Clinical trial NCT02469857
Conditions: Necrotizing Soft Tissue Infections Necrotizing Fasciitis Fournier's Gangrene
Keywords: AB103 Necrotizing fasciitis
Sponsor: Atox Bio Ltd
Start date: 2015-12-01; Completion date: 2019-10-18
Enrollment: 290 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether AB103 is safe and effective in the treatment of patients with necrotizing soft tissue infections (NSTI) receiving standard of care therapy.

Detailed description:
The primary hypothesis of this study is that in addition to standard of care treatment (which includes surgical intervention, antimicrobial therapy and critical care support for organ dysfunction or failure), AB103 will demonstrate a clinically significant treatment benefit over placebo.

This hypothesis will be addressed by measuring the effect of AB103 on a composite of clinical parameters associated with the disease course of patients with NSTI, using a responder analysis. A responding patient must meet all 5 parameters of the composite clinical success end point, while a non-responding patient can fail by not meeting any one of the parameters. These analyses are designed to demonstrate that in addition to being safe, one dose of 0.5 mg/kg of AB103 will:

Improve systemic signs of the infection by improving organ function of patients compared to placebo as measured by:

* Survival at Day 28
* Modified SOFA (mSOFA) score on Day 14 and change from baseline to Day 14 ≥ 3. A Day 14 mSOFA score of ≤1 and a change from baseline (pre-treatment) to Day 14 ≥3 will be required for a patient to achieve the primary composite clinical success endpoint (NICCE)

Improve the local signs of the infection, as measured by:

* Reduced number of debridements, counted to Day 14. No more than 3 debridements to Day 14 will be required for a patient to achieve composite clinical success
* No amputation after the first debridement (amputation on the first debridement is not considered a failure). A patient will be required to have had no amputations done after the first surgical procedure in order to achieve composite clinical success.

  290 patients will be recruited into the study and randomized to receive either 0.5 mg/kg AB103 or placebo in a 1:1 ratio. Randomization will be stratified within center by the diagnosis of Fournier's Gangrene and mSOFA score category (3-4 vs \>4) at screening. The study will be conducted with interim analyses for futility at 100 patients and safety monitored by an independent Data Monitoring Board at regular planned intervals.

Arms: arm 1: AB103 0.5 mg/kg, IV, single dose arm 2: NaCl 0.9%, IV, single dose
Interventions: intervention 1: AB103 0.5 mg/kg intervention 2: NaCl 0.9%
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
Final Protocol ATB-202 version 4.0 
23 Aug 2018 
 
Page 1 of 111 
 
 
CLINICAL STUDY PROTOCOL 
PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, PARALLEL-GROUP, STUDY OF AB103 AS 
COMPARED TO PLACEBO IN PATIENTS WITH NECROTIZING 
SOFT TISSUE INFECTIONS (NSTI) 
Product: AB103 
 
Protocol Number: ATB-202 
Study Title: ACCUTE (AB103 Clinical Composite Endpoint Study in Necrotizing Soft 
Tissue Infections) 
Development Phase: Phase 3 
IND Number: 67,785 
SPONSOR:  
Atox Bio Ltd. 
8 Pinhas Sapir St. 
Weizmann Science Park 
Ness Ziona, 7403631 
Israel 
Protocol Approval Date: 
Current protocol Version No./Date: Final Version/29 May 2015 
Current protocol Version No./Date: Final Version 2.0/08 Nov 2016 
Current protocol Version No/Date: Final Version 3.0-France/05 Jun 2018 
Current protocol Version No./Date: Final Version 4.0/23 Aug 2018 
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. 


Final Protocol A TB-202 version 4.0 
23 Aug20l8 
Signature Page 
The signature below constitutes approval of this protocol by the signatory on behalf of Atox 
Bio, Ltd. 
Atox Bio, Ltd (the Atox Bio) agrees that it will arrange for the supply of the clinical study 
drug (investigational medicinal products [IMP]) described in this protocol and undertakes 
to report adverse events to the relevant authorities in compliance with the regulations. It 
further agrees to inform the Investigators of any information that would place the patients 
at risk by their continuing participation in the study. 
Sponsor Representatives 
Anat Shirvan, PhD 
VP Research and Development 
AtoxBio Ltd 
Principal Biostatistician 
Biomedical Statistical Consulting 
r.{}_31fU62oik 
Date 
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AvaVit JJ 1.2012 
Date 
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Page2 oflll 


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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT ................................................................................................. 7 
PROTOCOL SYNOPSIS .............................................................................................................. 10 
ABBREVIATIONS ....................................................................................................................... 23 
1. 
INTRODUCTION .............................................................................................................. 26 
1.1 
Background Information ........................................................................................... 26 
1.1.1 
Necrotizing Soft Tissue Infections (NSTI) ................................................. 26 
1.1.2 
Indication .................................................................................................... 28 
1.1.3 
Investigational Medicinal Product .............................................................. 28 
1.1.3.1 Mechanism of action ................................................................... 28 
1.1.3.2 Non-clinical studies..................................................................... 30 
1.1.3.3 Clinical studies ............................................................................ 32 
1.2 
Risks and Benefit ...................................................................................................... 36 
1.3 
Study Treatment ........................................................................................................ 37 
1.4 
Compliance Statement............................................................................................... 37 
1.5 
Study Population ....................................................................................................... 37 
2. 
STUDY OBJECTIVES ...................................................................................................... 38 
2.1 
Primary Objective ..................................................................................................... 38 
2.2 
Secondary Objectives: ............................................................................................... 38 
2.3 
Exploratory Objectives:............................................................................................. 39 
2.4 
Study Hypothesis ...................................................................................................... 40 
3. 
SELECTION OF STUDY POPULATION ...................................................................... 41 
3.1 
Inclusion Criteria ....................................................................................................... 41 
3.2 
Exclusion Criteria ...................................................................................................... 42 
3.3 
Withdrawal ................................................................................................................ 43 
3.3.1 
Criteria for Premature Discontinuation from Study ................................... 43 
4. 
INVESTIGATIONAL PLAN ............................................................................................ 44 
4.1 
Study Rationale ......................................................................................................... 44 
4.1.1 
Dose Selection Rationale ............................................................................ 44 
4.2 
Allocation of Treatment, Randomization and Study Drug Administration ............... 45 
4.2.1 
Allocation of Treatment and Randomization ............................................. 45 
4.2.2 
Study Drug Administration ........................................................................ 45 
4.3 
Schedule of Procedures/Visits ................................................................................... 45 
4.3.1 
Visit 1: Screening ....................................................................................... 45 
4.3.2 
Visit 2 (Day 1) ............................................................................................ 47 
4.3.3 
Visit 3 (Day 2) ............................................................................................ 48 
4.3.4 
Visit 4 (Day 3) ............................................................................................ 48 
4.3.5 
Visit 5 (Day7 [±1 day]) .............................................................................. 49 
4.3.6 
Visit 6 (Day 10 [±1 day]; perform only if patient is still hospitalized): ..... 50 
4.3.7 
Visit 7 (Day 14 [±1 day]) ........................................................................... 50 
4.3.8 
Visit 8 (Day 21 [±1 day]) ........................................................................... 51 
4.3.9 
Visit 9 (Day 29 [+2 days]) .......................................................................... 52 
4.3.10 
Visit 10 (3 months [±5 days]) ..................................................................... 52 
4.3.11 
Follow-up of Patients ................................................................................. 52 
4.4 
Sub-study mSOFA = 2 .............................................................................................. 53 
4.4.1 
Screening Visit for patients with mSOFA =2 ............................................. 53 
4.4.2 
Day 7 or Day 10 Visit [±1 day] .................................................................. 53 


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4.4.3 
Day 14 Visit [±1 day] ................................................................................. 54 
4.4.4 
Day 29 Visit [+2 days] (via phone if patient no longer hospitalized) ......... 54 
5. 
TREATMENT OF PATIENTS ......................................................................................... 55 
5.1 
Investigational Medicinal Product ............................................................................. 55 
5.1.1 
Presentation and Formulation ..................................................................... 55 
5.1.2 
Storage ........................................................................................................ 56 
5.1.3 
Administration ............................................................................................ 56 
5.1.4 
Accountability and Destruction of Surplus Investigational Product ........... 56 
5.2 
Concomitant Medications ......................................................................................... 57 
5.2.1 
Disallowed Medications ............................................................................. 57 
5.2.2 
Allowed Medications ................................................................................. 57 
5.2.2.1 Antimicrobial agents ................................................................... 57 
5.2.2.2 Non-antimicrobial medications ................................................... 57 
5.3 
Study Medication Compliance .................................................................................. 57 
5.4 
Precautions and Overdose ......................................................................................... 57 
5.4.1 
Study Drug - AB103................................................................................... 57 
5.4.1.1 Precautions .................................................................................. 57 
5.4.1.2 Over dosage ................................................................................ 58 
5.4.2 
Placebo Comparator ................................................................................... 58 
5.4.2.1 Precautions .................................................................................. 58 
6. 
STUDY PROCEDURES .................................................................................................... 59 
6.1 
Informed Consent ...................................................................................................... 59 
6.2 
Clinical and Laboratory Procedures .......................................................................... 59 
6.2.1 
Start of Drug Administration Clock ........................................................... 59 
6.2.2 
Inclusion/Exclusion Criteria ....................................................................... 59 
6.2.3 
Medical and Surgical History ..................................................................... 59 
6.2.4 
Physical Examinations ............................................................................... 60 
6.2.4.1 Interim physical examinations (symptom-driven) ...................... 60 
6.2.5 
Concomitant Medication ............................................................................ 60 
6.2.6 
Primary Infection Site ................................................................................ 60 
6.2.6.1 Debridement ................................................................................ 60 
6.2.7 
Vital Signs .................................................................................................. 61 
6.2.8 
Clinical Scores ............................................................................................ 61 
6.2.8.1 SOFA score definition ................................................................ 61 
6.2.9 
Electrocardiogram ...................................................................................... 61 
6.2.10 
Clinical Laboratory Assessments ............................................................... 62 
6.2.11 
Immunogenicity ......................................................................................... 62 
6.2.12 
Biomarkers ................................................................................................. 62 
6.2.13 
RNA Expression ......................................................................................... 62 
6.2.14 
Total blood volume collected ..................................................................... 63 
6.2.15 
Microbiology .............................................................................................. 64 
6.2.16 
Use of additional rescue therapy ................................................................ 65 
7. 
EVALUATION MEASURES FOR EFFICACY ............................................................. 66 
7.1 
Primary Efficacy Measures ....................................................................................... 66 
7.2 
Secondary Measures .................................................................................................. 66 
7.3 
Exploratory Measures: .............................................................................................. 67 
8. 
EVALUATION CRITERIA FOR SAFETY .................................................................... 68 
8.1 
Primary Safety Measures .......................................................................................... 68 


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8.2 
Adverse Event Definitions and Classifications ......................................................... 68 
8.2.1 
Adverse Event ............................................................................................ 68 
8.2.2 
Serious Adverse Event ............................................................................... 68 
8.2.3 
Adverse Reaction ....................................................................................... 69 
8.2.4 
Expectedness of the Adverse Event ........................................................... 69 
8.2.5 
Serious and Unexpected Suspected Adverse Reaction (SUSAR) .............. 69 
8.2.6 
Adverse Events Based on Examinations and Tests .................................... 69 
8.2.7 
Pregnancies ................................................................................................. 70 
8.2.8 
Relationship to Investigational Medicinal Product ..................................... 70 
8.2.9 
Severity ...................................................................................................... 70 
8.3 
Reporting of Adverse Events .................................................................................... 71 
8.4 
Reporting of Serious Adverse Events ....................................................................... 71 
8.4.1 
Initial Report .............................................................................................. 71 
8.4.1.1 Electronic SAE reporting system back-up .................................. 72 
8.4.2 
Follow-up and Final Reports ...................................................................... 72 
8.5 
Disease Related Adverse Events ............................................................................... 73 
8.5.1 
List of Expected Adverse Events ............................................................... 73 
8.6 
Safety Monitoring ..................................................................................................... 73 
8.7 
Independent Data Monitoring Committee (iDMC) ................................................... 73 
9. 
STATISTICS ...................................................................................................................... 74 
9.1 
Synopsis of Key Statistical Approaches .................................................................... 74 
9.1.1 
Primary Efficacy Comparison .................................................................... 74 
9.1.2 
Sample Size Justification ............................................................................ 74 
9.1.3 
Futility Analysis ......................................................................................... 75 
9.1.4 
Control Of Blinding And IDMC ................................................................ 75 
9.2 
Summary of Other Elements of Analysis Plan .......................................................... 76 
9.2.1 
Randomization ........................................................................................... 76 
9.2.2 
Patient Populations ..................................................................................... 76 
9.2.3 
Preliminary And Descriptive Analyses ...................................................... 77 
9.2.4 
Secondary Endpoints .................................................................................. 77 
9.2.5 
Exploratory Analyses ................................................................................. 78 
9.2.6 
Assessment Of Poolability Among Sites .................................................... 78 
9.2.7 
Analysis Of Other Covariate Effects .......................................................... 78 
9.2.8 
Multiplicity ................................................................................................. 79 
9.2.9 
Longitudinal Data ....................................................................................... 79 
9.2.10 
Analysis Of Event-time .............................................................................. 80 
9.2.11 
Handling Of Missing Data.......................................................................... 80 
9.2.11.1 Intent-to-Treat ............................................................................. 80 
9.2.11.2 mSOFA Scores ............................................................................ 80 
9.2.11.3 Tipping Point Analysis for Primary Endpoint ............................. 81 
9.2.11.4 Mixed Model Repeated Measures ............................................... 81 
9.3 
Safety Analysis.......................................................................................................... 81 
10. 
SOURCE DATA ACCESS, DATA MANAGEMENT AND DATA HANDLING ....... 83 
10.1 
Data Quality Assurance ............................................................................................. 83 
10.2 
Database Management .............................................................................................. 83 
10.3 
Case Report Forms and Source Documentation ........................................................ 83 
10.4 
Data Collection .......................................................................................................... 84 
10.5 
Access to Source Data ............................................................................................... 84 


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10.6 
Archiving Study Records .......................................................................................... 85 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................ 86 
12. 
GENERAL STUDY ADMINISTRATION ...................................................................... 87 
12.1 
Ethical Aspects .......................................................................................................... 87 
12.1.1 
Good Clinical Practices / Local Regulations .............................................. 87 
12.2 
Informed Consent ...................................................................................................... 87 
12.3 
Institutional Review Board / Ethics Committee ........................................................ 88 
12.3.1 
Conditions for Modifying the Protocol ...................................................... 88 
12.4 
Patient Confidentiality............................................................................................... 89 
12.5 
Investigator Responsibilities ..................................................................................... 89 
12.6 
Laboratory Accreditation .......................................................................................... 89 
12.7 
Study Initiation .......................................................................................................... 89 
12.7.1 
Study Completion ....................................................................................... 89 
12.7.2 
Study Termination ...................................................................................... 89 
13. 
CONFIDENTIAL INFORMATION ................................................................................ 91 
13.1 
Confidential Information ........................................................................................... 91 
13.2 
ClinicalTrials.gov Study Registration ....................................................................... 91 
13.3 
Publication Policy ..................................................................................................... 91 
14. 
REFERENCES ................................................................................................................... 92 
15. 
APPENDICES .................................................................................................................... 96 
15.1 
Appendix A - Study visits and procedures ................................................................ 96 
15.2 
Appendix B - APACHE II Score ............................................................................ 100 
15.3 
Appendix C - modified SOFA ................................................................................ 104 
15.4 
Appendix D - Glascow Coma Scale ........................................................................ 106 
15.5 
Appendix E - Clinical Scores .................................................................................. 107 
15.6 
Appendix F - Recommendations for EXCLUSION OF Immunosuppressive Agents
 ................................................................................................................................. 108 
 
 
List of Tables 
Table 1: Summary of ATB-103 pharmacokinetic parameters in healthy volunteers .......................... 32 
Table 2: Non-parametric AB103 pharmacokinetic parameters in NSTI patients ............................... 34 
Table 3: Consistent response across multiple clinically relevant end points ...................................... 35 
Table 4: NICCE Components ............................................................................................................. 38 
Table 5: Comparative effect of high and low dose groups – Study ATB-201 .................................... 44 
Table 6: Maximal Blood Drawing by Visit ........................................................................................ 63 
Table 7: Clinical Scores Parameters ................................................................................................. 107 
 
List of Figures 
Figure 1: Th1 induction ...................................................................................................................... 29 
Figure 2: AB103 function ................................................................................................................... 30 
 


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INVESTIGATOR AGREEMENT 
Version 4.0 Approval Date 23 August 2018 
 
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 BioLtd. (“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 
AB103 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 AB103. 
 
Investigator’s Signature 
 
Date 
 
 
 
Name of Investigator (Typed or Printed) 
 
 
 
 
 


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Investigator Title 
 
 
 
Institution, Address* 
 
 
 
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 
919 439 3195 
Mobile Phone Number 
919 805 1632 
Office Fax Number 
919 765 6693 
E-mail Contact Information 
davidw@atoxbio.com  
 
 
Clinical Trial Manager  
Name 
Deborah Rosenbaum 
Company 
Atox Bio, Ltd 
Office Phone Number 
919 439 1766 
Office Fax Number 
919 765 6693 
E-mail Contact 
debbier@atoxbio.com 
SAE Reporting Phone Number 
Phone Number 
 
919 439 3400 
Data Management  
Company 
PharPoint Research, Inc 
Office Phone Number 
910 386 4282 
Email 
ashley.lee@pharpoint.com 
 
Home Visiting Nurse Service  
Company 
Symphony Clinical Research 
Office Phone Number 
866 333 1550 
Biomarker Sample Collection service  
Name 
Molly Griebel 
Company 
LabConnect, LLC 
Office Phone Number 
423 794 3766 
E-mail Contact 
mgriebel@labconnectllc.com 


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PROTOCOL SYNOPSIS 
Protocol Number 
ATB-202 
Protocol Title 
Phase III, randomized, double-blind, placebo-controlled, parallel-
group, study of AB103 as compared to placebo in patients with 
necrotizing soft tissue infections (NSTI) 
ACCUTE (AB103 Clinical Composite Endpoint Study in 
Necrotizing Soft Tissue Infections) 
Location(s) 
A multicenter study, that will be conducted in approximately 75 
qualified participating sites in the US and France 
Phase of 
Development 
Phase 3 
Study population 
Patients clinically diagnosed with necrotizing soft tissue infections 
(NSTI) who are scheduled for an urgent surgical intervention as part of 
their standard of care (SoC) for the treatment of their infection and who 
subsequently have a surgically confirmed diagnosis of NSTI. 
Study Objectives 
Primary objective: 
To demonstrate the efficacy of AB103 as compared to placebo, in 
patients diagnosed with NSTI, using a clinical composite success 
endpoint: 
The NSTI clinical composite score, NICCE (Necrotizing Infections 
Clinical Composite Endpoint) will be defined as the primary end point 
which will be composed of the following patient outcomes (i) Alive at 
Day 28, (ii) Day 14 debridements ≤3 (iii) No amputation done after the 
first debridement (iv) Day 14 modified SOFA (mSOFA) score ≤1 
(mSOFA includes respiratory, cardiovascular, central nervous system 
(CNS), renal, and hematologic organ components but not hepatic/liver 
component) (v) Reduction of ≥3 score points between Baseline and 
Day 14 mSOFA score. 
Component 
NICCE 
Survival 
• 
Alive at Day 28  
Local component 
• 
 ≤3 debridements throughout Day 
14 
• 
 No amputation beyond first 
debridement 
Systemic component 
• mSOFA score of ≤1 at Day 14 
• Reduction of ≥3 score points 
between Baseline and Day 14 
mSOFA score 
 
To be considered a success, patients must meet all components of the 
NICCE. A two-sided α=0.01 will be used to test superiority of AB103 
relative to placebo for the primary endpoint (NICCE). 


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Conditional co-primary end point: 
To demonstrate the efficacy of AB103 as compared to placebo, in 
patients diagnosed with NSTI, using a modified clinical composite 
success endpoint that includes (i) Alive at Day 28, (ii) Day 14 
debridements ≤3 (iii) No amputation done after the first debridement. 
To be considered a success, patients must meet all 3 components of this 
modified composite endpoint. 
The conditional co-primary end point will only be tested if superiority 
is demonstrated for the primary endpoint at a two-sided α=0.01 
significance level in order to account for multiple comparisons. A two-
sided α=0.05 will be used to test superiority of AB103 relative to 
placebo for the co-primary endpoint. 
Secondary objectives: 
o To demonstrate the safety of AB103 when administered as a 
single dose of 0.50 mg/kg to patients diagnosed with NSTI 
o To demonstrate the efficacy of AB103 as compared to placebo, 
in patients diagnosed with NSTI, using the 5 component 
clinical composite endpoint but with mSOFA ≤1 at Days 21 
and 28 
o Comparison of the distribution of mSOFA scores between 
treatment groups at Days 14 and 21 
o Kaplan-Meier analysis of the time to resolution of mSOFA 
score to ≤ 1 with censoring at Day 14 
o To demonstrate the efficacy of AB103 compared to placebo as 
related to the individual components of the NICCE in patients 
with NSTI 
o To demonstrate efficacy of AB103 in relation to the critical 
care and hospital stay parameters: 
a. Intensive care unit (ICU) days 
b. ICU-free days 
c. Days on ventilator 
d. Ventilator free days 
e. Vasopressor days 
f. Vasopressor free days 
g. Hospital length of stay 
o To demonstrate the efficacy of AB103 in patients with septic 
shock. 
o To determine the incidence of Stage 2 and 3 acute kidney 
injury (AKI) (using the KDIGO criteria) and compare the rates 
of complete recovery by Day 28 between the AB103 treated 
patients and the placebo treated patients. 
o Additional AKI endpoints: 
 
To determine the incidence of Stage 2 and 3 AKI 
(using the KDIGO criteria) and compare the rates of 
complete and partial recovery by Day 28 between 
AB103 and placebo treated patients 
 
Determine the incidence of Stage 1, 2 and 3 AKI and 
compare the rates of complete recovery between the 
AB103 and placebo treated patients 
 
Determine the incidence of Stage 1, 2 and 3 AKI and 
compare the rates of complete and partial recovery 
between the AB103 and placebo treated patients 


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 
Calculate time to complete recovery from AKI 
 
Calculate time to partial recovery from AKI 
o To demonstrate the safety of AB103 in regard to secondary 
infections 
Exploratory objectives: 
o 
To conduct an exploratory evaluation of the clinical response 
by baseline pathogen 
o 
To evaluate microbiological outcome in the microbiological 
evaluable population 
o 
To conduct an exploratory evaluation of plasma and urinary 
biomarkers in patients with AKI 
o 
To conduct an exploratory evaluation of blood leukocyte 
transcriptome (RNA expression) profiling in patients with 
NSTI and compare genomic profile in patients treated with 
AB103 versus placebo 
o 
To evaluate health economic and financial outcomes 
associated with the treatment 
o 
To evaluate NICCE outcome in screen failure patients with 
baseline mSOFA = 2 and post-operative mSOFA ≥ 3.  Note: 
These patients will not be included in the modified Intent-to-
Treat (mITT) population analysis (they will not receive 
blinded study drug) and only considered to be an observational 
cohort 
o 
To evaluate the immunogenicity of Reltecimod (formerly 
AB103) 
 
Study Hypothesis 
The primary hypothesis of this study is that in addition to SoC, AB103 
will demonstrate a clinically significant treatment benefit over placebo. 
This hypothesis will be addressed by measuring the effect of AB103 on 
a composite of clinical parameters associated with the disease course of 
patients with NSTI, using a responder analysis. A responding patient 
must meet all 5 parameters of the composite clinical success end point, 
while a non-responding patient can fail by not meeting any one of the 
parameters. These analyses are designed to demonstrate that in addition 
to being safe, one dose of 0.5 mg/kg of AB103 will: 
Improve systemic signs of the infection by improving organ 
function of patients compared to placebo as measured by: 
• 
Survival at Day 28 
• 
mSOFA score on Day 14 and change from baseline to Day 14 
≥ 3. A Day 14 mSOFA score of ≤1 and a change from baseline 
(pre-treatment) to Day 14 ≥3 will be required for a patient to 
achieve the primary composite clinical success endpoint 
(NICCE) 
Improve the local signs of the infection, as measured by: 
• 
Reduced number of debridements, counted to Day 14. No more 
than 3 debridements to Day 14 will be required for a patient to 
achieve composite clinical success 
• 
No amputation after the first debridement (amputation on the 
first debridement is not considered a failure). A patient will be 
required to have had no amputations done after the first 


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surgical procedure in order to achieve composite clinical 
success. 
Number of 
Patients: 
290 patients will be recruited into the study and randomized to receive 
either 0.5 mg/kg AB103 or placebo in a 1:1 ratio. Randomization will 
be stratified within center by the diagnosis of Fournier’s Gangrene and 
mSOFA score category (3-4 vs >4) at screening. The study will be 
conducted with interim analyses for futility at 100 patients.  
Inclusion Criteria: 
1. Age: ≥12 years 
2. 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, tense 
edema, crepitus and/or subcutaneous gas). 
• 
Patients with NSTI following intra-abdominal 
operation are eligible if adequate source control of 
intra-abdominal process has been established 
3. mSOFA score ≥3 (in any one or combination of the 5 major 
components of SOFA score with any one organ component 
having a score of at least 2: cardiovascular, respiratory, renal, 
coagulation, CNS), measured as close as possible to the first 
debridement, (but before first debridement is performed). 
4. IV drug administration within 6 hours from the clinical 
diagnosis and the decision at the study site, to have an urgent 
surgical exploration and debridement (drug should not be 
administered until surgical confirmation is established). 
5. If a woman is of childbearing potential, she must consistently 
use an acceptable method of contraception from baseline 
through Day 28. Acceptable birth control methods include oral 
contraceptive medication, an intrauterine device (IUD), an 
injectable contraceptive (such as Depo-Provera®), a birth 
control patch, a barrier method (such as condom or diaphragm 
with spermicide) or abstinence. 
o 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). 
6. 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. 
7. Signed and dated ICF as defined by the IRB 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. If patient is unable to comprehend or sign the ICF, 
patient’s legally acceptable representative may sign the ICF 


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Exclusion Criteria: 
1. BMI > 51; 
2. Patient who has been operated at least once for the current 
NSTI infection and had a curative deep tissue debridement 
(patients who underwent prior diagnostic minor surgery are 
allowed to enter into the study); 
3. Patients with overt peripheral vascular disease in the involved 
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; 
4. Diabetic patients with peripheral vascular disease who present 
with below the ankle infection; 
5. Patient with burn wounds; 
6. 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 screening despite the 
presence of vasopressors and IV fluids or (b) a patient with 
respiratory failure such that an SaO2 of 80% cannot be achieved 
or (c) a patient with refractory coagulopathy (INR >5) or 
thrombocytopenia (platelet count <20,000) that does not 
partially correct with administration of appropriate factors or 
blood products, 
7. Chronic neurological impairment that leads to a neuro mSOFA 
component ≥2  
8. Recent cerebrovascular accident in the last 3 months. 
9. Patients with cardiac arrest requiring cardiopulmonary 
resuscitation within the past 30 days; 
10. 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); 
11. Patient or patient’s family are not committed to aggressive 
management of the patient’s condition, or the combination of 
necrotizing skin infection and underlying illness makes it 
unlikely that life support will be maintained; 
12. 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: 
o CHF {NYHA class III-IV} 
o Severe COPD {GOLD stage III-IV. or chronic 
hypoxemia (PaO2 <55 mmHg) on room air, or chronic 
use of home ventilation, or unable to climb stairs or 
perform household duties due to chronic obstructive 
disease resulting in severe exercise restriction, 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)} 
o Liver dysfunction {Childs-Pugh class C} 
o Immunosuppression (see Appendix F, Section 15.6 for 
list of excluded immunosuppressive medications) 
o Neutropenia < 1,000 cells/mm3not due to the 
underlying infection 
o Idiopathic Thrombocytopenic Purpura (ITP) 


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o Receiving or about to receive chemotherapy or biologic 
anti-cancer treatment although hormonal manipulation 
therapies for breast and prostate malignancies are 
permitted 
o Hematological and lymphatic malignancies in the last 5 
years 
13. Known HIV infection with CD4 count < 200 cells/mm3 or < 
14% of all lymphocytes; 
14. Patients with known chronic kidney disease (documented pre-
illness creatinine value(s) ≥2.0) or patients receiving renal 
replacement therapy for chronic kidney disease: either 
hemodialysis, peritoneal dialysis, hemofiltration such as 
Continuous Veno-Venous Hemofiltration (CVVH) or 
hemodiafiltration 
15. Patients that are treated with continuous hemofiltration (e.g. 
Continuous Veno-Venous Hemofiltration) for acute kidney 
dysfunction, not due to NSTI, starting prior to study drug 
administration. 
Exception: Patients with acute kidney dysfunction due to 
NSTI may be enrolled in the event that the patient is off 
the treatment from time of study drug administration and 
up to at least one hour post study drug administration. 
16. Pregnant or lactating women; 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 this protocol, ATB-202, or the Phase 2 
NSTI trial of AB103, ATB-201, or the current Phase 2 SA-AKI 
trial of AB103, ATB-203.  
Investigational 
Product: type, dose 
and mode of 
administration 
AB103 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. 
AB103 will be supplied in glass vials as a lyophilized powder to be 
reconstituted with sterile water for injection (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 calculated based on 
the patient's weight plus adequate priming volume of the IV line. 
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 patients’ actual weight. 
The dose of AB103 will be 0.50 mg/kg, administered as a one-time 
dose, either during the first surgery or immediately after the first 
surgery, all within the 6 hour time-window from clinical diagnosis and 
decision for urgent surgical exploration and debridement (study drug 
should only be administered after NSTI diagnosis is confirmed 
surgically). Blinded placebo will be sterile normal saline (0.9%) 


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calculated similarly as for the active group according to the patient 
weight, plus adequate priming volume of the IV line. 


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Study design: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Flow chart: Study design from diagnosis to drug administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 
 
Step/timing from drug administration 
1 
Screening 
2 
Day 1: Randomization & study drug administration 
(≤6 hr from clinical diagnosis); 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 (+2 days) 
10 
Follow-up & Termination at 3 months (±5 days) 
Clinical Diagnosis & Urgent 
Operation Decision 
Drug administration (can be 
administered during or post-surgery 
  
  
<=6 hours 
Inclusion/exclusion 
Screening 
ICF 
Note:  ICF may be obtained prior to 
or post-surgery 
Randomization  
Note: Randomization may be 
performed prior to or after surgery 
but study drug not prepared until 
NSTI diagnosis confirmed 
Surgery 
Confirm NSTI diagnosis 


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This is a randomized, double-blind, placebo-controlled, parallel-group, 
multicenter study, to evaluate the efficacy and safety of a single dose of AB103 
versus placebo (both in addition to SoC). Screening starts upon notification of 
study team about a patient with possible NSTI and lasts until study drug 
administration. Screened patients meeting inclusion/exclusion criteria and able 
to provide written informed consent (legal patient representative consent 
acceptable) may be randomized to one of 2 treatment arms (AB103 or placebo) 
in a 1:1 ratio. Treatment regimen consists of a single dose of 0.50 mg/kg AB103 
or placebo, each administered as a single intravenous infusion over 10 minutes. 
Study drug administration may take place during or after the surgical exploration 
and debridement, but no later than 6 hours from clinical diagnosis of NSTI and a 
decision at the study site for urgent surgical wound exploration and debridement. 
All patients will receive SoC antimicrobial treatment and any other SoC 
treatment, as determined by the Investigator 
SOFA score definition: 
Screening mSOFA: 
Screening mSOFA score components are to be captured and the total score to be 
calculated prospectively and must be performed prior to first debridement: The 
screening mSOFA score should be evaluated any time after arrival at the 
hospital (may include referring hospital), although no more than 6 hours prior to 
anticipated first debridement. Screening mSOFA score must be ≥3, with one 
organ component having a score of at least 2, to be considered eligible for 
enrollment. Sites are encouraged to re-evaluate mSOFA score as close to surgery 
as feasible for patients not meeting mSOFA ≥3 inclusion criteria during initial 
screening. Screening mSOFA will include measurements of the score 
components in the following organ/systems: respiratory (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), cardiovascular, renal, coagulation and CNS. 
 mSOFA score: measurements of a 5 organ systems, including CNS. To be 
measured on days 1, 2, 3, 7, 10, 14, 21 and 28 and calculated retrospectively. 
mSOFA 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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Outcome measures 
Primary Efficacy Measure: 
• 
NICCE: Clinical composite success end point: Success is defined as 
meeting all 5 components of the composite score: Alive until Day 28, 
(ii) Day 14 debridements ≤3 (iii) No amputation done after the first 
debridement (iv) Day 14 mSOFA score ≤1 (v) Reduction of ≥3 score 
points between Baseline and Day 14 mSOFA score. 
Conditional Co-Primary Efficacy Measure: 
• 
Modified clinical composite endpoint: Success is defined as meeting all 
3 components of the composite score: Alive until Day 28, (ii) Day 14 
debridements ≤3 (iii) No amputation done after the first debridement 
Safety Measures: 
• 
Measures throughout Day 28: AEs (includes Serious Adverse Events 
(SAEs)), clinical safety laboratory (through Day 14), secondary infections, 
determination of survival through Day 28. 
Other measures: physical exam, vital signs, ECG (days 0 and 1); (specific times 
of these parameters are described in the table of study visits and procedures 
below) 
Secondary Measures: 
• 
5 component clinical composite endpoint but with mSOFA ≤1 at Days 21 
and 28 
• 
Distribution of mSOFA scores at Days 14 and 21 
• 
Kaplan-Meier analysis of the time to resolution of mSOFA score to ≤ 1 
with censoring at Day 14 
• 
Single components of the composite endpoint : 
o Alive at Day 28 
o Number of patients with debridements by Day 14 ≤3 
o Number of amputations (excision to a joint space) (done after first 
debridement) 
o mSOFA score on Day 14 ≤1 
o Reduction of ≥3 score points between Baseline and Day 14 
mSOFA score. 
• 
Critical care and hospital stay parameters, to be measured until Day 28: 
o ICU-free days 
o Days in ICU 
o Days on ventilator 
o Ventilator free days 
o Vasopressors days/ Vasopressors free days 
o Hospital length of stay (days) 
• 
Clinical local parameters: 
o Number of debridement to days 7, 10, 14 and 28 
o Proportion of patients needing (up to Day 14): 
 
 only one debridement to control the infection 
 
≥2 debridements to control the infection 
 
≥3 debridements to control the infection 
• 
Clinical systemic parameters: 
o Evaluation of organ function over time, using SOFA score 
o Recovery from AKI 
Exploratory Measures: 
• 
Evaluation of clinical response by baseline pathogen type 


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• 
Evaluation of microbiological outcome in the microbiological evaluable 
population 
• 
Correlation of plasma and urinary biomarkers with incidence of AKI, AKI 
staging and recovery from AKI 
• 
Evaluation of blood leukocyte transcriptome (RNA expression) profiling 
in patients with NSTI and compare genomic profile in patients treated with 
AB103 versus placebo 
• 
Evaluation of NICCE outcome in screen failure patients with baseline 
mSOFA = 2 and post-operative mSOFA ≥ 3 
• 
To evaluate the immunogenicity of Reltecimod (formerly AB103) 
Health economic 
information 
Details of health economic information will be collected throughout the 
hospital course and post hospital discharge. The health economic information 
will include several parameters: Hospital length of stay (includes both ICU 
and hospital ward stay), length of ICU stay, days on the ventilator, number of 
surgical operations, hospital readmission information, and mSOFA scores. 
Duration of study 
Overall, the study is expected to last approximately 48 months (from first 
patient in to last patient out). 
Statistical analysis 
 
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 represents the true probability that a patient achieves 
specific composite clinical success criteria, NICCE, designed to be sensitive 
to both local and systemic drug effects. Each probability represents the 
proportion of subjects on each arm expected to respond according to the 
primary efficacy endpoint. 
Sample Size Justification: 
This trial will enroll 290 subjects that will be randomized in a ratio of 1:1 to 
either AB103 0.50 mg/kg (n=145) or placebo (n=145), each in addition to 
SoC). Sample size analysis was performed assuming that all patients will be 
evaluable for the primary endpoint. This assumption is justified since all 
patients in the Phase 2a trial and in the retrospective study were evaluable for 
NICCE. The primary efficacy hypothesis will be tested using an unadjusted 
χ2 statistic with a 0.01 two-sided significance level. Statistical power was 
computed for a range of expected treatment group differences supported by 
the results of preliminary studies. For treatment group differences equal to 
0.30, 0.25, and 0.20, statistical power will be equal to 99%, 95.9%, and 
80.2%, respectively. These estimates were determined assuming an average 
success rate of 0.5 so that these power estimates are applicable across the 
range of expected response rates but may be conservative in some cases. The 
use of NICCE and this range of expected treatment effects is supported by 
preliminary studies. In the Phase 2a trial, 71.4% (5/7) patients with baseline 
mSOFA≥3 treated with AB103 0.50 mg/kg achieved NICCE. In contrast, 
40% (2/5) placebo patients with baseline mSOFA≥3 achieved NICCE, a 
difference of 0.314. The retrospective study provided further support for the 
untreated response rate. Among 69 patients with baseline mSOFA≥3, 33.3% 
(23/69) achieved NICCE, difference of 0.381 relative to Phase 2a treated 
group. If the observed differences are equal to 0.35, 0.25, and 0.20 (centered 
about 0.5), then the corresponding 2-sided p-values will be p<0.0001, 
p<0.0001, and p=0.0007, respectively. The observed difference will need to 
be larger than about 0.16 (e.g., 0.58 vs 0.42) for p<0.01. 


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Based on a similar evaluation of the co-primary endpoint, the study is 
designed to demonstrate statistical significance at two-sided α=0.05 for co-
primary success rates of 0.80 vs 0.60 in the AB103 and placebo groups, 
respectively. If these are the true success rates, then power will 96.4%. 
However, if the true rates are 0.78 vs 0.62 (difference = 0.16), then power is 
84.8%. The sample size has also been selected to obtain sufficient enrollment 
on the treatment arm for relevant secondary effectiveness endpoints and for 
safety endpoints. 
Futility Analysis: 
A futility analysis will be performed based on the results of the first 100 
patients (50 per group). The futility decision will be based on the predictive 
probability of eventual study success, conditioned on the data available at 
interim analysis. Independent, non-informative prior distributions will be used 
for each parameter: π0.50 ~ Beta(1,1), πPlacebo ~ Beta(1,1). The Bayesian 
predictive probability of study success (i.e., two-sided p ≤ 0.01) when the 
remaining patients are finally observed will be determined. The trial will stop 
enrollment for futility if the predictive probability of study success is below a 
lower bound threshold of 10%. The following table summarizes what the 
observed predictive probabilities will be as a function size of the treatment 
group differences and assuming an observed control success rate of 0.40. If 
there are 20 success and 30 failures among placebo controls (40% success 
rate), then the futility boundary will be crossed if the number of active 
success is 22 (44%) or less. 
 
The futility bound is ‘non-binding’ in the sense that no effort was made to 
‘recover’ alpha to increase power. 
Independent Data Monitoring Committee (iDMC): 
A detailed iDMC charter will be provided to clarify all relevant issues relating 
to the conduct of the 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. 
Secondary Analyses: 
Secondary endpoints have been specified from several domains including a 
similar composite endpoint but defined on the basis of Day 21 mSOFA, 
individual components of the primary composite endpoint, time to resolution 
of organ dysfunction, critical care and hospital stay parameters, clinical local 
parameters, and clinical systemic parameters. 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 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-organ dysfunction resolution endpoints. 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. AKI endpoints will be assessed in several 
ways include incidence of Stage 2/3 AKI and among incident cases, 
Diff
0.000
0.020
0.040
0.060
0.080
0.100
0.120
0.140
0.160
0.180
0.200
0.220
0.240
0.260
0.280
0.300
PP
0.029
0.050
0.082
0.127
0.187
0.261
0.348
0.444
0.543
0.639
0.728
0.804
0.866
0.913
0.946
0.969


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resolution of AKI. A similar analysis will be performed based on any stage 
AKI. Treatment groups will be compared using counts and percentages with 
nominal p-values determined through chi-statistics. 
Exploratory Analyses: 
Exploratory subgroup analysis will be performed. For these exploratory 
analyses, active dose versus placebo differences in NICCE will be evaluated 
in several subgroups defined by (i) severity of disease at baseline (3-4 vs >4), 
(ii) presence of non-Fournier’s gangrene (iii) involvement of suspected 
superantigen-producing bacteria and (iv) type of bacteria (Gram-positive vs. 
Gram-negative). Other similar comparisons may be performed. 
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. 
• 
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 NSTI based on surgical verification. 
The mITT analysis set will be used in primary effectiveness 
analyses with patients assigned to their intended randomized 
assignment. 
• 
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 with potential to 
confound estimates of drug effects or 2) post randomization 
protocol violations 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 evaluation critical care variables. 
The safety profiles will be compared using descriptive statistics as appropriate 
for continuous and categorical safety variables including laboratory values 
and incidence of adverse events. 
 
 
 


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ABBREVIATIONS 
Abbreviation 
Description 
AE 
Adverse Event 
AKI 
Acute kidney injury 
ALP 
Alkaline phosphatase  
ALT 
Alanine transaminase  
APC 
Antigen-Presenting Cell 
AST 
Aspartate transaminase 
ARDS 
Acute respiratory distress syndrome 
AT 
As-Treated 
AUC 
Area under the curve 
CBC 
Complete blood count 
CCS 
Composite Clinical Success 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CL 
Clearance (plasma) 
CLSI 
Clinical and Laboratory Standards Institute 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CVVH 
Continuous Veno-Venous Hemofiltration 
DVT 
Deep vein thrombosis 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FDA 
US Food and Drug Administration 
FiO2 
Fraction of Inspired Oxygen 
GAS 
Group A Streptococcus 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transpeptidase 
hCG 
Human Chorionic Gonadotropin 
hERG 
Human Ether-a-go-go Related Gene 
HEOR 
Health economics and outcomes research 
HIPAA 
Health Insurance Portability and Accountability Act 
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 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 


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Abbreviation 
Description 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
Intravenous 
IVIG 
Intravenous Immunoglobulin G 
IUD 
Intrauterine device 
IWR 
Interactive Web Randomization 
KLH 
Keyhole Limpet Hemocyanin 
LAR 
Legally authorized representative 
LOCF 
Last observation carried forward 
LPS 
LipoPolySaccharide 
LRINEC 
Laboratory Risk Indicator for Necrotizing Fasciitis 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
Major Histocompatibility Complex 
mITT 
modified Intent-to-Treat 
MMRM 
Mixed Model Repeated Measures 
MRSA 
Methicillin-resistant Staphylococcus Aureus 
mSOFA 
Modified Sequential Organ Failure Assessment 
MTD 
Maximum Tolerated Dose 
NICCE 
Necrotizing Infections Clinical Composite Endpoint 
NOAEL 
No Observed Adverse Event Level 
NSTI 
Necrotizing Soft Tissue Infection/s 
PAMP 
Pathogen associated molecular patterns 
PaO2 
Partial Pressure Oxygen in Arterial Blood 
PBMC 
Peripheral Blood Mononuclear Cell 
PE 
Physical Examination 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PP 
Per Protocol 
QTc 
QT interval corrected 
QTcF 
QT interval corrected Fridericia 
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
SD 
Standard Deviation 
SoC 
Standard of Care 
SOC 
System organ class 
SOP 
Standard Operating Procedure 
SUSAR 
Serious and Unexpected Suspected Adverse 
Reaction 
TCR 
T-cell Receptor 
TEAE 
Treatment Emergent Adverse Event 
Th1 
T Helper Cell 1 (CD4) subset 
Th2 
T Helper Cell 2 (CD4) subset 
TNF 
Tumor Necrosis Factor 


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Abbreviation 
Description 
VAC 
Vacuum Assisted closure 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WFI 
Water for Injection 


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1. INTRODUCTION 
1.1 
Background Information 
1.1.1 Necrotizing Soft Tissue Infections (NSTI) 
NSTI are rapidly progressing infections with significant local and systemic manifestations. 
They represent the most severe types of infections involving the skin, skin structures and 
soft tissue 1–9. The key clinical feature of NSTI is the presence of necrosis confined to the 
subcutaneous fascial tissues and often also to the deep fascial layers, fat, nerves, arteries 
and veins. This may not always be apparent by physical examination (PE) or imaging 
studies5. Examples for NSTI include necrotizing fasciitis due to streptococcal infection 
(Group A or non-group A), bacterial synergistic gangrene, clostridial gas gangrene, 
Fournier’s Gangrene, and haemolytic streptococcal gangrene. They all share the clinical 
features of severe local tissue necrosis, systemic toxaemia, bacteremia, and have a high 
mortality rate5,6. NSTI is a descriptive term which includes a variety of distinctive clinical 
diagnoses. While there is no unifying bacterial aetiology, the most frequently identified 
species in NSTI are Staphylococcus aureus, Streptococcus pyogenes, Clostridia species, 
enterobactereaciae, and non-clostridial anaerobes, sometimes as a mixed or multi-pathogen 
infection1,2. Although many specific variations of NSTI have been described on the basis 
of aetiology, microbiology and specific anatomical location of the infection, the initial 
approach to the diagnosis, antimicrobial treatment and decision to use operative 
management are similar for all forms and are more important than determining the specific 
variant7. 
NSTI develops when the initial, appropriate host response to an infection becomes 
amplified and is then dysregulated 10,11. The pathogenesis of NSTI is thought to be related 
to the local release of inflammatory cytokines and bacterial toxins8,9,12. This has been 
shown in both, experimental animal models and clinical studies, particularly for infections 
caused by S. pyogenes (Group A strep; GAS) and S. aureus10,13–16. 
These bacteria produce a variety of exotoxins, including among others, toxins known as 
superantigens which bypass the normal immune response for processing bacterial antigens, 
are a major inducer of the inflammatory response, and can spread into the systemic 
circulation. This leads to massive polyclonal expansion with the release of pro-
inflammatory cytokines, causing a T helper 1 “cytokine storm” and subsequent refractory 
shock and multi-organ failure. 
NSTI is a rare disease, with an estimated prevalence of 4.5 cases per 100,000 individuals 
in Europe and 6.8 cases per 100,000 in the US. Risk factors appear to be diabetes, obesity, 
intravenous drug use, peripheral vascular disease and immunosuppression. However, a 
large proportion of NSTI patients have no predisposition for their infection 3–5,8. 
NSTI is different from milder superficial skin infections with regard to clinical 
presentation, treatment strategies, coexisting systemic manifestations and its fatal 
outcome7. Although the survival of patients with NSTI has improved throughout recent 


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years17–21, mortality rates are still unacceptable, with up to 17% according to reports from 
2006 to 20111,2,8,22. 
Patients with NSTI require emergent operative and repeated exploration with wide 
debridement of all necrotic tissue, with acute resuscitation along with administration of 
broad spectrum antibiotics with specific coverage for methicillin-resistant Staphylococcus 
aureus (MRSA), beta haemolytic Streptococcus and clostridia, and patients with extensive 
necrosis of an extremity may require amputation. The duration of intensive care unit (ICU) 
stay is usually dependent on the degree of organ dysfunction and the need for mechanical 
ventilation for respiratory failure. The duration of hospital stay is dependent on the duration 
of antibiotic therapy and wound management issues. 
The current mainstay of therapy includes multiple surgical debridements performed during 
the first 7-14 days of the patient’s hospital stay, along with broad spectrum antibiotics and 
critical care support. To date no drug products have been approved for treatment of NSTI 
and the standard of care (SoC) is unsatisfactory. Patients with NSTI suffer from decreased 
physical function and pose a significant burden on health care. Following a retrospective 
review, a substantial number of patients discharged from hospital (30%) have a mild to 
severe functional limitation23. The frequent need for debridements may lead to loss of 
function at the site of infection, the creation of large disfiguring wounds requiring 
reconstruction, and amputations in 10-20% of patients when extremities are involved. 
Moreover, the systemic manifestations of the disease process can result in the development 
of multi-organ failure. 
Other morbidities: In patients with colonic and rectal involvement, colostomy (performed 
in 90% of these patients, and in 22.2 % of overall patients) is often required8,24 and in cases 
of groin involvement (Fournier’s Gangrene), genital or perineal changes are reported, 
which may lead to loss of function5. In cervical necrotizing fasciitis, complications include 
airway obstruction, jugular venous thrombosis, rupture of the great vessels, aspiration 
pneumonia, mediastinitis, empyema and lung abscess5. To recover from their acute illness, 
many of these patients (34%) are disposed to centers of rehabilitation, nursing homes, other 
sub-acute centers such as short term hospitals, or even burn units for proper wound care23,25; 
many of them require physical and occupational therapy support23 and psychological help 
to overcome their inconveniences. These sets of morbidities constitute a substantial 
economic burden on the hospitals and health care system. 
As neither surgical debridement nor antibacterial therapy directly addresses the 
immunological pathogenesis of NSTI, reducing the host inflammatory response by targeted 
immune therapies could lead to important clinical benefits in both morbidity and mortality. 
In many cases, the diagnosis of NSTI is not established when the patient first presents with 
acute symptoms, and the infection progresses rapidly despite the use of antibiotics. Delay 
in diagnosis, and thus delay in surgical debridement of necrotic tissue, is an independent 
variable for mortality. Since treatment of NSTI patients is often delayed due to the 
challenging diagnosis and inevitable delays in scheduling major surgery, a potential benefit 
of a therapy for NSTI is the speed with which it could be administered. 


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1.1.2 Indication 
The treatment indication is adjunctive treatment of NSTI. The Investigational Medicinal 
Product (IMP) AB103 acts as an immunomodulator to attenuate CD28 activation of Th1 
lymphocytes. AB103 is being developed for the treatment of NSTI in conjunction with SoC 
including surgical debridement, antibiotic therapy and supportive care. 
The current study, ATB-202, is a pivotal Phase 3 clinical trial that is designed to 
demonstrate improved efficacy and safety of AB103 over placebo in conjunction with SoC 
for the treatment of NSTI 
1.1.3 Investigational Medicinal Product 
AB103 (also known as p2TA; Reltecimod) is the acetate salt of the synthetic peptide that 
consists of 10 amino acids. AB103 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 AB103 to CD28 is postulated to prevent activation 
of CD28 by B7 on the antigen-presenting cell. AB103 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. 
AB103 is a lyophilized powder, formulated to contain 1 mg/mL of the AB103 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 filled to deliver 10 mL after reconstitution, or 10 mg of AB103. The reconstituted 
drug product is administered directly, and is not diluted prior to administration. It will be 
administered at a dose of 0.5 mg/kg as an intravenous infusion given over 10 minutes 
As NSTI is a complex and rare disease for which no approved therapy exist, AB103 has 
been granted Fast Track and Orphan Drug designations from FDA. Encouraging results 
from non-clinical (See Section 1.1.3.2) and clinical studies (Phase 1 and 2; see Section 
1.1.3.3) indicate a good safety profile with no reported toxicities in animals or humans as 
well as preliminary efficacy in this patient population. 
1.1.3.1 Mechanism of action 
There is growing appreciation that T-cell and antigen-presenting cell (APC) interactions 
play a critical role in inflammatory response of severe infections, and link the adaptive and 
innate immune systems. CD28 is a co-stimulatory receptor, expressed mostly on CD4+ and 
CD8+ lymphocytes. The CD28-mediated co-stimulatory signal is involved in the induction 
of many pro-inflammatory cytokines by T-cells, and is required to avoid an apoptotic or 
anergic response by the lymphocyte. CD28 is the receptor for APC molecules B7.1 (CD80) 
and B7.2 (CD86). CD28 signal is mediated by dimerization and binding to its ligands on 
the APC, and deliver a strong activation signal to the effector cell population. The role that 
CD28 plays in the adaptive immune system is well accepted as a co-stimulatory molecule; 
however, it also plays a significant role in immune surveillance and innate immune 
responses. 


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Major inducers of inflammatory response during bacterial infection are superantigens, 
stable proteins that stimulate virtually all T-cells, without a need for processing by antigen-
presenting cells (APC)26–28. 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 factor (TNF-β)29–31. 
Induction of these Th1 cytokines can occur through the binding of a superantigen (produced 
by Gram-positive bacteria such as Staphylococcus aureus and Streptococcus pyogenes) 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 T helper [Th]1 cell). However, 
this interaction is insufficient for activation. Superantigens must also bind to the dimer 
interface of 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). 
Figure 1: Th1 induction 
 
 
AB103 is a synthetic short peptide, that is capable of modulating the interaction between 
host T-cells (host factors) and pathogen associated molecular patterns (PAMPs) such as 
superantigens and endotoxins. AB103 is homologous to specific amino acid 8-15 residues 
of CD28, and belongs to a family of peptide modulators that mimic the dimer interface of 
CD28, and was shown to affect the downstream signaling of CD28. 
 


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Figure 2: AB103 function 
 
 
AB103 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. Indeed, AB103 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, 
AB103 could modulate the interaction between the host and pathogen factors, inhibit their 
harmful effects and provide a clinical benefit. 
Nevertheless, binding of AB103 to CD28 was found to intervene also with the downstream 
signaling of CD28 independently of superantigens: AB103 binds directly to CD28 on the 
opposing monomer, and can therefore intervene with the downstream signaling of CD28 in 
cases that are not mediated by superantigens. As such, AB103 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 mice36,37. 
Thus, AB103 is both a superantigen and a CD28 antagonist, its activity is not pathogen 
specific, and it is a host-oriented, broad spectrum attenuator of cytokine storm. AB103 can 
therefore be employed to treat infections from various sources having a substantial 
inflammatory component, such as NSTI that involve mixed infections. 
1.1.3.2 Non-clinical studies 
In safety pharmacology studies, AB103 at a concentration of 10 µg/mL had no significant 
effect on human ether-a-go-go related gene (hERG) tail current. In pigs, AB103 at up to 
5.0 mg/kg did not cause toxicologic effects on electrocardiogram (ECG) interval durations. 
The no observed adverse effect level (NOAEL) of AB103 for neurobehavioral measures of 


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a central nervous system (CNS) screen in mice was greater than 5 mg/kg (the highest dose 
tested). 
Immunotoxicology study was performed in mice where AB103 was administered by a slow 
bolus IV injection weekly for 4 weeks at doses of 1.25, and 5 mg/kg. On Day 15, the potent 
T-cell immunogen, keyhole limpet hemocyanin (KLH), was administered by 
intraperitoneal (IP) injection. Mice were observed for clinical signs and death. Blood 
immunophenotyping was conducted at scheduled necropsies as well as primary IgM and 
IgG antibody responses to KLH. AB103 given weekly for 4 weeks at doses of 1.25, and 5 
mg/kg/dose 
were 
well 
tolerated. 
No 
drug-related 
changes 
were 
seen 
in 
immunophenotyping measures or anti-KLH antibody responses. Statistically significant 
decreases in thymic weights in males given ≥1.25 mg/kg/dose of peptide AB103 were 
observed, which may have been related to the test article; 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. Thus, the high dose of 5 mg/kg/dose was 
concluded to be the NOAEL 
Non-clinical toxicology: The non-clinical toxicology and safety pharmacology of AB103 
has been tested in vitro and in vivo in single dose and repeat-dose toxicology studies 
performed in mice and pigs. Single doses of AB103 given intravenously (IV) at up to 16 
mg/kg to CD-1 mice were well tolerated with no toxicologically important clinical signs 
and no dose-related effects on body weight or food consumption. The maximum tolerated 
dose (MTD) is expected to be higher than 16 mg/kg body weight in mice. 
In repeat-dose toxicology studies in pigs and mice with doses up to 5 mg/kg/day given for 
14 days, no AB103-related clinically relevant changes were seen, indicating that the 
NOAEL in pigs and mice is greater than 5 mg/kg. 
The efficacy of AB103 was examined in several mice models of bacterial infections from 
various sources, including Gram-positive infections (S. pyogenes and S. pneumoniae), 
Gram-negative infections (E. coli) and mixed infections (intra-abdominal polymicrobial 
infection). It was tested either as a stand-alone treatment or in combination with antibiotics. 
Overall, AB103 was shown to be efficacious in protecting mice from lethal shock in these 
models as evident by increased survival 38,39. The effect of AB103 was tested also in a 
quantitative pig model for superantigen-induced incapacitation where by AB103 reduced 
the severity of both vomiting and diarrhea. In all models evaluated, a substantially high 
treatment benefit was demonstrated, indicating that AB103 has a broad spectrum of activity 
against infections. In addition, AB103 ameliorated disease symptoms both systemically and 
locally at the site of infection38. Moreover, treatment with AB103 did not compromise the 
host adaptive immune response or the humoral and long-term activities of the immune 
system38. 
Dose response studies were performed in various mice models of bacterial infections where 
AB103 was given as single dose. In all models evaluated, the optimal doses that provided 
the highest efficacy were within the same range of 2.5-5 mg/kg. 


Fi nal Pr ot oc ol A T B -2 0 2 versi o n 4. 0  
2 3 A u g 2 0 1 8  
 
Pa ge 3 2  of 1 1 1  
 
1. 1. 3. 3  Cli nic al st u dies 
A B 1 0 3 has bee n e val uate d i n 2 safet y a n d p har mac o ki netic ( P K) cli nical st u dies, a P hase 
1 st u d y i n healt h y v ol u nteers (st u d y n o. A T B- 1 0 1) a n d a P hase 2 first -i n-patie nts , pr o of of 
c o nce pt st u d y (st u d y n o. A T B- 2 0 1). 
1. 1. 3. 3. 1  P h ase I st u d y A T B - 1 0 1 
T he P hase 1 si n gle ce nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, se q ue ntial -d ose 
escalati o n  st u d y  was  c o n d ucte d  i n  2 5  healt h y  v ol u nteers.  F o ur  differe nt  escalati n g  d ose 
le vels of A B 1 0 3 were e val uate d: 7. 5 μ g/ k g, 3 7. 5 μ g/ k g, 1 5 0 μ g/ k g a n d 4 5 0 μ g/ k g wit h a 
place b o c o ntr ol ( 1 or 2 s u bjects) i ncl u de d i n eac h c o h ort; eac h s u bject recei ve d a si n gle 
i ntra ve n o us (I V) i nf usi o n of A B 1 0 3 or place b o (sali ne) c o ntr ol. Bl o o d was c ollecte d f or 
P K  a n d  fl o w  c yt o metr y  assess me nts  of  le u k oc yte  s u bsets  after  i nf usi o ns.  S u bjects  were 
assesse d 1 -da y a n d 6 - t o 8- da ys after t he i nf usi o ns f or a d verse e ve nts ( A Es), vital si g ns, 
a n d cli nical la b orat or y para meters. T he pri mar y o bjecti ve of t his st u d y was t o esta blis h t he 
safet y pr ofile a n d M T D  of A B 1 0 3 gi ve n as a si n gle I V i nf usi o n i n healt h y v ol u nteers. T he 
sec o n dar y o bjecti ve was t o deter mi ne t he P K pr ofile of A B 1 0 3 i n h u ma ns after a si n gle I V 
i nf usi o n. I n a d diti o n, ly m p h oc yte pr ofili n g  was perf or me d o n s u bjects fr o m t he hi g h d ose 
c o h ort 4. Peri p heral bl o o d m o n o n uclear cells ( P B M Cs) were o btai ne d a n d s u bjecte d t o fl o w 
c yto metric a nal ysis, f or p he n ot y pic a nal ysis a n d i ntracell ular c yt o ki ne e x pressi o n. St u d y 
d urati o n was 1 4 da ys. 
A t otal of 2 2 A Es were re p orte d d uri n g t he c o n d uct of t he trial, of w hic h 2 1 ( 9 5. 5 %) were 
mil d a n d o nl y o ne was m o derate i n se verit y. Of all t he s u bjects i n t he st u d y, 7 ha d A Es a n d 
1 8 ha d n o A Es. N o ne of t he A Es were c o nsi dere d relate d t o In vesti gati o nal P r o d uct. T here 
were  n o  d ose -li miti n g  t o xicities  n or  were  t here  a n y  S A Es.  T here  were  n o  cli nicall y 
mea ni n gf ul  c ha n ges  i n  vital  si g ns,  cli nical  la b or at or y  para meters,  E C G  para meters  or 
l y m p h oc yte s u bsets. 
L y m p h oc yte pr ofili n g: Alt h o u g h varia bilit y bet wee n s u bjects was a p pare nt, f or t he m ost 
part  wit hi n  a  s u bject  o ver  ti me,  t he  perce nta ges  of  p ositi ve  cells  a n d  a bs ol ute  c o u nts 
re mai ne d si milar t o t h ose at baseli ne 
P K i n he alt h y s u bjects: N o n -para metric p har mac o ki netic para meters esti mates are s h o w n 
bel o w: 
T a ble 1:  S u m m ar y of A T B -1 0 3 p h ar m ac o ki netic p ar a meters i n he alt h y v ol u nteers  
D ose  
μ g/ k g  
C m a x  
n g/ m L  
A U C 0-t 
n g mi n/ m L  
T 1/ 2  
mi n  
C L  
m L/ mi n/ k g  
7. 5  
1 0. 1 4 ± 2. 2 2  
6 1 ± 1 9  
N D  
N D  
3 7. 5  
5 6. 6 7 ± 3 0. 2 8  
5 2 3 ± 2 4 8  
1. 3 6 ± 0. 5 1  
8 5 ± 5 0  
1 5 0  
2 0 8. 8 0 ± 5 1. 3 7  
2 1 3 7 ± 3 7 0  
1. 2 6 ± 0. 2 8  
7 2 ± 1 1  
4 5 0  
7 0 7. 7 4 ± 2 6 9. 0 3  
6 0 8 2 ± 2 0 2 2  
1. 3 4 ± 0. 2 1  
8 0 ± 2 2  
N D = n ot deter mi ne d, i ns ufficie nt data t o calc ulate  
Plas ma  A B 1 0 3 c o nce ntrati o ns i n all c o h orts pea k near t he e n d of t he i nf usi o n a n d decli ne 
ra pi dl y wit h a T1/ 2 of a little o ver o ne mi n ute. T he a p pare nt eli mi nati o n T 1/ 2 was ver y si milar 


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across dose levels. Systemic exposure to AB103 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, AB103 given IV at doses up to 450 μg/kg was very well tolerated in 
healthy volunteers. Following a 10-minute IV infusion of AB103 to healthy volunteers, 
plasma concentrations peaked at the end of infusion and then decline rapidly with an 
apparent elimination half-life of a little over one minute. Exposure was dose-proportional. 
1.1.3.3.2. Phase II study ATB-201 
The Phase 2 study (ATB-201) was a multicenter, randomized, double blinded, first-in-
patients exploratory study in subjects who had a clinical diagnosis of NSTI and scheduled 
to undergo urgent surgical exploration and debridement. The study was conducted in 7 
clinical sites in the US, and included 40 patients. Patients were randomized to receive either 
AB103 as a single intravenous (IV) 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 AB103 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. 
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). Due to the 
natural severity of the underlying disease, a high incidence of adverse events 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 2 patients (11.8%) of the High dose group, 2 
patients (13%) of the Low dose group and 3 patients (27.3%) of the Placebo group. 
Five patients (29.4%), 8 patients (53.3%), and 4 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. 


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Four patients died during the study; one patient in each of the high and low dose groups 
and 2 patients in the placebo group. In both patients of the AB103-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 QTcF values. Treatment groups did not have higher mean change in 
QTc than placebo and outliers were similar in number and scale. 
In summary, no safety concerns were detected. 
PK in patients with NSTI: Following a 10-minute intravenous infusion of AB103 to NSTI 
patients before, during, or after surgery, plasma drug concentrations peaked at the end of 
infusion. Plasma AB103 concentrations declined with a half-life of approximately 5 
minutes in the high and low dose groups. Systemic AB103 exposure, as measured by Cmax 
and AUC, appeared to be dose-proportional when comparing these parameters across the 2 
dose groups (Table 2). There were no obvious differences in plasma AB103 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 
AB103 concentrations in patients treated before, during, or after surgery did not show any 
apparent differences. 
Table 2: Non-parametric AB103 pharmacokinetic parameters in NSTI patients 
Non-parametric 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. 
Efficacy results: Analysis of results from the Phase 2a study, indicated that patients in the 
AB103 treatment groups had a substantial improvement in their clinical status across 


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multiple endpoints when compared to patients in the placebo group. Patients in the AB103 
0.50 mg/kg and AB103 0.25 mg/kg treatment groups had a continuous resolution of organ 
dysfunction over time without subsequent worsening. Although not statistically significant, 
AB103 treated patients had a trend of spending fewer days in ICUs, requiring fewer days 
of assisted ventilation, and needing fewer surgical procedures to remove necrotic tissue. In 
addition, treatment of patients with AB103 reduced the levels of both systemic and local 
tissue cytokines and chemokines in a dose dependent manner. Tissue biomarkers, 
especially in the margins of the lesion, had reduced levels of cytokines, suggesting that 
administration of high dose AB103 may reduce progression of inflammation in marginally 
involved tissues. The overall tissue and systemic biomarkers are consistent with the 
mechanism of action of AB103, as attenuating the inflammatory response and possibly 
reducing the zone of tissue injury. The summary of the results is presented in Table 3 below: 
Table 3: Consistent response across multiple clinically relevant end points 
 
Placebo 
0.25 mg/kg 
0.5 mg/kg  
Days in ICU 
8.9 
4.9 
5.4 
Days on Ventilator 
5.2 
3.1 
2.7 
SOFA score Day 14* 
2.7 
1.1 
0.7 
% patients with organ failure at Day 14 
(defined as SOFA score ≥3) 
40 
14.3 
7.1 
% patients with organ dysfunction at Day 14 * 
(defined as SOFA score ≥2) 
66.7 
37.5 
11.1 
% of patients with only 1 debridement 
20 
26 
33 
% of patients with ≥4 debridement 
30 
20 
13 
% Mortality 
20 
6.7 
6.7 
*P<0.05 
Based on the reproducibility of the dose response in the various parameters, the 0.5 mg/kg 
dose was chosen for further clinical development. 
1.1.3.3.3 A retrospective, non-interventional analysis study ATB-201A 
This study was set up to better understand and characterize the clinical course of the disease 
under SoC treatment. The main goal was to evaluate potential clinical outcome parameters 
and to assess their suitability for the pivotal Phase 3 study program. Within this context, 
the study reviewed clinical data from 198 patients receiving SoC in 2013 at 12 US clinical 
sites. In a second step, the results of this retrospective putative placebo population were 
compared to those from the placebo- and AB103-treated population in the Phase 2 Study 
AB-201. The retrospective analysis employed a new composite endpoint, defined as 
necrotizing infection composite clinical endpoint (NICCE). Responders to the NICCE are 
(i) alive at Day 28, (ii) have Day 14 debridements ≤3 (iii) had no amputation done after the 
first debridement, and (iv) have a Day 14 mSOFA (modified Sequential Organ Failure 
Assessment [SOFA] evaluating 5 organ systems not including the liver organ component) 
score ≤1. The retrospective study demonstrated that early development of systemic organ 
dysfunction in patients with NSTI is associated with higher morbidity and mortality. Failure 
of resolution of organ dysfunction by Day 14 is also associated with poor outcome. mSOFA 


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score may be a useful marker for patient selection for inclusion in interventional trials and 
the resolution of organ dysfunction by d14 may be an important clinical endpoint. The 
study confirmed that the suggested composite endpoint NICCE is a clinically relevant 
endpoint which is highly correlated with several meaningful and relevant clinical patient 
outcome. In addition, the analysis determined that a more severe NSTI population (defined 
by a baseline mSOFA score of ≥3) demonstrate worse outcome compared to All-comers 
and would likely benefit most from AB103 treatment. 
1.2 
Risks and Benefit 
Efficacy results of the Phase 2 study ATB-201 suggest that patients treated with AB103 in 
addition to the SoC can experience improved clinical outcomes as compared to SoC alone. 
Patients randomized to receive placebo in the study will not benefit from the potential 
therapeutic effect of AB103, 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. 
Safety of AB103 has been studied extensively in a set of non-clinical studies (section 
1.1.3.2) in Phase 1 study of human healthy volunteers and in Phase 2a in NSTI patients (see 
section 1.1.3.3). In both clinical studies AB103 has demonstrated a good safety profile, and 
no specific drug-related safety concern has been identified to date. 
This study protocol details several safety measures: 
• Detailed exclusion criteria (Section 3.2) including: 
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: 
 CHF {NYHA class III-IV} 
 Severe COPD {GOLD stage III-IV. or chronic hypoxemia (PaO2 <55 
mmHg) on room air, or chronic use of home ventilation, or unable to 
climb stairs or perform household duties due to chronic obstructive 
disease resulting in severe exercise restriction, 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 F- Section 15.6 for list of excluded 
immunosuppressive medications) 
 Neutropenia < 1,000 cells/mm3not due to the underlying infection 
 Idiopathic Thrombocytopenic Purpura (ITP) 
 Receiving or about to receive chemotherapy or biologic anti-cancer 
treatment although hormonal manipulation therapies for breast and 
prostate malignancies are permitted 


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 Hematological and lymphatic malignancies in the last 5 years 
o Patients that are treated with continuous hemofiltration (e.g. 
CVVH) for acute kidney dysfunction, not due to NSTI, starting 
prior to study drug administration. 
o Pregnant or lactating women; Female of childbearing potential must have a 
negative βsubunit hCG pregnancy test immediately prior to study entry. 
 Frequent follow-up visits 
 A medical monitor and Independent Data Monitoring Committee 
(iDMC) will monitor the safety aspects of the study (see sections 8.6). 
1.3 
Study Treatment 
This is a blinded randomized clinical study in which each patient will receive a single 
treatment of either 0.50 mg/kg AB103 or placebo (0.9% Sodium Chloride sterile solution) 
administered intravenously at one of 2 time points: (A) during surgery or (B) shortly after 
surgery, as long as the administration will be at the earliest time possible and within 6 hours 
from the clinical diagnosis. Administration will be based on clinical diagnosis of bacterial 
NSTI at the study site and a decision for urgent surgical wound debridement, and upon 
confirming the diagnosis of NSTI during the debridement. 
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-202. 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 preparing the drug shall be 
unblinded to the treatment. 
1.4 
Compliance Statement 
This clinical study will be conducted according to the Declaration of Helsinki. The study 
will be conducted in compliance with this protocol, GCP (CPMP/ICH/135/95), designated 
SOPs, and with local laws and regulations relevant to the use of new therapeutic agents in 
the country of conduct. 
1.5 
Study Population 
The study population will consist of patients with a clinical diagnosis of NSTI scheduled 
to undergo urgent surgical exploration and debridement. At the time of surgery, the 
diagnosis of NSTI shall be confirmed. 
290 patients will be recruited into the study and randomized to either 0.5 mg/kg AB103 or 
placebo in a 1:1 ratio. Randomization will be stratified by the diagnosis of Fournier’s 
Gangrene and magnitude of mSOFA score at screening categorized as 3-4 versus >4. In the 
retrospective study analysis set with baseline mSOFA ≥ 3 (N=69), the median value was 4 
and 46.6% had values larger than 4. 


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2. STUDY OBJECTIVES 
2.1 
Primary Objective 
To demonstrate the efficacy of AB103 as compared to placebo, in patients diagnosed with 
NSTI, using a clinical composite success endpoint: 
The NSTI clinical composite score, NICCE will be defined as the primary end point which 
will be composed of the following patient outcomes (i) Alive at Day 28, (ii) Day 14 
debridements ≤3 (iii) No amputation done after the first debridement (iv) Day 14 modified 
SOFA (mSOFA) score ≤1 (mSOFA includes respiratory, cardiovascular, CNS, renal, and 
hematologic organ components but not hepatic/liver component) (v) Reduction of ≥3 score 
points between Baseline and Day 14 mSOFA score. 
Table 4: NICCE Components 
Component 
NICCE 
Survival 
• Alive at Day 28  
Local component 
•  ≤3 debridements throughout Day 14 
•  No amputation beyond first debridement 
Systemic component 
• mSOFA score of ≤1 at Day 14 
• Reduction of ≥3 score points between 
Baseline and Day 14 mSOFA score 
To be considered a success, patients must meet all components of the NICCE. A two-sided 
α=0.01 will be used to test superiority of AB103 relative to placebo for the primary 
endpoint (NICCE). 
Conditional co-primary end point: 
To demonstrate the efficacy of AB103 as compared to placebo, in patients diagnosed with 
NSTI, using a modified clinical composite success endpoint that includes (i) Alive at Day 
28, (ii) Day 14 debridements ≤3 (iii) No amputation done after the first debridement. To be 
considered a success, patients must meet all 3 components of this modified composite 
endpoint. 
The conditional co-primary end point will only be tested if superiority is demonstrated for 
the primary endpoint at a two-sided α=0.01 significance level in order to account for 
multiple comparisons. A two-sided α=0.05 will be used to test superiority of AB103 
relative to placebo for the co-primary endpoint. 
2.2 
Secondary Objectives: 
• To demonstrate the safety of AB103 when administered as a single dose of 0.50 
mg/kg to patients diagnosed with NSTI 
• To demonstrate the efficacy of AB103 as compared to placebo, in patients 
diagnosed with NSTI, using the 5 component clinical composite endpoint but with 
mSOFA ≤1 at Days 21 and 28 


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• Comparison of the distribution of mSOFA scores between treatment groups at Days 
14 and 21 
• Kaplan-Meier analysis of the time to resolution of mSOFA score to ≤ 1 with 
censoring at Day 14 
• To demonstrate the efficacy of AB103 compared to placebo as related to the 
individual components of the NICCE in patients with NSTI 
• To demonstrate efficacy of AB103 in relation to the critical care and hospital stay 
parameters: 
a. ICU days 
b. ICU-free days 
c. Days on ventilator 
d. Ventilator free days 
e. Vasopressor days 
f. Vasopressor free days 
g. Hospital length of stay 
• To demonstrate the efficacy of AB103 in patients with septic shock 
• To determine the incidence of Stage 2 and 3 acute kidney injury (AKI) (using the 
KDIGO criteria) and compare the rates of complete recovery by Day 28 between 
the AB103 treated patients and the placebo treated patients 
• Additional AKI endpoints: 
o To determine the incidence of Stage 2 and 3 AKI (using the KDIGO criteria) 
and compare the rates of complete and partial recovery by Day 28 between 
AB103 and placebo treated patient 
o Determine the incidence of Stage 1, 2 and 3 AKI and compare the rates of 
complete recovery between the AB103 and placebo treated patients 
o Determine the incidence of Stage 1, 2 and 3 AKI and compare the rates of 
complete and partial recovery between the AB103 and placebo treated 
patients 
o Calculate time to complete recovery from AKI 
o Calculate time to partial recovery from AKI 
• To demonstrate the safety of AB103 in regard to secondary infections 
2.3 
Exploratory Objectives: 
• To conduct an exploratory evaluation of the clinical response by baseline pathogen 
• To evaluate microbiological outcome in the microbiological evaluable population 
• 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 NSTI and compare genomic profile in patients 
treated with AB103 versus placebo 
• To evaluate health economic and financial outcomes associated with the treatment 
• To evaluate NICCE outcome in screen failure patients with baseline mSOFA = 2 
and post-operative mSOFA ≥ 3. Note: These patients will not be included in the 


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MITT population analysis (they will not receive blinded study drug) and only 
considered to be an observational cohort 
• To evaluate the immunogenicity of Reltecimod (formerly AB103) 
2.4 
Study Hypothesis 
The primary hypothesis of this study is that in addition to SoC, AB103 will demonstrate a 
clinically significant treatment benefit over placebo. 
This hypothesis will be addressed by measuring the effect of AB103 on a composite of 
clinical parameters associated with the disease course of patients with NSTI, using a 
responder analysis. A responding patient must meet all the 5 parameters of the composite 
clinical success end point, while a non-responding patient can fail by not meeting any one 
of the parameters. These analyses are designed to demonstrate that in addition to being safe, 
one dose of 0.5 mg/kg of AB103 will: 
Improve systemic signs of the infection by improving organ function of patients compared 
to placebo as measured by: 
• Survival at Day 28 
• mSOFA score on Day 14 and change from baseline to Day 14 ≥ 3. Day 14 mSOFA 
score of ≤1 and a change from baseline (pre-treatment) to Day 14 ≥3 will be 
required for a patient to achieve the primary composite clinical success endpoint 
(NICCE) 
Improve the local signs of the infection, as measured by: 
• Reduced number of debridements, counted to Day 14. No more than 3 debridements 
to Day 14 will be required for a patient to achieve composite clinical success 
• No amputation after the first debridement (amputation on the first debridement is 
not considered a failure). A patient will be required to have had no amputations 
done after the first surgical procedure in order to achieve composite clinical success. 
A full response will be considered as meeting all the above systemic and local criteria for 
response, in addition to being alive at Day 28. 
A conditional co-primary endpoint will be evaluated only if the two-sided p-value for the 
primary responder analysis is ≤ 0.01. 
The conditional co-primary endpoint also involves a responder analysis that involves being 
alive at Day 28 and demonstrating improvement in the local signs of infection as measured 
by: 
• A reduced number of debridements, counted to Day 14. A patient with ≤3 
debridements to Day 14 will be considered a responding patient 
• No amputation after the first debridement (amputation during the first debridement 
is not considered a failure). A patient with no amputations performed after the first 
surgical procedure will be considered a responding patient in relation to this 
parameter. 


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3. SELECTION OF STUDY POPULATION 
To be enrolled in the study, patients must meet ALL of the inclusion criteria and NONE of 
the exclusion criteria. 
3.1 
Inclusion Criteria 
1. Age: ≥12 years 
2. 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, tense edema, crepitus and/or subcutaneous gas). 
• Patients with NSTI following intra-abdominal operation are eligible if 
adequate source control of intra-abdominal process has been established 
3. mSOFA score ≥3 (in any one or combination of the 5 major components of 
SOFA score with any one organ component having a score of at least 2: 
cardiovascular, respiratory, renal, coagulation, CNS), measured as close as 
possible to the first debridement, (but before first debridement is performed). 
4. IV drug administration within 6 hours from the clinical diagnosis and the 
decision at the study site, to have an urgent surgical exploration and 
debridement (drug should not be administered until surgical confirmation is 
established). 
5. If a woman is of childbearing potential, she must consistently use an acceptable 
method of contraception from baseline through Day 28. Acceptable birth 
control methods include oral contraceptive medication, an intrauterine device 
(IUD), an injectable contraceptive (such as Depo-Provera®), a birth control 
patch, a barrier method (such as condom or diaphragm with spermicide) or 
abstinence. 
• 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). 
6. 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. 
7. Signed and dated ICF as defined by the IRB and, if applicable, California Bill 
of Rights. By signing the ICF, the patient agrees to release any medical records 
pursuant to current HIPAA Guidelines. If patient is unable to comprehend or 
sign the ICF, patient’s legally acceptable representative may sign the ICF. 


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3.2 
 Exclusion Criteria 
1. BMI >51; 
2. Patient who has been operated at least once for the current NSTI infection and had 
a curative deep tissue debridement (patients who underwent prior diagnostic minor 
surgery are allowed to enter into the study); 
3. Patients with overt peripheral vascular disease in the involved 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; 
4. Diabetic patients with peripheral vascular disease who present with below the ankle 
infection; 
5. Patient with burn wounds; 
6. 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 screening 
despite the presence of vasopressors and IV fluids or (b) a patient with respiratory 
failure such that an SaO2 of 80% cannot be achieved or (c) a patient with refractory 
coagulopathy (INR >5) or thrombocytopenia (platelet count <20,000) that does not 
partially correct with administration of appropriate factors or blood products; 
7. Chronic neurological impairment that leads to a neuro mSOFA component ≥2; 
8. Recent cerebrovascular accident in the last 3 months; 
9. Patients with cardiac arrest requiring cardiopulmonary resuscitation within the past 
30 days; 
10. 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); 
11. Patient or patient’s family are not committed to aggressive management of the 
patient’s condition, or the combination of necrotizing skin infection and underlying 
illness makes it unlikely that life support will be maintained; 
12. 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: 
o CHF {NYHA class III-IV} 
o Severe COPD {GOLD stage III-IV. or chronic hypoxemia (PaO2 <55 
mmHg) on room air, or chronic use of home ventilation, or unable to climb 
stairs or perform household duties due to chronic obstructive disease 
resulting in severe exercise restriction, 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)} 
o Liver dysfunction {Childs-Pugh class C} 
o Immunosuppression (see Appendix F, Section 15.6 for list of excluded 
immunosuppressive medications) 
o Neutropenia < 1,000 cells/mm3not due to the underlying infection 
o Idiopathic Thrombocytopenic Purpura 


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o Receiving or about to receive chemotherapy or biologic anti-cancer 
treatment although hormonal manipulation therapies for breast and prostate 
malignancies are permitted 
o Hematological and lymphatic malignancies in the last 5 years 
13. Known HIV infection with CD4 count < 200 cells/mm3 or < 14% of all 
lymphocytes; 
14. Patients with known chronic kidney disease (documented pre-illness creatinine 
value(s) ≥2.0) or patients receiving renal replacement therapy for chronic kidney 
disease: either hemodialysis, peritoneal dialysis, hemofiltration such as Continuous 
Veno-Venous Hemofiltration (CVVH) or hemodiafiltration 
15. Patients that are treated with continuous hemofiltration (e.g. Continuous Veno-
Venous Hemofiltration) for acute kidney dysfunction, not due to NSTI, starting 
prior to study drug administration. 
Exception: Patients with acute kidney dysfunction due to NSTI may be 
enrolled in the event that the patient is off the treatment from time of study 
drug administration and up to at least one hour post study drug administration. 
16. Pregnant or lactating women; 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 this protocol, ATB-202 or the Phase 2 NSTI trial of 
AB103, ATB-201, or the current Phase 2 SA-AKI trial of AB103, ATB-203. 
3.3 
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. 
3.3.1 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 
be: 
• Withdrawal of consent 
• Lost to follow-up 
• Other reasons such as administrative reasons 


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4. INVESTIGATIONAL PLAN 
4.1 
Study Rationale 
4.1.1 Dose Selection Rationale 
Selection of a dose regimen for the pivotal Phase 3 study was based on the safety results 
from the Phase 1 and 2 trials and efficacy results from Phase 2. Evidence for dose response 
in the Phase 2 study is based on consistency across multiple domains of outcome variables. 
In several efficacy parameters, a linear dose response emerged for individual endpoints. In 
addition, to adjust for group differences at baseline and for the distorted distribution of 
values, non-parametric comparisons between dose groups were used, which indicated that 
0.5 mg/kg had an advantage over the 0.25 mg/kg, especially in cases of patients that stayed 
for a longer time in the ICU or required ventilation. Overall, based on the reproducibility 
of the dose response in the various parameters, and given that there was no change in the 
safety profile when increasing the dose from 0.25 mg/kg to 0.50 mg/kg, Atox Bio believes 
that the 0.5 mg/kg given as a single dose is the optimal dose for the proposed Phase 3 ATB-
202 clinical trial. 
The comparative effect of high and low dose groups is shown in Table 5. 
Table 5: Comparative effect of high and low dose groups – Study ATB-201 
Outcome 
0.5 mg/kg 
0.25 mg/kg 
Total SOFA at Day 14 
√ 
 
Individual organ SOFA score at Day 14 
√ 
 
Changes in total score between days 1-14 
√ 
 
Percent of patients with organ failure at Day 14 
√ 
 
SOFA score in patients with established organ 
failure at Day 1 
√ 
 
Debridements to Day 7 or 28 
√ 
 
ICU stay 
√ 
√ 
Ventilation days 
√ 
√ 
Hospital stay 
√ 
√ 
Inflammatory biomarkers (systemic) 
√ 
 
Inflammatory biomarkers (local infection site) 
√ 
 
Mortality 
√ 
√ 
√= higher effect size compared to Placebo. 
The determination of this dose has also been discussed with the FDA. Overall, the dose and 
dosing regimen for the pivotal study is based on: (i) the Phase 2 results demonstrated a 
strong and consistent effect of the 0.5 mg/kg; (ii) the pre-clinical data demonstrated that the 
5 mg/kg dose (equivalent to human 0.5 mg/kg dose) consistently provided optimal efficacy; 
(iii) pre-clinical data demonstrated a bell shape dose response curve, common to many 
immunomodulatory and peptide therapies, in which a single dose of 5 mg/kg (mouse) is 
optimal, with higher doses being less efficacious. 


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Therefore, a single dose of 0.5 mg/kg was considered to provide the most favorable 
risk/benefit for this patient population with severe and potentially life-threatening 
necrotizing skin and skin structure infection. 
4.2 
Allocation of Treatment, Randomization and Study Drug Administration 
4.2.1 Allocation of Treatment and Randomization 
Once the patient has a clinical diagnosis of bacterial NSTI at the study site and a decision 
for urgent surgical wound exploration and debridement has been taken, all 
inclusion/exclusion criteria have to be verified and an ICF has to be obtained. The 
pharmacist should be notified. The pharmacist will get the treatment allocation via a web-
based dedicated (Interactive Web Response, IWR) software available only to the study 
pharmacist. All other study-related personnel, hospital care givers, the Sponsor and the 
patient will remain blinded. 
Following allocation of treatment and surgical confirmation of NSTI, the study pharmacist 
will prepare the study drug (sites may choose to have the study pharmacist prepare study 
drug after treatment allocation but before surgical confirmation of NSTI but study drug can 
only be administered upon surgical confirmation of NSTI). When the study drug is ready 
for infusion, last verification of inclusion/exclusion criteria will take place pertaining to the 
6 hours’ time limit for drug administration (and any significant change in patient condition 
that would warrant the patient’s exclusion from the study). 
4.2.2 Study Drug Administration 
The drug can be administered at either one of 2 time points: Option A: during surgery and 
Option B: after surgery. In both instances, the study drug administration must be initiated 
within 6 hours of the time at which the patient was clinically diagnosed at the study site as 
having NSTI and the decision was made to undergo urgent surgical debridement. The NSTI 
diagnosis should also be confirmed surgically, and in case it is not confirmed surgically the 
patient will not receive the drug and will be considered as a screening failure. 
In case study drug has been prepared but a patient did not receive it, the web-based 
dedicated software will be updated to ensure an overall 1:1 ratio between the AB103 and 
placebo treatment groups. 
4.3 
Schedule of Procedures/Visits 
A schedule of study assessments is shown in Appendix A, Section 15.1 the protocol.  
Visiting nursing services, including Symphony Clinical Research, are allowed for outpatient 
visits. Symphony Clinical Research is contracted to evaluate subjects as outpatients as early as 
Day 10 through Month 3. 
4.3.1 Visit 1: Screening 
Evaluation starts once a clinical diagnosis of NSTI was entertained and a decision for 
urgent surgical wound exploration and debridement was made: 
• Obtain ICF 


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• Verification of Inclusion/Exclusion criteria 
• Randomization & study drug preparation (study drug should not be prepared until 
there is surgical confirmation of NSTI) 
• Demographics, Medical history, Infected lesion history, Concomitant medications, 
Vital signs, Height, Weight, calculate BMI, PE 
• Urine output recording to start from time of ICU admission and while Foley catheter 
is in place (captured in 6 hour intervals based on calendar day) 
• Recording baseline signs and symptoms and AEs/SAEs (AEs of Day 0 are AEs/ 
SAEs starting after obtaining ICF until study drug administration) 
• Safety baseline laboratory tests: 
o Full chemistry panel 
o Obtain complete blood count (CBC) with differential and platelet count 
(sample can be same as that required to be taken in conjunction with the 
RNA expression profile test sample) 
• C-reactive protein (CRP) 
• Arterial blood gases and FiO2 (if applicable) -may use SpO2 value if arterial blood 
gas is not clinically indicated 
• Collect data on acute renal replacement therapy 
• Collect data on plasma or platelet transfusion 
• Blood culture for both aerobic and anaerobic bacteria 
• Pregnancy test if applicable (blood or urine whichever is faster) 
• Screening mSOFA score measurements must be performed prior to first surgery: 
should be evaluated any time after arrival at the hospital (may include referring 
hospital), although no more than 6 hours prior to anticipated first surgery. Sites are 
encouraged to re-evaluate mSOFA score as close to surgery as feasible for patients 
not meeting mSOFA ≥3 inclusion criteria during initial screening. Baseline mSOFA 
will include measurements of the score components in the following organ/systems 
(with any one organ having a score of at least 2 at screening): respiratory, 
cardiovascular, renal, coagulation and CNS 
• APACHE II score, LRINEC and Anaya scores (measurement for these scores will 
be collected and scores will be calculated retrospectively). The clinical parameters 
of these scores (respiratory, cardiovascular, vital signs) should be taken as close as 
possible to the surgery, but prior to the surgical anesthesia or any other surgical 
related procedures e.g. mechanical ventilation. The worst laboratory values 
available within 24 hours of surgical intervention for NSTI should be recorded. 
Critical care parameters (dates and times of assisted ventilation, vasopressor use, 
ICU and hospital admission and discharge) 
• Local lesion assessment and evidence of amputation (excision to a joint space) 
• Surgery for NSTI and confirmation of diagnosis. Record time of surgery 
• During surgery: Tissue samples for microbiology 
• 12 Lead ECG (can be performed any time during screening period or just prior to 
study drug administration) 


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• Upon study drug administration patient is transited to visit 2 (either during or after 
the surgery)  
• Collect blood for serum for storage (immunogenicity testing) 
• Collect urine and blood for plasma for storage (AKI biomarker analysis) 
• Collect whole blood for leukocyte transcriptome (RNA expression) profiling 
• Perform randomization 
4.3.2 Visit 2 (Day 1) 
Starts ONLY upon study drug administration and terminates at the end of the calendar day. 
Study drug may be given either during surgery or immediately after the surgery. 
• Drug administration should be completed within 6 hours from the clinical diagnosis 
of NSTI and a decision at the study site for urgent surgical wound exploration and 
debridement 
• Collect data on operative procedures(see Section 6.2.6.1 for description of 
adjudication of operative procedures for assignment of study defined debridement) 
• Collect data on acute renal replacement therapy 
• Collect data on plasma or platelet transfusion 
• Collection of AEs/ SAEs 
• Concomitant medications 
• Vital signs (first set of vitals on that day) 
• Symptom-driven interim PE 
• 12-Lead ECG at the end of study drug infusion, at 4-6 hours and 12-24 hours post 
administration of study drug 
• Urine output (should be recorded continuously from time of ICU admission to Day 
7, if still in ICU and Foley catheter in place, using 6 hour intervals and by calendar 
day) 
• Weight, only if not collected at screening 
• Collect data on additional amputations 
• Critical care parameters (dates and times of assisted ventilation, vasopressor use, 
ICU /hospital stay) 
• Systemic response: mSOFA score. Measurements will be collected within 16-24 
hours post study drug administration, unless the patient is scheduled to undergo 
additional debridement; in such case data collection for mSOFA parameters will be 
taken prior to the next debridement 
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 
o Obtain CBC with differential and platelet count (sample can be same as that 
required to be taken in conjunction with the RNA expression profile test 
sample) 
• Assess lesion status (healing/progression/significant change in appearance) if 
accessible for visible assessment at time of debridement or routine dressing change 


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• Collect whole blood for leukocyte transcriptome (RNA expression) profiling at 4-6 
hours post study drug dose 
• Survival 
4.3.3 Visit 3 (Day 2) 
• Collect data on operative procedures  
• Urine output (should be recorded continuously from time of ICU admission to Day 
7, if still in ICU and Foley catheter in place, using 6 hour intervals and by calendar 
day) 
• Collection of AEs/ SAEs 
• Collect data on additional amputations 
• Collect data on acute renal replacement therapy 
• Collect data on plasma or platelet transfusion 
• Concomitant medications 
• Vital signs (to be taken during the morning tests) 
• Critical care parameters (dates and times of assisted ventilation, vasopressor use, 
ICU /hospital stay) 
• Systemic response: mSOFA 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 if arterial blood gas is not 
clinically indicated 
o Obtain serum creatinine 
o Obtain CBC with differential and platelet count (sample can be same as that 
required to be taken in conjunction with the RNA expression profile test 
sample but must be on the same calendar day as study Day 2) 
• Assess lesion status (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±4 
hours after study drug administration 
• Collect whole blood for leukocyte transcriptome (RNA expression) profiling at 
24±4 hours after study drug administration 
o CBC with differential required to be obtained in conjunction with sample 
for RNA expression profile best 
• Record Survival 
4.3.4 Visit 4 (Day 3) 
• Collect data on operative procedures  
• Obtain tissue for microbiology if debridement performed on Day 3 
• Collect data on acute renal replacement therapy 
• Collect data on plasma or platelet transfusion 
• Urine output (should be recorded continuously from time of ICU admission to Day 
7, if still in ICU and Foley catheter in place, using 6 hour intervals and by calendar 


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day). Collection of AEs/ SAEs including secondary infections (based on CDC 
definitions for healthcare associated infections) 
• Collect data on additional amputations 
• 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: mSOFA 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 
o Obtain CBC with differential and platelet count (sample can be same as that 
required to be taken in conjunction with the RNA expression profile test 
sample) 
• Assess lesion status (healing/progression/significant change in appearance) if 
accessible for visible assessment at time of debridement or routine dressing change 
• Collect whole blood for leukocyte transcriptome (RNA expression) profiling 
o CBC with differential required to be obtained in conjunction with sample 
for RNA expression profile best 
• Record Survival 
4.3.5 Visit 5 (Day7 [±1 day]) 
• Collect data on operative procedures  
• Collect data on acute renal replacement therapy 
• Collect data on plasma or platelet transfusion 
• Urine output (should be recorded continuously from time of ICU admission to Day 
7, if still in ICU and Foley catheter in place, using 6 hour intervals and by calendar 
day) 
• Weight (if easily obtained) 
• Collection of AEs/ SAEs including secondary infections (based on CDC definitions 
for healthcare associated infections) 
• Collect data on additional amputations 
• Concomitant medications 
• Vital signs (to be taken during the morning tests) 
• PE 
• Safety laboratory tests (Chemistry, Hematology) 


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o Sample for CBC with differential and platelet count can be same as that 
required to be taken in conjunction with the RNA expression profile test 
sample 
• Assess lesion status (healing/progression/significant change in appearance) if 
accessible for visible assessment at time of debridement or routine dressing change 
• Critical care parameters (dates and times of assisted ventilation, vasopressor use, 
ICU /hospital stay) 
• Systemic response: collect data for mSOFA 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. 
• Collect urine and blood for plasma for storage (AKI biomarker analysis) 
• Collect whole blood for leukocyte transcriptome (RNA expression) profiling 
o CBC with differential required to be obtained in conjunction with sample 
for RNA expression profile best 
• Record Survival 
4.3.6 Visit 6 (Day 10 [±1 day]; perform only if patient is still hospitalized): 
• Collect data on operative procedures  
• Collection of AEs/SAEs, including secondary infections (based on CDC definitions 
for healthcare associated infections) 
• Collect data on additional amputations 
• Collect data on acute renal replacement therapy 
• Collect data on plasma or platelet transfusion 
• Selected concomitant medications (e.g. vasopressors, antimicrobials) 
• Symptom-driven interim PE 
• Vital signs 
• Critical care parameters (dates and times of assisted ventilation, vasopressor use, 
ICU /hospital stay) 
• Systemic response: collect data for mSOFA 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 Obtain serum creatinine 
o Obtain CBC and platelet count (differential not required for Day 10) 
• Assess lesion status (healing/progression/significant change in appearance) if 
accessible for visible assessment at time of debridement or routine dressing change 
• Record Survival 
4.3.7 Visit 7 (Day 14 [±1 day]) 
• Collect data on operative procedures  
• Weight 


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• Collection of AEs/SAEs, including secondary infections (based on CDC definitions 
for healthcare associated infections) 
• Collect data on additional amputations 
• Collect data on acute renal replacement therapy 
• Collect data on plasma or platelet transfusion 
• Selected concomitant medications (e.g. vasopressors, antimicrobials) 
• Safety laboratory tests (Chemistry, Hematology) 
• Collect blood for serum for storage (immunogenicity testing) 
• PE 
• Vital signs 
• CRP 
• Critical care parameters (dates and times of assisted ventilation, vasopressor use, 
ICU /hospital stay) 
• Systemic response: collect data for mSOFA 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 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 (healing/progression/significant change in appearance) if 
accessible for visible assessment at time of debridement or routine dressing change 
• Record Survival 
All efforts should be made to collect these data, but in case parameters cannot be collected, 
phone follow-up will be performed, and information that could be collected over the phone 
will apply. 
4.3.8 Visit 8 (Day 21 [±1 day]) 
• Collection of AEs/SAEs, including secondary infections (based on CDC definitions 
for healthcare associated infections) 
• Collect data on additional amputations 
• Collect data on acute renal replacement therapy 
• Collect data on plasma or platelet transfusion 
• Selected concomitant medications (e.g. vasopressors, antimicrobials) 
• Critical care parameters (dates and times of assisted ventilation, vasopressor use, 
ICU /hospital stay) 
• Vital Signs 
• Systemic response: collect data for mSOFA 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 Obtain serum creatinine 
o Obtain CBC and platelet count (differential not required for Day 21) 


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• Record Survival 
4.3.9 Visit 9 (Day 29 [+2 days]) 
• Weight 
• Collection of AEs/SAEs, including secondary infections 
• Collect data on additional amputations 
• Selected concomitant medications (e.g. vasopressors, antimicrobials) 
• Critical care parameters (dates and times of assisted ventilation, vasopressor use, 
ICU /hospital stay) 
• Systemic response: collect data for mSOFA 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 Obtain serum creatinine and albumin 
o Obtain CBC with differential and platelet count 
• Collect blood for serum for storage (immunogenicity testing) 
• Vital signs 
• Collect data on acute renal replacement therapy 
• Collect data on plasma or platelet transfusion 
• Collection of health economic information: will include several parameters, such as 
(but not limited to): ICU charges, hospital stay (regular floor) charges, direct costs, 
indirect costs, reimbursement payments 
• Record any hospital re-admissions (if previously discharged for original NSTI 
related hospitalization) 
• Record Survival 
All efforts should be made to collect these data, but in case parameters cannot be 
collected, phone follow-up will be performed, and information that could be collected 
over the phone will apply 
4.3.10 Visit 10 (3 months [±5 days]) 
The 3-month visit is a follow-up visit to assess the long-term health condition of the patients 
including assessment of renal function in patients with documented persisting AKI at the 
Day 29 visit and ascertainment of readmission(s) within 30 days of discharge from original 
NSTI related hospitalization. Creatinine should be obtained at this visit given the 
requirement to also obtain serum for storage (for immunogenicity testing).  The serum for 
storage (immunogenicity testing) has priority over creatinine in the order of blood draw if 
the blood drawn is limited.  
4.3.11 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. 


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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 with 
the Investigator's copy of the patient's eCRF. A clinical evaluation should be made based 
on the last contact with the patient. 
Serious Adverse Events (SAEs) occurring within 28 days of a patient receiving IMP will 
be recorded and processed as described in Section 8.4 of the protocol. 
4.4 
Sub-study mSOFA = 2 
Projected number of patients 60.  Note: These patients will not will not receive blinded 
study drug and are only considered to be an observational cohort. 
4.4.1 Screening Visit for patients with mSOFA =2 
Evaluation starts once a clinical diagnosis of NSTI was entertained and a decision for 
urgent surgical wound exploration and debridement was made: 
• Obtain ICF 
• Verification of Inclusion/Exclusion criteria 
• Register in IWR  
• Demographics, Medical history, Infected lesion history, Concomitant medications, 
Vital signs, Height, Weight, calculate BMI, PE 
• Recording baseline signs and symptoms and AEs/SAEs (AEs of Day 0 are AEs/ 
SAEs starting after obtaining ICF until study drug administration) 
• Pregnancy test if applicable (blood or urine whichever is faster) 
• Baseline mSOFA per section 4.3.1. Baseline mSOFA (where 2 organ components 
score a 1 or one component scores a 2) will include measurements of the score 
components in the following organ/systems: respiratory, cardiovascular, renal, 
coagulation and CNS. 
• Post-operative mSOFA score measurements to be performed after surgery and 
within 6 hours of decision for urgent surgical wound exploration and debridement 
o Repeat complete blood count (CBC) 
o Repeat creatinine 
o Arterial blood gases and FiO2 (if applicable) -may use SpO2 value if arterial 
blood gas is not clinically indicated 
• Critical care parameters (dates and times of assisted ventilation, vasopressor use, 
ICU and hospital admission and discharge) 
• Local lesion assessment and evidence of amputation (excision to a joint space) 
• Surgery for NSTI and confirmation of diagnosis. Record time of surgery 
• Record Survival 
4.4.2 Day 7 or Day 10 Visit [±1 day] 
• Collect data on operative procedures  


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• Collection of AEs/SAEs, including secondary infections (based on CDC definitions 
for healthcare associated infections) 
• Collect data on additional amputations 
• Collect CBC and creatinine 
• Systemic response: collect data for mSOFA 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 In case a patient is discharged from hospital prior to these days SOFA 
parameters should be obtained on the same day of discharge. 
• Record Survival 
4.4.3 Day 14 Visit [±1 day] 
• Collect data on operative procedures 
• Collection of AEs/SAEs, including secondary infections (based on CDC definitions 
for healthcare associated infections) 
• Collect data on additional amputations 
• Collect CBC and creatinine 
• Systemic response: collect data for mSOFA 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 In case a patient is discharged from hospital prior to these days SOFA 
parameters should be obtained on the same day of discharge. 
• Record Survival 
4.4.4 Day 29 Visit [+2 days] (via phone if patient no longer hospitalized) 
• Collect data on additional amputations 
• Record Survival 


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5. TREATMENT OF PATIENTS 
5.1 Investigational Medicinal Product 
This is a blinded randomized clinical study with 2 treatment groups consisting of 0.50 
mg/kg AB103 and placebo. Patients will be randomized in a 1:1 ratio. Each patient will be 
administered a single intravenous infusion of AB103 based on actual body weight to be 
infused over 10 minutes. Volume of administration will depend on patients’ actual weight. 
The study drug can be administered during or after surgical exploration and debridement 
but no later than 6 hours from the time of clinical diagnosis of NSTI and a decision at the 
study site for urgent surgical wound exploration and debridement. 
AB103 will be supplied in glass vials as a lyophilized powder to be reconstituted with 
sterile water for injection (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 calculated based on the patient's 
weight plus adequate priming volume of the IV line. 
Placebo will be pyrogen-free, preservative-free sterile 0.9% saline, USP calculated based 
on the patient’s weight, plus adequate priming volume of the IV line. 
5.1.1  Presentation and Formulation 
AB103 is the acetate salt of a 10 amino acid synthetic peptide. AB103 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 containing 10.5 mg of peptide AB103 per vial, 300 
mg of mannitol, and 36 mg of NaCl, to be reconstituted with 10.5 mL of sterile WFI. The 
reconstituted AB103 drug product contains 1 mg/mL of the AB103 peptide. 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 blue 
aluminum overseals. 
Each vial of the drug product to be used in clinical trials is reconstituted with 10.5 mL of 
WFI to deliver 10 mLof solution, or 10 mg of AB103. Each vial contains 10.5 mg of peptide 
AB103, 300 mg of mannitol, and 36 mg of NaCl to be reconstituted with 10.5 mL of WFI. 
The lyophilized AB103 drug product is stored at -20° C ±5° C. Prior to use, each vial of 
drug (10.5 mg) is solubilized in 10.5 mL of water for injection to generate a drug 
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 need to be pooled together by the study pharmacist, under sterile conditions. The 
number of vials would depend on the patient's weight, in order to achieve a dose of 0.5 
mg/kg. The AB103 drug product will be administered via a syringe infusion pump (may be 
manually pushed if approved by the medical monitor) in a separate catheter as a single 
intravenous infusion given over 10 minutes at a dose of 0.5 mg/kg. 


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The manufacturer of the clinical batches of the drug substance is Bachem Americas, Inc., 
Torrance CA. The manufacturer of the drug product is Pyramid Laboratories Inc., Costa 
Mesa, CA. 
5.1.2 Storage 
IMP will be stored in a limited access area, under appropriate environmental conditions. 
AB103 should be stored at -20°C ± 5°C in a secure, temperature-monitored freezer located 
in Investigational Drug Service. 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. 
5.1.3  Administration 
AB103 and placebo, formulation and/or preparation of each AB103 or placebo will be 
performed by the clinical site pharmacist. 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 will be unblinded. Administration will be by IV infusion using a syringe pump 
(may be manually pushed if approved by the medical monitor) over a 10 minute period. 
5.1.4  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 procedures 
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 return or disposal. The IMP supplied for this study is 
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 return 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 with returned or unused IMP. Appropriate IMP disposition documentation 
will be maintained as part of the source documentation. Permission may be granted for 
local disposal with supporting documentation. 


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5.2 
Concomitant Medications 
5.2.1 Disallowed Medications 
Study participants should not receive immunosuppressant agents or chemotherapy and 
should preferably not be given high doses of steroids (defined as >40 mg or 0.5 mg/kg 
prednisone (or steroid with equivalent activity)/day for ≥2 weeks (see Appendix F – Section 
15.6). 
 
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. 
5.2.2 Allowed Medications 
5.2.2.1 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). 
5.2.2.2 Non-antimicrobial medications 
All 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. 
5.3 
Study Medication Compliance 
Compliance will be monitored by recording the total volume of each investigational agent 
actually delivered to each study patient. 
5.4 
Precautions and Overdose 
5.4.1 Study Drug - AB103 
5.4.1.1 Precautions 
Currently available safety information does not require any special precautions to be 
exercised during treatment with AB103. Analysis of safety data collected in AB103 Phase 
1 and 2 studies, did not reveal AEs that were determined as related to AB103 (including 


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possibly, probably and definitely related to study drug). In animal toxicology studies no 
target organs were identified. 
5.4.1.2 Over dosage 
To date, throughout the AB103 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 0.5 mg/kg intended dose of AB103), the site staff should contact 
the medical monitor.  Additionally, the patient should be monitored and followed-up 
according to the best medical practice. 
5.4.2 Placebo Comparator 
No known or expected adverse reactions are associated with pyrogen-free, preservative-
free, physiologic saline. 
5.4.2.1 Precautions 
None for placebo comparator. 


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6. STUDY PROCEDURES 
6.1 
Informed Consent 
The ICF must be 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 must explain the nature of the study 
to each patient or legal representative, 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 legal representative must read and understand 
the ICF and voluntarily sign a consent form in the presence of the Investigator/designee. 
The patient will be given a copy of the signed/dated ICF. 
6.2 
Clinical and Laboratory Procedures 
6.2.1 Start of Drug Administration Clock 
The IV drug administration clock of maximal 6 hours starts once a clinical diagnosis has 
been made in the study site and a documented decision is made to take the patient into the 
operating room for a surgical exploration and debridement and confirmation of the 
diagnosis. The exact time of decision to operate should be recorded. 
6.2.2 Inclusion/Exclusion Criteria 
The inclusion and exclusion criteria are specified in Sections 3.1 and 3.2. 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. 
6.2.3 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. 
 
Baseline signs and symptoms should be captured on the Adverse Event eCRF with attempts 
to capture dates and times that would identify them as pre-treatment emergent events. 
 
Details of the NSTI will be recorded on the eCRF and include: “clinical diagnosis” (as a 
specific subset of NSTI) at the time of enrollment; location of primary infection; date of 
onset of symptoms, identified predisposing factors (trauma, surgery, IV drug use, and co-
morbidities such as diabetes or vascular insufficiency; prior surgical procedures related to 
the etiology of NSTI; prior surgical procedures for the treatment of the primary infection 
site; 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).  
 


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6.2.4 Physical Examinations 
Physical exam will include both the primary site of the NSTI and a clinically appropriate 
examination of vital organ systems. These should include cardiovascular, respiratory, 
abdomen, extremities, and neurologic body systems. 
6.2.4.1 Interim physical examinations (symptom-driven) 
Interim physical exam will be targeted to include clinically appropriate examination of 
specific organ systems based on patient related signs and symptoms. 
6.2.5 Concomitant Medication 
All concomitant medications antimicrobial & non-antimicrobial (with the exception of over 
the counter medications, 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 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 Principle Investigator. 
6.2.6 Primary Infection Site 
The primary 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. 
6.2.6.1 Debridement 
A debridement is defined as a surgical intervention, performed in the operating room to 
eliminate a substantial amount of necrotic tissue, based on the description by the surgeon 
in the operative note. Irrigation of the wound or dressing change in the operating room 
without tissue removal will not be considered a debridement. Also, minimal procedures to 
trim margins are not considered a true debridement, nor are bedside procedures, such as a 
dressing change or Vacuum Assisted Closure (VAC) change. 
All operative procedure reports (following appropriate de-identification) will be collected 
up through Day 14 and any operative reports related to amputations will be collected 
through Day 28.  An adjudication panel of 3 surgeons (investigators involved in the clinical 
trial) will evaluate the operative reports, in a blinded manner, to assign whether an operative 
procedure meets the debridement definition as noted above. 


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6.2.7 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 (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, Appendix A, Section 15.1. 
6.2.8 Clinical Scores 
Clinical scores/criteria components will be collected in the study. APACHE II, LRINEC 
and Anaya score criteria only at screening while mSOFA score throughout the study (see 
Appendix E, Section 15.5). APACHE II, LRINEC and Anaya criteria will be used to 
determine disease severity while mSOFA score will be used as a clinical endpoint. 
Individual parameters of the mSOFA score will be collected and will also be correlated to 
response. Clinical site personnel will calculate the mSOFA at screening to determine 
patient eligibility, otherwise all other clinical scores will be calculated retrospectively by 
the blinded statisticians. (See scores details in Appendix E, Section 15.5). Data will be 
recorded in the eCRF at specified time points according to time and events Section 15.1. 
6.2.8.1 SOFA score definition 
Screening mSOFA: includes measurements of 5 organ systems (cardiovascular, respiratory, 
renal, coagulation, CNS but not liver/hepatic component). Screening mSOFA score should 
be evaluated any time after arrival at the study site hospital, although no more than 6 hours 
prior to anticipated first debridement. Screening mSOFA score must be ≥3, with any one 
organ component having a score of at least 2, to be considered eligible for enrollment. Sites 
are encouraged to re-evaluate mSOFA score as close to surgery as feasible for patients not 
meeting mSOFA ≥3 inclusion criteria during initial screening. 
mSOFA score: measurements of a 5 organ systems, including CNS. To be measured on 
Days 1, 2, 3, 7, 10 14, 21 and 29 and calculated retrospectively by the blinded statisticians. 
mSOFA respiratory parameter: 
In case it is not possible to take arterial blood gases to determine the mSOFA respiratory 
parameter, SpO2/FiO2 ratio can be imputed for PaO2/FiO2 ratio. 
6.2.9 Electrocardiogram 
12-lead electrocardiogram will be collected at visits 1 (prior to study drug administration) 
and 2 [at the end of study drug administration (when site personnel can gain access to the 
patient), within 4-6 hours and 12-24 hours post study drug administration], according to 
time and events (Section 15.0). The ECG will be evaluated for any abnormality and the 
following parameters will be recorded for each ECG: PR interval, RR interval, QRS 
complex time, QT interval and Corrected QT interval (QTc). Two copies of the ECG 
tracing will be produced. One copy is to be saved at the study site and the other copy to be 
sent to the independent central ECG reviewer (ACI Clinical, Bala Cynwyd, PA). 


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6.2.10 Clinical Laboratory Assessments 
Safety laboratory investigations will include hematology (complete blood count including 
platelets and white cell differential), chemistry (Glucose; Electrolytes (Sodium, Potassium, 
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); Calcium; Phosphorus; CRP will be obtained 
during screening and at Day 14. Pregnancy testing will be done on all women of 
childbearing potential participating in the study, (using blood test or urine test whichever 
is faster). Those tests will be collected at intervals according to time and events Section 
15.1 
6.2.11 Immunogenicity 
Blood (6 mL) for serum will be collected at screening, Days 14 and 29, and Month 3 visits 
for immunogenicity testing.  The specific assay to test for immunogenicity against AB103 
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. 
6.2.12 Biomarkers 
Urine (5 mL) and blood (5 mL) for plasma will be collected for evaluations of biomarkers 
to assess AKI. The specific AKI biomarkers will be determined at the end of the trial. 
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 -70 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 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. 
6.2.13 RNA Expression 
The purpose of the whole blood leukocyte transcriptome (RNA expression) profile testing 
is to obtain insight in the effect of AB103 on the host response to NSTI by detailed and 
unbiased analysis of the blood leukocyte response. For this, 5 mL of whole blood will be 
collected in 2 Paxgene tubes (PreAnalytix, Hombrechtikon, Switzerland; 2.5 mL per tube) 
before initiation of AB103 administration and at 4-6 hours, 24 hours, 72-96 hours and 7 


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days thereafter. At each of these time points whole blood leukocyte counts and differentials 
will be determined by the local laboratory. Genome-wide whole blood RNA expression 
profiling will be performed on the Affymetrix GeneTitan instrument using the U219 96-
array microarray chip or equivalent. Samples may be stored for up to 5 years but will only 
be used for the evaluation of the effect of AB103 on host response to NSTI. Results will 
not be reported to the treating physician or the subjects (or their relatives). A detailed 
description of the collection, processing and storage of the samples can be found in a 
separate Laboratory Manual for the study. 
6.2.14 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. Less than a unit of blood (12.5 tablespoons) will be collected for each 
patient. 
Table 6: Maximal Blood Drawing 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 
AKI Biomarker 
5 
Blood leukocyte transcriptome profile 
5 
Immunogenicity sample 
6 
Total Volume 
52 
2 
Day 1 
Hematology (CBC with differential and platelets) 
4 
Arterial Blood Gas*  
2 
Creatinine & Hematology (For SOFA calculation 16-24h post study 
drug administration) 
7 
Blood leukocyte transcriptome profile (4-6 hour post study drug 
administration sample) 
5 
Total Volume 
18 
3 
Day 2 
AKI biomarker 
5 
Blood leukocyte transcriptome profile  
5 
Arterial Blood Gas* 
2 
Chemistry (only Creatinine) 
3 
Hematology (CBC with differential and platelets-) 
4 
Hematology (only platelet count)-obtain if full CBC to be done with 
transcriptome sample is not performed on same calendar day as 
study Day 2 
4 
Total Volume 
23 
4 
Day 3 
Chemistry (only Creatinine) 
3 
Hematology (CBC with differential and platelets-can be used for 
mSOFA data and for the transcriptome ) 
4 
Arterial Blood Gas* 
2 


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Visit 
Type 
Maximal 
Volume (cc) 
Blood leukocyte transcriptome profile 
5 
Total Volume 
14 
5 
Day 7 
Chemistry  
4 
Hematology (CBC with differential and platelets) 
4 
Arterial Blood Gas*  
2 
AKI biomarker 
5 
Blood leukocyte transcriptome profile 
5 
Total Volume 
20 
6 
Day 10 
Arterial Blood Gas*  
2 
Chemistry (only Creatinine)  
3 
Hematology (Platelets only) 
4 
Total Volume 
9 
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 
 
Arterial Blood Gas*  
2 
Chemistry (only Creatinine)  
3 
Hematology (Platelets only) 
4 
Total Volume 
9 
9 
Day 29 
Arterial Blood Gas*  
2 
Chemistry (only Creatinine & Albumin) 
3 
Hematology (CBC with differential and platelets) 
4 
Immunogenicity sample 
6 
Total Volume 
15 
10 
Month 
3 
Chemistry (only Creatinine)  
3 
Immunogenicity sample 
6 
Total Volume 
9 
Total Study 
188 
* Obtain ABG if clinically indicated. Otherwise record SpO2 value and also FiO2.  
6.2.15 Microbiology 
Microbiological testing will follow the SoC of treatment of NSTI patients. At the time of 
initial surgical exploration, and if surgical debridement is performed on study Day 3, a 
tissue sample will be cultured by the local microbiology laboratory. 
The deep tissue specimens will be obtained at the time of the first debridement at the 
operating room at the study site medical center. Antibiotics received prior to the primary 
surgical debridement will be identified as well as antibiotics received during the study 
evaluation window of Days 1-28. 
A specimen of infected tissue will be taken from the infected area, will be placed in a sterile 
container and transported by hand to the local designated clinical microbiology laboratory 
at the institution and according to the approved methods of each medical center. The 
specimens will then be processed as soon as possible by homogenization, the homogenate 
will be Gram stained, and cultured under 2 different conditions for testing of aerobic and 
anaerobic pathogens 


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Cultures of the NSTI wound will be obtained according to the schedule of events on Section 
15.1. 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 Microbiology 40. 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 screening 
process. 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). 
Bacterial isolates identified as Streptococcus pyogenes or Staphylococcus aureus will be 
stored frozen at the site and shipped to the Central Microbiology Laboratory (IHMA, 
Schaumburg, IL) for future testing. Instructions for freezing, storage and shipping of the 
bacterial isolates can be found in a separate Laboratory Manual for the study. 
6.2.16 Use of additional rescue therapy 
The following measures of medical rescue therapies will be recorded: 
• Hyperbaric oxygen 
• Corticosteroid use 
• IVIG use 
• Plasmapheresis 


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7. EVALUATION MEASURES FOR EFFICACY 
7.1 
Primary Efficacy Measures 
To demonstrate the efficacy of AB103 as compared to placebo, in patients diagnosed with 
NSTI, using a clinical composite success endpoint: 
The NSTI clinical composite score, NICCE will be defined as the primary end point which 
will be composed of the following patient outcomes (i) Alive at Day 28, (ii) Day 14 
debridements ≤3 (iii) No amputation done after the first debridement (iv) Day 14 modified 
SOFA (mSOFA) score ≤1 (mSOFA includes respiratory, cardiovascular, CNS, renal, and 
hematologic organ components but not hepatic/liver component) (v) Reduction of ≥3 score 
points between Baseline and Day 14 mSOFA score. 
Conditional Co-Primary Efficacy Measure: 
Modified clinical composite endpoint: Success is defined as meeting all 3 components of 
the composite score: Alive until Day 28, (ii) Day 14 debridements ≤3 (iii) No amputation 
done after the first debridement (See Section 2.1 and Table 4). 
7.2 
Secondary Measures 
• 5 component clinical composite endpoint but with mSOFA ≤1 at Days 21 and 28 
• Distribution of mSOFA scores at Days 14 and 21 
• Kaplan-Meier analysis of the time to resolution of mSOFA score to ≤1 with 
censoring at Day 14 
• Single components of the composite end point 
o Alive at Day 28 
o Number of patients with debridements by Day 14 ≤3 
o Number of amputations (excision to a joint space) (done after first 
debridement) 
o mSOFA score on Day 14 ≤1 
o Reduction of ≥3 score points between Baseline and Day 14 mSOFA score. 
• Critical care and hospital stay parameters, to be measured until Day 28 
o ICU-free days 
o Days in ICU 
o Days on ventilator 
o Ventilator free days 
o Vasopressors days/ Vasopressors free days 
o Hospital length of stay (days) 
• Clinical local parameters: 
o Number of debridement to days 7, 10, 14 and 28 
o Proportion of patients needing (up to Day 14): 
1.  only one debridement to control the infection 
2. ≥2 debridements to control the infection 
3. ≥3 debridements to control the infection 


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• Clinical systemic parameters: 
o Evaluation of organ function over time, using mSOFA score 
o Recovery from AKI 
7.3 
Exploratory Measures: 
• Evaluation of blood leukocyte transcriptome (RNA expression) profiling in patients 
with NSTI and compare genomic profile in patients treated with AB103 versus 
placebo 
• Evaluation of the clinical response by baseline pathogen 
• Evaluation of the microbiological outcome in the microbiological evaluable 
population 
o  By-Pathogen Bacteriological Response: The by-pathogen bacteriological 
response for each causative organism identified at baseline (BL) will be defined 
as follows: 
 Eradication: BL causative organism cannot be isolated from any culture(s) 
obtained from a debridement performed on or after study Day 3. 
 Persistence: The BL causative pathogen is isolated from a debridement 
performed on or after study Day 3. 
o By-Patient Bacteriological Response: The by-patient bacteriological response 
will be determined according to the following definitions: 
 Eradication: 
All BL causative organism(s) have a response of Eradication. 
 Persistence: 
All or some BL causative organism(s) have a response of 
Persistence. 
• Evaluation of plasma and urinary biomarkers in patients with AKI 
• 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 Related to ICU admission – the Sequential Organ Failure Assessment 
(SOFA) score is an important outcomes measure that should be incorporated 
into any health economics and outcomes research (HEOR) analysis 
o Relative reduction in any physical outcome (including in-hospital deaths) 
• 
To evaluate NICCE outcome in screen failure patients with baseline mSOFA = 2 and post-
operative mSOFA ≥ 3 
• Evaluation of the immunogenicity of AB103 


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8. EVALUATION CRITERIA FOR SAFETY 
8.1 
Primary Safety Measures 
Measures throughout to Day 28: AEs (includes SAEs), clinical safety laboratory (through 
Day 14). Secondary infections and determination of survival. Specific times of these 
parameters are described in Schedule of Procedures, Appendix A, Section 15.1. 
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. 
8.2 
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]. 
8.2.1 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 
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. 
8.2.2 Serious Adverse Event 
A serious adverse event (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, or 
• Is an important and significant medical event (e.g., allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 


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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. 
8.2.3 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. 
8.2.4 Expectedness of the Adverse Event 
Expected adverse events are adverse events 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. 
8.2.5 Serious and Unexpected Suspected 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 FDA requirement for expedited reporting 
must be met to qualify for expedited reporting to FDA: 1) Serious, 2) Unexpected, and 3) 
Suspected AR. AEs that do not meet the 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). 
8.2.6 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). 


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8.2.7 Pregnancies 
If pregnancy is detected after the administration of study drug, 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. 
8.2.8 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: 
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. 
8.2.9 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. 


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8.3 
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. 
The Investigator must report these events to the appropriate IRB/IEC in accordance with 
local regulations. 
8.4 
Reporting of Serious Adverse Events 
All SAEs occurring with any patient participating in this clinical study must be recorded. 
All SAEs must be reported within 24 hours of becoming aware of the event to the Sponsor 
or designee, with the exception of SAEs that are specifically attributed to underlying 
disease (see section 8.5). All SAEs beginning within 28 calendar days after the last 
exposure to IMP must be recorded. 
8.4.1 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 screens of the eCRF 
WITHIN 24 HOURS. The SAE screens 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 screens 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 “AB103/Placebo”)
•
Adverse event term (must be listed as serious)
•
Contact information for person reporting event
Once additional relevant information is received, the SAE screens in the eCRF should be 
updated WITHIN 24 HOURS. 


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The medical monitor is available on a 24-hour basis if clinical personnel wish to discuss 
any safety related events. 
8.4.1.1 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 and fax it to Atox Bio at 919 765 6693 
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 screens in the eCRF 
within 24 hours. The final valid information for regulatory reporting will be the information 
reported through the electronic SAE reporting system. 
8.4.2 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 CRO. 
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. 
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 reports should be reported in the SAE screens of 
the eCRF 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. 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 gastreoenteritis 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 


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8.5 
Disease Related Adverse Events 
It is recognized that the patient population with NSTIs 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 initial NSTI event are listed below. 
8.5.1 List of Expected Adverse Events 
Acute respiratory failure; respiratory distress; acute lung injury; acute respiratory distress 
syndrome (ARDS); acute renal failure; coagulation dysfunction; decreased platelet 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. 
8.6 
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 DMC on ad-hoc basis if safety concerns arise from the medical monitor 
review. 
8.7 
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 50, 100 and 200 patients have 
completed 28 days of the study. Futility analyses will also be performed after 100 patients 
have completed 28 days. After completion of the study the iDMC will meet again to 
evaluate the full study safety data and provide their evaluation to the Sponsor. 
For each planned iDMC review, all safety data on all patients who received one dose of 
AB103 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 iDMC review will be unaudited. A designated unblinded statistician will 
provide unblinded safety data to the DMC 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. 


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9. STATISTICS 
9.1 
Synopsis of Key Statistical Approaches 
9.1.1 Primary Efficacy Comparison 
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 that a patient achieves specific composite clinical success criteria, NICCE, 
designed to be sensitive to both local and systemic drug effects. Each probability represents 
the proportion of subjects on each arm expected to respond according NICCE. Success 
according to NICCE requires meeting all 5 components of the composite endpoint: (i) Alive 
until Day 28; (ii) Day 14 debridements ≤3; (iii) No amputation done after the first 
debridement; (iv) Day 14 mSOFA score ≤1; and (v) Reduction of ≥3 point in mSOFA 
between Baseline and Day 14. A two-sided α=0.01 will be used to test superiority of AB103 
relative to placebo for the primary endpoint (NICCE). A conditional co-primary end point 
will be tested for superiority if the primary endpoint is significant at a two-sided α=0.01 
significance level in order to account for multiple comparisons. A two-sided α=0.05 will 
be used to test superiority of AB103 relative to placebo for the co-primary endpoint which 
is defined as (i) Alive at Day 28; (ii) Day 14 debridements ≤3; and (iii) No amputation done 
after the first debridement. To be considered a success for the co-primary endpoint, patients 
must meet all 3 components. 
9.1.2 Sample Size Justification 
This trial will enroll 290 subjects that will be randomized in a ratio of 1:1 to either AB103 
0.50 mg/kg (n=145) or placebo (n=145), each in addition to SoC. Sample size analysis 
was performed assuming that all patients will be evaluable for the primary endpoint. This 
assumption is justified since all patients in the Phase 2a trial and in the retrospective 
study were evaluable for NICCE. The primary efficacy hypothesis will be tested using 
an unadjusted χ2 statistic with a 0.01 two-sided significance level. Statistical power was 
computed for a range of expected treatment group differences supported by the results 
of preliminary studies. For treatment group differences equal to 0.30, 0.25, and 0.20, 
statistical power will be equal to 99%, 95.9%, and 80.2%, respectively. These estimates 
were determined conservatively assuming an average success rate of 0.5. In this way 
these power estimates are applicable across the range of expected response rates but may 
be conservative in some cases. The use of NICCE and this range of expected treatment 
effects is supported by preliminary studies. In the Phase 2a trial, 71.4% (5/7) patients 
with baseline mSOFA≥3 treated with AB103 0.50 mg/kg achieved NICCE. In contrast, 
40% (2/5) placebo patients with baseline mSOFA≥3 achieved NICCE, a difference of 
0.314. The retrospective study provided further support for the untreated response rate. 
Among 69 patients with baseline mSOFA≥3, 33.3% (23/69) achieved NICCE, difference 
of 0.381 relative to Phase 2a treated group. If the observed differences are equal to 0.35, 
0.25, and 0.20 (centered about 0.5), then the corresponding 2-sided p-values will be 
p<0.0001, p<0.0001, and p=0.0007, respectively. The observed difference will need to 
be larger than about 0.16 (e.g., 0.58 vs 0.42) for p≤0.01. Based on a similar evaluation 


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of the co-primary endpoint, the study is designed to demonstrate statistical significance 
at two-sided α=0.05 for co-primary success rates of 0.80 vs 0.60 in the AB103 and 
placebo groups, respectively. If these are the true success rates, then power will 96.4%. 
However, if the true rates are 0.78 vs 0.62 (difference = 0.16), then power is 84.8%. The 
sample size has also been selected to obtain sufficient enrollment on the treatment arm 
for relevant secondary effectiveness endpoints and for safety endpoints. 
9.1.3 Futility Analysis 
A futility analysis will be performed based on the results of the first 100 patients (50 per 
group). The futility decision will be based on the predictive probability of eventual study 
success, conditioned on the data available at interim analysis. Independent, non-
informative prior distributions will be used for each parameter: π0.50 ~ Beta(1,1), πPlacebo 
~ Beta(1,1). The Bayesian predictive probability of study success (i.e., two-sided p ≤ 
0.01) when the remaining patients are finally observed will be determined. The trial will 
stop enrollment for futility if the predictive probability of study success is below a lower 
bound threshold of 10%. The following table summarizes what the observed predictive 
probabilities will be as a function size of the treatment group differences and assuming 
an observed control success rate of 0.40. If there are 20 success and 30 failures among 
placebo controls (40% success rate), then the futility boundary will be crossed if the 
number of active success is 22 (44%) or less.  The futility bound is ‘non-binding’ in the 
sense that no effort was made to ‘recover’ alpha to increase power. 
 
9.1.4 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 CRO. Therefore, only 
blinded study data will be available to the primary study statistician and responsible 
primary programming staff. 
 
An Independent Data Monitoring Committee (iDMC) will be utilized in this study. A 
detailed iDMC charter will be provided to clarify all relevant issues relating to the conduct 
of the futility analysis including specific details regarding the operational procedures with 
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 second, unblinded statistician will work with a iDMC to evaluate the unblinded data 
necessary to perform the futility analysis and to provide to the iDMC other unblinded data 
such as unblinded safety comparisons as requested by thei DMC. The primary statistical 
programmer under the direction of the primary study statistician will develop SAS based 
programs that processes clinical data provided by the blinded data management CRO to 
populate planned analysis tables and listings. This programming and other relevant 
Diff
0.000
0.020
0.040
0.060
0.080
0.100
0.120
0.140
0.160
0.180
0.200
0.220
0.240
0.260
0.280
0.300
PP
0.029
0.050
0.082
0.127
0.187
0.261
0.348
0.444
0.543
0.639
0.728
0.804
0.866
0.913
0.946
0.969


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instructions will be made accessible (one-way direction on information flow) to a second 
statistician. This second statistician will serve as the unblinded statistician. The unblinded 
statistician will maintain a secured version of the project analysis system not accessible to 
the primary study statistician or anyone else. The unblinded statistician will obtain the 
unblinding codes from directly from the randomization vendor. No one will have access to 
the project analysis system containing the true randomized treatment codes except for the 
unblinded statistician. The unblinded statistician will therefore be able to efficiently 
provide unblinded tables and listings developed by the primary study statistician and team 
directly to the iDMC. The unblinded study statistician will be capable of providing 
additional unblinded data upon request. The unblinded statistician will perform the 
necessary computations involving the Bayesian predictive power to be used in the planned 
futility assessment at the planned interim analysis based on the results from the first 100 
evaluable patients. These computations will be performed in accordance to prescribed plans 
and results provided to the iDMC for the futility assessment. Relevant details will be 
provided in a separate SAP and in the separate iDMC charter. 
9.2 
Summary of Other Elements of Analysis Plan 
9.2.1 Randomization 
290 patients will be recruited into the study and randomized to either 0.5 mg/kg AB103 or 
placebo in a 1:1 ratio. Randomization will be within site stratified by the diagnosis of 
Fournier’s Gangrene and magnitude of mSOFA score at screening categorized as 3-4 
versus >4. In the retrospective study analysis set with baseline mSOFA ≥ 3 (N=69), the 
median value was 4 and 46.6% had values larger than 4. Four computer generated, blocked 
randomization lists will be provided for each site corresponding to the cross-tabulation of 
Fournier’s Gangrene and baseline mSOFA category status. 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 will be done to insure balance through randomization. Every initial 
randomization code will end in ‘-1’. If randomization code is used but the patient does not 
receive drug due to no confirmatory NSTI diagnosis, then the randomization code is not 
reused. Instead, the next patient from that center meeting the same strata criteria as the non-
dosed patient, will receive the same allocation and the same randomization code except that 
the code will end in ‘-2’. In this way, randomization codes are not reassigned which can 
cause confusion but the same allocation is used preserving balance. 
9.2.2 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 


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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 
NSTI based on surgical verification. The mITT analysis set will be used in 
primary effectiveness analyses with patients assigned to their intended 
randomized assignment. 
• 
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 
with potential to confound estimates of drug effects or 2) post randomization 
protocol violations 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 evaluation critical care variables. 
9.2.3 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. For instance, some variables (e.g., physiologic measurements) may be 
transformed to log scales40 to reduce any marked positive skew. 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 overtime 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 curves41 as appropriate. 
9.2.4 Secondary Endpoints 
Secondary endpoints have been specified from several domains including a similar 
composite endpoint but defined on the basis of Day 21 mSOFA, individual components of 
the primary composite endpoint, time to resolution of organ dysfunction, critical care and 
hospital stay parameters (ICU and ICU-free days, ventilator days and –free days, 


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vasopressor days and –free days, hospital LOS), clinical local parameters (debridement 
history variables), and clinical systemic parameters (mSOFA over time, incidence and 
recovery from AKI). Analyses for these endpoint 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 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-organ dysfunction resolution endpoints. 
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. AKI endpoints will be assessed in several ways include incidence of 
Stage 2/3 AKI and among incident cases, resolution of AKI. A similar analysis will be 
performed based on any stage AKI. Treatment groups will be compared using counts and 
percentages with nominal p-values determined through chi-statistics. 
9.2.5 Exploratory Analyses 
Exploratory subgroup analysis will be performed. For these exploratory analyses, active 
dose versus placebo differences in NICCE will be evaluated in several subgroups defined 
by (i) severity of disease at baseline (3-4 vs >4), (ii) presence of non-Fournier’s gangrene 
(iii) involvement of suspected superantigen-producing bacteria and (iv) type of bacteria 
(Gram-positive vs. Gram-negative). Other similar comparisons may be performed. 
9.2.6 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 analysis42. 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 43. I2 is the fraction of τ2 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 
NICCE 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. 
9.2.7 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 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 


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produce balance between groups will be examined in supporting analyses. This will be done 
through stratified analyses and 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. 
9.2.8 Multiplicity 
There is a single primary hypothesis test utilizing a composite clinical success endpoint, 
NICCE and a conditional co-primary endpoint consisting of 3 of the 5 NICCE components. 
The use of a composite endpoint serves to address the multiplicity issue with regard to the 
key outcomes of mortality, local activity, and systemic activity44. The co-primary endpoint 
will only be test if two-sided p≤0.01 in order to avoid the need for multiplicity adjustment 
and will be tested using a two-side α=0.05. The 5 components of NICCE will be 
individually evaluated in supporting analyses will no adjustment for multiplicity. 
9.2.9 Longitudinal Data 
A number of secondary efficacy endpoints will be assessed over time including mSOFA 
total score. 
Where possible for continuous measures, statistical testing and estimation will be based on 
the results from a 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 in cases of where 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 [SAS Institutea]. 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 last observation carried forward 
(LOCF). The MMRM model generally includes a factor for group by time interaction in 
order to allow group difference in mean value 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 
Likelihood45,46 (REML) as implemented Proc Mixed [SAS Instituteb]. 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 
                                                 
 Capture data on any readm 
issions within 30 days of original hospital disc 


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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 last observation 
carried forward47. 
9.2.10 Analysis Of Event-time 
Time to event endpoints will be assessed in descriptive analyses using survival and life-
table methods as appropriate. Results will be displayed in terms of morbidity/mortality or 
event rate ratios (i.e., incidence density ratios [IDR]) along with 95% confidence intervals. 
Analyses will include time to symptom resolution. 
9.2.11 Handling Of Missing Data 
9.2.11.1 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 assignment48. Therefore, we 
will attempt to include all randomized patients, regardless of intervention or length of 
follow-up in the primary efficacy comparison. 
9.2.11.2 mSOFA Scores 
mSOFA scores will be assessed as 1) observed cases, 2) LOCF, 3) using MMRM, and 4) 
categorized and combined with mortality and local activity as part of the primary composite 
clinical success endpoint, NICCE. 
 
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 SOFA mean values 
using LOCF will focus on morbidity rather than mortality. 
 
Mixed model repeated measures analyses (MRMM) will utilize implicit imputed values for 
all missing values including those subsequent to patient death. 
 
In categorical analyses including formulation of the primary efficacy endpoint, an mSOFA 
value that is greater than 1 at Day 14 is considered a treatment failure in the same fashion 
as patient death. LOCF for SOFA is necessary to guarantee that every patient has a value 
at Day 14 for use in determining NICCE among patients that are alive at the Day 28 and 
who have not otherwise failed due to other NICCE components including more than 3 
debridements, or amputation beyond the first debridement. 


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9.2.11.3 Tipping Point Analysis for Primary Endpoint 
If there are any patients with missing primary endpoints, a tipping point sensitivity analysis 
will be conducted. In this analysis, missing values in each group are separately assumed to 
be either successes or failures. Treatment group differences are computed based on all 
possible combinations of assigning success or failure to NICCE to the patients in the 2 
groups. For example, one scenario will be that all missing AB103 observations are failures 
and all missing placebo observations are successes. The next scenario would have one 
success and the remaining missing values as failure for AB103 and all missing placebo 
outcomes as successes. For each scenario, the 1-sided p-value for testing the primary 
effectiveness hypothesis will be determined. These results will be plotted using a dot plot 
with the number of missings assumed as failures for AB103 on the x-axis and the number 
of missing assumed as failures for placebo on the Y-axis. The dots will be color coded to 
indicate whether or not the primary statistical conclusion changes under each individual 
scenario. If the fraction of scenarios in which the statistical conclusion changes is small, 
the primary results will have been shown to be robust against assumptions concerning 
missingness. If there are more than a very small amount of missing data, multiple 
imputation of missing endpoints may be performed in additional supporting analyses using 
the SAS procedures, Proc MI and Proc MI Analyze.  
 
9.2.11.4 Mixed Model Repeated Measures 
As describe above, continuous measure observed over time 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)’. 
9.3 
Safety Analysis 
The primary safety measures are AEs (including SAEs), clinical safety laboratory, physical 
exam, vital signs through Day 28 and ECG (days 0 and 1) 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 
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 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 (SOC). Electrocardiogram results from Day 0 and 
Day 1, and change from Day 0 to Day 1 will be summarized using mean, median, standard 
deviation, minimum, and maximum values. Results from physical exams will be tabulated 


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for the Day 0, 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 (Day 0, Day 1, Day 2, Day 3, Day 7, and Day 14 
separately by treatment group by N, Mean, and SD. 
 


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10. SOURCE DATA ACCESS, DATA MANAGEMENT AND DATA HANDLING 
10.1 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/EDC system for this study must be 
consistent with the patients’ source documentation (ie, medical records). 
10.2 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. 
Adverse events will be coded using the latest version of MedDRA (currently version 18.0). 
Prior and concomitant medications will be coded according to the World Health 
Organization (WHO) Drug Dictionary. 
10.3 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 Criterium site monitor. 
After review by the site monitor, completed eCRF/EDC system entries will be uploaded 
and forwarded to Criterium. Instances of missing or uninterpretable data will be discussed 
with the Investigator for resolution. 


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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. 
10.4 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. 
Data about all study drug dispensed to the patient will be tracked on the EDC 
system/eCRFs. 
10.5 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 


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confidentiality. The Investigator assures Criterium and the Sponsor of the necessary 
support at all times. 
10.6 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. 


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11. QUALITY CONTROL AND 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 CRO, 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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12. GENERAL STUDY ADMINISTRATION 
12.1 Ethical Aspects 
12.1.1 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. 
12.2 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 legally authorized representative (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 
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. 
12.3 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. 
12.3.1 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. 
12.4 Patient Confidentiality 
The anonymity of participating patients must be maintained. Patients will be identified on 
eCRF/EDC system and other documents submitted to Criterium by their patient number, 
initials and/or birth date, not by name. Documents not to be submitted to Criterium that 
identify the patient (e.g., the signed informed consent) must be maintained in confidence 
by the Investigator. 
12.5 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. 
12.6 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. 
12.7 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. 
12.7.1 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. 
12.7.2 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 
• Safety concerns 


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• Sufficient data suggesting lack of efficacy 
• Inadequate recruitment of patients by the Investigator 


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13. CONFIDENTIAL INFORMATION 
13.1 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. 
13.2 ClinicalTrials.gov Study Registration 
This clinical study, ABT-202, 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. 
13.3 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. 
 
 


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14. REFERENCES
1.
Anaya DA, Dellinger EP. Necrotizing soft-tissue infection: diagnosis and
management. Clin Infect Dis Off Publ Infect Dis Soc Am. 2007;44(5):705-710.
doi:10.1086/511638.
2.
Anaya DA, Bulger EM, Kwon YS, Kao LS, Evans H, Nathens AB. Predicting death
in necrotizing soft tissue infections: a clinical score. Surg Infect. 2009;10(6):517-
522. doi:10.1089/sur.2008.112.
3.
Bosshardt TL, Henderson VJ, Organ CH. Necrotizing soft-tissue infections. Arch
Surg Chic Ill 1960. 1996;131(8):846-852; discussion 852-854.
4.
Campbell A. Necrotizing Soft Tissue Infections. In: Vol ; 2011.
5.
Green RJ, Dafoe DC, Raffin TA. Necrotizing fasciitis. Chest. 1996;110(1):219-229.
6.
Pasternak M, Swartz M. Cellulitis, necrotizing faciitis, and subcutaneous tissue
infections. In: Mandell GL, ed. Mandell, Douglas, and Bennett’s Principles and
Practice of Infectious Diseases: Expert Consult Premium Edition - Enhanced Online
Features and Print. Vol 7 edition. Philadelphia, PA: Churchill Livingstone;
2009:1289-1312.
7.
Stevens DL. Dilemmas in the treatment of invasive Streptococcus pyogenes
infections. Clin Infect Dis Off Publ Infect Dis Soc Am. 2003;37(3):341-343.
doi:10.1086/376652.
8.
Young MH, Engleberg NC, Mulla ZD, Aronoff DM. Therapies for necrotising
fasciitis. Expert Opin Biol Ther. 2006;6(2):155-165. doi:10.1517/14712598.6.2.155.
9.
Wong C-H, Khin L-W, Heng K-S, Tan K-C, Low C-O. The LRINEC (Laboratory
Risk Indicator for Necrotizing Fasciitis) score: a tool for distinguishing necrotizing
fasciitis from other soft tissue infections. Crit Care Med. 2004;32(7):1535-1541.
10.
Darenberg J, Ihendyane N, Sjölin J, et al. Intravenous immunoglobulin G therapy in
streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-
controlled trial. Clin Infect Dis Off Publ Infect Dis Soc Am. 2003;37(3):333-340.
doi:10.1086/376630.
11.
Norrby-Teglund A, Muller MP, Mcgeer A, et al. Successful management of severe
group A streptococcal soft tissue infections using an aggressive medical regimen
including intravenous polyspecific immunoglobulin together with a conservative
surgical approach. Scand J Infect Dis. 2005;37(3):166-172.
doi:10.1080/00365540410020866.
12.
Lungstras-Bufler K, Bufler P, Abdullah R, et al. High cytokine levels at admission
are associated with fatal outcome in patients with necrotizing fasciitis. Eur Cytokine
Netw. 2004;15(2):135-138.
13.
Dellinger EP. Severe necrotizing soft-tissue infections. Multiple disease entities
requiring a common approach. JAMA. 1981;246(15):1717-1721.


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14.  Kaul R, McGeer A, Norrby-Teglund A, et al. Intravenous immunoglobulin therapy 
for streptococcal toxic shock syndrome--a comparative observational study. The 
Canadian Streptococcal Study Group. Clin Infect Dis Off Publ Infect Dis Soc Am. 
1999;28(4):800-807. doi:10.1086/515199. 
15.  Norrby-Teglund A, Thulin P, Gan BS, et al. Evidence for superantigen involvement 
in severe group a streptococcal tissue infections. J Infect Dis. 2001;184(7):853-860. 
doi:10.1086/323443. 
16.  Thulin P, Johansson L, Low DE, et al. Viable group A streptococci in macrophages 
during acute soft tissue infection. PLoS Med. 2006;3(3):e53. 
doi:10.1371/journal.pmed.0030053. 
17.  Anaya DA, McMahon K, Nathens AB, Sullivan SR, Foy H, Bulger E. Predictors of 
mortality and limb loss in necrotizing soft tissue infections. Arch Surg Chic Ill 1960. 
2005;140(2):151-157; discussion 158. doi:10.1001/archsurg.140.2.151. 
18.  May AK, Stafford RE, Bulger EM, et al. Treatment of complicated skin and soft 
tissue infections. Surg Infect. 2009;10(5):467-499. doi:10.1089/sur.2009.012. 
19.  Tillou A, St Hill CR, Brown C, Velmahos G. Necrotizing soft tissue infections: 
improved outcomes with modern care. Am Surg. 2004;70(10):841-844. 
20.  Kao LS, Lew DF, Arab SN, et al. Local variations in the epidemiology, 
microbiology, and outcome of necrotizing soft-tissue infections: a multicenter study. 
Am J Surg. 2011;202(2):139-145. doi:10.1016/j.amjsurg.2010.07.041. 
21.  Faraklas I, Stoddard GJ, Neumayer LA, Cochran A. Development and validation of 
a necrotizing soft-tissue infection mortality risk calculator using NSQIP. J Am Coll 
Surg. 2013;217(1):153-160.e3; discussion 160-161. 
doi:10.1016/j.jamcollsurg.2013.02.029. 
22.  Wong C-H, Chang H-C, Pasupathy S, Khin L-W, Tan J-L, Low C-O. Necrotizing 
fasciitis: clinical presentation, microbiology, and determinants of mortality. J Bone 
Joint Surg Am. 2003;85-A(8):1454-1460. 
23.  Pham TN, Moore ML, Costa BA, Cuschieri J, Klein MB. Assessment of functional 
limitation after necrotizing soft tissue infection. J Burn Care Res Off Publ Am Burn 
Assoc. 2009;30(2):301-306. doi:10.1097/BCR.0b013e318198a241. 
24.  Yildiz B, Karakoc D, Hamaloglu E, Ozdemir A, Ozenc A. What changed in 
necrotizing fasciitis in twenty-five years? Afr J Microbiol Res. 2011;5(16):2229-
2233. 
25.  McGillicuddy EA, Lischuk AW, Schuster KM, et al. Development of a computed 
tomography-based scoring system for necrotizing soft-tissue infections. J Trauma. 
2011;70(4):894-899. doi:10.1097/TA.0b013e3182134a76. 
26.  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. 


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Page 94 of 111 
 
27.  Fraser JD. High-affinity binding of staphylococcal enterotoxins A and B to HLA-
DR. Nature. 1989;339(6221):221-223. doi:10.1038/339221a0. 
28.  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. 
29.  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. 
30.  Marrack P, Kappler J. The staphylococcal enterotoxins and their relatives. Science. 
1990;248(4959):1066. 
31.  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. 
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.  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. 
37.  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. 
38.  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. 
39.  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. 


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40.  Keene ON. The log transformation is special. Stat Med. 1995;14(8):811-819. 
41.  Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc. 1958;53(282):457-481. 
42.  Viechtbauer W. Bias and efficiency of meta-analytic variance estimators in the 
random-effects model. J Educ Behav Stat. 2005;30(3):261-293. 
43.  Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-
analyses. BMJ. 2003;327(7414):557. 
44.  Sankoh AJ, D’Agostino RB, Huque MF. Efficacy endpoint selection and 
multiplicity adjustment methods in clinical trials with inherent multiple endpoint 
issues. Stat Med. 2003;22(20):3133-3150. 
45.  Diggle P, Heagerty P, Liang K-Y, Zeger S. Analysis of Longitudinal Data. Oxford 
University Press; 2002. 
46.  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. 
47.  Rubin DB. Inference and missing data. Biometrika. 1976;63(3):581-592. 
48.  Knickerbocker R. Intent-to-Treat Analyses. In: Chow S-C, ed. Encyclopedia of 
Biopharmaceutical Statistics. Vol Marcel Dekker; 2000. 
 
 
 


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15. APPENDICES 
15.1 Appendix A - Study visits and procedures 
Visit 
1 
Screening 
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 +2 
days 
10 
3 
months 
±5 days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Lesion history 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medicationsa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight & Heightb 
X 
 
 
 
X 
 
X 
 
X 
 
Urine outputc 
 
 
 
 
 
 
Vital Signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Examination (PE) 
X 
 
 
 
X 
 
X 
 
 
 
Interim PE (symptom-driven) 
 
X 
 
X 
 
X 
 
 
 
 
Baseline Signs & Symptomse 
X 
 
 
 
 
 
 
 
 
 
                                                 
a See Section 5.2 for instruction on level of detailed information required for recording concomitant medications 
b Height will be taken only at screening 
c Urine output is required for Days 1-7 (while the patient is in the ICU and has a Foley catheter in place) to assess for development or resolution of acute kidney injury. 
d Systolic & Diastolic blood pressure, Heart rate, Respiration rate, Temperature; (first set of vitals on that visit day) 
e Adverse events reported from ICF signature to AB103 administration 


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Visit 
1 
Screening 
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 +2 
days 
10 
3 
months 
±5 days 
12-Lead ECG 
X 
Xf 
 
 
 
 
 
 
 
 
Blood Chemistryg 
X 
Xh 
Xh 
Xh 
X 
Xh 
X 
Xh 
Xi 
Xh  
C-reactive protein 
X 
 
 
 
 
 
X 
 
 
 
Blood Hematologyj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy testk (if applicable) 
X 
 
 
 
 
 
 
 
 
 
Blood for leukocyte transcriptome (RNA expression) 
profilel  
X 
X 
X 
Xl 
X 
 
 
 
 
 
Urine and Plasma for Storagem 
X 
 
X 
 
X 
 
 
 
 
 
Arterial blood gases (if applicable) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
                                                 
f 12 lead ECG will be performed at the end of the study drug infusion, then within 4-6 hours and 12-24 hours of study drug administration, and the time of its performance 
should be recorded. 
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 Only Creatinine. At Visit 10 (3 months), creatinine obtained only if day 29 creatinine is abnormal. 
i Creatinine and Albumin only 
j Complete blood count including platelet count and white blood cell differential 
k Preferably the fastest pregnancy test method (urine or blood); 
l 5 mL (2 x 2.5 mL) of whole blood to be collected at screening, Day 1 at 4-6 hours post dose, Day 2 at 24±4 hours post dose, 72-84 hours post-dose and Day 7. Complete 
blood count with white blood cell differential to be obtained at same time of whole blood for genomic profile sample (Can be coordinated with CBC sample already requested 
at screening, Day 2, 3 and 7). Sample at 72-84 hours post-dose may require CBC sample to be obtained on Day 4. 
m 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. 


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Visit 
1 
Screening 
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 +2 
days 
10 
3 
months 
±5 days 
SpO2 and FiO2 (if unable to obtain arterial blood gases) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion & Exclusionn 
X 
Randomization 
X 
AB103/Placebo Administration 
X 
Debridemento 
X 
Blood culturep 
X 
Tissue for microbiologyq 
X 
Xq 
Adverse Events / Serious Adverse Eventsr 
Xs 
X 
X 
X 
X 
X 
X 
X 
X 
Lesion assessmentt 
X 
X 
X 
X 
X 
X 
X 
Collect data on additional amputations 
n 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 clinical diagnosis and evaluation of organ function/ patient status; 
o NSTI should be confirmed surgically, patients with non-NSTI should not receive drug; Subsequent surgical procedures through to Day 14 should be recorded in the eCRF
log as they occur (see Section 6.2.6.1 for definition of debridement).  Surgical procedures involving amputation(s) should be recorded in the eCRF log through Day 28.
p Blood culture for both aerobic and anaerobic bacteria should be repeated during the study in case of new systemic infection suspicion, as clinically indicated.
q Tissue for microbiology will be taken at the 1st debridement (performed at visit 1), to be used for identification of pathogen(s), susceptibility to antimicrobial drugs and
Gram stain. Obtain tissue for microbiological culture if debridement performed on Day 3 (Visit 4). If culture from debridement on Day 3 is positive, then repeat culture if
subsequent debridement(s) performed.
r 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.
s AEs of day 0 are baseline AEs (not TEAE) starting after obtaining ICF until study drug administration.
t Assess lesion status (healing/progression/significant change in appearance) if accessible for visible assessment at time of debridement or routine dressing change


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Visit 
1 
Screening 
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 +2 
days 
10 
3 
months 
±5 days 
Collect data on acute renal replacement therapy, plasma 
and/or platelet transfusion 
 
 
 
Evaluation of adequacy of antimicrobial treatment 
 
 
 
X 
 
 
 
 
 
 
Critical care and hospital stay parametersu 
 
 
mSOFA scorev 
X 
Xw 
X 
X 
X 
X 
X 
X 
X 
 
APACHE II scorex 
X 
 
 
 
 
 
 
 
 
 
LRINEC and Anayay scores 
X 
 
 
 
 
 
 
 
 
 
Survival 
 
 Hospital readmissionsz 
 
 
 
 
 
 
 
 
X 
X 
Serum for immunogenicityaa 
X 
 
 
 
 
 
X 
 
X 
X 
                                                 
u Hospital length of stay (days), ICU stay (days), ICU free days, Mechanical ventilation days/mechanical ventilation free days; 
v Screening mSOFA: To be calculated prospectively from time patient presents at the hospital (may include referring hospital) but within 6 hours prior to first debridement. 
Screening mSOFA may be reassessed up to actual time of surgery if initial mSOFA evaluation had score <3. To include measurements of 5 organ systems to achieve score of 
≥3, in any one or more organs, with any one organ having a score of at least 2: cardiovascular, respiratory, renal, coagulation 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), 
w Subsequent mSOFA data collection (Days 1, 2, 3, 7, 10, 14, 21 and 29): taken once a day, in the morning (between 6AM until 12 noon) adjusted to the time of normal 
routine assessment activities. However, if surgery is performed during the usual time of the assessments, these assessments should then be collected at a minimum of 2 hours 
post-surgery. The following blood samples must be taken: platelets, and creatinine. In addition, clinical parameters should be taken (see Section 15.5). For SpO2 ≤ 95%, 
check for the most consistent result and record that value.  
x For the required laboratory and clinical parameters (see Section 15.5) 
y For the required laboratory and clinical parameters (see Section 15.1). 
z Capture data on any readmissions within 30 days of original hospital discharge  
aa 6 mL blood for serum for storage (for immunogenicity testing) at Screening, Days 14 and 29, and Month 3 


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15.2 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 
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Chronic health Points = C
Age Points
= B
Glasgow Coma Scale
Apache-II Score
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!
verbal - nonintubated:
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/!7
2!&
verbal - intubated:
!$7
2!D$$7
!-.
Motor response
0!.$
!
/!&(&
2!
6!$
Points
#
6

Age
≤//
/ /
 0/
0 4/
≥4
2
0
(((.-
  -
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Chronic Health Points =
Age Points
=
Total
Apache II =
 	  
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C =
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 B =
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 A =
E
.-
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6..
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Page 103 of 111
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Page 104 of 111 
15.3 Appendix C - modified SOFA 
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 
Respiratory
>400
≤400 
≤300 
≤200 
with 
respiratory 
support 
≤100 
with 
respiratory 
support 
PaO2/FiO21 
Coagulation 
Platelets 
>150
≤150 
≤100 
≤50 
≤20 
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 
Creatinine 
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-202 version 4.0 
23 Aug 2018 
 
Page 105 of 111 
 
 
Oxygen Conversion tables 
 
Estimating Pa02 from a given Sp02  
 
 
 
 
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 
9 
90 
10 
95 


Final Protocol ATB-202 version 4.0 
23 Aug 2018 
Page 106 of 111 
15.4 Appendix D - Glascow Coma Scale 
Enter one score for each response (Eyes, Motor and Verbal). 
Eyes Open 
Motor Responses 
Verbal - Nonintubated 
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-202 version 4.0 
23 Aug 2018 
Page 107 of 111 
15.5 Appendix E - Clinical Scores 
Table 7: Clinical Scores Parameters 
Parameter 
LRINEC 
Anaya 
mSOFA 
APACHE II 
Clinical 
Cardiovascular system (Mean Arterial Pressure) 
+ 
+ 
Heart Rate 
+ 
+ 
Nervous system (Glasgow Coma Score) 
+ 
+ 
Oxygenation (Calculation) 
+ 
(PaO2/FiO2)* 
+ 
(Pao2 or A-a 
difference) 
Respiratory rate 
+ 
Temperature 
+ 
+ 
(rectal) 
Demographics 
Age 
+ 
+ 
Chronic health evaluation 
+ 
Laboratory 
Arterial pH 
+ 
Coagulation Function (Platelets) 
+ 
C-Reactive Protein
+ 
Renal system / Creatinine 
+ 
+ 
+ 
+ 
Glucose 
+ 
Hemoglobin/Hematocrit 
+ 
+ 
+ 
Sodium 
+ 
+ 
Potassium 
+ 
Total white cell count 
+ 
+ 
+ 
*In case it is not possible to obtain arterial blood gases to determine the SOFA respiratory parameter, SpO2/FioO2 ratio can be imputed for
PaO2/FiO2 ratio


Final Protocol ATB-202 version 4.0 
23 Aug 2018 
 
Page 108 of 111 
 
15.6 Appendix F - Recommendations for EXCLUSION OF 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 
b) Hydrocortisone 
c) Methylprednisolone 
d) Dexamethasone 
e) Cortisone 
f) Betamethasone 
40 mg 
160 mg 
32 mg 
6 mg 
200 mg 
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 (Restasis) is permitted 
6. FK506 (Tacrolimus) 
Excluded at any dose 
Topical formulation (Protopic) is permitted. 
7. Azathioprine 
Excluded at any dose. 
8. Cancer Chemotherapy 
Patients having received cancer chemotherapy in the 
previous 4 weeks are excluded. 


Final Protocol ATB-202 version 4.0 
23 Aug 2018 
Page 109 of 111 
Immunosuppressive Agenta 
Upper limit dosage use 
9. Mycophenolate Mofetil (MMF)
(CellCept)
Solid organ transplant and bone marrow transplant patients 
are excluded. 
10. Sirolimus (Rapamycin,
rapamune)
Excluded at any dose. 
11. Everolimus (Certican)
12. Temisirolimus (Torisel)
Excluded at any dose. 
Excluded at any dose. 
13. Thalidomide
Patients receiving this drug within the last 72 hours are 
excluded. 
Biologics 
(a)
Anti-tumor necrosis
factor (TNF) agents
−
Entanercept (Enbrel)
−
Adalimumab (Humira)
−
Infliximab (Remicade)
−
Certolizumab (Cimzia)
−
Golimumab (Simponi)
Patients receiving anti-TNF agents within the past 8 weeks 
are excluded. 
(b)
Interleukin-1 Receptor
Antagonist (IL-1 RA)
(Kineret)
Patients receiving IL-1 RA within the last 8 weeks are 
excluded. 


Final Protocol ATB-202 version 4.0 
23 Aug 2018 
Page 110 of 111 
Immunosuppressive Agenta 
Upper limit dosage use 
(c)
CTLA-4 Fusion Protein
−
Atapacept (Orencia)
−
Belatacept (Nulojix)
Patients receiving CTLA-4 Fusion protein within the past 8 
weeks are excluded. 
(d)
Anti-C20
−
Rituximab
(Rituxan/MabThera)
−
Obintuzumab
(Gazyva)
Patients receiving this drug within the last 2 years are 
excluded. 
(e)
Anti-CD52
−
Alemtuzumab
(Campath)
Patients receiving this drug within the last 2 years are 
excluded. 
(f)
Anti-IL2
−
Daclizumab or Anti-
Tac (Zenapax) 
−
Basiliximab
(Simulect)
Patients receiving any of these drugs within the last 2 years 
are excluded. 


Final Protocol ATB-202 version 4.0 
23 Aug 2018 
Page 111 of 111 
Immunosuppressive Agenta 
Upper limit dosage use 
(g)
Anti-IL6
–
Tocilizumab
(Actemra/RoActemra)
Patients receiving any of these drugs in the last 2 years are 
excluded. 
(h)
Anti-IL12/13
−
Ustekinumab
(Stelara)
(i)
Anti-BAFF (B-cell
activating factor)
−
Belimumab (Benlysta)
(j)
Integrin Inhibitor
−
Natalimumab
(Tysarbi)
Patients receiving any of these drugs within the last 2 years 
are excluded. 
Patients receiving this drug within the last 8 weeks are 
excluded. 
Patients receiving this drugs within 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: 
 
 
 
• 1357 GARDEN ROAD, WYNNEWOOD, PA 19096 • (610) 645-5708 FAX: (610) 645-5734 • BSC@biomedstat.com •  
                                                                               www.biomedstat.com 
 
 
Biomedical Statistical Consulting 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Version 4.0  
 
September 24, 2019 
 
Product:  Reltecimod 
 
Protocol Number:  ATB-202 
Phase III, randomized, double-blind, placebo-controlled, parallel-group, study 
of Reltecimod as compared to placebo in patients with necrotizing soft tissue 
infections (NSTI) 
Development Phase:  Phase 3 
IND Number: 67,785 
SPONSOR 
Atox Bio Ltd. 
8 Pinhas Sapir St. 
Weizmann Science Park 
Ness Ziona, 7403631 
Israel 
 
CONFIDENTIAL 
 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
Statistical Analysis Plan 
Version 4.0, 24 September 2019 
"Phase III, randomized, double-blind, placebo-controlled, parallel-group, study of 
Reltecimod as compared to placebo in patients with necrotizing soft tissue infections 
(NSTI)" 
SIGNATURE OF APPROVAL 
Wayne M Dankner, MD 
Chief Medical Officer 
Atox Bio, Ltd 
2 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
Statistical Analysis Plan 
Version 4.0, 24 September 2019 
"Phase III, randomized, double-blind, placebo-controlled, parallel-group, study of 
Reltecimod as compared to placebo in patients with necrotizing soft tissue infections 
(NSTI)" 
SIGNATURE OF APPROVAL 
-C)
--Y-'A"""--~
=A---~
-L.-C..-----=------ Date 
Greg Maislin, M.S, M.A. 
Principal Biostatistician 
Biomedical Statistical Consulting 
3 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
 
4 
 
Table of Contents 
1 
Purpose and scope of SAP ................................................................................................ 7 
1.1 
Revisions to SAP in Version 4.0......................................................................................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 
Primary Efficacy Endpoint ......................................................................................8 
2.1.3 
Conditional Co-Primary Efficacy Endpoint .............................................................8 
2.2 
Overall Study Success Criterion ......................................................................................9 
2.3 
Key Secondary AKI Endpoint .........................................................................................9 
2.4 
Sample Size Justification ...............................................................................................10 
2.4.1 
Primary Endpoint ...................................................................................................10 
2.4.2 
Conditional Co-Primary Endpoint .........................................................................11 
2.5 
Randomization ...............................................................................................................11 
2.6 
Analysis Sets ..................................................................................................................11 
2.7 
Futility analyses .............................................................................................................12 
2.8 
Control of blinding and DMC ........................................................................................13 
2.8.1 
Randomization and Unblinded Study Statistician .................................................13 
2.8.2 
Data Monitoring Committee and Unblinded DMC Statistician ............................13 
3 
Description of Variables to be Included in Statistical Analyses ................................. 15 
3.1 
Medical and Surgical History ........................................................................................15 
3.2 
Physical Examinations ...................................................................................................15 
3.3 
Concomitant Medication ................................................................................................15 
3.4 
Vital Signs ......................................................................................................................15 
3.5 
Clinical Scores ...............................................................................................................15 
3.5.1 
Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score ...................15 
3.5.2 
ANAYA criteria .....................................................................................................16 
3.5.3 
Acute Physiology and Chronic health Evaluation II (APACHE II) score .............16 
3.5.4 
Sequential Organ Failure Assessment (SOFA) Score ...........................................16 
3.6 
Electrocardiogram ..........................................................................................................16 
3.7 
Clinical Laboratory Assessments ...................................................................................16 
3.8 
Microbiology..................................................................................................................16 
3.9 
Use of additional concomitant therapy ..........................................................................16 
4 
Secondary and Exploratory Endpoints ......................................................................... 17 
4.1 
AKI Related Endpoints ..................................................................................................17 
4.1.1 
Freedom from Durable Loss of Renal Function at Day 28 ....................................17 
4.1.2 
Blinded Independently Adjudicated AKI Endpoints and Analyses .......................17 
4.1.3 
Other AKI Endpoints .............................................................................................17 
4.1.4 
Algorithmic Determinations ..................................................................................18 
4.1.5 
Processing of Adjudicated AKI Data .....................................................................21 
4.2 
Primary Endpoint Components and Other mSOFA Related Outcomes ........................21 
4.3 
Critical care and hospital stay parameters .....................................................................22 
4.4 
C - Reactive Protein (CRP) ............................................................................................23 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
 
5 
 
4.5 
Exploratory Endpoints ...................................................................................................23 
4.6 
Exploratory Subgroup Analysis .....................................................................................23 
4.7 
Microbiology..................................................................................................................24 
5 
Analysis Approaches ....................................................................................................... 26 
5.1 
Baseline Comparisons ....................................................................................................26 
5.2 
mSOFA ..........................................................................................................................26 
5.2.1 
Mean and Mean Changes Over Time ....................................................................27 
5.2.2 
mSOFA as Part of Primary Endpoint.....................................................................27 
5.2.3 
Time to Organ Dysfunction Resolution .................................................................27 
5.2.4 
Mixed Models for Repeated Measures (MMRM) .................................................28 
5.3 
Assessment of poolability among sites ..........................................................................28 
5.4 
Analyses Accounting for Stratification Factors .............................................................28 
5.5 
Analysis of other covariate effects .................................................................................29 
5.6 
Multiplicity ....................................................................................................................29 
5.7 
Descriptive Analyses of Additional Secondary Endpoints ............................................30 
5.8 
Analysis of Longitudinal Outcomes ..............................................................................30 
5.9 
ITT vs mITT ..................................................................................................................31 
5.10 
Handling of Missing Data ..............................................................................................32 
5.10.1 
mSOFA Scores.......................................................................................................32 
5.10.2 
Handling of Missing Primary Endpoints ...............................................................32 
5.10.3 
Mixed Model Repeated Measures .........................................................................33 
5.11 
Prior and Concomitant Medication ................................................................................33 
5.12 
Deviations from the Original Statistical Plan ................................................................34 
6 
Safety Analysis ................................................................................................................ 35 
6.1 
Adverse Events ..............................................................................................................35 
6.2 
Laboratory Values ..........................................................................................................35 
6.2.1 
Description of Value Over Time............................................................................35 
6.2.2 
Laboratory Shift Tables .........................................................................................35 
6.2.3 
Treatment of Clinical Laboratory Abnormalities ..................................................35 
6.3 
Electrocardiogram ..........................................................................................................36 
6.4 
Physical Exams ..............................................................................................................36 
6.5 
Vital Signs ......................................................................................................................36 
7 
Presentation of Enrollment and Baseline Characteristics .......................................... 37 
7.1 
Numbers of Patients by Analysis Set .............................................................................37 
7.2 
Demographic and Baseline Disease Characteristics of Cohorts ....................................37 
7.3 
Baseline Microbiology ...................................................................................................37 
7.4 
Prior and Concomitant Medication ................................................................................37 
7.5 
Medical History .............................................................................................................37 
7.6 
Presentation of NSTI......................................................................................................38 
7.7 
Drug Administration and Timing ...................................................................................38 
7.8 
Patient Disposition and End of Study Status .................................................................38 
8 
Presentation of Efficacy Results .................................................................................... 39 
8.1 
Primary and Conditional Co-Primary Endpoint in mITT Analysis Set .........................39 
8.2 
Primary and Co-Primary Endpoint in Per Protocol Analysis Set ..................................39 
8.3 
Evaluation of Site Heterogeneity in Primary Endpoint Treatment Effects ....................39 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
 
6 
 
8.4 
Evaluation of Stratification Factors ...............................................................................40 
8.5 
Sensitivity Analysis Removing the Reduction in mSOFA Component ........................40 
8.6 
Distribution of mSOFA scores Over Time ....................................................................40 
8.7 
Time to resolution of mSOFA score to ≤ 1....................................................................40 
8.8 
MMRM Analyses...........................................................................................................41 
8.9 
Critical care and hospital stay parameters, to be measured until Day 28 ......................41 
8.10 
Clinical local parameters (debridements) ......................................................................42 
8.11 
Freedom from Durable Loss of Renal Function ............................................................43 
8.12 
C - reactive protein (CRP) .............................................................................................43 
9 
Presentation of Safety Evaluations ................................................................................ 44 
9.1 
Adverse Events ..............................................................................................................44 
9.1.1 
Summary of adverse events ...................................................................................44 
9.1.2 
Specific adverse events ..........................................................................................44 
9.1.3 
Severity of adverse events .....................................................................................45 
9.1.4 
Comparisons between those with and without a drug-related AE .........................45 
9.1.5 
Day 0 Adverse Events ............................................................................................45 
9.1.6 
Adverse Events of Special Interest ........................................................................45 
9.1.7 
Safety listings .........................................................................................................45 
9.2 
Clinical Laboratory Assessments ...................................................................................46 
9.2.1 
Blood Chemistry ....................................................................................................46 
9.2.2 
Hepatic Safety ........................................................................................................46 
9.2.3 
Blood Hematology .................................................................................................46 
9.3 
Vital Signs ......................................................................................................................47 
9.4 
Electrocardiogram ..........................................................................................................47 
9.5 
Physical Examinations ...................................................................................................47 
9.6 
Term Survival ................................................................................................................47 
10 
Subgroup Analysis .......................................................................................................... 49 
11 
Appendix 1: Table TOC ................................................................................................. 50 
12 
Appendix 2: AE Listings TOC ....................................................................................... 62 
13 
Appendix 3: Patient Listings TOC ................................................................................ 63 
14 
Appendix 4: Figures TOC .............................................................................................. 65 
15 
Appendix 5:  Clinical Score Calculations ..................................................................... 67 
16 
Appendix 6: Randomization Program: SAS call to R program ................................. 70 
 
 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
 
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 provided in the Clinical Study Protocol and 
this SAP, the SAP prevails. This SAP will be finalized prior to unblinding of the treatment 
allocations 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 principals for clinical trials1. 
1.1 
Revisions to SAP in Version 4.0 
The prior version of this SAP was Version 3.0, September 14, 2015. The final updates included in 
this Version 4.0 of the SAP were made while treatment allocation remained blinded.  
There are two primary types of updates. The first type of update relates to the secondary efficacy 
endpoints concerning AKI. The AKI endpoints are now harmonized with the AKI endpoints to be 
used in the currently enrolling AKI pivotal trial. The primary efficacy endpoint from the ongoing 
AKI trial (ATB-203) has now been specified formally as the key secondary efficacy endpoint 
for this trial to allow the results from this trial (ATB-202) to support those from the AKI trial.  
This endpoint is 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.  
The second type of update generally relates to changes made to accommodate the needs of the 
NDA and future integrated summaries of safety and effectiveness in light of the observation that 
ATB-202 will form the bulk of the safety population for the NDA.  
 
 
1 ICH E9 Expert Working Group. Statistical Principles for Clinical Trials: ICH Harmonized Tripartite Guideline. Statistics in 
Medicine 1999; 18:1905–1942. 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
 
8 
 
2 Key Elements of the Analysis Plan 
2.1 
Primary Efficacy Analysis 
2.1.1 
Primary Superiority Hypothesis 
The primary efficacy hypothesis for this study concerns superiority of Reltecimod relative to 
placebo and may be symbolically represented as follows: 
 Ho:  − Placebo = 0 vs Ha:  − Placebo > 0;  
where  and Placebo represent the true probability that a patient achieves a specific composite 
clinical success criteria, NICCE (Necrotizing Infections Clinical Composite Endpoint), designed 
to be sensitive to both local and systemic drug effects. Each probability represents the proportion 
of subjects on each arm expected to respond according to NICCE. A validation study of the 
NICCE endpoint has recently published (Bulger et al 20172). 
2.1.2 
Primary Efficacy Endpoint 
To be considered a success in terms of the primary endpoint, each patient must meet all 
components of NICCE as summarized in the following table.   
Component 
NICCE 
Survival 
• Alive at Day 28  
Local component 
•  ≤3 debridements through Day 14 
• No amputation beyond first 
debridement* 
Systemic component 
• mSOFA score of ≤1 at Day 14 
• Reduction of ≥3 score points 
between baseline and Day 14 
mSOFA score 
  
 
*Amputation is defined as removal of a limb or portion of a limb to the level of a 
joint space 
An unadjusted chi-square test using a two-sided type 1 error of α=0.01 will be used to test 
superiority of Reltecimod relative to placebo for the primary endpoint (NICCE). Primary results 
will include the numbers and percentages of patients achieving NICCE in each treatment group, 
the p-value from the chi-square statistic, as well as the estimated treatment group difference in 
NICCE success rates with 99% confidence interval.   
2.1.3 
Conditional Co-Primary Efficacy Endpoint 
The following modified clinical composite endpoint will be evaluated as the conditional co-
primary endpoint (CCPE).  The CCPE removes the systemic component of composite endpoint. 
Analysis of the CCPE was added at the request of FDA.  
 
2 Bulger EM, May A, Dankner W, Maislin G, Robinson B, Shirvan A. Validation of a clinical trial composite endpoint for 
patients with necrotizing soft tissue infections. J Trauma Acute Care Surg. 2017 Oct;83(4):622-627. doi: 10.1097. 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
 
9 
 
 
Component 
CCPE 
Survival 
• Alive at Day 28  
Local component 
•  ≤3 debridements through Day 14 
• No amputation beyond first 
debridement* 
*Amputation is defined as removal of a limb or portion of a limb to the level of a joint space 
Patients must meet all three of the above components in order to be considered a success for the 
CCPE.   
A two-sided unadjusted chi-square test will be used to test superiority of Reltecimod relative to 
placebo in terms of the CCPE. The type 1 error rate for testing superiority in terms of the CCPE 
will be set to α=0.05. Results for the CCPE will include the numbers and percentages of patients 
achieving CCPE in each treatment group, the p-value from the chi-square statistic, as well as the 
estimated treatment group difference in CCPE success rates along with a 95% confidence 
interval. 
2.2 
Overall Study Success Criterion 
The overall Study Success criterion, agreed upon with FDA, is to simultaneously observe p≤0.01 
for the NICCE endpoint and p≤0.05 for the CCPE.  
2.3 
Key Secondary AKI Endpoint 
The same endpoint that is being currently employed in the ongoing ATB-203 study of AKI in 
sepsis will be evaluated as the key secondary endpoint in this study. The key secondary endpoint 
is freedom from durable loss of renal function at Day 28. Only subjects with AKI Stage 2 or 
Stage 3 prior to initial drug dosing will be included in this comparison. The key secondary  
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 Day 14 and 28 
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.  A sensitivity analysis will utilize an 
independently adjudicated reference value to determine baseline eGFR. 
To control type 1 error for the key secondary efficacy endpoint, superiority of Reltecimod relative 
to placebo in terms of freedom from durable loss of renal function at Day 28 among those 
presenting with Stage 2 or Stage 3 AKI will only be interpreted as a confirmatory hypothesis test 
if p≤0.01 for the primary endpoint (NICCE) and p≤0.05 for the co-primary endpoint (CCPE). 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
 
10 
 
Otherwise, treatment group comparisons in terms of the key secondary efficacy (AKI) endpoint 
will be interpreted as a descriptive endpoint. An unadjusted chi-square test using a two-sided type 
1 error of α=0.05 will be used to test superiority of Reltecimod relative to placebo for the key 
secondary AKI endpoint.   
2.4 
Sample Size Justification 
2.4.1 
Primary Endpoint  
This trial will enroll 290 subjects that will be randomized in a ratio of 1:1 to either Reltecimod 
0.50 mg/kg (n=145) or placebo (n=145), each in addition to standard of care. Sample size 
analysis was performed assuming that all patients will be evaluable for the primary endpoint. 
This assumption is justified on the basis of results from the Phase 2a trial and the Retrospective 
Study in which all patients were evaluable in terms of the definitions used to construct the 
NICCE endpoint.  
The primary efficacy hypothesis will be tested using an unadjusted 2 statistic with an α=0.01 
two-sided significance level. Statistical power was computed for a range of expected treatment 
group differences supported by the results of the preliminary studies noted above. For expected 
treatment group differences of 0.30, 0.25, and 0.20, statistical power will be 99%, 95.9%, and 
80.2%, respectively. These power determinations were conservatively made assuming an 
average success rate between treatment groups of 0.5. In this way power estimates are applicable 
across the range of expected response rates; but may be conservative in some cases.  
The use of NICCE and this range of expected treatment effects is supported by preliminary 
studies as summarized in the following table.  
 
Percentage 
Achieving 
NICCE 
(n/N) 
Phase 2a (mSOFA≥3) 
Reltecimod 0.50 mg/kg 
71.4% 
(5/7) 
Phase 2a (mSOFA≥3) 
Placebo 
20.0% 
(1/5) 
Retrospective 
Study 
(mSOFA≥3) 
30.4% 
(21/69) 
 
In the Phase 2a trial, 71.4% (5/7) patients with baseline mSOFA≥3 treated with Reltecimod (at a 
dose of 0.50 mg/kg) achieved NICCE. In contrast, only 20% (1/5) of placebo patients with 
baseline mSOFA≥3 achieved NICCE, a difference of 51.4%. The Retrospective Study provides 
further support for the untreated response rate. Among 69 patients with baseline mSOFA≥3, 
30.4% (21/69) achieved NICCE, a difference of 41.0% relative to Phase 2a patients in the 0.50 
mg/kg treated group presenting with screening mSOFA≥3.  
Given the selected sample sizes, if the observed differences in this study happen to be equal to 
35%, 25%, or 20% (centered about 50%), then the corresponding 2-sided p-values will be 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
 
11 
 
p<0.0001, p<0.0001, and p=0.0007, respectively. The observed difference will need to be larger 
than about 16% (e.g., 58% vs 42%) for p≤0.01 (again assuming that the average success rate 
between groups is 50%).   
2.4.2 
Conditional Co-Primary Endpoint 
Statistical significance for the co-primary endpoint will be evaluated using a two-sided type 1 
error rate of α=0.05. The conditional co-primary endpoint (CCPE) will only be formally tested 
for superiority if the primary NICCE endpoint demonstrates Reltecimod superiority at p≤0.01. 
Based on a similar evaluation of the preliminary studies discussed above, this study was 
designed to have very large statistical power for the conditional co-primary endpoint when the 
true expected CCPE success rates are 80% and 60% (difference of 20%) in the Reltecimod 0.5 
mg/kg and placebo treatment groups, respectively. Under these assumptions power is 96.4%.  
However, if the true rates are 78% vs 62% (difference of only 16%), then power remains 
relatively high at 84.8%. The total sample size has also been selected to obtain sufficient 
enrollment on the treatment arm for relevant secondary effectiveness endpoints and for safety 
endpoints. 
2.5 
Randomization 
290 patients will be recruited into the study and randomized to either Reltecimod 0.50 mg/kg or 
placebo in a 1:1 ratio. Randomization will be within site stratified by presence (+) of a diagnosis 
of Fournier’s Gangrene versus absence (-) and whether the screening mSOFA score is >4 (+) or 
3-4 (-) (See Tables 14.1.1.1 to 14.1.1.4).  In the Retrospective Study analysis set with screening 
mSOFA ≥ 3 (N=69), the median mSOFA value was 4 and 46.6% had values >4. Thus, the 
stratification for mSOFA is expected to roughly reflect a median split. 
Four computer generated, blocked randomization lists will be provided for each site 
corresponding to the cross-tabulation of Fournier’s Gangrene (+ vs -) and baseline mSOFA >4 (+ 
vs -) category status.  Within each block, half of the assignments will be to active drug and half to 
placebo, in random order.  Block sizes will be randomly varied as an additional masking feature.   
The following will be done to insure balance through randomization. Every initial randomization 
code will end in ‘-1’. If a randomization code is used but the patient does not receive drug due to 
lack of confirmatory surgical NSTI diagnosis3, then the randomization code is not reused. Instead, 
the next patient from same stratum, (+,+), (+,-), (-,+), or (-,-) as the non-dosed patient, will 
receive the same allocation and the same randomization code except that the new code will end in 
‘-2’ while the old code ended in ‘-1’.  In this way, randomization codes are not re-assigned which 
can cause confusion but the same drug allocation using the digits prior to the ‘-‘ are used, thereby 
preserving balance.  
2.6 
Analysis Sets 
The following analysis sets are defined: 
 
3 It is an unavoidable medical fact that NSTI diagnosis requires surgical confirmation and that randomization may occur prior 
to surgical confirmation in order for the treatment to begin at the optimal time frame.  This presents the need to add a 
design feature that maintains within stratum balance; yet avoids the operational need for never applying the exact same 
randomization ID to more than one patient.  


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• Intent-to-treat (ITT): The ITT (Randomized) Set is defined as all randomized patients 
according to the intended study treatment.  
• As-Treated (AT): The AT analysis set will include the subset of ITT patients who were 
exposed to study medication (active or placebo) and categorized according to the treatment 
actually received.  This analysis set will be often referred to as the As Treated (Safety) 
Analysis Set.  
• 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 NSTI based on surgical 
verification. The mITT analysis set will be used in primary effectiveness analyses with 
patients assigned to their intended randomized.  
• Per Protocol (PP): Optionally, a PP analysis set may be used in secondary effectiveness 
analyses. The PP analysis set would include patients in the mITT analysis set assigned 
according to actual treatment received rather than intended treatment; and excluding 
patients with one of the following:  
1. Significant violations of inclusion or exclusion criteria with a reasonably important 
potential to confound estimates of drug effects,   
2. Post randomization protocol violations with potential to confound estimates of 
treatment effects, or  
3. Patient death within 1 day of dosing. 
Exclusions from the PP analysis set will be determined based on blinded clinical data.  If a PP 
analysis set is defined, analyses will be limited to the subset of tables listed in Section 3.2 to be 
used in pre-planned exploratory sub group stratified analyses. 
2.7 
Futility analyses 
A futility analysis will be performed based on the results of the first 100 patients (50 per group). 
The futility decision will be based on the predictive probability of eventual study success, 
conditioned on the data available at interim analysis. Independent, non-informative Bayesian prior 
distributions are assumed for the expected NICCE success rates for both treatment groups, 
namely, π0.50 ~ Beta(1,1), πPlacebo ~ Beta(1,1) for the active and placebo groups, respectively.  
The Bayesian predictive probability of being able to demonstrate superiority of Reltecimod 
relative to placebo at a two-sided α=0.01 when the remaining patients are finally observed will be 
determined. The trial will stop enrollment for futility if this predictive probability is below a 
lower bound threshold of 10%.   
The following table summarizes what the observed predictive probabilities will be as a function 
of magnitude of the treatment group difference and assuming an observed control success rate of 
0.40.  For example, if there are 20 success and 30 failures among placebo controls (40% success 
rate) at the interim analysis, then the futility boundary will be crossed if the number of active 
successes is 22 (44%) or less, that is, if the observed treatment group difference is 4% or less.    


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Diff
0.000
0.020
0.040
0.060
0.080
0.100
0.120
0.140
0.160
0.180
0.200
0.220
0.240
0.260
0.280
0.300
PP
0.029
0.050
0.082
0.127
0.187
0.261
0.348
0.444
0.543
0.639
0.728
0.804
0.866
0.913
0.946
0.969  
The futility bound is ‘non-binding’ in the sense that no effort was made to ‘recover’ alpha to 
increase power. 
2.8 
Control of blinding and DMC 
2.8.1 
Randomization and Unblinded Study Statistician  
There are three statisticians in this study with different roles: 
Blinded primary study statistician – primary lead statistician 
Unblinded study statistician – performs randomization and provided back-up 
Unblinded DMC statistician  independent statistician supporting DMC operations 
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 DMC statistician, 
Serve as a backup unblinded statistician. 
In advance of study initiation, programming for the blocked randomized treatment allocation with 
randomized block size was developed. The program to perform this randomization was written in 
SAS with a Proc IML call to R and is provided in Appendix 6.   
A preliminary randomization ‘test’ seed was used to generate a set of preliminary randomization 
ID numbers. These were exported to site-specific Excel files and also summarized in a single SAS 
listing report (RTF format). The unblinded study statistician will use this program to determine  
final (blinded) randomized allocations and will provide these to the contract drug dispenser in an 
agreed upon format. A variable indicating the blinded treatment allocations will not be part of the 
clinical study data to be managed by the data management CRO. This is to eliminate any 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.  
2.8.2 
Data Monitoring Committee and Unblinded DMC Statistician 
A Data Monitoring Committee (DMC) will be utilized in this study which will be reviewing 
safety outcomes at a prescribed regularity in addition to helping to facilitate the unblinded futility 
analysis. The Charter will provide decision rules, composition of the DMC members and their 
conflict of interest statements.  This DMC will include an unblinded DMC statistician. 
Analysis staff under the direction of the primary study statistician will develop SAS based 
programs that process clinical data provided by the blinded data management CRO to populate 
planned safety analysis tables and listings, but in a blinded fashion. This includes using a pseudo 
randomization for purposes of table generation program development. This programming and 
relevant data will be provided to the independent unblinded DMC statistician.  
As mentioned above the unblinded study statistician has limited roles for this study. This 
individual will perform the final randomized allocation and will provide the unblinding codes to 


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the unblinded DMC statistician who will run programs to populate selected tables in an 
unblinded fashion. If needed, the unblinded study statistician may work with the unblinded DMC 
statistician to resolve difficulties and can serve as a backup unblinded statistician if needed.   
The independent unblinded DMC statistician will perform the necessary computations involving 
the Bayesian predictive power to be used in the planned futility assessment at the planned 
interim analysis based on the results from the first 100 evaluable patients.  


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3 Description of Variables to be Included in Statistical Analyses 
3.1 
Medical and Surgical History 
Details of the NSTI will be recorded on the case report form (CRF) and include: “clinical 
diagnosis” (as a specific subset of NSTI) at the time of enrollment; location of primary infection; 
date of onset, identified predisposing factors (trauma, surgery, IV drug use, and co-morbidities 
such as diabetes or vascular insufficiency; prior surgical procedures related to the etiology of the 
NSTI; prior surgical procedures for the treatment of the primary infection site;  antimicrobial use 
from the date of onset of current illness if available [may predate diagnosis of NSTI]).  A  medical 
history identifying active medical or surgical conditions will be reported on the CRF.  All chronic 
medications will be identified and characterized by dose and frequency as well as reason for use. 
3.2 
Physical Examinations 
Physical exam will include both the primary site of the necrotizing soft tissue infection and a 
clinically appropriate examination of vital organ systems. These include cardiovascular, 
respiratory, abdomen, extremities, neurologic body systems, and other. 
3.3 
Concomitant Medication 
All concomitant medications antimicrobial & non-antimicrobial will be entered into the CRF and 
identified by their generic or trade name.  Information will include the dose, dosing frequency, 
route of administration, duration (start and stop dates), and reason for administration. 
Concomitant medications will be collected up through Day 28.   
3.4 
Vital Signs 
Vital signs include weight, heart rate, systolic and diastolic blood pressure, mean arterial blood 
pressure (MAP) respiratory rate (spontaneous or controlled) and temperature.  While these may 
be determined many times during the course of the patient hospitalization, recording vital signs in 
the CRF will be based on once daily readings for specified time sequences according to the time 
and events schedule. 
3.5 
Clinical Scores 
Clinical scores/criteria components will be collected in the study. APACHE II and LRINEC 
scores along with Anaya criteria are obtained only at screening while SOFA score is obtained 
throughout the study.  Computational details for all scores are presented in the Appendix 5. 
3.5.1 
Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score 
The LRINEC score (Wong, Khin et al. 2004)4 is only obtained at screening and will be used to 
described baseline disease severity.  LRINEC ≥ median vs LRINEC < median will be used in the 
exploratory stratified analyses. 
 
4 Wong CH, Khin LW, et al. The LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) score: a tool for 
distinguishing necrotizing fasciitis from other soft tissue infections. Crit Care Med 2004: 32(7): 1535-1541 


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3.5.2 
ANAYA criteria 
The ANAYA criteria (Anaya, Bulger et al. 2009) are only obtained at screening and will be used 
to described baseline severity. ANAYA ≥ median vs ANAYA < median will be used in the 
exploratory stratified analyses. 
3.5.3 
Acute Physiology and Chronic health Evaluation II (APACHE II) score 
APACHE II scores are another measure of disease severity to be obtained at screening.    
APACHE II ≥ 10 vs APACHE < 10 will be used in the exploratory stratified analyses. 
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.  If this is the case then the APACHE 
II scores will not be considered part of the audited clinical data set provided by the data 
management CRO. 
3.5.4 
Sequential Organ Failure Assessment (SOFA) Score 
A modified version of the SOFA score will be used as a clinical end point and will be calculated 
as described in Section 5.2 and Appendix 5. The modification is that the liver component is not 
used. Individual parameters of the SOFA score will be collected as summarized as well as the 
modified SOFA total score (mSOFA). Data will be recorded in the CRF at specified time points 
according to the time and events schedule.  Additionally, SOFA will be computed and described 
for screening, Day 7, and Day 14. Additional handling of the neuro deficit component is 
described below.  
3.6 
Electrocardiogram 
12-lead electrocardiogram will be according to time and events schedule. The following 
parameters will be recorded for each ECG: PR interval, RR interval, QRS complex time, QT 
interval and Corrected QT interval (QTc).  Additionally, descriptive text will be provided for any 
ECG abnormalities as evaluated by site personnel. 
The primary ECG results will be obtained from an independent and blinded cardiology central 
reader including QTcB and QTcF as well as the measures listed above.  
3.7 
Clinical Laboratory Assessments 
Safety laboratory assessments will be performed according to the to the time and events schedule 
(See Clinical Study Protocol). 
3.8 
Microbiology 
Microbiological testing will be performed as described in the Clinical Study Protocol and time 
and events schedule.  
3.9 
Use of additional concomitant therapy  
The following measures of additional medical therapies will be recorded: 
• Hyperbaric oxygen 
• Intravenous gamma globulin (IVIG) 
• Plasmapheresis 


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4 Secondary and Exploratory Endpoints 
4.1 
AKI Related Endpoints 
4.1.1 
Freedom from Durable Loss of Renal Function at Day 28 
The same endpoint that is being currently employed in the ongoing ATB-203 study of AKI in 
sepsis will be the key secondary endpoint in this study. Only subjects with AKI Stage 2 or Stage 
3 prior to drug dosing will be included in this comparison.  
The key secondary AKI endpoint is freedom from durable loss of renal function at Day 28 
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. 
Reference creatinine values, baseline AKI stage and percentage loss of eGFR at Day 14 and 28 
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.  A sensitivity analysis will utilize an 
independently adjudicated reference value to determine baseline eGFR. 
To control type 1 error for the key secondary efficacy endpoint, superiority of Reltecimod 
relative to placebo in terms of freedom from durable loss of renal function among those with 
Stage 2 or Stage 3 AKI prior to dosing, will only be interpreted as a confirmatory hypothesis test 
if p≤0.01 for the primary endpoint (NICCE) and p≤0.05 for the co-primary endpoint (CPEP). 
Otherwise, treatment group comparisons in terms of the key secondary efficacy (AKI) endpoint 
will be interpreted as a descriptive endpoint. An unadjusted chi-square test using a two-sided 
type 1 error of α=0.05 will be used to test superiority of Reltecimod relative to placebo for the 
key secondary AKI endpoint.  
4.1.2 
Blinded Independently Adjudicated AKI Endpoints and Analyses 
Reference creatinine values, maximal AKI stage, and AKD stage at Day 14 will be determined 
by a blinded independent adjudication committee as described in the Clinical Study Protocol. 
AKI Stage assigned through blinded independent adjudication will be for Maximal stage by 
KDIGO criteria using creatinine and/or urine output over the first 7 days post screening.  For 
these analyses, subjects with a maximal AKI Stage 2 or AKI Stage 3 will be included.   
Descriptive comparisons will be made between the Screening (pre-dose) AKI stage and Maximal 
AKI stage and between the Day 14 algorithmically determined endpoints to the Day 14 
independently adjudicated endpoint. 
4.1.3 
Other AKI Endpoints 
Exploratory AKI endpoints include the primary endpoint evaluated at Day 14, 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 evaluated at Day 14 and Day 28, and AKD stage 
evaluated at Day 14 and Day 28. 


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4.1.4 
Algorithmic Determinations 
4.1.4.1 
Reference 
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.  
Exhibit 1. Algorithmic Determination of Reference Creatinine 
Pre processing 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 formula5,6 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; 
 
 
5 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. 
6 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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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)  ; 
        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; 
4.1.4.2 
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. 
 
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. 


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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).  
As a sensitivity analysis, when determining AKI endpoints, the adjudicated reference 
creatinine will be used in place of the algorithmically determined reference value.  
4.1.4.3 
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.  
4.1.4.4 
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. 
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.  
4.1.4.5 
Determining AKD Stage at Day 28 
Exhibit 2 will also be used to determine AKD Stage at Day 28 except that the criterion for 
renal replacement therapy is an ongoing need rather than initiation.  
4.1.4.6 
Determining AKD Stage at Day 14 
Similarly, Exhibit 2 will be used to determine AKD Stage at Day 14 except that the criterion 
for renal replacement therapy is an ongoing need rather than initiation.  
4.1.4.7 
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”.  


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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 14-28 day range as the recovery 
creatinine.  
4.1.5 
Processing of Adjudicated AKI Data 
Three independent adjudicators will determine: 
• Reference Creatinine 
• Maximal AKI Stage (over first seven days) 
• AKD Stage at Day 14 
The adjudicated reference will be the mean of the three adjudicated values. 
The adjudicated Maximal AKI Stage and AKD Stage at Day 14 will be determined through ‘vote 
counting’.   
Independent adjudication of AKD stage will be used to determining Achieving Freedom from 
Durable Loss of Renal Function at Day 14 and Improvement in Durable Loss of Renal 
Function at Day 14 in sensitivity analyses.  
4.2 
Primary Endpoint Components and Other mSOFA Related Outcomes 
The primary endpoint components and other mSOFA related outcomes will be evaluated as 
additional secondary efficacy endpoints in descriptive treatment group comparisons using the 
statistical methods summarized below. 
• Distribution of mSOFA scores at Day 14 
• Kaplan-Meier analysis of the time to resolution of mSOFA score to ≤ 1 with censoring at 
Day 14 
• Kaplan-Meier analysis of the time to resolution of mSOFA score to ≤ 1 up to Day 28 
• Single components of the primary composite end point: 
o Alive at Day 28 
o Debridements by Day 14 ≤3 
o Number of amputations (removal of a limb or portion of a limb to the level of a 
joint space) (done after first debridement) 
o mSOFA score on Day 14 ≤1  
o Reduction of ≥3 score points between baseline and Day 14 mSOFA score. 
 
• Clinical local parameters: 
o Number of debridements to days 7, 10,  and 14 Proportion of patients needing (up 
to Day 14): 
•  only one debridement to control the infection 
• 2 debridements to control the infection 
• 3 debridements to control the infection 
• ≥3 debridements to control the infection 
• >3 debridements to control the infection 


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• Clinical systemic parameters: 
o Evaluation of organ function over time, using mSOFA score (total score and organ 
specific score) 
4.3 
Critical care and hospital stay parameters 
The following critical care and hospital stay parameters will be measured up to Day 28. These 
parameters relate to medical and procedures costs: 
o ICU free days 
o Days in ICU 
o Days on ventilator 
o Ventilator free days 
o Vasopressors days/ Vasopressors free days 
o Hospital length of stay (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. 19997). 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 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 a 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/vasopressor 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.  
 
7 Rubenfeld GD, Angus DC, et al. Outcomes reserach in critical care. Am J Respir Crit Care Med 
1999: 160(358-367).  


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The table summarizing critical care related outcomes will also be presented stratified according to 
the set of baseline covariate stratified analyses defined below. In addition, critical care related 
outcomes will be similarly summarized and compared between patients with NICCE success and 
NICCE failure.    
4.4 
C - Reactive Protein (CRP) 
CRP will be summarized for measurements made at Screening, Day 14, and for changes from 
Screening to Day 14. CRP is not considered a safety endpoint. Therefore, CRP will be 
summarized in the mITT Analysis Set . 
4.5 
Exploratory Endpoints 
The following will be assessed as exploratory endpoint. 
• Distribution of observed mSOFA at Days 21 and 28. 
4.6 
Exploratory Subgroup Analysis 
Exploratory subgroup analysis will be performed. For these exploratory analyses, primary 
efficacy, selected secondary efficacy, selected safety tables will be repeated stratified according 
to the following classifications: 
 
1. Age ≥ 65 years vs. < 65 years 
2. Gender 
3. BMI (<30 versus 30-<40 vs. ≥ 40 kg/m2),  
4. White vs. non-white 
5. AKI Status (Any AKI, Stage 2/3 AKI, non-AKI).  
6. Patients Achieving Freedom from Durable Loss of Renal Function vs. not (among patients 
presenting with Stage 2 or Stage 3 AKI) 
7. Presence of cardiovascular organ failure (SOFA component >=3 at baseline) vs. those without 
CV organ failure (except SOFA related tables) 
8. Presence of respiratory organ failure (SOFA component >=3) at baseline vs. those without 
(except SOFA related tables) 
9. LRINEC ≥  median vs. LRINEC < median 
10. ANAYA ≥  median vs. ANAYA < median 
11. APACHE II ≥ 10 vs. APACHE <10 
12. Type of bacteria (Gram-positive vs. Gram-negative and possibly a ‘mixed’ type if needed), list to 
be provided by Sponsor and other prevalent pathogens. 
13. Prevalent sub types and classes of identified pathogens 
14. Bacteremic vs. non-bacteremic (blood culture) 


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The results for any subgroup analysis will not be interpreted if there are fewer than five patients in 
either treatment group within that subgroup analysis. 
The following tables will be provided for stratifications 1 through 11 listed above. These tables 
are described in more detail below. Only the primary endpoint table (Table 14.2.1.1) will be 
stratified for the subgroups 12, 13, and 14.  
 
14.2.1.1 
Comparisons of the Percentages of Patients Achieving 
Primary Composite Clinical Success Endpoint (NICCE) and its Components 
mITT Analysis Set† 
14.2.1.2 
Comparisons of the Percentages of Patients Achieving 
Conditional Co-Primary Endpoint (CCPE) and its Components 
mITT Analysis Set† 
14.2.2.2 
Modified SOFA Total Score and Organ Specific Scores Over Time to Day 14 
Last Observation Carried Forward (LOCF) 
mITT Analysis Set† 
14.2.2.4 
Modified SOFA Total Score and Organ Specific Scores Over Time to Day 14 
Change from Day 0 (Screening) - Last Observation Carried Forward (LOCF) 
mITT Analysis Set† 
14.2.2.6 
Modified SOFA Total Score and Organ Specific Scores Over Time to Day 14 
Change from Day 1 - Last Observation Carried Forward (LOCF) 
mITT Analysis Set† 
14.2.4.1 
Critical Care and Hospital Stay Parameters Over Days 1 to 28 
By Treatment Group 
mITT Analysis Set† 
14.2.5.1 
Cumulative Number of Debridements to Days 7, 10, and 14 
By Treatment Group 
mITT Analysis Set† 
14.2.5.2 
Percentage of Patients Requiring 1, 2, 3, >=3, and >3 Debridements 
Through Day 14 
By Treatment Group 
mITT Analysis Set† 
14.2.6.2.1 
Numbers and Percentages of Subjects 
Achieving Freedom from Durable Loss of Renal Function and  
Improvement in Durable Loss of Renal Function at Day 28 
Algorithmic Determination of Reference Creatinine 
Algorithmic Determination of AKI at Screening 
Algorithmic Determination of Day 28 Status Using LOCF& 
Among mITT Subjects with Stage 2 or Stage 3 Screening AKI Using Algorithmic 
Reference 
14.3.1.1 
Summary of Treatment-Emergent Adverse Events (TEAEs) 
Overall and by Treatment Group 
As Treated (Safety) Analysis Set† 
 
4.7 
Microbiology 
By-Pathogen and By-Patient bacteriological responses will be summarized as follows:  


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o By-Pathogen Bacteriological Response: The by-pathogen bacteriological response for each 
causative organism identified at baseline (BL) will be defined as follows: 
▪ Eradication: BL causative organism cannot be isolated from any culture(s) obtained from 
a debridement performed on or after study Day 3. 
▪ Persistence: The BL causative pathogen is isolated from a debridement performed on or 
after study Day 3. 
 
o By-Patient Bacteriological Response: The by-patient bacteriological response will be 
determined according to the following definitions: 
▪ Eradication: 
All BL causative organism(s) have a response of Eradication. 
▪ Persistence: 
All or some BL causative organism(s) have a response of Persistence. 
Presence of pathogens will be determined using blood and tissue cultures. Treatment group 
comparisons of response rates will only be performed if there at least 5 instances of a unique 
pathogen in both groups and are limited to patients with microbiological samples at screening and 
at follow-up (i.e., day 3).  By-patient microbial responses will be based on worst response.   
Pathogens will also be categorized into Gram-positive / Gram-negative and into aerobic and 
anaerobic sub types. 
Prevalent sub types and classes of identified pathogens will be used in sub group analyses of 
clinical response as described above.  
 
 


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5 Analysis Approaches 
5.1 
Baseline Comparisons 
Demographic and baseline characteristics will be summarized for each analysis set overall and by 
treatment group. Categorical variables including race, ethnicity, and gender will be summarized 
by counts and percentages. Continuous variables will be summarized using mean, median, 
standard deviation (SD), and minimum and maximum values. Continuous variables evaluated will 
include age, BMI, height, weight, systolic BP, diastolic BP, MAP, heart rate, and temperature; as 
well as ANAYA, LRINEC, and APACHE II scores. Presence of baseline sepsis will be 
summarized according to the numbers and percentages of patients with baseline cardiovascular 
and respiratory organ failure as reflected in screening component SOFA scores of 3 or 4.  In 
addition presence of any AKI at baseline algorithmically determined, Stage 2/3 AKI at screening, 
and  maximal AKI Stage 2/3 as assigned by the blinded adjudication panel will be summarized.  
Analyses will be performed 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. If there are clinically important baseline differences, multiple logistic 
regression will be used in supporting analyses to assess the impact of the imbalance on 
significance levels. 
5.2 
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)8,9.  Each of six organ systems are 
evaluated (see Appendix 5) with ordinal scores 0 to 4.  A total score is the sum of the component 
scores.  For this study, the liver component is excluded 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.   
mSOFA scores will be assessed as 1) observed cases, 2) last observation carried forward (LOCF), 
3) using MMRM, and 4) categorized and combined with mortality and local activity as part of the 
primary composite clinical success endpoint, NICCE. 
The following will be defined as OBSERVED mSOFA.  
1. If a single individual organ score is missing but other scores for that day are non-missing, the 
organ system that were not evaluated are assumed to be free of organ failure and are given a 
value of zero when determining the sum score.   
 
8 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. 
9 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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2. If two or more individual organ scores are missing for mSOFA on Day 14 or earlier, but at 
least one individual organ score is non-missing, the individual organ scores will be imputed 
using last observation carried forward. In this case, it is possible that different components 
come from different visits.  This will not be done at Day 21 and Day 28.  
The following will defined mSOFA LOCF. 
3. If all organ scores are missing on Day 14 or earlier, the mSOFA total score from that day will 
be imputed using last observation carried forward with the following exception.  
a. LOCF will not be performed after patient death.    
b. Note that LOCF will not be performed for unavailable mSOFA total scores at Day 21 
and Day 28.    
4. When summarizing the individual organ scores apart from the mSOFA total scores, the same 
rules as above will apply.  
5. Patients with recorded screening mSOFA inflated by GCS scores due to mechanical 
ventilation or due medications will have their GCS score removed when determining 
screening mSOFA.  This is to prevent subjects meeting trial inclusion just on the basis of 
GCS. 
Since LOCF will not be applied to missing mSOFA scores after patient death in analyses that 
employ LOCF to describe mean values of time, there may be some ‘diminishing n’ and focus is 
therefore on morbidity rather than mortality. 
5.2.1 
Mean and Mean Changes Over Time 
Mean values (SD) for the mSOFA and for the 5 specific organ components will be summarized 
over time with and without last-observation-carried-forward (LOCF). Similarly, mean (SD) 
changes scores from both day 0 and day 1 will be summarized with and without LOCF. 
5.2.2 
mSOFA as Part of Primary Endpoint 
The primary efficacy endpoint (NICCE) employs mSOFA in two of its five components.  
NICCE success requires mSOFA at Day 14 ≤ 1 and the improvement from screening Day 0 to 
Day 14 that is ≥ 3.   
5.2.3 
Time to Organ Dysfunction Resolution 
Time to organ dysfunction resolution will be evaluated as a time-to-event endpoint. This will be 
assessed in descriptive analyses using survival and life-table methods10 and calculated from time 
of drug administration.  Organ dysfunction resolution will be defined as mSOFA score ≤ 1.  Two 
analyses will be performed.  The first corresponds to the primary efficacy endpoint and evaluates 
time to mSOFA score ≤ 1 censoring at Day 14.  The second extends the follow-up range to Day 
28 using available observed mSOFA. 
 
10 Kaplan EL and Meier P. Nonparametric estimation from incomplete observations, Journal of the American Statistical 
Association 1959, 53:457-481.  


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5.2.4 
Mixed Models for Repeated Measures (MMRM) 
Supporting longitudinal analyses comparing mSOFA means and mean changes over time will be 
implemented using mixed models for repeated measures (MMRM). The analysis set for the 
MMRM will not include LOCF imputation.  Methods for this approach are described below. 
5.3 
Assessment of poolability among sites 
Site poolability for the primary and co-primary endpoints will be evaluated using a random 
effects meta-analysis approach using the R package metafor to implement the analysis11. True 
effects will be evaluated on the logit scale and 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 12. I2 is the fraction of 2 
that is due to effect size heterogeneity (among sites), as opposed to sampling variance (within 
site).  Fractions 25% and less are considered small (see references).  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 NICCE is the same for 
treated and placebo patients accounting for site-to-site heterogeneity in treatment effects.    
5.4 
Analyses Accounting for Stratification Factors 
As noted above, randomization will be within site stratified by presence (+) of a diagnosis of 
Fournier’s Gangrene versus absence (-) and whether the screening mSOFA score is >4 (+) or 3-4 
(-).  An unadjusted chi-square test using a two-sided type 1 error of α=0.01 will be used to test 
superiority of Reltecimod relative to placebo for the primary endpoint (NICCE). The 
corresponding 99% confidence interval will be determined. 
Analyses will be performed to evaluate the potential impact of the stratification factors (presence 
versus absence of Fournier’s gangrene and screening mSOFA equal to 3-4 versus >4). The 
estimated overall treatment group difference controlling for these two stratification factors, the 
stratum adjusted significance level for testing the superiority hypothesis, and the corresponding 
95% confidence interval for the group difference in Month 24 CCS will be determined using a 
generalized linear model. The model covariates are treatment group and a categorical variable 
(df=3) for randomization stratum. The model parameters will be estimated using SAS Proc 
Genmod with distribution set to binomial and link set to logit. The stratum adjusted success rates 
and standard errors of the success rates are determined on the probability scale using the ilink 
option in a lsmeans statement with a diff option. This statement produces a stratum adjusted 
significance level. The standard error on the probability scale for the difference in NICCE success 
rates needed for the 99% confidence interval will be determined as the square root of the sum of 
the device group specific standard errors which are generated as part of model estimation. The 
significance level for the stratum by treatment group difference interaction will be reported from a 
model in which the interaction is added.  Within stratum differences and 95% confidence intervals 
will be summarized in descriptive analyses.  
 
11 Viechtbauer W. Bias and efficiency of meta-analytic variance estimators in the random-effects model. J Educ Behav Stat. 
2005;30(3):261-293. 
12 Higgins JP, Thompson SG, Deeks JJ. Altman DG. Measuring inconsistency in meta-analyses. BMJ: 327(7414):557 


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The goal of the stratified randomization is to promote good balance of the stratification factors 
within site between the two treatment groups. It is possible that subjects will be assigned to a 
randomization stratum in error. If there are any subjects that are assigned to the incorrect stratum, 
then these analyses will be repeated using the subjects’ true stratification status. To this end, 
significance levels and relative success rates with confidence intervals will be determined and 
compared for the primary and conditional co-primary endpoints for three scenarios. These three 
scenarios are: 
1) Not accounting for stratified randomization (primary),  
2) control for the actual stratification using a generalized linear model, and  
3) control for strata defined based on actual subject status using a generalized linear model.  
For example, if a subject was identified with a diagnosis of Fournier’s Gangrene but it is later 
discovered that the subject actually did not actually have Fournier’s Gangrene, then this subject 
would be moved into the correct stratum in scenario 3. In addition to the overall summary 
measures across strata, results within strata for scenarios 2 and 3 will be summarized.  
5.5 
Analysis of other covariate effects 
Covariates may be assessed for potential confounding (due to imperfect randomization balance) 
or effect modification (subgroup efficacy heterogeneity) using multiple logistic regression. 
Covariates to be considered will include age, race, sex, site, and severity  scores at baseline (i.e., 
APACHE II, Anaya13 and LRINEC14). Other baseline variables in which randomization failed to 
produce adequate balance between groups (if any) will be examined in supporting analyses. This 
will be done through stratified analyses or multiple logistic regression. Covariate effects on 
estimates and interactions with treatment effects will be assessed as needed to evaluate treatment 
effect heterogeneity. Results from all subgroup analyses will be considered supportive and/or 
hypothesis-generating. 
5.6 
Multiplicity 
The overall study success criterion, agreed upon with FDA, is to simultaneously observe p≤0.01 
for the primary endpoint (NICCE) and p≤0.05 for the conditional co-primary endpoint (CCPE). 
Therefore, there is no concern regarding type 1 error inflation due to multiplicity for the overall 
study success criterion.  
To control type 1 error for the key secondary efficacy endpoint, superiority of Reltecimod relative 
to placebo in terms of freedom from durable loss of renal function among those presenting with 
Stage 2 or Stage 3 AKI will only be interpreted as a confirmatory hypothesis test if p≤0.01 for the 
primary endpoint (NICCE) and p≤0.05 for the co-primary endpoint (CCPEP). Otherwise, 
treatment group comparisons in terms of the key secondary efficacy (AKI) endpoint will be 
interpreted as a descriptive endpoint. An unadjusted chi-square test using a two-sided type 1 error 
of α=0.05 will be used to test superiority of Reltecimod relative to placebo for the key secondary 
AKI endpoint.  
 
13 Anaya, D. A., E. M. Bulger, et al. Predicting Death in Necrotizing Soft Tissue Infections: A Clinical Score. Surgical 
Infections 2009: 10(6): 517-522. 
14 Wong, C. H., L. W. Khin, et al. The LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) score: a tool for 
distinguishing necrotizing fasciitis from other soft tissue infections. Crit Care Med 2004: 32(7): 1535-1541. 


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There will be no attempt to control type 1 error for other secondary NSTI or AKI endpoints.   
5.7 
Descriptive Analyses of Additional Secondary Endpoints 
Additional secondary endpoints have been specified from several domains including individual 
components of the primary composite endpoint (NICCE), time to resolution of organ dysfunction, 
critical care and hospital stay parameters (ICU and ICU-free days, ventilator days and –free days, 
vasopressor days and –free days, hospital LOS), clinical local parameters (debridement history 
variables), and clinical systemic parameters (mSOFA over time, incidence and recovery from 
AKI). Analyses for these endpoints will generally be descriptive, with emphasis on characterizing 
clinical effect sizes15. Nominal p-values will be presented in some cases as an aid to interpretation 
but with no adjustment for multiplicity. 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 compared 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. The c-stat is the probability that a randomly 
selected patient treated with Reltecimod has a better (e.g., greater number of free-days) than a 
randomly selection patient treatment with placebo. Methods appropriate for time-to-event 
endpoints including survival and life-table methods will be used for time-to-organ dysfunction 
resolution endpoints. Additional analyses of mSOFA over time will employ methods appropriate 
for longitudinal data. For these analyses, statistical testing and estimation will be based on a 
Mixed Model Repeated Measures (MMRM)16.   
5.8 
Analysis of Longitudinal Outcomes 
Supporting analysis will be performed for mSOFA over time using the Mixed Model for 
Repeated Measures (MMRM) analysis of covariance (ANCOVA) approach17. The following 
baseline covariates will be included in the primary MMRM analysis to mSOFA over time. 
• 
Day 0 mSOFA = 3-4 versus >4 
• 
Presence versus absence of Fournier’s gangrene 
• 
APACHE II score 
• 
mSOFA Day 1 
• 
Presence of Stage 2/3 AKI at Screening 
mSOFA Day 1 is included because this score reflects patient status post initial surgery. In 
addition to this variable, the Day 0 stratification factors are included to reflect the experimental 
design. Screening APACHE II is included to account for variation in medical status at screening.  
Presence of Stage 2/3 AKI at screening is included given emerging evidence of its impact on 
clinical outcomes. Inclusion of covariates can increase power by explaining variance and also 
help with the implicit imputation of missing values that is inherent in the MMRM approach.  
MMRM is a direct likelihood approach that requires specialized statistical software for optimizing 
the likelihood function. For this study, all MMRM parameters will be estimated using SAS PROC 
MIXED [SAS Institute18]. 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’ 
 
15 Cohen, J. Statistical power analysis for the behavioral sciences (2nd ed.). New York, Academic Press, 1988. 
16 Verbeke G and Molenberghs G. Linear Mixed Models for Longitudinal Data, New York: Springer, 2000. 
17 Verbeke G and Molenberghs G. Linear Mixed Models for Longitudinal Data, New York: Springer, 2000. 
18 SAS Institute, Cary NC. 


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or arbitrary assignment of values as in ‘last-observation-carried-forward’ (LOCF). The MMRM 
model generally includes a factor for treatment group by time interaction in order to allow group 
differences in mean value 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 at each time point between the 
Reltecimod 0.50 mg/kg dose and placebo with a key emphasis on the Day 14 contrast. Model 
parameters will be estimated using Restricted Maximum Likelihood19,20(REML) as implemented 
Proc Mixed [SAS Institute21]. A generalized Satterthwaite approximation will be used to 
determine accurate estimates of denominator degrees of freedom for statistical tests22. 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). MAR based 
inferences are valid under broader assumptions than complete case analysis or analyses utilizing 
LOCF23. The modeling results will be graphically presented by plotting the individual least 
squares predicted mean values. 
5.9 
ITT vs mITT 
A modified intent-to-treat (mITT) analysis set will be used in the primary and secondary 
evaluation of efficacy. This is due to the nature of the disease progression and necessity of 
surgical confirmatory diagnosis. It therefore cannot be avoided that there will be randomized 
subjects not belonging to the indicated population. These patients are excluded prior to receiving 
study medication but after randomization. For such patients their randomized allocation is re-used 
to preserve with strata balance but not their precise randomization ID to avoid confusion (see plan 
in Randomization section above). 
Generally, the purpose of intent-to-treat (ITT) 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 assignment24. Therefore, mITT comparisons 
will be according to randomized treatment assignment and we will attempt to include all mITT 
patients, regardless of intervention or length of follow-up in the primary efficacy comparison.  
 
19 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 
20 Diggle P, Heagerty P, Liang K-Y, Zeger S. Analysis of Longitudinal Data. Oxford University Press; 2002. 
21 SAS Institute, Proc Mixed, SAS/STAT Software.  
22 Hrong-Tai Fai A, Cornelius PL. Approximate F-tests of multiple degree of freedom hypotheses in generalized least squares 
analyses of unbalanced split-plot experiments. J Stat Comput Simul. 1996;54(4):363-378. 
23 Rubin DB. Inference and missing data. Biometrika. 1976;63(3):581-592. 
24 Knickerbocker R. Intent-to-Treat Analyses. In: Chow S-C, ed. Encyclopedia of Biopharmaceutical Statistics. Marcel 
Dekker; 2000. 


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5.10 Handling of Missing Data 
5.10.1 mSOFA Scores 
mSOFA scores will be assessed as 1) observed cases, 2) last observation carried forward 
(LOCF), 3) using MMRM, and 4) categorized and combined with mortality and local activity as 
part of the primary composite clinical success endpoint, NICCE. 
The following will be defined as OBSERVED mSOFA.  
1. If a single individual organ score is missing but other scores for that day are non-missing, the 
organ system that were not evaluated are assumed to be free of organ failure are given a value 
of zero when determining the sum score.   
2. If two or more individual organ scores are missing for mSOFA on Day 14 or earlier, but at 
least one individual organ score is non-missing, the individual organ scores will be imputed 
using last observation carried forward. In this case, it is possible that different components 
come from different visits.  This will not be done at Day 21 and Day 28.  
The following will defined mSOFA LOCF. 
3. If all organ scores are missing on Day 14 or earlier, the mSOFA total score from that day will 
be imputed using last observation carried forward with the following exception..  
c. LOCF will not be performed after patient death.    
d. Note that LOCF will not be performed for unavailable mSOFA total scores at Day 21 
and Day 28.    
4. When summarizing the individual organ scores apart from the mSOFA total scores, the same 
rules as above will apply.  
Since LOCF will not be applied to missing mSOFA scores after patient death in analyses that 
employ LOCF to describe mean values of time, there may be some ‘diminishing n’ and focus is 
therefore on morbidity rather than mortality. 
In contrast, the mixed model repeated measures analyses (MRMM) will utilize implicitly 
imputed values for all missing values including those subsequent to patient death. 
In categorical analyses including formulation of the primary efficacy endpoint, an mSOFA value 
that is greater than 1 at Day 14 is considered a primary treatment failure in the same fashion as 
patient death at any time throughout the 28 day follow-up period. LOCF for SOFA is necessary 
to guarantee that every patient has a value at Day 14 for use in determining NICCE among 
patients that are alive at the Day 28 and who have not otherwise failed due to other NICCE 
components including more than 3 debridements, amputation beyond the first debridement.  
5.10.2 Handling of Missing Primary Endpoints 
As noted above, it is expected to be able to evaluate NICCE in all patients based on the a priori 
specification for this endpoint. If there are any patients with missing primary endpoints, these 
subjects will be treated as NICCE and CPPE failures in primary analyses and tipping point 
sensitivity analyses will be conducted. In these analyses, missing values in each group are 
separately assumed to be either successes or failures. Treatment group differences are computed 


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based on all possible combinations of assigning success or failure to NICCE to the patients in the 
two groups.  For example, one scenario will be that all missing Reltecimod observations are 
failures and all missing placebo observations are successes. The next scenario would have one 
success and the remaining missing values as failure for Reltecimod and all missing placebo 
outcomes as successes, etc. For each scenario, the hypothetical p-value for testing the primary 
effectiveness hypothesis will be determined. If there is more than a very few missing values, 
these results will be plotted using a dot plot with the number of missings assumed as failures for 
Reltecimod on the x-axis and the number of missing assumed as failures for placebo on the Y-
axis.  The dots will be color coded to indicate whether or not the primary statistical conclusion 
changes under each individual scenario. If the fraction of scenarios in which the statistical 
conclusion changes is small, the primary results will have been shown to be robust against 
assumptions concerning missingness. If there is more than a small amount of missing data, 
multiple imputation of missing endpoints may be performed in additional supporting analyses 
using the SAS procedures, Proc MI and Proc MI Analyze.  However, this is not expected to be 
necessary. 
 
5.10.3 Mixed Model Repeated Measures 
The use of MMRM is another method used to address missing data and is considered an optimal 
approach in many settings. The use of MMRM results in implicit imputations for missing data 
which are valid under missing at random (MAR), a more general set of assumptions than 
‘missing completely at random (MCAR)’.  For these analyses, there will be implicit imputation 
of expected mSOFA after patient death. Methods assuming Not Missing at Random (NMAR) 
require extensive modelling and sensitivity analyses regarding inherently untestable assumptions 
concerning the missingness mechanism; and will not be used in these analyses.  
5.11 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 
28  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 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 also 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 (most accurately and specifically) represents 
the reported term.  If a reported term is a trade name, then it will generally be coded to the trade 


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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. 
5.12 Deviations from the Original Statistical Plan 
Any deviations from the original statistical plan will be described and justified in the final report. 
 
 


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6 Safety Analysis 
The safety measures for this study are AEs, clinical safety laboratory, physical exam, vital signs, 
ECG (screening day 0 and day 1 post drug) and SAEs including determination of survival through 
Day 90. The safety profiles will be compared between Reltecimod and placebo groups using 
descriptive statistics as appropriate for continuous and categorical safety variables.  
6.1 
Adverse Events 
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 
for treatment emergent adverse events (TEAEs) defined as those with onset on day 1 or later. 
TEASs will also be summarized by relationship to study drug, severity, and whether they are 
serious.  
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 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/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). 
 


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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 
Electrocardiogram 
ECG data will be reviewed by the principal investigator and by an external independent and 
blinded cardiologist. The blinded core lab evaluation is referred to as “Central Reader”.  Results 
will be summarized for the investigator based and central reader based results.  
Electrocardiogram results from screening, immediately post drug administration, 4-6 hours post 
drug administration, and 12-24 hours post drug administration; and changes from screening will 
be summarized using the As Treated (Safety) Analysis set.  Descriptive statistics will include N, 
mean, median, standard deviation, minimum, and maximum values. Electrocardiogram 
characteristics to be summarized include heart rate, RR interval, PR interval, QRS complex time, 
QT interval, and the QTc interval. The results from the central reader will include the QTcB and 
QTcF intervals.  
ECG abnormalities observed during a study will be encompassed under a reported adverse event 
describing a clinical syndrome. In these cases, the ECG abnormality itself does not need to be 
recorded as an adverse event. 
Similar to that described for laboratory abnormalities, deterioration in baseline ECG parameters 
as compared to baseline should only be reported as AEs if they fulfil 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 to completing 
an unscheduled ECG eCRF with the information on the clinically significant test abnormality. 
6.4 
Physical Exams 
Results from physical exams will be tabulated for the Safety Anaysis Set on screening day 0 
(‘Normal’ vs ‘Abnormal’) as well as for days 3, 7, and 14. The following systems will be 
assessed: abdomen; cardiovascular; extremities; eyes, ears, nose, and throat; general appearance; 
head and neck; lymph nodes; neuorlogical; respiratory; and skin. On days 3, 7, and 14, patients 
will be categorized according to ‘Normal’, ‘Abnormal, improved or same as screening’, 
‘Abnormal, new or aggrevated’ and ‘Not done’. These data will be summarized as shift tables 
from the screening visit with results descriptively compared between the Reltecimod and Placebo 
drug groups.   
6.5 
Vital Signs 
Vital signs include height, weight, BMI, temperature, systolic BP, diastolic BP, MAP, respiration 
rate, and heart rate. Height and BMI will be summarized at the screening visit by treatment group.  
The remaining vital sign variables will be summarized as values and as changes from screening 
across time (day 1, day 2, day 3, day 7, day 10, day 14, day 21, and day 28), separately by 
treatment group using N, mean, SD, median, minimim, and maximum values. Vital signs will be 
summarized for the As Treated (Safety) Analysis Set. 
 


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7 Presentation of Enrollment and Baseline Characteristics 
7.1 
Numbers of Patients by Analysis Set 
 
Table 14.1.1.1 summarizes the numbers of patients screened, randomized, and in each analysis set 
(ITT, As Treated, mITT, and Per Protocol).  
Table 14.1.1.2 summarizes the numbers of patients in each analysis set by treatment group and 
site.  
Table 14.1.1.3 summarizes the numbers of patients by site, treatment group, and randomization 
stratum in the As Treated (Safety) analysis set. Randomization strata are defined as follows: 
 (+,+) = (mSOFA>4, Fournier’s)       (+,-) = (mSOFA>4,    No Fournier's)  
 (-,+) = (mSOFA=3-4, Fournier's)     (-,-) = (mSOFA=3-4, No Fournier's) 
Tables 14.1.1.4 and 14.1.1.5 provide the same summaries for the mITT and Per Protocol analysis 
sets, respectively.  Totals across all sites will be provided for both of these tables.  
7.2 
Demographic and Baseline Disease Characteristics of Cohorts 
Demographic and baseline characteristics of each analysis set are summarized in Tables 14.1.2.1, 
14.1.2.2, and 14.1.2.3, and 14.1.2.4 for the ITT, AT (safety), mITT, and Per Protocol analysis 
sets, respectively. 
Tables 14.1.3.1, 14.1.3.2, 14.1.3.3, and 14.1.3.3 summarize the numbers of patients overall and by 
treatment group, age category, and gender, for the ITT, AT, mITT, Per Protocol analysis sets 
respectively.   
7.3 
Baseline Microbiology 
Table 14.1.3.5 summarizes pathogens in tissue samples and blood cultures, overall and by 
treatment group. The data used are based on verbatim text.   
7.4 
Prior and Concomitant Medication 
Prior and concomitant medication, lifetime and current medications, will be summarized for the 
All Treated (Safety) analysis set as are all Safety endpoints. 
Table 14.1.4.1 will summarize the numbers (%) of patients with prior ancillary (e.g., non-
antimicrobial or non-immunosuppressant) medications by category and by specific medication, 
overall and by treatment group. 
Table 14.1.4.2 will present same for antimicrobial and immunosuppressant medications.  
Table 14.1.4.3 will summarize the numbers (%) of patients with concomitant ancillary 
medications by category and by specific medication by treatment group. 
Table 14.1.4.4 will present same for antimicrobial and immunosuppressant medications.  
7.5 
Medical History 
Table 14.1.5.1 will summarize the numbers and percentages of patients that experienced prior 
medical conditions during their lifetime by body system and specific medical condition, overall 
and by treatment group.   


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Table 14.1.5.2 will summarize the numbers and percentages of patients with ongoing medical 
conditions by body system and specific medical condition by treatment group.  
7.6 
Presentation of NSTI 
A summary of factors related to presentation and diagnosis of NSTI will be provided in Table 
14.1.6.1. Table 14.1.6.2 will list extensions of NSTI within initial debridement surgery categories. 
7.7 
Drug Administration and Timing 
Day 1 information regarding time from clinical diagnosis 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. Drug exposure will be summarized in Table 14.1.7.2. 
7.8 
Patient Disposition and End of Study Status 
Table 14.1.8.1 summarizes patient disposition and end of study status by treatment group based 
on the As Treated (Safety) Analysis Set.  
 


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8 Presentation of Efficacy Results 
8.1 
Primary and Conditional Co-Primary Endpoint in mITT Analysis Set 
The numbers and percentages of patients in the mITT analysis for each group meeting the primary 
efficacy endpoint (NICCE) and the conditional co-primary efficacy endpoint (CCPE) are 
summarized in Tables 14.2.1.1 and 14.2.1.2, respectively. These tables include the statistical 
significance of the group difference based on unadjusted two-sided chi-square statistics. Study 
success requires p ≤ 0.01 for the primary endpoint and p ≤ 0.05 for the conditional co-primary 
endpoint. These tables also provide the estimated treatment group differences for both endpoints 
as well as the 99% confidence interval for the primary endpoint and the 95% confidence interval 
for the conditional co-primary endpoint.  Figures 1 and 2 will be bar charts that illustrate these 
primary study results.  Figures 3 and 4 will be forest plots that summarize the point estimates and 
confidence intervals of the endpoints and their components.  
Tables 14.2.1.1 and 14.2.1.2 also summarize the components of the NICCE and the conditional 
co-primary endpoint.  P-values are provided for descriptive purposes only since there were no a 
priori hypotheses concerning the components, other than they would generally show group 
differences in the same direction. 95% confidence intervals are provided in order to facilitate an 
evaluation of the statistical precision in the estimated group differences. 
The components of NICCE are: 
• Alive at Day 28 
• <=3 debridements through Day 14 
• No amputation beyond first debridement 
• mSOFA score of <=1 at Day 14 
• Reduction of >=3 between baseline and Day 14 in mSOFA 
 
The components of the conditional co-primary endpoint (CCPE) are: 
• Alive at Day 28 
• <=3 debridements through Day 14 
• No amputation beyond first debridement 
 
8.2 
Primary and Co-Primary Endpoint in Per Protocol Analysis Set 
Tables 14.2.1.3 and 14.2.1.4 repeat the analyses above in the Per Protocol analysis set.  
8.3 
Evaluation of Site Heterogeneity in Primary Endpoint Treatment Effects 
Table 14.2.1.5 provides comparisons of the percentages of patients achieving NICCE by site and 
treatment group. Site-to-site heterogeneity will be evaluated with these data using a random 
effects ‘meta-analysis approach as described in Section 4.3 above. Table 14.2.1.6 provides the 
same summary for the conditional co-primary endpoint.   


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8.4 
Evaluation of Stratification Factors 
Table 14.2.1.7.1 summarizes the numbers and percentages of subjects achieving the NICCE 
within each level of the randomized stratification. The generalized linear model stratum adjusted 
risk difference, 99% confidence interval, and the adjusted p-value is presented for comparison to 
primary unadjusted results. A test for stratum by treatment group interaction will also be 
presented.   
Table 14.2.1.7.2 provides the same analysis but based on the true stratification status.  If there are 
no subjects that were placed in the incorrect stratum, this table will not be produced.  
8.5 
Sensitivity Analysis Removing the Reduction in mSOFA Component 
Table 14.2.1.8 provides a sensitivity analysis for the primary NICCE endpoint. In this analysis, 
the requirement that there be at least a 3 point reduction in mSOFA from screening to Day 14 is 
removed.  This was the original formulation of the NICCE endpoint before FDA requested that 
that the reduction component be included for this trial. 
8.6 
Distribution of mSOFA scores Over Time 
Table 14.2.2.1 summarizes mSOFA and its 5 components over time, from screening to Day 28.  
Since bilirubin is collected only at screening and at Day 7 and 14, observed SOFA total scores 
will also be summarized at these three timepoints.  
Table 14.2.2.2 provides the same summary after application of last-value-carried forward (LOCF) 
to Day 14. LOCF was not applied after patient death or for missing Day 21 or Day 28 mSOFA. 
Table 14.2.2.3 summarizes changes from Day 0 in mSOFA and in each of its components to Days 
1, 2, 3, 7, 10, 14, 21, and 28 without applying LOCF. 
Table 14.2.2.4 provides the same summary after application of LOCF to Day 14.  This table only 
summarizes mSOFA to Day 14 because there was no LOCF imputation for missing mSOFA after 
Day 14 and so the results for Days 21 and 28 are identical to the table summarizing mSOFA 
without LOCF. 
Tables 14.2.2.5 and 14.2.2.6 provides the same summaries for observed and LOCF imputed 
mSOFA and components to Days 28 and 14, respectively, but for changes from Day 1 rather than 
Day 0. 
The data displayed in Tables 14.2.2.1 to 14.2.2.6 will be graphically displayed in line plots 
comparing between treatment groups using line plot (Figures 5 to 10) and box and whiskers plots 
(Figures 11 to 14). 
Table 14.2.2.7 will summarize mSOFA and organ specific values at screening, 16 - 24 hours post 
dose, and changes from screening to 16 – 24 hours post dose. 
Table 14.2.2.8 will summarize mSOFA without the Glasgow Coma Score and without the 
Glasgow Coma Score Among Patients on Ventilation and Medications Affecting GCS to Day 28. 
8.7 
Time to resolution of mSOFA score to ≤ 1  
Life tables for time to resolution of mSOFA score ≤ 1 will be provided in Tables 14.2.3.1 and 
14.2.3.2 for the 0.50 mg/kg and placebo treated groups, respectively, to Day 14. Comparative 
Kaplan-Meier survival curves will be provided in Figure 15.   


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For these analyses, patients who die prior to Day 14 will be considered censored at one day past 
Day 14 and assumed to have never achieved mSOFA ≤ 1.  Log rank statistic will be used to 
assess if the distributions of times to symptom resolution differ between treatment groups.   
These analyses will be repeated using follow-up through Day 28 in Tables 14.2.3.3 and 14.2.3.4 
and in Figure 16.  For these analyses, patients who die after Day 14 but prior to Day 28 will be 
evaluated for meeting the mSOFA≤1 and will be considered a success in these analyses if they 
achieve mSOFA≤1 (prior to their post Day 14 death).   
8.8 
MMRM Analyses 
Figure 17 will be a line graph of least squares predicted mean values over time based on the 
mixed model for repeated measures (MMRM). This figure will summarize the MMRM results for 
values over time. 
Figure 18 will be a line graph of least squares predicted mean change values over time based on 
the mixed model for repeated measures (MMRM). This figure will summarize the MMRM results 
for values over time. 
8.9 
Critical care and hospital stay parameters, to be measured until Day 28 
The following critical care and hospital stay parameters will be assessed in the mITT analysis set.   
o ICU free days 
o Days in ICU 
o Days on ventilator 
o Ventilator free days 
o Vasopressors days 
o Vasopressors free days 
o Hospital length of stay (days) 
Because of the expected skewness in the distributions of these parameters, non-parametric 
Wilcoxon rank sum tests will be used assess the statistical significance of treatment group 
differences in these parameters. Table 14.2.4.1 will provide summary statistics by treatment 
groups including mean, median, standard deviation, 25th percentile, 75th percentile, minimum, and 
maximum values. Analyses will focus on clinical effect sizes. The non-parametric clinical effect 
size to be used is the concordance statistic (c-stat) determined from a logistic regression.  The c-
stat is the probability that a randomly selected subject treated with Reltecimod has a better 
outcome (e.g., more free-days) than a randomly selected placebo subject and is related to the area 
under a receiver operating characteristic (ROC) curve25. Graphical comparisons of distributions 
between treatment groups will be provided using box and whiskers plots (Figures 19 to 25).   
Table 14.2.4.2 will summarize hospital discharge status in the mITT analysis set. 
Table 14.2.4.3 will summarize hospital readmissions in the mITT analysis set.  
Table 14.2.4.4 will summarize critical care and hospital stay parameters over days 1 to 28 
comparing NICCE successes to NICCE failures. Figures 26 to 33 will graphically compare these 
distributions using box and whiskers plots. 
 
25 Hanley JA and McNeil BJ. The Meaning and Use of the Area under a Receiver Operating Characteristic Curve (ROC), 
Radiology 1982: 143: 29-36. 


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Additional graphical analyses will include displaying the percentages of patients staying in the 
ICU, needing ventilation, and staying in the hospital over time by treatment group (Figures 34, 
35, and 36).  
Table 14.2.4.5 will summarize critical care and hospital stay parameters over days 1 to 28 
comparing subjects with and without freedom from durable loss of renal function status among 
patients in the mITT analysis presenting with Stage 2 or Stage 3 AKI.  
Tables 14.2.4.6, 14.2.4.7, and 14.2.4.8 repeat the treatment group comparisons of critical care and 
hospital stay parameters, hospital discharge status, and hospital readmissions, but in the Per 
Protocol analysis set.  
8.10 Clinical local parameters (debridements) 
The following debridement secondary endpoints were specified: 
o Number of debridement to days 7, 10, 14  
o Proportion of patients needing (up to Day 14): 
•  only one debridement to control the infection 
• 2 debridements to control the infection 
• 3 debridements to control infection 
• ≥3 debridements to control the infection 
• >3 debridements to control infection 
Tables 14.2.5.1 will summarize the cumulative numbers of debridements to Days 7, 10, and 14, 
using means, medians, standard deviations, and ranges. Wilcoxon rank-sum tests will be provided 
for descriptive pair-wise group comparisons.   
Table 14.2.5.2 will summarize the proportions of patients requiring  only one debridement, 2 
debridements, 3 debridements, ≥ 3 debridements and > 3 debridements up to an including Day 14 
for all patients in the mITT Analysis Set and for both treatment groups. Chi-square tests will be 
used to assess the degree to which observed treatment difference could be attributable to chance 
variation.    
Figure 37 will graphically display the data from Table 14.2.5.1. Figure 38 will graphically display 
the data from table 14.2.5.2. 
 


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8.11 Freedom from Durable Loss of Renal Function 
Tables 14.2.6.1.1 to 14.2.6.6 summarize AKI at pre-dose screening and Maximal AKI determined 
over the first seven days though independent adjudication.  
Tables 14.2.6.2.1 to 14.2.6.2.4 summarize treatment group comparisons of the AKI endpoints at 
Day 28 including the key secondary endpoint, Achieving Freedom from Durable Loss of Renal 
Function at Day 28 and the exploratory endpoint, Improvement in Durable Loss of Renal 
Function at Day 28. The summarized analyses differ with regard to whether there was 
algorithmic determination (primary) or independent adjudication of reference creatinine 
(sensitivity analysis) and whether the algorithmic determination of Day 28 status was based on 
LOCF (primary) or using the mean value over days 14 to 28 (sensitivity analysis). The results 
from Table 14.2.6.2.1 will contain the results from the key secondary endpoint.  
Tables 14.2.6.3.1 to 14.2.6.3.3 summarize treatment group comparisons of the AKI endpoints at 
Day 14 including Achieving Freedom from Durable Loss of Renal Function at Day 14 and 
Improvement in Durable Loss of Renal Function at Day 14.  The summarized analyses differ 
with regard to whether there was algorithmic determination or independent adjudication of 
reference creatinine and whether there was algorithmic or independent adjudication of Day 14 
status.  
Figure 39 will graphically summarize the percentages of subjects in each group achieving 
Freedom from Durable Loss of Renal Function at Days 14 and 28.  Similarly, Figure 40 will 
graphically summarize the percentages of subjects in each group achieving Improvement in 
Durable Loss of Renal Function at Days 14 and 28.  
Tables 14.2.6.4.1 to 14.2.6.4.2 summarize treatment group comparisons of AKD stage at Day 28.  
The summarized analyses differ with regard to whether there was algorithmic determination or 
independent adjudication of reference creatinine.  
Tables 14.2.6.5.1 to 14.2.6.5.3 summarize treatment group comparisons of AKD stage at Day 14. 
The summarized analyses differ with regard to whether there was algorithmic determination or 
independent adjudication of reference creatinine and whether Day 14 status was determined 
algorithmically or through independent adjudication.  
8.12 C - reactive protein (CRP) 
Table 14.3.4.1 summarizes CRP at Screening, at Day 14, and changes from Screening to Day 14 
for CRP values by treatment group in the mITT 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 
treatment emergent adverse event (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 adverse event categories (SOC) are reported in upper case letters and specific 
adverse events (PT) 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 
Comparisons between those with and without a drug-related AE 
Table 14.3.1.12 will provide a comparison of demographic and baseline disease characteristics 
between actively treatment patients experiencing and not experience at least one drug-related 
adverse event.  This table will only be included if there are at least 5 subjects with at least one 
drug-related adverse event.  
9.1.5 
Day 0 Adverse Events 
Table 14.3.1.13 provides a summary of specific adverse events occurring prior to study drug 
initiation. This table is not stratified by drug group.  
9.1.6 
Adverse Events of Special Interest 
Infection and infestation adverse events are of special interest. Table 14.3.1.14 summarizes the 
incidence rates and event counts for infections and infestations TEAEs by preferred term.  
 
9.1.7 
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 


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AE Listings 
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 
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. 
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 14.3.2.4 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 baseline, Day 1, Day 2, Day 3, Day 7, and 
Day 14 by treatment group.   


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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.  
Table 14.3.2.3 provides the same information but for shifts to Day 14. 
9.3 
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).   
9.4 
Electrocardiogram 
Table 14.3.6.1 summarizes ECG results at screening and immediately, 4-6 hours, and 12-24 hours 
post study drug, and changes from screening by treatment group based on investigator provided 
results.  
Table 14.3.6.2 provides the same summary but based on the cardiology central reader.  
Table 14.3.6.3 summarizes the number and percentages of patients meeting threshold criteria for 
QTc ECG evaluations by the investigator in the As Treated (Safety) analysis set. 
Table 14.3.6.4 provides the same summary for QTcB ECG evaluations determined through 
cardiology central reader. 
Table 14.3.6.5 provides the same summary for QTcF ECG evaluations determined through 
cardiology central reader. 
9.5 
Physical Examinations 
Physical exam results will be summarized for the screening visit, Day 3, Day 7 and at Day 14.  
For each test, the number of patients evaluated, and the numbers and percentages of patients with 
‘Normal’, ‘Abnormal, improved or same as screening’, ‘Abnormal, new or aggravated’ and ‘Not 
done’ will be tabulated, except for screening when results will be categorized as ‘Normal’, 
‘Abnormal’ or ‘Not done’. Results for the following assessments will be summarized for 
cardiovascular, respiratory, abdomen, extremities, neurological, and other. 
Baseline status will be summarized in Table 14.3.7.1. For each of these tests, changes from the 
screening to Day 3, Day 7, and Day 14 will be summarized in Table 14.3.7.2, 14.3.7.3, and 
14.3.7.4, respectively.  
9.6 
Term Survival  
Tables 14.3.8.1 and 14.3.8.2 summarize survival (mortality) to Day 90 for Reltecimod and 
Placebo, respectively.  Figure 41 provides the corresponding Kaplan-Meier survival curve.  


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Tables 14.3.8.3, 14.3.8.4, and 14.3.8.5 summarize survival (mortality) from Day 14 to Day 90 
comparing subjects with Day 14 mSOFA<=1 to Day 14 mSOFA>1 among all mITT subjects, in 
the Reltecimod subjects alone and among Placebo subject alone, respectively.  Figures, 42, 43, 
and 44 provide the corresponding Kaplan-Meier survival curves.    


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10 Subgroup Analysis 
As noted above, the following tables will be stratified for the pre-specific subgroups noted above. 
In addition, results for the primary endpoint NICCE, the conditional co-primary endpoint (CCPE), 
and the key secondary (AKI) will be summarized across subgroups using forest plots (Figures 47, 
49, and 49). 
14.2.1.1 
Comparisons of the Percentages of Patients Achieving 
Primary Composite Clinical Success Endpoint (NICCE) and its Components 
mITT Analysis Set† 
14.2.1.2 
Comparisons of the Percentages of Patients Achieving 
Conditional Co-Primary Endpoint (CCPE) and its Components 
mITT Analysis Set† 
14.2.2.2 
Modified SOFA Total Score and Organ Specific Scores Over Time to Day 14 
Last Observation Carried Forward (LOCF) 
mITT Analysis Set† 
14.2.2.4 
Modified SOFA Total Score and Organ Specific Scores Over Time to Day 14 
Change from Day 0 (Screening) - Last Observation Carried Forward (LOCF) 
mITT Analysis Set† 
14.2.2.6 
Modified SOFA Total Score and Organ Specific Scores Over Time to Day 14 
Change from Day 1 - Last Observation Carried Forward (LOCF) 
mITT Analysis Set† 
14.2.4.1 
Critical Care and Hospital Stay Parameters Over Days 1 to 28 
By Treatment Group 
mITT Analysis Set† 
14.2.5.1 
Cumulative Number of Debridements to Days 7, 10, and 14 
By Treatment Group 
mITT Analysis Set† 
14.2.5.2 
Percentage of Patients Requiring 1, 2, 3, >=3, and >3 Debridements 
Through Day 14 
By Treatment Group 
mITT Analysis Set† 
14.2.6.2.1 
Numbers and Percentages of Subjects 
Achieving Freedom from Durable Loss of Renal Function and  
Improvement in Durable Loss of Renal Function at Day 28 
Algorithmic Determination of Reference Creatinine 
Algorithmic Determination of AKI at Screening 
Algorithmic Determination of Day 28 Status Using LOCF& 
Among mITT Subjects with Stage 2 or Stage 3 Screening AKI Using Algorithmic 
Reference 
14.3.1.1 
Summary of Treatment-Emergent Adverse Events (TEAEs) 
Overall and by Treatment Group 
As Treated (Safety) Analysis Set† 
 
 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
 
50 
 
11 Appendix 1: Table TOC 
Enrollment 
1 
14.1.1.1 
Number of Patients Screened, Randomized, and in Each Analysis Set†  
By Site 
2 
14.1.1.2 
Number of Patients in Each Analysis Set†  
By Treatment Group and Site 
3 
14.1.1.3 
Number of Patients by Site, Treatment Group, and Randomization Stratum 
As Treated (Safety) Analysis Set† 
4 
14.1.1.4 
Number of Patients by Site, Treatment Group, and Randomization Stratum 
mITT Analysis Set† 
5 
14.1.1.5 
Number of Patients by Site, Treatment Group, and Randomization Stratum 
Per Protocol Analysis Set† 
 
 
 
 
 
Demographic and Baseline Characteristics 
6 
14.1.2.1 
Demographics and Baseline Disease Characteristics 
Overall and By Treatment Group 
ITT (Randomized) Set† 
7 
14.1.2.2 
Demographics and Baseline Disease Characteristics 
Overall and By Treatment Group 
As Treated (Safety) Analysis Set† 
8 
14.1.2.3 
Demographics and Baseline Disease Characteristics 
Overall and By Treatment Group 
mITT Analysis Set† 
9 
14.1.2.4 
Demographics and Baseline Disease Characteristics 
Overall and By Treatment Group 
Per Protocol Analysis Set† 
 
 
 
10 
14.1.3.1 
Patients by Gender and Age Category 
Overall and by Treatment Group 
ITT (Randomized) Set† 
11 
14.1.3.2 
Patients by Gender and Age Category 
Overall and by Treatment Group 
As Treated (Safety) Analysis Set† 
12 
14.1.3.3 
Patients by Gender and Age Category 
Overall and by Treatment Group 
mITT Analysis Set† 
13 
14.1.3.4 
Patients by Gender and Age Category 
Overall and by Treatment Group 
Per Protocol Analysis Set† 
 
 
Summary of Baseline Microbiology 
14 
14.1.3.5 
Pathogen in Tissue Samples & Blood Culture 
As Treated (Safety) Analysis Set† 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
 
51 
 
 
 
 
 
Prior and Concomitant Medications 
15 
14.1.4.1 
Number (%) of Patients with Prior Ancillary Medications 
by Category and Specific Medication 
Overall and By Treatment Group 
As Treated (Safety) Analysis Set† 
16 
14.1.4.2 
Number (%) of Patients with Prior Antimicrobial or Immunosuppressant Medications 
by Category and Specific Medication 
Overall and By Treatment Group 
As Treated (Safety) Analysis Set† 
17 
14.1.4.3 
Number (%) of Patients with Concomitant Ancillary Medications 
by Category and Specific Medication 
By Treatment Group 
As Treated (Safety) Analysis Set† 
18 
14.1.4.4 
Number (%) of Patients with Concomitant  
Antimicrobial or Immunosuppressant Medications 
by Category and Specific Medication 
By Treatment Group 
As Treated (Safety) Analysis Set† 
 
 
 
 
 
Medical 
19 
14.1.5.1 
Number (%) of Patients Experiencing Prior Medical Conditions During Lifetime 
by Body System and Specific Medical Condition 
As Treated (Safety) Analysis Set† 
20 
14.1.5.2 
Number (%) of Patients with Ongoing Medical Conditions 
by Body System and Specific Medical Condition 
As Treated (Safety) Analysis Set† 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
 
52 
 
 
 
 
NSTI Presentation 
21 
14.1.6.1 
NSTI Presentation and Initial Debridement Surgery 
Overall and By Treatment Group 
mITT Analysis Set† 
22 
14.1.6.2 
NSTI Primary Infection Location and Extension of Infection 
Overall and By Treatment Group 
mITT Analysis Set† 
 
 
Drug Timing and Administration 
23 
14.1.7.1 
Drug Administration and Timing 
Overall and by Treatment Group 
As Treated (Safety) Analysis Set† 
24 
14.1.7.2 
Extent of Drug Exposure 
Reltecimod 0.5 mg/kg 
As Treated (Safety) Analysis Set† 
 
 
 
 
 
Patient Disposition and End of Study 
25 
14.1.8.1 
Patient Disposition and End of Study Status 
By Treatment Group 
As Treated (Safety) Analysis Set† 
 
 
 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
 
53 
 
 
 
 
Efficacy Analyses 
 
 
Primary and Conditional Co-Primary Endpoints 
26 
14.2.1.1 
Comparisons of the Percentages of Patients Achieving 
Primary Composite Clinical Success Endpoint (NICCE) and its Components 
By Treatment Group 
mITT Analysis Set† 
27 
14.2.1.2 
Comparisons of the Percentages of Patients Achieving 
Conditional Co-Primary Endpoint (CCPE) and its Components 
By Treatment Group 
mITT Analysis Set† 
28 
14.2.1.3 
Comparisons of the Percentages of Patients Achieving 
Primary Composite Clinical Success Endpoint (NICCE) and its Components 
By Treatment Group 
Per Protocol Analysis Set† 
29 
14.2.1.4 
Comparisons of the Percentages of Patients Achieving 
Conditional Co-Primary Endpoint (CCPE) and Its Components 
By Treatment Group 
Per Protocol Analysis Set† 
30 
14.2.1.5 
Comparisons of the Percentages of Patients Achieving 
the Primary Composite Clinical Success Endpoint (NICCE) 
By Treatment Group and Site 
mITT Analysis Set† 
31 
14.2.1.6 
Comparisons of the Percentages of Patients Achieving 
the Conditional Co-Primary Endpoint (CCPE) 
By Treatment Group and Site 
mITT Analysis Set 
32 
14.2.1.7.1 
Comparisons of the Percentages of Patients Achieving 
Primary Composite Clinical Success Endpoint (NICCE*) by Randomization Stratification 
By Treatment Group 
mITT Analysis Set† 
33 
14.2.1.7.2 
Comparisons of the Percentages of Patients Achieving 
Primary Composite Clinical Success Endpoint (NICCE*) by True Baseline mSOFA and Fournier's 
Status 
By Treatment Group 
mITT Analysis Set† 
34 
14.2.1.8 
Comparisons of the Percentages of Patients Achieving 
Modified NICCE Endpoint with the Reduction in mSOFA Component Removed 
By Treatment Group 
mITT Analysis Set† 
 
 
 
 
 
SOFA 
35 
14.2.2.1 
Modified SOFA Total Score, Organ Specific Scores, and SOFA Total Score Over Time to Day 28 
Observed Cases 
By Treatment Group 
mITT Analysis Set† 
36 
14.2.2.2 
Modified SOFA Total Score and Organ Specific Scores Over Time to Day 14 
By Treatment Group 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
 
54 
 
Last Observation Carried Forward (LOCF) 
By Treatment Group 
mITT Analysis Set† 
37 
14.2.2.3 
Modified SOFA Total Score and Organ Specific Scores Over Time to Day 28 
Change from Day 0 (Screening) - Observed Cases 
By Treatment Group 
mITT Analysis Set† 
38 
14.2.2.4 
Modified SOFA Total Score and Organ Specific Scores Over Time to Day 14 
Change from Day 0 (Screening) - Last Observation Carried Forward (LOCF) 
By Treatment Group 
mITT Analysis Set† 
38 
14.2.2.5 
Modified SOFA Total Score and Organ Specific Scores Over Time to Day 28 
Change from Day 1 - Observed Cases 
By Treatment Group 
mITT Analysis Set† 
40 
14.2.2.6 
Modified SOFA Total Score and Organ Specific Scores Over Time to Day 14 
Change from Day 1 - Last Observation Carried Forward (LOCF) 
By Treatment Group 
mITT Analysis Set† 
41 
14.2.2.7 
Modified SOFA Total Score and Organ Specific  
Screening, 16 to 24 Hours Post Dose, and Changes from Screening to 16-24 Hours Post Dose  
Observed cases 
By Treatment Group 
mITT Analysis Set 
42 
14.2.2.8 
Modified SOFA Total Score without Glasgow Coma Score and without Glasgow Coma Score 
Among Patients on Ventilation and Medications Affecting GCS to Day 28 
Observed cases  
By Treatment Group 
mITT Analysis Set 
43 
14.2.3.1 
Life Table Analysis to Day 14 
Time to Resolution of Organ Dysfunction (mSOFA<=1) 
Reltecimod 0.5 mg/kg 
mITT Analysis Set† 
44 
14.2.3.2 
Table 14.2.3.2 
Life Table Analysis to Day 14 
Time to Resolution of Organ Dysfunction (mSOFA<=1) 
Placebo 
mITT Analysis Set† 
45 
14.2.3.3 
Life Table Analysis to Day 28 
Time to Resolution of Organ Dysfunction (mSOFA<=1) Reltecimod 0.5 mg/kg 
mITT Analysis Set† 
46 
14.2.3.4 
Life Table Analysis to Day 28 
Time to Resolution of Organ Dysfunction (mSOFA<=1)  Placebo 
mITT Analysis Set† 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
 
55 
 
 
 
 
Critical Care and Hospital Stay 
47 
14.2.4.1 
Critical Care and Hospital Stay Parameters Over Days 1 to 28 
By Treatment Group 
mITT Analysis Set† 
48 
14.2.4.2 
Hospital Discharge Status 
By Treatment Group 
mITT Analysis Set† 
49 
14.2.4.3 
Hospital Readmissions 
By Treatment Group, Safety Analysis Set 
mITT Analysis Set 
50 
14.2.4.4 
Critical Care and Hospital Stay Parameters Over Days 1 to 28 
By NICCE* Success vs. Failure 
mITT Analysis Set† 
51 
14.2.4.5 
Critical Care and Hospital Stay Parameters Over Days 1 to 28 
By Freedom from Durable Loss of Renal Function Status 
Among Subjects Presenting with AKI Stage 2 or 3 
mITT Analysis Set† 
52 
14.2.4.6 
Critical Care and Hospital Stay Parameters Over Days 1 to 28 
By Treatment Group 
Per Protocol Analysis Set† 
53 
14.2.4.7 
Hospital Discharge Status 
By Treatment Group 
Per Protocol Analysis Set† 
54 
14.2.4.8 
Hospital Readmissions 
By Treatment Group, Safety Analysis Set 
Per Protocol Analysis Set 
 
 
 
 
 
Debridement Outcomes 
55 
14.2.5.1 
Cumulative Number of Debridements to Days 7, 10, and 14 
By Treatment Group 
mITT Analysis Set† 
56 
14.2.5.2 
Percentage of Patients Requiring 1, 2, 3, >=3, and >3 Debridements 
Through Day 14 
By Treatment Group 
mITT Analysis Set† 
 
 
 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
 
56 
 
 
 
 
Analyses of AKI 
 
 
Screening AKI and Maximal AKI  
57 
14.2.6.1.1 
Comparisons of Percentages of Subjects 
With Each AKI Stage at Pre-Dose Screening  
by Algorithmic Determination 
By Treatment Group 
mITT Analysis Set† 
58 
14.2.6.1.2 
Numbers and Percentages of Subjects 
With Any AKI and with AKI Stage 2 or 3 Based on Screening AKI 
by Algorithmic Determination 
By Treatment Group 
mITT Analysis Set† 
59 
14.2.6.1.3 
Comparisons of Percentages of Subjects 
With Each Maximal AKI Stage  
by Independent Adjudication 
By Treatment Group 
mITT Analysis Set† 
60 
14.2.6.1.4 
Numbers and Percentages of Subjects 
With Any AKI and with AKI Stage 2 or 3 Based on Maximal AKI 
by Independent Adjudication 
By Treatment Group 
mITT Analysis Set† 
61 
14.2.6.1.5 
Comparisons between AKI Stage at Screening and Maximal AKI 
Using Algorithmic Reference for AKI Stage at Screening 
By Treatment Group 
mITT Analysis Set† 
62 
14.2.6.1.6 
Comparisons between AKI Stage at Screening and Maximal AKI 
Using Independent Adjudicated Reference for AKI Stage at Screening 
By Treatment Group 
mITT Analysis Set† 
 
 
Day 28 Endpoints 
63 
14.2.6.2.1 
Numbers and Percentages of Subjects 
Achieving Freedom from Durable Loss of Renal Function and  
Improvement in Durable Loss of Renal Function at Day 28 
Algorithmic Determination of Reference Creatinine 
Algorithmic Determination of AKI at Screening 
Algorithmic Determination of Day 28 Status Using LOCF 
Among mITT Subjects with Stage 2 or Stage 3 Screening AKI Using Algorithmic Reference 
64 
14.2.6.2.2 
Numbers and Percentages of Subjects 
Achieving Freedom from Durable Loss of Renal Function and  
Improvement in Durable Loss of Renal Function at Day 28 
Independent Adjudication of Reference Creatinine 
Algorithmic Determination of AKI at Screening 
Algorithmic Determination of Day 28 Status Using LOCF 
Among mITT Subjects with Stage 2 or Stage 3 Screening AKI Using Adjudicated Reference 
65 
14.2.6.2.3 
Numbers and Percentages of Subjects 
Achieving Freedom from Durable Loss of Renal Function and  
Improvement in Durable Loss of Renal Function at Day 28 
Algorithmic Determination of Reference Creatinine 
Algorithmic Determination of AKI at Screening 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
 
57 
 
Algorithmic Determination of Day 28 Status Using Mean of Day 14 to Day 28 
Among mITT Subjects with Stage 2 or Stage 3 Screening AKI Using Algorithmic Reference 
66 
14.2.6.2.4 
Numbers and Percentages of Subjects 
Achieving Freedom from Durable Loss of Renal Function and  
Improvement in Durable Loss of Renal Function at Day 28 
Independent Adjudication of Reference Creatinine 
Algorithmic Determination of AKI at Screening 
Algorithmic Determination of Day 28 Status Using Mean of Day 14 to Day 28 
Among mITT Subjects with Stage 2 or Stage 3 Screening AKI Using Adjudicated Reference 
 
 
Day 14 Endpoints 
67 
14.2.6.3.1 
Numbers and Percentages of Subjects 
Achieving Freedom from Durable Loss of Renal Function and  
Improvement in Durable Loss of Renal Function at Day 14 
Algorithmic Determination of Reference Creatinine 
Algorithmic Determination of AKI at Screening 
Algorithmic Determination of Day 14 Status 
Among mITT Subjects with Stage 2 or Stage 3 Screening AKI Using Algorithmic Reference 
68 
14.2.6.3.2 
Numbers and Percentages of Subjects 
Achieving Freedom from Durable Loss of Renal Function and  
Improvement in Durable Loss of Renal Function at Day 14 
Independent Adjudication of Reference Creatinine 
Algorithmic Determination of AKI at Screening 
Algorithmic Determination of Day 14 Status 
Among mITT Subjects with Stage 2 or Stage 3 Screening AKI Using Adjudicated Reference 
69 
14.2.6.3.3 
Numbers and Percentages of Subjects 
Achieving Freedom from Durable Loss of Renal Function and  
Improvement in Durable Loss of Renal Function at Day 14 
Independent Adjudication of Reference Creatinine 
Algorithmic Determination of AKI at Screening 
Independent Adjudication of Day 14 Status& 
Among mITT Subjects with Stage 2 or Stage 3 Screening AKI Using Adjudicated Reference 
 
 
AKD Stages at Day 28 
70 
14.2.6.4.1 
Numbers and Percentages of Subjects 
with Specific AKD Stages at Day 28 
Algorithmic Determination of Reference Creatinine 
Algorithmic Determination of AKI at Screening 
Algorithmic Determination of Day 28 Status 
Among mITT Subjects with Stage 2 or Stage 3 Screening AKI 
Using Algorithmic Reference 
71 
14.2.6.4.2 
Numbers and Percentages of Subjects 
with Specific AKD Stages at Day 28 
Independent Adjudication of Reference Creatinine 
Algorithmic Determination of AKI at Screening 
Algorithmic Determination of Day 28 Status 
Among mITT Subjects with Stage 2 or Stage 3 Screening AKI 
Using Adjudicated Reference 
 
 
AKD Stages at Day 14 
72 
14.2.6.5.1 
Numbers and Percentages of Subjects 
with Specific AKD Stages at Day 14 
Algorithmic Determination of Reference Creatinine 
Algorithmic Determination of AKI at Screening 
Algorithmic Determination of Day 14 Status 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
 
58 
 
Among mITT Subjects with Stage 2 or Stage 3 Screening AKI 
Using Algorithmic Reference 
73 
14.2.6.5.2 
Numbers and Percentages of Subjects 
with Specific AKD Stages at Day 14 
Independent Adjudication of Reference Creatinine 
Algorithmic Determination of AKI at Screening 
Algorithmic Determination of Day 14 Status& 
Among mITT Subjects with Stage 2 or Stage 3 Screening AKI 
Using Adjudicated Reference 
74 
14.2.6.5.3 
Numbers and Percentages of Subjects 
with Specific AKD Stages at Day 14 
Independent Adjudication of Reference Creatinine 
Algorithmic Determination of AKI at Screening 
Independent Adjudication of Day 14 Status& 
Among mITT Subjects with Stage 2 or Stage 3 Screening AKI  
Using Adjudicated Reference 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
 
59 
 
 
 
Adverse Events 
75 
14.3.1.1 
Summary of Treatment-Emergent Adverse Events (TEAEs) 
By Treatment Group 
As Treated (Safety) Analysis Set† 
76 
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† 
77 
14.3.1.3 
Incidence Rates (%) and Event Counts of TEAEs 
Sorted by Descending Incidence of Preferred Term  
As Treated (Safety) Analysis Set† 
78 
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† 
79 
14.3.1.5 
Incidence Rates (%) and Event Counts of Serious TEAEs 
by System Organ Class and Preferred Term 
As Treated (Safety) Analysis Set† 
80 
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† 
81 
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† 
82 
14.3.1.8 
Incidence Rates (%) and Events Counts of Severe TEAEs 
by System Organ Class and Preferred Term 
As Treated (Safety) Analysis Set† 
83 
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† 
84 
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† 
85 
14.3.1.11 
Counts of Drug-Related* TEAEs 
by Severity, System Organ Class, and Preferred Term 
Placebo 
As Treated (Safety) Analysis Set† 
86 
14.3.1.12 
Demographic and Baseline Disease Characteristics of Patients With and Without a Drug-
Related TEAE in As Treated (Safety) Analysis Set Receiving Reltecimod 0.5 mg/kg 
87 
14.3.1.13 
Incidence Rates (%) and Event Counts of AEs 
by System Organ Class and Preferred Term on Day 0 Prior to Drug Administration 
As Treated (Safety) Analysis Set† 
88 
14.3.1.14 
Incidence Rates (%) and Events Counts of Infections and Infestations TEAEs 
by Preferred Term 
As Treated (Safety) Analysis Set† 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
 
60 
 
 
 
  
Laboratory Data 
89 
14.3.2.1 
Screening, Day 7, Day 14, and Changes from Screening 
Blood Chemistry 
by Treatment Group 
As Treated (Safety) Analysis Set† 
90 
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† 
91 
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† 
92 
14.3.2.4 
Summary of Potential Drug Induced Liver Injury (DILI) 
By Treatment Group 
As Treated (Safety) Analysis Set† 
93 
14.3.2.5 
Blood Chemistry Frequencies By Visit With Respect To 
Normal Ranges and Critical Values 
by Treatment Group 
As Treated (Safety) Analysis Set† 
94 
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† 
95 
14.3.3.2 
Blood Hematology Panel Shift Tables Summarizing Changes in Test Status from Screening 
(Baseline) to Day 7 Early Discontinuation 
96 
14.3.3.3 
Blood Hematology Panel Shift Tables Summarizing Changes in Test Status from Screening 
(Baseline) to Day 14 Early Discontinuation 
97 
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 
 
 
 
 
 
C-Reactive Protein 
98 
13.3.4.1 
C-Reactive Protein at Screening and Day 14, and Changes from Screening 
by Treatment Group 
mITT Analysis Set† 
 
 
 
 
 
Vital Signs 
99 
14.3.5.1 
Vital Signs at Screening, Day 1, Day 2, Day 3, Day 7, Day 14, Day 21, Day 28 
and Changes from Screening 
By Treatment Group 
As Treated (Safety) Analysis Set† 
 
 
 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
 
61 
 
 
 
 
ECG 
100 
14.3.6.1 
Screening, Immediately Post Dose, 4-6 Hours, and 12-24 Hours Post Study Drug 
Electrocardiogram Results Evaluated by Investigator 
by Treatment Group 
As Treated (Safety) Analysis Set† 
101 
14.3.6.2 
Screening, Immediately Post Dose, 4-6 Hours, and 12-24 Hours Post Study Drug 
Electrocardiogram Results Evaluated by Central Reader 
by Treatment Group 
As Treated (Safety) Analysis Set† 
102 
14.3.6.3 
Number (%) of Patients Meeting Threshold Criteria 
for QTc ECG Results Evaluated by Investigator 
As Treated (Safety) Analysis Set† 
103 
14.3.6.4 
Number (%) of Patients Meeting Threshold Criteria 
for QTcB ECG Results Evaluated by Central Reader 
As Treated (Safety) Analysis Set† 
104 
14.3.6.5 
Number (%) of Patients Meeting Threshold Criteria 
for QTcF ECG Results Evaluated by Central Reader 
As Treated (Safety) Analysis Set† 
 
 
 
 
 
Physical Exam 
105 
14.3.7.1 
Physical Exam Assessments at Screening 
Overall and By Treatment Group 
As Treated (Safety) Analysis Set† 
106 
14.3.7.2 
Summary of Physical Exam Assessments at Screening and at Day 3 
Overall and By Treatment Group 
As Treated (Safety) Analysis Set† 
107 
14.3.7.3 
Summary of Physical Exam Assessments at Screening and at Day 7 
Overall and By Treatment Group 
As Treated (Safety) Analysis Set† 
108 
14.3.7.4 
Summary of Physical Exam Assessments at Screening and at Day 14 
Overall and By Treatment Group 
As Treated (Safety) Analysis Set† 
 
 
Survival 
109 
14.3.8.1 
Life Table Analysis to Day 90, Mortality - Reltecimod 0.50 mg/kg, mITT Analysis Set 
110 
14.3.8.2 
Life Table Analysis to Day 90, Mortality - Placebo, mITT Analysis Set 
111 
14.3.8.3 
Life Table Analysis from Day 14 to Day 90 
Comparing Subjects with Day 14 mSOFA<=1 to Day 14 mSOFA>1 
mITT analysis Set - Pooled 
112 
14.3.8.4 
Life Table Analysis from Day 14 to Day 90 
Comparing Subjects with Day 14 mSOFA<=1 to Day 14 mSOFA>1 
mITT analysis Set - Reltecimod 
113 
14.3.8.5 
Life Table Analysis from Day 14 to Day 90 
Comparing Subjects with Day 14 mSOFA<=1 to Day 14 mSOFA>1 
mITT analysis Set - Placebo 
 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
 
62 
 
12 Appendix 2: AE Listings TOC 
 
 
 
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 
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 
 
 
 


Statistical Analysis Plan 
Biomedical Statistical Consulting 
 
63 
 
13 Appendix 3: Patient Listings TOC 
 
 
 
Patient Listings 
1 
16.2.8.1 
Form: Demographics 
2 
16.2.8.2 
Form: Medical History 
3 
16.2.8.3 
Form: Vital Signs 
4 
16.2.8.4 
Form: Physical Exam 
5 
16.2.8.5 
Form: Necrotizing Soft Tissue Infection Information 
6 
16.2.8.6 
Form: Primary Infection Site Assessment 
7 
16.2.8.7 
Form: Initial Debridement 
8 
16.2.8.8 
Form: Modified SOFA (mSOFA) 
9 
16.2.8.9 
Form: Glasgow Coma Score 
10 
16.2.8.10 
Form: Drug Randomization and Administration 
11 
16.2.8.11 
Form: Blood Culture 
12.1 
16.2.8.12.1 Form: Tissue Microbiology 
12.2 
16.2.8.12.2 
Pathogen Assignment (Tissue and Blood Culture) 
13 
16.2.8.13 
Form: 12-Lead ECG (Screening) 
14 
16.2.8.14 
Form: 12-Lead Electrocardiogram (Post Drug) 
14.1 
16.2.8.14.1 
Post drug ECG Among Subjects with >500 msec and/or >60 msec from baseline Cardiology 
Overread QTcB 
14.2 
16.2.8.14.2 
Post drug ECG Among Subjects with >500 msec and/or >60 msec from baseline Cardiology 
Overread QTcF 
15 
16.2.8.15 
Form: Month 3 Visit Status 
16 
16.2.8.16 
Form: Chemistry1 
17 
16.2.8.17 
Form: Hematology 
18 
16.2.8.18 
Form: C-Reactive Protein 
19 
16.2.8.19 
Form: Chemistry 2 
20 
16.2.8.20 
Form: Apache 
21 
16.2.8.21 
Form: LRINEC and Anaya Score Parameters 
22 
16.2.8.22 
Form: Follow-up Lesion Assessment 
23 
16.2.8.23 
Form: ICU Admission/Discharge 
24 
16.2.8.24 
Form: Adequacy of Microbial Treatment 
25 
16.2.8.25 
Form: Follow-Up Debridement 
26 
16.2.8.26 
Form: Amputation 


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64 
 
27 
16.2.8.27 
Form: Urine Output 
28 
16.2.8.28 
Form: Renal Replacement Therapy 
29 
16.2.8.29 
Form: Transfusion History 
30 
16.2.8.30 
Form: Ventilator Assistance - Log 
31 
16.2.8.31 
Form: Hyperbaric Oxygen 
32 
16.2.8.32 
Form: Plasmapheresis 
33 
16.2.8.33 
Form: ICU Admittance 
34 
16.2.8.34 
Form: Hospital Length of Stay 
35 
16.2.8.35 
Form: Hospital Readmission 
36 
16.2.8.36 
Form: Prior and Concomitant Ancillary Medications 
37 
16.2.8.37 
Form: Prior and Concomitant Antimicrobial and Immunosuppressant Medications 
38 
16.2.8.38 
Form: Death Form 
39 
16.2.8.39 
Form: End of Study/Early Discontinuation 
40 
16.2.8.40 
Form: Pregnancy 
 
 
 
 
 


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Biomedical Statistical Consulting 
 
65 
 
14 Appendix 4: Figures TOC 
 
Figure 
Topic 
Type of Graph 
Showing  
Data Source 
1 
NICCE 
Bar graph 
Percent of Patients Achieving Primary Efficacy Endpoint in (NICCE) 
in mITT Analysis Set 
Table 14.2.1.1 
2 
CCPE 
Bar graph 
Percent of Patients Achieving Conditional Co-Primary Endpoint 
(CCPE) 
in mITT Analysis Set 
Table 14.2.1.2 
3 
NICCE and 
Components  
Forrest Plot 
99% CI for NICCE and 95% CI’s for Components of NICCE 
Table 14.2.1.1 
4 
Conditional Co-
Primary and 
Components  
Forrest Plot 
95% CI for conditional co-primary and components 
Table 14.2.1.2 
5 
mSOFA 
Line plot  
mSOFA Over Time to Day 28 - Observed cases 
Table 14.2.2.1 
6 
mSOFA 
Line plot  
mSOFA Over Time to Day 14 -  LOCF 
Table 14.2.2.2 
7 
mSOFA 
Line plot  
mSOFA Over Time to Day 28  
Change From Day 0 (Screening) - Observed Cases 
Table 14.2.2.3 
8 
mSOFA 
Line plot  
mSOFA Over Time to Day 14  
Change From Day 0 (Screening) - LOCF 
Table 14.2.2.4 
9 
mSOFA 
Line plot  
mSOFA  Over Time to Day 28  
Change From Day 1  - Observed cases 
Table 14.2.2.5 
10 
mSOFA 
Line plot  
mSOFA Over Time to Day 14  
Change From Day 1 - LOCF 
Table 14.2.2.6 
11 
mSOFA 
Box and Whiskers 
Reltecimod vs Placebo mSOFA at Day 14 – Observed cases 
Table 14.2.2.1 
12 
mSOFA 
Box and Whiskers 
Reltecimod vs Placebo mSOFA at Day 14 – LOCF 
Table 14.2.2.2 
13 
mSOFA 
Box and Whiskers 
Reltecimod vs Placebo mSOFA at Day 21 – Observed cases 
Table 14.2.2.3 
14 
mSOFA 
Box and Whiskers 
Reltecimod vs Placebo mSOFA at Day 28 – Observed cases 
Table 14.2.2.5 
14 
mSOFA 
Kaplan-Meier survival 
curves 
Comparing Time to mSOFA <=1 censored at Day 14 
Table 14.2.3.1 
Table 14.2.3.2 
16 
mSOFA 
Kaplan-Meier survival 
curves 
Comparing Time to mSOFA <=1 to Day 28 
Table 14.2.3.3 
Table 14.2.3.4 
17 
mSOFA 
Line graph 
Least squares predicted mean mSOFA over time based on the mixed 
model for repeated measures (MMRM). 
Table 14.2.2.1 
18 
mSOFA 
Line graph 
Least squares predicted mean change in mSOFA over time based on the 
mixed model for repeated measures (MMRM). 
Table 14.2.2.3 
19 
Critical care and 
hospital stay  
Box and Whiskers 
ICU free days By Treatment Group 
Table 14.2.4.1 
20 
Critical care and 
hospital stay  
Box and Whiskers 
Days in ICU By Treatment Group 
Table 14.2.4.1 
21 
Critical care and 
hospital stay  
Box and Whiskers 
Days on ventilator By Treatment Group 
Table 14.2.4.1 
22 
Critical care and 
hospital stay  
Box and Whiskers 
Ventilator free days By Treatment Group 
Table 14.2.4.1 
23 
Critical care and 
hospital stay  
Box and Whiskers 
Vasopressors days By Treatment Group 
Table 14.2.4.1 
24 
Critical care and 
hospital stay  
Box and Whiskers 
Vasopressors free days By Treatment Group 
Table 14.2.4.1 
25 
Critical care and 
hospital stay  
Box and Whiskers 
Hospital Length of Stays By Treatment Group 
Table 14.2.4.1 
26 
Critical care and 
hospital stay  
Box and Whiskers 
ICU free days By NICCE Success versus Failure 
Table 14.2.4.3 
27 
Critical care and 
hospital stay 
Box and Whiskers 
Days in ICU By NICCE Success versus Failure 
Table 14.2.4.3 
28 
Critical care and 
hospital stay 
Box and Whiskers 
Days on ventilator By NICCE Success versus Failure 
Table 14.2.4.3 
29 
Critical care and 
hospital stay 
Box and Whiskers 
Ventilator free days By NICCE Success versus Failure 
Table 14.2.4.3 
30 
Critical care and 
hospital stay  
Box and Whiskers 
Vasopressors days By NICCE Success versus Failure 
Table 14.2.4.3 
31 
Critical care and 
hospital stay  
Box and Whiskers 
Vasopressors free days By NICCE Success versus Failure 
Table 14.2.4.3 
32 
Critical care and 
hospital stay  
Box and Whiskers 
Hospital Length of Stay By NICCE Success versus Failure 
Table 14.2.4.3 
33 
Critical care and 
hospital stay  
Box and Whiskers 
Hospital Length of Stay By NICCE Success versus Failure 
Table 14.2.4.4 


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Figure 
Topic 
Type of Graph 
Showing  
Data Source 
34 
Critical care and 
hospital stay  
Line graph 
% of patients staying in ICU over time by treatment group 
Figure34.sas 
35 
Critical care and 
hospital stay  
Line graph 
% of patients needing ventilation over time by treatment group 
Figure35.sas 
36 
Critical care and 
hospital stay  
Line graph 
% of patients staying at Hospital over time 
Figure36.sas 
37 
Debridement 
Bar chart with mean (SD) 
Cumulative Numbers of Debridements to Days 7, 10, 14, and 28 
Overall and by Treatment Group By Treatment Group 
Table 14.2.5.1 
38 
Debridement 
Bar graphs with %’s and 
Fisher’s p-values. 
Percentages of Patients Requiring 1, 2, ≥ 2, and ≥ 3 Debridements 
Though Day 14,  By Treatment Group 
Table 14.2.5.2 
39 
AKI 
Bar graph 
Percent of patients Achieving Freedom from Durable Loss of Renal 
Function 
Table 14.2.6.2.1 
Table 14.2.6.3.1 
 
40 
AKI 
Bar graph 
Percent of patients Achieving Improvement in Durable Loss of Renal 
Function at Day 14 and at Day 28 
Table 14.2.6.2.1 
Table 14.2.6.3.1 
41 
Mortality 
Kaplan-Meier 
Mortality to Day 90 
Table 14.3.8.1 
Table 14.3.8.2 
42 
Mortality 
Kaplan-Meier 
Mortality from Day 14 to Day 90 Comparing mSOFA<=1 at Day 14 to 
mSOFA>1 at Day 14 - Pooled 
Table 14.3.8.3 
43 
Mortality 
Kaplan-Meier 
Mortality from Day 14 to Day 90 Comparing mSOFA<=1 at Day 14 to 
mSOFA>1 at Day 14 - Reltecimod 
Table 14.3.8.4 
44 
Mortality 
Kaplan-Meier 
Mortality from Day 14 to Day 90 Comparing mSOFA<=1 at Day 14 to 
mSOFA>1 at Day 14 - Placebo 
Table 14.3.8.5 
45 
NICCE and 
Components  
Forrest Plot 
99% CI for NICCE and 95% CI’s for Components of NICCE 
Table 14.2.1.1 
46 
Conditional Co-
Primary and 
Components  
Forrest Plot 
95% CI for conditional co-primary and components 
Table 14.2.1.2 
47 
NICCE 
Forrest Plot 
Point estimates and 95% CI for NICCE in subgroups 
Stratified versions 
of Table 14.2.1.1 
48 
CCPE 
Forrest Plot  
Point estimates and 95% CI for CCPE in subgroups 
Stratified versions 
of Table 14.2.1.2 
49 
AKI endpoint 
Forrest Plot 
Point estimates and 95% CI for AKI endpoint in subgroups 
Stratified versions 
of Table 14.2.6.3 


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Biomedical Statistical Consulting 
 
67 
 
15 Appendix 5:  Clinical Score Calculations 
 
 
Clinical Scores Parameters 
Parameter 
LRINEC 
Anaya 
SOFA 
Clinical 
 
 
 
Cardiovascular system (Mean Arterial Pressure calculation) 
 
 
+ 
Heart Rate 
 
+ 
 
Nervous system (Glasgow Coma Score) 
 
 
+ 
Oxygenation (Calculation) 
 
 
+ 
(PaO2/FiO2) 
Temperature 
 
+ 
 
Demographics 
 
 
 
Age 
 
+ 
 
Laboratory 
 
 
 
Coagulation Function (Platelets) 
 
 
+ 
C-Reactive Protein 
+ 
 
 
Renal system / Creatinine  
+ 
+ 
+ 
Glucose 
+ 
 
 
Hemoglobin/Hematocrit 
+ 
+ 
 
Liver Function Test / Bilirubin 
 
 
+ 
Sodium 
+ 
 
 
Total white cell count 
+ 
+ 
 
 
 
SOFA – Sequential Organ Failure Assessment score 
Can range from 0 -24 
 
Respiratory system: 
PaO2 / FiO2 (mmHg) 
SOFA score 
=>400 
0 
< 400 
1 
< 300 
2 
< 200 and mechanically ventilated 3 
< 100 and mechanically ventilated 4 
 
Nervous System: 
Glasgow Coma Scale SOFA score 
15 
0 
13-14 
1 
10-12 
2 
6-9 
3 
< 6 
4 


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Cardiovascular System 
Mean Arterial Pressure (MAP) OR administration of vasopressors 
(mcg/Kg/minute)   
SOFA score 
MAP => 70 mmHg 
0 
MAP < 70 mmHg 
1 
Dopamine <= 5 OR Dobutamine any dose 
2 
Dopamine > 5 <=15 OR epinephrine <=0.1 OR norepinephrine <= 0.1  3 
Dopamine > 15 OR epinephrine > 0.1 OR norepinephrine > 0.1  
4 
 
MAP= (Systolic pressure + (2*Diastolic pressure))/3 
 
Liver: 
Bilirubin (mg/dl) SOFA score 
<1.2 
0 
1.2-1.9 
1 
2.0-5.9 
2 
6.0-11.9 
3 
>= 12.0 
4 
 
Coagulation: 
Platelets x 103/mcl SOFA score 
=>150 
0 
< 150 
1 
< 100 
2 
< 50 
3 
< 20 
4 
 
Renal System: 
Creatinine (mg/dl) (or urine output) SOFA score 
<1.2 
0 
1.2 – 1.9 
1 
2.0 – 3.4 
2 
3.5 – 4.9 (or < 500 ml/day) 
3 
>=5.0 (or < 200 ml/day) 
4 
 
Anaya score 
Can range from 0 - 12 
Variable on admission 
Points 
Heart Rate > 110 beats per minute 
1 
Temperature < 36.0 0C 
1 
Serum Creatinine > 1.5 mg/dl 
1 
Age > 50 
3 
White blood cells count > 40,000/mcl 3 
Hematocrit > 50% 
3 
 


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LRINEC – Laboratory Risk Indicator for Necrotizing Fasciitis 
 
Can range from 0 – 13 
 
Variable, Units 
Score 
C-Reactive Protein mg/L 
 
< 150 
0 
>= 150 
4 
Total White Blood cells count per  mm3  
< 15 
0 
15 - 25 
1 
>25 
2 
Hemoglobin g/dL 
 
>13.5 
0 
11.0 – 13.5 
1 
< 11 
2 
Sodium mmol/L or meq/L 
 
>= 135  
0 
< 135  
2 
Creatinine µmol/L (mg/dL) 
 
<= 141 (1.595) 
0 
>141 (1.595) 
2 
Glucose mmol/L (mg/dL) 
 
<=10 (180.18) 
0 
>10 (180.18) 
1 
 


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16 Appendix 6: Randomization Program: SAS call to R program  
 
proc format; 
 value treatment_fmt 
  1 = 'Placebo' 
  2 = 'Active' 
 ; 
run; 
 
proc iml; 
submit / R; 
  
library(doParallel) 
site_hold <- seq(10,49, by = 1) 
strata_hold <- c(1,2,3,4) 
block_4 <- c(1,1,2,2) 
block_6 <- c(1,1,1,2,2,2) 
 
theseed = 42 
set.seed(theseed) 
site_loop <- foreach (si = site_hold, .combine=rbind) %do% { 
  site_num <- si 
   
  strata_loop <- foreach (s = strata_hold, .combine=rbind) %do% { 
    strata_num <- s 
     
    full_block <- foreach (i =1:5, .combine=rbind) %do% { 
      get_random_block <- rbinom(1, 1, 0.5) 
       
      if (get_random_block == 1) { 
        block <- sample(block_6, 6, replace = FALSE) 
      } 
       
      if (get_random_block == 0) { 
        block <- sample(block_4, 4, replace = FALSE) 
      } 
       
      full_block <- as.matrix(block) 
    } 
    strata <- rep(s, length(full_block)) 
    seqnum <- seq(1,(length(full_block)), by = 1) 
     
    strata_seq_treat <- cbind(strata,seqnum, full_block) 
     
  } 
  site <- rep(site_num, nrow(strata_loop)) 
  with_site <-cbind(strata_loop, site) 
   
} 
 
site_loop_df <- as.data.frame(site_loop) 
seq_num      <- sprintf("%02d", as.numeric(site_loop_df$seqnum)) 
 
seed <- rep(theseed, nrow(site_loop_df)) 


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random_id   <- cbind(paste(site_loop_df$site, site_loop_df$strata, seq_num, 
sep='')) 
full_random <- cbind(site_loop_df$site, site_loop_df$strata, seq_num, 
site_loop_df$V3, seed) 
 
 
endsubmit; 
 
run importdatasetfromr ("random_id", "random_id"); 
run importdatasetfromr ("full_random", "full_random"); 
quit; 
 
data full_random; 
 formerge + 1; 
 set full_random; 
 rename v1 = site; 
 rename v2 = strata; 
 rename v4 = treatment; 
run; 
 
data random_id; 
 set random_id; 
 formerge + 1; 
run; 
 
data randomid; 
 merge random_id full_random; 
 by formerge; 
 rename v1 = randomid; 
 
 label 
  v1 = 'RandomID' 
  site = 'Site Number (10-49)' 
  strata = 'Strata Number (1-4)' 
  seq_num = 'Number of patient (1- ~26)' 
  /*v3 = 'Treatment (1/2)'*/ 
  treatment = 'Treatment (Placebo/Active)' 
  seed = 'Seed' 
 ;  
 
 drop formerge; 
 format treatment treatment_fmt.; 
run; 
 
 
title1 'ATXBIO'; 
title2 'Randomization'; 
 
%macro to_excel(site); 
%do i = 10 %to &site; 
%let site = %sysfunc(putn(&i,z2.)); 
 
data randomid_&site; 
 set randomid; 
 where site = &site; 
run; 


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proc export data = randomid_&site  
 outfile = 'c:\users\dgm\box sync\atxbio\Randomization Tables.xlsx' 
 dbms = xlsx replace; 
 sheet = "Site &site"; 
run; 
 
title3 "Site &site"; 
ods rtf file = "c:\users\dgm\box sync\atxbio\site&site..rtf";   
proc print data = randomid_&site label; run; 
ods rtf close; 
%end; 
%mend to_excel; 
 
%to_excel(site=49);