was 
considered to be the no-observed-adverse-effect level (NOAEL) for maternal 
toxicity and embryo/fetal development when Reltecimod sodium was 
administered via intravenous injection (bolus) to Crl:CD1(ICR) mice. This 
corresponded to a mean Cmax value of 289,000 ng/mL and a mean AUC0-20min 
value of 950,000 (ng·min/mL) on Gestation Day 15. The exposures of 
Reltecimod in this study were at least 100-fold above the exposure in healthy 
human volunteers, and at least 50-fold above the exposure in NSTI patient. 
• In an embryo-fetal developmental toxicity GLP study in female NZW rabbits 
(Study G17034), Reltecimod sodium was administered via 1-min intravenous 
infusion once daily from implantation on Gestation Day (GD) 6 to closure of 
the hard palate on GD 18 at dose levels of 5, 15, and 50 mg/kg/day. There were 
no mortalities and no adverse clinical signs in any of the treated females at any 
of the doses tested. The mean body weight, body weight gain and food 
consumption of rabbits at all test item-treated groups were statistically 
comparable to the vehicle control group. There were no test item-related 
macroscopic findings at any dosage level at the scheduled necropsy on GD 29. 


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Maternal parameters comprising of uterine weight, number of corpora lutea, 
implantations and early and late resorptions in the test-item-treatment groups 
were comparable to the vehicle control. Gross evaluation of placenta revealed 
no findings. The litter parameters comprising of total number of fetuses, number 
of live fetuses, male and female fetal weights were comparable to the vehicle 
control group at all tested doses. No abnormality related to the test item was 
noticed at the external, visceral and skeletal examination of fetuses at any of the 
doses tested. Based on the absence of adverse findings under the conditions and 
doses employed in this study, it is concluded that No Observed Adverse Effect 
Level (NOAEL) for maternal and fetal developmental toxicity is 50 mg/kg/day, 
the highest dose tested.  This corresponded to a mean Cmax value of 387,000 
ng/mL and a mean AUClast value of 1,130,000 (ng·min/mL) on Gestation Day 
18. The exposures of Reltecimod in this study were at least 100-fold above the 
exposure in healthy human volunteers, and at least 50-fold above the exposure 
in NSTI patient. 
• In an immunotoxicology study in male and female mice (Study 302111), 
Reltecimod was administered by a slow bolus IV injection on Days 1, 8, 15, and 
22. On Day 15, the potent T-cell immunogen, keyhole limpet hemocyanin 
(KLH), (0.5 mL of 0.2 mg/mL in sterile water; 100 μg) was administered by 
intraperitoneal injection. Mice were observed for clinical signs and death. Blood 
immunophenotyping was conducted at scheduled necropsies as well as primary 
immunoglobulin M (IgM) and immunoglobulin g (IgG) antibody responses to 
KLH. Reltecimod given weekly for 4 weeks at doses of 1.25, and 5 mg/kg/dose 
were well tolerated. Although there were some variations in the immunotoxicity 
assessments, these were deemed not to be significant Reltecimod-related 
changes (blood immunophenotyping) or related to the administration with 
peptide. Statistically significant decreases in thymic weights in males given 
≥1.25 mg/kg/dose of peptide Reltecimod may have been related to test article 
administration; however, these had no histologic correlate and were reversible. 
In addition, higher thymus weights in females, as compared to males, are 
regarded as a normal phenomenon for mice, which was also consistent with the 
historical data and published observations. The NOAEL in this study was 
considered to be 5 mg/kg due the reduction in thymus weights in male mice. 
Safety Pharmacology Studies 
• Reltecimod at a concentration of 10 µg/mL had no significant effect on human 
ether-à-go-go related gene (hERG) tail current, in human embryonic kidney 
cells (HEK-293) stably transfected with hERG ion channel cDNA. This is a 
measurement of potential QT interval corrected (QTc) prolongation (GLP study 
GCF0014). 
• In the repeat dose toxicology GLP study in Yorkshire pigs (Study MPS00025) 
described above, Reltecimod at up to 5.0 mg/kg did not cause toxicologic effects 


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on electrocardiogram (ECG) interval durations. In particular, there was no effect 
of treatment on QT or QTc intervals. 
• In the repeat dose toxicology GLP study in male and female Gottingen minipigs 
(Study 20156690) described above, relevant safety pharmacology measures 
were incorporated into the study and included respiration rate and 
electrocardiographic parameters. Reltecimod was administered intravenously 
with syringe pumps over 10-minutes once weekly for a minimum of 14 days 
(i.e., dosing on Days 1, 7, and 14) at dosages of 0 (phosphate buffered saline), 
5, 15, and 50 mg/kg. For respiratory assessment, animals were monitored for 
respiratory rates on Day 7 at approximately 120 minutes post start of infusion. 
Respiratory rates were visually examined at 6-second intervals and multiplied 
to average breaths taken per minute prior to electrocardiogram (ECG) 
collection.  ECG measurements were obtained from all animals using leads I, 
II, III, aVR, aVL, and aVF. The ECG measurements were obtained once 
pretreatment (Day -7), on Day 7 at approximately 120 minutes post start of 
infusion, and during the last week of the recovery period (Day 25). Only lead II 
was evaluated by a board-certified veterinary cardiologist. Tracings were 
evaluated for the ECGs performed pretreatment and on Day 7.  Quantitative 
ECG parameters measured included HR, RR interval, PR interval, QRS 
duration, QT and QTc (Fridericia’s) interval. Reltecimod did not alter 
respiration rates or ECG rhythm, morphology, or quantitative ECG 
measurements in male or female minipigs examined on Days -7, 7 and 25. 
Reltecimod had no physiologically relevant effects on respiratory rate or 
electrocardiographic parameters in minipigs at doses up to 50 mg/kg. 
• In a mouse CNS safety pharmacology GLP study (Study MPS00023), 
Reltecimod was administered once by bolus IV injection on Day 1 of the study 
at doses of 0, 0.3, 1.25, and 5 mg/kg. A CNS screen was performed 2 minutes 
and 24 hours after dosing. There were no biologically important differences 
among the dose groups for the male and female mice in the measures of 
behavior, autonomic functions, appearance, grip strength or body temperature 
during the 2 minute or 24 hour post dosing CNS screen. Based on these data, 
the NOAEL of Reltecimod for neurobehavioral measures of the CNS screen in 
mice is greater than 5 mg/kg (the highest dose tested). 
Non-Clinical Pharmacology Studies 
Reltecimod has been shown in animal models to: 
1. Protect mice from SEB-induced lethal shock. 
2. Protect mice from LPS-induced lethal shock. 
3. Protect mice (improve survival and inflammatory response) from lethal Gram-
positive and Gram-negative bacterial infections (S. pyogenes, S. pneumonia, 
E. Coli, Polymicrobial infections [CLP]). 


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4. Improve survival and functional renal outcome of mice in a model of sepsis-induced 
AKI. 
Thus, Reltecimod shows activity in both Gram-positive and Gram-negative models of 
sepsis and septic shock. For an extensive description of the non-clinical pharmacology 
studies, refer to the Investigator’s Brochures. 
4.1.3.3 Clinical Studies 
Reltecimod has been evaluated in two safety and pharmacokinetic (PK) clinical studies, a 
Phase 1 study in healthy volunteers (study no. ATB-001) and a Phase 2 study in NSTI 
patients (study no. ATB-201). 
4.1.3.3.1 Phase 1 Study ATB-001 
The Phase 1 single center, randomized, double-blind, placebo-controlled, sequential-dose 
escalation study was conducted in 25 healthy volunteers. Four different escalating dose 
levels of Reltecimod were evaluated: 7.5 μg/kg, 37.5 μg/kg, 150 μg/kg and 450 μg/kg with 
a placebo control (1 or 2 subjects) included in each cohort; each subject received a single 
intravenous infusion of Reltecimod or placebo (saline) control. Blood was collected for PK 
and flow cytometry assessments of leukocyte subsets after infusions. Subjects were 
assessed 1-day and 6- to 8-days after the infusions for adverse events (AEs), vital signs, 
and clinical laboratory parameters. The primary objective of this study was to establish the 
safety profile and MTD of Reltecimod given as a single intravenous infusion in healthy 
volunteers. The secondary objective was to determine the PK profile of Reltecimod in 
humans after a single intravenous infusion. In addition, lymphocyte profiling was 
performed on subjects from the high dose cohort 4. PBMCs were obtained and subjected 
to flow cytometric analysis, for phenotypic analysis and intracellular cytokine expression. 
Study duration was 14 days. 
A total of 22 AEs were reported during the conduct of the trial, of which 21 (95.5%) were 
mild and only one was moderate in severity. Of all the subjects in the study, seven had AEs 
and 18 had no AEs. None of the AEs were considered related to Investigational Product. 
There were no dose-limiting toxicities nor were there any serious adverse events (SAEs). 
There were no clinically meaningful changes in vital signs, clinical laboratory parameters, 
ECG parameters or lymphocyte subsets. 
Lymphocyte profiling: Although variability between subjects was apparent, for the most 
part within a subject over time, the percentages of positive cells and absolute counts 
remained similar to those at baseline. 
PK in healthy subjects: Pharmacokinetic parameter estimates are shown below: 


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Table 1: Summary of Reltecimod pharmacokinetic parameters in healthy volunteers 
Dose 
μg/kg 
Cmax ± SD 
ng/mL 
AUC0-t ± SD 
ng-min/mL 
T1/2 ± SD 
Min 
CL ± SD 
mL/min/kg 
7.5 
10.14 ± 2.22 
61 ± 19 
ND 
ND 
37.5 
56.67 ± 30.28 
523 ± 248 
1.36 ± 0.51 
85 ± 50 
150 
208.80 ± 51.37 
2,137 ± 370 
1.26 ± 0.28 
72 ± 11 
450 
707.74 ± 269.03 
6,082 ± 2022 
1.34 ± 0.21 
80 ± 22 
AUC0-t =area under the curve from time zero to the last measurable time point, CL=clearance, Cmax= 
maximum concentration, ND = not determined, insufficient data to calculate, SD=standard deviation, T1/2 
=half-life. 
Plasma Reltecimod concentrations in all cohorts peaked near the end of the infusion and 
declined rapidly with a T1/2 of a little over one minute. The apparent elimination T1/2 was 
very similar across dose levels. Systemic exposure to Reltecimod as measured by Cmax and 
area under the curve (AUC) appeared to be dose-proportional. Consequently, plasma 
clearance (CL), which was derived from AUC and dose, was similar for all doses. The 
apparent volume of distribution, approximately 200 mL/kg, is much larger than plasma 
volume, which is consistent with distribution to sites outside the plasma compartment. 
Summary: Overall, Reltecimod given IV at doses up to 450 μg/kg was very well tolerated 
in healthy volunteers. Following a 10-minute intravenous infusion of Reltecimod to healthy 
volunteers, plasma concentrations peaked at the end of infusion and then declined rapidly 
with an apparent elimination half-life of a little over one minute. Exposure was dose-
proportional. 
4.1.3.3.2 Phase 2 study ATB-201 
The Phase 2 study (ATB-201) was a multicenter, randomized, double blind, first-in-patients 
exploratory study in subjects who had a clinical diagnosis of necrotizing soft tissue 
infection (NSTI) and scheduled to undergo urgent surgical exploration and debridement. 
The study was conducted in seven clinical sites in the US and included 40 patients evaluated 
for efficacy. Patients were randomized to receive either Reltecimod as a single intravenous 
infusion of 0.50 mg/kg or 0.25 mg/kg, or placebo (saline), over 10 minutes. Study drug or 
placebo was administered within 6 hours from clinical diagnosis, in addition to SoC 
(including prompt and repeated aggressive surgical debridement, aggressive resuscitation 
and physiologic support, and antimicrobial drugs). 
The study objectives were to determine safety and PK of Reltecimod and the potential 
treatment benefit compared to placebo, by clinical benefit (measured by resolution of 
systemic inflammatory parameters, resolution of organ dysfunction or failure, and the need 
for repeated surgeries for the primary infection), assess critical care/ pharmacoeconomic 
benefit by hospital length of stay, ICU length of stay/ICU-free days, vasopressors free days, 
and mechanical ventilation days/ free days, and define potential surrogate biomarkers. 
Study duration was 28 days. A post-hoc analysis was performed to determine the incidence 


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of AKI in this population of patients with NSTI and to evaluate the effect of Reltecimod in 
improving the recovery from AKI as compared to placebo. 
Safety results: Safety was evaluated in the ITT population, comprised of all study 
participants who were randomized and received study drug or placebo (n=43; includes 3 
patients who were dosed but not evaluated for efficacy due to not meeting 
inclusion/exclusion criteria). Due to the natural severity of the underlying disease, a high 
incidence of AEs was expected in the study population. Patients in the High dose group 
presented with a more severe state of the disease, as exemplified by a higher rate of AEs, 
SAEs, and abnormal labs on Day 0 (before study drug administration). Post Day 0 (after 
drug administration) and over the course of the study, AEs were reported in 94.1%, 93.3% 
and 81.8% of patients in the High dose, Low dose and placebo groups, respectively, with 
no statistically significant difference. No study drug-related AEs were reported. Most of 
the AEs were mild or moderate. Severe AEs were reported in two patients (11.8%) of the 
High dose group, two patients (13%) of the Low dose group and three patients (27.3%) of 
the placebo group. 
Five patients (29.4%), 8 patients (53.3%), and four patients (36.4%) in the high dose, Low 
dose, and placebo groups, respectively experienced an SAE after Day 0. All SAEs (except 
one SAE of acute renal failure in a patient of the placebo group that had a background 
condition of chronic renal disease) were assessed as related to the underlying disease of 
NSTI, and none was regarded as study drug-related. 
Four patients died during the study; one patient in each of the high and low dose groups 
and two patients in the placebo group. In both patients of the Reltecimod-treated groups, 
the cause of death was multi-organ failure related to the underlying disease of NSTI, and 
in the placebo group one patient died of respiratory failure and cardiac arrest, and the 
second patient died of septic shock that started already at Day 0 and multi-organ failure 
related to NSTI. 
In addition, there were no significant trends or findings related to laboratory abnormalities 
that could be attributed to study drug administration. 
An ECG was performed on Day 0 prior to study drug administration and within 6 hours 
post study drug administration on Day 1. Comparator groups demonstrated similar means 
and distribution of QT interval corrected Fridericia (QTcF) values. Treatment groups did 
not have higher mean change in QTc than placebo and outliers were similar in number and 
scale. 
Overall, intravenous infusion of Reltecimod at doses of 0.50 mg/kg and 0.25 mg/kg over a 
10-minute infusion period was well tolerated in this patient population and no significant 
safety signals or trends were observed. 
PK results: Following a 10-minute intravenous infusion of Reltecimod to NSTI patients 
before, during, or after surgery, plasma drug concentrations peaked at the end of infusion. 
Plasma Reltecimod concentrations declined with a half-life of approximately 5 minutes in 
the high and low dose groups. Systemic Reltecimod exposure, as measured by Cmax and 
AUC, appeared to be dose-proportional when comparing these parameters across the two 
dose groups (Table 2). There were no obvious differences in plasma Reltecimod 


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concentrations between samples collected from venous lines compared to those collected 
from arterial lines. There also did not appear to be a clear effect of dosing time relative to 
surgery. Plasma Reltecimod concentrations in patients treated before, during, or after 
surgery did not show any apparent differences. 
Table 2: Reltecimod pharmacokinetic parameters in NSTI patients 
PK Parameters 
Treatment 
group 
Statistic 
Cmax 
ng/mL 
Tmax 
min 
AUC0-∞ 
ng-min/mL 
T1/2 
min 
CL 
mL/min/kg 
0.50 mg/kg 
Mean 
1,503 
10.60 
16,020 
5.75 
39.89 
SD 
655 
4.82 
7,086 
3.64 
24.46 
Median 
1,352 
10.00 
16,921 
4.89 
29.55 
 
0.25 mg/kg 
Mean 
961 
6.73 
7,733 
4.80 
43.17 
SD 
681 
2.80 
4,021 
6.30 
26.68 
Median 
899 
5.00 
8,497 
2.61 
29.42 
The PK studies in human confirm the short elimination half-life of the product, and that the 
systemic clearance (CLs) values demonstrate that the clearance processes involved are of 
high capacity and rate. 
4.1.3.3.3 Post-hoc analysis in SA-AKI patients (Study ATX1002K) 
The clinical efficacy of Reltecimod in SA-AKI was for the first time evaluated in a post-
hoc analysis (Study ATX1002K), using the subset of NSTI patients from Study ATB-201 
who developed AKI as part of their disease process. AKI patients were defined as patients 
having at least one creatinine value (from baseline through Study Day 7), which was at 
least 1.5 times higher than the pre-illness reference value.  
The primary objective of this post-hoc analysis was to identify the subset of patients with 
NSTI that also suffered from AKI, and to assess the clinical benefit of Reltecimod on AKI 
in this specific population of NSTI patients with AKI. Clinical measures for assessment of 
efficacy were serum creatinine (also used for calculating recovery rate from AKI) and 
neutrophil gelatinase-associated lipocalin (NGAL) in plasma.   
Patients were staged according to the Kidney Disease Improving Global Outcomes 
(KDIGO guidelines, 2012) criteria38. Based on KDIGO staging, 18 patients (45%) were 
identified as having AKI, as part of their disease condition. The incidence of AKI among 
the 3 treatment groups was similar, with 7 patients (47%) each in the 0.50 mg/kg and 
0.25 mg/kg Reltecimod groups, and 4 patients (40%) in the placebo group, respectively. 
The overall AKI rate in this study was found to be similar to literature data, e.g. 51% in 
patients with septic shock as reported by Si Nga and colleagues39.   


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Recovery from AKI was used to evaluate the potential benefit of Reltecimod, and efficacy 
was determined based on definition of full recovery, partial recovery or no recovery on Day 
14 following Reltecimod drug administration.  
Definitions were as follows: 
• Complete recovery was assumed if follow-up observed creatinine value(s) noted 
through Study Day 14 was <1.5 times the patient’s reference creatinine.  
• Partial recovery was assumed if a decrease in observed creatinine value(s) through 
Study Day 14 leading to a lower AKI stage (e.g. Stage 3 to Stage 2 or 1) but still 
with a final observed creatinine ≥1.5 times their pre-illness reference creatinine.  
• No recovery was assumed if there was no change in AKI stage as assessed from 
the observed creatinine values available through Study Day 14 or the patient was 
receiving renal replacement therapy (RRT) at the time of last observed creatinine 
value(s) or patient death. 
Recovery from AKI: Patients in the Reltecimod treatment groups experienced higher rates 
of complete recovery through Day 14 than the placebo group. Of the 7 patients treated with 
0.50 mg/kg Reltecimod, 6 patients (86%) experienced complete recovery. Similar results 
were seen in the 0.25 mg/kg Reltecimod group, with complete recovery in 5 of the 7 patients 
(71%). On the other hand, only 2 of the 4 placebo-treated patients (50%) were completely 
recovered from AKI through Day 14. Of note, about 50% of spontaneous recovery is 
expected in this patient population, as observed in a retrospective clinical study of patients 
with NSTI40. 
The rates of no recovery were highest in the placebo group (50%), and comparably lower 
with Reltecimod (14% each in the high and low dose groups).  
Recovery rates through Day 14 are illustrated by treatment group in Figure 4. Individual-
patient data (including also baseline AKI stage) are presented in Table 3.  
Figure 4: AKI recovery rates through Day 14 by treatment group (Study ATX1002K) 
 
CR=complete recovery, NR=no recovery, PR=partial recovery. 
 
14%
14%
50%
0%
14%
0%
86%
71%
50%
0%
20%
40%
60%
80%
100%
High dose
Low dose
Placebo
Outcome Day 14
% NR
% PR
% CR


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Table 3: Recovery from AKI through Day 14 by patient (Study ATX1002K) 
0.50 mg/kg 
Reltecimod 
(N=7) 
0.25 mg/kg 
Reltecimod 
(N=7) 
Placebo 
(N=4) 
Patient 
No. 
AKI 
Stage 
Recovery 
Status 
Patient 
No. 
AKI 
Stage 
Recovery 
Status 
Patient 
No. 
AKI 
Stage 
Recovery 
Status 
31006* 
1 
CR 
31007 
2 
CR 
31002 
3 
NR 
31014 
2 
CR 
31010 
2 
PR 
31029 
2 
CR 
31034 
2 
CR 
31015 
1 
CR 
35001 
2 
NR 
31039 
1 
CR 
31019 
3 
CR 
37004 
1 
CR 
35003 
1 
NR 
33003 
1 
CR 
 
 
 
37001 
3 
CR 
33005* 
2 
NR 
 
 
 
37007 
1 
CR 
37006 
2 
CR 
 
 
 
AKI=acute kidney injury, CR=complete recovery, LOCF=last observation carried forward, N=number of 
subjects, NR=no recovery, PR=partial recovery. 
AKI stage refers to stage at baseline 
Individual-patient data indicate that complete recovery was not reserved to patients with 
mild AKI at baseline (KDIGO Stage 1) but was also observed in patients with more severe 
AKI (KDIGO Stage 2 or 3). 
Patients were further followed using a biomarker for early renal damage, NGAL. NGAL is 
a sensitive and specific biomarker for early renal damage41. In agreement with NGAL being 
an early marker, Day 3 post-administration was chosen for the comparison of Reltecimod 
vs. placebo. This is supported by literature data from Di Somma et al.42, showing that 
increased NGAL values are associated with AKI within the first 72 hours of hospitalization. 
Results for NGAL are based on data from a subset of AKI patients (16 of the 18) considered 
for this post-hoc analysis. 
NGAL levels are summarized by patient in Table 4. 


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Table 4: NGAL levels (ng/mL) by patient (Study ATX1002K) 
Treatment group 
Patient Number 
NGAL Levels 
Day 0 
NGAL Levels 
Day 3 
AKI Recovery Status 
through Day 14 
0.50 mg/kg Reltecimod 
31006 
111 
100 
CR 
31014 
388 
94 
CR 
31034 
86 
99 
CR 
31039 
223 
129 
CR 
37001 
774 
314 
CR 
37007 
180a 
82 
CR 
0.25 mg/kg Reltecimod 
31007 
271 
106 
CR 
31010 
139 
114 
PR 
31015 
211 
117 b 
CR 
31019 
321 
140 
CR 
33003 
143 
103 
CR 
33005 
712 
164 
NR 
37006 
102 
34 
CR 
Placebo 
31002 
100 
106 
NR 
31029 
820 
230 
CR 
37004 
463 
(150 a) 
93 
CR 
a Pre-surgery value 
b Day 2 value 
AKI=acute kidney injury, CR=complete recovery, NGAL= neutrophil gelatinase-associated lipocalin, 
NR=no recovery, PR=partial recovery. 
Reductions in NGAL between Day 0 and Day 3 were seen in all patients, except for one 
patient in the placebo group (patient 31002) who did not recover from AKI, and for one 
patient in the high dose group (patient 31034), who recovered completely from AKI. 
Reductions in NGAL levels were generally associated with favorable AKI recovery status, 
except for one patient in the 0.25 mg/kg group (patient 33005), who showed reduction in 
NGAL, but did not recover from AKI. 
In light of the small patient numbers (especially in the placebo group) and the large 
variations in NGAL levels between subjects, a presentation of NGAL levels using mean 
and standard deviations would not be meaningful. Therefore, an alternative approach was 
used. 
Values of around 90 ng/mL NGAL are reported to be “normal” levels43. In the literature, a 
cut-off of 150 ng/mL NGAL has been established as high sensitivity threshold for AKI 
prediction42. It is also the published 95th percentile of normal for the assay. 
When using this cut-off, the rates of patients with NGAL values below 150 ng/mL on Day 
0 were similar among Reltecimod- and placebo-treated patients (38.5% versus 33.3%). 
However, on Day 3 a higher percentage of Reltecimod-treated patients had NGAL levels 
below 150 ng/mL (11 of 13 patients, 84.6%), compared to placebo-treated patients (2 of 3 
patients, 66.7%), suggesting an improvement with Reltecimod. 


Page 54 of 131 
Final Protocol ATB-203 v6.0 
31 July 2019 
4.2 
Risks and Benefit 
Patients randomized to receive placebo in addition to SoC intervention in the study will not 
benefit from the potential therapeutic effect of Reltecimod, however they stand to benefit 
from the safety measures and close observation included in the study as detailed below. 
No compensation, monetary or otherwise is offered to study participants except to cover 
customary cost of travel and/or meals associated with any study required visits that may 
occur after hospital discharge. 
Reltecimod has been evaluated in a set of toxicological and safety pharmacology studies. 
No dose limiting toxicities (DLTs) were detected in any of the animal toxicology studies, 
performed in mice, pigs, minipigs, and rabbits. The highest dose tested was 50 mg/kg, and 
based on the results of all studies, the apparent NOAEL is greater than 50 mg/kg. 
In completed clinical studies, Reltecimod has been administered as a single intravenous 
infusion to 20 healthy subjects (at doses between 7.5 and 450 µg/kg), and to 32 NSTI 
patients (at doses of 0.25 or 0.50 mg/kg).  In a fully-enrolled NSTI study (data blinded), 
Reltecimod has been administered as a single intravenous infusion to approximately 145 
NSTI patients (dose 0.50 mg/kg) in ATB-202 without apparent safety concerns following 
unblinded review by an  Independent Data Monitoring Committee (iDMC) for the first 
200 randomized patients in that trial. 
The single dose administration of Reltecimod was well tolerated in both study populations, 
and no specific drug-related concerns have been identified to date. Electrolyte 
abnormalities that were frequently seen in NSTI patients in ATB-201 are considered typical 
for this patient population. 
Potential risks with CD28 antagonists include excessive pro-inflammatory response 
(measured by T cells activation and cytokine production) due to binding to CD28. In non-
clinical studies, Reltecimod had no detectable agonist activity by itself, as no induction of 
interleukin-2 (IL-2), interferon-γ (IFN-γ) or tumor necrosis factor-α (TNF-α) was observed 
in human PBMCs after exposure to Reltecimod alone. 
In clinical studies in healthy volunteers, administration of Reltecimod was shown to have 
no agonistic effect on various leukocytes subsets, as demonstrated by monitoring various 
lymphocytes subsets (CD4, CD3, CD8, Tregs, B cells) over time following Reltecimod 
administration. Both the percentage of positive cells and absolute counts remained similar 
to those at baseline. 
Thus, the completed clinical studies as well as the ongoing study in NSTI did not raise any 
safety concerns. 
Additionally, this study protocol details several safety measures 
•
Detailed exclusion criteria (Section 6.2) including: 


Final Protocol ATB-203 v6.0 
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o
Any concurrent medical condition, which in the opinion of the Investigator, may
compromise the safety of the patient or the objectives of the study or the patient
will not benefit from treatment such as:
•
Congestive heart failure (CHF) {New York Heart Association (NYHA)
class III-IV}
•
Very Severe chronic obstructive pulmonary disease (COPD) {GOLD
Stage IV or use of continuous home oxygen prior to hospital admission
(sleep apnoea treated with continuous positive airway pressure or biphasic
positive airway pressure oxygen during sleep is acceptable)}
•
Liver dysfunction {Childs-Pugh class C}
•
Immunosuppression 
(see 
Appendix 
G 
for 
list 
of 
excluded
immunosuppressive medications)
•
Known HIV infection with CD4 count < 200 cells/mm3 or < 14% of all
lymphocytes
•
Neutropenia < 1,000 cells/mm3 not due to the underlying infection
•
Receiving or about to receive chemotherapy or biologic anti-cancer
treatment, although hormonal manipulation therapies for breast and
prostate malignancies are permitted
•
Hematological and lymphatic malignancies in the last 5 years
o
Patient with >20% body surface area burn wounds
o
Patient has acute pancreatitis with no established source of infection,
uncomplicated appendicitis, or cholangitis or cholecystitis without peritonitis
(necrotic or gangrenous gallbladder or appendix with peritonitis is allowed)
o
Pregnant or breastfeeding women (lactating women must not breastfeed and must
discard breastmilk for at least 28 days after receiving study drug); Women of
childbearing potential must have a negative β-subunit hCG pregnancy test
immediately prior to study entry.
•
Frequent follow-up visits
•
A medical monitor and iDMC will monitor the safety aspects of the study (see section 
11.6). 
Reltecimod will be investigated for treatment of SA-AKI in conjunction with SoC. 
Proof of concept for use in this indication originates from a non-clinical study using a 
mouse model of sepsis-induced AKI, and from a post-hoc analysis of NSTI patients who 
developed AKI as part of their disease course. Efficacy data suggest a clinical benefit of 
Reltecimod with regard to recovery from AKI through 14 days post-administration. 
Overall, the risk-benefit assessment is considered positive for investigation of Reltecimod 
in a clinical study in SA-AKI patients. The use of the established dose regimen (0.50 mg/kg 
Reltecimod as intravenous infusion) appears justified. 


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4.3 
Study Treatment 
This is a blinded randomized clinical study in which each patient will receive a single 
treatment of either 0.50 mg/kg Reltecimod or placebo (0.9% Sodium Chloride sterile 
solution) administered intravenously. 
The intravenous infusion will be delivered by a syringe pump (may be manually pushed if 
approved by the medical monitor) over 10 minutes in a separate catheter than that used to 
deliver other medications. The syringe will identify the contents as “study drug” for 
protocol ATB-203. All study personnel and clinical staff, as well as the patient, shall remain 
blinded as to the actual composition of the study drug administered to a given patient. Only 
the assigned study pharmacist or authorized qualified designate (unblinded study-
nurse/physician) preparing the drug shall be unblinded to the treatment. 
4.3.1 Investigational Medicinal Product (IMP) 
Reltecimod drug product is an injection, powder, lyophilized, for solution dosage form. It 
is formulated to contain 1 mg/mL of the Reltecimod peptide, 30 mg/mL mannitol, and 3.6 
mg/mL sodium chloride after reconstitution with sterile WFI. The drug product to be used 
in clinical trials will be supplied in 20 mL vials. Each vial contains nominal amounts of the 
drug substance and excipients as follows: 10.5 mg of Reltecimod, 315 mg of mannitol, and 
37.8 mg of NaCl.  
Prior to use, each vial of drug product (containing 10.5 mg Reltecimod) is reconstituted in 
10.5 mL of sterile WFI to generate a peptide concentration of 1 mg/mL. 10 mL of 
reconstituted solution (containing 10 mg Reltecimod) will be withdrawn from each vial and 
pooled together with 10 mL from additional reconstituted vials, to constitute the final 
amount (volume) of drug needed for each patient (based on individual patient’s actual body 
weight). 
The reconstituted drug product is administered directly and is not diluted prior to 
administration.  The Reltecimod drug product will be administered as a single intravenous 
infusion at a dose of 0.50 mg/kg based on the patient’s actual body weight. The drug 
product is infused over 10 minutes at a rate dependent on the dosing volume. 
4.3.2 Comparator Product 
The control product is 0.9% Sodium Chloride sterile solution administered as a single 
infusion at a volume based on the patient’s actual body weight, 0.50 mL/kg (a volume 
equivalent with Reltecimod dosing schema).  Placebo “study drug” will be administered 
intravenously over 10 minutes via syringe pump (may be manually pushed if approved by 
the medical monitor) in a manner similar to that used for the IMP. 
4.4 
Compliance Statement 
This clinical study will be conducted according to the Declaration of Helsinki. The study 
will be conducted in compliance with this protocol, Good Clinical Practice (GCP) 
(CPMP/ICH/135/95), designated standard operating procedures (SOPs), and with local 
laws and regulations relevant to the use of new therapeutic agents in the country of conduct. 


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4.5 
Study Population 
Patients with  
• Suspected or confirmed abdominal infection (planned or completed surgical 
(laparotomy or laparoscopy) or interventional radiologic procedures for control of 
underlying abdominal infection within 24 hours of evaluation by medical personnel); 
or surgically confirmed necrotizing soft tissue infection (NSTI)  
• Requiring hospital admission to an intensive care unit (ICU) or step-down unit (or 
equivalent) 
• Total Sequential Organ Failure Assessment (SOFA) score >2, and  
• In whom the diagnosis of Stage 2 or 3 acute kidney injury (AKI; as defined by Kidney 
Disease Improving Global Outcomes (KDIGO) criteria) is established at initial 
presentation for medical evaluation; or up to 48 hours from the suspected or confirmed 
diagnosis of abdominal infection or surgical confirmation of NSTI. 
Patients will be stratified at time of randomization to two stratification variables: 
• Acuity of AKI: whether or not AKI is diagnosed at time of presentation of 
abdominal infection or surgically confirmed NSTI; or during the 48 hours after the 
suspected diagnosis of abdominal infection or surgical confirmation of NSTI.  
• Subject Age: >18 to <75 or >75 to ≤85 years old. 
 
5. STUDY OBJECTIVES 
5.1 
Primary Objective 
• To compare the rates of achieving the primary endpoint of freedom from 
durable loss of renal function (defined as alive, free of dialysis, and less than a 
37% loss of estimated Glomerular Filtration Rate (eGFR; measured with the 
Modification of Diet in Renal Disease (MDRD) formula from the patient’s 
reference eGFR)) at Day 28 between the Reltecimod- and placebo-treated 
patients 
• To demonstrate the safety and tolerance of Reltecimod when administered as a 
single dose of 0.50 mg/kg to patients diagnosed with SA-AKI 
5.2 
Secondary Objectives 
• To compare the rates of the primary endpoint at Day 14 between the 
Reltecimod- and placebo-treated patients.  
• To compare time to the primary endpoint between the Reltecimod- and placebo-
treated patients 
• To compare AKI-free days over 14 and 28 days between the Reltecimod- and 
placebo-treated patients 
• To compare the resolution of organ dysfunction (organ resolution is defined as 
having a SOFA score of ≤1 at Day 14, for individual organs and for total SOFA 


Final Protocol ATB-203 v6.0 
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score) between the Reltecimod- and placebo-treated patients over time and at 
Day 14 
•
To evaluate the effect of Reltecimod (compared to placebo-treated patients) in
relation to the critical care and hospital stay parameters in patients with sepsis
and AKI
o
Hospital length of stay
o
ICU length of stay
o
ICU free days in 28 days
o
Ventilator days
o
Ventilator free days in 28 days
o
Vasopressor days
o
Vasopressor free days in 28 days
o
RRT free days (days alive and free of RRT) in 28 days
•
To compare survival status at Days 14 and 28 between the Reltecimod- and
placebo-treated patients
•
To tabulate the incidence of Stages 1, 2 and 3 AKI (using the KDIGO criteria)
in patients with abdominal sepsis or NSTI
•
To demonstrate the safety of Reltecimod in regard to susceptibility to secondary
infections
5.3 
Exploratory Objectives 
•
To compare the primary endpoint at Day 90 between the Reltecimod- and
placebo-treated patients
•
To compare the rates of improvement in durable loss of renal function (defined
as alive, free of dialysis, and improvement leading to a lower AKI stage but no
better than Stage 1 AKI) at Days 14, 28, and 90, between the Reltecimod- and
placebo-treated patients
•
To compare the distributions of acute kidney disease (AKD) stages (AKD 0, 1,
2, 3, and 3F) at Days 14 and 28 between the Reltecimod- and placebo-treated
patients
•
To conduct an exploratory evaluation of the incidence of CKD at Day 90
•
To conduct an exploratory evaluation of survival status at Day 90 in the
Reltecimod- and placebo-treated patients
•
To conduct an exploratory evaluation of the primary endpoint by baseline
pathogen
•
To conduct an exploratory evaluation of RRT use (i.e., type of RRT)
•
To evaluate the immunogenicity of Reltecimod
•
To conduct an exploratory evaluation of plasma and urinary biomarkers in
patients with AKI
•
To conduct an exploratory evaluation of blood leukocyte transcriptome (RNA
expression) profiling in patients with SA-AKI and compare genomic profile in
patients treated with Reltecimod versus placebo
•
To define potential surrogate biomarkers (systemic) that exhibit change from


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baseline due to treatment with Reltecimod 
5.4 
Study Hypothesis 
The clinical hypothesis of this study is that in addition to SoC, Reltecimod will demonstrate 
a clinically significant treatment benefit over placebo. 
This hypothesis will be addressed by measuring the effect of Reltecimod in achieving 
freedom from durable loss of renal function in patients with sepsis due to abdominal 
infection or NSTI. 
Specifically, the primary effectiveness hypothesis to be tested in this study is that in 
addition to SoC, the probability of durable loss of kidney function (defined as alive, free of 
dialysis and less than a 37% loss of eGFR (measured with the MDRD formula from the 
patient’s reference eGFR)) at Day 28 will be larger among Reltecimod-treated patients 
compared to placebo-treated patients. 
6. SELECTION OF STUDY POPULATION 
To be enrolled in the study, patients must meet ALL of the inclusion criteria and NONE of 
the exclusion criteria. 
6.1 
Inclusion Criteria 
1. Age: 18 up to and including 85 years. 
 
2. Has either suspected or confirmed diagnosis of abdominal infection with planned 
or completed surgical (laparotomy or laparoscopy) or interventional radiologic 
procedures within 24 hours of evaluation by medical personnel, or surgically 
confirmed NSTI, requiring treatment with parenteral antibiotics.  Recommended 
surgical or interventional radiologic procedures for abdominal infection be 
performed with 12 hours of evaluation by medical personnel. 
 
A. Abdominal Infection 
a. Suspected clinical diagnosis of abdominal infection as evaluated by the 
attending surgeon including any of the following clinical criteria 
- Abdominal pain and/or tenderness 
- Localized or diffuse abdominal wall rigidity 
- Mass 
- Ileus 
AND 
- Any of the following radiologic findings 
 Free air (Plain film, CT or MRI scans) 
 Intraabdominal abscess (ultrasound, CT or MRI scans) 
 Free peritoneal fluid (ultrasound, CT or MRI scans) 
OR 
b. Confirmed diagnosis of abdominal infection by any of the of the following 
criteria 
- Perforation and/or necrotic bowel with surgical confirmation of 
peritonitis 
- Presence of intraabdominal abscess by surgical confirmation or 


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drainage of purulent fluid from interventional radiologic procedure 
OR 
B. Necrotizing Soft Tissue Infection 
- Surgical confirmation of NSTI by attending surgeon (e.g., presence of 
necrotic tissue, thrombosed vessels in the subcutaneous tissue, lack of 
bleeding and “dishwater” (cloudy, thin, gray) fluid due to presumed 
bacterial infection (necrotizing cellulitis (most commonly group A 
strep), necrotizing fasciitis, necrotizing myositis and myonecrosis, 
NSTI of the perineum, bacterial synergistic gangrene, Clostridial gas 
gangrene) that may be supported by specific signs and symptoms (e.g., 
tense edema outside area of compromised skin, pain disproportionate 
to appearance, skin discoloration, ecchymosis, blisters/bullae, 
necrosis,, crepitus, and or subcutaneous gas). 
 
3. SOFA score >2 (in any one or combination of the 6 major components of the SOFA 
score), measured as close as possible to study drug administration (but before study 
drug is administered). 
 
4. Planned or current admission to an ICU or step down unit (or equivalent). 
 
5. Initial diagnosis of AKI established either upon presentation to medical care at the 
study site in those patients with suspected or confirmed abdominal infection or 
surgically confirmed NSTI; or in those patients in whom the initial diagnosis of 
AKI is established during the 48-hour period from the suspected or confirmed 
diagnosis of abdominal infection or surgical confirmation of NSTI. 
AKI Stage 2 or 3 according to the following KDIGO AKI criteria: 
a. Stage 2 AKI 
i. Increase in serum creatinine to > 200% (≥ 2.0–fold) from a reference 
creatinine value (see below) in the absence of primary underlying renal 
disease (eGFR >30 mL/min) 
OR  
ii. Urine output < 0.5 mL/kg/hr x 12 hours following adequate fluid 
resuscitation [the aggregate over any 12-hour period can be used with 
hourly rate being relatively persistent over the 12-hour period] 
Urine output should be calculated using Ideal Body Weight (IBW; using 
the Miller Formula52) 
b. Stage 3 AKI 
i. Increase in serum creatinine to > 300% (≥ 3.0–fold) from a reference 
creatinine value in the absence of primary underlying renal disease 
(eGFR >30 mL/min) 
OR  
ii. Serum creatinine >4 mg/dL 
OR  
iii. Planned or initiation of RRT for acute AKI 


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 Order for RRT must be in place 
 RRT may be started prior to study drug administration as long as the 
patient is off RRT during study drug administration and up to at least 
one hour post study drug administration 
OR 
iv. Urine output < 0.3 mL/kg/hr x 24 hours or anuria x 12 hours following 
adequate fluid resuscitation 
 Urine output should be calculated using IBW (using the Miller 
Formula) 
The reference creatinine value is the serum creatinine value according to the 
following order: 
i. Value within 3 months of the hospital admission 
- If single value available, then use the single value for reference 
- If two values available, then use the average of two values for 
reference 
- If three or more values available, then use the median of the three 
most recent values for reference 
ii. Value between 3 and 12 months prior to hospital admission 
- If single value available, then use the single value for reference 
- If two values available, then use the average of two values for 
reference 
- If three or more values available, then use the median of the three 
most recent values for reference 
iii. At hospital admission (if the patient is admitted without an acute 
illness) 
c. 
Patients without a reference creatinine value would also be considered to 
have Stage 2 or 3 AKI if they have a serum creatinine > 200% (≥ 2.0-fold) 
the normal creatinine value for age, race, and gender (Appendix F) and a 
renal ultrasound (US) or computed tomography (CT) showing normal 
kidney size within the past 90 days.  Normal kidney size is defined as 
i. Computed Tomographic Scan  
ii. If either kidney is >9 cm length  
iii. Renal Ultrasound54 
- <60 years if either kidney is >10 cm length 
- >60 years if either kidney is >9.5 cm length 
6. Study medication must be administered within 6 hours of confirmation of onset of 
Stage 2 or 3 AKI as established at the study site, under the following criteria 
• After the decision is made by the attending surgeon at the study site for a 
surgical or interventional radiology procedure for the abdominal infection 
OR 


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• After confirmed diagnosis of abdominal infection has been established by a 
surgical or interventional radiology procedure 
OR 
• After surgical confirmation of NSTI 
7. Females of childbearing potential must consistently use an acceptable method of 
contraception from baseline through Day 28. Females of childbearing potential 
must have a negative β-subunit hCG pregnancy test (urine or blood whichever if 
faster; blood only in France) immediately prior to study entry. 
• Non-childbearing potential is defined as current tubal ligation, hysterectomy, or 
ovariectomy or post-menopause (1 year without menses with an appropriate 
clinical profile at the appropriate age e.g. >45 years). 
• Acceptable methods of contraception for this study is defined as abstinence, 
hormonal therapy (e.g., oral contraceptives, hormone implants), intra-uterine 
(IUD) device, diaphragm with spermicide, condom with spermicide. 
8. If a male patient’s sexual partner is of childbearing potential, the male patient must 
acknowledge that they will consistently use an acceptable method of contraception 
(defined above) from baseline through Day 28. 
9. Signed and dated informed consent form (ICF) as defined by the institutional review 
board (IRB) or Ethics Committee (EC) and, if applicable, California Bill of Rights. 
By signing the ICF, the patient agrees to release any medical records pursuant to 
current Health Insurance Portability and Accountability Act (HIPAA) Guidelines 
or to local country privacy regulations. If patient is unable to comprehend or sign 
the ICF, patient’s legally acceptable representative (or an independent physician if 
allowed by local rules and regulations) may sign the ICF. 
6.2 
Exclusion Criteria 
1. Has known prior history of CKD with a documented eGFR < 30 mL/min by a 
commonly used formula such as MDRD or Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI), or known GFR < 30 mL/min. 
a. Exception: Patients with history of CKD but no available prior eGFR who 
have documented normal kidney size on ultrasound or computed 
tomography (normal size defined above) evaluation (performed within 90 
days of screening) will be eligible 
 
2. Patients receiving RRT for chronic kidney disease: either hemodialysis, peritoneal 
dialysis, hemofiltration such as Continuous Veno-Venous Hemofiltration (CVVH) 
or hemodiafiltration. 
 
3. Previously diagnosed with documented AKI in the last 30 days. 
 
4. Documented primary glomerular disease or toxic tubulo-interstitial nephritis or 
other underlying renal diseases significantly effecting renal function (e.g., renal 
amyloidosis, polycystic kidney disease, renal cancer, renal abscess) at the time of 
AKI diagnosis. 
 


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5. Patients with overt peripheral vascular disease in the involved NSTI area -
associated with ischemic wounds/ulcers or gangrene, and/or other significant
symptoms of inadequate vascular supply or where limb amputation is considered
likely within 7 days due to the peripheral vascular disease.
6. Diabetic patients with peripheral vascular disease who present with below the ankle
NSTI.
7. Current condition of
(a) Inability to maintain a mean arterial pressure > 50 mmHg and/or systolic blood
pressure > 70 mmHg for at least 1 hour prior to dosing despite the presence of
vasopressors and IV fluids, or
(b) a patient with respiratory failure such that an SaO2 of 80% for at least 1 hour
prior to dosing cannot be achieved, or
(c) a patient with refractory coagulopathy (INR >5) or thrombocytopenia (platelet
count <20,000) that does not partially correct for at least 1 hour prior to dosing
with administration of appropriate factors or blood products
8. Severe neurological impairment due to cerebrovascular accident or cardiac arrest.
9. Recent cerebrovascular accident in the last 3 months.
10. Patients with cardiac arrest requiring cardiopulmonary resuscitation within the past
30 days.
11. Patient is not expected to survive throughout 28 days of study due to underlying
medical condition, such as poorly controlled neoplasm (e.g. Stage III or IV cancer).
12. Classified as “Do Not Resuscitate”, or “Do Not Treat”, or the patient’s family is not
committed to aggressive management of the patient’s condition. A “no
cardiopulmonary resuscitation (CPR)” order is acceptable if the patient and/or the
family are still committed to aggressive care short of CPR.
13. Any concurrent medical condition, which in the opinion of the Investigator, may
compromise the safety of the patient or the objectives of the study or the patient will
not benefit from treatment such as
•
Congestive heart failure (CHF) {New York Heart Association (NYHA)
class III-IV}
•
Very severe chronic obstructive pulmonary disease (COPD) {GOLD Stage
IV or use of continuous home oxygen prior to hospital admission (sleep
apnoea treated with continuous positive airway pressure or biphasic positive
airway pressure oxygen during sleep is acceptable)}
•
Liver dysfunction {Childs-Pugh class C}
•
Primary or acquired immunodeficiency or immunosuppression due to
treatment with immunosuppressive medications (see Appendix G for list of
excluded immunosuppressive medications)
•
Known HIV infection with CD4 count < 200 cells/mm3 or < 14% of all
lymphocytes
•
Neutropenia < 1,000 cells/mm3 not due to the underlying infection
•
Receiving or about to receive chemotherapy or biologic anti-cancer


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treatment, although hormonal manipulation therapies for breast and prostate 
malignancies are permitted 
•
Hematological and lymphatic malignancies in the last 5 years
14. Patient with >20% body surface area burn wounds.
15. Patient has acute pancreatitis with no established source of infection, uncomplicated
appendicitis, or cholangitis or cholecystitis. Note - necrotic or gangrenous
gallbladder or appendix with peritonitis is allowed.
16. Pregnant or breastfeeding women (lactating women must not breastfeed and must
discard breastmilk for at least 28 days after receiving study drug); Women of
childbearing potential must have a negative β-subunit hCG pregnancy test
immediately prior to study entry.
17. Previous enrollment in a clinical trial involving investigational drug or a medical
device within 30 days before provision of written informed consent for the study or
within five half-lives of the investigational drug, whichever is longer.
18. Previous enrollment in any Reltecimod protocol (ATB-001, ATB-201, ATB-202 or
ATB-203).
19. Patients under guardianship or trusteeship (France only).
20. Absence of social insurance (France only).
6.3 
Withdrawal 
Patients will be informed that they are free to withdraw from the study at any time and for 
any reason. The date the patient is withdrawn from the study and the reason for withdrawal 
will be recorded in the eCRF and in the source documentation. 
Whenever possible, all patients who discontinue study treatment or withdraw from the 
study prematurely will undergo all end-of-study assessments. Patients who fail to return for 
final assessments will be contacted by the site in an attempt to have them comply with the 
protocol. 
It is vital to obtain follow-up data on any patient withdrawn because of an AE or SAEs. In 
every case, efforts must be made to undertake protocol-specified, safety, follow-up 
procedures. 
The reason for withdrawal of a patient must be recorded on the eCRF, if it can be 
ascertained. Any further treatment will be at the Investigator’s discretion and should be 
recorded. Every effort must be made to follow-up the patient and obtain information on 
clinical outcome and AEs. All data from withdrawals will be included in the safety analysis. 
6.3.1 Criteria for Premature Discontinuation from Study 
In rare instances, the patient (or Investigator) may determine that he/she is not able to make 
all visits required by the protocol. Possible reasons for discontinuation from the study may 
include: 


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31 July 2019 
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•
Withdrawal of consent
•
Lost to follow-up
•
Other reasons such as administrative reasons
7. INVESTIGATIONAL PLAN
7.1 
Dose Selection Rationale
The formulation in the two completed clinical studies (ATB-001, ATB-201) and the 
ongoing clinical study with Reltecimod (ATB-202) is identical to the formulation used in 
this clinical study in patients with SA-AKI (ATB-203). Reltecimod will be dosed according 
to the patient’s actual body weight, at 0.50 mg/kg, and will be administered as an 
intravenous infusion over 10 minutes. 
The rationale for the proposed dose in the planned SA-AKI study is based on data from the 
Phase 2 study in NSTI. In this study with two Reltecimod dose groups (0.25 and 0.50 
mg/kg), evidence for a dose response was seen across multiple domains of efficacy 
variables. A linear dose response emerged for individual endpoints such as: SOFA score 
(measured either as total score at Day 14, individual organ score at Day 14, change in total 
score between days 1-14, percent of patients with organ failure at Day 14, SOFA score over 
time in patients presenting with organ failure at Day 1), debridements (measured as number 
of debridements to Day 7 or 28, percent of patients needing only one debridement, percent 
of patients needing less than 4 debridement to resolve the infection), and response of 
inflammatory biomarkers (measured systemically in plasma and at the tissue level from the 
site of infection). 
Overall, these results suggest that the 0.50 mg/kg dose is superior to the 0.25 mg/kg dose 
regarding efficacy in NSTI patients. The safety profile was similar for the two Reltecimod 
doses. Thus, the 0.50 mg/kg dose was chosen for further clinical studies. This dose was 
shown to be efficacious in the post–hoc analysis of NSTI patients with AKI. The 
0.50 mg/kg dose provided the highest treatment benefit in these patients, as judged by the 
rate of complete recovery from AKI. Thus, it was chosen for further studies in patients with 
SA-AKI. 
7.2 
Allocation of Treatment, Randomization and Study Drug Administration 
The pharmacist (or unblinded study-nurse/physician if performing study drug preparation 
at individual institution) will get the treatment allocation via fax and email notification after 
randomization in the RAVE™ EDC by site personnel available only to the study 
pharmacist (or unblinded study-nurse/physician if performing study drug preparation at 
individual institution). All other study-related personnel, hospital care givers, the Sponsor 
and the patient will remain blinded. 
Following allocation of treatment, the study pharmacist (or unblinded study-
nurse/physician if performing study drug preparation at individual institution) will prepare 
the study drug. 


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7.3 
Schedule of Procedures/Visits 
A schedule of study assessments is shown in Section 18-Appendix A (“Study Visits and 
Procedures”) of the protocol.  Homecare services will be offered through a third party 
vendor (i.e., Symphony Clinical Research) using trained, qualified homecare professionals. 
Provision of this service is intended to help ensure patient retention and data collection 
when travel to the clinical trial sites may be overly burdensome for the participants given 
their disease state.  Symphony Clinical Research is contracted to evaluate subjects as 
outpatients from Day 7 through Day 90. 
Local laboratories will be used during hospitalization and clinic visits while the home 
health service will send samples to a central laboratory.  Outpatient samples may be 
evaluated by other local laboratories if acceptable accreditation. 
Patients who are registered and randomized for the study, but do not receive study drug 
(part of the Intent-to-Treat (ITT) population) should continue to be followed through Day 
90 with as much data collected as part of SOC entered into the eCRF.  No additional 
procedures or laboratory studies should be performed beyond SOC as part of the research 
study.  The entered data will match as closely as possible the SoC assessments and 
laboratory evaluations with the visit days.    
Visit 1: Screening 
Evaluation starts once a patient presents with clinical diagnosis of abdominal infection. 
•
Obtain ICF
•
Verification of Inclusion/Exclusion criteria
•
Demographics, medical history, infection history, concomitant medications, vital 
signs, height, weight, physical exam (PE).  Race is not entered for European 
countries.
•
Record urine output from presentation or around (before) time of diagnosis of 
abdominal infection or NSTI recorded to study drug administration or until 48 hour 
window to develop Stage 2 or 3 AKI ends
•
Record serum creatinine values every 6 hours from presentation or around (before) 
time of diagnosis of abdominal infection until study drug administration or until 48 
hour window to develop Stage 2 or 3 AKI ends (blood draws may be adjusted to 
when blood is normally collected on the unit)
•
Determine kidney size by CT or renal ultrasound if patient does not have a reference 
creatinine value within the past 12 months
•
Recording baseline signs and symptoms and AEs/SAEs (AEs of Screening are AEs/
SAEs starting after obtaining ICF until study drug administration)
•
Safety baseline laboratory tests:
o
Full chemistry panel (see Section 9.2.11)
o
Complete blood count (CBC) with differential and platelet count
•
Spot urine for albumin to creatinine ratio
•
Standard C-reactive protein (CRP) 


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•
Arterial blood gas and FiO2 (if applicable) or SpO2 and FiO2 if arterial blood gas
is not clinically indicated
•
Blood culture for both aerobic and anaerobic bacteria
•
Pregnancy test if applicable (blood or urine whichever is faster; blood only in
France)
•
Screening SOFA score will include measurements must be performed prior to study
drug administration:  SOFA score should be evaluated any time after arrival at the
hospital (may include data from referring hospital), although no more than 6 hours
prior to study drug administration.  Baseline SOFA score will include the following
organ/systems (with the total score being at least a 2): respiratory, cardiovascular,
renal, coagulation, GI/hepatic and CNS.
•
APACHE II score (measurement for this score will be collected and the score will
be calculated retrospectively) using the worst values within the 24-hour period prior
to enrollment
•
Critical care parameters (dates and times of assisted ventilation, vasopressor use,
ICU and hospital admission and discharge)
•
Collect data on acute RRT
•
Record additional relevant procedures related to the kidney (e.g., renal biopsy)
•
Record any imaging that evaluates the kidney
•
Local lesion assessment and evidence of amputation (excision to a joint space) if
NSTI
•
During surgery, peritoneal or abscess fluid, abdominal tissue samples, or NSTI
tissue samples for microbiology
•
Collect blood for serum for storage (immunogenicity testing)
•
Collect urine and blood for plasma for storage (AKI biomarker analysis) – optional
sub-study
•
Collect blood for systemic inflammatory biomarkers – leukocyte transcriptome
(RNA expression) profiling and chemokines / cytokines – optional sub-study
•
Record Survival
•
Perform randomization and study drug preparation if patient has confirmed
diagnosis of Stage 2 or 3 AKI
o
Patients with suspected or confirmed abdominal infection or surgically
confirmed NSTI who do not meet AKI criteria at time of abdominal infection
presentation or surgical confirmation of NSTI should be followed every 6
hours with a repeat creatinine test and monitoring of urine output every 1 to 6
hours, for up to 48 hours after the suspected diagnosis of abdominal infection
or surgical confirmation of NSTI, to determine if they develop Stage 2 or 3
AKI
•
Upon study drug administration patient is transitioned to Visit 2 (Day 1)
Visit 2 (Day 1) 
Starts only upon study drug administration and terminates at the end of the calendar day.  
For abdominal sepsis, study drug may be given prior to, during, or after surgery if meets 


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all criteria. For NSTI, study drug may only be given during surgery or immediately after 
surgery (after surgical confirmation of NSTI). 
•
Drug (to be infused over 10 minutes) should be administered within 6 hours, under 
the following criteria, whichever is later, (as described in inclusion criteria Section 
6.1): 
o After confirmation of Stage 2 or 3 AKI as established at the study site 
AND 
A. Abdominal Infection
o
After the decision is made by the attending surgeon at the study site for a
surgical or interventional radiology procedure for the abdominal infection
OR
o
After confirmed diagnosis of abdominal infection has been established by a
surgical or interventional radiology procedure
OR 
B. Necrotizing Soft Tissue Infection
o
After surgical confirmation of NSTI (drug should not be administered until
surgical confirmation of NSTI is established)
Note: If a surgical or interventional radiology procedure for the abdominal 
infection, or surgical confirmation of NSTI, occurred at an outside hospital prior 
to transfer to the study site, study medication must be administered within 6 
hours of re-established diagnosis of Stage 2 or 3 AKI at the study site. 
•
Record if overdose
•
Record any follow-up surgical or interventional radiologic procedures for
previously documented abdominal infection or NSTI
•
Collection of AEs/ SAEs
•
Concomitant medications
•
Vital signs (first set of vitals on that day)
•
Symptom-driven interim PE
•
Fluid balance (total in/out-I/O) for calendar day starting from the time accurate I/Os
recorded (start time may be prior to study drug administration)
•
Detailed urine output
o
Should be recorded continuously from time of study drug administration to
Day 7 (if still in ICU or step down unit), using most frequent hourly intervals
available and by calendar day with or without Foley catheter in place
•
Spot urine for albumin to creatinine ratio
•
Collect data on acute RRT
•
Record additional relevant procedures related to the kidney (e.g., renal biopsy)
•
Record any imaging that evaluates the kidney
•
Weight, only if not collected at screening
•
Collect data on additional amputations if NSTI


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•
Critical care parameters (dates and times of assisted ventilation, vasopressor use,
ICU /hospital stay)
•
Systemic response: SOFA score.
o
All efforts should be made to obtain the actual measurements of SOFA
parameters at these visits - may use SpO2 value (and record FiO2) if arterial
blood gas is not clinically indicated
o
Obtain serum creatinine and total bilirubin
o
Obtain CBC with differential and platelet count
•
Assess lesion status if NSTI (healing/progression/significant change in appearance)
if accessible for visible assessment at time of debridement or routine dressing
change
•
Collect blood for systemic inflammatory biomarkers – leukocyte transcriptome
(RNA expression) profiling and chemokine / cytokines at 4-6 hours post study drug
administration – optional sub-study
•
Survival
Visit 3 (Day 2) 
•
Fluid balance (total I/O) for calendar day
•
Detailed urine output
o
Should be recorded continuously from time of study drug administration to
Day 7 (if still in ICU or step down unit), using most frequent hourly intervals
available and by calendar day, with or without Foley catheter in place
•
Collect data on additional amputations if NSTI
•
Collect data on acute RRT
•
Record additional relevant procedures related to the kidney (e.g., renal biopsy)
•
Record any imaging that evaluates the kidney
•
Collection of AEs/ SAEs
•
Record any follow-up surgical or interventional radiologic procedures for
previously documented abdominal infection or NSTI
•
Concomitant medications
•
Vital signs (to be taken during the morning tests)
•
Serum creatinine
•
Critical care parameters (dates and times of assisted ventilation, vasopressor use,
ICU /hospital stay)
•
Assess lesion status if NSTI (healing/progression/significant change in appearance)
if accessible for visible assessment at time of debridement or routine dressing
change
•
Collect urine and blood for plasma for storage (AKI biomarker analysis) at 24±6
hours after study drug administration – optional sub-study
•
Collect blood for systemic inflammatory biomarkers - leukocyte transcriptome
(RNA expression) profiling and chemokine / cytokines at 24+4 hours post study
drug administration – optional sub-study
•
Record Survival


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Visit 4 (Day 3) 
•
Fluid balance (total I/O) for calendar day
•
Detailed urine output
o
Should be recorded continuously from time of study drug administration to
Day 7 (if still in ICU or step down unit), using most frequent hourly intervals
available and by calendar day with or without Foley catheter in place
•
Collect data on additional amputations if NSTI
•
Collect data on acute RRT
•
Record additional relevant procedures related to the kidney (e.g., renal biopsy)
•
Record any imaging that evaluates the kidney
•
Collection of AEs/ SAEs including secondary infections
•
Record any follow-up surgical or interventional radiologic procedures for
previously documented abdominal infection or NSTI
•
Concomitant medications
•
Vital signs (to be taken during the morning tests)
•
Symptom-driven interim PE
•
Evaluation of adequacy of antimicrobial treatment, based on results from
susceptibility testing once the data is available
•
Critical care parameters (dates and times of assisted ventilation, vasopressor use,
ICU /hospital stay)
•
Systemic response: SOFA score (measurements will be collected, and scores will
be calculated retrospectively)
o
All efforts should be made to obtain the actual measurements of SOFA
parameters at these visits - may use SpO2 value (and record FiO2) if arterial
blood gas is not clinically indicated
o
Obtain serum creatinine and total bilirubin
o
Obtain CBC with differential and platelet count
•
Assess lesion status if NSTI (healing/progression/significant change in appearance)
if accessible for visible assessment at time of debridement or routine dressing
change
•
Spot urine for albumin to creatinine ratio
•
Collect blood for systemic inflammatory biomarkers - leukocyte transcriptome
(RNA expression) profiling and chemokine / cytokines at 48+4 hours post study
drug administration – optional sub-study
•
Record Survival
(Days 4 to 6) 
•
Fluid balance (total I/O) for calendar day
•
Detailed urine output
o
Should be recorded continuously from time of study drug administration to
Day 7 (if still in ICU or step down unit), using most frequent hourly intervals
available and by calendar day with or without Foley catheter in place


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•
Collect data on additional amputations if NSTI
•
Collect data on acute RRT
•
Record additional relevant procedures related to the kidney (e.g., renal biopsy)
•
Record any imaging that evaluates the kidney
•
Collection of AEs/ SAEs including secondary infections
•
Record any follow-up surgical or interventional radiologic procedures for
previously documented abdominal infection or NSTI
•
Concomitant medications
•
Critical care parameters (dates and times of assisted ventilation, vasopressor use,
ICU /hospital stay)
•
Collect blood for systemic inflammatory biomarkers - leukocyte transcriptome
(RNA expression) profiling and chemokine / cytokines at 72+4 hours post study
drug administration – optional sub-study (Day 4 only)
•
Record survival
Visit 5 (Day 7 [±1 day]) 
•
Fluid balance (total I/O) for calendar day
•
Detailed urine output
o
Should be recorded continuously from time of study drug administration to 
Day 7 (if still in ICU or step down unit (or equivalent), using most frequent 
hourly intervals available and by calendar day with or without Foley catheter 
in place
•
Collect data on additional amputations if NSTI
•
Collect data on acute RRT
•
Record additional relevant procedures related to the kidney (e.g., renal biopsy)
•
Record any imaging that evaluates the kidney
•
Weight (if easily obtained)
•
Collection of AEs/ SAEs including secondary infections
•
Record any follow-up surgical or interventional radiologic procedures for 
previously documented abdominal infection or NSTI
•
Concomitant medications
•
Vital signs (to be taken during the morning tests)
•
PE (visiting nursing service does not perform if outpatient)
•
Standard CRP
•
Spot urine for albumin to creatinine ratio
•
Safety laboratory tests
o
Full chemistry panel (see Section 9.2.11)
o
CBC with differential and platelet count
•
Critical care parameters (dates and times of assisted ventilation, vasopressor use, 
ICU /hospital stay)
•
Record any hospital re-admissions (if previously discharged for original sepsis-
related hospitalization) 


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•
Systemic response: collect data for SOFA parameters
o
All efforts should be made to obtain the actual measurements of SOFA
parameters at these visits-may use SpO2 value (and record FiO2) if arterial
blood gas is not clinically indicated.
o
Platelet count, creatinine and total bilirubin values required for SOFA
components can be obtained from safety laboratories performed at this visit.
•
Assess lesion status if NSTI (healing/progression/significant change in appearance)
if accessible for visible assessment at time of debridement or routine dressing
change
•
Collect urine and blood for plasma for storage (AKI biomarker analysis) – optional
sub-study
•
Record Survival
Visit 6 (Day 10 [±1 day]; perform only if patient is still hospitalized) 
•
Concomitant medications
•
Collection of AEs/SAEs, including secondary infections
•
Collect data on additional amputations if NSTI
•
Collect data on acute RRT
•
Record additional relevant procedures related to the kidney (e.g., renal biopsy)
•
Record any imaging that evaluates the kidney
•
Record any follow-up surgical or interventional radiologic procedures for
previously documented abdominal infection or NSTI
•
Symptom-driven interim PE
•
Vital signs (to be taken during the morning tests)
•
Critical care parameters (dates and times of assisted ventilation, vasopressor use,
ICU /hospital stay)
•
Record any hospital re-admissions (if previously discharged for original sepsis-
related hospitalization)
•
Serum creatinine
•
Assess lesion status if NSTI (healing/progression/significant change in appearance)
if accessible for visible assessment at time of debridement or routine dressing
change
•
Record Survival
Visit 7 (Day 14 [±1 day]) 
•
Weight
•
Collection of AEs/SAEs, including secondary infections
•
Collect data on acute RRT
•
Record additional relevant procedures related to the kidney (e.g., renal biopsy)
•
Record any imaging that evaluates the kidney
•
Record any follow-up surgical or interventional radiologic procedures for
previously documented abdominal infection or NSTI
•
Concomitant medications


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•
Safety laboratory tests (Chemistry, Hematology)
o
Full chemistry panel (see Section 9.2.11)
o
CBC with differential and platelet count
•
Spot urine for albumin to creatinine ratio
•
PE (visiting nursing service does not perform if outpatient)
•
Vital signs (to be taken during the morning tests if still hospitalized)
•
Standard CRP
•
Collect blood for serum for storage (immunogenicity testing)
•
Critical care parameters (dates and times of assisted ventilation, vasopressor use, 
ICU /hospital stay)
•
Record any hospital re-admissions (if previously discharged for original sepsis-
related hospitalization)
•
Systemic response: collect data for SOFA parameters
o
All efforts should be made to obtain the actual measurements of SOFA 
parameters at these visits-may use SpO2 value (and record FiO2) if arterial 
blood gas is not clinically indicated.
o
Platelet count, creatinine and total bilirubin values required for SOFA 
components can be obtained from safety laboratories performed at this visit.
o
In case a patient is discharged from hospital prior to these days SOFA 
parameters should be obtained on the same day of discharge.
•
Assess lesion status if NSTI (healing/progression/significant change in appearance) 
if accessible for visible assessment at time of debridement or routine dressing 
change
•
Record Survival 
Visit 8 (Day 21 [±1 day]) 
•
Collection of AEs/SAEs, including secondary infections
•
Collect data on additional amputations if NSTI
•
Collect data on acute RRT
•
Record additional relevant procedures related to the kidney (e.g., renal biopsy)
•
Record any imaging that evaluates the kidney
•
Concomitant medications
•
Critical care parameters (dates and times of assisted ventilation, vasopressor use,
ICU /hospital stay)
•
Record any hospital re-admissions (if previously discharged for original sepsis-
related hospitalization)
•
Vital Signs (to be taken during the morning tests if still hospitalized)
•
Serum creatinine
•
Record Survival
Visit 9 (Day 29 [+3 days]) 
•
Weight
•
Collection of AEs/SAEs, including secondary infections


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•
Collect data on acute RRT
•
Record additional relevant procedures related to the kidney (e.g., renal biopsy)
•
Record any imaging that evaluates the kidney
•
Collect data on additional amputations if NSTI
•
Concomitant medications
•
Critical care parameters (dates and times of assisted ventilation, vasopressor use,
ICU /hospital stay)
•
Vital signs (to be taken during the morning tests if still hospitalized)
•
Serum creatinine and albumin
•
CBC with differential and platelet count
•
Standard CRP
•
Spot urine for albumin to creatinine ratio
•
Collect blood for serum for storage (immunogenicity testing)
•
Record any hospital re-admissions (if previously discharged for original sepsis-
related hospitalization)
•
Record Survival
All efforts should be made to collect these data, especially laboratory data, with Day 28 
being the primary endpoint, but in case parameters cannot be collected, phone follow-
up will be performed, and information that could be collected over the phone will apply. 
Visit 10 (3 to 21 Days after Visit 9) 
•
Serum creatinine
Visit 11 (Day 90 [+5 days]) 
The 3-month visit is a follow-up visit to assess the long-term health condition of the patients 
including assessment of 
•
Serum creatinine
•
Spot urine for albumin to creatinine ratio
•
Serum for storage (immunogenicity test)
•
Record survival
•
Record any hospital readmission(s) within 30 days of discharge from original
sepsis-related hospitalization.
Follow-up of Patients 
Patients who received the study drug are required to complete the procedures outlined for 
this clinical study. Exceptions would only include the withdrawal of consent, lost to follow-
up or death. 
If a patient misses a scheduled visit, attempts to complete the patient data will be made via 
telephone or rescheduling the visit. After waiting one week for the response, a return-
receipt, certified letter containing instructions to call for an appointment will be sent. If no 
response is obtained within one week after sending the return-receipt letter, the patient 
should then be considered as lost to follow-up. The returned receipt should be filed in the 


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Investigator's regulatory binder to document the site’s attempt to arrange patient follow-up. 
A clinical evaluation should be made based on the last contact with the patient. 
SAEs occurring within 28 days of a patient receiving IMP will be recorded and 
processed as described in Section 11.3 of the protocol.  
8. TREATMENT OF PATIENTS
8.1 
Investigational Medicinal Product
This is a blinded randomized clinical study with two treatment groups consisting of 
0.50 mg/kg Reltecimod and placebo. Patients will be randomized in a 1:1 ratio. Each patient 
will be administered a single intravenous infusion of Reltecimod based on actual body 
weight to be infused over 10 minutes at a rate dependent on the dosing volume. Volume of 
administration will depend on the patients’ actual body weight. 
The study drug should be administered within 6 hours of the laboratory confirmed diagnosis 
of Stage 2 or 3 AKI as established at the study site, only after the decision is made by the 
attending surgeon at the study site for a surgical or interventional radiology procedure for 
the abdominal infection or after confirmed diagnosis of abdominal infection has been 
established by a surgical or interventional radiology procedure; or after surgical 
confirmation of NSTI as described in the inclusion criteria (Section 6.1).   
Reltecimod will be supplied in glass vials as a lyophilized powder to be reconstituted with 
sterile WFI. Drug will be reconstituted on the day of its administration, in close proximity 
to infusion time, and several vials will be pooled together to compose the requested dose. 
Final volume for infusion will be based on the patient’s actual body weight plus adequate 
priming volume of the IV line. 
Placebo will be pyrogen-free, preservative-free sterile 0.9% saline, USP administered as a 
single infusion at a volume calculated and based on the patient’s actual body weight, 
0.50 mL/kg (a volume equivalent with Reltecimod dosing schema), plus adequate priming 
volume of the IV line. 
8.1.1 
Presentation and Formulation 
Reltecimod is the sodium salt of a 10 amino acid synthetic peptide. Reltecimod has 
homology to amino acid residues 8-15 of the T-lymphocyte molecule CD28 and has D-Ala 
residues abutted to N- and C-termini to render them more protease resistant. The final 
formulated drug product is a lyophilized powder, formulated to contain 1 mg/mL of the 
Reltecimod peptide, 30 mg/mL mannitol, and 3.6 mg/mL sodium chloride after 
reconstitution with sterile WFI.  
The drug product is filled into clear, 20 mL Type I glass vials with a 20 mm neck and is 
then lyophilized. Flurotec-coated rubber lyophilization stoppers are used and 20 mm white 
aluminum overseals.  
Each vial of drug contains nominal amounts of the drug substance and excipients as 
follows: 10.5 mg of Reltecimod, 315 mg of mannitol, and 37.8 mg of NaCl.  Prior to use, 


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each vial of drug product (10.5 mg Reltecimod) is reconstituted in 10.5 mL of water for 
injection to generate a peptide concentration of 1 mg/mL. 
The reconstituted drug product is administered directly and is not diluted prior to 
administration. To prepare the drug quantity needed for infusion, the contents of several 
vials are pooled together by the study pharmacist (or unblinded study-nurse/physician if 
performing study drug preparation at individual institution), under sterile conditions. The 
number of vials would depend on the patient's actual body weight, in order to achieve a 
dose of 0.50 mg/kg. The Reltecimod drug product will be administered at a dose of 
0.50 mg/kg via a syringe pump (may be manually pushed if approved by the medical 
monitor) in a separate catheter as a single intravenous infusion given over 10 minutes. 
The manufacturer of the clinical batches of the drug substance is PolyPeptide Laboratories, 
Inc., Torrance CA. The manufacturer of the drug product is Emergent BioSolutions Inc, 
Baltimore, MD. 
8.1.2 
Storage 
IMP will be stored in a limited access area, under appropriate environmental conditions. 
Reltecimod should be stored at -20°C ± 5°C in a secure, temperature-monitored freezer 
located in Investigational Drug Service or main pharmacy. Reconstituted investigational 
agents may be stored at room temperature for up to 6 hours.  Study drug infusion should be 
performed as soon as possible but within the 6-hour window previously described. If 
reconstituted drug is not administered, it should be discarded. 
8.1.3 
Administration 
Formulation and/or preparation of Reltecimod or placebo will be performed by the clinical 
site pharmacist (or unblinded study-nurse/physician if performing study drug preparation 
at individual institution). This process will be performed so that the clinical staff and 
Investigators will be blinded to each patient’s treatment assignment and only the pharmacist 
(or unblinded study-nurse/physician if performing study drug preparation at individual 
institution) will be unblinded. Administration will be by intravenous infusion using a 
syringe pump (may be manually pushed if approved by the medical monitor) over a 10-
minute period.  RRT may be started prior to study drug administration as long as the patient 
is off RRT during study drug administration and up to at least one hour post study drug 
administration. 
8.1.4 
Accountability and Destruction of Surplus Investigational Product 
Authorization of the site to receive supplies of IMP will be given by Atox Bio/designee 
upon receipt of relevant essential documentation (for details refer to the Study Procedure 
Manual). A designated individual at each site will maintain a log of IMP dispensed for each 
patient. In addition, the Investigator or designated individual at each site will maintain an 
IMP Accountability Log. This will include the description and quantity of IMP received at 
the study site, as well as a record of when and to whom it was dispensed. 
All used and unused supplies will be retained at the investigational site until the study 
monitor gives instructions for their disposal or return. The IMP supplied for this study is 


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Final Protocol ATB-203 v6.0 
31 July 2019 
investigational and under no circumstances may be used for purposes other than those 
described in this protocol. 
The Investigator agrees not to supply the IMP to any person other than the patients 
participating in the study. IMP may not be relabeled or reassigned for use by other patients 
except under special circumstances previously approved by Atox Bio. 
The Investigator will retain and store all original vials until these vials are inventoried by 
the unblinded study site monitor. Unless otherwise instructed by the Atox Bio medical 
monitor, the Investigator agrees to destroy (per the site’s drug destruction policy) all 
original vials at the end of the study, whether empty or containing IMP, to Atox Bio or 
designee. The Investigator agrees neither to dispense the IMP from, nor store it at any site 
other than the study sites agreed upon. 
A separate unblinded study monitor will ensure proper disposition of original vials whether 
empty or full of IMP. Appropriate IMP disposition documentation will be maintained as 
part of the source documentation.  
8.1.5 
Disallowed Medications 
Study participants should not receive immunosuppressant agents or chemotherapy and 
should not be given high doses of steroids (defined as >40 mg or 0.50 mg/kg prednisone 
(or steroid with equivalent activity)/day for ≥2 weeks (see Appendix G – Section 18.7). 
NOTE: Adrenal replacement therapy (corticosteroids) is permitted in patients with septic 
shock at the discretion of the Investigator balancing the potential benefits and risks in this 
situation. The optimal treatment regimen in this setting is not resolved. Investigators are 
referred to current Surviving Sepsis Campaign guidelines (www.survivingsepsis.org) as a 
reasonable source of guidance for steroid replacement therapy in septic shock patients. 
Use of agents that can cause significant nephrotoxicity (e.g. non-steroidal anti-
inflammatory drugs (NSAIDS), aminoglycosides, colistin, amphotericin B) should be 
avoided where possible.  A list of potentially nephrotoxic medications is provided in the 
Study Procedure Manual. 
8.1.6 Allowed Medications 
8.1.6.1 Antimicrobial Agents 
All patients will receive one or more antimicrobial drugs used as SoC to treat the primary 
or subsequent infections. Antimicrobial agents include antibacterial, anti-fungal, anti-viral 
and anti-parasitic drugs. Topically applied antimicrobial agents should be included. Any 
other medications whether drugs or biologics used to treat the patient should be identified 
as non-antimicrobial medications. 
Each antimicrobial agent will be identified by its generic or trade name and reported in the 
eCRF. Information should include the dose, dosing frequency, route of administration, 
duration (start and stop times and dates), and reason for administration (to treat primary or 
secondary infection or for surgical prophylaxis). 


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8.1.6.2 Non-antimicrobial Medications 
Contrast-enhancing agents used to evaluate patients for abdominal infection (or other 
complications following study entry) are allowed but should be captured as described 
below for other non-antimicrobial drugs. 
Non-antimicrobial (ancillary) drugs administered from the time of patient screening until 
end of study will be recorded in the eCRF. Information to be collected should include 
generic or trade name, route of administration, duration (start and stop dates) and reason 
for administration. A list of medications that are not required to be captured in the ancillary 
medication eCRF is provided in the Study Procedure Manual. 
8.2 
Study Medication Compliance 
Compliance will be monitored by recording the total volume of each investigational agent 
actually delivered to each study patient. 
8.3 
Precautions and Overdose 
8.3.1 Study Drug - Reltecimod 
8.3.1.1 Precautions 
Currently available safety information does not require any special precautions to be 
exercised during treatment with Reltecimod. Analysis of safety data collected in 
Reltecimod Phase 1 and 2 studies, did not reveal AEs that were determined as related to 
Reltecimod (including possibly, probably and definitely related to study drug). In animal 
toxicology studies no target organs were identified. 
8.3.1.2 Over Dosage 
To date, throughout the Reltecimod clinical development program, a single patient (study 
ATB-201) received an accidental overdose of approximately 30% (received 0.67 mg/kg 
instead of 0.50 mg/kg). This patient had no AEs determined as related to study drug. He 
had an SAE of acute renal failure that is expected in NSTI patients and was related to the 
patient's underlying NSTI. All the patient's AEs were resolved. In case of an overdose 
(defined as a 100% increase over the 0.50 mg/kg intended dose of Reltecimod), the site 
staff should contact the medical monitor. Additionally, the patient should be monitored and 
followed-up according to the best medical practice. 
8.3.2 Placebo Comparator 
No known or expected adverse reactions are associated with pyrogen-free, preservative-
free, physiologic saline. 
8.3.2.1 Precautions 
None for placebo comparator. 


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9. STUDY PROCEDURES
9.1 
Informed Consent
The ICF is in compliance with ICH GCP Guidelines, and in accordance with the Federal 
Regulations as detailed in 21 CFR §50.25 and the Declaration of Helsinki. 
Prior to entering the study, the Investigator/designee will explain the nature of the study to 
each patient or LAR its purpose, expected duration, alternative forms of therapy available 
and the benefits and risks of study participation. After this explanation and before entering 
the study, the patient or LAR will read and understand the ICF and voluntarily sign a 
consent form in the presence of the Investigator/designee. LAR may utilize 
phone/fax/email/e-consent or written consent as allowed by the local institutional policies 
and procedures. 
The patient will be given a copy of the signed/dated ICF. 
9.2 
Clinical and Laboratory Procedures 
9.2.1 Start of Drug Administration Clock 
The IV drug administration clock of maximal 6 hours starts once the patient is diagnosed 
with Stage 2 or 3 AKI as established at the study site, only after the decision is made by the 
attending surgeon at the study site for a surgical or interventional radiology procedure for 
the abdominal infection or after confirmed diagnosis of abdominal infection has been 
established by a surgical or interventional radiology procedure; or after surgical 
confirmation of NSTI as described in the inclusion criteria (Section 76.1). 
9.2.2 Inclusion/Exclusion Criteria 
The inclusion and exclusion criteria are specified in Sections 6.1 and 6.2. These criteria 
determine patient eligibility for recruitment. All patients must be evaluated for the presence 
of all inclusion criteria and the absence of all exclusion criteria before they are eligible to 
receive study drug. 
9.2.3 Medical and Surgical History 
A complete medical history identifying clinically relevant past medical and surgical 
conditions and active medical or surgical conditions will be reported on the Medical History 
eCRF. All chronic medications will be identified and characterized by trade or generic 
name, route of administration as well as reason for use from 14 days prior to study drug 
administration to Day 28. 
Baseline signs and symptoms, defined as pre-emergent adverse events, should be captured 
on the Baseline Signs and Symptoms eCRF form.  
9.2.4 Physical Examinations 
Physical examination will include a clinically appropriate examination of vital organ 
systems. These should include at minimum cardiovascular, respiratory, abdomen, 
extremities, and neurologic body systems.  Physical exams do not need to be performed if 
subject is being evaluated by a visiting nursing service as an outpatient.  


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9.2.4.1 Interim Physical Examinations (Symptom-driven) 
Interim PE will be targeted to include clinically appropriate examination of specific organ 
systems based on patient related signs and symptoms. 
9.2.5 Concomitant Medications 
All concomitant medications, antimicrobial & non-antimicrobial, (with the exception of 
over the counter medications (unless nephrotoxic), vitamins, laxatives, intravenous fluid 
and electrolyte replacement, parenteral nutrition, topical medications and other selected 
medications as described in the Study Procedure Manual) will be entered into the eCRF 
and identified by their generic or trade name. 
Information about antimicrobial medications, immunosuppressants, and nephrotoxic drugs 
should include the dose, dosing frequency, route of administration, duration (start and stop 
times and dates), and reason for administration (to treat primary or secondary infection or 
for surgical prophylaxis). 
Information to be collected about non-antimicrobial medications, immunosuppressants, or 
nephrotoxic drugs should include generic or trade name, route of administration, duration 
(start and stop dates) and reason for administration. 
Timing and adequacy of antibiotic therapy (based on institutional guidelines, baseline 
pathogens and antimicrobial sensitivity) will be reviewed by the Principle Investigator. 
9.2.6 Abdominal Infection Type 
The cause and type of the abdominal process (e.g. complicated appendicitis or diverticulitis, 
peritonitis due to perforation of small or large intestine, post-traumatic peritonitis) causing 
peritonitis and abdominal infection along with factors predisposing to abdominal infection 
will be captured.  The date and time of diagnosis of abdominal infection and type of surgical 
or interventional procedure(s) to establish source control through Day 14 will be recorded. 
9.2.7 NSTI Infection Site 
Details of the NSTI will be recorded on the eCRF and include: “clinical characteristics” (as 
a specific subset of NSTI) at the time of enrollment; location of primary infection; 
extension of infection; date of onset of symptoms, identified predisposing factors (trauma, 
surgery, IV drug use, comorbidities such as diabetes or obesity, bites; prior surgical 
procedures related to the etiology of NSTI; prior surgical procedures for the treatment of 
the primary infection site and whether those procedures were considered adequate; 
antimicrobial use from the date of onset of current illness (may predate diagnosis of NSTI); 
description of the NSTI lesion; date and time of surgical intervention for NSTI and surface 
area of NSTI debridement (when available). 
The primary NSTI infection site will be described in detail. Any visible wound or drainage 
will be characterized as to amount, and cellular composition (purulent, sero-sanguineous, 
sanguineous, other). Tissue edema, focal pain and presence of subcutaneous crepitus, the 
presence of tissue discoloration, blisters, bullae or necrosis will be identified. The extent of 
progression of necrosis as well as the need for repeated surgical procedures will be 
documented by the Investigator. 


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9.2.8 Acute Kidney Injury 
During screening, it will be recorded whether the patient presented with Stage 2 or 3 AKI, 
or developed Stage 2 or 3 AKI within 48 hours after the suspected or confirmed diagnosis 
of abdominal infection, or surgical confirmation of NSTI.  If a reference (baseline) serum 
creatinine value(s) is/are available from the past 12 months, the reference serum creatinine 
value(s) and date(s) obtained will be entered.  If the subject does not have a reference serum 
creatinine value, it will be noted if the serum creatinine is >2.0 fold normal for age, race, 
and gender, and the length of the largest kidney by CT or renal ultrasound. 
The stage of AKI (Stage 2 or 3) and how AKI was diagnosed (serum creatinine or urine 
output or both) will be recorded.  The screening creatinine value prior to study drug 
administration as well as additional creatinine values from presentation or around (before) 
time of diagnosis of abdominal infection or NSTI should be entered.  Urine output should 
be computed from presentation or around (before) time of diagnosis of abdominal infection 
or NSTI after accurate urine output is recorded.  After study drug administration, urine 
output is collected while subject is in the ICU or step-down unit (or equivalent) with or 
without a Foley catheter in place through Day 7. 
If receiving RRT, then the type of RRT and net fluid removed per RRT session will be 
collected through Day 28.  Additional renal imaging or renal procedures (e.g., renal biopsy) 
performed as part of SoC through Day 28 will be entered in the eCRF.  
9.2.9 Vital Signs 
Vital signs include heart rate, systolic and diastolic blood pressure, respiratory rate 
(spontaneous, assisted or controlled) and temperature. While these may be determined 
many times during the course of the patient’s hospitalization, recording vital signs (to be 
taken during the morning tests) in the eCRF will be based on once daily readings for 
specified time sequences according to time and events, Section 18.1. 
9.2.10 Clinical Scores 
Clinical scores/criteria components will be collected in the study.  APACHE II 
score criteria will be determined only at screening (see Section 18.2) while SOFA 
score will be determined throughout the study (see Section 18.3). APACHE II will be 
used to determine disease severity while SOFA score will be evaluated as an 
inclusion criteria and as a secondary clinical endpoint. Individual parameters of the 
SOFA score will be collected and will also be correlated to response. All 
scores, except the Screening SOFA, will be calculated retrospectively. Data will 
be recorded in the eCRF at specified time points according to time and events, see 
Section 18.1. 
9.2.10.1 SOFA Score Definition 
Screening SOFA  
Includes measurements of 6 organ systems (cardiovascular, respiratory, renal, coagulation, 
GI/hepatic, CNS).  Screening SOFA score should be evaluated any time after arrival at 
study site hospital and within 6 hours prior to study drug administration. 
SOFA Score 


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Measurements of 6 organ systems, including CNS. To be measured on Days 1, 3, 7, and 
14, and calculated retrospectively. 
SOFA Respiratory Parameter 
In case it is not possible to take arterial blood gases to determine the SOFA respiratory 
parameter, SpO2/FiO2 ratio can be imputed for PaO2/FiO2 ratio. 
9.2.11 Clinical Laboratory Assessments 
Safety laboratory investigations will include hematology (CBC including platelets and 
white cell differential), chemistry (Glucose; Electrolytes (Sodium, Potassium, Chloride, 
Bicarbonate); renal function tests (Urea/BUN, Serum Creatinine); liver function tests 
(Albumin, Bilirubin Total, Alanine transaminase (ALT), Aspartate transaminase (AST), 
Alkaline phosphatase (ALP); Total Protein); Calcium; Phosphorus. 
CRP (standard test, not high sensitivity-hsCRP) to evaluate inflammatory response will be 
obtained at Screening and at Days 7, 14 and 29. Spot urine (preferably from first morning 
void) will be obtained for albumin to creatinine ratio. 
Pregnancy testing will be done on all women of childbearing potential participating in the 
study (using blood test or urine test whichever is faster; blood test only in France). 
Clinical laboratory assessments will be collected at intervals according to time and 
events in Section 18.1. 
9.2.11.1 Immunogenicity 
Blood (6 mL) for serum will be collected at screening, Days 14, 29 and 90 visits for 
immunogenicity testing.  The specific assay to test for immunogenicity against Reltecimod 
will be determined at the end of the trial. The study blood samples will be processed then 
aliquoted into three cryovials, flash frozen, stored in -70oC freezer prior to transport to the 
Central Lab. The study sites shall send all blood (serum) samples collected under this 
protocol to the Central Lab (see Laboratory Manual). The results of any analyses of the 
samples will be blinded to the study staff during the study and will not impact the medical 
management of the patient. 
9.2.11.2 AKI Biomarker – Optional Sub-study 
Urine (5 mL) and blood (5 mL) for plasma will be collected for evaluations of biomarkers 
to assess AKI as an optional sub-study. The specific AKI biomarkers will be determined at 
the end of the trial, dependent of the effects of the intervention on the renal endpoints. 
Numerous novel candidate protein AKI biomarker targets may be analyzed by 
immunoassay in the samples from the preliminary studies. Analyzed biomarkers may 
include novel targets not previously described in the literature as well as existing 
biomarkers, which will be measured for comparison.  
The study blood and urine samples will be processed, flash frozen, stored in -70o C freezer 
prior to analysis. The results of any analyses of the samples will be blinded to the study 
staff during the study and will not impact the medical management of the patient. The study 


Final Protocol ATB-203 v6.0 
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sites shall send all blood (plasma) and urine samples collected under this protocol to the 
Central Lab (see Laboratory Manual). The samples may be stored up to 5 years but will be 
used by the Investigators only to identify and validate biomarker targets for assessment of 
at-risk patients and will not be used for any other purpose. Samples will be stored at the 
Central Lab. Any excess sample will not be destroyed but will be maintained for additional 
study as described above. Each sample will not be individually identifiable. 
9.2.11.3 Systemic Inflammatory Biomarkers – Optional Sub-study 
The whole blood leukocyte transcriptome (RNA expression) profile testing and evaluation 
of systemic inflammatory biomarkers is an optional sub-study of the main protocol.   
The purpose of the leukocyte transcriptome (RNA Expression Profile) is to obtain insight 
in the effect of Reltecimod on the host response to SA-AKI by detailed and unbiased 
analysis of the blood leukocyte response. For this, 5 mL of whole blood will be collected 
at each time point.  Systemic inflammatory biomarkers will include serum cytokines or 
chemokines such as (but not limited to): IL-6, IL-8, INF-γ, TNF-α, IL-17A, IL-3 and 
RANTES.  For this, 10 mL of whole blood will be collected at each time point. 
Blood will be collected before initiation of Reltecimod administration and at 4-6 hours, 
24+4 hours, 48+4 hours, and 72+4 hours post study drug administration. At each of these 
time points whole blood leukocyte counts and differentials will be determined by the local 
laboratory.  Samples may be stored for up to 5 years but will only be used for the evaluation 
of the effect of Reltecimod on host response to SA-AKI. Results will not be reported to the 
treating physician or the subjects (or their relatives). 
All patients that have at least 3 systemic biomarkers samples taken: one before study drug 
administration, and at two additional time points post dosing will be included in the 
systemic biomarker analysis. 
9.2.11.4 Total Blood Volume Collected 
The total maximal volume of blood to be collected in the study is composed of study 
specific tests as well as tests that are part of the SoC. The list below represents the combined 
blood quantities. Approximately 9 tablespoons (125 mL) of blood will be collected from 
each patient with an additional 6 tablespoons (90 mL) of blood collected if the patient also 
participates in the both optional biomarker sub-studies. 
Table 5: Maximal blood draw by visit 
Visit 
Type 
Maximal 
Volume (cc) 
1 
SCR 
CRP 
3 
Chemistry 
4 
Hematology 
4 
Arterial Blood Gas* 
2 
Pregnancy test 
2 
Blood Culture 
20 
Immunogenicity sample 
6 
AKI Biomarker 
5 


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Page 84 of 131 
Visit 
Type 
Maximal 
Volume (cc) 
Systemic Inflammatory Biomarkers - blood leukocyte 
transcriptome profile and cytokines / chemokines 
15 
Total Volume 
61 
2 
Day 1 
Arterial Blood Gas* 
2 
Chemistry (only Creatinine and Bilirubin) 
3 
Hematology 
4 
Systemic Inflammatory Biomarkers - blood leukocyte 
transcriptome profile and cytokines / chemokines 
15 
Total Volume 
24 
3 
Day 2 
AKI biomarker 
5 
Chemistry (only Creatinine) 
3 
Systemic Inflammatory Biomarkers - blood leukocyte 
transcriptome profile and cytokines / chemokines 
15 
Total Volume 
23 
4 
Day 3 
Chemistry (only Creatinine and Bilirubin) 
3 
Hematology 
4 
Arterial Blood Gas* 
2 
Systemic Inflammatory Biomarkers - blood leukocyte 
transcriptome profile and cytokines / chemokines 
15 
Total Volume 
24 
Day 4 
Systemic Inflammatory Biomarkers - blood leukocyte 
transcriptome profile and cytokines / chemokines 
15 
Total Volume 
15 
5 
Day 7 
CRP 
3 
Chemistry 
4 
Hematology (CBC with differential and platelets) 
4 
Arterial Blood Gas* 
2 
AKI biomarker 
5 
Total Volume 
18 
6 
Day 10 
Chemistry (only Creatinine) 
3 
Total Volume 
3 
7 
Day 14 
Arterial Blood Gas* 
2 
CRP 
3 
Chemistry 
4 
Hematology (CBC with differential and platelets) 
4 
Immunogenicity sample 
6 
Total Volume 
19 
8 
Day 21 
Chemistry (only Creatinine) 
3 
Total Volume 
3 
9 
Day 29 
Chemistry (only Creatinine & Albumin) 
3 
Hematology (CBC with differential and platelets) 
4 
Immunogenicity sample 
6 
CRP 
3 
Total Volume 
16 
Visit 10  
3 to 21 Days 
after Visit 9 
Chemistry (only Creatinine) 
3 
Visit 11 
Day 90 
Chemistry (only Creatinine) 
3 
Immunogenicity sample 
6 


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Visit 
Type 
Maximal 
Volume (cc) 
Total Volume 
9 
Total Study 
215 
* Obtain arterial blood gases (ABG) if clinically indicated. Otherwise record SpO2 value and
also FiO2.
9.2.11.5 Microbiology 
Microbiological testing will follow the SoC of treatment of patients with abdominal 
infection or NSTI. At the time of initial surgical exploration, a sample from the abdominal 
infection site (peritoneal fluid, abscess fluid, tissue) or NSTI site (tissue) will be cultured 
by the local microbiology laboratory. Results from blood cultures (if available) drawn at 
the onset of infection, will retrospectively be registered. 
Antibiotics received prior to the primary surgical intervention will be identified as well as 
antibiotics received during the study evaluation window of Days 1 to 28. 
Bacterial isolates obtained from the patients in the study and considered to be pathogens 
will be identified by genus and species using the methods established in the Manual of 
Clinical Microbiology40. Results will be used to categorize patients according to 
microbiology organism group (Gram-positive, Gram negative, anaerobic, mixed infection). 
Susceptibility testing will be performed on all aerobic pathogens according to clinical 
laboratory standards institute (CLSI) criteria. 
Blood culture for both aerobic and anaerobic bacteria will be taken during the screening 
process if not already obtained previously during evaluation of acute abdominal infection 
or NSTI presentation. Repeat blood cultures for microbiology will also be obtained 
according to physician discretion, if the patient is suspected to have a new or progressive 
infection (if deterioration in the hospitalized patient’s condition is observed (e.g. spiking a 
fever). 
9.2.11.6 Renal Replacement Therapy Guidelines 
Renal replacement therapy guidelines are provided only to guide the clinicians.  Initiation 
and stopping of renal replacement therapy can occur based on the clinicians/institution’s 
protocols/judgement.  Continuous and intermittent-non-continuous modalities such as 
intermittent hemodialysis (IHD) are allowed after administration of study drug.  RRT may 
be started prior to study drug administration as long as the patient is off the treatment from 
time of study drug administration and up to at least one hour post study drug administration. 
9.2.11.6.1 Initiation of Renal Replacement Therapy 
Initiation of RRT is based on the conventional criteria described by Bellomo 201244. 
Conventional criteria for initiation of RRT in AKI: 
1.
Anuria (negligible urine output for 6 hours)
2.
Severe oliguria (urine output < 200 mL over 12 hours)


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3.
Hyperkalemia (Potassium concentrations >6.5 mmol/L)
4.
Severe metabolic acidosis (pH <7.2 despite normal or low partial pressure of carbon
dioxide in arterial blood)
5.
Volume overload (especially pulmonary oedema unresponsive to diuretics)
6.
Pronounced azotemia (urea concentrations >30 ml/L or creatinine concentrations
>300 umol/L)
7.
Clinical complications of uremia (e.g., encephalopathy, pericarditis, neuropathy)
9.2.11.6.2 Timing of Stopping Renal Replacement Therapy 
Termination of dialysis is based on criteria as used in the VA/NIH Acute Renal Failure 
Trial Network Study45. If (on Continuous Renal Replacement Therapy (CRRT) or between 
IHD sessions) diuresis >30 mL/hour and there are no other indications for RRT, then the 
endogenous creatinine clearance (ECC) should be calculated using a 6-hour urine collection 
period. If ECC >20 mL/min, CRRT should be discontinued. If ECC <12 mL/min, RRT 
should be continued. If ECC >12 and <19 mL/min, continuation/termination will be the 
decision of the treating physician. Exact criterion or criteria, corresponding values (e.g. 
Na+, K+ or pH) and deviations (e.g. RRT not started when indicated or RRT started when 
not indicated) need to be meticulously recorded in the eCRF. 
10. EVALUATION MEASURES FOR EFFICACY
Efficacy measures are described in Section 5, “Study Objectives”.
10.1 Primary Efficacy Measure
•
Rates of achieving the primary endpoint of freedom from durable loss of renal 
function (defined as alive, free of dialysis, and less than a 37% loss of eGFR 
(measured with the MDRD formula from the patient’s reference eGFR)) at Day 28. 
AKI stage and recovery will be determined by a blinded adjudication committee 
as described in Section 10.4. 
10.2 Secondary Efficacy Measures 
•
Rates of the primary endpoint at Day 14 between the Reltecimod- and placebo-
treated patients
•
To compare time to the primary endpoint between the Reltecimod- and placebo-
treated patients
•
AKI-free days over 14 and 28 days
•
Resolution of organ dysfunction (organ resolution is defined as having a total SOFA
score of ≤1) at Day 14
•
Resolution of specific organ dysfunction defined as having an individual organ
SOFA score of ≤1 at Day 14
•
Critical care and hospital stay parameters
o
Hospital length of stay


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o
ICU-free days in 28 days
o
Ventilator days
o
Ventilator free days in 28 days
o
Vasopressor days
o
Vasopressor free days in 28 days
o
RRT free days (days alive and free of RRT) in 28 days
•
Patient survival at Days 14 and 28
•
Presence of Stages 1, 2 or 3 AKI (using the KDIGO criteria) in patients with
abdominal sepsis or NSTI
10.3 Exploratory Efficacy Measures 
•
Rates of improvement in durable loss of renal function (defined as alive, free of
dialysis and improvement leading to a lower AKI stage but no better than Stage 1
AKI) at Days 14, 28 and 90
•
AKD stages (AKD 0, 1, 2, 3 and 3F) at Days 14 and 28
•
Incidence of CKD at Day 90
•
Survival at Day 90
•
Primary endpoint by baseline pathogen
•
Evaluation of RRT use (i.e., type of RRT)
•
Plasma and urinary biomarkers in patients with AKI
•
To conduct an exploratory evaluation of blood leukocyte transcriptome (RNA
expression) profiling in patients with SA-AKI and compare genomic profile in
patients treated with Reltecimod versus placebo
•
To define potential surrogate biomarkers (systemic) that exhibit change from
baseline due to treatment with Reltecimod
•
Data (including financially related data) will be gathered to evaluate possible health
economic outcomes from the study, including but not limited to:
o
Length of stay (ICU and overall hospital)
o
Number of re-admissions
o
Reduction in ICU admission rates (depending on patient population being
selected – i.e. severity of patients
o
Relative reduction in any physical outcome (including in-hospital deaths)
o
Persistent kidney injury
10.4 Adjudication Committee for Evaluation of AKI Stage and Recovery 
Experts chosen for the AKI Adjudication Committee will be independent of the Sponsor 
and neither they nor their institutions participated in the sample collection or sample 
measurement studies. 
The procedures for adjudication will be defined in advance of the study by consensus 
among the three adjudicators and the Principal Investigator in a series of face-to-face and 
teleconference meetings. Adjudicators collectively will determine which variables would 
be extracted from the medical record and provided to them for adjudication. These variables 
will include reference creatine values (as defined in the Inclusion Criteria) and serum 


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creatinine values up to 90 days after enrollment, all available urine output data prior to 
dosing and up to 7 days after enrollment when in the ICU or step-down unit, daily fluid 
balance and use of diuretics. In addition, the date(s) of RRT, death and ICU discharge will 
be provided, as well as age, sex, race, weight, reason for hospital and ICU or step-down 
unit admission and medical history. Adjudicators may also request additional information 
for individual patients. 
Each adjudicator will be provided a form for each patient containing all the clinical 
information described above. Adjudicators will be blinded to group assignment and clinical 
data will be identified only by anonymized identification number. Adjudicators will 
indicate their assessment of AKI staging and recovery independently without consultation 
with each other. The basis for the adjudication will be the KDIGO consensus criteria (based 
on RIFLE/AKIN definitions for AKI) corresponding to Stages 1to 3 (mild to severe). A 
two thirds majority was predefined for use as the final adjudication. The forms will be 
provided to the external statisticians for analysis. 
11. EVALUATION CRITERIA FOR SAFETY
11.1 Safety Measures
Safety measures in this study include AEs, clinical safety laboratory, clinical parameters 
(HR, BP, vital signs), secondary infections and determination of survival. These 
are described in more detail in Section 5, “Study Objectives”, and the specific times of 
these parameters are described under “Study Visits and Procedures” in Section 18, 
Appendix A. 
AEs including SAEs will be assessed throughout to Day 28, and clinical safety laboratory 
throughout to Day 14.  Survival will be determined throughout 90 days. 
Timely, accurate, and complete reporting and analysis of safety information from clinical 
studies are crucial for the protection of patients, Investigators, and the Sponsor, and 
is mandated by regulatory agencies worldwide. The Sponsor or its affiliate has 
established SOP in conformity with worldwide regulatory requirements to ensure 
appropriate reporting of safety information; all clinical studies sponsored by Sponsor 
or its affiliates will be conducted in accordance with these procedures. 
Patients (or their designee, if appropriate) must be provided with information indicating the 
name of the IMP, the study number, the Investigator's name and a 24-hour emergency 
contact number, and, if applicable, excluded concomitant medications. 
11.1.1 Adverse Event Definitions and Classifications 
The following definitions of terms are guided by the ICH and the United States Code of 
Federal Regulations [21 CFR § 312.32]. 
11.1.1.1 Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and that does not necessarily have a 
causal relationship with this treatment. An AE could therefore be any unfavorable and 
unintended sign (including abnormal laboratory findings), symptom, or disease 
temporally associated 


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with the use of an IMP, whether or not considered related to the IMP. This definition 
includes illnesses or injuries, and exacerbations of pre-existing conditions. 
11.1.1.2 Serious Adverse Event 
A SAE is an AE occurring during any study phase (i.e., treatment, follow-up), and at any 
dose of the IMP or placebo, that fulfils one or more of the following criteria: 
•
Results in death (for purposes of this trial deaths will be captured as clinical
outcomes and only recorded as an SAE if deemed related to IMP)
•
Is life-threatening (i.e., the patient was, in the opinion of the Investigator, at
immediate risk of death from the event as it occurred)
•
Requires or prolongs hospitalization
•
Results in persistent or significant disability or incapacity (i.e., the event causes a
substantial disruption of a person’s ability to conduct normal life functions)
•
Is a congenital anomaly or birth defect
•
Is an important and significant medical event (e.g., allergic bronchospasm requiring
intensive treatment in an emergency room or at home, blood dyscrasias or
convulsions that do not result in in-patient hospitalization, or the development of
drug dependency or drug abuse) that, based upon appropriate medical judgment,
may jeopardize the patient and/or may require medical or surgical intervention to
prevent one of the other outcomes defining SAE.
11.1.1.3 Adverse Reaction 
Any AE for which there is a reasonable possibility that the IMP caused the AE. “Reasonable 
possibility” means there is evidence to suggest a causal relationship between the IMP and 
the AE. 
11.1.1.4 Expectedness of the Adverse Event 
Expected AEs are AEs consistent with the applicable product information provided by the 
Sponsor (the Investigator’s Brochure for an investigational product). The Sponsor, in 
consultation with the medical monitor, determines expectedness. If a SAE is expected no 
further action is required. If the Sponsor and medical monitor determine that SAE is 
unexpected, then the event may meet criteria for expedited SAE notification to the 
regulatory agencies. 
From preclinical data and completed clinical studies to date, there are no expected adverse 
events for Reltecimod. 
11.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
An adverse reaction that is both unexpected (not consistent with the observed or expected 
risk information applicable to the IMP) and also meets the definition of “serious” described 
above. All 3 of the definitions contained in the US Food and Drug Administration (FDA) 
requirement for expedited reporting must be met to qualify for expedited reporting to FDA: 
1) Serious, 2) Unexpected, and 3) Suspected adverse reaction. AEs that do not meet the


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requirements for expedited reporting will be reported to FDA in the IND Annual Report. 
SUSARs that are fatal or life-threatening will be reported to FDA as soon as possible, but 
no later than 7 calendar days after Sponsor’s initial receipt of the information (21 CFR 
312.32(c)(2)). Other SUSARs will be reported to FDA within 15 calendar days of initial 
receipt or after determining that the information qualifies for reporting under 21 CFR 
312.32(c)(1). 
European sites will comply with International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) E6 and E2A reporting 
requirements or local country regulatory authority requirements.  
11.1.3 Adverse Events Based on Examinations and Tests 
Deterioration as compared to baseline in protocol mandated laboratory values, vital signs 
and other safety variables should only be reported as AEs if they fulfil any of the SAE 
criteria or are the reason for discontinuation of treatment with the IMP. However, the 
Investigator may record such findings as an AE at his/her discretion in addition to 
completing an unscheduled laboratory/vital signs page with the information on the 
clinically significant test abnormality. If a deterioration in a laboratory value/vital sign is 
associated with clinical signs and symptoms, the sign/symptom will be reported as an AE 
and the associated laboratory result/vital sign will be considered as additional information. 
Any new or aggravated clinically relevant abnormal medical finding at a PE, dermal 
examination or lung auscultation as compared with the baseline assessment will be reported 
as an AE. Clinically relevant deterioration in unscheduled assessments of laboratory/vital 
signs/ECG parameters should be reported on additional eCRF pages. 
Wherever possible, the reporting Investigator uses the higher level medical concept, rather 
than the laboratory term (e.g., anemia versus low hemoglobin value). 
11.1.4 Pregnancies 
If pregnancy is detected after the administration of study drug through Day 90, the patient 
will be followed-up until resolution. The Investigator must immediately record the 
pregnancy 
on 
the 
pregnancy 
reporting 
form 
and 
notify 
Sponsor/designee 
Pharmacovigilance by telephone and fax form within 24 hours of becoming aware of the 
event. In addition, the Investigator must report follow-up information regarding the course 
of the pregnancy, including perinatal and neonatal outcome. If pregnancy is reported in a 
female partner of a male patient, the female partner will be asked to sign a separate consent 
form to allow the site personnel to capture data about the pregnancy and to follow the 
pregnancy until completion. No information about such pregnancies will be captured 
without informed consent from the female partner.   
11.1.5 
Relationship to Investigational Medicinal Product 
The relationship of an AE to the administration of IMP (unrelated, probable or definite) is 
a clinical decision based on all available information at the time of the completion of the 
eCRF. 
IMP relationship will be evaluated according to the following definitions: 


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Unrelated: includes the existence of a clear alternative explanation (e.g., mechanical 
bleeding at surgical site) or non-plausibility (e.g., the patient is struck by an automobile, at 
least where there is no indication that the IMP caused disorientation that may have led to 
the event; cancer developing a few days after IMP administration). 
Probable: The AE, including clinical laboratory abnormality, follows a reasonable 
sequence from the time of IMP administration, follows a known response pattern of the 
IMP class, is unlikely to be attributed to the patient’s clinical state, and is confirmed by 
improvement on stopping the IMP (de-challenge). 
Definite: The AE, including clinical laboratory abnormality, follows a plausible sequence 
from the time of IMP (or placebo) administration; follows a known or expected response 
pattern to the IMP class; cannot be explained by disease or it disappears or decreases on 
cessation or reduction in IMP dose; and/or it reappears or worsens when the IMP is re-
administered. 
11.1.6 Severity 
The Investigator will determine the intensity of each AE using the following terms and 
definitions: 
Mild: An AE that was usually transient required no intervention or special treatment and 
did not interfere with usual/normal activities. 
Moderate: An AE that interfered with usual/normal activities but was ameliorated by 
therapeutic measures. 
Severe: An AE that was intense or debilitating and which interfered with usual/normal 
activities. Recovery was usually aided by therapeutic measures. Discontinuation of IMP 
might have been required. 
11.2 Reporting of Adverse Events 
All AEs that occur between randomization through Day 28 visit will be reported. AEs that 
start prior to study drug administration will also be captured. Worsening signs and 
symptoms of the underlying disease will be reported as AEs. 
The course of each event should be followed until resolution. All unresolved AEs should 
be followed-up by the Investigator until the events are resolved, or the AE is stabilized and 
otherwise explained. 
AEs should be recorded according to findings and abnormalities detected by the 
Investigator. Specific capturing of potential secondary infections will take place. In 
addition, patients should report AEs voluntarily and in response to general, non-directed 
questioning. For each AE reported by the patient, or observed by the Investigator, the 
Investigator should obtain all the information required to complete the AE page of the 
eCRF, in accordance with the guidelines that accompany it. 
Atox Bio or designee assumes responsibility for appropriate reporting of SAEs to the 
regulatory authorities. Atox Bio or designee will also report to the Investigators all SAEs 
that are unexpected and associated with the use of the drug. 


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The Investigator must report these events to the appropriate IRB/IEC in accordance with 
local regulations. 
11.3 Reporting of Serious Adverse Events 
All SAEs occurring with any patient participating in this clinical study must be recorded. 
All deaths and SAEs must be reported within 24 hours of becoming aware of the event to 
the Sponsor or designee. All SAEs beginning within 28 calendar days after the last 
exposure to IMP must be recorded. 
11.3.1 Initial Report 
Once an Investigator becomes aware that a SAE has occurred in a study subject, the 
Investigator (or designate) must complete the information in the SAE eCRF pages WITHIN 
24 HOURS. The SAE eCRF pages will always be completed as thoroughly as possible with 
all available details of the event. Even if the Investigator does not have all information 
regarding a SAE, the SAE eCRF pages should still be completed within 24 hours. The 
report should contain, at a minimum, the following information: 
• Subject identifiers (i.e., subject number) 
• Suspected medicinal product (or if related to IMP, note “Reltecimod/Placebo”) 
• Adverse event term (must be listed as serious) 
• Contact information for person reporting event 
Once additional relevant information is received, the SAE eCRF pages should be updated 
WITHIN 24 HOURS. 
The medical monitor is available on a 24-hour basis if clinical personnel wish to discuss 
any safety related events. 
11.3.1.1 Electronic SAE Reporting System Back-up 
If the electronic SAE reporting system does not work, the Investigator (or designate) must 
complete, then date and sign a SAE Report Form.  The site should scan the document and 
email it to the medical monitor at davidw@atoxbio.com and wayned@atoxbio.com within 
24 hours. 
This back-up system should only be used if the electronic SAE reporting system is not 
working and NOT if the system is slow. As soon as the electronic SAE reporting system is 
working again, the Investigator (or designate) must complete the SAE eCRF pages within 
24 hours. The final valid information for regulatory reporting will be the information 
reported through the electronic SAE reporting system. 
11.3.2 Follow-up and Final Reports 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
subject and provide further information on the subject’s condition to Atox Bio. 
All SAEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until the 
end of the study. 


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All AEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until study 
end. 
Follow-up information to an initial SAE report should be reported in the SAE eCRF pages 
within 3 business days. At the time of resolution of a SAE, a final report must be provided 
to the Sponsor by completing the appropriate SAE Report Form. 
Any AE, regardless of severity, and whether or not ascribed to the IMP administration, will 
be recorded as such using medical terminology in the source documentation and on the 
appropriate eCRF pages. Whenever possible, diagnoses should be given when signs and 
symptoms are due to a common etiology (e.g. nausea and vomiting should be reported as 
"gastroenteritis" if gastroenteritis is the etiology of both). However, worsening sign(s) and 
symptom(s) of a diagnosis should be recorded separately. Patients withdrawn from the 
study due to AEs will be followed by the Investigator until the outcome is determined and, 
when appropriate, additional written reports and documentation will be provided. 
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the patient's participation in the study, must be followed-up until either: 
• the event resolves 
• the event stabilizes 
• the event returns to baseline, if a baseline value is available 
• the event can be attributed to agents other than the study drug, or 
• the event can be attributed to factors unrelated to study conduct 
11.4 Disease Related Adverse Events 
It is recognized that the patient population with abdominal sepsis or NSTI who require 
critical care support will experience a number of common aberrations in laboratory values, 
signs, and symptoms due to the severity of the underlying disease and the impact of 
standard therapies. These will not necessarily constitute an AE unless they require 
significant intervention, lead to discontinuation of blinded study medication, felt to be 
related to blinded study medication or are considered to be of concern, in the Investigator’s 
clinical judgment. Examples of the type of AEs that may be associated with the abdominal 
infection, NSTI and sepsis are listed below. 
11.4.1 List of Adverse Events that may be Associated with Abdominal Infection, 
NSTI, and Sepsis 
Acute respiratory failure; respiratory distress; acute lung injury; acute respiratory distress 
syndrome (ARDS); acute renal failure; coagulation dysfunction; decreased platelets count; 
neutropenia; hypothermia; fever, bacteremia; sepsis, septic shock; hypotension; metabolic 
acidosis, 
pleural 
effusion; 
abdominal 
compartment 
syndrome; 
repeated 
surgeries/debridement; amputation. 
For purposes of this study, deaths will be captured as clinical outcomes and do not need to 
be reported as SAEs unless felt related to study drug administration. 


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11.5 Safety Monitoring 
The study medical monitor will assess all SAEs on an ongoing basis. Attention will be 
given to SAEs assessed as drug-related. The medical monitor may request unblinding of 
the treatment allocation of a patient for regulatory reporting purposes. The medical monitor 
will convene the independent data monitoring committee (iDMC) on ad-hoc basis if safety 
concerns arise from the medical monitor review. 
11.6 Independent Data Monitoring Committee (iDMC) 
An iDMC will be established to evaluate the safety of the study.  An iDMC review of the 
safety data is planned after 60 patients (and possibly a second review depending on sample 
size re-estimation) have completed 28 days of the study. 
For each planned iDMC review, all safety data on all patients who received one dose of 
Reltecimod will be made available to the iDMC. The data reviewed by the iDMC will be 
unblinded and presented by group to facilitate recommendations to the Sponsor. Data 
submitted to the iDMC review may be unaudited. A designated unblinded statistician will 
provide unblinded safety data to the iDMC using programs constructed and validated by 
the blinded Study Statistician and Statistical Programming Team. Further details on data 
management will be provided in the statistical analysis plan (SAP). 
The iDMC may also meet on an ad-hoc basis when immediate safety concerns arise. In 
case of urgency, the chair of the committee could address any questions or concerns 
regarding the safety of the patients. 
12.  STATISTICS 
12.1 Primary Effectiveness Endpoint 
The primary effectiveness endpoint for this study is: 
• Rates of achieving the primary endpoint of freedom from durable loss of renal 
function (defined as alive, free of dialysis, and less than a 37% loss of eGFR; 
(measured with the MDRD formula from the patient’s reference eGFR)) at Day 28. 
12.2 Secondary Effectiveness Endpoints 
The secondary effectiveness endpoints for this study: 
• Rates of the primary endpoint at Day 14 between the Reltecimod- and placebo-
treated patients.  
• To compare time to the primary endpoint between the Reltecimod- and placebo-
treated patients over 14 days 
• AKI-free days over 28 days 
• Time to the primary endpoint 
• Resolution of organ dysfunction (organ resolution is defined as having a total SOFA 
score of ≤1) at Day 14 


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• Resolution of specific organ dysfunction defined as having an individual organ 
SOFA score of ≤1 at Day 14 
• Critical care and hospital stay parameters 
o Hospital length of stay 
o ICU length of stay 
o ICU-free days in 28 days 
o Ventilator days 
o Ventilator free days in 28 days 
o Vasopressor days 
o Vasopressor free days in 28 days 
o RRT free days (days alive and free of RRT) in 28 days 
• Patient survival at Days 14 and 28  
• Presence of Stages 1, 2 or 3 AKI (using the KDIGO criteria) in patients with 
abdominal sepsis or NSTI 
12.3 Exploratory Measures 
• Rates of improvement in durable loss of renal function (defined as alive, free of 
dialysis and improvement leading to a lower AKI stage but no better than Stage 1 
AKI) at Days 14, 28 and 90 
• AKD stages (AKD 0, 1, 2, 3 and 3F) at Days 14 and 28 
• Incidence of CKD at Day 90  
• Survival at Day 90 
• Primary endpoint by baseline pathogen 
• Evaluation of RRT use (i.e., type of RRT) 
• Plasma and urinary biomarkers in patients with AKI 
• To conduct an exploratory evaluation of blood leukocyte transcriptome (RNA 
expression) profiling in patients with SA-AKI and compare genomic profile in 
patients treated with Reltecimod versus placebo 
• To define potential surrogate biomarkers (systemic) that exhibit change from 
baseline due to treatment with Reltecimod 
12.4 Safety Endpoints 
The following will be evaluated as safety endpoints: AEs, clinical parameters (HR, BP, 
vital signs), laboratory parameters (clinical chemistry and hematology) and survival. 
12.5 Synopsis of Key Statistical Approaches 
12.5.1 Primary Efficacy Comparison 
The primary efficacy comparison involves testing the following one-sided superiority 
hypotheses: Ho: π0.50 − πplacebo ≤ 0 vs Ha: π0.50 − πplacebo > 0; where π0.50 and πplacebo 
represent the true probability of freedom from durable loss of kidney function (alive, free 
of dialysis, and less than a 37% loss of eGFR (measured with the MDRD formula from the 
patient’s reference eGFR)) at Day 28. Each probability represents the proportion of subjects 
on each arm expected to achieve freedom from durable loss of renal function. These 


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hypotheses will be tested using an unadjusted chi-square test at a one-sided type 1 error 
rate of α=0.025. The null hypothesis will only be rejected if the proportion of responders is 
larger in the active drug group compared to placebo.  It is a noteworthy advantage of the 
sample size re-estimation approach to be used (see details below) that the conventional test 
statistic may be used to test the primary hypothesis and there is no need to weight subjects 
randomized after the sample size re-estimation differently from those randomized before 
the sample size re-estimation.  
12.5.2 Sample Size Justification 
This trial will enroll 120 subjects who will be randomized in a ratio of 1:1 to either 
Reltecimod 0.50 mg/kg or placebo, each in addition to SoC. Sample size analysis was 
performed assuming that all patients will be evaluable for the primary endpoint using last 
observation carried forward (LOCF) for patients missing creatinine on Day 28. The 
primary efficacy hypothesis will be tested using an unadjusted χ2 statistic with a one-sided 
α=0.025 significance level. Rejection the null hypothesis will only occur if investigational 
drug superiority is demonstrated. Statistical power was computed for a range of expected 
treatment group differences supported by the results of preliminary studies. Table 6 
summarizes the statistical power for a fixed sample design with a total sample size of 
N=120 (60 per group) for various assumptions regarding the success rate in the 
investigational arm and assuming a success probability of 0.50 among controls. This 
sample size results in 81.6% power if the true success rates are 75% and 50% for the 
investigational and placebo, respectively, a group difference of 25%.   
12.5.3 Sample Size Re-Estimation 
A “Promising Zone” sample size re-estimation (SSR) interim analysis (IA) is planned for 
when between 50% and 67% of the initial sample size is evaluable for the primary efficacy 
endpoint (Mehta and Pocock 2011)53.  The purpose of the SSR is to maintain (conditional) 
power when the treatment group difference is smaller than 0.25, but still clinically 
meaningful.  
A pre-specified maximum sample size expansion will be specified prior to providing 
unblinded results to the iDMC but in no case will the sample size expansion exceed an 
additional 200 subjects. With this restriction, only clinically meaningful treatment effects 
are detectable with good statistical power at the maximum sample size. The specific rules 
for determining if sample size expansion is permittable and if so, by how much, will ensure 
control of type 1 error. 
Specifically, the sample size will be increased up to the maximum to maintain conditional 
power to as close to 80% as possible, but only if conditional power at the interim analysis 
is above a pre-specified threshold that results in control of type 1 error to the desired 
nominal value. If conditional power falls within the Promising Zone, increasing the sample 
size up to the pre-specified maximum is at the discretion of the Sponsor. 
The pre-specified conditional power threshold is the lower bound of the Promising Zone 
and its value may be obtained from Table 1 in Mehta and Pocock 2011. It depends on the 
ratio of the maximum sample size to the initial sample size (1.5, 2, 3, or infinite), the 


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fraction of the initially planned sample size included in the IA for SSR (0.25, 0.5, or 0.75), 
and the level of conditional power to be maintained (80% or 90%). Additional scenarios 
can be determined using linear interpolation. For 80% power, the lower bounds of the 
Promising Zone range from 0.30 to 0.42 depending on these three parameters. If 
conditional power falls within the Promising Zone, increasing the sample size up to the 
pre-specified maximum up to the discretion of the Sponsor.  
Table 6 provides a simple evaluation of how the size of maximum sample expansion relates 
to statistical power for detecting various clinical effect sizes. Table 6 compares statistical 
power for fixed sample designs with total sample sizes of 120 (the initially planned sample 
size), 180 (allowing up to 60 more subjects), and 320 (allowing up to 200 more subjects).  
The selected maximum will be no larger than 200 additional subjects.  As noted above, a 
fixed sample size design randomizing 120 subjects achieves 81.6% power if the treatment 
group difference is 25% (i.e., 75% versus 50%). Similarly, a fixed sample size design with 
180 subjects achieves 82.7% power if the treatment group difference is 21% (i.e., 71% 
versus 50%).  Finally, a fixed sample size design with 320 subjects achieves 82.9% power 
if the treatment group difference is 16% (i.e., 66% versus 50%). A 16% treatment group 
difference is still considered clinically meaningful. Therefore, even if a maximum increase 
of 200 is selected, the study will only have large statistical power to detect clinically 
meaningful treatment effects.  
Additionally, the lower bounds of the Promising Zone when the IA for SSR is performed 
with 67% of the initially planned sample size is 0.39 when the maximum increase is 60 
subjects; but is reduced to 0.31 when the maximum increase is set to 200.  If the observed 
proportions of responders are 0.66 (0.65) and 0.50 for active and placebo subjects, 
respectively, conditional power will be 0.3905 (0.3148). Therefore, in any case, the 
observed treatment group differences will need to larger than about 0.15 depending on the 
scenario, for any sample size expansion to be even allowed under the Promising Zone 
approach. This makes it unlikely that the treatment group difference will be found to be 
statistically significant unless the true treatment effect exceeds about 0.15.  


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Table 6: Examples of power for fixed sample design (1-sided α=0.025) 
Control 
Reltecimod 
Power 
(N=120) 
Power 
(N=180) 
Power 
(N=320) 
0.5 
0.60 
0.194 
0.269 
0.435 
0.5 
0.61 
0.226 
0.316 
0.508 
0.5 
0.62 
0.261 
0.367 
0.581 
0.5 
0.63 
0.299 
0.420 
0.651 
0.5 
0.64 
0.339 
0.475 
0.717 
0.5 
0.65 
0.382 
0.530 
0.777 
0.5 
0.66 
0.426 
0.586 
0.829 
0.5 
0.67 
0.472 
0.641 
0.874 
0.5 
0.68 
0.518 
0.693 
0.909 
0.5 
0.69 
0.565 
0.742 
0.937 
0.5 
0.70 
0.611 
0.787 
0.958 
0.5 
0.71 
0.656 
0.827 
0.973 
0.5 
0.72 
0.700 
0.863 
0.983 
0.5 
0.73 
0.741 
0.894 
0.990 
0.5 
0.74 
0.780 
0.919 
0.994 
0.5 
0.75 
0.816 
0.940 
0.997 
 
12.5.4 Futility Analysis 
In addition to sample size re-estimation, a non-binding futility analysis will be conducted 
at the time of the interim analysis.  If conditional power is below a pre-specified futility 
threshold, enrollment may be immediately stopped at the discretion of the Sponsor. The 
pre-specified threshold will be determined prior to unblinding the data for the interim 
analysis. 
12.5.5 Control of Blinding and iDMC 
This study will remain blinded as to treatment allocation. The actual randomized treatment 
allocations will be kept by a contracted third-party responsible only for managing the 
randomization process. A variable indicating the blinded treatment allocations will not be 
part of the clinical study data to be managed by the data management contract research 
organization (CRO). Therefore, only blinded study data will be available to the primary 
study statistician and responsible primary programming staff. 
An iDMC will be utilized in this study. A detailed iDMC charter will be provided to clarify 
all relevant issues relating to fire-walls to protect against potential operational biases. The 
charter will provide decision rules, composition of the iDMC members and their conflict 
of interest statements. A separate unblinded interim analysis statistician will work with the 


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iDMC to provide unblinded data as necessary for iDMC deliberations.  The unblinded 
statistician will determine the interim analysis conditional power and summarize the 
implications to members of the iDMC.  The iDMC will inform specifically designated 
individuals from the Sponsor whether conditional power is below the futility zone, above 
the futility zone but below the Promising Zone, within the Promising Zone, or above the 
Promising. If within the Promising Zone, the iDMC will be informed as to the increase in 
sample size required to maintain conditional power to at least 80%, or if this is not 
possible, that the maximum allowed increase in sample size may be enrolled. The iDMC 
will 
then 
inform 
specifically 
designated 
Sponsor 
representatives 
of 
their 
recommendations based on the a priori plan.   
12.6 Summary of Other Elements of Analysis Plan 
12.6.1 Randomization 
120 patients will be recruited into the study and randomized to either 0.50 mg/kg 
Reltecimod or placebo in a 1:1 ratio. Randomization will be performed within site and 
according to two stratification variables: 
•
Acuity of AKI: whether or not AKI is diagnosed at time of presentation of
abdominal infection or surgically confirmed NSTI; or during the 48 hours the
suspected diagnosis of abdominal infection or surgical confirmation of NSTI.
•
Subject Age: >18 to <75 or >75 to ≤85 years old.
Four computer generated, blocked randomization lists will be provided for each site, one 
for each of four strata defined on the basis of the 2 by 2 cross-tabulation of the two 
stratification variables. Within each block, half of the assignments will be to active drug 
and half to placebo, in random order. Block sizes will be varied. 
12.6.2 Patient Populations 
The following analysis sets are defined: 
•
Intent-to-treat (ITT): The ITT analysis set will include all randomized patients.
•
As-Treated (AT): The AT analysis set will include all randomized patients who
were exposed to study medication (active or placebo). The AT analysis set will
be used in primary safety analyses with patients assigned to actual treatment
received.
•
Modified Intent-to-treat (mITT): The mITT analysis set will include patients
who were exposed to study medication and who had a definitive diagnosis of
abdominal sepsis or NSTI with patients assigned to their intended randomized
assignment. The mITT analysis set will be used in primary effectiveness
comparisons.
•
Per Protocol (PP): Optionally, a PP analysis set may be used in secondary
effectiveness analyses. The PP analysis would include patients in the mITT
analysis set assigned according to actual treatment received and excluding
patients with either 1) significant violations of inclusion or exclusion criteria


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with potential to confound estimates of drug effects or 2) post randomization 
protocol violations or intercurrent events with potential to confound estimates of 
treatment effects. Exclusions from the PP analysis set will be determined based 
on blinded clinical data. The PP analysis may be further restricted to include 
patients that survive at 3 least days when evaluating critical care variables. 
12.6.3 Preliminary and Descriptive Analyses 
Before proceeding with between-group comparisons of primary and secondary clinical 
endpoints, data quality will be assessed by descriptive summaries and graphical methods 
(e.g., histograms and scatterplots) in order to examine assumptions such as normality that 
underlie statistical models. Transformations will be used, if needed, to produce variables 
that conform to the distributional assumptions underlying the analytic techniques 
employed. Descriptive analyses will be performed in order to characterize the treatment 
groups and to confirm that the randomization resulted in no clinically significant group 
differences at baseline. Although emphasis will be on clinical significance, baseline 
comparisons will include t-tests or Wilcoxon rank sum tests as appropriate for interval 
variables and chi-square or Fisher's exact tests as appropriate for nominal variables to aid 
in the screening for baseline differences. Similarly, changes in clinical endpoints over time 
will be summarized within each treatment group using summary statistics including mean 
and median change scores, standard deviations and ranges. Pearson or Spearman rank 
correlation coefficients will be used to characterize associations among variables within 
treatment group. When summarizing across groups, partial correlations may be computed 
controlling for treatment group. For time-to-event outcomes (i.e., event-free survival), 
descriptive analyses will include construction of group specific Kaplan-Meier survival 
curves as appropriate 
12.6.4 Secondary Endpoints 
Secondary endpoints have been specified from several domains. Additional secondary 
endpoints include SOFA over time, time to the primary endpoint, critical care and hospital 
stay parameters (hospital length of stay (LOS), ICU and ICU-free days, ventilator days and 
–free days, vasopressor days and –free days). Analyses for these endpoints will generally
be descriptive, with emphasis on characterizing clinical effect sizes. Nominal p-values will
be presented. Categorical outcomes will be described using counts and percentages with
nominal p-values determined through chi-square or exact methods. Critical care and hospital
stay endpoints will be described using non-parametric approaches including using
concordance statistics to characterize clinical effect sizes and Wilcoxon rank sum tests to
determine nominal statistical significance. Methods appropriate for time-to-event endpoints
including survival and life-table methods will be used for time-to-recovery endpoints.
12.7 Sub-group Analysis 
Subgroup analysis will be performed. The primary subgroup analyses to be performed 
include: 
Patients presenting with either Stage 2 or Stage 3 AKI. 


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By acuity of AKI (i.e., whether or not AKI is diagnosed at time of presentation of 
abdominal infection or surgically confirmed NSTI, or during the 48 hours from the 
suspected diagnosis of abdominal infection or surgical confirmation of NSTI). 
By subject age >18 to <75 or >75 to <85 years old. 
For these sub-group analyses, active dose versus placebo differences in likelihood of 
freedom from durable loss of renal function will be evaluated as well other selected 
secondary endpoints. 
Other sub-groups to be evaluated will include patients who developed AKI up to ≤24 hours 
or 25-48 hours after the suspected diagnosis of abdominal infection or surgical 
confirmation of NSTI or if AKI diagnosed via creatinine criteria vs urine output criteria. 
12.8 Assessment of Poolability Among Sites 
Site poolability will be evaluated using a random effects meta-analysis approach using the 
R package metafor to implement the analysis46. True effects are assumed to be normally 
distributed with mean µ and variance τ2. By imposing a specified distribution on the site-
to-site variability, i.e. a normal distribution with mean µ and variance τ2, sensitivity to small 
sample sizes in individual sites is reduced and the parameters reflecting the magnitude of 
site-to-site variability are naturally derived. The quantitative measure of the magnitude of 
heterogeneity is I2 47. I2 is the fraction of τ2 that is due to site to site differences in treatment 
effects (effect size heterogeneity), as opposed to sampling variance. Fractions 25% and less 
are considered small. If there is significant site-to-site variability, the impact on this 
variability will be evaluated using a random effects logistic regression to test the null 
hypothesis that the likelihood of achieving freedom from durable loss of renal function is 
the same for treated and placebo patients accounting for a random site effect. Poolability 
according to baseline demographic, disease severity status, and number of levels treated 
will be evaluated using descriptive stratified analyses. 
12.9 Analysis of Other Covariate Effects 
Covariates will be assessed for potential confounding (due to lack of perfect randomization 
balance) or effect modification (subgroup efficacy heterogeneity) using multiple logistic 
regression. Covariates will include but are not limited to age, race, sex, site, and clinical 
severity scores at baseline. Other baseline variables in which randomization failed to 
produce adequate balance between groups will be examined in supporting analyses. This 
will be done through stratified analyses and/or multiple logistic regression. Covariate 
effects on estimates and interactions will be assessed to see if there is evidence of efficacy 
heterogeneity. Results from all subgroups analyses will be considered hypothesis-
generating. 
12.10  Multiplicity 
There is a single primary hypothesis test utilizing a single clinical success endpoint, 
freedom from durable loss of renal function. Therefore, there is no issue with regard to 
multiplicity. 


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12.10.1Longitudinal Data 
A number of secondary efficacy endpoints will be assessed over time including SOFA total 
score. 
Where appropriate for continuous measures, statistical testing and estimation will be based 
on the results from a Mixed Model Repeated Measures (MMRM) analysis of covariance 
(ANCOVA) model. This model will include the baseline value of the outcome variable if 
appropriate. Other clinically relevant baseline variables predictive of outcome will be 
considered if there is missing outcome data over time. Inclusion of such covariates helps 
with the implicit imputation of missing values inherent in the MMRM approach. MMRM 
is a direct likelihood approach requiring specialized statistical software for optimizing the 
likelihood function. For this study, all MMRM parameters will be estimated using SAS 
PROC MIXED version 9.4 or higher [SAS Institute, Cary, NC]. The MMRM model is 
notable for its ability to include all available data from all eligible subjects and does not 
require their exclusion as in complete case analysis or arbitrary assignment of values as in 
LOCF. The MMRM model generally includes a factor for group by time interaction in 
order to allow group differences in mean values to vary over time. Inclusion of outcome 
data from all time points informs the implicit imputation of values missing at specific time 
points through the outcome covariance matrix. Inclusion of baseline covariates has 
potential for further reduction of potential bias due from missing values. 
Specifically, MMRM will be used to compare mean values over time between the 0.50 
mg/kg dose and placebo. Model parameters will be estimated using Restricted Maximum 
Likelihood48,49 (REML) as implemented Proc Mixed [SAS Institute, Proc Mixed, 
SAS/STAT Software]. A generalized Satterthwaite approximation will be used to 
determine accurate estimates of denominator degrees of freedom for statistical tests. 
Analyses will characterize changes over time as functions of the baseline value, treatment 
group, time, and treatment by time interaction. Between-group differences at each time 
point will be evaluated using contrasts derived from mixed model parameter estimates. This 
approach produces inferences that are valid under the assumption of missing at random 
(MAR) which produces valid inference under broader assumptions than complete case 
analysis or analyses utilizing LOCF50. 
12.10.2Analysis of Event-time and Overall Survival 
Time-to-event endpoints will be assessed in descriptive analyses using survival and life-
table methods as appropriate. Analyses will include time to freedom from durable loss of 
renal function and time to at least durable loss of renal function. Similarly, overall survival 
through 90 days will be compared between groups using Kaplan-Meier survival curves. 
The significance of treatment differences will be assessed using log rank statistics. 
12.11  Handling of Missing Data 
12.11.1Intent-to-Treat 
The purpose of intent-to-treat comparisons is to ensure that randomization is protected (i.e., 
all groups have comparable baseline characteristics and that any differences besides therapy 
are due to chance) and to preclude the possibility of bias due to selectively excluding 


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subjects from therapy groups. This is intended to avoid systematic differences among the 
groups attributable to factors other than therapy assignment51. Therefore, we will attempt 
to include all randomized patients in the primary effectiveness analysis, regardless of 
intervention or length of follow-up in the primary efficacy comparison, with the exception 
of subjects that are subsequently confirmed to not have Stage 2 or 3 AKI, abdominal sepsis 
or NSTI.  Due to the critical nature of this indicated population, it is sometimes necessary 
to begin drug administration prior to disease confirmation. Subjects confirmed to not have 
abdominal sepsis or NSTI will be excluded from the mITT analysis set to be used in primary 
and secondary efficacy analysis but included in the As Treated analysis set to be used in 
primary safety analysis.  
12.11.2LOCF of Day 28 Creatinine 
In order to determine the primary endpoint, freedom from durable loss of renal function, 
Day 28 creatinine is necessary. Patients surviving to Day 28 or later but with missing Day 
28 creatinine will have their Day 28 creatinine values determined through last observation 
carried forward (LOCF) of earlier values.  Creatinine values will be confirmed 3 to 21 Days 
after Visit 9. 
12.11.3SOFA Scores 
SOFA scores over time will be assessed as 1) observed cases, 2) LOCF, and 3) using 
MMRM. 
Individually missing SOFA component values due to non-measurement are conventionally 
assumed as normal and this convention will be followed for this study. 
LOCF will not be applied to missing SOFA scores after patient death in analyses that 
employ LOCF to describe mean values of time. Therefore, analysis of SOFA mean values 
using LOCF will focus on morbidity rather than mortality. 
Mixed model repeated measures analyses will utilize implicit imputed values for all 
missing values including those subsequent to patient death. 
In categorical analyses including formulation of the secondary effectiveness endpoint, total 
SOFA score at Day 14 ≤ 1, LOCF is necessary to guarantee that every patient has a value 
at Day 14. 
12.11.4Mixed Model Repeated Measures 
As describe above, continuous measure observed over time including SOFA will be 
assessed using MMRM where possible. MMRM uses all available data and results in 
implicit imputations for missing data which are valid under MAR, a more general set of 
assumptions than missing completely at random (MCAR). 
12.12 Safety Analysis 
The primary safety measures are AEs (including SAEs), clinical safety laboratory, PE, vital 
signs through Day 28 and including determination of survival through Day 28. 
The safety profiles will be compared between active and placebo groups using descriptive 
statistics as appropriate for continuous and categorical safety variables. Changes in 


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continuous safety measures such as laboratory values will be summarized by mean changes 
over time using descriptive statistics (mean, SD, median, minimum and maximum). The 
presence of clinically significant safety findings will be summarized by shift tables 
separately for each group using counts and percentages. AEs will be classified according 
to system organ class and preferred term and summarized by counts and percentages 
separately for those recorded at Screening (prior to drug administration) and those with 
onset on Day 1 or later. AEs will also be summarized by relationship to study drug, severity, 
and whether they are serious. Specific summaries will involve AEs and SAEs in the 
Infection/Infestation system organ class. Results from PEs will be tabulated for the 
Screening, Day 7, and Day 14. For each test, the number of patients evaluated, and the 
numbers and percentages of patients with Normal and Abnormal results will be tabulated. 
Vital signs including weight, temperature, systolic BP, diastolic BP, respiration rate, and 
heart rate will be summarized across time (Screening, Day 1, Day 2, Day 3, Day 7, and Day 
14 separately by treatment group by N, Mean, and SD. 
 
13. SOURCE DATA ACCESS, DATA MANAGEMENT AND DATA HANDLING 
13.1 Data Quality Assurance 
The Sponsor or Sponsor’s designee will conduct a site visit to verify the qualifications of 
each Investigator, inspect the site facilities, and inform the Investigator of responsibilities 
and the procedures for ensuring adequate and correct documentation. 
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. All information recorded on the eCRF/electronic data capture (EDC) system 
for this study must be consistent with the patients’ source documentation (i.e., medical 
records). 
13.2 Database Management 
Data Management services will be provided by the Sponsor or designee. The data 
management system will be specified in the Data Management Plan. 
After the data have been entered and verified, various edit checks will be performed for the 
purpose of ensuring the accuracy, integrity and validity of the database. These edit checks 
may include: 
-  Range checks 
-  Consistency checks 
-  Sequence checks 
-  Protocol adherence checks 
Queries generated from these checks will be sent to the investigational site for resolution, 
and the database will be updated to reflect query resolutions as appropriate. 


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AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA). Prior and concomitant medications will be coded according to the World 
Health Organization (WHO) Drug Dictionary. 
13.3 Case Report Forms and Source Documentation 
All data obtained during this study should be entered in the EDC system promptly. All 
source documents from which eCRF/EDC system entries are derived should be placed in 
the patient’s medical records. Measurements for which source documents are usually 
available include laboratory assessments, ECG, and microbiological outcome. 
Data that will be entered directly into the eCRF/EDC system are considered to be source 
data. 
The original eCRF/EDC system entries for each patient may be checked against source 
documents at the study site by the Sponsor site monitor. 
After review by the site monitor, completed eCRF/EDC system entries will be uploaded 
for data check by the Sponsor’s data management CRO. Instances of missing or 
uninterpretable data will be discussed with the Investigator for resolution. 
The specific procedures to be used for data entry and query resolution using the EDC 
system/eCRF will be provided to study sites in a study manual. In addition, site personnel 
will receive training on the EDC system/eCRF. 
13.4 Data Collection 
The Investigators (and appropriately authorized staff) will be given access to an online 
web-based EDC system which is compliant with 21 CFR Part 11. This system is 
specifically designed for the collection of the clinical data in electronic format. Access and 
right to the EDC system will be carefully controlled and configured according to each 
individual’s role throughout the study. In general, only the Investigator and authorized staff 
will be able to enter data and make corrections in the eCRF/EDC system. 
The EDC system/eCRF should be completed for each patient included in the study and 
should reflect the latest observations on the patients participating in the study. Therefore, 
the EDC system/eCRFs are to be completed as soon as possible (within 5 working days) 
after the patient’s visit or assessment. The Investigator must verify that all data entries in 
the EDC system/eCRFs are accurate and correct. If some assessments cannot be done, or if 
certain information is unavailable, not applicable or unknown, the Investigator should 
indicate this in the EDC system/eCRFs. 
Computerized data-check programs and manual checks will identify any clinical data 
discrepancies for resolution. Corresponding queries will be loaded into the system and the 
site will be informed about new issues to be resolved online. All discrepancies will be 
solved online directly by the Investigator or by authorized staff. Off-line edit checks will 
be done to examine relationships over time and across panels to facilitate quality data. 
After completion, the Investigator will be required to electronically sign off the clinical 
data. 


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Data about all study drug dispensed to the patient will be tracked on the EDC 
system/eCRFs. 
13.5 Access to Source Data 
During the study, a monitor will make site visits to review protocol compliance, compare 
EDC system/eCRFs entries and individual patient’s medical records, assess drug 
accountability, and ensure that the study is being conducted according to pertinent 
regulatory requirements. EDC system/eCRFs entries will be verified with source 
documentation. The review of medical records will be performed in a manner to ensure that 
patient confidentiality is maintained, and the study blind is respected. 
Checking of the EDC system/eCRFs entries for completeness and clarity, and cross-
checking with source documents, will be required to monitor the progress of the study. 
Moreover, Regulatory Authorities of certain countries, IRBs, IECs, and/or the Sponsor’s 
Clinical Quality Assurance Group may wish to carry out such source data checks and/or 
on-site audit inspections. Direct access to source data will be required for these inspections 
and audits; they will be carried out giving due consideration to data protection and medical 
confidentiality. The Investigator assures the Sponsor of the necessary support at all times. 
13.6 Archiving Study Records 
According to ICH guidelines, essential documents should be retained for a minimum of 2 
years after the last approval of a marketing application in an ICH region and until there are 
no pending or contemplated marketing applications in an ICH region or at least 2 years 
have elapsed since the formal discontinuation of clinical development of the investigational 
Product. However, these documents should be retained for a longer period if required by 
the applicable legal requirements. 
 
14. QUALITY ASSURANCE 
To comply with ICH GCP Guidelines, an independent audit at the study site may take place 
at any time during or after the study. The independent audit can be conducted by the Quality 
Assurance Department of the Sponsor or a regulatory authority. ICH GCP Guidelines state 
that investigational sites and all data, including source data, must be available for inspection 
by competent authorities. The Investigator shall inform patients that their medical records 
will be reviewed during these audits, however, pursuant to current HIPAA regulations; the 
patients’ privacy must be respected. Sufficient prior notice will be provided to allow the 
Investigator to properly prepare for the audit. 


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15. GENERAL STUDY ADMINISTRATION 
15.1 Ethical Aspects 
15.1.1 Good Clinical Practices / Local Regulations 
This study will be carried out according to the Declaration of Helsinki, the Notes for 
Guidance on Good Clinical Practice (2000) (CPMP/ICH/135/95), with ICH GCP, and any 
local applicable regulations. 
The Sponsor will be responsible for reporting all serious, life-threatening or fatal adverse 
Investigational Product events with a causal relationship to the Investigational Product to 
appropriate regulatory agencies within their required timelines. 
The Principal Investigator will ensure that this study is conducted in full compliance with 
the protocol, the Declaration of Helsinki, the ICH guideline for GCP, and all other 
applicable local laws and regulations. Compliance with these standards provides assurance 
that the rights, safety, and well-being of patients are protected. 
In agreeing to the provisions of the protocol, these responsibilities are accepted by the 
Investigator. 
15.2 Informed Consent 
Prior to initiation of the study, the Investigator will provide the Sponsor with a copy of the 
investigational site’s IRB/EC approved study ICF. The ICF must contain all elements 
required by ICH GCP (E6). The ICF must also adhere to local privacy requirements as well 
as any other elements required by state, local and institutional policies. 
All prospective patients or the patient’s LAR will be given a copy of the approved study 
ICF to read. 
Before being admitted to the clinical study, the patient must have given written consent, or 
the LAR must have given phone/fax/email/e-consent or written consent to participate in the 
study, after the nature, scope, and possible consequences of the study (including insurance 
and other procedures for compensation in case of injury) have been explained in an 
understandable form by the Investigator or nominee. 
It will be pointed out that patients/LARs can refuse to participate in the study or withdraw 
from the study without prejudice to further care and treatment. 
Ample time and opportunity will be allowed for each patient/LAR to inquire about details 
of the study and to decide whether or not to participate in the study. 
Both the patient/LAR and the person who conducts the informed consent discussion will 
sign and personally date the document. The acquisition of informed consent should be 
documented in the patients’ medical records. 
Where consent has been obtained from a LAR, if the patient is deemed by the Investigator 
able to provide informed consent on their own behalf any time during the study period, 


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informed consent from the patient will be obtained. The patient has the ability to withdraw 
from the study at any time, for any reason. 
Patients/LARs will be informed of any significant new finding which arises during the 
course of the research that may affect their decision to continue participation. 
15.3 Institutional Review Board / Ethics Committee 
The protocol will be submitted for approval to the appropriate IRB/EC. Prior to initiation 
of the study, the Investigator must provide the Sponsor with a copy of the written IRB/EC 
approval of the protocol and study ICF. This approval letter will identify the study ICF by 
date or version number, and the study protocol by protocol number, title, and date. The 
Investigators will receive all the documentation needed for submitting the present protocol 
to the IRB/EC. The composition of the IRB/EC will also be provided to the Sponsor. If 
approval is suspended or terminated by the IRB/EC, the Investigator will notify the Sponsor 
immediately. 
It is the responsibility of the Investigator to report study progress to the IRB/EC as required 
or at intervals not greater than one year. 
The Principal Investigator or his/her nominee will be responsible for reporting any SAEs 
to the IRB/EC as soon as possible, and in accordance with the guidelines of the IRB/EC. 
15.3.1 Conditions for Modifying the Protocol 
No changes (amendments) to the protocol may be implemented without prior approval from 
the Sponsor and the appropriate IRB/EC, except where necessary to eliminate an immediate 
hazard to patients, or when the change involves only logistical or administrative aspects of 
the study. 
Once the final protocol has been issued and signed by the Investigator and the authorized 
signatories, it shall not be informally altered. Protocol amendments are alterations to a legal 
document and have the same legal status. Therefore, they must pass through appropriate 
steps before being implemented. In general, any important change that theoretically 
increases risk to patients constitutes an amendment. Protocol modifications that impact on 
patients’ safety or the validity of the study will be approved by the IRB/EC. Minor changes 
such as administrative changes may be documented without approval, if permissible by the 
IRB/EC. 
The Investigator will not modify the protocol without first obtaining the concurrence of the 
Sponsor in writing. Should the Sponsor modify the protocol, they will provide the 
Investigator with a written amendment. It is the responsibility of the Investigator to submit 
the amendment to the IRB/EC for their approval; written approval should be obtained, and 
a copy provided to the Sponsor. The Sponsor is responsible for determining whether or not 
the local regulatory authority must be notified of the protocol change. Completed and 
signed protocol amendments will be circulated to all those who were on the circulation list 
for the original protocol. 
The original signed copy of amendments will be kept in the Study File with the original 
protocol. It should be noted that where an amendment to the protocol substantially alters 


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the study design or the potential risks to the patient, each patient’s consent to continue 
participation should be obtained. 
If a protocol amendment requires changes to the ICF, the revised ICF, prepared by the 
Investigator, must be approved by the IRB/EC. 
15.4 Patient Confidentiality 
The anonymity of participating patients must be maintained. Patients will be identified on 
eCRF/EDC system and other documents submitted to the Sponsor by their patient number, 
initials and/or birth date, not by name. Documents not to be submitted to the Sponsor that 
identify the patient (e.g., the signed informed consent) must be maintained in confidence 
by the Investigator.  A Data Protection Officer (DPO) will be used in this study by MyData-
TRUST. 
15.5 Investigator Responsibilities 
The Investigator is responsible for ensuring that the clinical study is performed in 
accordance with the protocol, the Declaration of Helsinki, current ICH GCP Guidelines, 
and applicable regulatory requirements. These documents set forth that the informed 
consent of the patients is an essential precondition for participation in the clinical study. 
15.6 Laboratory Accreditation 
Any laboratory facility to be used for analysis of routine clinical laboratory samples 
required by this protocol should provide reference values and/or normal ranges for the test 
results used in conducting this protocol. 
15.7 Study Initiation 
All personnel expected to be involved in the conduct of the study will undergo an 
orientation to include review of the study protocol, instructions for record completion, and 
overall responsibilities. 
15.7.1 Study Completion 
The Investigator will complete the study and complete all patients’ eCRFs in satisfactory 
compliance with the protocol within 2 weeks after study completion. Continuation of this 
study beyond this time must be agreed upon in writing by both the Investigator and Sponsor 
and may be implemented without amendment to the protocol. 
15.7.2 Study Termination 
An initiative for center closure or study termination can be taken at any time either by the 
Sponsor/designee or by the Investigator, provided there is reasonable cause and sufficient 
notice is given in advance of the intended termination. Reasons for such action taken by 
the Sponsor/designee include, but are not limited to: 
• Successful completion of the study at the center 
• The required number of patients for the study has been recruited 
• Failure of the Investigator to comply with the protocol, the Sponsor's/designee’s 
procedures, or ICH GCP Guidelines 


Final Protocol ATB-203 v6.0 
31 July 2019 
 
Page 110 of 131 
 
• Safety concerns 
• Sufficient data suggesting lack of efficacy 
• Inadequate recruitment of patients by the Investigator 
 
16. CONFIDENTIAL INFORMATION 
16.1 Confidential Information 
All information obtained as a result of this study or during the conduct of this study 
concerning Atox Bio operations, patent application, formulas, manufacturing processes, 
basic scientific data, and formulation information, supplied by the Atox Bio to the 
Investigator and not previously published, is considered confidential and remains the sole 
property of the Atox Bio. The Investigator agrees to use this information only to conduct 
this study and will not use it for other purposes without Atox Bio prior written consent. 
16.2 ClinicalTrials.gov Study Registration 
This clinical study, ATB-203, will be registered on www.ClincalTrials.gov prior to 
enrollment of the first patient. Patients are to be made aware of this study registration 
through the informed consent process prior to study participation. Final study results will 
be posted on ClinicalTrial.gov according to US regulatory guidelines. 
16.3 Publication Policy 
By signing the study protocol, the Investigator agrees with the use of results of the study 
for the purposes of national and international registration, publication and information for 
medical and pharmaceutical professionals. If necessary, Regulatory Authorities will be 
notified of the Investigator's name, address, qualifications, and extent of involvement. 
An Investigator shall not publish any data (poster, abstract, paper, etc.) without having 
consulted with the Sponsor in advance. Details are provided in a separate document. 


Final Protocol ATB-203 v6.0 
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Page 111 of 131 
 
17. REFERENCES 
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Uchino S. The epidemiology of acute renal failure in the world. Curr Opin Crit 
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Bagshaw SM, George C, Bellomo R, ANZICS Database Management Committee. 
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Australian intensive care units. Crit Care Lond Engl. 2007;11(3):R68. 
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4.  
Bihorac A, Brennan M, Ozrazgat-Baslanti T, et al. National surgical quality 
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6.  
Hobson C, Ozrazgat-Baslanti T, Kuxhausen A, et al. Cost and Mortality Associated 
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doi:10.1097/SLA.0000000000000732. 
7.  
Korenkevych D, Ozrazgat-Baslanti T, Thottakkara P, et al. The Pattern of 
Longitudinal Change in Serum Creatinine and 90-Day Mortality After Major 
Surgery. Ann Surg. July 2015. doi:10.1097/SLA.0000000000001362. 
8.  
Ozrazgat-Baslanti T, Thottakkara P, Huber M, et al. Acute and chronic kidney 
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9.  
Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill patients: a 
multinational, multicenter study. JAMA. 2005;294(7):813-818. 
doi:10.1001/jama.294.7.813. 
10.  Kellum JA. Diagnostic Criteria for Acute Kidney Injury: Present and Future. Crit 
Care Clin. 2015;31(4):621-632. doi:10.1016/j.ccc.2015.06.001. 
11.  Faubel S, Chawla LS, Chertow GM, et al. Ongoing clinical trials in AKI. Clin J Am 
Soc Nephrol CJASN. 2012;7(5):861-873. doi:10.2215/CJN.12191111. 
12.  Ko GJ, Zakaria A, Womer KL, Rabb H. Immunologic research in kidney 
ischemia/reperfusion injury at Johns Hopkins University. Immunol Res. 2010;47(1-
3):78-85. doi:10.1007/s12026-009-8140-7. 
13.  Keir I, Kellum JA. Acute kidney injury in severe sepsis: pathophysiology, diagnosis, 
and treatment recommendations. J Vet Emerg Crit Care San Antonio Tex 2001. 
2015;25(2):200-209. doi:10.1111/vec.12297. 


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14.  Kinsey GR, Okusa MD. Expanding role of T cells in acute kidney injury. Curr Opin 
Nephrol Hypertens. 2014;23(1):9-16. doi:10.1097/01.mnh.0000436695.29173.de. 
15.  Choi YW, Herman A, DiGiusto D, Wade T, Marrack P, Kappler J. Residues of the 
variable region of the T-cell-receptor beta-chain that interact with S. aureus toxin 
superantigens. Nature. 1990;346(6283):471-473. doi:10.1038/346471a0. 
16.  Fraser JD. High-affinity binding of staphylococcal enterotoxins A and B to HLA-
DR. Nature. 1989;339(6221):221-223. doi:10.1038/339221a0. 
17.  Janeway CA, Yagi J, Conrad PJ, et al. T-cell responses to Mls and to bacterial 
proteins that mimic its behavior. Immunol Rev. 1989;107:61-88. 
18.  Hackett SP, Stevens DL. Superantigens associated with staphylococcal and 
streptococcal toxic shock syndrome are potent inducers of tumor necrosis factor-beta 
synthesis. J Infect Dis. 1993;168(1):232-235. 
19.  Marrack P, Blackman M, Kushnir E, Kappler J. The toxicity of staphylococcal 
enterotoxin B in mice is mediated by T cells. J Exp Med. 1990;171(2):455-464. 
20.  Marrack P, Kappler J. The staphylococcal enterotoxins and their relatives. Science. 
1990;248(4959):1066. 
21.  Mattern T, Flad HD, Brade L, Rietschel ET, Ulmer AJ. Stimulation of human T 
lymphocytes by LPS is MHC unrestricted, but strongly dependent on B7 
interactions. J Immunol Baltim Md 1950. 1998;160(7):3412-3418. 
22.  Ulmer AJ, Flad H, Rietschel T, Mattern T. Induction of proliferation and cytokine 
production in human T lymphocytes by lipopolysaccharide (LPS). Toxicology. 
2000;152(1-3):37-45. 
23.  Wang R, Fang Q, Zhang L, et al. CD28 ligation prevents bacterial toxin-induced 
septic shock in mice by inducing IL-10 expression. J Immunol Baltim Md 1950. 
1997;158(6):2856-2861. 
24.  Singbartl K, Ley K. Leukocyte recruitment and acute renal failure. J Mol Med Berl 
Ger. 2004;82(2):91-101. doi:10.1007/s00109-003-0498-8. 
25.  Nolan A, Kobayashi H, Naveed B, et al. Differential role for CD80 and CD86 in the 
regulation of the innate immune response in murine polymicrobial sepsis. PloS One. 
2009;4(8):e6600. doi:10.1371/journal.pone.0006600. 
26.  Nolan A, Weiden M, Kelly A, et al. CD40 and CD80/86 act synergistically to 
regulate inflammation and mortality in polymicrobial sepsis. Am J Respir Crit Care 
Med. 2008;177(3):301-308. doi:10.1164/rccm.200703-515OC. 
27.  Cao Y, Fei D, Chen M, et al. Role of the nucleotide-binding domain-like receptor 
protein 3 inflammasome in acute kidney injury. FEBS J. 2015;282(19):3799-3807. 
doi:10.1111/febs.13379. 


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28.  Yokota N, Daniels F, Crosson J, Rabb H. Protective effect of T cell depletion in 
murine renal ischemia-reperfusion injury. Transplantation. 2002;74(6):759-763. 
doi:10.1097/01.TP.0000020413.44576.65. 
29.  Burne MJ, Daniels F, El Ghandour A, et al. Identification of the CD4(+) T cell as a 
major pathogenic factor in ischemic acute renal failure. J Clin Invest. 
2001;108(9):1283-1290. doi:10.1172/JCI12080. 
30.  De Greef KE, Ysebaert DK, Dauwe S, et al. Anti-B7-1 blocks mononuclear cell 
adherence in vasa recta after ischemia. Kidney Int. 2001;60(4):1415-1427. 
doi:10.1046/j.1523-1755.2001.00944.x. 
31.  Pickkers P, Heemskerk S, Schouten J, et al. Alkaline phosphatase for treatment of 
sepsis-induced acute kidney injury: a prospective randomized double-blind placebo-
controlled trial. Crit Care Lond Engl. 2012;16(1):R14. doi:10.1186/cc11159. 
32.  Singbartl K, Bockhorn SG, Zarbock A, Schmolke M, Van Aken H. T cells modulate 
neutrophil-dependent acute renal failure during endotoxemia: critical role for CD28. 
J Am Soc Nephrol JASN. 2005;16(3):720-728. doi:10.1681/ASN.2004050381. 
33.  Hazlett LD, McClellan S, Barrett R, Rudner X. B7/CD28 costimulation is critical in 
susceptibility to Pseudomonas aeruginosa corneal infection: a comparative study 
using monoclonal antibody blockade and CD28-deficient mice. J Immunol Baltim 
Md 1950. 2001;166(2):1292-1299. 
34.  Honstettre A, Meghari S, Nunès JA, et al. Role for the CD28 molecule in the control 
of Coxiella burnetii infection. Infect Immun. 2006;74(3):1800-1808. 
doi:10.1128/IAI.74.3.1800-1808.2006. 
35.  van Berkel MEAT, Schrijver EHR, van Mourik A, et al. A critical contribution of 
both CD28 and ICOS in the adjuvant activity of Neisseria meningitidis H44/76 LPS 
and lpxL1 LPS. Vaccine. 2007;25(24):4681-4688. 
doi:10.1016/j.vaccine.2007.04.016. 
36.  Ramachandran G, Tulapurkar ME, Harris KM, et al. A peptide antagonist of CD28 
signaling attenuates toxic shock and necrotizing soft-tissue infection induced by 
Streptococcus pyogenes. J Infect Dis. 2013;207(12):1869-1877. 
doi:10.1093/infdis/jit104. 
37.  Ramachandran G, Kaempfer R, Chung C-S, et al. CD28 homodimer interface 
mimetic peptide acts as a preventive and therapeutic agent in models of severe 
bacterial sepsis and gram-negative bacterial peritonitis. J Infect Dis. 
2015;211(6):995-1003. doi:10.1093/infdis/jiu556. 
38.  Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron 
Clin Pract. 2012;120(4):c179-c184. 
39.  Nga HS, Medeiros P, Menezes P, Bridi R, Balbi A, Ponce D. Sepsis and AKI in 
Clinical Emergency Room Patients: The Role of Urinary NGAL. BioMed Res Int. 
2015;2015:413751. doi:10.1155/2015/413751. 


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40.
Bulger EM, May A, Bernard A, et al. Impact and Progression of Organ Dysfunction
in Patients with Necrotizing Soft Tissue Infections: A Multicenter Study. Surg
Infect. 2015;16(6):694-701. doi:10.1089/sur.2015.098.
41.
Vaidya VS, Ferguson MA, Bonventre JV. Biomarkers of acute kidney injury. Annu
Rev Pharmacol Toxicol. 2008;48:463-493.
doi:10.1146/annurev.pharmtox.48.113006.094615.
42.
Di Somma S, Magrini L, De Berardinis B, et al. Additive value of blood neutrophil
gelatinase-associated lipocalin to clinical judgement in acute kidney injury diagnosis
and mortality prediction in patients hospitalized from the emergency department.
Crit Care Lond Engl. 2013;17(1):R29. doi:10.1186/cc12510.
43.
Clerico A, Galli C, Fortunato A, Ronco C. Neutrophil gelatinase-associated lipocalin
(NGAL) as biomarker of acute kidney injury: a review of the laboratory
characteristics and clinical evidences. Clin Chem Lab Med. 2012;50(9):1505-1517.
doi:10.1515/cclm-2011-0814.
44.
Bellomo R, Kellum JA, Ronco C. Acute kidney injury. Lancet Lond Engl.
2012;380(9843):756-766. doi:10.1016/S0140-6736(11)61454-2.
45.
VA/NIH Acute Renal Failure Trial Network, Palevsky PM, Zhang JH, et al.
Intensity of renal support in critically ill patients with acute kidney injury. N Engl J
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Viechtbauer W. Bias and efficiency of meta-analytic variance estimators in the
random-effects model. J Educ Behav Stat. 2005;30(3):261-293.
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Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-
analyses. BMJ. 2003;327(7414):557.
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Diggle P, Heagerty P, Liang K-Y, Zeger S. Analysis of Longitudinal Data. Oxford
University Press; 2002.
49.
Burton P, Gurrin L, Sly P. Extending the simple linear regression model to account
for correlated responses: An introduction to generalized estimating equations and
multilevel mixed modelling. 2004. http://espace.library.uq.edu.au/view/UQ:259851.
Accessed April 26, 2015.
50.
Rubin DB. Inference and missing data. Biometrika. 1976;63(3):581-592.
51.
Knickerbocker R. Intent-to-Treat Analyses. In: Chow S-C, ed. Encyclopedia of
Biopharmaceutical Statistics. Marcel Dekker; 2000.
52. Miller DR, Carlson JD, Lloyd BJ, Day BJ. Determining ideal body weight (and
mass).       Am J Hosp Pharm 1983;40:1622-5.
53. Mehta CR, Pocock SJ.  Adaptive increase in sample size when interim results are
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54. Emamian SA, Nielsen MB, Pedersen JF, et al. Kidney dimensions at sonography:
correlation with age, sex and habitus in 665 adult volunteers Am J Roentgenol.1993;
160: 83-86.


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18. APPENDICES
18.1 Appendix A - Study Visits and Procedures 
Visit 
1 
Screeninga 
2 
Day 1 
3 
Day 
2 
4 
Day 
3 
5 
Day 
7 
±1 
day 
6 
Day 
10 
±1 
day 
7 
Day 14 
±1 days 
8 
Day 
21 
±1 
days 
9 
Day 
29 
+3
days
10 
3 to 21 
Days 
after 
Visit 9 
11 
Day 
90 
+5
days
Informed Consent 
X 
Demographics 
X 
Medical History 
X 
Lesion History 
(NSTI) 
X 
Concomitant 
Medicationsb 
Weight & Heightc 
X 
X 
X 
X 
Fluid Balance 
(input/output) 
Detailed Urine 
Outputd 
Vital Signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
Examination (PE) 
X 
X 
X 
Interim PE 
(symptom-driven) 
X 
X 
X 
a Screening period can be 48 hours after suspected diagnosis of abdominal infection 
b See Section 9.2.5 for instruction on level of detailed information required for recording concomitant 
medications 
c Height will be taken only at screening or first time that patient height can be measured 
d Urine output is required for Days 1-7 (while the patient is in the ICU or step-down unit (or equivalent); 
patients on a general ward only monitor urine output if a Foley catheter is in place as part of standard of 
care) to assess for development or resolution of acute kidney injury 
e Systolic & diastolic blood pressure, mean arterial pressure, heart rate, respiration rate, temperature; (first 
set of vitals on that visit day) 


Final Protocol ATB-203 v6.0 
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Page 117 of 131 
Visit 
1 
Screeninga 
2 
Day 1 
3 
Day 
2 
4 
Day 
3 
5 
Day 
7 
±1 
day 
6 
Day 
10 
±1 
day 
7 
Day 14 
±1 days 
8 
Day 
21 
±1 
days 
9 
Day 
29 
+3
days
10 
3 to 21 
Days 
after 
Visit 9 
11 
Day 
90 
+5
days
Baseline Signs & 
Symptomsf 
X 
Blood Chemistryg 
Xh 
Xi 
Xj 
Xi 
X 
Xj 
X 
Xj 
Xk 
Xj 
Xj 
Spot Urine 
Albumin/ 
Creatininel 
X 
X 
X 
X 
X 
X 
X 
Standard C-
Reactive Proteinm 
X 
X 
X 
X 
Blood 
Hematologyn 
X 
X 
X 
X 
X 
X 
Pregnancy Test (if 
applicable)o 
X 
Serum for 
Immunogenicityp 
X 
X 
X 
X 
Urine and Plasma 
for Storageq 
X 
X 
X 
f Adverse events reported from ICF signature to Reltecimod administration 
g Glucose; Electrolytes - Sodium, Potassium, Calcium; Phosphorus, Chloride, Bicarbonate; Renal function 
tests – Urea/BUN, Creatinine; Liver function tests – Albumin, Bilirubin Total, Alanine transaminase 
(ALT), Aspartate transaminase (AST), Alkaline phosphatase (ALP), Protein Total. In case of abnormal 
results at the end of the study the results should be followed by the investigator until the abnormalities are 
resolved or determined as stabilized 
h If AKI diagnosis not established at time of initial evaluation for abdominal infection, then obtain 
creatinine every 6 hours for up to 48 hours after suspected or confirmed diagnosis of abdominal infection to 
identify development of AKI 
i Only creatinine and bilirubin 
j Only creatinine 
k Creatinine and albumin only 
l Obtain urine specimen for spot albumin/creatinine ratio. First morning void is preferred
m Use standard CRP test (do not use cardiac or high-sensitivity CRP)
n Complete blood count including platelet count and white blood cell differential
o Preferably the fastest pregnancy test method (urine or blood)
p 6 mL blood for serum for storage (for immunogenicity testing) at screening, Days 14 29, and 90
q Obtain 5 mL urine and 5 mL blood for plasma for storage for AKI biomarker analysis. Second sample to
be collected 24±6 hours (Day 2) after study medication administration. Final sample to be obtained at Day 7


Final Protocol ATB-203 v6.0 
31 July 2019 
Page 118 of 131 
Visit 
1 
Screeninga 
2 
Day 1 
3 
Day 
2 
4 
Day 
3 
5 
Day 
7 
±1 
day 
6 
Day 
10 
±1 
day 
7 
Day 14 
±1 days 
8 
Day 
21 
±1 
days 
9 
Day 
29 
+3
days
10 
3 to 21 
Days 
after 
Visit 9 
11 
Day 
90 
+5
days
Systemic 
Inflammatory    
Biomarkers 
• RNAr
• Cytokines /
Chemokiness
X 
X 
X 
X 
X 
X 
X 
X 
Arterial Blood 
Gases (if 
applicable) 
X 
X 
X 
X 
X 
SpO2 and FiO2 
(if arterial blood 
gases not 
indicated or 
unable to obtain) 
X 
X 
X 
X 
X 
Peritoneal Fluid, 
Tissue or Abscess 
Fluid for 
Abdominal 
Infection, or 
Tissue for NSTI 
for Microbiology 
X 
Inclusion & 
Exclusiont 
X 
Randomization 
X 
r 5 mL (2 x 2.5 mL) of whole blood to be collected at screening, Day 1 at 4 to 6 hours post-dose, Day 2 at 
24 +4 hours post dose, Day 3 at 48 hours +4 hours post-dose, and Day 4 72 +4 hours post dose.  Complete 
blood count with white blood cell differential to be obtained at same time of whole blood for genomic 
profile sample 
s Systemic Biomarkers will be taken at screening, 4 to 6 hours, 24±4, 48±4 and 72±4 hours post drug 
administration; However, if practical consideration allow collection of fewer plasma samples, this will not be 
considered a protocol deviation.  Systemic blood inflammatory biomarkers will include serum cytokines or 
chemokines such as (but not limited to): IL-6, IL-8, INF-γ, TNF-α, IL-17A, IL-3 and RANTES.
t Should be verified twice: a full list of criteria will be verified once before instructing the pharmacist to 
prepare study drug and a second time immediately before study drug administration according to a partial 
list to include verification that 6 hours has not elapsed from time to study drug administration 


Final Protocol ATB-203 v6.0 
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Page 119 of 131 
Visit 
1 
Screeninga 
2 
Day 1 
3 
Day 
2 
4 
Day 
3 
5 
Day 
7 
±1 
day 
6 
Day 
10 
±1 
day 
7 
Day 14 
±1 days 
8 
Day 
21 
±1 
days 
9 
Day 
29 
+3
days
10 
3 to 21 
Days 
after 
Visit 9 
11 
Day 
90 
+5
days
Reltecimod / 
Placebo 
Administration 
X 
Blood Cultureu 
X 
Adverse Events / 
Serious Adverse 
Eventsv 
w
Lesion 
Assessment 
(NSTI)x 
X 
X 
X 
X 
X 
X 
X 
Collect data on 
Additional 
Amputations 
(NSTI) 
Collect Data on 
Acute Renal 
Replacement 
Therapy 
Collect Data on 
Renal Imaging 
Collect Data on 
Additional Renal 
Procedures (e.g., 
Renal Biopsy) 
Record any 
Follow-up 
Surgical or 
u Blood culture for both aerobic and anaerobic bacteria will be repeated during the study in case of new
systemic infection suspicion
v Adverse events including SAEs will be collected from obtaining ICF through day 28; AEs that are not
resolved should be followed-up until resolution or until determined as stable and due to known cause
w AEs of Screening are baseline AEs (not TEAE) starting after obtaining ICF until study drug
administration
x Assess lesion status (healing/progression/significant change in appearance) if accessible for visible
assessment at time of debridement or routine dressing change


Final Protocol ATB-203 v6.0 
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Page 120 of 131 
Visit 
1 
Screeninga 
2 
Day 1 
3 
Day 
2 
4 
Day 
3 
5 
Day 
7 
±1 
day 
6 
Day 
10 
±1 
day 
7 
Day 14 
±1 days 
8 
Day 
21 
±1 
days 
9 
Day 
29 
+3
days
10 
3 to 21 
Days 
after 
Visit 9 
11 
Day 
90 
+5
days
Interventional 
Radiologic 
Procedures for 
Previously 
Documented 
Abdominal 
Infection 
Evaluation of 
Adequacy of 
Antimicrobial 
Treatment 
X 
Critical Care and 
Hospital Stay 
Parametersy 
SOFA Scorez 
X 
Xaa 
X 
X 
X 
APACHE II 
Scorebb 
X 
Survival 
Hospital 
Readmissions 
X 
Xcc 
y Hospital length of stay (days), ICU stay (days), ICU free days, mechanical ventilation days/mechanical 
ventilation free days 
z Screening SOFA: To include measurements of 6 organ system: cardiovascular, respiratory, renal, 
coagulation, GI/hepatic and CNS (To include evaluation of oxygenation either directly by arterial blood gas 
test or by calculation of PaO2 from SpO2, in case it is not possible to obtain arterial blood to determine the 
SOFA respiratory parameter) 
aa Subsequent SOFA measurement (Days 1, 3, 7, and 14): taken once a day, in the morning adjusted to the 
time of normal routine assessment activities. To be calculated retrospectively. The following blood samples 
must be taken: CBC with platelet count, serum creatinine and bilirubin. In addition, clinical parameters 
should be evaluated and recorded (see Section 18.3) 
bb For the required laboratory and clinical parameters (see Section 18.2 of the protocol) 
cc Capture data on any readmissions within 30 days of original hospital discharge 


Final Protocol ATB-203 v6.0 
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Page 121 of 131 
18.2 Appendix B – APACHE II Score 
APACHE II Score: 
- 
For each variable used in the APACHE II Score, the value from the previous 24 hours
yielding the most points should be used
Since it is not possible to assess the Glasgow Coma Scale (GCS) in patients who are
sedated and paralyzed, by convention it is regarded as normal, unless it is known that
there was a brain injury prior to sedation, as in the case of head injury (but not confusion
associated with tiredness, hypoxia, etc.). This will result in a GCS of 15 and a neurologic
score of 0 (zero).
Chronic Health Evaluation
- 
- 
If any of these conditions are marked "Y", assign points based on the patient's condition at the
time of ICU admission (or in the 24-hour period prior to screening) - See Section C on last page.
Organ insufficiency or immuno-compromised state must have been evident prior to this hospital 
admission and conform to the following criteria. 
LIVER: Biopsy-proven cirrhosis and documented portal hypertension. or episodes of past upper 
GI bleeding attributed to portal hypertension, or prior episodes of hepatic 
failure/encephalopathy/coma. 
Y N 
CARDIOVASCULAR: New York Heart Association Class IV. 
Y N 
RESPIRATORY: Chronic restrictive, obstructive, or vascular disease resulting in severe exercise 
restriction, (i.e., unable to climb stairs or perform household duties); or documented chronic 
hypoxia, hypercapnia, secondary polycythemia, severe pulmonary hypertension (>40 mm Hg), or 
respirator dependency. 
Y N 
RENAL: Receiving chronic hemo- or peritoneal dialysis. 
Y N 
IMMUNO-COMPROMISED: 
(1)
The patient has received therapy that suppresses resistance to infection, eg immuno-
suppressive agents, chemotherapy, radiation, long term low dose steroids, 10 mg/day
prednisone for >1 month prior to hospitalization) or recent high dose steroids (> 15
mg/kg/day of hydrocortisone or >3 mg/kg/day of methylprednisolone for >5 days).
Y N 
(2)
The patient has a disease that is sufficiently advanced to suppress resistance to infection,
eg leukemia, lymphoma, AIDS, documented diffuse metastatic cancer.
Y N 
 


Final Protocol ATB-203 v6.0 
31 July 2019 
Page 122 of 131 


Final Protocol ATB-203 v6.0 
31 July 2019 
Page 123 of 131 
18.3 
Appendix C – SOFA Score 
1. For patients on supplemental oxygen via nasal cannula, nasopharyngeal catheter or mask and for converting SpO2
values to PaO2 use the attached oxygen conversion tables.
2. Doses of dopamine (Dopa), epinephrine (Epi), norepinephrine (NE) are in micrograms/kg/min; phenylephrine (PE)
is micrograms/min; vasopressin (VP) is U/min. Vasopressors must have been administered for at least one hour.
3. Total bilirubin and creatinine are in mg/dL.
Value 
0 
1 
2 
3 
4 
Respiratory
>400
≤400 
≤300 
≤200 
with 
respiratory 
support 
≤100 
with 
respiratory 
support 
PaO2/FiO21 
Coagulation 
Platelets 
>150
≤150 
≤100 
≤50 
≤20 
GI 
Total Bilirubin3 
<1.2 
1.2-1.9 
2.0-5.9 
6.0-11.9 
≥12.0 
Cardiovascular2 
No hypo- 
tension 
MAP 
<70 
Dopa ≤5 
PE <100 
Dopa > 5 
Epi ≤ 0.1 
NE ≤ 0.1 
PE 100- 
300 
Dopa>15 
Epi>0.1 
NE>0.1 
PE>300 
VP>0.01 
Neuro 
GCS 
15 
13-14
10-12
6-9
<6 
Serum 
Creatinine3 
OR 
Urine 
Output 
<1.2 
1.2-1.9 
2.0-3.4 
3.5-4.9 
<500cc/ 
day 
≥5.0 
<200cc/ 
day 


Final Protocol ATB-203 v6.0 
31 July 2019 
Page 124 of 131 
Oxygen Conversion Tables 
SpO2 (%)
PaO2 (mmHg) 
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
Estimating Fi02 
Method
O2 flow
(l/
i )
Estimated FiO2 (%)
Nasal cannula
1
24
2
27
3
30
4
33
5
36
6
40
Nasopharyngeal catheter
4
40
5
50
6
60
Face mask
5
40
6-7
50
7-8
60
Face mask with reservoir
6
60
7
70
≥8
80


Final Protocol ATB-203 v6.0 
31 July 2019 
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18.4 Appendix D – Glasgow Coma Scale 
Enter one score for each response (Eyes, Motor and Verbal). 
Eyes Open 
Motor Responses 
Verbal – Non-Intubated 
Verbal – Intubated 
4 = spontaneously 
3 = to verbal 
2 = to painful stimuli 
1 = no response 
6 = to verbal command 
5 = localized to pain 
4 = withdraws to pain 
3 = decorticate 
2 = decerebrate 
1 = no response 
5 = oriented and converses 
4 = disoriented and talks 
3 = inappropriate words 
2 = incomprehensible words 
1 = no response 
5 = seems able to talk 
3 = questionable ability to talk 
1 = generally unresponsive 
Total Glasgow Coma Score (Eyes + Motor + Verbal) 


Final Protocol ATB-203 v6.0 
31 July 2019 
Page 126 of 131 
18.5 Appendix E – AKI Staging (KDIGO Criteria) 
Stage 
Serum Creatinine 
Urine Output1 
1 
1.5-1.9 times baseline 
OR 
≥0.3 mg/dL increase 
< 0.5 mL/kg/h for 6 h 
2 
2-2.9 times baseline
< 0.5 mL/kg/h for 12 h 
 
3 
3 times baseline 
OR 
Increase in serum creatinine to ≥4 mg/dL 
OR 
Initiation of renal replacement therapy 
< 0.3 mL/kg/h for 24 h 
OR 
Anuria for ≥12 h 
 
1.
Urine output should be calculated using IBW (using the Miller Formula).  Urine output for patients in a
non-ICU setting (e.g., general ward) can only be used to assess AKI staging if urine collection (and
subsequent recording) is obtained from patients with a Foley catheter in place as part of standard of care.


Final Protocol ATB-203 v6.0 
31 July 2019 
Page 127 of 131 
18.6 
Appendix F – Twice the Serum Creatinine for Age, Race, and Gender 
Age 
(years) 
Black Males 
mg/dL 
(µmol/L) 
Other Males 
mg/dL 
(µmol/L) 
Black Females 
mg/dL 
(µmol/L) 
Other Females 
mg/dL 
(µmol/L) 
20 – 24 
3.0 
(266) 
2.6 
(230) 
2.4 
(212) 
2.0 
(166) 
25 – 29 
3.0 
(266) 
2.4 
(212) 
2.2 
(194) 
2.0 
(166) 
30 – 39 
2.8 
(248) 
2.4 
(212) 
2.2 
(194) 
1.8 
(160) 
40 – 54 
2.6 
(230) 
2.2 
(194) 
2.0 
(176) 
1.8 
(160) 
55 – 65 
2.6 
(230) 
2.2 
(194) 
2.0 
(176) 
1.6 
(142) 
>65
2.4 
(212) 
2.0 
(166) 
1.8 
(160) 
1.6 
(142) 
Bellomo R, Ronco C, Kellum JA et al. Acute renal failure – definition, outcome, animal models, fluid therapy and 
information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative 
(ADQI)Group. Crit Care 2004;8: R204-212.


Final Protocol ATB-203 v6.0 
31 July 2019 
 
Page 128 of 131 
 
18.7 Appendix G - Immunosuppressive Agents 
Immunosuppressive Agenta 
Upper Limit Dosage Use 
1. Corticosteroid 
> 40 mg/day of prednisone or its 
equivalent daily for > 2 weeks 
Equivalent Dose (mg) 
a) Prednisone 
40 mg 
b) Hydrocortisone 
160 mg 
c) Methylprednisolone 
32 mg 
d) Dexamethasone 
6 mg 
e) Cortisone 
200 mg 
f) Betamethasone 
4.8 mg 
2. Methotrexate (Rheumatrex, Trexall) 
Excluded at any dose 
3. Leflunomide (Arava)/Teriflunomide  
    (Aubagio) 
Acceptable if being used as 
monotherapy 
4. Cyclophosphamide (Cytoxan) 
Excluded at any dose 
5. Cyclosporine A 
Excluded at any dose (ophthalmic 
formulation (Restatis) is permitted) 
6. FK506 (Tacrolimus) 
Excluded at any dose (optical 
formulation (Protopic) is permitted) 
7. Azathioprine 
Excluded at any dose 
8. Cancer Chemotherapy 
Patients receiving cancer 
chemotherapy in the previous 4 
weeks are excluded 
9. Mycophenolate Mofetil (MMF) (CellCept) 
Excluded at any dose (all solid 
organ and bone marrow transplant 
patients are excluded) 
10. Sirolimus (Rapamycin, Rapamune) 
Excluded at any dose 
11. Everolimus (Certican) 
Excluded at any dose 
12. Temsirolimus (Torisel) 
Excluded at any dose 
13. Gusperimus 
Excluded at any dose 


Final Protocol ATB-203 v6.0 
31 July 2019 
 
Page 129 of 131 
 
14. Thalidomide 
Patients receiving Thalidomide 
within the last 72 hours are 
excluded. 
Immunosuppressive Agenta 
Upper Limit Dosage Use 
Biologics 
(a) Anti-tumor necrosis factor (TNF) agents 
- Entanercept (Enbrel) 
 
- Entanercept (Enbrel) 
 
- Afelimomab (Fab 2) 
 
- Infliximab (Remicade) 
 
- Certolizumab (Cimzia) 
 
- Golimumab (Simponi) 
Patients receiving Anti-TNF drugs 
within the last 8 weeks are 
excluded. 
(b)  Interleukin-1 Receptor Antagonist (IL-1RA) 
          - Kineret 
Patients receiving IL-1RA within 
the last 8 weeks are excluded. 
(c)   CTLA-4 Fusion Protein 
- Abatacept (Orencia) 
 
- Alefacept (Amevive) 
 
- Belatacept (Nulojix) 
Patients receiving CTLA-4 Fusion 
protein within the last 8 weeks are 
excluded. 
(d)  Anti-CD20 
- Rituximab (Rituxan/MabThera) 
 
- Obintuzumab (Gazyva) 
 
- Ocrelizumab (Ocrevus) 
 
- Ofatumumab (Arzerra) 
Patients receiving Anti-CD20 drugs 
within the last 2 years are excluded. 
(e)   Anti-CD52 
- Alemtuzumab (Campath) 
Patients receiving Anti-CD52 drugs 
within the last 2 years are excluded. 
(f)    Anti-IL2 
- Daclizumab (Anti-Tac, Zenapax) 
 
- Basiliximab (Simulect) 
Patients receiving Anti-IL2 drugs 
within the last 2 years are excluded. 


Final Protocol ATB-203 v6.0 
31 July 2019 
 
Page 130 of 131 
 
(g)   Anti-IL6 
- Tocilizumab (Actemra/RoActemra) 
Patients receiving Anti-IL-6 drugs 
in the last 2 years are excluded. 
(h)   Anti-IL12/13 
- Ustekinumab (Stelara) 
Patients receiving Anti-IL 12/13 
drugs in the last 2 years are 
excluded. 
(i)    Anti-BAFF (B-cell activating factor) 
- Belimumab 
Patients receiving Anti-BAFF drugs 
in the last 8 weeks are excluded. 
(j)    Integrin Inhibitor 
- Natalizumab (Tysarbi) 
Patients receiving Integrin Inhibitor 
drugs in the last 2 years are 
excluded. 
(k)   Anti-CTLA 4 
- Ipilimumab 
Patients receiving Anti-CTLA 4 
drugs in the last 8 weeks are 
excluded. 
(l)   Other Interleukins 
- Aldesleukin (Proleukin) 
 
- Canakinumab (Ilaris) 
 
- Oprelvekin (Neumega) 
Patients receiving any of these 
Interleukin drugs in the last 2 years 
are excluded. 
(m)  Anti-PDL1 
- Avelumab (Bavencio) 
Patients receiving any Anti-PDL1 
drugs in the last 2 years are 
excluded. 
(n)   Other Selective Immunosuppressants 
- Muromonab or OKT-3: 
 
- Efalizumab (Raptiva): anti-CD11a 
 
- Fingolimod (Gilenya): Sphingosine 1- 
   phosphate receptor modulator 
 
- Eculizumab (Soliris): anti-complement  
   protein C5 
 
- Tofacitinib (Xeljanz): JAK-STAT  
   Inhibitor 
Patients receiving any of these 
drugs in the last 3 months are 
excluded. 


Final Protocol ATB-203 v6.0 
31 July 2019 
 
Page 131 of 131 
 
- Apremilast (Otezla): PDE-4 inhibitor 
 
- Vedolizumab (Entyvio): Integrin α4β7 
Patients receiving any of these 
drugs in the last 2 years are 
excluded. 
a For agents not listed, patients should be off such therapies for a time sufficient to restore immune function. 

SAP_001.pdf: 
    Biomedical Statistical Consulting 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Version 1.0 
 
January 6, 2020 
 
Product:  Reltecimod (AB103) 
 
Protocol Number:  ATB-203 
Phase 3 randomized, double-blind, placebo-controlled, parallel-group study to 
evaluate the safety and efficacy of Reltecimod as compared to placebo in 
addition to standard of care in patients with sepsis-associated acute kidney 
injury (SA-AKI) 
Development Phase:  Phase 3 
IND Number: 128,927 
EudraCT Number:  2018-002547-29 
 
SPONSOR 
ATOX BIO LTD. 
8 PINHAS SAPIR ST.  
WEIZMANN SCIENCE PARK 
 NESS ZIONA, 7403631 
ISRAEL 


Statistical Analysis Plan 
Version 1.0, 06 January 2020 
2 
Phase 3 randomized, double-blind, placebo-controlled, parallel-group study to evaluate 
the safety and efficacy of Reltecimod as compared to placebo in addition to standard of 
care in patients with sepsis-associated acute kidney injury (SA-AKI) 
SIGNATURE OF APPROVAL 
/ 
Wayne M Dankner, MD 
Chief Medical Officer 
Atox Bio, Ltd 
Date 


ATB-203 SAP 
Statistical Analysis Plan 
Version 1.0, 06 January 2020 
3 
Phase 3 randomized, double-blind, placebo-controlled, parallel-group study to evaluate 
the safety and efficacy of Reltecimod as compared to placebo in addition to standard of 
care in patients with sepsis-associated acute kidney injury (SA-AKJ) 
SIGNATURE OF APPROVAL 
Greg Maislin, M.S, M.A. 
Principal Biostatistician 
Biomedical Statistical Consulting 
Date 


ATB-203 SAP 
 
 
4 
 
  
Table of Contents 
1 
Purpose and Scope of SAP ............................................................................................... 7 
2 
Key Elements of the Analysis Plan .................................................................................. 8 
2.1 
Primary Efficacy Analysis ...............................................................................................8 
2.1.1 
Primary Superiority Hypothesis ...............................................................................8 
2.1.2 
Sample Size Justification .........................................................................................8 
2.2 
Randomization .................................................................................................................9 
2.3 
Analysis Sets ..................................................................................................................10 
2.4 
Control of Blinding and iDMC ......................................................................................10 
3 
Description of variables to be included in statistical analyses .................................... 13 
3.1 
Medical and Surgical History ........................................................................................13 
3.2 
Physical Examinations ...................................................................................................13 
3.3 
Interim Physical Examinations (Symptom-Driven) .......................................................13 
3.4 
Concomitant Medication ................................................................................................13 
3.5 
Abdominal Infection and NSTI Type ............................................................................13 
3.6 
Vital Signs ......................................................................................................................14 
3.7 
Clinical Scores ...............................................................................................................14 
3.7.1 
SOFA Score Definition ..........................................................................................14 
3.7.2 
Acute Physiology and Chronic Health Evaluation II (APACHE II) .....................14 
3.8 
Clinical Laboratory Assessments ...................................................................................14 
3.9 
Microbiology..................................................................................................................15 
3.10 
Creatinine, AKI, AKD, and eGFR .................................................................................15 
3.10.1 
Reference Creatinine ..............................................................................................15 
3.10.2 
Screening AKI and Screening eGFR .....................................................................17 
3.10.3 
Day 28 eGFR .........................................................................................................18 
3.10.4 
Day 14 eGFR .........................................................................................................18 
3.10.5 
Day 90 eGFR .........................................................................................................19 
3.10.6 
Additional Processing Details ................................................................................19 
3.10.7 
Alternative Algorithmic Determination of Day 28 Creatinine ..............................19 
4 
Endpoints ......................................................................................................................... 20 
4.1 
Primary Effectiveness Endpoint ....................................................................................20 
4.2 
Secondary Effectiveness Endpoints ...............................................................................20 
4.3 
Exploratory Effectiveness Endpoints .............................................................................21 
4.4 
Discussion Regarding ‘Event-Free Days’ ......................................................................21 
4.5 
Safety Endpoints ............................................................................................................22 
5 
Analysis Approaches ....................................................................................................... 23 
5.1 
Preliminary and Descriptive Analyses ...........................................................................23 
5.2 
Primary Endpoint ...........................................................................................................23 
5.3 
Secondary Endpoints .....................................................................................................23 
5.4 
mSOFA ..........................................................................................................................24 
5.5 
Assessment of Site to Site Variability in Relative Efficacy ..........................................24 
5.6 
Subgroup Analysis .........................................................................................................24 


ATB-203 SAP 
 
 
5 
 
5.7 
Analysis of Other Covariate Effects ..............................................................................25 
5.8 
Multiplicity ....................................................................................................................25 
5.9 
Descriptive Analyses of Secondary Endpoints ..............................................................26 
5.10 
Analysis of Event-time and Overall Survival ................................................................26 
5.11 
Handling of Missing Data ..............................................................................................26 
5.11.1 
Intent-to-Treat ........................................................................................................26 
5.11.2 
LOCF of Day 28 and Day 90 Creatinine ...............................................................26 
5.11.3 
mSOFA Scores.......................................................................................................26 
5.12 
Prior and Concomitant Medication ................................................................................27 
6 
Safety Analysis ................................................................................................................ 29 
6.1 
Adverse Events ..............................................................................................................29 
6.2 
Laboratory Values ..........................................................................................................29 
6.2.1 
Description of Value Over Time............................................................................29 
6.2.2 
Laboratory Shift Tables .........................................................................................29 
6.2.3 
Treatment of Clinical Laboratory Abnormalities ..................................................29 
6.3 
Physical Exams ..............................................................................................................30 
6.4 
Vital Signs ......................................................................................................................30 
7 
Presentation of Enrollment and Baseline Characteristics .......................................... 31 
7.1 
Site Specific Numbers of Patients by Analysis Set .......................................................31 
7.2 
Demographic and Baseline Characteristics of Cohorts .................................................31 
7.3 
Baseline Microbiology ...................................................................................................31 
7.4 
Prior and Concomitant Medication ................................................................................32 
7.5 
Medical and Surgical History ........................................................................................32 
7.6 
Drug Administration and Timing ...................................................................................33 
7.7 
Patient Disposition and End of Study Status .................................................................33 
8 
Presentation of Efficacy Results .................................................................................... 34 
8.1 
Primary AKI Endpoint ...................................................................................................34 
8.2 
Evaluation of Site Heterogeneity in Primary Endpoint Treatment Effects ....................34 
8.3 
Secondary and Exploratory AKI Recovery Endpoints ..................................................34 
8.4 
mSOFA Scores...............................................................................................................35 
8.5 
Critical Care and Hospital Stay Parameters, to be Measured until Day 28 ...................35 
8.6 
Time-to-Event and Survival Analyses ...........................................................................36 
8.7 
CRP ................................................................................................................................36 
8.8 
Subgroup Analysis .........................................................................................................36 
9 
Presentation of Safety Evaluations ................................................................................ 38 
9.1 
Adverse Events ..............................................................................................................38 
9.1.1 
Summary of adverse events ...................................................................................38 
9.1.2 
Specific adverse events ..........................................................................................38 
9.1.3 
Severity of adverse events .....................................................................................39 
9.1.4 
Day 0 Adverse Events ............................................................................................39 
9.1.5 
Safety listings .........................................................................................................39 
9.2 
Clinical Laboratory Assessments ...................................................................................40 
9.2.1 
Blood Chemistry ....................................................................................................40 
9.2.2 
Hepatic Safety ........................................................................................................40 
9.2.3 
Blood Hematology .................................................................................................40 


ATB-203 SAP 
 
 
6 
 
9.3 
Urinary Albumin/Creatine Ratio....................................................................................41 
9.4 
Incidence of Chronic Kidney Disease (CKD) at Day 90 ...............................................41 
9.5 
Vital Signs ......................................................................................................................41 
9.6 
Physical Examinations ...................................................................................................41 
10 
Deviations from the Original Statistical Plan ............................................................... 42 
11 
Appendix 1: Tables and Listing TOC ........................................................................... 43 
12 
Appendix 2: AE Listings ................................................................................................ 52 
13 
Appendix 3: Patient Listings .......................................................................................... 53 
14 
Appendix 5: Study Visits and Procedures .................................................................... 55 
15 
Appendix 6:  Clinical Score Calculations ..................................................................... 60 
15.1 
AKI Staging (KDIGO Criteria) .....................................................................................60 
15.2 
Twice the Serum Creatinine for Age, Race, and Gender ...............................................61 
15.3 
SOFA – Sequential Organ Failure Assessment Score ...................................................62 
16 
Appendix 7:  Prior and Concomitant Medications ...................................................... 63 
16.1 
Nephrotoxic Medications ...............................................................................................63 
16.2 
Immunosuppresant Medications ....................................................................................63 
17 
Appendix 8: CKD Definition and Classification .......................................................... 66 
17.1 
CKD Definition:.............................................................................................................66 
17.2 
CKD Classification ........................................................................................................66 


ATB-203 SAP 
 
 
7 
 
1 
Purpose and Scope of SAP 
The purpose of this Statistical Analysis Plan (SAP) is to provide details regarding the analyses sets, 
endpoints, and statistical analysis methods to be used to meet the objectives of this trial. When 
differences exist in descriptions or explanations in the Clinical Study Protocol and this SAP, the SAP 
prevails. This SAP will be finalized prior to unblinding of the treatment allocation codes.  
This document is designed to be a stand-alone document in terms of conveying essential statistical 
approaches to the analysis of the data. Additional definitions and details regarding variables 
collected are provided in the Clinical Study Protocol.  
Statistical approaches were developed to be consistent with accepted statistical and clinical trial 
principles including ICH E9, Statistical Principles for Clinical Trials1. 
 
 
1 ICH E9 Expert Working Group. Statistical Principles for Clinical Trials: ICH Harmonized Tripartite Guideline. Statistics in 
Medicine 1999; 18:1905–1942. 
 


ATB-203 SAP 
 
 
8 
 
2 
Key Elements of the Analysis Plan 
2.1  Primary Efficacy Analysis 
2.1.1 
Primary Superiority Hypothesis 
The primary effectiveness endpoint is freedom from durable loss of renal function at Day 
28. Success requires: 
• Alive at Day 28,  
• Free of dialysis at Day 28, and  
• Less than a 37% loss of estimated Glomerular Filtration Rate (eGFR; measured with 
the Modification of Diet in Renal Disease (MDRD) formula from the patient’s 
reference eGFR)) at Day 28.  
Reference creatinine values, baseline AKI stage and percentage loss of eGFR will be 
determined through algorithmic determination (see details below). Percentage loss of eGFR 
determined algorithmically will be based on a comparison of eGFR at screening compared to 
an algorithmically determined reference creatinine value.   
The primary efficacy comparison involves testing the following one-sided superiority 
hypotheses: Ho: π0.50 − πplacebo ≤ 0 vs Ha: π0.50 − πplacebo > 0; where π0.50 and πplacebo represent 
the true probability of freedom from durable loss of renal function at Day 28. Each probability 
represents the proportion of subjects on each arm expected to achieve complete recovery. 
These hypotheses will be tested using a one-sided type 1 error rate of α=0.05. The null 
hypothesis will only be rejected if the investigational drug demonstrates superiority. An 
unadjusted chi-square test will be used to test this hypothesis.   
2.1.2 
Sample Size Justification 
This trial will enroll 120 subjects randomized in a 1:1 ratio to either Reltecimod 0.5 mg/kg 
(n=60) or placebo (n=60), both in addition to standard of care (SoC). Sample size analysis was 
performed assuming all patients will be evaluable for the primary endpoint due to using last 
observation carried forward (LOCF) for patients missing the creatinine value on Day 28. The 
primary efficacy hypothesis will be tested using an unadjusted χ2 statistic with a one-sided 
α=0.05 significance level. Rejection of the null hypothesis will only occur if investigational 
drug superiority is demonstrated. Statistical power was computed for a range of expected 
treatment group differences supported by the results of preliminary studies. The following 
table summarizes the statistical power for a total sample size of N=120 (60 per group) for 
various assumptions regarding the success rate in the investigational arm and assuming a 
success probability of 0.50 among controls. This sample size results in 89% power if the true 
success rates are 75% and 50% for the investigational drug and placebo, respectively, for a 
group difference of 25%. Power remains above 80% if the true group difference is at least 
22% (Table 1). 


ATB-203 SAP 
 
 
9 
 
 
Table 1. Computed Power 
Index 
Control 
AB103 
Power 
1 
0.5 
0.65 
0.507 
2 
0.5 
0.70 
0.727 
3 
0.5 
0.71 
0.766 
4 
0.5 
0.72 
0.802 
5 
0.5 
0.73 
0.834 
6 
0.5 
0.74 
0.864 
7 
0.5 
0.75 
0.890 
 
2.2 Randomization 
120 patients will be recruited into the study and randomized to either 0.5 mg/kg Reltecimod or 
placebo in a 1:1 ratio. Randomization will be performed within site and according to the following  
stratification factors:  
• Acuity of AKI: reflects whether or not AKI is diagnosed at time of presentation of abdominal 
infection or during the 48 hours following the suspected diagnosis of abdominal infection. 
• Subject Age:  ≥18 to ≤75 and >75 to ≤85 years old 
• Four computer-generated, blocked randomization lists will be provided for each site, one for 
each of the four strata defined on the basis of the 2 by 2 cross-tabulation of the two stratification 
variables. Within each block, half of the assignments will be to active drug and half to placebo, 
in random order. Block sizes will be varied. 
The following provide details regarding randomization. 
Biomedical Statistical Consulting will utilize software written in R Software (acceptable R versions 
>3.1) to create the randomization schedule. The randomization inputs to this validated software are 
provided in Exhibit 1, with the exception of the final random seed utilized to generate the blinded 
randomization schedule. A draft randomization schedule will be generated with clearly marked 
“dummy” randomization treatment assignment (e.g., ‘DUMMY-Placebo’ and ‘DUMMY-Active’), 
and then exported to the necessary format for upload into the online randomization and study 
management system (RAVE Balance RTSM by Medidata Solution) administered by the Sponsor’s 
CRO (PharPoint Research, Inc.). The accurate upload of this “dummy” randomization schedule will 
then be verified by the unblinded study statistician, following the schedule provided by PharPoint 
Research, Inc. After verification, the process is repeated by the unblinded study statistician by 
rerunning the randomization software with updated seeds to determine the final (blinded) 
randomization schedule, with any “dummy-specific” notation removed. This final (blinded) 
randomization schedule is then uploaded to the online study management system utilizing the 


ATB-203 SAP 
 
 
10 
 
identical process verified through the “dummy” randomization schedule. A variable indicating the 
blinded treatment allocations will not be part of the clinical study data to be managed by the data 
management CRO to avoid risk of unblinding through inadvertent data transfer. Therefore, only 
blinded study data will be available to the blinded primary study statistician and blinded analysis 
staff.  The randomization schedule parameters were set so that there would be an excess number of 
potential sites to over at least 60 sites in the US and at least 50 sites in France, Belgium and 
Netherlands.  For every potential site, the maximum number of possible subjects was 30. Block sizes 
were randomly set to 2 or 4. Within each block, an equal number of allocations were made to the 
active and placebo groups. Separate randomization schedules were provided for each of 4 strata 
defined on the baseline of the acuity of AKI diagnosis and age category as described above.  
2.3 Analysis Sets 
The following analysis sets are defined: 
• 
Intent-to-treat (ITT): The ITT analysis set will include all randomized patients. 
• 
As-Treated (AT): The AT analysis set will include all randomized patients who were exposed 
to study medication (active or placebo). The AT analysis set will be used in primary safety 
analyses with patients assigned to actual treatment received and in supporting effectiveness 
analyses. 
• 
Modified Intent-to-treat (mITT): The mITT analysis set will include patients who were 
exposed to study medication and who had a definitive diagnosis of abdominal sepsis and Stage 
2 or Stage 3 AKI with patients assigned to the treatment actually received. The mITT analysis 
set may be used in supporting effectiveness analyses if more than a small number of such 
exclusions are made or more than a small number of patients are not treated with their 
randomly assigned treatment allocation.  
• 
Per Protocol (PP): Optionally, a PP analysis set may be used in secondary effectiveness 
analyses. The PP analysis set includes patients in the mITT analysis set assigned according to 
actual treatment received and excluding patients with either: 1) significant violations of 
inclusion or exclusion criteria with potential to confound treatment effect estimates, or 2) post 
randomization protocol violations with potential to confound treatment effect estimates. 
Exclusions from the PP analysis set will be determined based on blinded clinical data. The PP 
analysis may be further restricted to exclude patients who do not survive at 3 least days when 
evaluating critical care variables. 
2.4 Control of Blinding and iDMC 
An independent data monitoring committee (iDMC) will be established to evaluate the safety of the 
study. A detailed iDMC charter will be provided to clarify all relevant issues relating to firewalls to 
protect against potential operational biases. The charter will provide decision rules, composition of 
the iDMC members, and their conflict of interest statements. 


ATB-203 SAP 
 
 
11 
 
The iDMC reviews of the safety data are is planned for after 60 patients (and possibly a second 
review depending on sample size re-estimation) have completed 28 days of the study. 
For each planned iDMC review, all safety data on all patients who received one dose of study drug 
will be made available to the committee. The data reviewed by the iDMC will be unblinded and 
presented by treatment group to facilitate recommendations to the Sponsor. Data submitted to iDMC 
review will be unaudited.  
A designated unblinded statistician will provide unblinded safety data to the iDMC using programs 
constructed and validated by the blinded Study Statistician and Statistical Programming Team.  
The iDMC may also meet on an ad-hoc basis when immediate safety concerns arise. Thus, in case of 
urgency, the chair of the committee could address any questions or concerns regarding the safety of 
the patients. 
As noted above, this study will remain blinded as to treatment allocation. The actual randomized 
treatment allocations will be kept by an unblinded statistician responsible only for managing the 
randomization process. The data variable indicating the blinded treatment allocations will not be part 
of the clinical study data to be managed by the data management CRO. Therefore, only blinded 
study data will be available to the primary study statistician and responsible primary programming 
staff. 
There are three statisticians in this study with different roles: 
• Unblinded study statistician - performs randomization and provides backup 
• Unblinded iDMC statistician - independent statistician supporting iDMC operations 
• Blinded primary study statistician – primary lead statistician 
The role of the unblinded study statistician is: 
• Perform final randomization 
• Provide the randomization to the pharmacy vendor 
• Provide randomized allocations in electronic form to the unblinded iDMC statistician 
• Serve as a backup unblinded statistician 
A second, unblinded statistician will work with the iDMC to provide unblinded data as necessary for 
iDMC deliberations. This second, unblinded statistician is from ACI, the CRO responsible for 
supporting the iDMC. 
Analysis staff under the direction of the primary lead statistician, will develop SAS based programs 
to process clinical data provided by the blinded data management CRO and to populate all planned 
safety analysis tables and listings. This development phase includes using a pseudo randomization 


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for purposes of table generation. The programming and relevant data will be provided to the 
independent unblinded iDMC statistician.  


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3 
Description of variables to be included in statistical analyses 
3.1 Medical and Surgical History 
A complete medical history identifying both clinically relevant past medical and surgical conditions 
as well as active medical or surgical conditions will be reported on the Medical History eCRF. All 
chronic medications will be identified and characterized by trade or generic name, route of 
administration, as well as reason for use. 
Baseline signs and symptoms, or adverse events occurring between signing the informed consent to 
receiving study drug, should be captured on the Baseline Signs and Symptoms eCRF. 
3.2 Physical Examinations 
Physical examinations will include a clinically appropriate examination of vital organ systems. 
These should include at a minimum the cardiovascular, respiratory, abdomen, extremities, and 
neurologic body systems. 
3.3 Interim Physical Examinations (Symptom-Driven) 
Interim PE will be targeted to include clinically appropriate examination of specific organ systems 
based on patient related signs and symptoms. 
3.4 Concomitant Medication 
All concomitant medications, including ancillary, antimicrobials, immunosuppressant, and 
nephrotoxic drugs (with the exception of over the counter medications (unless an antimicrobial, 
immunosuppressant or nephrotoxic drug), vitamins, laxatives, intravenous fluid and electrolyte 
replacement, parenteral nutrition, topical medications (unless an antimicrobial) and other selected 
medications as described in the Study Procedure Manual), will be entered into the eCRF and 
identified by their generic or trade name. Information about antimicrobial medications 
immunosuppressants, and nephrotoxic drugs should include the dose, dosing frequency, route of 
administration, duration (start and stop times and dates), and reason for administration (to treat 
primary or secondary infection or for surgical prophylaxis). Information to be collected about non-
antimicrobial medications should include generic or trade name, route of administration, duration 
(start and stop dates) and reason for administration. 
Timing and adequacy of antibiotic therapy (based on institutional guidelines, baseline pathogens and 
antimicrobial sensitivity) will be reviewed by the Principal Investigator.   
3.5 Abdominal Infection and NSTI Type 
The type of intra-abdominal process (e.g. complicated appendicitis or diverticulitis, peritonitis due to 
perforation of the stomach or small or large intestine, gangrenous or necrotic infected bowel or 
organ; or post-traumatic peritonitis) causing peritonitis and abdominal sepsis will be captured along 
with the type of surgical or interventional procedure to establish source control. NSTI type will be 
categorized as Necrotizing Fasciitis, Fournier Gangrene, Gas Gangrene and Other. 


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3.6 Vital Signs 
Vital signs include heart rate, systolic and diastolic blood pressure, respiratory rate (spontaneous, 
assisted or controlled) and temperature. While these data points may be determined many times 
during the course of the patient’s hospitalization, recording vital signs (first set of vitals on that day) 
in the eCRF will be based on once daily readings for specified time sequences according to time and 
events (see Appendix A, Section 18.1 of the Clinical Study Protocol). 
3.7 Clinical Scores 
Clinical scores/criteria components will be collected in the study. APACHE II score criteria will only 
be collected at screening (see Section 18.2 of the Clinical Study Protocol) while SOFA score will be 
collected throughout the  study  (see  Section 18.3 of the Clinical Study Protocol). APACHE II will 
be used to determine disease severity while SOFA score will be evaluated as a secondary clinical 
endpoint. Individual parameters of the SOFA score will be collected and be correlated to response. 
All scores will be calculated retrospectively. Data will be recorded in the eCRF at specified time 
points according to time and events (see Section 18.1 of the Clinical Study Protocol).   
3.7.1 
SOFA Score Definition 
Screening SOFA score: includes measurements of six organ systems (cardiovascular, 
respiratory, renal, coagulation, GI/hepatic, and CNS) with data values evaluated any time after 
arrival at study site hospital. Follow-up SOFA scores: measurements of (the same) six organ 
systems with data values measured on Days 1, 3, 7, and 14, and calculated retrospectively. 
Where it is not possible to take arterial blood gases to determine the SOFA respiratory 
parameter, SpO2value can be converted to a PaO2 value to allow calculation of  the 
PaO2/FiO2 ratio. 
For this study, the liver component is excluded in the primary total sum score, and the 
resulting sum score is referred to in this study as ‘mSOFA’.  
3.7.2 
Acute Physiology and Chronic Health Evaluation II (APACHE II)  
APACHE II scores measure disease severity and will be obtained at screening. Exploratory 
stratified analyses will be based on APACHE II scores of greater than or equal to 10 vs. 
APACHE less than 10. 
If there are missing data in the components comprising the APACHE II, then some factors 
may only be evaluable based on medical judgment. If this is the case, Sponsor will provide 
completed screening APACHE II scores for each randomized patient and the APACHE II 
scores will not be considered part of the audited clinical data set provided by the data 
management CRO. 
3.8 Clinical Laboratory Assessments 
Safety laboratory investigations will include results of hematology labs (CBC including platelets and 
white blood cell differential), and of blood chemistry labs (Glucose; Electrolytes (Sodium, 
Potassium, Chloride, Bicarbonate, Calcium, Phosphorus); Renal function tests (Urea/BUN, Serum 
Creatinine); Liver function tests (Albumin, Bilirubin Total, Alanine transaminase (ALT), Aspartate 


ATB-203 SAP 
 
 
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transaminase (AST), Alkaline phosphatase (ALP); Total Protein). Also, urine albumin / creatine 
ratio will be evaluated.  
Pregnancy testing will be done on all women of childbearing potential participating in the study 
(using the quicker of a blood test or urine test). 
Clinical laboratory assessments will be collected at intervals according to time and events in Section 
18.1 of the Clinical Trial Protocol. 
Hematology will be collected at Screening, Day 1, Day 3, Day 7, Day 14, and Day 29.  
Blood chemistry will be collected at Screening, Day 1 (bilirubin and creatinine only), Day 2 
(creatinine only), Day 3 (bilirubin and creatinine only), Day 7, Day 10 (creatinine only), Day 14, 
Day 21 (creatinine only), Day 29 (albumin and creatinine only), 3 to 21 days after Day 29 visit 
(creatinine only), and at 3 months (creatinine only). The standard C-Reactive Protein (CRP) test (not 
the high sensitivity-hsCRP) will be used to evaluate inflammatory response and will be obtained at 
Screening and Days 7, 14, and 29. 
Urine will be collected at Screening, Day 1, Day 3, Day 7, Day 14, Day 29 and Month 3 to measure  
albumin/creatinine ratio to evaluate renal function and potential injury.   
3.9 Microbiology 
Microbiological testing will be performed as described in the Clinical Study Protocol time and 
events schedule.  Testing will be performed on blood specimens at Screening and intra-abdominal 
specimens from the first surgical or interventional radiology procedure, respectively. 
3.10 Creatinine, AKI, AKD, and eGFR 
3.10.1 Reference Creatinine 
Exhibit 1 summarizes the algorithmic determination of reference creatinine.  The algorithmic 
determination of baseline AKI stage will be based on comparing screening creatinine to the 
reference creatinine determined by Exhibit 1.  
Note: If there is any discrepancy between the algorithm and the assignment by the site as to 
reference creatinine then this will generate a medical review which may result in a modified 
baseline AKI stage different from the algorithmic determination. All such cases will be 
documented in the clinical study report.  Sensitivity analyses will be conducted as needed to 
evaluate the impact of any modifications from the algorithmic determination.  


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Exhibit 1. Algorithmic Determination of Reference Creatinine 
Preprocessing step:  
Creatinine values obtained within 2 days of dosing will be handled as follows: 
If there is only one value, this value will be excluded as input to the algorithm below. 
If there are more than one value, compare the maximum to the minimum, and if within 25%, then 
all values will be included as input to the algorithm below.  If greater than 25%, then the values 
obtained within 2 days will be excluded as input to the algorithm below.  
This table indicates the rules to be used to determine reference creatinine based on the numbers of 
historical values available during the last 3 months prior to screening and available 4 to 12 months 
prior to screening.  In general, the algorithm prioritizes use of historical creatinine values obtained 
within the last 3 months.  
Number of last 
3 month values 
Number of 4 to 
12 months 
Rule 
0 
0 
Use MDRD to determine reference creatinine. 
0 
1 
Use the 4- to 12-month value. 
0 
>=2 
Use median of 4 to 12 month values. 
1 
0 
Use <= 3-month value. 
>=2 
>=0 
Use median of <= 3-month values. 
1 
1 
Use the mean of the two available values. 
1 
>=2 
Use the median of all available values. 
>=2 
1 
Use the median of all available values.  
The SAS code used to implement the MDRD formula1,2 to determine a reference creatinine 
when no historical values are available is: 
if sex='Male' and black=0 then do; 
        t1 = der_age**(-0.203) ; 
        t2 = 1; 
        t3 = 1; 
        t4 = 186 * t1 *t2 *t3 ; 
        Scrt = (75 / t4 )**(-0.887)  ; 
        end; 
 
if sex='Female' and black=0 then do; 
    t1 = der_age**(-0.203) ; 
        t2 = 0.742; 
        t3 = 1; 
        t4 = 186 * t1 *t2 *t3 ; 
        Scrt = (75 / t4 )**(-0.887)  ; 
 
1 Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D; Modification of Diet in Renal Disease Study Group. A more 
accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 
1999 Mar;130(6):461-470. 
2 Levey AS, Greene T, Kusek I, Beck G. A simplified equation to predict glomerular filtration from serum creatinine 
(Abstract). J Am Soc Nephrol 2000;11:155A] 


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        end; 
 
if sex='Male' and black=1 then do; 
        t1 = der_age**(-0.203) ; 
        t2 = 1; 
        t3 = 1.21; 
        t4 = 186 * t1 *t2 *t3 ; 
        Scrt = (75 / t4 )**(-0.887)  ; 
        end; 
 
if sex='Female' and black=1 then do; 
    t1 = der_age**(-0.203) ; 
        t2 = 0.742; 
        t3 = 1.21; 
        t4 = 186 * t1 *t2 *t3 ; 
        Scrt = (75 / t4 )**(-0.887)  ; 
        end; 
3.10.2 Screening AKI and Screening eGFR 
Screening (pre-dose) AKI will be determined by comparing screening (pre-dose) creatinine to 
the algorithmic determination of reference as described in Exhibit 1 based on the rules 
summarized in Exhibit 2.   
The screening creatinine is necessary to establish baseline eGFR.  However, according to the 
Clinical Protocol, the AKI stage used to determine eligibility into the study may be 
determined through urine outcome criteria. If there is any discrepancy between the algorithm 
and the assignment by the site as to reference creatinine then this will generate a medical 
review which may result in a modified baseline AKI stage different from the algorithmic 
determination. However, in all cases, the algorithmic determination will be used when 
determining eGFR.  All such cases will be documented in the clinical study report.  Sensitivity 
analyses will be conducted as needed to evaluate the impact of any modifications from the 
algorithmic determination in Screening AKI stage.  


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Exhibit 2. Algorithmic Determination of Screening (pre dose) AKI Stage 
Stage 
Serum Creatinine 
0 
<1.5 times reference  
1 
1.5 to <2.0 times reference 
2 
≥2 to 3 times reference 
3 
≥ 3  times reference 
OR 
Increase in serum creatinine to ≥4 mg/dL 
OR 
Initiation of renal replacement therapy 
Reference may be either algorithmically determined or independently adjudicated 
depending on analysis. 
 
Screening eGFR will be determined using the following formula. 
Screening eGFR  (mL/min/1.73 m²) = 175 × (Screening Cr)-1.154 × (Age)-0.203 × (0.742 if 
female) × (1.212 if African American).  
3.10.3 Day 28 eGFR 
Day 28 eGFR will be determined by converting Day 28 creatinine to Day 28 eGFR using the 
following formula: 
Day 28 eGFR  (mL/min/1.73 m²) = 175 × (Cr Day 28)-1.154 × (Age)-0.203 × (0.742 if female) × 
(1.212 if African American).  
Percentage loss in eGFR at Day 28 will be determined using the following formula. 
Percentage loss in eGFR at Day 28 = 100% times [Screening eGFR - (Day 28 eGFR) / 
Screening eGFR].  If percentage loss ≥ 37% then patient fails key secondary endpoint.  
3.10.4 Day 14 eGFR 
Day 14 eGFR will be determined by converting Day 14 creatinine to Day 14 eGFR using the 
following formula: 
Day 14 eGFR  (mL/min/1.73 m²) = 175 × (Cr Day 14)-1.154 × (Age)-0.203 × (0.742 if female) × 
(1.212 if African American).  
Percentage loss in eGFR at Day 14 will be determined using the following formula. 


ATB-203 SAP 
 
 
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Percentage loss in eGFR at Day 14 = 100% times [Screening eGFR - (Day 14 eGFR) / 
Screening eGFR].  If percentage loss ≥ 37% then patient fails the Day 14 endpoint.  
3.10.5 Day 90 eGFR 
Day 90 eGFR will be determined by converting Day 90 creatinine to Day 90 eGFR using the 
following formula: 
Day 90 eGFR (mL/min/1.73 m²) = 175 × (Cr Day 14)-1.154 × (Age)-0.203 × (0.742 if female) × 
(1.212 if African American).  
Percentage loss in eGFR at Day 90 will be determined using the following formula: 
Percentage loss in eGFR at Day 90 = 100% times [Screening eGFR - (Day 90 eGFR) / 
Screening eGFR].  If percentage loss ≥ 37% then patient fails the Day 90 endpoint.  
3.10.6 Additional Processing Details 
Based on experience gained through processing of AKI endpoints in the recently completed 
ATB-202 study, the following data processing convention will be employed. 
• To account for renal replacement therapy (RRT), the exact dates on which the patient 
is on dialysis will be determined and compared to the exact date on which the labs 
were drawn for the creatinine sample. If the sample was drawn within 2 days from 
RRT start then it was excluded from all analyses.  
• If the reference creatinine is greater than 1.4, then all available creatinine values 
obtained on Day 10 and after, including unscheduled visits, will be evaluated. If the 
maximum is 1.5x the minimum, then the reference creatinine is replaced by the 
MDRD. 
• LOCF will be used for missing Day 14 creatinine starting from Day 10.   
• LOCF will be used for missing Day 28 creatinine starting from Day 7.  
3.10.7 Alternative Algorithmic Determination of Day 28 Creatinine 
If Day 28 creatinine is missing, LOCF will be used to impute Day 28 creatinine in primary 
analyses.  
As a sensitivity analysis, the following alternative approach to determining the recovery 
creatinine is as follows. 
1. Take all creatinine values between Day 14 and Day 28 and determine if they are consistent 
–if high and low value in the range are different by >50% (example 1.0 and 1.6) flag as 
“unstable”.  
2. If unstable, take the LAST value in the range as the recovery creatinine.  
3. If not unstable, take the MEAN of all values in the 14 to 28 day range as the recovery 
creatinine.  
 


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4 
Endpoints 
4.1 Primary Effectiveness Endpoint 
The primary effectiveness endpoint is freedom from durable loss of renal function at Day 28. The 
primary effectiveness endpoint requires: 
(i) 
Alive at Day 28,  
(ii) 
Free of dialysis at Day 28, and  
(iii) 
Less than a 37% loss of estimated Glomerular Filtration Rate (eGFR; measured with the 
Modification of Diet in Renal Disease (MDRD) formula from the patient’s reference 
eGFR)) at Day 28.  
Reference creatinine values, baseline AKI stage and percentage loss of eGFR at 28 will be 
determined through algorithmic determination (see details above). Percentage loss of eGFR 
determined algorithmically will be based on a comparison of eGFR at screening compared to an 
algorithmically determined reference creatinine value.   
Note: The Clinical Protocol allows subjects to quality for enrollment in terms of AKI stage through 
urine outcome.   
4.2 Secondary Effectiveness Endpoints 
The secondary effectiveness endpoints for this study are: 
• Freedom from durable loss of renal function at Day 14 
• Freedom from durable loss of renal function at Day 90 
Reference creatinine values, baseline AKI stage and percentage loss of eGFR at Days 14 and 90 will 
be determined through algorithmic determination (see details above). Percentage loss of eGFR 
determined algorithmically will be based on a comparison of eGFR at screening compared to an 
algorithmically determined reference creatinine value 
• Resolution of organ dysfunction (organ resolution is defined as having a total mSOFA 
score of ≤1) at Day 14 
• Resolution of specific organ dysfunction (defined as having an individual organ 
mSOFA score of ≤1) at Day 14 
• Critical care and hospital stay parameters 
o 
Hospital length of stay 
o 
ICU length of stay 
o 
ICU-free days in 28 days 
o 
Days on ventilator 
o 
Ventilator free days in 28 days 
o 
Vasopressor days 
o 
Vasopressor free days in 28 days 
o 
Discharge status 


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• 
Patient survival at Days 14, 28 and 90. 
• 
Presentation of Stages 1, 2, or 3 AKI (using the KDIGO criteria) 
• 
Stratifications involving Day 14 mSOFA<=1 vs Day 14 mSOFA>=2 
o Compare critical care between Day 14 mSOFA<=1 vs Day 14 mSOFA>=2 
o Compare dose groups in those with Day 14 mSOFA<=1 
o Compare dose groups in those with Day 14 mSOFA>=2 
 
• 
Among patients presenting with cardiovascular failure (shock), dose group 
predicting Day 14 mSOFA<=1 
• 
Survival to Day 90 as a function of freedom from durable loss of renal function at 
28 (overall and by dose group 
4.3 Exploratory Effectiveness Endpoints 
The following are exploratory endpoints for this study: 
• Improvement or freedom from durable loss at Day 14 
• Improvement or freedom from durable loss at Day 28 
• Improvement or freedom from durable loss at Day 90 
• Incidence of chronic kidney disease (CKD) at Day 90 as determined by detection of albuminuria 
and estimated glomerular filtration rate (eGFR) using CKD-EPI equation 
• Urinary albumin/creatinine ratio will be summarized for measurements made at Screening, Day 
1, Day 3, Day 7, Day 14, Day 29 and Month 3. The measure is used to assess kidney injury and 
is a marker of CKD  
• CRP will be summarized for measurements made at Screening, Day 7, Day 14, and Day 29, and 
for changes from Screening to Day 7, Day 14, and Day 29.  
• Evaluation of RRT use (i.e., type of RRT) 
4.4 Discussion Regarding ‘Event-Free Days’ 
Outcomes like duration of mechanical ventilation and incidence of organ failure may be lower in the 
group with higher mortality simply because of the competing effect of mortality (Rubenfeld, Angus 
et al 1999)3. Patients who die are not at risk to develop further organ failures or prolonged ventilator 
dependence. One proposed solution to this problem is to calculate life-support-free days. For 
example, ventilator-free days can be calculated over a predefined measurement period of (typically) 
28 days.  Patients who die or are mechanically ventilated longer than this period are assigned zero 
ventilator-free days for any days on which the patient is not alive or any day beyond the 28 days.  
All survivors accrue one ventilator-free day for each day after entry into the study that they are both 
alive and free of mechanical ventilation.  By combining mortality and morbidity in one measure, the 
 
3 Rubenfeld, GD, Angus DC, et al. Outcomes reserach in critical care. Am J Respir Crit Care Med 1999, 160(358-367).  


ATB-203 SAP 
 
 
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“free-day” outcome avoids the problem of competing mortality. A similar approach will be used to 
determine ICU-free days and vasopressors-free days.  
The 28-day horizon will be used when determining ICU-free days, vasopressor-free days, and 
mechanical ventilation-free days. ICU time will be calculated using calendar days starting on the day 
of admission to the ICU and ending on the day of ICU discharge, inclusive.     
A vasopressor-free day or ventilator-free day will be defined based on calendar days starting from 
the day of drug administration. Any day upon which a patient experienced no part of a calendar day 
on a vasopressor or a ventilator is a ventilator/vasopressors-free day.  For example, if the patient was 
on a ventilator for one hour on any given day, or for even one minute, this day will not count as 
a ventilator-free day. The same method will be used in calculating vasopressor-free days; a 
vasopressor-free day means a day alive and not on a vasopressor at any time during that day. This 
method is a convention generally accepted for these parameters.  Events that occur under general 
anesthesia are not counted. Hospital length of stay will be calculated according the total number of 
calendar days in the hospital. Where indicated as such in the patient’s medical record the hospital 
discharge date will be recorded as the date when the hospital staff indicate that the patient is ‘ready 
for discharge’ (to avoid extending hospital length of stay solely because the patient is waiting to be 
placed in skilled nursing facility or equivalent setting but had recovered adequately from their illness 
to meet hospital discharge criteria). 
4.5 Safety Endpoints 
Adverse events and clinical parameters (HR, BP, vital signs), laboratory parameters (clinical 
chemistry and hematology), and survival will be evaluated as safety endpoints. 


ATB-203 SAP 
 
 
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5 
Analysis Approaches 
5.1 Preliminary and Descriptive Analyses 
Descriptive analyses will be performed in order to characterize the treatment groups and to confirm 
that the randomization resulted in no clinically significant group differences at baseline. Baseline 
variables will be compared between groups using means, standard deviations, median, minimum and 
maximum values for continuous variables and counts and percentages for categorical variables. 
Although emphasis will be on clinical significance, baseline comparisons will include t-tests or 
Wilcoxon rank sum tests as appropriate for interval variables and chi-square or Fisher's exact tests as 
appropriate for nominal variables to aid in the screening for baseline differences. Similarly, changes 
in clinical endpoints over time will be summarized within each treatment group using summary 
statistics including mean and median change scores, standard deviations and ranges. Pearson or 
Spearman rank correlation coefficients will be used to characterize associations among variables 
within treatment group. For time-to-event outcomes (i.e., event-free survival), descriptive analyses 
will include construction of group specific Kaplan-Meier survival curves as appropriate. 
5.2 Primary Endpoint 
The primary efficacy comparison involves testing the following one-sided superiority hypotheses: 
Ho: π0.50 − πplacebo ≤ 0 vs Ha: π0.50 − πplacebo > 0; where π0.50 and πplacebo represent the true probability 
of freedom from durable loss of renal function at Day 28. Each probability represents the proportion 
of subjects on each arm expected to achieve complete recovery. These hypotheses will be tested 
using a one-sided type 1 error rate of α=0.05. The null hypothesis will only be rejected if the 
investigational drug demonstrates superiority. An unadjusted chi-square test will be used to test this 
hypothesis. The corresponding two-sided type 1 error rate is α=0.10.  Therefore, the null hypothesis 
will be rejected if the chi-square p-value is less than 0.10. The corresponding 90% two-sided 
confidence interval will be provided.  The lower bound of the 90% confidence interval is equivalent 
to the lower bound of a 1-sided 95% confidence interval. Based on the study data, it can be 
concluded that the true difference in success rates is at least equal to the lower bond of the 1-sided 
95% confidence interval. 
5.3 Secondary Endpoints 
The same analysis as described above will be performed for freedom from durable loss of renal 
function at Days 14 and 90 and from improvement for freedom from durable loss of renal function 
as Days 14, 28, and 90.  
Additional secondary endpoints include mSOFA over time, critical care and hospital stay parameters 
(ICU and ICU-free days, ventilator days and –free days, vasopressor days and –free days, and 
hospital length of stay (LOS)). Analyses for these endpoints will generally be descriptive, with 
emphasis on characterizing clinical effect sizes. Nominal p-values will be presented. Categorical 
outcomes will be described using counts and percentages with nominal p-values determined through 
chi-square or exact methods. Critical care and hospital stay endpoints will be described using non-
parametric approaches including using concordance statistics to characterize clinical effect sizes and 
Wilcoxon rank sum tests to determine nominal statistical significance. Methods appropriate for time-
to-event endpoints including survival and life-table methods will be used for time-to-recovery 
endpoints. 


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5.4 mSOFA 
The Sequential Organ Failure Assessment score or SOFA was originally developed to track a 
patient’s status during a stay in an intensive care unit (ICU)4,5.  Each of six organ systems are 
evaluated and assigned ordinal scores from 0 to 4.  A total score is the sum of the component scores.  
For this study, the liver component is excluded from the sum score and the resulting sum score is 
referred to in this study as ‘mSOFA’.  
Several approaches will be taken to summarize changes over time and between treatment groups in 
the clinical scores as described below.  Special handling of mSOFA scores includes the following: 
1. If an individual organ score is missing but other scores for that day are non-missing, the organ 
systems that were not evaluated are assumed to be free of organ failure and given a value of 
zero when determining the sum score.   
2. If all organ scores are missing for a specific day, the mSOFA total score from that day will be 
imputed using LOCF with the following exception, LOCF will not be performed after patient 
death. 
3. When summarizing the individual organ scores apart from the mSOFA total scores, the same 
rules as above will apply.  
Mean values and standard deviations (SD) for the SOFA and for the five specific organ 
components will be summarized over time with and without LOCF.  Similarly, mean change 
scores from baseline (SD) will be summarized with and without LOCF. 
5.5 Assessment of Site to Site Variability in Relative Efficacy 
Site to site variability in relative efficacy will be evaluated using a random effects meta-analysis 
approach using the R package metafor to implement the analysis. True effects are assumed to be 
normally distributed with mean  and variance 2. By imposing a specified distribution on the site- 
to-site variability, i.e. a normal distribution with mean  and variance 2, sensitivity to small sample 
sizes in individual sites is reduced and the parameters reflecting the magnitude of site-to-site 
variability are naturally derived. The quantitative measure of the magnitude of heterogeneity is I2. I2 
is the fraction of 2 that is due to effect size heterogeneity, as opposed to sampling variance. 
Fractions 25% and less are considered small. If there is significant site-to-site variability, the impact 
on this variability will be evaluated using a random effects logistic regression to test the null 
hypothesis that the likelihood of achieving  freedom from durable loss of renal function at Day 28 is 
the same for treated and placebo patients accounting for a random site effect.  
5.6 Subgroup Analysis 
Subgroup analysis will be performed.  The following variables will define subgroups.   
 
4 Vincent JL, Moreno R, Takala J, et al: The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ 
dysfunction failure: On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive 
Care Medicine. Intensive Care Med 1996; 22:707–710. 
5 Vincent JL, Angus DC, Artigas A, Kalis A, Basson BR, Jamal HH, Johnson III G., Bernard GR for the PROWESS Study 
Group. Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS trial. Crit Care Med 2003; 31:834 –
840. 


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• Stage 2 and Stage 3 AKI  
• Acuity of AKI (i.e., whether or not AKI is diagnosed at time of presentation of abdominal 
infection or surgically confirmed NSTI, or during the 48 hours from the suspected diagnosis 
of abdominal infection or surgical confirmation of NSTI; developed AKI up to <24 hours or 
25 to 48 hours after the suspected diagnosis of abdomianl infection or surgical confirmation 
of NSTI) 
• AKI diagnosed via creatinine criteria vs. urine output criteria 
• Abdominal infection or NSTI 
• Age ≥18 to ≤75  and >75 to ≤85 years old 
• Baseline APACHE II ≥10 and < 10 
• Cardiovascular failure yes and no 
• Respiratory failure yes and no 
• Gender male and female 
• Causcasian and other 
• BMI category (<30, 30-40, >40) 
• Day 14 mSOFA≤1 and Day 14 mSOFA≥2 
The following tables will be provided for each subgroup. Results for the primary endpoint will be 
summarized in a forest plot.  
14.2.1.1 
Numbers and Percentages of Subjects 
Achieving Freedom from Durable Loss of Renal Function and 
Improvement in Durable Loss of Renal Function at Day 28 Using LOCF 
ITT Analysis Set 
14.2.2.1 
Numbers and Percentages of Subjects 
Achieving Secondary Freedom from or Improvement in Durable Loss 
of Renal Function Endpoints at Days 14, 28, and 90  
ITT Analysis Set 
 
5.7 Analysis of Other Covariate Effects 
Covariates will be assessed for potential confounding (due to lack of perfect randomization balance) 
or effect modification (subgroup efficacy heterogeneity) using Mantel-Haenszel stratified analyses 
and/or multiple logistic regression. Covariates will include the set of variables listed above for 
subgroup analyses. Other baseline variables in which randomization failed to produce balance 
between groups will be examined in supporting analyses. Covariate effects on estimates and 
interactions will be assessed to see if there is evidence of efficacy heterogeneity. Results from all 
subgroups analyses will be considered hypothesis-generating. 
5.8 Multiplicity 
There is a single primary hypothesis test utilizing a clinical success endpoint, freedom from durable 
loss of renal function at Day 28. Therefore, there is no issue with regard to multiplicity .  


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5.9 Descriptive Analyses of Secondary Endpoints 
Secondary endpoints have been specified from several domains including critical care and hospital 
stay parameters (ICU days and ICU-free days, ventilator days and –free days, vasopressor days and 
–free days, hospital LOS, and clinical systemic parameters (SOFA over time, incidence and recovery 
from AKI). Analyses for these endpoints will generally be descriptive, with emphasis on 
characterizing clinical effect sizes6.  Nominal p-values will be presented as an aid to interpretation. 
Categorical outcomes will be summarized using counts and percentages with nominal p-values 
determined through chi-square or exact methods. Critical care and hospital stay endpoints will be 
described using non-parametric approaches including using concordance statistics (c-stat) to 
characterize clinical effect size and Wilcoxon rank sum tests to determine nominal statistical 
significance. Methods appropriate for time-to-event endpoints including survival and life-table 
methods will be used for time-to-event endpoints.    
5.10 Analysis of Event-time and Overall Survival 
Time-to-event endpoints will be assessed in descriptive analyses using survival and life table 
methods as appropriate and illustrated using Kaplan-Meier survival curves7. The significance of 
group will be assessed using logrank statistics. 
5.11 Handling of Missing Data 
5.11.1 Intent-to-Treat 
The purpose of intent-to-treat comparisons is to ensure that randomization is protected (i.e., all 
groups have comparable baseline characteristics and that any differences besides therapy are 
due to chance) and to preclude the possibility of bias due to selectively excluding subjects 
from therapy groups. This is intended to avoid systematic differences among the groups 
attributable to factors other than therapy assignment8. Therefore, we will attempt to include all 
randomized patients, regardless of intervention or length of follow-up in the primary efficacy 
comparison.  
5.11.2 LOCF of Day 28 and Day 90 Creatinine 
In order to determine the primary endpoint, freedom from durable loss of eGFR at Day 28, 
creatinine is necessary. Patients surviving to Day 28 or later but with missing Day 28 
creatinine will have their Day 28 creatinine values determined through LOCF. The same 
procedure will be used for Day 90 Creatinine. 
5.11.3 mSOFA Scores 
mSOFA scores over time will be assessed as 1) observed cases, and 2) LOCF. 
 
6 Cohen, J. (1988). Statistical power analysis for the behavioral sciences (2nd ed.). New York, Academic Press. 
7 Kaplan EL and Meier P. Nonparametric estimation from incomplete observations, Journal of the American Statistical 
Association, 53:457-481, 1959 
8 Knickerbocker R. Intent-to-Treat Analyses. In: Chow S-C, ed. Encyclopedia of Biopharmaceutical Statistics.  Marcel 
Dekker; 2000. 
 


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Individually missing mSOFA component values due to non-measurement are conventionally 
assumed as normal and this convention will be followed for this study. 
LOCF will not be applied to missing mSOFA scores after patient death in analyses that 
employ LOCF to describe mean values of time. Therefore, analysis of mSOFA mean values 
using LOCF will focus on morbidity rather than mortality. Also, LOCF will not be used for 
missing mSOFA after Day 14.  
In categorical analyses including formulation of the secondary effectiveness endpoint, total 
mSOFA score at Day 14 ≤ 1, LOCF is necessary to guarantee that every patient has a value at 
Day 14.  LOCF will not be performed after patient death.  
5.12 Prior and Concomitant Medication 
Medication start and stop dates will be compared to the date of first dose of study medication to 
allow medications to be classified as either prior or concomitant and will be recorded up to Day 29.  
If the start and/or stop dates of medications are missing or partially missing, the dates will be 
compared as far as possible with the date of administration of study drug. Medications starting after 
the completion/withdrawal date will be listed but will not be classified or summarized. 
Medications that start and stop prior to the date of first dose of study medication will be classified as 
prior only.  
A medication will be regarded as concomitant if it started on or after the date of first dose of study 
treatment. 
A medication will be regarded concomitant if: 
• 
it started prior to date of first dose of study treatment but was ongoing at the time of the first dose 
of study treatment. 
• 
the start date of medication is completely unknown. 
Medications are coded prior to delivery of the validated clinical data base. The following describes 
this process. 
Drugs are coded to the WHO Drug entry that best represents (most accurately and specifically) the 
reported term.  If a reported term is a trade name, then it will generally be coded to the trade name 
entry in WHO Drug that contains the correct active ingredients for that trade name.  If a reported 
term is a generic name, then it will generally be coded to the generic entry in WHO Drug with that 
ingredient or combination of ingredients. 
 A WHO Drug entry may have one or more ATC (Anatomic-Therapeutic-Chemical) codes assigned 
to it within the dictionary. If a WHO Drug entry has only one ATC code, then that ATC code is 
additionally returned for that WHO Drug entry.  If a WHO Drug entry has more than one ATC code 
assigned, then a single ATC code is selected based on the most common usage for the drug and the 
selected ATC code is additionally returned for the WHO Drug entry.  


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Separate sets of tables will be provided for non-antimicrobial or non-nephrotoxic medications, 
antimicrobial medications, and nephrotoxic medications. 


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6 
Safety Analysis 
The primary safety measures are AEs (including SAEs), deaths, clinical safety laboratory, PE, and 
vital signs through Day 29 including determination of survival through Day 29. 
The safety profiles will be compared between active and placebo groups using descriptive statistics 
as appropriate for continuous and categorical safety variables. Changes in continuous safety 
measures such as laboratory values will be summarized by mean changes over time using 
descriptive statistics (sample size (N), mean, SD, median, minimum and maximum). The presence 
of clinically significant safety findings will be summarized by shift tables separately for each group 
using counts and percentages. AEs will be classified according to system organ class and preferred 
term and summarized by counts and percentages separately for those recorded on Day 0 (prior to 
drug administration) and those with onset on Day 1 or later. AEs will also be summarized by 
relationship to study drug, severity, and whether they are serious. Specific summaries will involve 
AEs and SAEs in the Infection/Infestation system organ class. Vital signs including weight, 
temperature, systolic BP, diastolic BP, respiration rate, and heart rate will be summarized across 
time (Day 0, Day 1, Day 2, Day 3, Day 7, Day 10, Day 14, Day 21 and Day 29) and separately by 
treatment group by N, Mean, and SD.  
6.1 Adverse Events 
Treatment emergent adverse events (TEAEs) are defined as those with onset on Day 1 or later. 
TEAEs will be classified according to system organ class and preferred term and summarized. by 
counts and percentages. TEAEs will also be summarized by relationship to study drug, severity, and 
whether they are serious. AE recorded prior to study drug administration will be included in listings 
but not included in summary tables.   
6.2 Laboratory Values 
6.2.1 
Description of Value Over Time 
Laboratory values over time including blood chemistry and hematology will be summarized 
using descriptive statistics and compared between treatment groups. Values over time and 
changes over time will be summarized.  
6.2.2 
Laboratory Shift Tables 
The presence of clinically significant changes in laboratory values will be further evaluated 
using shift tables for blood chemistry and blood hematology changes from screening to Day 7 
and from screening to Day 14. These tables will summarize the numbers and percentages of 
patients that went from a lab value in the normative range at screening to one that is in the 
higher than normal range or lower than normal range. 
6.2.3 
Treatment of Clinical Laboratory Abnormalities 
Deterioration as compared to baseline in protocol mandated laboratory values, vital signs and 
other safety variables will only be reported as AEs only if they fulfill any of the SAE criteria 
or are the reason for discontinuation of treatment with the investigational medical product. 
However, the Investigator may record such findings as an AE at his/her discretion in addition 


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to completing an unscheduled laboratory/vital signs eCRF with the information on the 
clinically significant test abnormality. If a deterioration in a laboratory value/vital sign is 
associated with clinical signs and symptoms, the sign/symptom will be reported as an AE and 
the associated laboratory result/vital sign will be considered as additional information. Any 
new or aggravated clinically relevant abnormal medical finding at a PE, dermal examination 
or lung auscultation as compared with the baseline assessment will be reported as an AE. 
Clinically relevant deterioration in unscheduled assessments of laboratory or vital sign 
parameters should be reported on additional eCRF pages. 
Wherever possible, the reporting Investigator uses the higher level medical concept, rather 
than the laboratory term (e.g., anemia versus low hemoglobin value). 
Additionally, for blood chemistry and blood hematology, results at each visit will be 
summarized according the frequency of “Critical High”, “Above”, “Within”, “Below”, and 
“Critical Low” results.    
6.3 Physical Exams 
Physical exam data on Days 1, 7, and 10 will be summarized in patient specific listings.  
6.4 Vital Signs 
Vital signs including weight, temperature, systolic BP, diastolic BP, respiration rate, and heart rate 
will be summarized across time (Day 0, Day 1, Day 2, Day 3, Day 7, Day 10, Day 14, Day 21, and 
Day 29), separately by treatment group using N, Mean, and SD. Vital signs will be summarized for 
the Safety Analysis Set. 
 


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7 
Presentation of Enrollment and Baseline Characteristics 
7.1 Site Specific Numbers of Patients by Analysis Set 
 
Table 14.1.1.1 summarizes the numbers of patients screened and for each analysis set by site.  
Table 14.1.1.2 summarizes the numbers of patients by site, analysis set, and treatment group.   
Table 14.1.1.3 summarizes the numbers of patients by site, treatment group, and randomization 
stratum in the mITT Analysis set.  The primary efficacy analyses will be performed in the mITT 
analysis set.  
Randomization strata are defined as follows: 
• Acuity of AKI: whether or not AKI is diagnosed at time of presentation of abdominal 
infection or during the 48 hours following the suspected diagnosis of abdominal infection.  
• Subject Age : ≥18 to ≤75 or >75 to ≤85 years old. 
Table 14.1.1.4 provides the same summary for the As Treated (primary Safety) analysis set.  
Table 14.1.1.5 provides the same summary for the PP (secondary efficacy analysis set).  
Totals across all sites will be provided for these tables.  
7.2 Demographic and Baseline Characteristics of Cohorts 
Demographic and baseline characteristics for each analysis set are summarized in Tables 14.1.2.1, 
14.1.2.2, and 14.1.2.3 for the mITT (primary efficacy), AT (safety), and PP (secondary efficacy) 
analysis sets, respectively.  The same table is provided for the ITT (randomized) analysis in order to 
evaluate baseline covariate balance achieved through randomization (Table 14.1.2.4).  
Tables 14.1.3.1, 14.1.3.2, and 14.1.3.3 summarize the numbers of patients overall and by treatment 
group, age category, and gender, for the mITT, AT, and PP analysis sets respectively.   
Prior and concomitant medication, lifetime and current medications, and surgical history will be 
summarized for the Safety (AT) analysis set as are all Safety endpoints. Primary and secondary 
efficacy endpoints are summarized for the Primary Efficacy (mITT) analysis set.   
7.3 Baseline Microbiology 
Table 14.1.3.4 summarizes pathogens in blood cultures and surgical samples in the ITT analysis set 
overall and by treatment group. Table 14.1.3.5 summarizes pathogen (genus / species) in  blood 
culture specimens. Table 14.1.3.6 summarizes pathogen (genus / species) in  intra-abdominal or 
debridement specimens. The data used will be based on verbatim text.   
 


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7.4 Prior and Concomitant Medication 
. For all prior and concomitant medication tables, the drug class will be capitalized, and the generic 
drug name will be listed in small letters.  The following is an example for the drug class 
‘corticosteroids’. 
CORTICOSTEROIDS 
fluticasone 
fluticasone propionate 
hydrocortisone 
All drug classes and all generic drug names will be reported in summary tables and in patient 
listings.  Nephrotoxic drugs as defined in the Appendix 7. 
Table 14.1.4.1 will summarize the numbers (%) of patients with prior non-antimicrobial or non-
nephrotoxic medications by category and by specific medication. 
Table 14.1.4.2 will summarize the numbers (%) of patients with prior antimicrobial medications by 
category and by specific medication. 
Table 14.1.4.3 will summarize the numbers (%) of patients with prior nephrotic medications by 
category and by specific medication. 
Tables 14.1.4.4, 14.1.4.5 and 14.1.4.6 will provide the same summaries for concomitant 
medications.   
7.5 Medical and Surgical History 
Table 14.1.5.1 will summarize the numbers and percentages of patients that experienced medical 
conditions during their lifetime by body system and specific medical conditions when experienced 
by more than one patient in either group.  
Table 14.1.5.2 will summarize the numbers and percentages of patients with current medical 
conditions by body system and specific medical conditions when experienced by more than one 
patient in either group.  
Table 14.1.6.1 will summarize the numbers and percentages of patients that underwent specific 
surgical procedures at any time during their lifetime summarized body system and specific surgical 
procedures.  
Table 14.1.6.2 will summarize the numbers and percentages of patients with specific types of 
surgical or interventional procedures to establish source control and location of source control.  
Table 14.1.6.3 will summarize the numbers and percentages of patients according to acuity of AKI,, 
whether or not a reference pre-infection creatinine value was used, and whether the diagnosis of AKI 
was based on creatinine alone, urine outcome alone, or both..  
 


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7.6 Drug Administration and Timing 
Drug administration and timing will be performed for two sets of subjects separately.   
• Patients presenting with abdominal sepsis or NSTI and AKI are to have drug administered within 
6 hours of decision to go to abdominal surgery or interventional radiology procedure, or surgical 
confirmation of NSTI. 
•  Patients who present just with abdominal infection or NSTI and then followed for development 
of AKI are to have drug administered within 6 hours of diagnosis of AKI 
Time to drug allocation, drug administration time point (during, or after surgery), and the actual 
volume of drug infused will be described in Table 14.1.7.1. 
7.7 Patient Disposition and End of Study Status 
Table 14.1.8.1 summarizes Day 29 study status by treatment group.  


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8 
Presentation of Efficacy Results 
8.1 Primary AKI Endpoint 
The numbers and percentages of patients in each group meeting the primary efficacy endpoint of 
complete recovery (freedom from durable loss of renal function at Day 28 is summarized in Table 
14.2.1.1 for the mITT (primary efficacy) analysis set. This table also includes the statistical 
significance of this endpoint based on an unadjusted chi-square statistic. Study success requires one-
sided p ≤ 0.05 for this endpoint which is equivalent to a two-sided p ≤ 0.10 as long as the percentage 
of subjects achieving the endpoint is larger in the actively treated group compared to placebo. This 
table also provides the estimated treatment group difference and 90% confidence interval 
corresponding to the one-sided significance level. The lower bound of the 90% confidence interval is 
equivalent to the lower bound of a 1-sided 95% confidence interval. Based on the study data, it can 
be concluded that the true difference in success rates is at least equal to the lower bond of the 1-sided 
95% confidence intervals.  Table 14.2.1.1 also provide the same summaries for the components of 
the primary endpoint. 
• Alive at Day 28,  
• Free of dialysis at Day 28, and  
• Less than a 37% loss of estimated Glomerular Filtration Rate (eGFR; measured with 
the Modification of Diet in Renal Disease (MDRD) formula from the patient’s 
reference eGFR) at Day 28.  
Table 14.2.1.2, and 14.2.1.3 repeat these analyses in the AT and PP analysis sets, respectively.  
8.2 Evaluation of Site Heterogeneity in Primary Endpoint Treatment Effects 
Table 14.2.1.4 provides comparisons of the percentages of patients achieving the primary efficacy 
endpoint by site, overall and by treatment group in the mITT analysis. If needed, site-to-site 
heterogeneity will be evaluated with these data using a random effects meta-analysis approach as 
described above.  
8.3 Secondary and Exploratory AKI Recovery Endpoints 
Table 14.2.2.1 summarizes treatment group comparisons based on secondary AKI recovery 
endpoints in the mITT analysis set including:  
• Freedom from durable loss of renal function at Day 14 
• Freedom from durable loss of renal function at Day 90 
• Improvement or freedom from durable loss at Day 14 
• Improvement or freedom from durable loss at Day 28 
• Improvement or freedom from durable loss at Day 90 
Tables 14.2.2.2 and 14.2.2.3 repeat these comparisons in the AT and PP analysis sets, respectively. 


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8.4 mSOFA Scores  
Table 14.2.4.1 summarizes observed modified total score, organ specific scores, and mSOFA total 
scores at Screening, Day 1, Day 3, Day 7, and Day 14.    
Table 14.2.4.2 provides the same summary after application of last-value-carried forward (LOCF).  
LOCF was not applied after patient death.  
Table 14.2.4.3 summarizes mSOFA at Screening and changes from Screening to Day 1, Day 7, and 
Day 14 for observed cases.  
Table 14.2.4.4 provides the same summary after application of LOCF.   
Table 14.2.4.5 summarizes the percentages of subjects with resolution of organ dysfunction (organ 
resolution is defined as having a total mSOFA score of ≤1) at day 14 and the resolution of specific 
organ dysfunction defined as having an individual organ SOFA score of ≤1 at Day 14.  
8.5 Critical Care and Hospital Stay Parameters, to be Measured until Day 28  
The following critical care and hospital stay parameters will be assessed.   
o Hospital length of stay (days) 
o ICU free days 
o Days in ICU 
o Days on ventilator 
o Ventilator free days 
o Vasopressors days 
o Vasopressors free days 
o Discharge status 
Because of the expected skewness in the distributions of these parameters, non-parametric Wilcoxon 
rank sum tests will be used assess the nominal statistical significance of treatment group differences 
in these parameters.  Table 14.2.5.1 will provide summary statistics by treatment groups including 
N, mean, median, standard deviation, and minimum, and maximum values. 
Table 14.2.5.2 summarizes hospital discharge status. 
Table 14.2.5.3 summarizes hospital readmissions. 
Table 14.2.5.4 will summarize critical care and hospital stay parameters over days 1 to 28 comparing 
by primary effectiveness status (success versus failure).    
Table 14.2.5.5 will summarize critical care and hospital stay parameters over days 1 to 28 comparing 
subjects with Day 14 mSOFA≤1 versus Day 14 mSOFA≥2.  
Table 14.2.5.6 provides the same information as in Table 14.2.5.6 but for the PP analysis set. 
Tables 14.2.5.7 and 14.2.5.8 provide the same information as Tables 14.2.5.1 and 14.2.5.6 but 
restricted to subjects alive at Day 14.  


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8.6 Time-to-Event and Survival Analyses 
Tables 14.2.6.1 and 14.2.6.2 provide life table analyses for mortality to Day 90 in the Reltecimod 
and Placebo groups, respectively in the mITT analysis set.  Tables 14.2.6.6 and 14.2.6.7 repeat these 
analyses in the PP analysis set. Tables 14.2.6.3, 14.2.6.4, and 14.2.6.5 provide life table analyses for 
mortality to Day 90 for subjects randomized to Reltecimod, Placebo, and for both groups, 
respectively, among subjects achieving Freedom from Durable Loss of Renal Function at Day 28. 
Kaplan-Meier survival curves will be provided for each of these analyses with cumulative mortality 
plotted on the y-axis.  
8.7 CRP 
Table 14.2.7.1 summarizes CRP (standard test, not high sensitivity-hsCRP) at Screening and at Days 
7, 14 and 29 and changes from Screening.  
8.8 Subgroup Analysis 
As noted in Section 5.6, the following variables will define subgroups.   
• Stage 2 and Stage 3 AKI  
• Acuity of AKI (i.e., whether or not AKI is diagnosed at time of presentation of abdominal 
infection or surgically confirmed NSTI, or during the 48 hours from the suspected diagnosis 
of abdominal infection or surgical confirmation of NSTI; developed AKI up to <24 hours or 
25 to 48 hours after the suspected diagnosis of abdomianl infection or surgical confirmation 
of NSTI) 
• AKI diagnosed via creatinine criteria vs. urine output criteria 
• Abdominal infection or NSTI 
• Age ≥18 to ≤75  and >75 to ≤85 years old 
• Baseline APACHE II ≥10 and < 10 
• Cardiovascular failure yes and no 
• Respiratory failure yes and no 
• Gender male and female 
• Causcasian and other 
• BMI category (<30, 30-40, >40) 
• Day 14 mSOFA≤1 and Day 14 mSOFA≥2 
• Selected baseline pathogen type 
 
The following tables will be provided for each subgroup. Results for the primary endpoint will be 
summarized in a forest plot.  
 
14.2.1.1 
Numbers and Percentages of Subjects 
Achieving Freedom from Durable Loss of Renal Function and 
Improvement in Durable Loss of Renal Function at Day 28 Using LOCF 


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ITT Analysis Set 
14.2.2.1 
Numbers and Percentages of Subjects 
Achieving Secondary Freedom from or Improvement in Durable Loss 
of Renal Function Endpoints at Days 14, 28, and 90  
ITT Analysis Set 


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9 Presentation of Safety Evaluations 
9.1 
Adverse Events 
Treatment-emergent AEs (TEAE) reported during the study will be summarized by treatment 
group according to Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class 
(SOC) and Preferred Term (PT). Incidence rates of TEAE will be tabulated by class. The 
distributions of severity will be provided for drug-related AEs, separately by treatment group. 
Further tabulations by relationship and severity of AE may be provided. 
9.1.1 
Summary of adverse events 
All analyses of adverse events will be based on the As Treated (Safety) Analysis Set. A 
summary of the numbers and percentages of patients within each treatment group 
experiencing at least one TEAE will be provided in Table 14.3.1.1. TEAEs will be defined as 
an AE occurring from Day 1 to end of study which is defined as Day 28. ‘Drug-related’ is 
defined as ‘possibly’, ‘probably’, or ‘definitely’ caused by the study medication.   
The AE endpoints summarized in this table are:   
• With one or more TEAE 
• With one or more drug-related TEAE 
• With one or more serious TEAEs 
• With one or more serious drug-related TEAE 
• With one or more severe TEAE 
• With one or more moderate or severe TEAE 
• TEAE with outcome of death 
• TEAE with outcome of drug related death  
• Discontinued study drug due to AE/SAE 
• Discontinued from study due to AE/SAE 
9.1.2 
Specific adverse events 
The incidence rates (%) and event counts of TEAEs by system organ class (SOC) and by 
preferred term (PT) will be summarized by treatment group in Table 14.3.1.2. This table will 
be organized so that SOCs are reported in upper case letters and PT’s are reported in 
lowercase.   
Table 14.3.1.3 will summarize the incidence rates (%) of specific TEAE PTs, sorted by 
descending incidence of PT in the active drug group.  
The incidence rates (%) and event counts of drug-related TEAEs by SOC and by PT will be 
summarized by treatment group in Table 14.3.1.4. 
The incidence rates (%) and event counts of serious drug-related TEAEs by SOC and by PT 
will be summarized by treatment group in Table 14.3.1.5. 


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Table 14.3.1.6 will summarize the incidence rates (%) of serious TEAE PTs, sorted by 
descending incidence of PT in the active drug group.  
The incidence rates (%) and event counts of serious drug-related TEAEs by SOC and by PT 
will be summarized by treatment group in Table 14.3.1.7. 
9.1.3 
Severity of adverse events 
The incidence rates (%) and event counts of severe TEAEs by SOC and by PT will be 
summarized by treatment group in Table 14.3.1.8. 
Table 14.3.1.9 will summarize the incidence rates (%) of severe TEAE PTs, sorted by 
descending incidence of PT in the active drug group.  
Counts of drug-related TEAEs in the active drug group will be summarized by severity, SOC 
and PT in Table 14.3.1.10. Similarly, counts of drug-related TEAEs in the placebo group will 
be summarized by severity, SOC and PT in Table 14.3.1.11.  
9.1.4 
Day 0 Adverse Events 
A listing will be provided contain any events that occur prior to drug administration.  
9.1.5 
Safety listings 
The following listings will be provided for all patients in the Safety Analysis Set. Adverse 
event listings will include SOC, PT, relationship, severity, onset and resolution dates, and 
action taken. 
 
 
AE Listings 
1 
16.2.7.1 
All TEAEs Sorted by Specific AE: Day1+ 
by Treatment Group, Sorted by SOC and PT 
As Treated (Safety) Analysis Set 
2 
16.2.7.2 
All TEAEs Sorted by Specific AE: Day1+ 
by Treatment Group, Sorted by Patient ID and Onset 
As Treated (Safety) Analysis Set 
3 
16.2.7.3 
Drug-Related TEAEs Sorted by Specific AE: Day1+ 
by Treatment Group, Sorted by SOC and PT 
As Treated (Safety) Analysis Set 
4 
16.2.7.4 
Serious TEAEs Sorted by Specific AE: Day1+ 
by Treatment Group, Sorted by SOC and PT 
As Treated (Safety) Analysis Set 
5 
16.2.7.5 
Serious Drug-Related TEAEs Sorted by Specific AE: Day1+ 
by Treatment Group, Sorted by SOC and PT 
As Treated (Safety) Analysis Set 
6 
16.2.7.6 
All TEAEs with Outcome of Death Sorted by Specific AE: Day1+ 
by Treatment Group, Sorted by SOC and PT 
As Treated (Safety) Analysis Set 
7 
16.2.7.7 
All TEAEs with Outcome of Drug-Related Death Sorted by 
Specific AE: Day1+ 
by Treatment Group, Sorted by SOC and PT 
As Treated (Safety) Analysis Set 


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AE Listings 
8 
16.2.7.8 
All TEAEs with Outcome of Study Drug Discontinuation  
Sorted by Treatment Group, SOC, and PT 
As Treated (Safety) Analysis Set 
9 
16.2.7.9 
All TEAEs with Outcome of Discontinuation from Study 
Sorted by Treatment Group, SOC, and PT 
As Treated (Safety) Analysis Set 
 
9.2 Clinical Laboratory Assessments 
9.2.1 
Blood Chemistry 
Table 14.3.2.1 summarizes the values and changes from screening (baseline) for each of 15 
tests included in the chemistry panels at Screening, Day 7 and Day 14.  
Table 14.3.2.2 provides a shift table summarizing the numbers and percentages of patients 
going from a normal blood chemistry value to a normal, low or high value at Day 7; going 
from a low baseline blood chemistry value to normal, low or high at Day 7; and going from a 
high baseline blood chemistry value to normal, low or high at Day 7.  The percentages 
presented in this table correspond to each baseline status. For example, the one of the reported 
percentages will indicate the percentage of subjects that started with a normal value but ended 
with a high value. This will be done separately for each treatment group.   
Table 14.3.2.3 provides the same information but for shifts to Day 14. 
Table 14.3.2.4 provides a summary of blood chemistry frequencies by visit  with respect to 
normal ranges and critical values by treatment group.  
Table 14.3.2.5 provides a summary of creatinine values at screening and at Days 1, 2, 3, 7, 10, 
14, 21, 29, and 90 by treatment group. 
9.2.2 
Hepatic Safety 
The chemistry data will be evaluated for any cases of Hy’s Law or Drug Induced Liver Injury 
(DILI). These were defined as patients with ALT more than 3 X ULN, Total Bilirubin >2 X 
ULN with a normal Alkaline Phosphatase.  Table 14.3.2.6 summarizes these results.  
9.2.3 
Blood Hematology 
Similarly, Table 14.3.3.1 summarizes the values and changes from baseline for each of the 15 
tests included in the hematology panels at Screening, Day 1, Day 3, Day 7, Day 14, Day 29 by 
treatment group.   
Table 14.3.3.2 provides a shift table summarizing the numbers and percentages of patients 
going from a normal blood hematology value to a normal, low or high value at Day 7; going 
from a low baseline blood hematology value to normal, low or high at Day 7; and going from 
a high baseline blood hematology value to normal, low or high at Day 7.  The percentages 
presented in this table correspond to each baseline status. For example, one of the reported 
percentages will indicate the percentage of subjects that started with a normal value but ended 
with a high value. This will be done separately for each treatment group.  


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Table 14.3.3.3 provides the same information but for shifts to Day 14. 
9.3 Urinary Albumin/Creatine Ratio 
Table 14.3.4.1 summarizes urinary albumin/creatinine ratio at Screening, Day 1, Day 3, Day 7, Day 
14, Day 29 and Month 3 and changes in albumin/creatinine ratio. The measure is used to assess 
kidney injury and is a marker of CKD. 
9.4 Incidence of Chronic Kidney Disease (CKD) at Day 90 
Table 14.3.4.2 summarizes the incidence of chronic kidney disease (CKD) at Day 90 in the As 
Treated (Safety) Analysis Set by treatment group.  The definitions provided in Appendix 8 will be 
sued.  
9.5 Vital Signs 
Baseline height (cm), weight (kg), and BMI (kg/m2) are summarized for the As Treated (Safety) 
analysis set in the Demographics and Baseline Disease Characteristics, Table 14.1.2.2.  
The following vital sign variables are summarized by treatment group at screening and then at Days 
1, 2, 3, 7, 14, 21, and 28 in Table 14.3.5.1.  For follow-up visits, changes from screening are also 
summarized: Weight (kg), Temperature (Celsius), Systolic BP (mmHg), Diastolic BP (mmHg), 
MAP, Respiratory Rate (breaths/min), and Heart Rate (beats/min).   
9.6 Physical Examinations 
Results from physical examinations will be provided in the patient listings.    


ATB-203 SAP 
 
 
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10 Deviations from the Original Statistical Plan 
Any deviations from the original statistical plan will be described and justified in the final report. 
 


ATB-203 SAP 
 
 
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11 Appendix 1: Tables and Listing TOC 
Enrollment 
1 
14.1.1.1 Number of Patients by Site 
Screened and by Analysis Set 
2 
14.1.1.2 Numbers of Patients by Site, Treatment Group, and Analysis Set 
3 
14.1.1.3 Number of Patients by Site, Treatment Group, and Randomization Stratum 
Modified Intent-to-Treat (mITT) Analysis Set 
4 
14.1.1.4 Number of Patients by Site, Treatment Group, and Randomization Stratum 
As Treated (Safety) Analysis Set 
5 
14.1.1.5 Number of Patients by Site, Treatment Group, and Randomization Stratum 
Per Protocol (PP) Analysis Set 
Demographic and Baseline Characteristics 
6 
14.1.2.1 Demographics and Baseline Disease Characteristics 
Overall and By Treatment Group 
mITT (Randomized and Treated) Analysis Set 
7 
14.1.2.2 Demographics and Baseline Disease Characteristics 
Overall and By Treatment Group 
AT (Safety) Analysis Set 
8 
14.1.2.3 Demographics and Baseline Disease Characteristics 
Overall and By Treatment Group 
Per Protocol Analysis Set 
9 
14.1.2.4 Demographics and Baseline Disease Characteristics 
Overall and By Treatment Group 
Intent-to-Treat Analysis Set 
10 
14.1.3.1 Patients by Gender and Age Category 
Overall and by Treatment Group 
mITT (Randomized and Treated) Analysis Set 
11 
14.1.3.2 
Patients by Gender and Age Category 
Overall and by Treatment Group 
AT (Safety) Analysis Set 
12 
14.1.3.4 Patients by Gender and Age Category 
Overall and by Treatment Group 
Per Protocol Analysis Set 
Summary of Baseline Microbiology  
13 
14.1.3.5 Pathogen (genus / species) in Blood Culture and Tissue Samples in ITT (Randomized) Subjects 
Overall and By Treatment Group 
14 
14.1.3.6 Pathogen (genus / species) in  Blood Culture Specimens in ITT (Randomized) Subjects 
Overall and By Treatment Group 
15 
14.1.3.7 Pathogen (genus / species) in Intra-Abdominal Specimens in ITT (Randomized) Subjects 
Overall and By Treatment Group 


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Prior and Concomitant Medications 
16 
14.1.4.1 
Number (%) of Patients with Prior Non-Antimicrobial Medications or Non-Nephrotoxic Medications 
by Category and Specific Medication 
Overall and By Treatment Group 
As Treated (Safety) Analysis Set 
17 
14.1.4.2 
Number (%) of Patients with Prior Antimicrobial Medications 
by Category and Specific Medication 
Overall and By Treatment Group 
As Treated (Safety) Analysis Set 
20 
14.1.4.3 
Number (%) of Patients with Prior Nephrotoxic Medications 
by Category and Specific Medication 
Overall and By Treatment Group 
As Treated (Safety) Analysis Set 
18 
14.1.4.4 
Number (%) of Patients with Concomitant  Non-Antimicrobial Medications or Non-Nephrotoxic Medications 
by Category and Specific Medication 
By Treatment Group 
As Treated (Safety) Analysis Set 
19 
14.1.4.5 
Number (%) of Patients with Concomitant Antimicrobial Medications  
by Category and Specific Medication 
By Treatment Group 
As Treated (Safety) Analysis Set 
21 
14.1.4.6 
Number (%) of Patients with Concomitant Nephrotoxic Medications 
by Category and Specific Medication 
By Treatment Group 
As Treated (Safety) Analysis Set 
Medical History 
22 
14.1.5.1 
Number (%) of Patients Experiencing Prior Medical Conditions During Lifetime 
by Body System and Specific Medical Condition 
Overall and By Treatment Group 
As Treated (Safety) Analysis Set† 
23 
14.1.5.2 
Number (%) of Patients with Ongoing Medical Conditions 
by Body System and Specific Medical Condition 
Overall and Treatment Group 
As Treated (Safety) Analysis Set† 
24 
14.1.6.1 
 
Number (%) of Patients With Specific Abdominal Infection Presentation 
Overall and By Treatment Group 
As Treated (Safety) Analysis Set† 
25 
14.1.6.2 
 
Number (%) of Patients With Specific Type of Surgical or Interventional Procedure to Establish Source 
Control 
Overall and By Treatment Group 
As Treated (Safety) Analysis Set† 
26 
14.1.6.3  
 
Number (%) of Patients With AKI Presentation Status  
As Treated (Safety) Analysis Set† 


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Efficacy Analyses 
29 
14.2.1.1 
Numbers and Percentages of Subjects 
Achieving Freedom from Durable Loss of Renal Function and 
Improvement in Durable Loss of Renal Function at Day 28 Using LOCF 
mITT Analysis Set 
30 
14.2.1.2 
Numbers and Percentages of Subjects 
Achieving Freedom from Durable Loss of Renal Function and 
Improvement in Durable Loss of Renal Function at Day 28 Using LOCF 
AT Analysis Set 
31 
14.2.1.3 
Numbers and Percentages of Subjects 
Achieving Freedom from Durable Loss of Renal Function and 
Improvement in Durable Loss of Renal Function at Day 28 Using LOCF 
PP Analysis Set 
32 
14.2.1.4 
Site Variability in Primary Efficacy Endpoint in the mITT Analysis Set 
33 
14.2.2.1 
Numbers and Percentages of Subjects 
Achieving Secondary Freedom from or Improvement in Durable Loss 
of Renal Function Endpoints at Days 14, 28, and 90  
mITT Analysis Set 
34 
14.2.2.2 
Numbers and Percentages of Subjects 
Achieving Secondary Freedom from or Improvement in Durable Loss 
of Renal Function Endpoints at Days 14, 28, and 90  
AT (Safety) Analysis Set 
36 
14.2.2.3 
Numbers and Percentages of Subjects 
Achieving Secondary Freedom from or Improvement in Durable Loss 
of Renal Function Endpoints at Days 14, 28, and 90  
Per Protocol Analysis Set 
 
 
 
 
 
 
 
Drug Timing and Administration 
27 
14.1.7.1 
Drug Administration and Timing, Overall and By Treatment Group 
Patient Disposition 
28 
14.1.8.1 
Day 29 Study Status 
by Treatment Group 
 
 
 


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SOFA 
37 
14.2.4.1 
 
Modified SOFA Total Score, Organ Specific Scores, and SOFA Total Score  
At Screening, Day 1, Day 3, Day 7, and Day 14 
By Treatment Group 
Observed Cases 
mITT Analysis Set 
38 
14.2.4.2 
Modified SOFA Total Score and Organ Specific Scores Over Time to Day 14 
By Treatment Group 
Last Observation Carried Forward (LOCF) 
By Treatment Group 
mITT Analysis Set† 
39 
14..2.4.3 
Modified SOFA Total Score, Organ Specific Scores, and SOFA Total Score  
At Screening and Changes from Screening to Day 1, Day 3, Day 7, and Day 14 
By Treatment Group 
Observed Cases 
mITT Analysis Set† 
40 
14.2.4.4 
Modified SOFA Total Score, Organ Specific Scores, and SOFA Total Score  
At Screening and Changes from Screening to Day 1, Day 3, Day 7, and Day 14 
By Treatment Group 
Last Observation Carried Forward (LOCF) 
mITT Analysis Set† 
41 
14.2.4.5 
Resolution of Organ Dysfunction to Days 14  
Overall and by Individual Organ 
By Treatment Group 
mITT Analysis Set 
42 
14.2.4.6 
 
Resolution of Organ Dysfunction to Days 14  
Overall and by Individual Organ 
By Treatment Group 
mITT Analysis Set Among Subjects Presenting with Shock 
43 
14.2.4.7 
Resolution of Organ Dysfunction to Days 14  
Overall and by Individual Organ 
By Treatment Group 
PP Analysis Set 
44 
14.2.4.8 
 
Resolution of Organ Dysfunction to Days 14  
Overall and by Individual Organ 
By Treatment Group 
PP Analysis Set Among Subjects Presenting with Shock 
 
 
 
 
 
 


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Critical Care 
45 
14.2.5.1 
 
Critical Care and Hospital Stay Parameters Over Days 1 to 28 
By Treatment Group 
mITT Analysis Set† 
46 
14.2.5.2 
Hospital Discharge Status 
By Treatment Group 
mITT Analysis Set 
47 
14.2.5.3 
Hospital Readmissions 
By Treatment Group 
mITT Analysis Set 
48 
14.2.5.4 
Critical Care and Hospital Stay Parameters Over Days 1 to 28 
By Primary Effectiveness Endpoint* Success vs. Failure 
mITT Analysis Set 
49 
14.2.5.5 
Critical Care and Hospital Stay Parameters Over Days 1 to 28 
Comparing Subjects with Day 14 mSOFA≤1 to Day 14 mSOFA≥2 
mITT Analysis Set 
50 
14.2.5.6 
 
Critical Care and Hospital Stay Parameters Over Days 1 to 28 
By Treatment Group 
PP Analysis Set† 
51 
14.2.5.7 
 
Critical Care and Hospital Stay Parameters Over Days 1 to 28 
By Treatment Group 
mITT Analysis Set† Alive at Day 14 
52 
14.2.5.8 
 
Critical Care and Hospital Stay Parameters Over Days 1 to 28 
By Treatment Group 
PP Analysis Set Alive at Day 14† 
 
 
 


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Survival and Time-to-Event Analyses 
53 
14.2.6.1 
Life Table Analysis to Day 90 
Mortality – Reltecimod 0.5 mg/kg 
mITT Analysis Set 
54 
14.2.6.2 
Life Table Analysis to Day 90 
Mortality – Placebo 
mITT Analysis Set 
55 
14.2.6.3 
Life Table Analysis to Day 90 
Mortality – Subjects with Freedom from Durable Loss of Renal Function at Day 28 
mITT Analysis Set – Reltecimod 0.5 mg/kg 
56 
14.2.6.4 
Life Table Analysis to Day 90 
Mortality – Subjects with Freedom from Durable Loss of Renal Function at Day 28 
mITT Analysis Set – Placebo 
57 
14.2.6.5 
Life Table Analysis to Day 90 
Mortality – Subjects with Freedom from Durable Loss of Renal Function at Day 28 
mITT Analysis Set – All  
58 
14.2.6.6 
Life Table Analysis to Day 90 
Mortality – Reltecimod 0.5 mg/kg 
PP Analysis Set 
59 
14.2.6.7 
Life Table Analysis to Day 90 
Mortality – Placebo 
PP Analysis Set 
60 
14.2.6.8 
Life Table Analysis to Day 90 
Mortality – Reltecimod 0.5 mg/kg  
mITT Analysis Set in Subjects Presenting with Shock 
61 
14.2.6.8 
Life Table Analysis to Day 90 
Mortality - Placebo 
mITT Analysis Set in Subjects Presenting with Shock 
62 
14.2.6.8 
Life Table Analysis to Day 90 
Mortality – Day 14 mSOFA ≤ 1 
mITT Analysis Set 
63 
14.2.6.8 
Life Table Analysis to Day 90 
Mortality – Day 14 mSOFA ≥ 2  
mITT Analysis Set 
 
 
 
 
 
C-Reactive Protein 
64 
4.2.7.1 
C-Reactive Protein at Screening and at Days 7, 14, and 29 
and Changes from Screening  
by Treatment Group 
mITT Analysis Set† 
 
 
 
 
 
 
 
 


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Adverse Events 
65 
14.3.1.1 
Summary of Treatment-Emergent Adverse Events (TEAEs) 
By Treatment Group 
As Treated (Safety) Analysis Set† 
66 
14.3.1.2 
Incidence Rates (%) and Event Counts of TEAEs 
by System Organ Class and Preferred Term 
By Treatment Group 
As Treated (Safety) Analysis Set† 
67 
14.3.1.3 
Incidence Rates (%) and Event Counts of TEAEs 
Sorted by Descending Incidence of Preferred Term  
As Treated (Safety) Analysis Set† 
68 
14.3.1.4 
Incidence Rates (%) and Event Counts of Drug-Related* TEAEs 
by System Organ Class and Preferred Term 
As Treated (Safety) Analysis Set† 
69 
14.3.1.5 
Incidence Rates (%) and Event Counts of Serious TEAEs 
by System Organ Class and Preferred Term 
As Treated (Safety) Analysis Set† 
70 
14.3.1.6 
Incidence Rates (%) and Events Counts of Serious TEAEs 
Sorted by Descending Incidence of Preferred Term in Subjects Receiving Reltecimod 
As Treated (Safety) Analysis Set† 
71 
14.3.1.7 
Incidence Rates (%) and Events Counts of Serious Drug-Related* TEAEs 
by System Organ Class and Preferred Term 
As Treated (Safety) Analysis Set† 
71 
14.3.1.8 
Incidence Rates (%) and Events Counts of Severe TEAEs 
by System Organ Class and Preferred Term 
As Treated (Safety) Analysis Set† 
72 
14.3.1.9 
Incidence Rates (%) and Events Counts of Severe TEAEs 
Sorted by Descending Incidence of Preferred Term in Subjects Receiving Reltecimod 
As Treated (Safety) Analysis Set† 
73 
14.3.1.10 
Counts of Drug-Related* TEAEs 
by Severity, System Organ Class, and Preferred Term 
Reltecimod 0.5 mg/kg 
As Treated (Safety) Analysis Set† 
74 
14.3.1.11 
Counts of Drug-Related* TEAEs 
by Severity, System Organ Class, and Preferred Term 
Placebo 
As Treated (Safety) Analysis Set† 
 
 
 


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Laboratory Data  
75 
14.3.2.1 
Screening, Day 7, Day 14, and Changes from Screening 
Blood Chemistry 
by Treatment Group 
As Treated (Safety) Analysis Set† 
76 
14.3.2.2 
Blood Chemistry Panel Shift Tables Summarizing Changes in Test Status 
from Screening (Baseline) to Day 7 or Early Discontinuation 
As Treated (Safety) Analysis Set† 
77 
14.3.2.3 
Blood Chemistry Panel Shift Tables Summarizing Changes in Test Status 
from Screening (Baseline) to Day 14 or Early Discontinuation 
As Treated (Safety) Analysis Set† 
78 
14.3.2.4 
Blood Chemistry Frequencies By Visit With Respect To 
Normal Ranges and Critical Values 
by Treatment Group 
As Treated (Safety) Analysis Set† 
79 
14.3.2.5 
Creatinine Values at Screening and at  Days 1, 2, 3, 7, 10, 14, 21, 29, and 90 
by Treatment Group 
As Treated (Safety) Analysis Set† 
80 
14.3.2.6 
Summary of Potential Drug Induced Liver Injury (DILI) 
By Treatment Group 
As Treated (Safety) Analysis Set† 
81 
14.3.3.1 
Screening, Days 1, 2, 3, 7 and 14, and Changes from Screening 
Blood Hematology 
by Treatment Group 
As Treated (Safety) Analysis Set† 
82 
14.3.3.2 
Blood Hematology Panel Shift Tables Summarizing Changes in Test Status from Screening 
(Baseline) to Day 7 Early Discontinuation 
83 
14.3.3.3 
Blood Hematology Panel Shift Tables Summarizing Changes in Test Status from Screening 
(Baseline) to Day 14 Early Discontinuation 
84 
14.3.3.4 
Blood Hematology Frequencies by Visit with Respect to Normal Ranges and Critical Values 
by Treatment Group 
As Treated (Safety) Analysis Set 


ATB-203 SAP 
 
 
51 
 
 
 
 
 
85 
14.3.4.1 
Screening, Days 1, 3, 7, 14, 29 and 29 and Changes from Screening 
Urinary albumin/creatinine ratio  
by Treatment Group 
As Treated (Safety) Analysis Set† 
86 
14.3.4.2 
Incidence of chronic kidney disease (CKD) at Day 90  
by Treatment Group 
As Treated (Safety) Analysis Set† 
 
 
 
 
 
Vital Signs 
87 
14.3.5.1 
Vital Signs at Screening, Day 1, Day 2, Day 3, Day 7, Day 14, Day 21, Day 29 
and Changes from Screening 
By Treatment Group 
As Treated (Safety) Analysis Set† 
 


ATB-203 SAP 
 
 
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12 Appendix 2: AE Listings 
 
 
 
AE Listings 
1 
16.2.7.1 
All TEAEs Sorted by Specific AE 
by Treatment Group, Sorted by SOC and PT 
As Treated (Safety) Analysis Set 
2 
16.2.7.2 
All TEAEs Sorted by Specific AE 
by Treatment Group, Sorted by Patient ID and Onset 
As Treated (Safety) Analysis Set 
3 
16.2.7.3 
Drug-Related TEAEs Sorted by Specific AE 
by Treatment Group, Sorted by SOC and PT 
As Treated (Safety) Analysis Set 
4 
16.2.7.4 
Serious TEAEs Sorted by Specific AE + 
by Treatment Group, Sorted by SOC and PT 
As Treated (Safety) Analysis Set 
5 
16.2.7.5 
Serious Drug-Related TEAEs Sorted by Specific AE 
by Treatment Group, Sorted by SOC and PT 
As Treated (Safety) Analysis Set 
6 
16.2.7.6 
All TEAEs with Outcome of Death Sorted by Specific AE 
by Treatment Group, Sorted by SOC and PT 
As Treated (Safety) Analysis Set 
7 
16.2.7.7 
All TEAEs with Outcome of Drug-Related Death Sorted by Specific AE 
by Treatment Group, Sorted by SOC and PT 
As Treated (Safety) Analysis Set 
8 
16.2.7.8 
All TEAEs with Outcome of Study Drug Discontinuation  
Sorted by Treatment Group, SOC, and PT 
As Treated (Safety) Analysis Set 
9 
16.2.7.9 
All TEAEs with Outcome of Discontinuation from Study 
Sorted by Treatment Group, SOC, and PT 
As Treated (Safety) Analysis Set 
10 
16.2.7.10 
Day 0 AE’s Sorted by SOC and PT 
As Treated (Safety) Analysis Set 
 
 
 


ATB-203 SAP 
 
 
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13 Appendix 3: Patient Listings 
 
 
Patient Listings 
 
16.2.8.1 
Form: Randomization and Administration 
 
16.2.8.2 
Form: Demographics 
 
16.2.8.3 
Form: Abdominal Sepsis 
 
16.2.8.4 
Form: Abdominal Sepsis Information 
 
16.2.8.5 
Form: Primary Infection Site Assessment 
 
16.2.8.6 
Form: Initial Source Control 
 
16.2.8.7 
Form: Follow-Up Source Control 
 
16.2.8.8 
Form Acute Kidney Injury 
 
16.2.8.9 
Form: Inclusion/Exclusion 
 
16.2.8.10 
Form: Ventilator Assistance Screening 
 
16.2.8.11 
Form: Ventilator Assistance Log 
 
16.2.8.12 
Form: Medical History 
 
16.2.8.13 
Form: Vital Signs 
 
16.2.8.14 
Form: Physical Exam 
 
16.2.8.15 
Form: Fluid Balance 
 
16.2.8.16 
Form: Urine Output Screening 
 
16.2.8.17 
Form: Urine Output Log 
 
16.2.8.18 
Form: Baseline Signs and Symptoms 
 
16.2.8.19 
Form: Chemistry 
 
16.2.8.20 
Form: Hematology 
 
16.2.8.21 
Form: Spot Urine Albumin/Creatinine 
 
16.2.8.22 
Form: C-Reactive Protein 
 
16.2.8.23 
Form: Blood Culture 
 
16.2.8.24 
Form: Pregnancy Test 
 
16.2.8.25 
Form: Glasgow Coma Score 
 
16.2.8.26 
Form: SOFA 
 
16.2.8.27 
Form: APACHE II 
 
16.2.8.28 
Form: Abdominal Sample Microbiology 
 
16.2.8.29 
Form: Drug Randomization and Administration 
 
16.2.8.30 
Form: Vital Signs 


ATB-203 SAP 
 
 
54 
 
 
16.2.8.31 
Form: Physical Exam 
 
16.2.8.32 
Form: Fluid Balance 
 
16.2.8.34 
Form: Chemistry Bilirubin and Creatinine 
 
16.2.8.35 
Form: Adequacy of Microbial Treatment 
 
16.2.8.36 
Form: Renal Replacement Therapy 
 
16.2.8.37 
Form: ICU Admittance 
 
16.2.8.38 
Form: ICU Admission / Discharge 
 
16.2.8.39 
Form: Hospital Readmission 
 
16.2.8.40 
Form: End of Study/Early Discontinuation 
 
16.2.8.41 
Form: Death Form 
 
16.2.8.42 
Form: Hospital Length of Stay 
 
16.2.8.43 
Form: Prior and Concomitant Medications 
 
16.2.8.44 
Form: Prior and Concomitant Antimicrobial, Immunosuppressant, and Nephrotoxic Medications 
 
16.2.8.45 
Form: Month 3 Visit Status 
 
 


14 Appendix 5: Study Visits and Procedures 
 
Visit 
1 
Screeninga 
2 
Day 1 
3 
Day 
2 
4 
Day 
3 
5 
Day 
7 
±1 
day 
6 
Day 
10 
±1 
day 
7 
Day 14  
±1 days 
8 
Day 
21 
±1 
days 
9 
Day 
29 
+3 
days 
10 
3 
months 
±5 
days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Concomitant 
Medicationsb 
 
 
Weight & Heightc 
X 
 
 
 
X 
 
X 
 
X 
 
Fluid Balance 
(input/output) 
 
 
 
 
 
 
Detailed Urine 
Outputd 
 
 
 
 
 
 
Vital Signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical 
Examination (PE) 
X 
 
 
 
X 
 
X 
 
 
 
Interim PE 
(symptom-driven) 
 
X 
 
X 
 
X 
 
 
 
 
Baseline Signs & 
Symptomsf 
X 
 
 
 
 
 
 
 
 
 
 
a Screening period can be 48 hours after suspected diagnosis of abdominal sepsis 
b See Section Error! Reference source not found. for instruction on level of detailed information required for recording 
concomitant medications 
c Height will be taken only at screening or first time that patient height can be measured 
d Urine output is required for Days 1-7 (while the patient is in the ICU or step-down unit (or equivalent); patients on a general 
ward only monitor urine output if a Foley catheter is in place as part of standard of care) to assess for development or 
resolution of acute kidney injury 
e Systolic & diastolic blood pressure, mean arterial pressure, heart rate, respiration rate, temperature; (first set of vitals on that 
visit day) 
f Adverse events reported from ICF signature to Reltecimod administration 


ATB-203 SAP 
 
 
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Visit 
1 
Screeninga 
2 
Day 1 
3 
Day 
2 
4 
Day 
3 
5 
Day 
7 
±1 
day 
6 
Day 
10 
±1 
day 
7 
Day 14  
±1 days 
8 
Day 
21 
±1 
days 
9 
Day 
29 
+3 
days 
10 
3 
months 
±5 
days 
Blood Chemistryg 
Xh 
Xi 
Xj 
Xi 
X 
Xj 
X 
Xj 
Xk 
Xj 
Spot Urine 
Albumin/ 
Creatininel  
X 
X 
 
X 
X 
 
X 
 
X 
X 
Standard C-
Reactive Proteinm 
X 
 
 
 
X 
 
X 
 
X 
 
Blood 
Hematologyn 
X 
X 
 
X 
X 
 
X 
 
X 
 
Pregnancy 
Test 
(if applicable)o 
X 
 
 
 
 
 
 
 
 
 
Serum for 
Immunogenicityp 
X 
 
 
 
 
 
X 
 
X 
X 
Urine and Plasma 
for Storageq 
X 
 
X 
 
X 
 
 
 
 
 
 
Systemic 
Inflammatory    
Biomarkers  
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
g Glucose; Electrolytes - Sodium, Potassium, Calcium; Phosphorus, Chloride, Bicarbonate; Renal function tests – Urea/BUN, 
Creatinine; Liver function tests – Albumin, Bilirubin Total, Alanine transaminase (ALT), Aspartate transaminase (AST), 
Alkaline phosphatase (ALP), Protein Total. In case of abnormal results at the end of the study the results should be 
followed by the investigator until the abnormalities are resolved or determined as stabilized 
h If AKI diagnosis not established at time of initial evaluation for abdominal sepsis, then obtain creatinine every 6 hours for 
up to 48 hours after suspected or confirmed diagnosis of abdominal sepsis to identify development of AKI 
i Only creatinine and bilirubin 
j Only creatinine 
k Creatinine and albumin only 
l Obtain urine specimen for spot albumin/creatinine ratio. First morning void is preferred 
m Use standard CRP test (do not use cardiac or high-sensitivity CRP) 
n Complete blood count including platelet count and white blood cell differential 
o Preferably the fastest pregnancy test method (urine or blood) 
p 6 mL blood for serum for storage (for immunogenicity testing) at screening, Days14 and 29, and Month 3 
q Obtain 5 ml urine and 5 ml blood for plasma for storage for AKI biomarker analysis. Second sample to be collected 24±6 
hours (Day 2) after study medication administration. Final sample to be obtained at Day 7 


ATB-203 SAP 
 
 
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Visit 
1 
Screeninga 
2 
Day 1 
3 
Day 
2 
4 
Day 
3 
5 
Day 
7 
±1 
day 
6 
Day 
10 
±1 
day 
7 
Day 14  
±1 days 
8 
Day 
21 
±1 
days 
9 
Day 
29 
+3 
days 
10 
3 
months 
±5 
days 
• RNAr 
• Cytokines / 
Chemokiness 
X 
X 
X 
X 
Arterial Blood 
Gases (if 
applicable) 
X 
X 
 
X 
X 
 
X 
 
 
 
SpO2 and FiO2 
(if arterial blood 
gases not 
indicated or 
unable to obtain) 
X 
X 
 
X 
X 
 
X 
 
 
 
Peritoneal Fluid, 
Tissue or Abscess 
Fluid for 
Microbiology 
X 
 
 
 
 
 
 
 
 
Inclusion & 
Exclusiont 
X 
 
 
 
 
 
 
 
 
 
Randomization  
X 
 
 
 
 
 
 
 
 
 
Reltecimod / 
Placebo 
Administration  
 
X 
 
 
 
 
 
 
 
 
Blood Cultureu 
X 
 
 
 
 
 
 
 
 
 
 
r 5 ml (2 x 2.5 mL) of whole blood to be collected at screening, Day 1 at 4 to 6 hours post-dose, Day 2 at 24 +4 hours post 
dose, Day 3 at 48 hours +4 hours post-dose, and Day 4 72 +4 hours post dose.  Complete blood count with white blood cell 
differential to be obtained at same time of whole blood for genomic profile sample 
s Systemic Biomarkers will be taken at screening, 4 to 6 hours, 24±4, 48±4 and 72±4 hours post drug administration; However, if 
practical consideration allow collection of fewer plasma samples, this will not be considered a protocol deviation.  Systemic blood 
inflammatory biomarkers will include serum cytokines or chemokines such as (but not limited to): IL-6, IL-8, INF-γ, TNF-α, IL-
17A, IL-3 and RANTES. 
t Should be verified twice: a full list of criteria will be verified once before instructing the pharmacist to prepare study drug 
and a second time immediately before study drug administration according to a partial list to include verification that 6 
hours has not elapsed from time to study drug administration 


ATB-203 SAP 
 
 
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Visit 
1 
Screeninga 
2 
Day 1 
3 
Day 
2 
4 
Day 
3 
5 
Day 
7 
±1 
day 
6 
Day 
10 
±1 
day 
7 
Day 14  
±1 days 
8 
Day 
21 
±1 
days 
9 
Day 
29 
+3 
days 
10 
3 
months 
±5 
days 
Adverse Events / 
Serious Adverse 
Eventsv 
w 
 
 
Collect Data on 
Acute Renal 
Replacement 
Therapy 
 
 
Record any 
Follow-up 
Surgical or 
Interventional 
Radiologic 
Procedures for 
Previously 
Documented 
Abdominal 
Infection 
 
X 
X 
X 
X 
X 
X 
 
 
 
Evaluation of 
Adequacy of 
Antimicrobial 
Treatment 
 
 
 
X 
 
 
 
 
 
 
Critical Care and 
Hospital Stay 
Parametersx 
 
 
SOFA Scorey 
X 
Xz 
 
X 
X 
 
X 
 
 
 
 
u Blood culture for both aerobic and anaerobic bacteria will be repeated during the study in case of new systemic infection 
suspicion 
v Adverse events including SAEs will be collected from obtaining ICF through day 28; AEs that are not resolved should be 
followed-up until resolution or until determined as stable and due to known cause 
w AEs of Day 0 are baseline AEs (not TEAE) starting after obtaining ICF until study drug administration 
x Hospital length of stay (days), ICU stay (days), ICU free days, mechanical ventilation days/mechanical ventilation free days 
y Screening SOFA: To include measurements of 6 organ system: cardiovascular, respiratory, renal, coagulation, GI/hepatic 
and CNS (To include evaluation of oxygenation either directly by arterial blood gas test or by calculation of PaO2 from 
SpO2, in case it is not possible to obtain arterial blood to determine the SOFA respiratory parameter) 


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Visit 
1 
Screeninga 
2 
Day 1 
3 
Day 
2 
4 
Day 
3 
5 
Day 
7 
±1 
day 
6 
Day 
10 
±1 
day 
7 
Day 14  
±1 days 
8 
Day 
21 
±1 
days 
9 
Day 
29 
+3 
days 
10 
3 
months 
±5 
days 
APACHE II 
Scoreaa 
X 
 
 
 
 
 
 
 
 
 
Survival 
 
Hospital 
Readmissions 
 
 
 
 
 
 
 
 
X 
Xbb 
 
 
 
 
z Subsequent SOFA measurement (Days 1, 3, 7, and 14): taken once a day, in the morning adjusted to the time of normal 
routine assessment activities. To be calculated retrospectively. The following blood samples must be taken: CBC with 
platelet count, serum creatinine and bilirubin. In addition, clinical parameters should be evaluated and recorded (see 
Section Error! Reference source not found.) 
aa For the required laboratory and clinical parameters (see Section Error! Reference source not found. of the protocol) 
bb Capture data on any readmissions within 30 days of original hospital discharge 


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15 Appendix 6:  Clinical Score Calculations 
 
15.1 AKI Staging (KDIGO Criteria) 
The following is provided in the Clinical Trial Protocol and is repeated here for convenience.  
 
Stage 
Serum Creatinine 
Urine Output 
 
1 
1.5-1.9 times baseline 
 
OR 
 
≥0.3 mg/dL increase 
 
< 0.5 mL/kg/h for 6 h 
 
2 
2-2.9 times baseline 
< 0.5 mL/kg/h for 12 h 
 
 
3 
3 times baseline 
 
OR 
 
Increase in serum creatinine to ≥4 mg/dL 
 
OR 
 
Initiation of renal replacement therapy 
 
 
< 0.3 mL/kg/h for 24 h 
 
OR 
 
Anuria for ≥12 h 
 


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15.2 Twice the Serum Creatinine for Age, Race, and Gender 
The following is provided in the Clinical Trial Protocol and is repeated here for convenience.  
 
Age 
(years) 
Black Males 
mg/dL 
(µmol/L) 
Other Males 
mg/dL 
(µmol/L) 
Black Females 
mg/dL 
(µmol/L) 
Other Females 
mg/dL 
(µmol/L) 
20 – 24 
3.0 
(266) 
2.6 
(230) 
2.4 
(212) 
2.0 
(166) 
25 – 29 
3.0 
(266) 
2.4 
(212) 
2.2 
(194) 
2.0 
(166) 
30 – 39 
2.8 
(248) 
2.4 
(212) 
2.2 
(194) 
1.8 
(160) 
40 – 54 
2.6 
(230) 
2.2 
(194) 
2.0 
(176) 
1.8 
(160) 
55 – 65 
2.6 
(230) 
2.2 
(194) 
2.0 
(176) 
1.6 
(142) 
>65 
2.4 
(212) 
2.0 
(166) 
1.8 
(160) 
1.6 
(142) 
 
 


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15.3 SOFA – Sequential Organ Failure Assessment Score 
The following is provided in the Clinical Trial Protocol and is repeated here for convenience.  
Can range from 0-24. 
 
1. For patients on supplemental oxygen via nasal cannula, nasopharyngeal catheter or mask and for converting SpO2 values 
to PaO2 use the attached oxygen conversion tables. 
2. Doses of dopamine (Dopa), epinephrine (Epi), norepinephrine (NE) are in micrograms/kg/min; phenylephrine (PE) is 
micrograms/min; vasopressin (VP) is U/min. Vasopressors must have been administered for at least one hour. 
 
Value 
0 
1 
2 
3 
4 
 
>400 
≤400 
≤300 
≤200 
with respiratory 
support 
≤100 
with respiratory 
support 
Respiratory 
PaO2/FiO21 
Coagulation 
Platelets 
>150 
≤150 
≤100 
≤50 
≤20 
GI 
Total Bilirubin 
<1.2 
1.2-1.9 
2.0-5.9 
6.0-11.9 
≥12.0 
Cardiovascular2 
No hypo- 
tension 
MAP 
<70 
Dopa ≤5 
PE <100 
Dopa > 5 
Epi ≤ 0.1 
NE ≤ 0.1 
PE 100- 
300 
Dopa>15 Epi>0.1 
NE>0.1 PE>300 
VP>0.01 
Neurology 
GCS 
15 
13-14 
10-12 
6-9 
<6 
Serum 
Creatinine 
OR 
Urine Output 
<1.2 
1.2-1.9 
2.0-3.4 
3.5-4.9 
 
<500cc/ day 
≥5.0 
 
<200cc/ day 


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16 Appendix 7:  Prior and Concomitant Medications 
16.1 Nephrotoxic Medications 
• Acetaminophen 
• Acetylsalicylic Acid 
• Allopurinol 
• Benazepriol 
• Captopril 
• Celecoxib 
• Enalapril 
• Esmoprazole 
• Famotidine 
• Furosemide 
• Hydrochlorothiazide 
• Ibuprofen 
• Iodixanol 
• Iohexol 
• Iopamidol 
• Irbesartan 
• Ketorolac 
• Lansoprazole 
• Lisiopril 
• Losartan 
• Metolazone 
• Omeprazole 
• Pantoprazole 
• Perflutren 
• Ramipril 
• Ranitidine 
• Sodium Amiotrizoate 
• Technetium (99 M) Mebrofenin 
• Valsartan 
• Zesoretic 
16.2 Immunosuppresant Medications 
• Corticosteroids 
o Prednisone >40 mg/day 
o Hydrocortisone 160 mg/day 
o Methylprednisolone >32 mg 
o Dexamethasone >6 mg 
o Cortisone >200 mg 
o Betamethasone >4.8 mg 


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• Methotrexate 
• Leflunomide (Arava) / Teriflunomide (Aubagio) 
• Cyclophosphamide (Cytoxan) 
• Cyclosporine A 
• FK506 (Tacrolimus) 
• Azathioprine 
• Mycophenolate Mofetil (MMF) (CellCept) 
• Sirolimus (Rapamycin, Rapamune) 
• Everolimus (Certican) 
• Temsirolimus (Torisel) 
• Gusperimus 
• Thalidomide 
• Antitumor Necrosis Factor (TNF) Agents 
o Entanercept (Enbrel) 
o Afelimomab (Fab 2) 
o Infliximab (Remicade) 
o Certolizumab (Cimzia) 
o Golimumab (Simponi) 
• Interleukin-1 Receptor Antagonist (IL-1RA) 
o Kineret 
• CTLA-4 Fusion Protein 
o Abatacept (Orencia) 
o Alefacept (Amevive) 
o Belatacept (Nulojix) 
• Anti-CD20 
o Rituximab (Rituxan/MabThera) 
o Obintuzumab (Gazyva) 
o Ocrelizumab (Ocrevus) 
o Ofatumumab (Arzerra) 
• Anti-CD52 
o Alemtuzumab (Campath) 
• Anti-IL2 


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o Daclizumab (Anti-Tac, Zenapax) 
o Basiliximab (Simulect) 
• Anti-IL6 
o Tocilizumab (Actemra/RoActemra) 
• Anti-BAFF (B-cell activating factor) 
o Belimumab 
• Integrin Inhibitor 
o Natalizumab (Tysarbi) 
• Anti-CTLA 4 
o Ipilimumab 
• Other Interleukins 
o Aldesleukin (Proleukin) 
o Canakinumab (ilaris) 
o Oprelvekin (Neumega) 
• Anti-PDL1 
o Avelumab (Bavencio) 
• Other Selective Immunosuppressants 
o Muromonab or OKT-3 
o Efalizumab (Raptiva): Anti-CD11a 
o Fingolimod (Gilenya): Spingosine 1-phosphate receptor modulator 
o Eculizumab (Soliris): Anti-complement protein C5 
o Tofacitinib (Xeljanz): JAK-Stat Inhibitor 
o Apremilast (Otezla): PDE-4 Inhibitor 
o Vedolizumab (Entyvio): Integrin α4β7 


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17 Appendix 8: CKD Definition and Classification 
17.1 CKD Definition:  
A patient is said to have chronic kidney disease (CKD) if they have abnormalities of kidney function 
or structure present for more than 3 months. The definition of CKD includes all individuals with 
markers of kidney damage (see below*) or those with an eGFR of less than 60 ml/min/1.73m2 on at 
least 2 occasions 90 days apart (with or without markers of kidney damage). 
*Markers of kidney disease may include: albuminuria (ACR > 3 mg/mmol), haematuria (or 
presumed or confirmed renal origin), electrolyte abnormalities due to tubular disorders, renal 
histological abnormalities, structural abnormalities detected by imaging (e.g. polycystic kidneys, 
reflux nephropathy) or a history of kidney transplantation. 
17.2 CKD Classification 
CKD is classified based on the eGFR and the level of proteinuria and helps to risk stratify 
patients.Patients are classified as G1-G5, based on the eGFR, and A1-A3 based on the ACR 
(albumin:creatinine ratio) as detailed below:  


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