Conditions: Staphylococcus Aureus Bacteremia Staphylococcus Aureus Endocarditis
Keywords: S. aureus bloodstream infection S. aureus bacteremia S. aureus right-sided infective endocarditis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 259
Healthy volunteers: no

Brief summary:
The purpose of this superiority study is to evaluate the efficacy and safety of exebacase in addition to standard of care antibiotics (SoCA) compared with SoCA alone for the treatment of patients with Staphylococcus aureus (S. aureus) bloodstream infections (BSI), including right-sided infective endocarditis (IE). Patients will be randomized to receive a single intravenous dose of exebacase or placebo. Patients will receive SoCA selected by the investigators based on the protocol.

Exebacase, a direct lytic agent, is an entirely new treatment modality against S. aureus. Exebacase is a recombinantly-produced, purified cell wall hydrolase enzyme that results in rapid bacteriolysis, potent biofilm eradication, synergy with antibiotics, low propensity for resistance, and the potential to suppress antibiotic resistance when used together with antibiotics. Exebacase represents a first-in-field, first-in-class treatment with the potential to improve clinical outcome when used in addition to SoCA to treat S. aureus BSI including IE.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Exebacase intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive a single IV infusion of exebacase in addition to SoCA selected by the investigator. Participants with normal renal function or mild renal impairment will be administered a dose of 18 mg; participants with moderate or severe renal impairment will be administered a dose of 12 mg of exebacase; participants with end-stage renal disease, including those on hemodialysis, will be administered a dose of 8 mg of exebacase. intervention 2: Participants will receive a single IV infusion of placebo in addition to SoCA selected by the investigator.

Protocol document:
Prot_SAP_000.pdf: 
ContraFect Protocol CF-301-105 
Protocol Amendment 5 (CF-301-105-5)
The DISRUPT Study 
February 10, 2022
Page 1 of 152 
Clinical Trial Protocol 
The DISRUPT Study 
Direct Lysis of Staphylococcus aureus Resistant Pathogen Trial 
Exebacase (CF-301) 
A Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and 
Safety of a Single Dose of Exebacase in Patients Receiving Standard-of-Care 
Antibiotics for the Treatment of Staphylococcus aureus Bloodstream Infections 
(Bacteremia), Including Right-Sided Infective Endocarditis 
Protocol Number CF-301-105 
Protocol Amendment 5 (CF-301-105-5) 
Sponsor: 
ContraFect Corporation 
28 Wells Ave 
Yonkers, NY 10701 
Original Protocol Date: October 18, 2019 
Protocol Amendment 1 Date: May 21, 2020 
Protocol Amendment 2 Date: October 15, 2020 
Protocol Amendment 3 Date: January 29, 2021 
Protocol Amendment 4 Date: July 22, 2021 
Protocol Amendment 5 Date: February 10, 2022 
IND Number: 113473 
CONFIDENTIALITY STATEMENT 
This document contains confidential information, which should not be copied, referred to, released or 
published without written approval from ContraFect Corporation. Investigators are cautioned that the 
information given in this protocol might be subject to change and revision. Any conclusion regarding 
efficacy and safety must be considered provisional. 
clinicaltrials.gov NCT04160468


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SUMMARY OF CHANGES 
The primary purpose of this Protocol Amendment is to further clarify and refine the inclusion 
and exclusion criteria and streamline the study procedures to facilitate patient identification and 
enrollment. Daily assessment of signs and symptoms is removed in this Protocol Amendment to 
reduce the number of study-related patient encounters as a result of COVID-19-related 
restrictions and staffing challenges. The signs and symptoms will continue to be assessed at 
screening and on Day 7 and at the endpoint-determining study visits on Days 14, 30, and 60 to 
support the objectives of the study.
The table below describes the changes that were made from the prior version of the protocol:
Section(s) 
Brief Description of Changes 
1 
Revised contact information.
2, 4, 9.1, 
11.5, 12.10, 
12.11, 12.12, 
12.13 
 
Removed daily assessment of signs/symptoms, vital signs, and metastatic 
foci/septic emboli. Signs/symptoms, vital signs, and metastatic foci/septic emboli 
will continue to be assessed at screening and on Days 7, 14, 30, and 60. 
Additionally, if SoCA is changed after study drug dosing due to lack of clinical 
response, signs and symptoms will be assessed on the day of the SoCA change.
2, 4, 9.1, 
11.5, 12.10, 
12.11, 12.12, 
12.13 
As previously communicated in Protocol Clarification Letter #8, clarified that in 
rare instances in which it is not feasible to conduct study visits “in person” or by 
telephone/telehealth, medical records alone may be used for physical 
examinations, signs/symptoms, and metastatic foci/septic emboli assessments after 
contacting the Medical Monitor or designee. 
 
Clarified that when medical records are used alone or to supplement information 
collected during the telephone/telehealth visit, the physical examinations, 
signs/symptoms, and metastatic foci/septic emboli assessments extracted from the 
medical record will be recorded in the site’s source documents and entered in the 
relevant eCRFs. The Investigator/Sub-Investigator (or other delegated medically 
qualified person listed on the FDA Form 1572 and trained on the protocol) is 
expected to review, sign, and date the assessments extracted from the medical 
record and recorded in the site’s source documents. The eCRFs will be verified by 
the site monitor using these source documents. 
 
For symptoms (Section 12.13), provided guidelines for assessing symptoms that 
are not specifically documented as “absent” in the medical record.
2, 4, 11.3, 
12.13 
 
Clarified that pre-BSI/IE is the patient’s “usual state of health” before the BSI/IE 
started. Pre-BSI/IE is established by asking the patient or legally acceptable 
representative about symptoms and severity (using Table 9) prior to onset of the 
BSI/IE. The medical record may also be used. 
4, 11.3, 
12.8.2.5, 
12.8.2.6 
As already stated in the protocol, clarified the wording that the results of all blood 
cultures/other cultures from the initial S. aureus-positive blood culture ‘collected 
pre-study’ through the Day 60 visit will be entered in the eCRF, and the S. aureus 
isolates from the initial S. aureus-positive blood culture/other cultures ‘collected 
pre-study’ through the Day 60 visit should be sent to the central laboratory.
2, 4, 9.1, 
11.5, 12.14 
Removed the follow-up TTE or TEE between 7 to 14 days after the initial 
echocardiogram or up to the Day 30 visit. Clarified that follow-up 
echocardiograms will be performed as clinically indicated. 


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Section(s)
Brief Description of Changes
2, 4, 9.1, 
11.3, 11.4, 
11.5, 
12.2.8.5, 
12.8.1, 
12.8.2.1 
For adolescents, added that the results of local clinical laboratory testing during the 
screening window and at all other timepoints corresponding to the protocol can 
substitute for central safety laboratory tests and will be entered into the eCRF; 
samples for ADA and IgE must be collected at the timepoints specified in the 
protocol and sent to the central laboratory. 
 
Added that the Day 14 safety laboratory sample does not need to be collected for 
adolescents; if results from local clinical laboratory testing are available within the 
Day 14 visit window, these results should be entered into the eCRF, if feasible. 
Added that blood cultures may be collected ‘every other day’ for adolescents.
2, 4, 11.3, 
11.4, 
12.8.2.1, 
12.8.2.3, 
12.8.2.4, 12.9
 
Clarified that the pre-dose/screening timepoint for ECGs, safety laboratory tests, 
blood cultures, ADA, IgE, and PK samples can be performed during screening or 
‘after randomization and before dosing’. 
2, 10.1, 10.2
Inclusion criterion #2 and exclusion criterion #3: Added text to indicate that there 
is an approximately +1-hour window to randomize the patient after the 72-hour 
window (i.e., approximately 73 hours) to account for any technical issues with 
randomization. If the patient is randomized within the approximately +1-hour 
window, please inform the Medical Monitor or designee. 
2, 4, 9.1, 
10.1, 11.4, 
11.5, 12.5 
 
Inclusion criterion #4.b.ii: As previously communicated in Protocol Clarification 
Letter #7, added text to clarify that clots in the vein at the catheter site may be 
identified on ultrasound or other method (e.g., MRI, echocardiogram, surgery). 
Also clarified that the clots may be at ‘or near’ the catheter site. 
2, 10.1, 12.5
 
Inclusion criterion #4.b.iii: Clarified that patients who present with acute 
osteomyelitis as the first manifestation of S. aureus BSI (e.g., adolescents) may be 
enrolled even if original source of infection is not known. 
2, 10.1, 12.5
Inclusion criterion 4.b.vi.: As previously communicated in Protocol Clarification 
Letter #7, added text to clarify that in order for post-organ transplant patients to 
meet the protocol definition of ‘significantly immunocompromised’, the patient 
needs to be on immunosuppressant therapy for the organ transplant around the 
time of presentation with the S. aureus BSI/IE.
2, 10.1, 12.5, 
23.4 
(Appendix 4) 
 
Inclusion criterion 4.b.vi.: As previously communicated in Protocol Clarification 
Letter #7, the dose of prednisone considered to be immunosuppressive therapy was 
. Clarified that this includes ‘patients who have 
taken 
 of prednisone or equivalent for 5 days or more’. 
A list of immunosuppressive therapy was added to Section 23.4 (Appendix 4). 
2, 10.1, 12.5
Inclusion criterion 4.b.vi.: Clarified that the criterion for complicated BSI of AIDS 
includes HIV positive with an AIDS-defining condition or a CD4 count of 
 cells/mm³ ‘within approximately 90 days’. 
2, 10.1, 12.5
Inclusion criterion 4.b.vi.: Clarified that the criterion for complicated BSI of severe 
leukopenia is defined as absolute neutrophil count (ANC) of approximately 
 cells/mL in the 7 days prior to the qualifying blood culture or ‘during the 
screening window’.
2, 10.1, 12.5
Inclusion criterion 4.b.vi.: Added ‘advanced cirrhosis’ to the list of criteria for 
significantly immunocompromised. 


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Section(s)
Brief Description of Changes
2, 4, 9.1, 
10.2, 11.4, 
12.14 
Exclusion criterion #2: As already stated in other sections of the protocol, clarified 
the situations in which a TEE is required. Added that, in cases where there is an 
alternative cause of new heart failure or cerebral emboli, a patient with a negative 
TTE for L-IE may be discussed with the Medical Monitor for potential enrollment.
2, 9.4.2, 10.2, 
13.7 
 
Exclusion criterion #4: Clarified the note to indicate that patients with persistent 
S. aureus bacteremia for which treatment with ceftaroline fosamil or other 
non-protocol-recommended antibiotic (e.g., rifampin, gentamicin, other beta 
lactam) was instituted prior to randomization due to lack of response or intolerance 
may remain on the non-protocol-recommended antibiotic after randomization, 
if approved by the Medical Monitor. 
2, 10.2 
Exclusion criterion #7: Added that patients with planned surgery for known or 
suspected infected non-cardiac hardware or prosthetic joint may be enrolled if 
surgical removal is planned within 5 days after randomization, with approval of the 
Medical Monitor.
2, 10.2 
Exclusion criterion #8 was removed. Patients with known or suspected brain 
abscess or meningitis due to S. aureus are no longer excluded from the study.
2. 10.2 
 
Exclusion criterion #14: added a note that patients who have received agents under 
FDA Emergency Use Authorization (EUA) for COVID-19 prevention 
(e.g., vaccines or Evusheld or similar agents) or for COVID-19 treatment under 
FDA EAU are not excluded. 
2, 12.18, 15.5
For the clinical outcome definitions, clarified the timing of SoCA change due to 
persistence, worsening, or recurrence or new signs/symptoms of S. aureus BSI/IE 
as ‘after study drug dosing’. 
 
As previously communicated in Protocol Clarification Letter #9, clarified that new 
septic emboli are defined as an acute presentation of septic emboli after dosing and 
are a reason for failure for clinical outcome; septic emboli that are incidentally 
found on imaging are considered part of the patient’s baseline S. aureus BSI/IE if 
found before Day 7.
7.1.6 
 
Added a summary of 30-day all-cause mortality and time to symptom resolution in 
the Phase 2 study.
7.1.7 
Added a summary of patients treated with exebacase under compassionate 
use/expanded access.
9.4.2 
 
Reduced the timeframe between vancomycin and study drug dosing from 2 hours 
to 1 hour, as follows: Study drug should be administered either prior to the start of 
vancomycin infusion or a minimum of ‘1 hour’ after vancomycin infusion is 
complete.
14.12
 
Clarified that AEs and SAEs will be followed to resolution, or until an outcome is 
reached, or until ‘deemed to be stable.’
23.4 
(Appendix 4) 
New section added with list of immunosuppressive and myelosuppressive therapy, 
as previously communicated in Protocol Clarification Letter #7.
Various 
Made minor administrative and editorial changes throughout the document for 
clarity and consistency.


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SPONSOR SIGNATURE PAGE 
Protocol CF-301-105 
Protocol Amendment 5 (CF-301-105-5) 
A Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of a  
Single Dose of Exebacase in Patients Receiving Standard-of-Care Antibiotics for the Treatment 
of Staphylococcus aureus Bloodstream Infections (Bacteremia), Including Right-Sided Infective 
Endocarditis 
 
 
Sponsor’s Approval 
 
 
 
Cara Cassino, MD
Chief Medical Officer / Executive Vice President of 
Research and Development 
ContraFect Corporation 
 
Date 


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Protocol Amendment 5 (CF-301-105-5)
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INVESTIGATOR’S AGREEMENT 
Protocol CF-301-105 
Protocol Amendment 5 (CF-301-105-5) 
A Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of a  
Single Dose of Exebacase in Patients Receiving Standard-of-Care Antibiotics for the Treatment 
of Staphylococcus aureus Bloodstream Infections (Bacteremia), Including Right-Sided Infective 
Endocarditis 
 
I, the undersigned, have received and reviewed the CF-301-105 protocol and I agree to conduct 
this study as outlined in this protocol and in accordance with the ethical principles set forth in the 
Declaration of Helsinki, current Good Clinical Practice, and all applicable local laws and 
requirements. I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator
 
 
 
 
Signature of Investigator 
 
Date


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1. 
CONTACT INFORMATION 
Table 1: 
Contact Information 
Role in Study 
Name 
Contact Information 
Sponsor Responsible 
Physician / Medical 
Lead / Primary 
Medical Monitor 
Cara Cassino, MD 
Chief Medical Officer / 
Executive Vice President of 
Research and Development 
ContraFect Corporation 
28 Wells Ave, Yonkers, NY 10701 
Telephone: 914-330-2983 
Email: Ccassino@contrafect.com 
Sponsor Project 
Manager / 
Development 
Operations 
Nancy Capra 
Vice President,  
Project Management and 
Development Operations 
ContraFect Corporation 
28 Wells Ave, Yonkers, NY 10701 
Telephone: 215-760-3490 
Email: Ncapra@contrafect.com 
Sponsor Clinical 
Operations 
Kerry McConie
Director, Clinical 
Operations 
ContraFect Corporation
28 Wells Ave, Yonkers, NY 10701 
Telephone: 516-721-6653 
Email: Kmcconie@contrafect.com 
Sponsor Clinical 
Operations 
Francine Pisana 
Director, Clinical 
Operations 
ContraFect Corporation 
28 Wells Ave, Yonkers, NY 10701 
Telephone: 917-833-2610 
Email: Fpisana@contrafect.com 
Sponsor Clinical 
Operations 
Jill Steely 
CRA Manager 
ContraFect Corporation 
28 Wells Ave, Yonkers, NY 10701 
Telephone: 845-656-5681 
Email: Jsteely@contrafect.com 
Sponsor Clinical 
Operations 
Beth Soffer 
Clinical Operations 
ContraFect Corporation 
28 Wells Ave, Yonkers, NY 10701 
Telephone: 215-738-6285 
Email: Bsoffer@contrafect.com 
Sponsor Protocol 
Author 
Joy Lipka-Diamond 
Clinical Operations 
ContraFect Corporation 
28 Wells Ave, Yonkers, NY 10701 
Telephone: 215-872-3791 
Email: Jlipka@contrafect.com 
Labcorp Project Lead 
Lee Anna Loehr 
Senior Project Manager 
Labcorp Drug Development 
210 Carnegie Center Drive, Princeton, NJ 08540 
Telephone: 713-204-4442 
Email: lee.loehr@labcorp.com 


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2. 
SYNOPSIS 
Name of Sponsor/Company: ContraFect Corporation 
Investigational Product: Exebacase (CF-301) 
Active Ingredient: Exebacase 
Title of Study: A Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of a 
Single Dose of Exebacase in Patients Receiving Standard-of-Care Antibiotics for the Treatment of 
Staphylococcus aureus Bloodstream Infections (Bacteremia), Including Right-Sided Infective 
Endocarditis 
Study Name: The DISRUPT Study (Direct Lysis of Staphylococcus aureus Resistant Pathogen Trial) 
Protocol Number: CF-301-105 Protocol Amendment 5 (CF-301-105-5)
Phase of Development: 3 
Study Centers: Up to approximately 100 study centers, predominantly in the United States (US), will 
participate in this study. Site selection will take into account the prevalence of methicillin-resistant 
Staphylococcus aureus (MRSA) at the study center. 
Objectives: 
Primary: 
 
Efficacy: To determine if exebacase in addition to standard-of-care antibiotics (SoCA) is superior to 
SoCA alone for clinical responder rate at Day 14 in patients with MRSA bloodstream infections 
(BSI), including infective endocarditis (IE) (i.e., the MRSA population) in the microbiological 
intent-to-treat (mITT) analysis set 
 
Safety: To determine the safety and tolerability of exebacase in addition to SoCA compared with 
SoCA alone in the safety analysis set 
Secondary: 
 
To determine if exebacase in addition to SoCA is superior to SoCA alone for clinical responder rate 
at Day 14 in all patients with S. aureus (i.e., the overall population) in the mITT analysis set 
 
To determine if exebacase in addition to SoCA is superior to SoCA alone for 30-day survival in the 
MRSA population in the mITT analysis set 
 
To determine if exebacase in addition to SoCA is superior to SoCA alone for clinical responder rate 
at Day 60 in the MRSA population in the mITT analysis set 
 
To determine if exebacase in addition to SoCA is superior to SoCA alone for clinical responder rate 
at Day 60 in the overall population in the mITT analysis set 
 
To determine clinical responder rate at Day 60 in the overall right-sided IE (R-IE) and MRSA R-IE 
populations in the mITT analysis set 


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Additional:
 
To determine the survival time through Day 60 in the overall and MRSA populations in the 
mITT analysis set 
 
To determine clinical responder rate at Day 14 in the overall R-IE and MRSA R-IE populations in 
the mITT analysis set 
 
To determine clinical responder rate at Day 30 in the overall and MRSA populations, and overall 
R-IE and MRSA R-IE populations in the mITT analysis set 
 
To determine clinical responder rate at Day 14 by source of S. aureus infection in the overall and 
MRSA populations in the mITT analysis set 
 
To evaluate bacteremia clearance rate at Days 4 and 7 in the overall and MRSA populations in the 
mITT analysis set 
 
To describe post-dose immunologic response (anti-drug antibody to exebacase) in the safety 
analysis set 
 
To describe the relationship between baseline and post-dose immunologic parameters and efficacy 
and safety endpoints in the mITT and safety analysis sets, respectively 
 
To evaluate impact of exebacase on health resource utilization in the mITT analysis set 
 
To characterize the PK parameters of exebacase in the study population in the PK analysis set 
Study Design: 
This is a randomized, multicenter, double-blind, placebo-controlled study to evaluate the efficacy and 
safety of exebacase in addition to SoCA compared with SoCA alone for the treatment of adult and 
adolescent patients with S. aureus BSI including R-IE (excluding patients with left-sided endocarditis 
[L-IE]). Patients who meet all screening criteria and have a blood culture positive for S. aureus 
determined by rapid diagnostic or conventional methods, or Gram stain showing Gram-positive cocci in 
clusters plus either positive tube coagulase test or positive latex slide agglutination test from blood 
culture specimens collected within approximately 72 hours before randomization are eligible for the 
study. 
Approximately 348 patients will be randomly assigned in a 2:1 ratio to receive a single dose of 
exebacase (232 patients) or placebo (116 patients). Patients will receive exebacase or placebo as soon as 
possible after randomization. The randomization will be stratified by poorly controlled diabetes 
(yes or no) as defined below and susceptibility of the S. aureus isolate (MRSA, methicillin susceptible 
S.  aureus [MSSA], or unknown). For stratification, poorly controlled diabetes is defined as a 
 A HgA1C test is 
not required for patients with no medical history of diabetes and no suspicion of diabetes during the 
screening period. These patients will be stratified to “no” for poorly controlled diabetes. A HgA1C test 
should be performed in patients with medical history of diabetes of suspicion of diabetes during 
screening for whom a HgA1C test result within approximately 90 days prior to randomization is not 
available. If a HgA1C is unavailable and testing cannot be performed for these patients prior to 
randomization, contact the Medical Monitor to determine how the patient should be stratified based on 
available clinical information. All efforts will be made to obtain susceptibility results from blood 
cultures before randomization to enable stratification by MRSA or MSSA. If a blood culture was 


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performed for the current S. aureus infection prior to the qualifying blood culture, susceptibility results 
from the prior blood culture may be used. If the patient has a concomitant S. aureus infection at another 
body site from which susceptibility results are available (e.g., skin, abscess), the susceptibility results 
from this other culture may be used. If the patient is known to be colonized with MRSA, MRSA may be 
selected for the stratification factor. 
Patients will receive SoCA selected by the Investigator/Sub-Investigator (or other delegated medically 
qualified person listed on the US Food and Drug Administration (FDA) Form 1572 and trained on the 
protocol) based on recommendations in the protocol. These are based on authoritative treatment 
guidelines [Liu 2011, Baddour 2015] and include daptomycin or vancomycin for MRSA and 
semi-synthetic penicillins (e.g., nafcillin, oxacillin, cloxacillin, flucloxacillin) and first-generation 
cephalosporins (e.g., cefazolin) for MSSA. Daptomycin or vancomycin may be used for patients with 
MSSA with a known history of beta-lactam allergy or other reason that a beta-lactam cannot be used. 
The duration of SoCA will generally be from 2 to 8 weeks (14 to 56 days). If a longer duration of 
treatment with SoCA is anticipated, this must be discussed prior to randomization with the 
Medical Monitor. Long-term oral antibiotic suppression therapy (e.g., for osteomyelitis), is not 
considered to be SoCA for S. aureus BSI/IE and would be considered a “concomitant medication”. 
Treatment with oral step-down antibiotics is not permitted, except in adolescents. The SoCA will be 
administered as specified in the manufacturer’s prescribing information. 
All efforts will be made to determine the source of S. aureus BSI/IE (e.g., full physical examination, 
imaging as needed, cultures of other infected body sites or catheters that may be considered the source), 
preferably during screening or within 1 week after randomization. The resolution of the source of 
S. aureus BSI/IE will be evaluated at Days 7, 14, 30, and 60. 
Patients will be evaluated for signs and symptoms attributable to S. aureus BSI/IE and metastatic foci 
(e.g., deep tissue abscess, septic arthritis, etc.) and septic emboli (e.g., to the brain, lung, etc.) during 
screening and at the Day 7, 14, 30, and 60 visits. Additionally, if SoCA is changed after study drug 
dosing due to lack of clinical response, signs and symptoms will be assessed on the day of the SoCA 
change. The Investigator/Sub-Investigator (or other delegated medically qualified person listed on the 
FDA Form 1572 and trained on the protocol) will assess whether each sign or symptom is attributable to 
S. aureus BSI/IE or provide an alternative attribution and will assess the symptom severity per the 
definitions described in Table 1. Some symptoms may be considered ‘medically not evaluable’ due to 
certain medical circumstances or treatments, such as a patient in a medically induced coma or after 
surgery to remove a metastatic focus. 
Every effort should be made to perform study visits “in person”, including physical examinations, 
assessment of signs and symptoms, and evaluation of metastatic foci/septic emboli, by the 
Investigator/Sub-Investigator (or other delegated medically qualified person listed on the FDA Form 
1572 and trained on the protocol), and preferably by the same person at all visits. If it is not feasible to 
evaluate the patient “in person” at study visits, the signs and symptoms should be evaluated during the 
telephone/telehealth visits by detailed questioning and a complete medical review of systems. Medical 
records may be used to supplement the telephone/telehealth evaluation for physical examination, signs 
and symptoms, and metastatic foci/septic emboli (see Sections 12.10, 12.13, and 12.12, respectively). 
In rare instances in which it is not feasible to conduct study visits “in person” or by telephone/telehealth, 
medical records alone may be used for evaluation of signs and symptoms and presence of new or 
worsening metastatic foci after contacting the Medical Monitor or designee. The Investigator/ 


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Sub-Investigator (or other delegated medically qualified person listed on the FDA Form 1572 and 
trained on the protocol) must review, sign, and date the physical exam, sign and symptom, and 
metastatic foci/septic emboli data extracted from the medical record and recorded in the site’s source 
documents. 
Diagnostic testing will be performed as clinically indicated to assess metastatic foci or septic emboli 
(e.g., imaging, aspiration, and/or cultures). Metastatic foci identified through Day 7 are considered part 
of the patient’s baseline S. aureus BSI/IE; new metastatic foci identified after Day 7 or new septic 
emboli after study drug dosing are considered complications of S. aureus BSI/IE for the purpose of 
assessing clinical outcome. New septic emboli are defined as an acute presentation of septic emboli after 
dosing and are a reason for failure for clinical outcome; septic emboli that are incidentally found on 
imaging are considered part of the patient’s baseline S. aureus BSI/IE if found before Day 7. 
Intravenous catheters known or suspected to be infected must be removed, and as clinically needed 
replaced, preferably at a different site, as soon as possible within approximately 72 hours after 
randomization. Other hemodialysis access types (i.e., arteriovenous [AV] fistulas or AV grafts) and 
surgically managed infection sources that are known or suspected to be infected will be evaluated for 
removal/replacement, if clinically feasible. If removal/debridement is not feasible based on standard 
medical practice, the patient should be discussed with the Medical Monitor for potential enrollment. 
In patients with central venous catheters (CVC), ultrasounds to evaluate clots in the vein should be 
performed within approximately 48 hours after randomization, unless the clot in the vein has been 
detected within this timeframe via other method (e.g., imaging such as CT scan or MRI or direct 
visualization during surgery). 
In addition to the study-qualifying blood culture from specimens collected within approximately 
72 hours before randomization (described earlier in this section), 1 aerobic blood culture will be 
collected during screening (or after randomization and before dosing), collected via peripheral 
venipuncture when possible. One aerobic blood culture will be collected daily during the study until 
2 consecutive negative cultures followed out to negative for at least 48 hours on 2 different days are 
obtained after exebacase/placebo administration (Note: blood cultures may be collected every other day 
for adolescents). Additional blood cultures will be performed as clinically indicated. Other (non-blood) 
cultures should be performed to determine the source of S. aureus BSI/IE and evaluate metastatic foci, 
and as clinically indicated during the study. All S. aureus isolates from blood and other (non-blood) 
cultures will be sent to a central laboratory. 
Complete physical examinations and review of body systems will be performed during screening and on 
Days 7, 14, 30, and 60 for visits performed “in person” by the Investigator/Sub-Investigator (or other 
delegated medically qualified person listed on the FDA Form 1572 and trained on the protocol). 
A physical examination is not required for visits performed remotely by telephone/telehealth; however, 
a complete medical review of body systems will be performed during the telephone/telehealth visit and 
medical record data may be used to supplement these visits (e.g., sign and symptom evaluation and 
physical exam findings) to assess the patient’s clinical status, primary source of infection, and the status 
of any pre-existing or presence of new metastatic foci. The physical examinations will include a close 
evaluation for any new areas of pain or other signs or symptoms of metastatic foci of infection or septic 
emboli; new signs or symptoms (e.g., pain, shortness of breath) will trigger diagnostic testing for 
metastatic foci or septic emboli (e.g., imaging, aspiration, and/or cultures). The physical examination 
will also include an evaluation of the primary source of S. aureus BSI/IE.  


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echocardiogram (TEE) within 3 days before or after randomization. All efforts will be made to perform 
the TTE or TEE before randomization. Where possible, a TEE will be performed [Baddour 2015, 
Habib 2010, Habib 2015] and is recommended in patients with body mass index (BMI) >30 kg/m2; the 
TEE may be performed within 3 days before or after randomization unless the TEE is performed due to 
clinical suspicion of L-IE. In patients that have clinical findings suggestive of L-IE (new murmur, 
worsening cardiac function, and/or peripheral or central nervous embolic phenomenon), a TEE will be 
performed before randomization to rule out mitral and/or aortic valve vegetation(s) or the patient will be 
excluded from the study per exclusion criterion #2. In cases where there is an alternative cause of new 
heart failure or cerebral emboli, a patient with a negative TTE for L-IE may be discussed with the 
Medical Monitor for potential enrollment. 
(i.e., blood cultures positive for S. aureus 
), an echocardiogram will be performed before 
randomization to rule out L-IE. A TTE may be performed with permission from the Medical Monitor. 
If this echocardiogram is not performed or L-IE is not ruled out by this echocardiogram, the patient 
should not be randomized. In adolescents (12 to <18 years of age), echocardiograms (TTE or TEE) will 
be performed as clinically indicated taking into consideration risk factors for endocarditis 
(e.g., structurally abnormal heart [including pacemakers]), clinical features suggestive of endocarditis 
(e.g., new murmur), or persistent bacteremia [McMullan 2020], described in Section 12.14. If the patient 
had an echocardiogram performed prior to the study that was intended to evaluate the current infection, 
an additional TTE or TEE is not required unless as indicated above, but should be discussed with the 
Follow-up echocardiograms will be 
performed as clinically indicated. Images from all echocardiograms through the Day 60 visit will be 
provided to the central echocardiography laboratory as directed by the Sponsor. 
Safety monitoring will include adverse event (AE) monitoring, physical examinations, clinical safety 
laboratory tests, vital sign measurements, and 12-lead electrocardiograms (ECG). Safety monitoring will 
be performed from screening through the last follow-up visit (Day 60). An independent Data Safety 
Monitoring Board (DSMB) will review unblinded safety data throughout the study as defined in the 
DSMB charter. All fatal serious adverse events (SAE) and suspected unexpected serious adverse 
reactions (SUSARs) will be provided to the DSMB on an ongoing basis allowing the DSMB to monitor 
fatal and unexpected serious events in a timely manner. 
Blood samples for PK and immunogenicity (exebacase-specific anti-drug antibody [ADA] and 
immunoglobulin E [IgE]) will be collected. Samples for ADA testing will be collected during screening 
and on any day between the Day 30 and Day 60 visit windows (i.e., between Day 26 and Day 67). 
The sample for IgE testing will be collected during screening and will be stored at the site unless the 
patient later develops clinical signs or symptoms of a potential allergic reaction that may be attributed to 
study drug. If a patient has clinical signs or symptoms of a potential allergic reaction that may be 
attributed to study drug, a blood sample for IgE will be collected as soon as possible within 2 hours of 
the event, if feasible, and both this sample and the IgE sample at screening will be sent to a central 
laboratory for testing. 
Clinical outcome will be assessed by the Investigator/Sub-Investigator (or other delegated medically 
qualified person listed on the FDA Form 1572 and trained on the protocol). An independent blinded 
clinical endpoint Adjudication Committee (AC) will determine study eligibility, final diagnosis, primary 


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source of BSI/IE, adequacy of source control, and clinical outcome on Days 14, 30, and 60. 
The adjudicated diagnosis, source, and clinical outcomes will be used for the analysis. 
Visits Performed Remotely by Telephone/Telehealth, Use of Medical Records, and Use of Mobile 
Health Services: 
Telephone/telehealth visits may be performed under the circumstances described in Section 11.5.1 of the 
protocol. During the telephone/telehealth visit, information on the following will be collected: any AEs 
that may have occurred since the last visit and outcome of any ongoing AEs, thorough medical review 
of body systems to assess signs and symptoms of S. aureus BSI/IE, outcome of pre-existing or presence 
of new metastatic foci, outcome of primary source of infection, SoCA and reasons for any changes in 
SoCA, concomitant medications, surgeries/procedures, vital status, and clinical outcome. Medical 
records* may be used to supplement information obtained during the telephone/telehealth visit. 
In rare instances in which it is not feasible to conduct study visits “in person” or by telephone/telehealth, 
medical records* alone may be used for assessments after contacting the Medical Monitor or designee. 
* When medical records are used alone or to supplement information collected during the
telephone/telehealth visit, the signs/symptoms, vital signs, and metastatic foci/septic emboli
assessments extracted from the medical record will be recorded in the site’s source documents and
entered in the relevant eCRFs. The Investigator/Sub-Investigator (or other delegated medically
qualified person listed on the FDA Form 1572 and trained on the protocol) is expected to review,
sign, and date the assessments extracted from the medical record and recorded in the site’s source
documents. Symptom severity assessments must be made in accordance with Table 1. The eCRFs
will be verified by the site monitor using these source documents.
Local laboratory, vital signs, and ECG data obtained in conjunction with the Day 7, 14, 30, or 60 visits 
may be used for the study if available (including using data from medical records of another hospital, 
skilled nursing facility or other similar institution). 
Mobile health services, specifically contracted for the study, may be used to supplement 
telephone/telehealth visits to perform study visit procedures, such as collecting laboratory samples, 
evaluating vital signs, and/or obtaining a 12-lead ECG, after approval by the Medical Monitor or 
designee, as described in Section 11.5.1. 
Number of Patients (planned): Approximately 348 patients will be randomized (2:1) to receive a 
single dose of exebacase or placebo. 
Inclusion Criteria: 
The following inclusion criteria must be met at the time of screening (i.e., within approximately 
24 hours before randomization), unless otherwise noted below, in order for the patient to be eligible for 
enrollment: 
1.
Male or female, 12 years of age or older.
2.
Within 72 hours* before randomization, blood culture positive for S. aureus determined by rapid
diagnostic test or conventional method, or Gram stain showing Gram-positive cocci in clusters and
either positive tube coagulase test or positive latex slide agglutination test from blood culture
specimens.


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Note: The 72-hour* time period starts at the time the specimen is collected for blood culture.
Any S. aureus-positive blood culture collected within the 72 hours* before randomization can be 
used to support enrollment of the patient. 
*There is an approximately +1-hour window to randomize the patient after the 72-hour window
(i.e., approximately 73 hours) to account for any technical issues with randomization. If the patient
is randomized within the approximately +1-hour window, please inform the Medical Monitor or
designee.
3.
At least two of the following signs or symptoms attributable to S. aureus BSI/IE within
approximately 24 hours before randomization. If more than one measurement is taken within the
approximately 24 hours before randomization, the most abnormal value is used for inclusion.
a.
Shortness of breath
b.
Sweating
c.
Chills and/or rigors
d.
Fatigue
e.
Confusion
f.
Pain associated with metastatic foci
g.
h.
Leukocytosis (white blood cell [WBC] count >10,000/µL) [CTCAE 2017], leukopenia
(WBC 
peripheral WBC)
i.
Tachycardia (heart rate >100 bpm)
j.
Tachypnea (respiratory rate >20 breaths/min)
k.
Hypotension (systolic blood pressure <90 mmHg)
4.
Patient must have:
a.
Known or suspected R-IE (involvement of pulmonic and/or tricuspid valve[s]) based on
Modified Duke Criteria (defined in protocol)
or
b.
Known or suspected complicated S. aureus BSI, demonstrated as one or more of the following:
i.
Blood culture positive for S. aureus on more than one day
ii.
Clots in the vein at or near the catheter site seen on ultrasound or other method
(e.g., MRI, echocardiogram, surgery)
iii.
Signs or symptoms of metastatic foci of S. aureus infection (e.g., splenic abscess, deep
tissue abscess not associated with open wound or other local source of infection, septic
pulmonary emboli) or hematogenous seeding (e.g., of the renal system evidenced by
S. aureus bacteriuria [in absence of other source such as indwelling ureteral catheter],
septic arthritis, osteomyelitis) confirmed by physical examination, imaging, and/or culture
(as described in the study procedures sections of the protocol)
Note: Patients who present with acute osteomyelitis as the first manifestation of S aureus
BSI (e.g., adolescents) may be enrolled even if original source of infection is not known.
iv.
) for 72 hours or more


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v. Met criteria for sepsis or septic shock using the Sequential (sepsis-related) Organ Failure 
Assessment (SOFA) score (definition in protocol [adapted from Singer 2016]) during the 
time of diagnosis/presumptive diagnosis of BSI. If the SOFA score is the only criteria for 
complicated S. aureus BSI that is met, contact the Medical Monitor prior to 
randomization. 
vi. Significantly immunocompromised: 
 
AIDS (HIV positive with an AIDS-defining condition or a CD4 count of 
approximately 200 cells/mm³ within approximately 90 days) 
 
Severe leukopenia defined as absolute neutrophil count (ANC) of approximately 
500 cells/mL in the 7 days prior to the qualifying blood culture or during the 
screening window 
 
Post organ transplantation including autologous bone marrow or stem cell 
transplantation and on immunosuppressive therapy for the organ transplant around the 
time of presentation with the S. aureus BSI/IE 
 
On treatment for active graft vs. host disease 
 
On immunosuppressive therapy such as: 
 
Biologics such as infliximab, monoclonal antibodies such as daclizumab, 
methotrexate, cyclophosphamide, or similar agents. A list of similar agents is in 
Appendix 4 in Section 23.4. 
 
Patients who have taken 10 mg of prednisone or equivalent for 5 days or more. 
 
On myelosuppressive chemotherapy or immunotherapy 
 
Advanced cirrhosis 
or 
c. At least one of the following risk factors for complicated S. aureus BSI: 
i. 
Preexisting right-sided valvular heart disease 
ii. 
Surgery (e.g., orthopedic, cardiothoracic, or intraabdominal surgery) within the previous 
30 days that puts the patient at risk for nosocomial bacteremia 
iii. 
Extravascular foreign material. Note: Catheters including ports, AV fistulas and related 
dialysis access points are considered intravascular foreign material. 
iv. 
Hemodialysis 
5. Patient is not pregnant or breastfeeding and meets one of the following criteria: 
a. A female patient who is not of childbearing potential is eligible without requiring the use of 
contraception. This includes female patients who have not undergone menarche or who are 
documented to be surgically sterile (e.g., hysterectomy, or removal of both ovaries, or tubal 
ligation) or postmenopausal (i.e., amenorrhea >1 year and follicle stimulating hormone [FSH] 
>40 mIU/mL) with a negative pregnancy test. FSH and pregnancy testing is not required in 
postmenopausal females with amenorrhea for >2 years. 
b. Female patients of childbearing potential and male patients with partners of childbearing 
potential must agree to remain abstinent* or use 2 methods of contraception and refrain from 
donating sperm (male patients) from screening through 30 days after receiving the study drug. 


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*Abstinence is defined as refraining from heterosexual intercourse from screening through 
30 days after receiving the study drug; the Investigator/Sub-Investigator (or other delegated 
medically qualified person listed on the FDA Form 1572 and trained on the protocol) will 
consider whether abstinence is consistent with the preferred and usual lifestyle of the patient. 
Acceptable methods of contraception include either: 
 
Hormonal contraception (injection, implant, pill, patch, or vaginal ring) and a condom or 
diaphragm with spermicide, or 
 
Intrauterine device (IUD) and a condom or diaphragm 
c. A male patient who is not of reproductive potential is eligible without requiring the use of 
contraception. This includes males who have undergone a successful vasectomy, defined as 
(1) microscopic documentation of azoospermia, or (2) a vasectomy more than 2 years ago with 
no resultant pregnancy despite sexual activity post vasectomy. 
6. Willing and able to provide written informed consent or assent. If the patient is not able to provide 
written informed consent or assent, written informed consent may be provided by the patient’s 
legally acceptable representative as permissible based on local laws and regulations. For patients 
12 to <18 years of age, written informed consent from the patient’s parent/guardian or other legally 
acceptable representative will be obtained according to the site’s IRB requirements. For 
emancipated minors, written informed consent will be obtained according to the site’s IRB 
requirements. 
Exclusion Criteria: 
1. Patient previously received exebacase. 
2. Known or suspected left-sided IE (involvement of mitral and/or aortic valve[s]) based on 
Modified Duke Criteria (defined in protocol). 
Note: In adult patients that have clinical findings suggestive of L-IE (new murmur, worsening 
cardiac function, and/or peripheral or central nervous embolic phenomenon), a TEE will be 
performed before randomization to rule out mitral and/or aortic valve vegetation(s) or the patient 
will be excluded from the study. In cases where there is an alternative cause of new heart failure or 
cerebral emboli, a patient with a negative TTE for L-IE may be discussed with the Medical Monitor 
for potential enrollment. In patients 
positive for S. aureus 
rule out L-IE. A TTE may be performed with permission from the Medical Monitor. If this 
echocardiogram is not performed or L-IE is not ruled out by this echocardiogram, the patient should 
not be randomized. In adolescents (12 to <18 years of age), echocardiograms (TTE or TEE) will be 
performed as clinically indicated taking into consideration risk factors for endocarditis 
(e.g., structurally abnormal heart [including pacemakers]), clinical features suggestive of 
endocarditis (e.g., new murmur), or persistent bacteremia [McMullan 2020]. 
3. Treatment with any potentially effective systemic anti-staphylococcal antibiotic for more than 
72 hours* within 7 days before randomization. 
Exception: Documented S. aureus resistance to the prior systemic antibiotics and/or persistent 
S. aureus-positive blood cultures while on the systemic antibiotics. 
 


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*There is an approximately +1-hour window to randomize the patient after the 72-hour window 
(i.e., approximately 73 hours) to account for any technical issues with randomization. If the patient 
is randomized within the approximately +1-hour window, please inform the Medical Monitor or 
designee. 
4. Current or planned treatment within the 14 days after randomization with dalbavancin or 
oritavancin. 
Notes: 
 
Patients who are receiving teicoplanin, linezolid, telavancin, beta-lactam/beta-lactam 
inhibitors (e.g., piperacillin-tazobactam), carbapenems, fourth- or fifth-generation 
cephalosporins (e.g., cefepime, ceftaroline fosamil), and/or sulfamethoxazole/trimethoprim are 
eligible for the study provided that treatment is switched to a protocol-specified appropriate 
SoCA (appropriate SoCA includes daptomycin and vancomycin for MRSA and semi-synthetic 
penicillins [e.g., nafcillin, oxacillin, cloxacillin, flucloxacillin] and first-generation 
cephalosporins [e.g., cefazolin] for MSSA. 
 
Daptomycin or vancomycin may be used for patients with MSSA with a known history of 
beta-lactam allergy or other reason that beta-lactam cannot be used.  
 
Patients with persistent S. aureus bacteremia for which treatment with ceftaroline fosamil or 
other non-protocol-recommended antibiotic (e.g., rifampin, gentamicin, other beta lactam) was 
instituted prior to randomization due to lack of response or intolerance (i.e., added to or 
switched from a protocol-recommended SoCA) may remain on the non-protocol-
recommended antibiotic after randomization, if approved by the Medical Monitor. 
 
Vancomycin or daptomycin used in combination with beta-lactams has not been shown to 
offer benefit and may increase the risk of kidney injury [Tong 2020]; therefore, this 
combination should not routinely be used as first-line therapy. 
5. Removed (Protocol Amendment 4). 
6. Presence of any removable or surgically managed infection source (e.g., intravascular catheter, 
abscess) that will not be removed or debrided based upon standard medical practice within 
approximately 72 hours after randomization. 
Note: Other hemodialysis access types (i.e., AV fistulas or AV grafts) and surgically managed 
infection sources that are known or suspected to be infected will be evaluated for 
removal/replacement if clinically feasible. If removal/debridement is not feasible based on standard 
medical practice, the patient should be discussed with the Medical Monitor for potential enrollment. 
7. Presence of prosthetic valve or cardiac valve support ring, or presence of known or suspected 
infected hardware* (e.g., orthopedic), prosthetic joint*, or cardiac device (e.g., implantable 
cardioverter defibrillator [ICD], permanent pacemaker). Note: Patients who have S. aureus 
bacteremia after the removal of infected hardware or cardiac device may be included in the study. 
*Patients with planned surgery for known or suspected infected non-cardiac hardware or prosthetic 
joint may be enrolled if surgical removal is planned within 5 days after randomization, with 
approval of the Medical Monitor. 
8. Removed (Protocol Amendment 5) 


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9.
Patient with BOTH asplenia and creatinine clearance (CrCl) <60 mL/min including those on
dialysis (risk for reduced ability to catabolize exebacase). Note: CrCl will be calculated by 
Cockcroft-Gault formula (provided in protocol) using ideal body weight in patients with 
BMI 
 kg/m2 and serum creatinine result obtained locally. 
10. Patient receiving continuous renal replacement therapy (CRRT) within 4 hours prior to dosing 
and/or within 8 hours after dosing. 
11. Known polymicrobial BSI (i.e., more than one pathogen in the blood). Note: Culture results that 
include organisms that are considered contaminants do not exclude the patient. 
12. Patient with known, ongoing systemic infection caused by other bacterial pathogen(s) 
(i.e., other than S. aureus) and/or fungal pathogen(s) and/or patient who has a known positive 
coronavirus disease 2019 (COVID-19) diagnostic test at the time of screening. Patients who 
previously had COVID-19 and are COVID-19-negative by diagnostic test are eligible for 
enrollment. Note: COVID-19 testing should be performed as clinically indicated in accordance with 
local standard medical practice.  
13. Patient is not expected to survive through Day 14 of the study due to underlying comorbidity 
(e.g., terminal end-stage cancer) and/or patient has an Acute Physiology and Chronic Health 
Evaluation II (APACHE II) score of >30. 
14. Patient participated or plans to participate in another interventional investigational drug, device, or 
diagnostic trial involving administration of an investigational agent within 30 days or 5 half-lives of 
investigational drug, whichever is longer, prior to or during the study.  
Note: Patients who have received agents under FDA Emergency Use Authorization (EUA) for 
COVID-19 prevention (e.g., vaccines or Evusheld or similar agents) or for COVID-19 treatment 
under FDA EAU are not excluded. 
15. Other comorbid condition or laboratory abnormality that would, in the opinion of the 
Investigator/Sub-Investigator (or other delegated medically qualified person listed on the 
FDA Form 1572 and trained on the protocol), pose a safety risk for the patient to participate or pose 
a risk to the patient’s ability to complete the study. 
16. Patient is employed by the Sponsor or a member of the investigational site study team 
(i.e., on the Delegation of Authority Log) or is a first degree relative of a person employed by the 
Sponsor or a member of the investigational site study team (i.e., on the Delegation of Authority 
Log). Patient is institutionalized by administrative or court order. 
17. Patient is not willing or able to comply with the protocol requirements. 
Investigational Product, Dosage and Mode of Administration: 
Exebacase will be provided as frozen, sterile, injectable solution for dilution. Exebacase will be diluted 
and administered as approximately a 2-hour IV infusion, as specified in the Pharmacy Manual. 
The dosing scheme is as follows: 
 
administered a dose of 18 mg of exebacase. 
 
Patients with moderate or severe renal impairment (CrCl* of 15 to <60 mL/min) will be 
administered a dose of 12 mg of exebacase. 


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Patients with end-stage renal disease (ESRD; CrCl* <15 mL/min), including those on hemodialysis, 
will be administered a dose of 8 mg of exebacase. In patients receiving hemodialysis, study drug 
will be administered 
 
hemodialysis. 
*Note: CrCl will be calculated by Cockcroft-Gault formula (provided in protocol) using ideal body 
weight 
2 and serum creatinine result obtained locally as close to the start 
of study drug dosing as possible (but not more than approximately 24 hours before the start of study 
drug dosing). 
Reference Therapy, Dosage and Mode of Administration: 
Placebo will be provided as frozen, sterile, injectable solution for dilution. Placebo is similar in 
appearance to exebacase. Placebo will be diluted and administered as approximately a 2-hour IV 
infusion, as specified in the Pharmacy Manual. 
Duration of Treatment: Patients will receive a single dose of exebacase or placebo in addition to 
SoCA. The duration of SoCA will generally be from 2 to 8 weeks (14 to 56 days). If a longer duration of 
treatment with SoCA is anticipated, this must be discussed prior to randomization with the Medical 
Monitor. Long-term oral antibiotic suppression therapy (e.g., for osteomyelitis), is not considered to be 
SoCA for S. aureus BSI/IE and would be considered a “concomitant medication”. 
Duration of Study (for each patient): The duration of the study for each patient will be approximately 
60 days (±7 days). 
Criteria for Evaluation: 
Efficacy: 
Metastatic foci, septic emboli, signs and symptoms attributable to S. aureus BSI/IE, blood cultures and 
other (non-blood) cultures, physical examinations (including a close evaluation for any new areas of 
pain or other signs or symptoms of metastatic foci or septic emboli), imaging (as needed for determining 
diagnosis and assessing metastatic foci or septic emboli), and echocardiography will be assessed or 
performed at the timepoints described previously in this Synopsis. 
The Investigator/Sub-Investigator (or other delegated medically qualified person listed on the 
FDA Form 1572 and trained on the protocol) will assess whether each sign or symptom is attributable to 
S. aureus BSI/IE or provide an alternative causality. The signs and symptoms attributable to S. aureus 
BSI/IE that will be assessed are described in the inclusion criteria earlier in this Synopsis. Each patient 
is required to have at least 2 signs or symptoms attributable to S. aureus BSI/IE at screening (within 
approximately 24 hours before randomization) in order to be enrolled in the study. Signs and symptoms 
will be assessed during screening and at the Day 7, 14, 30, and 60 visits. Additionally, if SoCA is 
changed after study drug dosing due to lack of clinical response, signs and symptoms will be assessed 
on the day of the SoCA change. Select symptoms (shortness of breath, fatigue, confusion) will also be 
evaluated at pre-BSI/IE. Pre-BSI/IE is the patient’s “usual state of health” before the BSI/IE started. 
Pre-BSI/IE is established by asking the patient or legally acceptable representative about these 
symptoms and severity (using Table 1) prior to onset of the BSI/IE. The medical record may also be 
used. 
 


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The Investigator/Sub-Investigator (or other delegated medically qualified person listed on the 
FDA Form 1572 and trained on the protocol) will assess the severity of specific symptoms attributable 
to S. aureus as absent, mild, moderate, or severe, as defined in Table 1. Symptoms of sweating and 
chills/rigors and signs attributable to S. aureus will be assessed as present or absent. The Investigator/ 
Sub-Investigator (or other delegated medically qualified person listed on the FDA Form 1572 and 
trained on the protocol) and the AC will assess the resolution of or persistence, worsening, or recurrence 
of signs and symptoms attributable to S. aureus BSI/IE which were present at screening, or any new 
signs or symptoms attributable to S. aureus BSI/IE, when evaluating clinical outcome, according to the 
clinical outcome definitions in Table 2. All signs and symptoms attributable to S. aureus that were 
present at screening must be absent or improve by 2 grades (i.e., from severe to mild) in order to be 
considered as resolved. Symptoms attributable to S. aureus that were present at screening and only 
improve by 1 grade (i.e., from severe to moderate or from moderate to mild) are considered persistence. 
Table 1: 
Severity Definitions for Symptoms Attributable to S. aureus 
Symptom 
Absent 
Mild 
Moderate 
Severe 
Shortness 
of breath 
(SOB)1 
Resolution 
(to pre-BSI/IE) or 
absence of SOB 
SOB with moderate 
exertion 
(e.g., climbing stairs) 
SOB with minimal 
exertion (e.g., normal/ 
routine activities 
(e.g., walking on flat 
surface, performing 
usual daily activities 
[i.e., instrumental 
ADL]) 
SOB at rest and/or 
requiring oxygen 
(or increase in oxygen 
requirement in patients 
who required oxygen 
pre-BSI/IE); limits ability 
to perform self-care ADL 
Fatigue1 
Resolution 
(to pre-BSI/IE) or 
absence of fatigue 
Transient, relieved by 
rest; does not 
interfere with usual 
activities 
Frequent, interferes 
with usual daily 
activities 
(i.e., instrumental ADL) 
Fatigue not relieved by 
rest; limits ability to 
perform self-care ADL 
Confusion1,2 
Resolution 
(to pre-BSI/IE) or 
absence of 
confusion 
(e.g., disorientation) 
Transient confusion 
(e.g., mild 
disorientation that 
does not interfere 
with usual activities). 
Moderate 
disorientation; 
interferes with ability to 
do usual activities 
(i.e., instrumental ADL) 
Severe, continuous 
confusion state 
(e.g., delirium) 
disorientation limiting 
ability to perform 
self-care ADL 
Pain assoc. 
with 
metastatic 
foci 
Absence of pain 
from metastatic foci 
Transient mild pain; 
does not interfere 
with usual activities 
or sleep 
Frequent pain; 
interferes with usual 
activities or sleep 
Constant pain interferes 
with usual activities or 
sleep and/or ability to 
perform self-care ADL 
Reference: Adapted from NIH Common Terminology Criteria for Adverse Events (CTCAE) 
Abbreviation: ADL=activities of daily living; assoc.=associated; SOB=shortness of breath 
Note: Some symptoms may be considered µmedically not evaluable¶ due to certain medical circumstances or treatments, such as 
a patient in a medically induced coma or after surgery to remove a metastatic focus. 
1. 
A pre-BSI/IE assessment will be done for shortness of breath, fatigue, and confusion. Pre-BSI/IE is the patient¶s ³usual 
state of health´ before the BSI/IE started. 
2. 
Confusion is defined as a disorder characterized by a lack of clear and orderly thought and behavior. Confusion may 
include disorientation, illusions, movement changes, inattentiveness, agitation, and/or hallucinations 


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Clinical outcome will be assessed by the Investigator/Sub-Investigator (or other delegated medically 
qualified person listed on the FDA Form 1572 and trained on the protocol) and the AC at Days 14, 30, 
and 60 according to the definitions in Table 2. 
Table 2: 
Clinical Outcome Definitions at Days 14, 30, and 60 
Clinical Outcome 
Definition 
Responder
All of the following criteria are met:
 
Resolution of signs and symptoms attributable to S. aureus BSI/IE which were 
present at screening1, 
 
No new signs or symptoms attributable to S. aureus BSI/IE, 
 
No complications of S. aureus BSI/IE, including: 
 
No development of a new metastatic focus of S. aureus infection 
(e.g., deep tissue abscess, septic arthritis) after Day 72, 
 
No development of new septic emboli (e.g., to the brain, lung, etc.) after study 
drug dosing3, 
 
No change in the SoCA after study drug dosing due to persistence, worsening, or 
recurrence or new signs/symptoms of S. aureus BSI/IE4, 
 
Blood culture(s) negative for S. aureus by Day145, and 
 
The patient is alive. 
Failure
At least 1 of the following criteria is met:
 
Persistence, worsening, or recurrence of signs or symptoms attributable to S. aureus 
BSI/IE which were present at screening,1
 
New signs or symptoms attributable to S. aureus BSI/IE, 
 
Complications of S. aureus BSI/IE, including: 
 
Development of a new metastatic focus of S. aureus infection (e.g., deep tissue 
abscess, septic arthritis) after Day 72, 
 
Development of new septic emboli (e.g., to the brain, lung, etc.) after study drug 
dosing3, 
 
SoCA was changed after study drug dosing due to persistence, worsening, or 
recurrence or new signs/symptoms of S. aureus BSI/IE4, 
 
Failure to clear blood cultures by Day145, or 
 
Death due to any cause.
Indeterminate 
The patient is not available for the evaluation of clinical outcome for any reason 
including: 
 
Lost to follow-up 
 
Withdrawal of consent/assent 
 
Other reason for not performing assessment
Note: Visit windows are as follows: Day 14 (±1 day), Day 30 (±4 days), Day 60 (±7 days). 
1. 
Specific symptoms attributable to S. aureus will be assessed as absent, mild, moderate, and severe according to the 
definitions in Table 1 Sweating and chills/rigors and signs attributable to S. aureus will be assessed as present or absent. 
All signs and symptoms attributable to S. aureus that were present at screening must be absent or improve by 2 grades 
(i.e., from severe to mild) in order to be considered as resolved. Symptoms attributable to S. aureus that were present at 
screening and only improve by 1 grade (i.e., from severe to moderate or from moderate to mild) are considered 
persistence. 
2. 
Metastatic foci identified through Day 7 are considered part of the patient’s baseline S. aureus BSI/IE; new metastatic foci 
identified after Day 7 are considered complications of S. aureus BSI/IE for the purpose of assessing clinical outcome. 
3. 
New septic emboli are defined as an acute presentation of septic emboli after dosing and are a reason for failure for clinical 
outcome; septic emboli that are incidentally found on imaging are considered part of the patient’s baseline S. aureus 
BSI/IE if found before Day 7. 
4. 
Patients may be treated empirically and SoCA may be changed after susceptibility data become available. A change in 
SoCA based on susceptibility data from the blood culture collected within approximately 72 hours before randomization 
does not count as “failure”. 
5. 
Failure to attain negative blood cultures on or before Day 14. Only applies to Day 14 assessment. 


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Microbiological outcome will be determined programmatically at Days 4 and 7 according to the 
definitions in Table 3. 
Table 3: 
Microbiological Outcome Definitions at Days 4 and 7 
Microbiological Outcome
Definitions 
Clearance of bacteremia1
Two consecutive blood cultures collected on 2 different days on or prior to 
assessment were negative for S. aureus. 
Ongoing bacteremia1
Blood culture on the day of assessment or the most recent blood culture prior to 
the day of assessment was positive for S. aureus.
If the patient does not meet the criteria for clearance or ongoing bacteremia, including because follow-up blood 
cultures were not done, microbiological outcome is presumed from clinical outcome as follows:
Presumed clearance of 
bacteremia1
The patient is a responder at Day 14 (per the adjudicated clinical 
outcome, as defined in Table 2. 
Presumed ongoing 
bacteremia1
The patient is a failure at Day 14 (per the adjudicated clinical outcome, 
as defined in Table 2).
Indeterminate 
The patient is indeterminate for clinical outcome at Day 14 
(per the adjudicated clinical outcome, as defined in Table 2. 
1.
For the analysis, clearance of bacteremia will include both clearance and presumed clearance of bacteremia, and ongoing 
bacteremia will include both ongoing and presumed ongoing bacteremia. 
Safety: 
Adverse events will be monitored from the time of consent/assent through the last follow-up visit 
(Day 60). 
Patients must be observed during exebacase/placebo infusion by someone from the clinical care team or 
research team with patient care experience. Vital signs (blood pressure, respiratory rate, heart rate, and 
temperature) will be performed approximately 30 to 40 minutes after the start of infusion and as 
clinically indicated during the infusion and at the Day 7, 14, 30, and 60 visits for visits performed “in 
person” or may be obtained via the study-specific mobile health service. 
While not observed in the Phase 2 study (Study CF-301-102), if a patient has clinical signs and 
symptoms of a potential allergic reaction that may be attributed to study drug, the infusion must be 
stopped immediately and vital signs checked; if hypotension or oxygen desaturation are present with or 
without skin flushing, hives, or rash, epinephrine should be administered immediately intramuscularly. 
Additional treatments for sequelae of suspected anaphylactic reaction should be provided in accordance 
with standard medical practice. A blood sample for exebacase-specific IgE will be collected as soon as 
possible within 2 hours of the event, if feasible, and both this sample and the IgE sample at screening 
will be sent to a central laboratory for testing. 
Blood and urine samples for safety laboratory tests (biochemistry, hematology, coagulation, and 
urinalysis) will be collected during screening, approximately 24 hours after study drug administration 
(Day 2), on Day 14 for adults*, and Day 30; the samples will be sent to a central laboratory for testing. 
*The collection of Day 14 samples is not required for adolescents. Results from local clinical laboratory 
testing completed within the Day 14 visit window should be entered into the eCRF if available and 
feasible. For all patients, if a blood or urine sample for safety laboratory testing by the central laboratory 
is not able to be obtained at a given timepoint/visit, the local laboratory results may be collected for that 
timepoint/visit, if feasible. If a blood or urine sample for safety laboratory testing by the central 
laboratory or local laboratory results are not able to be obtained at the Day 30 visit, samples may be on 


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any day between the Day 30 and 60 visit windows (i.e., between Day 26 and Day 67) when collecting 
the blood sample(s) for exebacase-specific ADA and pregnancy test (if applicable). For adolescents, the 
results of local clinical laboratory testing during the screening window and at all other timepoints 
corresponding to the protocol can substitute for central safety laboratory tests and will be entered into 
the eCRF; samples for ADA and IgE must be collected at the timepoints specified in the protocol and 
sent to the central laboratory. 
A 12-lead ECG will be performed during screening (or after randomization and before dosing) and on 
Day 14. Additional ECGs will be performed as clinically indicated. 
Complete physical examinations and review of body systems will be performed during screening and on 
Days 7, 14, 30, and 60 for visits performed “in person” by the Investigator/Sub-Investigator 
(or other delegated medically qualified person listed on the FDA Form 1572 and trained on the 
protocol). A physical examination/vital signs are not required for visits performed remotely by 
telephone/telehealth; however, a complete medical review of body systems will be performed during the 
telephone/telehealth visit and medical record data may be used to supplement these visits 
(e.g., sign and symptom evaluation and physical exam findings) to assess the patient’s clinical status, 
primary source of infection, and the status of any pre-existing or presence of new metastatic foci. 
The complete physical examinations/medical review of symptoms will include evaluation of general, 
head, eye, ear, nose, and throat (HEENT), cardiovascular, skin for any evidence of emboli, 
musculoskeletal, respiratory, gastrointestinal, neurological systems, and signs of pain. The physical 
examinations/medical review of symptoms will include a close evaluation for any new or worsening 
signs or symptoms (e.g., pain, shortness of breath) of suspected new metastatic foci of infection or 
suspected septic emboli. Diagnostic testing (e.g., imaging, aspiration, and/or cultures) will be performed 
to confirm suspected new metastatic foci or septic emboli. The physical examination/medical review of 
symptoms will also include an evaluation of the primary source of S. aureus BSI/IE. Additional physical 
examinations will be performed as clinically indicated. 
Vital status (whether the patient is alive or dead, or last known date alive if vital status is unknown) will 
be obtained at Days 14, 30, and 60 for all patients, including patients that discontinue the study or 
withdraw consent/assent (as described in the informed consent/assent form). The patient’s vital status 
will be determined using available sources (e.g., the patient, patient’s contacts, hospital and other 
medical records, and public records, such as social media, obituaries, social security death index) as 
described in the informed consent/assent form and FDA guidance (described in Section 12.17 of the 
protocol). 
An independent DSMB will review accruing safety and tolerability data in an unblinded manner 
throughout the study. All fatal SAEs and SUSARs will be provided to the DSMB on an ongoing basis. 
The DSMB will also review results from a futility analysis of the primary efficacy parameter in the 
in the MRSA population in the mITT analysis 
set have primary (Day 14) adjudicated clinical outcome data available. Details of the roles and 
responsibilities of the DSMB, timing of data reviews, and the futility stopping threshold will be 
documented in the DSMB charter. The Sponsor and study staff will remain blinded throughout the 
study. The DSMB will monitor the overall safety of patients in order to minimize unacceptable risk to 
patients. As a result, the DSMB may recommend changes to study conduct on the basis of emerging 
safety information to protect the safety and welfare of clinical study patients. Enrollment will continue 
during the DSMB reviews. 


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Immunogenicity: 
Blood samples will be collected for exebacase-specific ADA during screening and on any day between 
the Day 30 and Day 60 visit windows (i.e., between Day 26 and Day 67); ADA samples will be sent to a 
central laboratory for testing. A blood sample for IgE will be collected during screening and retained at 
the site. If a patient has clinical signs or symptoms of a potential allergic reaction that may be attributed 
to study drug, a blood sample for IgE will be collected as soon as possible within 2 hours of the event, if 
feasible, and both this sample and the IgE sample at screening will be sent to a central laboratory for 
testing. 
Health Resource Utilization:
The following health resource utilization information will be collected through Day 60: in-hospital 
mortality, hospital length-of-stay, intensive care unit (ICU) length-of-stay, discharge location 
(e.g., home, nursing home and skilled nursing facility/long-term acute care, rehabilitation, palliative 
care/hospice), outpatient SoCA administration by outpatient facility or home health care, 30-day 
all-cause readmission, and 30-day readmission for S. aureus BSI/IE or complication of S. aureus BSI/IE 
(e.g., metastatic foci, septic emboli). 
Pharmacokinetics: 
All patients will be assigned to one of two PK sampling schemes and blood samples will be collected at 
3 timepoints as listed below, and sent to a central laboratory for measurement of exebacase: 
 
PK Group 1: pre-dose (collected during screening), within 5 to 25 minutes after the end of infusion, 
and between 3 to 5 hours after the end of infusion 
 
PK Group 2: pre-dose (collected during screening), within 5 to 25 minutes after the end of infusion, 
and between 8 to 12 hours after the end of infusion. 
The actual time of PK sample collection, actual time of start and end of infusion, actual rate of volume 
and rate of infusion, and dosing information will be recorded. 
Statistical Methods: 
A Statistical Analysis Plan (SAP) will be prepared and finalized before database lock and analyses of 
unblinded data. Summary data will be tabulated and presented by treatment group. Treatment groups 
will be referred to as “exebacase + SoCA” and “SoCA alone” for patients randomly assigned to 
exebacase and placebo, respectively. 
Analysis Sets:
 
Intent-to-treat (ITT) analysis set: all randomized patients 
 
Safety analysis set: all randomized patients who receive any amount of study drug 
 
Microbiological ITT (mITT) analysis set: all randomized patients who receive any amount of study 
drug and had documented S. aureus BSI/IE based on a blood culture prior to administration of study 
drug. Determination of S. aureus is based on the central laboratory determination of genus and 
species unless no central result is available. In this case, the local laboratory result will be used. 
 
Per-Protocol (PP) analysis set: all randomized patients who have no confounding factors 
(as defined in the SAP) potentially affecting the evaluation of efficacy 
 
PK analysis set: all randomized patients receiving exebacase with PK samples valid for exebacase 
assay 


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Sample Size: 
The study is designed to have sufficient power for the primary efficacy outcome in patients with MRSA 
(clinical outcome at Day 14 in the mITT analysis set) and the first two secondary efficacy outcomes 
(clinical outcome at Day 14 in the overall population in the mITT analysis set and 30-day all-cause 
mortality in the MRSA population in the mITT analysis set). Based on data from the Phase 2 study, 
(exebacase + SoCA group) 
(SoCA alone group) 30-day all-cause mortality rate 
2:1 randomization ratio, and a 2-sided alpha of 0.05, a total of 135 patients are required in the 
mITT analysis set in the MRSA population (90 and 45 patients in the exebacase + SoCA and 
SoCA alone groups, respectively) based on the log rank test. A total of 135 patients in the 
MRSA 
oups 
alone group, using a 2-sided alpha of 0.05, and a Fisher’s exact test. In the overall population 
(MRSA 
 size of 339 patients (226 and 113 patients 
in the exebacase + SoCA and SoCA alone groups, respectively) in the mITT analysis set provides 
 
exebacase + SoCA g
-sided alpha of 0.05 and 
a Fisher’s exact test. 
Table 4 
patients are in the overall population mITT analysis set, a total of 348 patients will be required. 
Table 4: 
Sample Size Calculations (2:1 Randomization Ratio, 2-sided Alpha=0.05) 
Primary Outcome
Clinical Responder Day 14
(MRSA Population)
Secondary Outcome
Clinical Responder Day 14 
(Overall Population)
Secondary Outcome
30-Day All-Cause Mortality
(MRSA Population) 
Exebacase + 
SoCA 
SoCA 
Alone
Exebacase + 
SoCA 
SoCA 
Alone
Exebacase + 
SoCA
SoCA 
Alone 
Outcome Rate
 
 
Power 
 
 
Sample Size
(mITT analysis set)
90
45 
226 
113
90
45
Efficacy: 
The primary efficacy outcome is clinical responder rate at Day 14 in patients with MRSA in the 
mITT analysis set. The number and percentage of patients classified as responder, failure, and 
indeterminate will be determined by treatment group. The clinical responder rate will be compared 
between the treatment groups using Fisher’s exact test. 
To control for the inflation of the overall type I error rate, a hierarchical testing procedure will be used. 
If statistical significance is declared for the primary efficacy outcome, testing will be done for the 
secondary efficacy outcomes in the order listed below. Testing will proceed to the next secondary 
outcome only if statistical significance (2-sided alpha=0.05) is declared for the preceding secondary 
outcome being tested. 
 
Clinical responder rate at Day 14 in the overall population (MRSA and MSSA) in the mITT analysis 
set. The number and percentage of patients classified as responder, failure, and indeterminate will be 
determined by treatment group. The clinical responder rate will be compared between the treatment 
groups using Fisher’s exact test. 


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30-day survival in the MRSA population in the mITT analysis set. Time to death through Day 30 
will be analyzed using the Kaplan-Meier method. Differences between treatment groups will be 
determined using the log-rank test. 
 
Clinical responder rate at Day 60 in the MRSA population in the mITT analysis set. The number and 
percentage of patients classified as responder, failure, and indeterminate will be determined by 
treatment group. The clinical responder rate will be compared between the treatment groups using 
Fisher’s exact test. 
 
Clinical responder rate at Day 60 in the overall population (MRSA and MSSA) in the mITT analysis 
set. The number and percentage of patients classified as responder, failure, and indeterminate will be 
determined by treatment group. The clinical responder rate will be compared between the treatment 
groups using Fisher’s exact test. 
Analyses of other secondary and additional efficacy outcomes will be conducted to support the findings 
of the primary efficacy outcome and secondary efficacy outcomes in the hierarchical testing procedure. 
Clinical response at Day 14, Day 30 and Day 60 and survival through Day 60 will be evaluated in the 
MSSA population (mITT analysis set) as an additional efficacy analysis. 
Analyses of the primary efficacy outcome and key secondary efficacy outcomes will also be conducted 
in the PP analysis set. 
Safety: 
Safety will be evaluated by presenting summaries of treatment-emergent AEs (TEAEs), clinical 
laboratory evaluations (biochemistry, hematology, and coagulation), vital signs (blood pressure, 
respiratory rate, heart rate, and temperature), and ECG parameters. A TEAE is one that occurs on or 
after the administration of study drug through the Day 60 visit (Day 60 ± 7 days). 
Adverse events will be coded using the Medical Dictionary of Regulatory Activities (MedDRA). 
An overall summary of AEs will be provided by treatment group. The incidence of TEAEs will be 
presented by system organ class (SOC) and preferred term (PT) through Day 7 and Day 60, by SOC, 
PT and relationship to study drug, and by SOC, PT and severity. Serious adverse events, SAEs with an 
outcome of death, and TEAEs that lead to discontinuation of the study drug will also be presented by 
SOC and PT. Descriptive statistics for clinical laboratory results, vital signs, and ECG parameters, 
including change from baseline, will be presented by timepoint collected and for the overall most 
abnormal post-baseline value (clinical laboratory results and vital signs only). Incidences of potentially 
clinically significant clinical laboratory results, vital signs, and ECG parameters, as defined in the SAP, 
will also be summarized by timepoint collected and the overall most abnormal post-baseline value 
(clinical laboratory results and vital signs only). Urinalysis results will be presented in a listing. 
Interim Analysis: 
Interim analyses of safety data (unblinded) will be provided to the DSMB throughout the study as 
defined in the DSMB charter. A futility analysis of the primary efficacy outcome in the MRSA 
in the MRSA 
population in the mITT analysis set will also be reviewed by the DSMB. The futility analysis will be 
based on conditional power and the threshold for stopping the study due to futility will be provided in 
the SAP and DSMB charter. The futility boundary is non-binding. 
Immunogenicity: 
ADA results will be defined as positive and negative. ADA-positive samples will be further classified as 
neutralizing or non-neutralizing. Baseline and Day 30-60 ADA results will be summarized by result and 
in a shift table. For ADA positive patients, the number and percentage with neutralizing or 


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non-neutralizing ADA will be provided. The number and percentage of patients who had treatment-
emergent ADA (defined as ADA-negative at baseline and ADA-positive at Day 30-60) will be 
summarized. The number and percentage of patients who had treatment-boosted ADA 
(defined as increased ADA titers in patients who were positive at baseline) will be summarized. 
TEAEs by baseline ADA result and clinical outcome at Day 14 by baseline ADA result will also be 
summarized. IgE results will be presented in a listing. 
Health Resource Utilization: 
The following with be evaluated in the exebacase + SoCA and SoCA alone treatment groups 
(mITT analysis set) for patients enrolled in the US for both the overall population and the MRSA 
population: in-hospital mortality, hospital length-of-stay and ICU length-of-stay (post-study drug 
administration), discharge location, outpatient SoCA administration by outpatient facility or home health 
care, 30-day all-cause readmission, 30-day readmission for S. aureus BSI/IE or complication of 
S. aureus BSI/IE (e.g., metastatic foci, septic emboli), and insurance type. 
Pharmacokinetics: 
All PK data, dosing, and covariate information collected in this study will be pooled with the data 
collected from the prior studies to update the previously developed population PK model. 
The population PK analysis will be described in a separate SAP. 
The relationship between PK parameters of exebacase (area under the plasma concentration versus time 
curve [AUC] and maximum plasma drug concentration [Cmax]), derivative parameters 
(such as parameter over minimum inhibitory concentration [MIC]), and the clinical outcome and ADA 
will be explored. The relationship between PK parameters and most frequent or most clinically 
significant AEs may be explored. 




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4.
SCHEDULE OF ASSESSMENTS
Study Procedures (Protocol Section) 
Screening1 
Day 1: Dosing1,2 
Day 7 (±1)2 
Day 14 (±1)2 
Day 30 (±4)2 
Day 60 (±7)2 
Informed consent/assent (12.1) 
X 
Inclusion/exclusion criteria (12.2) 
X 
SOFA/APACHE II (12.2.2/12.2.3)3 
X 
Medical history (12.4)4 
X 
Diagnosis (12.5) 
X 
X 
Risk factors (12.6) 
X 
Source of infection (12.7)5  
X 
X 
X 
X 
X 
Safety labs (12.8.1, 12.8.2.1)6 
X 
24 hr post-dose (Day 2) 
X (adults) 
X 
Pregnancy test (12.8.1, 12.8.2.2)7 
X 
X (between Day 30 to Day 60) 
ADA (12.8.2.3)8 
X 
X (between Day 30 to Day 60) 
IgE (12.8.2.3)9 
X 
PK (12.8.2.4)10
X
X
Blood cultures (12.8.2.5)11
X
Daily until 2 consecutive negatives on 2 different days post-dose & as clinically indicated
Other cultures (12.8.2.6)12
To determine source of infection (at screening or within 1 week)5, evaluate metastatic foci15, & as clinically indicated thru Day 60
12-Lead ECG (12.9)
X
X
Physical exam (12.10)13
X
X
X
X
X
Weight and height (12.10)
X
Vital signs (12.11)14
X
30-40 min post-study drug start14
X
X
X
X
Metastatic foci/septic emboli (12.12)15
X
X
X
X
X
X
Signs/symptoms of infection (12.13)16
X
X
X
X
X
X
Echocardiography (12.14)17
±3 days of rand (before rand preferred/required for some patients); and as clinically indicated17
Randomization (12.3)1,18
X
Remove infected IV catheter (12.15)19
Within 72 hr after randomization
Ultrasound of CVC site (12.16)20
Within 48 hr after randomization
Vital status (12.17)21
X
X
X
Clinical outcome (12.18)
X
X
X
Microbiological outcome (12.19)
Days 4 & 7
Health resource utilization (12.20)
Through Day 60 visit
Study drug dosing (9.4.1, 13)22
X
SoCA dosing (9.4.2)
Approximately 14 to 56 days
Medications (13.6, 13.7)
Prior/concomitant medications from 28 days before randomization through Day 60 visit
Adverse event assessment (14)
From time of consent/assent through Day 60 visit


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Abbreviations and Footnotes: 
Abbreviations: ADA=anti-drug antibody; APACHE II = Acute Physiology and Chronic Health Evaluation II; AV= arteriovenous; BSI=bloodstream infection; CVC=central venous catheter; 
ECG=electrocardiogram; eCRF=electronic case report form; hr=hour; IE=infective endocarditis; IgE=immunoglobulin E; IRT=interactive response technology; IV=intravenous; 
MRSA=methicillin-resistant S. aureus; MSSA=methicillin-sensitive S. aureus; PK=pharmacokinetic; rand=randomization; (q)SOFA=(quick) sequential (sepsis-related) organ failure 
assessment; SoCA=standard-of-care antibiotics; TEE=transesophageal echocardiogram; TTE=transthoracic echocardiogram. 
1. 
Patients will be randomized as soon as possible after confirmation of study eligibility. To provide flexibility, screening assessments may be performed within approximately 24 hours 
before randomization, unless otherwise noted. Study drug dosing will occur as soon as possible after randomization. 
2. 
When a specific “Day” is noted (e.g., Day 14), the day is relative to exebacase/placebo administration (Day 1). Visit windows are as follows: Day 7 (±1 day), Day 14 (±1 day), Day 30 
(±4 days), Day 60 (±7 days). 
3. 
During screening, the qSOFA score will be determined for all patients (Section 12.2.2). In patients that have at least 2 criteria of qSOFA, a SOFA score will be performed 
(Section 23.1) to determine whether the patient has sepsis and/or septic shock per the inclusion criteria and the diagnosis definition. Baseline APACHE II score will be calculated for all 
patients (Sections 12.2.3 and 23.2). Patients with APACHE II score of >30 are excluded from the study. 
4. 
Medical history for 1 year prior to screening, including relevant previous and current medical diagnoses and major surgical procedures. 
5. 
All efforts will be made to determine the source of S. aureus BSI/IE (e.g., full physical examination, imaging as needed, cultures of other infected body sites or catheters that may be 
considered the source) preferably during screening or within 1 week after randomization. The resolution of the source of S. aureus BSI/IE will be evaluated at Days 7, 14, 30, and 60. 
6. 
Local Laboratory: Limited laboratory tests may need to be performed by the site’s local laboratory during screening for study eligibility determination, and to determine the dose of 
study drug (based on CrCl using ideal body weight and serum creatinine result obtained as close to the start of study drug dosing as possible (but not more than approximately 24 hours 
before the start of study drug dosing) (Section 9.4.1). The specific laboratory tests that are required to be available locally are described in Section 12.8.1. 
Central Laboratory: Blood and urine samples for safety laboratory tests (biochemistry, hematology, coagulation, and urinalysis) will be collected during screening (for patients who 
meet eligibility criteria and are expected to be randomized) or after randomization and before dosing, approximately 24 hours after study drug administration (Day 2), on Day 14 for 
adults*, and Day 30; samples will be sent to a central laboratory for testing. The collection of Day 14 samples is not required for adolescents. Results from local clinical laboratory 
testing completed within the Day 14 visit window should be entered into the eCRF if available and feasible. For all patients, if a blood or urine sample for safety laboratory testing by 
the central laboratory is not able to be obtained at a given timepoint/visit, the local laboratory results may be entered into the eCRF for that timepoint/visit, if feasible. If a blood or urine 
sample for safety laboratory testing by the central laboratory or local laboratory results are not able to be obtained at the Day 30 visit, samples may be collected on any day between the 
Day 30 and 60 visit windows (i.e., between Day 26 and Day 67) when collecting the blood sample(s) for exebacase-specific ADA and pregnancy test (if applicable). For adolescents, 
the results of local clinical laboratory testing during the screening window and at all other timepoints corresponding to the protocol can substitute for central safety laboratory tests and 
will be entered into the eCRF; samples for ADA and IgE must be collected at the timepoints specified in the protocol and sent to the central laboratory. 
7.
For females of childbearing potential only: Urine or serum pregnancy test performed locally during screening for eligibility determination; blood samples for serum pregnancy test will 
be collected during screening (for patients who meet eligibility criteria and are expected to be randomized) and between the Day 30 and 60 visits and samples are sent to the central 
laboratory for testing. 
8.
Blood samples for exebacase-specific ADA will be collected during screening (for patients who meet eligibility criteria and are expected to be randomized) or after randomization and 
before dosing and on any day between the Day 30 and Day 60 visit windows (i.e., between Day 26 and Day 67); samples are sent to the central laboratory. 
9.
Blood samples for exebacase-specific IgE testing will be collected during screening (for patients who meet eligibility criteria and are expected to be randomized) or after randomization 
and before dosing and retained at the site. If a patient has clinical signs or symptoms of a potential allergic reaction that may be attributed to study drug (Section 9.4.1.1), a blood 
sample for exebacase-specific IgE will be collected as soon as possible within 2 hours of the event, if feasible, and both this sample and the IgE sample at screening will be sent to a 
central laboratory for testing.
10.
All patients will be assigned to a PK sampling scheme and blood samples will be collected at 3 timepoints as follows: PK Group 1: pre-dose (collected during screening for patients 
who meet eligibility criteria and are expected to be randomized or after randomization and before dosing), within 5 to 25 minutes after the end of infusion, and between 3 to 5 hours 
after the end of infusion. PK Group 2: pre-dose (collected during screening for patients who meet eligibility criteria and are expected to be randomized or after randomization and 
before dosing), within 5 to 25 minutes after the end of infusion, and between 8 to 12 hours after the end of infusion.


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11. 
Blood cultures will be collected from a peripheral venipuncture site when possible. Results of all blood cultures performed (from the initial S. aureus-positive blood culture collected 
pre-study through the Day 60 visit) will be entered in the eCRF (whether positive or negative for S. aureus). All S. aureus isolates (from the initial S. aureus-positive blood culture 
collected pre-study through the Day 60 visit) should be sent to the central lab. Blood cultures will be performed as follows: 
•
Qualifying blood culture: The “qualifying” blood culture from specimens collected within approximately 72 hours before randomization (per the inclusion criteria in Section 10.1) 
will be recorded in the eCRF and the S. aureus isolate should be sent to the central laboratory. The site will make all efforts to work with the local microbiology laboratory to 
ensure that, wherever possible, the S. aureus isolate from the qualifying blood culture is retained and sent to the central laboratory. Note: Since susceptibility of the S. aureus 
isolate is a stratification factor (Section 12.3), the site will make all efforts to work with the local microbiology laboratory to ensure that susceptibility results from blood cultures 
are obtained before randomization to enable stratification by MRSA or MSSA. If a blood culture was performed for the current S. aureus infection prior to the qualifying blood 
culture, susceptibility results from the prior blood culture may be used. If the patient has a concomitant S. aureus infection at another body site from which susceptibility results are 
available (e.g., skin, abscess), the susceptibility results from this other culture may be used. If the patient is known to be colonized with MRSA, MRSA may be selected for the 
stratification factor. 
• 
Screening: One aerobic blood culture will be collected during screening (or after randomization and before dosing). 
• 
Daily: One aerobic blood culture will be collected daily during the study until 2 consecutive negative cultures followed out to negative for at least 48 hours on 2 different days are 
obtained after exebacase/placebo administration. Note: blood cultures may be collected every other day for adolescents. 
• 
Additional blood cultures will be performed as clinically indicated.
12. 
“Other” (non-blood) cultures, which are cultures from catheter tips or body sites or body fluids other than blood, should be performed to determine the source of S. aureus BSI/IE 
(Section 12.7) and evaluate metastatic foci (Section 12.12), and as clinically indicated during the study. Results of all other (non-blood) cultures (whether positive or negative for 
S. aureus) collected pre-study through the Day 60 visit will be recorded in the eCRF. S. aureus isolates from all other (non-blood) cultures collected pre-study through the Day 60 visit 
should be sent to the central laboratory. 
13.
Complete physical examinations and review of body systems will be performed during screening and at the Days 7, 14, 30, and 60 visits. Additional physical examinations will be 
performed as clinically indicated. The physical examinations will include a close evaluation for any new areas of pain or other signs or symptoms of metastatic foci of infection or 
septic emboli; new signs or symptoms (e.g., pain, shortness of breath) will trigger diagnostic testing for metastatic foci or septic emboli (e.g., imaging, aspiration, and/or cultures). 
The physical examination will also include an evaluation of the primary source of S. aureus BSI/IE. Every effort should be made to perform study visits “in person” by the 
Investigator/Sub-Investigator (or other delegated medically qualified person listed on the FDA Form 1572 and trained on the protocol). If it is not feasible to evaluate the patient “in 
person” at study visits, telephone/telehealth visits may be performed under the circumstances described in Section 11.5.1. A physical examination is not required for visits performed 
remotely by telephone/telehealth; however, a complete medical review of body systems will be performed during the telephone/telehealth visit and medical record data may be used to 
supplement these visits (e.g., sign and symptom evaluation and physical exam findings) to assess the patient’s clinical status, primary source of infection, and the status or any 
pre-existing or presence of new metastatic foci. In rare instances in which it is not feasible to conduct study visits “in person” or by telephone/telehealth, medical records alone may be 
used for physical examinations after contacting the Medical Monitor or designee as described in Section 12.10. 
14.
Vital signs (blood pressure, respiratory rate, heart rate, and temperature) will be performed during screening, approximately 30 to 40 minutes after the start of exebacase/placebo 
infusion and as clinically indicated during the infusion and at the Day 7, 14, 30, and 60 visits for visits performed “in person” or may be obtained via the study-specific mobile health 
service (Section 11.5.1). If it is not possible to perform vital signs “in person” or via the study-specific mobile health service, medical records may be used as described in 
Section 12.11. At screening, if more than one measurement is taken within the approximately 24 hours before randomization, the most abnormal value is recorded in the eCRF. 
At Days 7, 14, 30, and 60, if more than one measurement is taken on a given day, the most abnormal value is recorded in the eCRF. 
15.
Patients will be evaluated for existing and new metastatic foci (e.g., deep tissue abscess, septic arthritis, etc.) and septic emboli (e.g., to the brain, lung, etc.) during screening and at the 
Day 7, 14, 30, and 60 visits. Diagnostic testing will be performed as clinically indicated to assess metastatic foci or septic emboli (e.g., imaging, aspiration, and/or cultures). 
For non-blood sites of S. aureus infection that are present at screening, the Investigator/Sub-Investigator (or other delegated medically qualified person listed on the FDA Form 1572 
and trained on the protocol) will determine whether this is the source of S. aureus BSI/IE (Section 12.7) or a metastatic focus (Section 12.12). The Investigator/Sub-Investigator 
(or other delegated medically qualified person listed on the FDA Form 1572 and trained on the protocol) will consider the development of new metastatic foci or septic emboli, and 
timing for metastatic foci (i.e., before or after Day 7), when evaluating clinical outcome (Section 12.18). Metastatic foci identified through Day 7 are considered part of the patient’s 


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baseline S. aureus BSI/IE; new metastatic foci identified after Day 7 or new septic emboli after study drug dosing are considered complications of S. aureus BSI/IE for the purpose of 
assessing clinical outcome. New septic emboli are defined as an acute presentation of septic emboli after dosing and are a reason for failure for clinical outcome; septic emboli that are 
incidentally found on imaging are considered part of the patient’s baseline S. aureus BSI/IE if found before Day 7. Every effort should be made to perform study visits “in person” by 
the Investigator/Sub-Investigator (or other delegated medically qualified person listed on the FDA Form 1572 and trained on the protocol), and preferably by the same person at all 
visits. If it is not feasible to evaluate the patient “in person” at study visits, telephone/telehealth visits may be performed under the circumstances described in Section 11.5.1. Metastatic 
foci/septic emboli should be evaluated during the telephone/telehealth visit by detailed questioning and a complete review of systems. Medical records may be used to supplement the 
telehealth/telephone evaluation. In rare instances in which it is not feasible to conduct study visits “in person” or by telephone/telehealth, medical records alone may be used alone after 
contacting the Medical Monitor or designee as described in Section 12.12. 
16. 
Signs and symptoms attributable to S. aureus BSI/IE will be evaluated during screening and at the Day 7, 14, 30, and 60 visits. Additionally, if SoCA is changed after study drug dosing 
due to lack of clinical response, signs and symptoms will be assessed on the day of the SoCA change and entered into the eCRF. The Investigator/Sub-Investigator (or other delegated 
medically qualified person listed on the 1572 and trained on the protocol) will assess whether each sign or symptom is attributable to S. aureus BSI/IE or provide an alternative 
attribution and will assess the symptom severity per the definitions in Table 9. Select symptoms will also be evaluated at pre-BSI/IE, which is the patient’s “usual state of health” before 
the BSI/IE started. Specific symptoms attributable to S. aureus will be assessed as absent, mild, moderate, and severe according to the definitions in Table 9. Sweating and chill/rigors 
and signs attributable to S. aureus will be assessed as present or absent. The Investigator/Sub-Investigator (or other delegated medically qualified person listed on the FDA Form 1572 
and trained on the protocol) will assess the severity (see Section 12.12) and consider the progression of attributable signs and symptoms when evaluating clinical outcome 
(Section 12.18). Some symptoms may be considered ‘medically not evaluable’ due to certain medical circumstances or treatments, such as a patient in a medically induced coma or 
after surgery to remove a metastatic focus. Every effort should be made to perform study visits “in person” by the Investigator/Sub-Investigator (or other delegated medically qualified 
person listed on the FDA Form 1572 and trained on the protocol), and preferably by the same person at all visits. If it is not feasible to evaluate the patient “in person” at study visits, 
telephone/telehealth visits may be performed under the circumstances described in Section 11.5.1. Signs and symptoms should be evaluated during the telephone/telehealth visits by 
detailed questioning and a complete medical review of systems. Medical records may be used to supplement the telehealth/telephone evaluation of signs and symptoms. In rare 
instances in which it is not feasible to conduct study visits “in person” or by telephone/telehealth, medical records may be used alone after contacting the Medical Monitor or designee 
as described in Section 12.13. 
17.
Images from all echocardiograms from the initial echocardiogram performed to evaluate the current infection through the Day 60 visit will be provided to the central echocardiography 
laboratory, as directed by the Sponsor, and recorded in the eCRF. The results of any prior echocardiograms that are part of the patient’s medical history (i.e., from the 1 year prior to 
screening) will be recorded in the eCRF. Echocardiograms will be performed as follows: 
• 
 made to perform the TTE or TEE before 
randomization. 
Where possible, a TEE will be performed [Baddour 2015, Habib 2010, Habib 2015] and is recommended in patients with BMI >30 kg/m2; the TEE may be performed within 
3 days before or after randomization unless the TEE is performed due to clinical suspicion of L-IE (see below). 
In patients that have clinical findings suggestive of L-IE (new murmur, worsening cardiac function, and/or peripheral or central nervous embolic phenomenon), a TEE will be 
performed before randomization to rule out mitral and/or aortic valve vegetation(s) or the patient will be excluded from the study per exclusion criterion #2 (Section 10.2). 
In cases where there is an alternative cause of new heart failure or cerebral emboli, a patient with a negative TTE for L-IE may be discussed with the Medical Monitor for 
potential enrollment. 
S. aureus
will be performed before randomization to rule out 
L-IE. A TTE may be performed with permission of the Medical Monitor. If this echocardiogram is not performed or L-IE is not ruled out by this echocardiogram, the patient 
should not be randomized. 
•
In adolescents (12 to <18 years of age), echocardiograms (TTE or TEE) will be performed as clinically indicated taking into consideration risk factors for endocarditis 
(e.g., structurally abnormal heart [including pacemakers]), clinical features suggestive of endocarditis (e.g., new murmur), or persistent bacteremia [McMullan 2020], described in 
Section 12.14. 


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• 
If the patient had an echocardiogram performed prior to the study that was intended to evaluate the current infection, it will be sent to the central echocardiography laboratory, as 
directed by the Sponsor, and an additional TTE or TEE is not required unless as indicated above but 
randomization. 
• 
Follow-up echocardiograms will be performed as clinically indicated. 
18. 
Patients will be randomized via the IRT system. The randomization will be stratified by poorly controlled diabetes (yes or no) as defined as a 
90 days before randomization and susceptibility of the S. aureus isolate (MRSA, MSSA, or unknown). A HgA1C test is not required for patients with no medical history of diabetes and 
no suspicion of diabetes during the screening period. These patients will be stratified to “no” for poorly controlled diabetes. A HgA1C test should be performed in patients with medical 
history of diabetes or suspicion of diabetes during screening for whom a HgA1C test result within the approximately 90 days prior to randomization is not available. If a HgA1C is 
unavailable and testing cannot be performed for these patients prior to randomization, contact the Medical Monitor to determine how the patient should be stratified based on available 
clinical information. All efforts will be made to obtain susceptibility results before randomization to enable stratification by MRSA or MSSA (see Section 12.8.2.5). Creatinine 
clearance value will be entered into the IRT system and the system will provide the dose of study drug based on the CrCl value (Section 9.4.1). The Cockcroft-Gault formula for 
2 and serum creatinine result obtained locally is provided in Section 12.8.1.1. The IRT system will also provide 
the PK group (Section 12.8.2.4). 
19.
If not already done prior to the study, intravenous catheters known or suspected to be infected must be removed, and as clinically needed replaced, preferably at a different site, as soon 
as possible within approximately 72 hours after randomization. Other hemodialysis access types (i.e., AV fistulas or AV grafts) and surgically managed infection sources that are 
known or suspected to be infected will be evaluated for removal/replacement, if clinically feasible. If removal/debridement is not feasible based on standard medical practice, the patient 
should be discussed with the Medical Monitor for potential enrollment. 
20. 
In patients with CVCs, ultrasounds to evaluate clots in the vein should be performed within approximately 48 hours after randomization, unless the clot in the vein has been detected 
within this timeframe via other method (e.g., imaging such as CT scan or MRI or direct visualization during surgery). 
21.
Vital status (whether the patient is alive or dead, or last known date alive if vital status is unknown) will be obtained at Days 14, 30, and 60 for all patients, including patients that 
discontinue the study or withdraw consent/assent (as described in the informed consent/assent form). Vital status will be determined using available sources (e.g., the patient, patient’s 
contacts, hospital and other medical records, and public records, such as social media, obituaries, social security death index), as described in the informed consent/assent form and 
FDA guidance (see Section 12.17). 
22. 
Study drug (exebacase or placebo) dosing will occur as soon as possible after randomization. The dose is based on CrCl as described in Section 9.4.1. Study drug will be infused over 
approximately 2 hours as described in the Pharmacy Manual. Patients must be observed during study drug infusion by a medically qualified person from the clinical care team or 
research team with patient care experience (Section 9.4.1.1). 


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5. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1.
CONTACT INFORMATION................................................................................... 7
2. 
SYNOPSIS............................................................................................................... 8
3. 
STUDY SCHEMATIC ........................................................................................... 28
4. 
SCHEDULE OF ASSESSMENTS ......................................................................... 29
5. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES.............. 34
6. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................... 40
7. 
INTRODUCTION .................................................................................................. 43
7.1.
Background ............................................................................................................ 43
7.1.1. 
Summary................................................................................................................ 43
7.1.2.
Overview of S. aureus Bloodstream Infections........................................................ 44
7.1.3. 
Current Treatments and Drug Resistance ................................................................ 45
7.1.4. 
Exebacase for the Treatment of S. aureus ............................................................... 46
7.1.5. 
Preclinical Studies .................................................................................................. 47
7.1.6. 
Clinical Studies....................................................................................................... 50
7.1.7. 
Compassionate Use/Expanded Access .................................................................... 58
7.2.
Benefits and Risks .................................................................................................. 59
7.3.
Population to be Studied......................................................................................... 60
7.4.
Rationale for Route and Dose ................................................................................. 60
7.5.
Rationale for Inclusion of Adolescent Patients ........................................................ 62
7.6.
Rationale for Inclusion of Patients with Renal Impairment ...................................... 63
7.7.
Statement of Compliance........................................................................................ 64
8. 
TRIAL OBJECTIVES AND PURPOSE................................................................. 64
8.1.
Primary Objectives ................................................................................................. 64
8.2.
Secondary Objectives ............................................................................................. 64
8.3.
Additional Objectives............................................................................................. 65
9. 
INVESTIGATIONAL PLAN ................................................................................. 65
9.1.
Overall Study Design.............................................................................................. 65
9.2.
Number of Patients................................................................................................. 70
9.3.
Treatment Assignment............................................................................................ 70


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9.4.
Dosing and Dose Adjustment Criteria..................................................................... 71
9.4.1. 
Study Drug ............................................................................................................. 71
9.4.1.1. 
Observation During Study Drug for Potential Allergic 
Reactions/Anaphylaxis ........................................................................................... 71
9.4.2. 
Standard-of-Care Antibiotics (SoCA) ..................................................................... 72
10. 
SELECTION AND DISCONTINUATION OF PATIENTS ................................... 74
10.1.
Inclusion Criteria.................................................................................................... 74
10.2.
Exclusion Criteria................................................................................................... 77
10.3.
Discontinuation Criteria.......................................................................................... 80
10.3.1. 
Discontinuation of Study Drug ............................................................................... 80
10.3.2. 
Discontinuation from the Study .............................................................................. 81
10.4.
Replacement of Patients.......................................................................................... 81
10.5.
Rescreening of Patients........................................................................................... 81
10.6.
Criteria for Study Termination................................................................................ 82
11. 
SCHEDULE OF OBSERVATIONS....................................................................... 82
11.1.
Study Duration ....................................................................................................... 82
11.2.
Visit Windows ........................................................................................................ 82
11.3.
Screening................................................................................................................ 82
11.4.
Day 1: Study Drug Dosing...................................................................................... 85
11.5.
Days 7, 14, 30, 60, and Daily Assessments ............................................................. 89
11.5.1. 
Visits Performed Remotely by Telephone/Telehealth, Use of Medical 
Records, and Use of Mobile Health Services........................................................... 92
12. 
STUDY ASSESSMENTS....................................................................................... 94
12.1.
Informed Consent/Assent........................................................................................ 94
12.2.
Inclusion/Exclusion Criteria Review....................................................................... 94
12.2.1. 
Contraception Requirements ................................................................................... 94
12.2.2. 
Quick SOFA and SOFA Scores .............................................................................. 95
12.2.3. 
APACHE II Score .................................................................................................. 95
12.3.
Randomization........................................................................................................ 95
12.4.
Medical History...................................................................................................... 96
12.5.
Diagnosis................................................................................................................ 96
12.6.
Risk Factors............................................................................................................ 99
12.7.
Source of S. aureus Infection.................................................................................. 99


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12.8.
Laboratory Tests..................................................................................................... 99
12.8.1. 
Laboratory Tests Performed by the Local Laboratory ............................................. 99
12.8.1.1. 
Estimated Creatinine Clearance by Cockcroft-Gault ............................................. 101
12.8.2. 
Laboratory Sample Collection for Sending to Central Laboratory ......................... 101
12.8.2.1. 
Samples for Safety Laboratory Testing ................................................................. 101
12.8.2.2. 
Samples for Pregnancy Testing ............................................................................. 102
12.8.2.3. 
Samples for Immunogenicity................................................................................ 102
12.8.2.4. 
Samples for Pharmacokinetics .............................................................................. 102
12.8.2.5. 
Blood Cultures ...................................................................................................... 103
12.8.2.6. 
Other (Non-Blood) Cultures ................................................................................. 105
12.8.3. 
Laboratory Tests Performed by the Central Laboratory(ies) .................................. 105
12.9.
12-Lead Electrocardiogram................................................................................... 106
12.10. 
Physical Examination and Weight/Height............................................................. 107
12.11. 
Vital Signs............................................................................................................ 108
12.12. 
Metastatic Foci and Septic Emboli........................................................................ 108
12.13. 
Signs and Symptoms of Infection.......................................................................... 109
12.14. 
Echocardiography ................................................................................................. 113
12.15. 
Management of IV Catheters ................................................................................ 114
12.16. 
Ultrasounds of Central Venous Catheter Site ........................................................ 114
12.17. 
Vital Status........................................................................................................... 114
12.18. 
Clinical Outcome .................................................................................................. 115
12.19. 
Microbiological Outcome ..................................................................................... 117
12.20. 
Health Resource Utilization .................................................................................. 117
12.21. 
Discharge Summaries ........................................................................................... 118
12.22. 
DSMB .................................................................................................................. 118
12.23. 
Adjudication Committee....................................................................................... 118
13. 
TREATMENT OF PATIENTS............................................................................. 118
13.1.
Description of Study Drugs ................................................................................... 118
13.2.
Dosage and Dose Regimen ................................................................................... 119
13.3.
Study Drug Preparation and Administration.......................................................... 119
13.4.
Storage/Stability................................................................................................... 120
13.5.
Drug Accountability ............................................................................................. 120
13.6.
Prior and Concomitant Medications...................................................................... 120


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13.7.
Prohibited Medications ......................................................................................... 121
13.8.
Treatment Compliance.......................................................................................... 121
13.9.
Randomization and Blinding................................................................................. 122
14. 
ADVERSE AND SERIOUS ADVERSE EVENTS............................................... 123
14.1.
Timeframe for Collecting Adverse Events ............................................................ 123
14.2.
Reporting of Serious Adverse Events.................................................................... 123
14.3.
Definition of Adverse Event ................................................................................. 124
14.4.
Definition of Serious Adverse Event..................................................................... 124
14.5.
Study Endpoints ................................................................................................... 125
14.6.
Pre-Existing Conditions ........................................................................................ 125
14.7.
Relationship to Study Drug ................................................................................... 126
14.8.
Grading of Adverse Events................................................................................... 126
14.9.
Adverse Events of Clinical Interest....................................................................... 127
14.10. 
Overdose .............................................................................................................. 127
14.11. 
Pregnancy............................................................................................................. 127
14.12. 
AE and SAE Follow-up ........................................................................................ 127
14.13. 
Regulatory Reporting Requirements for SAEs...................................................... 128
14.14. 
Expectedness Determination ................................................................................. 128
15. 
STATISTICS........................................................................................................ 129
15.1.
Populations ........................................................................................................... 129
15.2.
Analysis Sets ........................................................................................................ 129
15.3.
Sample Size .......................................................................................................... 129
15.4.
Patient Population and Characteristics .................................................................. 130
15.5.
Efficacy Analyses................................................................................................. 131
15.5.1. 
Primary Efficacy Analyses.................................................................................... 131
15.5.2. 
Secondary Efficacy Analyses ................................................................................ 132
15.5.3. 
Additional Efficacy Analyses................................................................................ 134
15.6.
Safety Analyses .................................................................................................... 134
15.7.
Interim Analysis ................................................................................................... 135
15.8.
Immunogenicity Analysis ..................................................................................... 135
15.9.
Health Resource Utilization Analysis.................................................................... 136
15.10. 
Pharmacokinetic Analysis..................................................................................... 136
15.11. 
Handling of Missing Data..................................................................................... 137


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16.
DATA MANAGEMENT .........................................................................................137
16.1.
Data Collection .........................................................................................................137
16.2.
Access to Source Documents ....................................................................................137
17.
ADMINISTRATIVE ................................................................................................138
17.1.
Statement of Good Clinical Practices .......................................................................138
17.2.
Protocol Adherence ..................................................................................................138
17.3.
Study Termination ....................................................................................................138
18.
QUALITY CONTROL AND ASSURANCE ..........................................................138
18.1.
Sponsor Audits ..........................................................................................................138
18.2.
Inspection by Regulatory Authorities .......................................................................139
19.
ETHICS ....................................................................................................................139
19.1.
Institutional Review Board or Independent Ethics Committee ................................139
19.2.
Informed Consent/Assent .........................................................................................140
19.3.
Data Privacy ..............................................................................................................140
20.
RECORD KEEPING/RETENTION OF RECORDS ...............................................141
20.1.
Confidentiality ..........................................................................................................141
21.
USE OF STUDY RESULTS ....................................................................................142
22.
LIST OF REFERENCES ..........................................................................................142
23.
APPENDICES ..........................................................................................................147
23.1.
Appendix 1: Sequential (Sepsis-Related) Organ Failure Assessment Score 
(SOFA) .....................................................................................................................147
23.2.
Appendix 2: APACHE II Score ................................................................................148
23.3.
Appendix 3: Oxygen Conversion Tables ..................................................................150
23.4.
Appendix 4: Common Categories of Immunosuppressive and 
Myelosuppressive Agents .........................................................................................151


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LIST OF TABLES 
Table 1: 
Contact Information.................................................................................................. 7
Table 2:
Abbreviations and Specialist Terms........................................................................ 40
Table 3: 
Phase 1 Study: Pharmacokinetic Parameters for Exebacase ..................................... 51
Table 4: 
Phase 2 Study: Clinical Outcome at Day 14 Assessed by Adjudication 
Committee by MRSA and MSSA Subgroup (mITT Population) ............................. 53
Table 5: 
Phase 2 Study: Clinical Responders at Day 14 Assessed by Adjudication 
Committee by Diagnosis (mITT Population)........................................................... 54
Table 6: 
Phase 2 Study: Overview of Adverse Events (Safety Population)............................ 57
Table 7: 
Clinical Criteria for Diagnosing Anaphylaxis.......................................................... 72
Table 8: 
Diagnosis Definitions ............................................................................................. 97
Table 9: 
Severity Definitions for Symptoms Attributable to S. aureus ................................ 111
Table 10: Clinical Outcome Definitions at Days 14, 30, and 60 ............................................ 116
Table 11: Microbiological Outcome Definitions at Days 4 and 7.......................................... 117
Table 12: Description of Study Drugs (Exebacase and Placebo) ........................................... 119
Table 13: Sample Size Calculations (2:1 Randomization Ratio, 2-sided Alpha=0.05) ........... 130
Table 14: Oxygen Saturation (SpO2) to Partial Pressure of Oxygen (PaO2) ......................... 150
Table 15: Estimation of FiO2 ............................................................................................... 150


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6. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms 
Abbreviation or 
Specialist Term 
Explanation 
ABG 
arterial blood gas 
AC 
Adjudication Committee 
ADA 
anti-drug antibody 
AE 
adverse event 
AECI 
adverse event of clinical interest 
ANSM
Agence Nationale de Sécurité du Médicament et des Produits de Santé
APACHE II 
Acute Physiology and Chronic Health Evaluation II 
ATU 
Autorisation Temporaire D'utilisation 
AUC 
area under the plasma concentration versus time curve 
AUC0-24
area under the plasma concentration versus time curve from time 0 to 24 hours 
AUC0-  
area under the plasma concentration versus time curve from time 0 to infinity 
AUC/MIC 
area under the plasma concentration versus time curve/minimum inhibitory 
concentration 
AV 
arteriovenous 
BAT
basophil activation test 
BMI 
body mass index 
BSI 
bloodstream infection 
CDC 
Centers for Disease Control 
CL 
clearance 
Cmax 
maximum plasma drug concentration 
CoNS 
coagulase negative Staphylococci 
COVID-19 
coronavirus disease 2019 
CVC 
central venous catheter 
DAIR 
Debridement, antibiotics, irrigation, and retention 
DSMB 
Data Safety Monitoring Board 
ECG
electrocardiogram 
eCRF 
electronic case report form 
EDC
electronic data capture 
EOT 
end-of-treatment with standard-of-care antibiotics 


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Abbreviation or 
Specialist Term 
Explanation 
ESRD 
end-stage renal disease 
EUA 
Emergency Use Authorization 
FDA
Food and Drug Administration 
FiO2 
fraction of inspired oxygen 
FSH 
follicle stimulating hormone
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice
HgA1C 
hemoglobin A1C 
HIV 
human immunodeficiency virus 
hVISA 
heterogeneous vancomycin-intermediate S. aureus 
ICD 
implantable cardioverter defibrillator 
ICH 
International Conference on Harmonization 
ICU 
intensive care unit 
IA 
intraarticular 
IE 
infective endocarditis 
IEC 
Independent Ethics Committee
IgE 
immunoglobulin E 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
L-IE 
left-sided infective endocarditis 
MedDRA 
Medical Dictionary of Regulatory Activities 
MIC 
minimum inhibitory concentration 
mITT 
microbiological intent-to-treat 
MRSA 
methicillin-resistant S. aureus 
MSSA 
methicillin-susceptible S. aureus 
NOAEL 
no observed adverse effect level 
NOEL 
no observed effect level 
PaO2 
partial pressure of oxygen 
PJI 
prosthetic joint infection 
PK 
pharmacokinetic(s) 
PK-PD 
pharmacokinetic-pharmacodynamic 


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Abbreviation or 
Specialist Term 
Explanation 
PP 
per protocol
PT 
preferred term 
qSOFA 
quick Sequential (sepsis-related) Organ Failure Assessment 
R-IE 
right-sided infective endocarditis 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SoCA 
standard-of-care antibiotics 
SOC 
system organ class 
SOFA 
Sequential (sepsis-related) Organ Failure Assessment 
SpO2 
oxygen saturation 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TEE 
transesophageal echocardiogram 
t1/2
elimination half-life 
TK 
toxicokinetic 
Tmax
time to maximum plasma concentrations 
TOC
test-of-cure 
TTE 
transthoracic echocardiogram 
US 
United States 
Vz 
volume of distribution 
VISA 
vancomycin intermediate S. aureus 
VRSA 
vancomycin resistant S. aureus 
WBC 
white blood cell 
WHO 
World Health Organization 


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7. 
INTRODUCTION 
7.1. 
Background 
7.1.1.
Summary 
Exebacase, a direct lytic agent, is an entirely new treatment modality against Staphylococcus 
aureus. Exebacase is a recombinantly-produced, purified cell wall hydrolase enzyme that results 
in rapid bacteriolysis, potent biofilm eradication, synergy with antibiotics, low propensity for 
resistance, and the potential to suppress antibiotic resistance when used together with antibiotics 
[Schuch 2014, Schuch 2017]. Exebacase represents a first-in-field, first-in-class treatment with 
the potential to improve clinical outcome when used in addition to standard-of-care antibiotics 
(SoCA) to treat S. aureus bloodstream infections (BSI) including infective endocarditis (IE). 
In 2015, the United States (US) Food and Drug Administration (FDA) granted Fast Track 
designation for the development of an intravenous (IV) formulation of CF-301 (exebacase) to 
treat S. aureus bacteremia/endocarditis. In 2020, the FDA granted Breakthrough Therapy 
designation for exebacase in 2020 for the indication of treatment of methicillin-resistant 
S. aureus (MRSA) BSI (bacteremia), including right-sided endocarditis (R-IE), when used in 
addition to standard-of-care anti-staphylococcal antibiotics in adult patients. 
S. aureus, a virulent pathogen in humans, is a leading cause of BSI including IE, which are 
associated with substantial morbidity and mortality. In 2017, the US Centers for Disease Control 
(CDC) estimated that there were approximately 119,000 episodes of S. aureus BSI in the US, 
and approximately 20,000 patients died of these infections [Kourtis 2019]. S. aureus BSI is often 
associated with complications, including metastatic bone and soft tissue infections, IE, and 
recurrent infections. Complicated S. aureus BSI requires extended duration treatment with 
SoCA, often accompanied by surgical intervention (e.g., in the setting of prosthetic devices, or 
metastatic soft tissue infections). S. aureus BSI associated with prosthetic devices can be 
particularly difficult to treat due to the presence of biofilms, which conventional SoCA are 
unable to penetrate. The availability of a new, highly effective treatment for S. aureus BSI 
remains an area of high unmet medical need due to the high degree of morbidity and mortality, 
potentially lengthy treatment, and the increasing prevalence of multidrug resistant strains. 
In in vitro experiments, exebacase exhibited potent activity against all strains of S. aureus, 
including methicillin-resistant strains and those that demonstrated resistance to vancomycin, 
daptomycin, and linezolid. In vitro and in vivo studies have demonstrated exebacase has a rapid 
onset of bactericidal action and synergistic effect when administered in combination with SoCA 
for S. aureus BSI (e.g., daptomycin). More recently, in vitro studies have demonstrated synergy 
when exebacase was used together with daptomycin against vancomycin-intermediate (VISA), 
heterogeneous vancomycin-intermediate (hVISA), and vancomycin-resistant (VRSA) strains of 
S. aureus. Importantly, while biofilm formation limits the efficacy of SoCA in the treatment of 
complicated S. aureus BSI including IE, exebacase demonstrates potent ability to clear biofilms 
in in vivo and in vitro models. In vitro, exebacase exhibits low potential to develop resistance and 
can reduce the propensity for the development of resistance to SoCA when co-administered. 


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Exebacase has been evaluated in a Phase 1 randomized, double-blind, placebo-controlled, 
dose-escalating study in 20 healthy subjects, and a Phase 2 multinational, randomized, 
double-blind, placebo-controlled, superiority-design, proof-of-concept study in 121 patients with 
complicated S. aureus BSI including IE being treated with standard-of-care antibiotics (SoCA). 
In the Phase 1 and Phase 2 studies, exebacase was generally safe and well tolerated, with no 
adverse clinical safety signals. There were no treatment-emergent adverse events (TEAEs) of 
hypersensitivity to exebacase or immune-related events in either study. The Phase 2 study 
established proof-of-concept for exebacase as a potential therapeutic used in addition to SoCA to 
treat patients with S. aureus BSI including R-IE, with a focus on MRSA. Amongst all patients 
with S. aureus
patients in the exebacase + SoCA group and 
patients in the SoCA alone (placebo) group were clinical responders at Day 14 
(p-value=0.3137). In the prespecified MRSA subgroup, the clinical responder rate at Day 14 was 
42.8 percentage points higher in the exebacase + SoCA group compared with the SoCA alone 
group (ad hoc p-value=0.0101). In patients with BSI/R-IE, 
f patients in the 
exebacase + SoCA and SoCA alone groups, respectively, were responders at Day 14 
(ad hoc p-value=0.0280). In the Phase 2 study, the TEAEs were consistent with the patient 
population with severe, potentially life-threatening S. aureus BSI including right- and left-sided 
IE (R-IE and L-IE) and underlying comorbid conditions and the incidence was similar between 
treatment groups. The clinical studies are described in more detail in Section 7.1.6. 
Full details of the background and development of exebacase are described in the Investigator's 
Brochure. 
7.1.2. 
Overview of S. aureus Bloodstream Infections 
S. aureus is a leading cause of BSI and is associated with substantial morbidity including a range 
of potentially serious and life-threatening complications that may be difficult to recognize and 
manage (e.g., IE) [Fowler 2003]. Intravenous drug users and patients with human 
immunodeficiency virus (HIV) and renal insufficiency, especially those requiring hemodialysis, 
are particularly at risk for developing S. aureus 
S. aureus BSI develop metastatic complications such as IE. The incidence of IE in the setting of 
S. aureus BSI has been estimated to be 10
 
[Fowler 2003, Chang 2003, Valente 2005], 
[Chang 2003]. Risk factors for IE in the 
setting of S. aureus BSI include presence of prosthetic heart valve, predisposing cardiac 
abnormalities, injection drug use, intravascular catheter infection, bacteremia of unclear origin, 
and persistent bacteremia [Chang 2003, El-Ahdhab 2005, Hill 2007]. 
Infective endocarditis due to S. aureus BSI is associated with substantial morbidity and mortality 
and is associated with complications more frequently than other causative pathogens 
(stroke, 
-hospital 
[Fowler 2005a]. The likelihood of 
developing complications depends on several factors including the infecting pathogen, duration 
of illness prior to therapy, and underlying comorbidities. Symptomatic cerebrovascular 


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[Ruttman 2006, Snygg-Martin 2008, 
García-Cabrera 2013]. Silent cerebrovascular complications (including ischemia and 
[Snygg-Martin 2008, Cooper 2009]. The 
in-
-month mortality rate 
has been 
[Wallace 2002, Chu 2004, Hasbun 2003, 
Hill 2007, Wang 2007]. 
7.1.3. 
Current Treatments and Drug Resistance 
Current treatment of S. aureus BSI includes prompt control or removal of the source of infection 
(e.g., removal of implicated catheters and/or drainage of abscess, if present) [López-Cortès 2013] 
and early initiation of effective antibiotic therapy. Antibiotic resistance, toxicity related to high 
dose/long duration therapy, and biofilm formation that cannot be cleared by SoCA contribute to 
treatment failure. Despite the availability of conventional antibiotic treatments, the 30-day 
all-cause mortality of S. aureus 
[Anantha 2014, Van Hal 2012] and mortality rates have not improved over recent decades 
[Souli 2019, Turner 2019, Tong 2015]. 
The antibiotic resistance among bloodstream S. aureus isolates, including methicillin resistance 
and the emergence of resistance to vancomycin, daptomycin, and linezolid is of concern. 
Mortality associated with MRSA bacteremia has been reported to be higher than mortality 
associated with methicillin-sensitive S. aureus (MSSA) bacteremia [Shurland 2007, 
Cosgrove 2003]. Treatment failure is fairly common in patients with S. aureus BSI, particularly 
among those patients with infection due to MRSA [Lodise 2008]. Both the CDC and the World 
Health Organization (WHO) regard antibiotic resistance as one of the greatest threats to human 
health worldwide, with MRSA, categorized as a “serious threat” by the CDC and a 
“high priority” by the WHO [CDC 2019, WHO 2017]. MRSA infections occurred in an 
estimated 323,700 hospitalized patients in the Untied Statues (US) in 2017, and approximately 
10,600 patients died [Jernigan 2020, CDC 2019]. 
The treatment of S. aureus BSI, particularly drug-resistant strains, is challenging due to the 
limited number of treatment options, and the requirements for longer duration, high-dose 
treatment regimens. Both vancomycin and daptomycin, the only antibiotics indicated for the 
treatment of MRSA, are associated with dose-limiting toxicities. Evidence suggests that 
emerging resistance to current therapies for MRSA (e.g., vancomycin minimum inhibitory 
gh-level VRSA are associated with worse 
clinical outcomes [Bayer 2013]. 
Daptomycin, the newest drug developed for MRSA BSI, is over 10 years old and was approved 
based on noninferiority to older comparator antibiotics (e.g., vancomycin) with clinical cure rates 
Fowler 2006]. Despite the availability of antibiotics with 
activity against MRSA, attempts to develop new antibiotic treatments for S. aureus BSI have 
been unsuccessful [Geriak 2019]. While a number of clinical trials have evaluated the utility of 


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adjunct agents for treatment of S. aureus BSI, none have shown a significant impact on efficacy. 
Immunotherapeutic agents all failed to advance to confirmatory clinical trials [Weems 2006, 
Rupp 2007, Weisman 2011, Otto 2010]. The addition of adjunct conventional antibiotics such as 
gentamicin [Cosgrove 2009], rifampin [Thwaites 2018] or a beta-lactam antibiotic [Tong 2020] 
to conventional therapy for S. aureus or MRSA BSI were similarly unsuccessful. 
While the introduction of penicillin to treat S. aureus BSI drastically decreased the case fatality 
rate of S. aureus BSI from approximately 
-antibiotic era, case fatality rates 
reported over recent decades have plateaued to the approximately 15
[Fowler 2005b]. This continued high mortality rate may be, at least in part, reflective of a 
relative plateau in antibiotic efficacy. The last major advance in the treatment of MRSA 
bacteremia was the introduction of vancomycin, over 60 years ago. Thus, there is an urgent need 
for novel treatments for S. aureus BSI in general, and MRSA BSI in particular. 
Exebacase, a targeted treatment for S. aureus BSI, with limited propensity for resistance, potent 
antibiofilm activity, and the potential for synergistic efficacy and reduced resistance when used 
in combination with existing agents has the potential to address this need. 
The Phase 2 study of exebacase (CF-301-102) is the first to show promising improvement in 
clinical outcome among patients who receive adjunctive therapy for S. aureus BSI. This 
improvement was particularly marked in the pre-specified MRSA subgroup. The results of the 
Phase 2 study of exebacase are described in Section 7.1.6. 
7.1.4. 
Exebacase for the Treatment of S. aureus 
Exebacase, a direct lytic agent, is an entirely new treatment modality for S. aureus and a member 
of a new class of antimicrobials known as lysins (cell wall hydrolase enzymes). In nature, lysins 
are one of the most potent killing agents produced by bacteriophages to digest the bacterial cell 
wall to allow phage progeny release. Lysin technology has enabled the production of lysins as 
purified biologic therapeutics for human medicinal use, completely devoid of bacteriophage. 
Exebacase is a recombinantly-produced, purified protein that represents a first-in-field, 
first-in-class treatment with the potential to improve clinical outcome when used in addition to 
SoCA to treat S. aureus BSI including IE. Exebacase is new treatment modality, fundamentally 
distinct from conventional antibiotics. When added externally to S. aureus bacteria, exebacase 
creates immediate lysis upon contact with the cell wall, causing log-fold death of the target 
bacterium. Whereas most conventional antibiotics typically target a broad spectrum of bacteria, 
including normal flora, lysins are highly targeted to specific bacterial species. Exebacase 
specifically targets staphylococci, including MSSA and MRSA as well as strains that are 
non-susceptible to vancomycin and daptomycin. The highly targeted nature of exebacase reduces 
the potential for biological toxicity associated with negative effects of broad-spectrum antibiotics 
on the human gastrointestinal microbiome (e.g., killing of beneficial normal flora). 


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Exebacase is distinct from current SoCA due to: (1) its novel mechanism of action; (2) rapid, 
potent bactericidal activity against antibiotic-resistant S. aureus; (3) potent ability to eradicate 
biofilms; (4) synergy with SoCA; (5) narrow spectrum of lytic action; (6) low propensity to 
develop bacterial resistance; and (7) ability to protect against the emergence of resistance to 
SoCA when used in combination. Exebacase activity has been extensively evaluated in vitro and 
in vivo, in animal models of infection. These studies indicate that exebacase is complimentary to 
and synergistic with conventional antibiotics, and thereby has the ability to address the 
limitations of the current standard-of-care antibiotics against S. aureus. 
Full details of the background and development of exebacase are available in the Investigator's 
Brochure. 
7.1.5. 
Preclinical Studies
Nonclinical Efficacy Studies
The efficacy of exebacase administered as a single dose or multiple doses, either alone or in 
addition to anti-staphylococcal antibiotics (daptomycin, vancomycin, or oxacillin) was 
demonstrated in two murine S. aureus bacteremia models. The results from these studies 
demonstrated that: (1) exebacase as single-agent significantly enhanced 24-hour survival in 
MRSA infections; (2) In a higher inoculum infection model, exebacase in addition to 
daptomycin, vancomycin, or oxacillin, was effective against S. aureus, including MSSA and 
MSRA, whereas monotherapy with human equivalent therapeutic doses of antibiotics was 
ineffective; (3) Single and repeat doses of exebacase administered in addition to 7 daily doses of 
daptomycin significantly improved survival when compared to either exebacase alone or 
daptomycin alone. 
The efficacy of exebacase in addition to daptomycin or vancomycin was also demonstrated in the 
rat and rabbit IE models. In both animal models of IE, the addition of exebacase to daptomycin 
or vancomycin resulted in a substantially reduced bacterial density in all tissues compared to 
vehicle control, a single dose of exebacase alone or daptomycin or vancomycin administered 
alone for 4 days. Using the murine neutropenic thigh infection model, area under the plasma 
concentration versus time curve/ minimum inhibitory concentration ratio (AUC/MIC) ratio was 
determined to be the pharmacokinetic-pharmacodynamic (PK-PD) index most predictive of 
efficacy of exebacase 
administered in addition to daptomycin, vancomycin, or oxacillin. In the murine neutropenic 
 was associated 
with efficacy of exebacase administered in addition to daptomycin. 
In an in vitro and in vivo study in mice, exebacase synergized with daptomycin at 
sub-MIC levels to kill a range of MSSA and MRSA isolates in the presence of pulmonary 
surfactant (an inhibitor of daptomycin alone) [Schuch 2015]. 


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Nonclinical Safety Studies 
The PK/toxicokinetic (TK), safety pharmacology, and toxicity of exebacase have been 
investigated in the rat and the dog. Key findings by study type are summarized below. 
Safety Pharmacology, PK, and Toxicology:
 In both species, exposure (AUC) and maximum plasma drug concentration (Cmax) generally 
increased with increasing dose in an approximately dose proportionate fashion. Following a 
single dose and repeat doses, the terminal half-life (t1/2) was short: For a single dose, t1/2 was 
<1 hour in rats and 1.2 to 1.4 hours in dogs. 
Exebacase has no direct pharmacological effects on the central nervous system (CNS) in rats 
or on cardiovascular or respiration function in dogs. In dogs, evidence of a hypersensitivity 
or anaphylactoid-like response was observed in some animals, but this required the 
administration of at least 3 doses administered 1 week apart. A similar response was not 
observed after a single administration, even at a high dose. 
The immunological response to exebacase in the rat and the dog following single and repeat 
doses: 
 Following single exebacase doses in the rat up to 25 mg/kg, exebacase-specific ADA was 
detected 14 days after dosing, with increasing numbers of positive samples identified with 
increasing doses.
Following 7 daily repeat doses of up to 50 mg/kg/day in the rat and the dog, titers of 
exebacase-specific ADA were detected in most animals by Day 8 (following last dose) and 
increased in incidence and titer by days 15 and 29 post-dose.
The presence of exebacase-specific ADA did not affect the clearance of or exposure to 
exebacase. These results were consistent with a typical immune response of animals to a 
foreign protein with regard to the timeline of appearance of ADA. 
A Good Laboratory Practice (GLP) extended single-dose toxicity study in the rat and repeat-dose 
toxicity studies in the rat and the dog characterized the dose-limiting toxicity following 
exebacase dosing: 
 Following a single-dose of exebacase administered as a 2-hour infusion in the rat, 
microscopic observations of perivascular/adventitial inflammation surrounding the 
pulmonary arteries were the primary toxicological observation. These adventitial findings 
occurred at low incidence and minimal severity at single doses of 10 and 25 mg/kg at the 
Day 3 necropsy and resolved during a 14-day recovery period. No adventitial findings were 
observed at the 2.5 mg/kg dose and therefore it was reported as the no observed effect level 
(NOEL) for the study. Based on exebacase-specific ADA, that was not associated with 
adventitial findings or adverse immunological effects, the 2.5 mg/kg dose could be 
considered a no observed adverse effect level (NOAEL). 


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 A subsequent review of the study results by a Pathology Working Group determined 
that, based on a lack of adventitial findings at the 5.0 mg/kg dose, the 
Pathology Working Group considered the 5.0 mg/kg dose as the NOEL for the study. 
This review is described in detail in the Investigator’s Brochure. 
 In the GLP 7-day, repeat-dose toxicity studies, adventitial findings in both the rat and the dog 
were the dose-limiting toxicity findings. However, compared to a single dose of exebacase 
where the adventitial finding was of low incidence, minimal severity, and reversible at dose 
ollowing repeat doses of exebacase, the adventitial finding increased in 
incidence, severity, and tissue distribution in medium to larger blood vessels of multiple 
tissues. 
A series of special toxicity studies were conducted in the rat: 
 Enzymatically-active exebacase was associated with the development of the adventitial 
vascular findings whereas enzymatically-inactive exebacase was not. 
 Exebacase produced signs and symptoms of hypersensitization response in specialized rat 
models of hypersensitivity of the Brown Norway and Lewis rats. However, the precise nature 
of the hypersensitivity response (Type I or Type III) was not definitively identified; studies in 
rodents may not necessarily be predictive for humans in terms of the nature of 
hypersensitivity reactions [Finkelman 2007]. Of note, in the Phase 1 and 2 clinical studies, 
exebacase did not appear to be sensitizing for allergic hypersensitivity; further information 
on clinical immunogenicity is in Section 7.1.6. 
A series of exploratory studies in the rat were performed to identify the PK parameter most 
predictive of adventitial/perivascular findings in the great vessels of the cardio-pulmonary 
circulation and to more accurately predict the exposures associated with this finding. Overall, 
the exploratory studies and Neural Network analyses concluded that AUC is the PK parameter 
most associated with an observation of adventitial/perivascular findings in the pulmonary 
arteries.  
From cross-species population PK modeling of all PK/TK data sets from 9 studies that included 
270 rats and 78 dogs, an accurate estimate of the exposure levels associated with the 2.5 mg/kg 
was obtained. Based on this collective analysis, the predicted mean area under the concentration 
versus time curve from time 0 to 24 hours (AUC0-24) was 3,596 ng*hr/mL and the predicted 
mean Cmax was 1,754 ng/mL following a single 2.5 mg/kg 2-hour infusion of exebacase in the 
rat. The predicated mean AUC0-24 and Cmax were 7,192 ng*hr/mL and 3,508 ng/mL following a 
single 5.0 mg/kg 2-hour infusion of exebacase in the rat. 
Additional detail on the preclinical studies can be found in the Investigator’s Brochure. 


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7.1.6.
Clinical Studies 
Exebacase has been evaluated in two clinical studies:
 Study CF-301-101, entitled “A Phase 1, Placebo-Controlled, Dose-Escalating Study to 
Examine the Safety and Tolerability of Single Intravenous Doses of CF-301 in Healthy Male 
and Female Subjects” 
 Study CF-301-102, a Phase 2 study, entitled “A Multicenter, Double-Blind, Randomized, 
Comparative Study of the Safety, Tolerability, Efficacy, and Pharmacokinetics of 
CF-301 vs. Placebo in Addition to Standard-of-Care Antibacterial Therapy for the Treatment 
of Adult Patients with Staphylococcus aureus Bloodstream Infections (Bacteremia) Including 
Endocarditis” 
Study CF-301-101: 
The Phase 1 clinical study, CF-301-101, was a double-blind, randomized, study to evaluate the 
safety, tolerability, and PK of single, escalating IV doses of exebacase in healthy male and 
female subjects. Pre-defined stopping rules were included in the protocol and an independent 
Data Safety Monitoring Board (DSMB) reviewed unblinded safety and PK data at pre-specified 
timepoints throughout the study and rendered a recommendation to the Sponsor as to whether or 
not dosing should progress as planned.
A total of 143 males and females were screened for participation in the study and 97 of those 
potential subjects were screened for the presence of exebacase-specific ADA, exebacase-specific 
immunoglobulin E (IgE), and ex vivo exebacase-specific basophil activation test (BAT). Thirteen 
potential subjects were excluded due to positive ADA, 5 were excluded due to positive BAT, 
and 1 was excluded due to positive BAT and IgE. A total of 20 healthy male and female subjects 
were enrolled in the study. Thirteen subjects received exebacase (4 subjects at the 0.04 mg/kg 
dose level; 4 subjects at the 0.12 mg/kg dose level; 4 subjects at the 0.25 mg/kg dose level; 
and 1 subject at the 0.4 mg/kg dose level) and 7 subjects received placebo. 
Exebacase was generally safe and well tolerated during study CF-301-101. There were no 
deaths, no serious adverse events (SAE), and no discontinuations due to AEs during the study. 
There were no infusion reactions or AEs of hypersensitivity related to exebacase. A total of 
5 non-serious TEAEs were reported by 4 subjects: 2 subjects who received exebacase reported 
headache, contact dermatitis, and allergic rhinitis and 2 subjects who received placebo reported 
viral upper respiratory tract infection and viral infection. All TEAEs were mild in intensity and 
resolved. Only 1 TEAE (headache in the exebacase group) was considered related to study drug. 
The number of TEAEs observed in the placebo and exebacase groups was similar and the 
incidence of TEAEs among subjects who received exebacase was not dose dependent. 


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Pharmacokinetic parameters of exebacase are summarized in Table 3. After infusion of 
exebacase, plasma concentrations and PK parameters (Cmax and AUC) increased in a linear and 
dose proportional manner with a slope less than 1 (i.e., for a 2-fold increase in dose, AUC or 
Cmax increased by 1.75-fold). However, there was no evidence of a plateau in exposures by 
increasing dose within the range studied in healthy volunteers. The geometric mean terminal 
elimination half-life (t1/2) ranged from 4.37 to 6.58 hours for subjects that received 0.04 mg/kg, 
0.12 mg/kg, and 0.25 mg/kg of exebacase, independent of dose, and was 11.3 hours for the 
1 subject that received 0.4 mg/kg of exebacase, with individual subject values ranging from 
4.33 to 14.7 hours across the 4 dose levels with no apparent relationship to dose. 
Table 3: 
Phase 1 Study: Pharmacokinetic Parameters for Exebacase 
 
Abbreviations: z = elimination rate constant; AUC(0-t) = area under the curve from zero to the time of the last quantifiable 
concentration; AUC(inf) = area under the curve to infinity; CL = clearance; Cmax = maximum plasma concentration; 
CV = coefficient of variation; hr = hour; IV = intravenous; Tmax = time to Cmax; t1/2 = half-life; Vz = volume of distribution.  
*Geometric mean (geometric CV) (N) except Tmax for which the median (N) [Range] is reported. 
Results of immunogenicity testing showed that a total of 9 of 13 subjects (69.2
exebacase developed exebacase-specific ADA (7 subjects by Day 28 and 2 subjects by Day 90). 
The ADA titers at Day 28 were variable and ranged from 1:10 to 1:2560 and were waning or 
absent by Day 180. Only 1 subject developed a low-level treatment-emergent IgE signal that 
resolved by Day 90 and remained resolved at Day 180. No AEs related to hypersensitivity to 
exebacase were reported. No subjects tested positive for exebacase-specific BAT. Consideration 
of this single, transient low-level signal for exebacase-reactive IgE, along with the lack of any 
-specific BAT, suggests a low risk for allergic-type hypersensitivity. 
In conclusion, exebacase was generally well tolerated at doses of 0.04, 0.12, 0.25, and 
0.4 mg/kg/dose, and no clinical adverse safety signals were observed. The increase in plasma 
AUC and Cmax of exebacase across the dose range of 0.04 to 0.4 mg/kg/dose was less than 
dose-proportional with no evidence of a plateau in exposures. While 69.2
developed exebacase-specific ADA, no correlation between ADA titers and either IgE or BAT 
was observed. ADA response signals were decreasing or absent by Day 180. There was no 
detectable exebacase in urine. 


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Study CF-301-102: 
The Phase 2 study, CF-301-102, was a multinational, randomized, double-blind, 
placebo-controlled, superiority-design, proof-of-concept study to evaluate the safety, tolerability, 
efficacy, and PK of exebacase in addition to SoCA versus SoCA alone for the treatment of adult 
patients with S. aureus BSIs including IE. 
Patients received a single dose of exebacase or placebo in addition to appropriate SoCA, which 
included vancomycin, daptomycin, semi-synthetic penicillins, and first generation 
cephalosporins. The dose of exebacase was 0.25 mg/kg based on target attainment, with a dose 
adjustment to 0.12 mg/kg for patients with CrCl <60 mL/min and patients >50 years of age. 
An independent DSMB reviewed unblinded safety and PK data throughout the core study. 
An independent blinded Adjudication Committee (AC) determined the final diagnosis and 
clinical response based on clinical response definitions in the protocol and centralized 
echocardiographic readings. 
A total of 121 patients were randomized in a 3:2 ratio to exebacase (73 patients) or placebo 
(48 patients). The safety population included 119 patients who received study drug, and the 
microbiological intent-to-treat (mITT) population included 116 patients, consisting of 71 patients 
in the exebacase + SoCA group and 45 patients in the SoCA alone (placebo) group with 
documented S. aureus from blood cultures who received study drug. 
well balanced with respect to demographics. There was a greater percentage of patients with 
poorly controlled diabetes, severe renal impairment, and on dialysis in the exebacase + SoCA 
group. In the mITT population, 27 of 71
exebacase + SoCA group and 
16 of 45 
SoCA alone group had MRSA. 
The majority of patients in both treatment groups had a final adjudicated diagnosis of S. aureus 
exebacase + SoCA and SoCA alone groups, respectively). There 
was a higher rate of L-IE in the exebacase + SoCA group 
SoCA alone group (3 
 
Efficacy: 
The primary efficacy outcome was clinical outcome at Day 14 in the mITT population, as 
assessed by the AC. As shown in Table 4
exebacase + SoCA group and 
SoCA alone group were clinical responders at Day 14 (p-value=0.3137). 
In the prespecified analysis in the MRSA subgroup, the clinical responder rate at Day 14 was 
42.8 percentage points higher in the exebacase + SoCA group compared with the SoCA alone 
group
 
exebacase + SoCA and SoCA alone groups, 
respectively, were responders at Day 14 (ad hoc p-value=0.0101). Responder rates in the MSSA 
subgroup were 
exebacase + SoCA group and 
SoCA alone group, but results were affected by a difference in the number of 


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patients with left-sided endocarditis between treatment groups, as discussed in the paragraphs 
that follow the table. 
Table 4: 
Phase 2 Study: Clinical Outcome at Day 14 Assessed by Adjudication 
Committee by MRSA and MSSA Subgroup (mITT Population) 
Total Population
MRSA1
MSSA1
Exebacase 
+ SoCA 
(N=71) 
n (%) 
SoCA 
Alone 
(N=45) 
n (%) 
Exebacase
+ SoCA 
(N=27) 
n (%)
SoCA 
Alone 
(N=16) 
n (%) 
Exebacase 
+ SoCA 
(N=44) 
n (%) 
SoCA
Alone 
(N=30) 
n (%)
 
 
 
 
Responder2
50 (70.4) 
27 (60.0) 
20 (74.1) 
5 (31.3) 
30 (68.2) 
22 (73.3) 
3
[58.4, 80.7]
[44.3 74.3]
[53.7, 88.9] 
[11.0, 58.7] 
[52.4, 81.4] 
[54.1, 87.7] 
4 
10.4 [-6.3, 27.2]
42.8 [14.3, 71.4] 
-5.2 [-25.6, 15.3]
p-value4 
0.3137
0.0101 
0.7964
Improvement
44 (62.0) 
25 (55.6) 
19 (70.4) 
4 (25.0) 
25 (56.8) 
21 (70.0) 
Response
6 (8.5) 
2 (4.4) 
1 (3.7)
1 (6.3) 
5 (11.4) 
1 (3.3) 
Non-response 
18 (25.4) 
13 (28.9) 
4 (14.8) 
8 (50.0) 
14 (31.8) 
6 (20.0)
Indeterminate 
3 (4.2) 
5 (11.1) 
3 (11.1) 
3 (18.8) 
0 
2 (6.7) 
 
 
 
 
Abbreviations: MRSA=methicillin-resistant S. aureus; MSSA=methicillin-sensitive S. aureus; SoCA=standard-of-care 
antibiotics. 
Note: Denominator is all patients in the mITT population with noted infection, within each treatment group. 
One patient in the SoCA alone group had both MRSA and MSSA and was counted in both subgroups. 
1. 
Responder=clinical outcome of improvement or response. 
2. 
Confidence intervals (CIs) calculated using Clopper-Pearson method. 
3. 
CI for the difference in percentage improvement/response between exebacase + SoCA and SoCA alone groups calculated 
using a continuity corrected Z-statistic. 
4. 
P-value is based on Fisher's exact test. 
In patients with L-IE
exebacase + SoCA group and 
2 of 3 
SoCA alone group were responders at Day 14. The difference in 
the number of patients with L-IE between treatment groups (11 and 3 patients in the 
exebacase + SoCA and SoCA alone groups, respectively) was unexpected. Due to the inherent 
differences in clinical severity, SoCA treatment modalities, and outcome rates for patients with 
L-IE, this difference between treatment groups affected the efficacy analysis, and an ad hoc 
analysis excluding patients with L-IE was conducted. As shown in Table 5, in patients with 
BSI/R-IE (excluding L-IE
exebacase + SoCA and SoCA 
alone groups, respectively, were responders at Day 14 (ad hoc p-value=0.0280). 
The ad hoc analysis of clinical outcome by diagnosis was also analyzed by MRSA and MSSA 
subgroups, given the difference in the number of patients with left-sided endocarditis in the 
MSSA subgroup (8 and 3 patients in the exebacase + SoCA and SoCA alone groups, 
respectively). In patients with MRSA BSI/R-IE
exebacase + SoCA group were responders at Day 
the SoCA alone group (ad hoc p-value=0.0036). The analysis of MSSA patients excluding 
patients with left-sided endocarditis indicated that in the subpopulation of patients with MSSA 
BSI/R-IE, 29 of 36 
exebacase + SoCA group were responders at Day 14 
compared with 20 of 27 
SoCA alone group (ad hoc p-value=0.5571). 


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Table 5: 
Phase 2 Study: Clinical Responders at Day 14 Assessed by Adjudication 
Committee by Diagnosis (mITT Population) 
Total Population
MRSA1
MSSA1
Exebacase 
+ SoCA 
(N=71) 
n/N (%)
SoCA 
Alone 
(N=45) 
n/N (%)
Exebacase
+ SoCA 
(N=27) 
n/N (%)
SoCA 
Alone 
(N=16) 
n/N (%) 
Exebacase 
+ SoCA 
(N=44) 
n/N (%) 
SoCA
Alone 
(N=30) 
n/N (%)
 
 
 
 
IE
5/16 (31.3) 
3/6 (50.0)
2/5 (40.0)
0/1 (0)
3/11 (27.3) 
3/5 (60.0)
R-IE 
3/5 (60.0) 
1/3 (33.3)
1/2 (50.0)
0/1 (0)
2/3 (66.7)
1/2 (50.0)
L-IE2
2/11 (18.2) 
2/3 (66.7)
1/3 (33.3)
0 
1/8 (12.5)
2/3 (66.7)
 
 
 
 
 
BSI 
45/55 (81.8)
24/39 (61.5)
18/22 (81.8)
5/15 (33.3) 
27/33 (81.8)
19/25 (76.0)
Complicated 
33/42 (78.6)
21/36 (58.3)
13/17 (76.5)
3/13 (23.1) 
20/25 (80.0)
18/24 (75.0)
Uncomplicated
12/13 (92.3)
3/3 (100) 
5/5 (100) 
2/2 (100) 
7/8 (87.5)
1/1 (100) 
 
 
 
 
 
BSI/R-IE
48/60 (80.0)
25/42 (59.5)
19/24 (79.2)
5/16 (31.3) 
29/36 (80.6)
20/27 (74.1)
p-value3
0.0280
0.0036 
0.5571
 
 
 
 
 
Complicated BSI/R-IE
36/47 (76.6)
22/39 (56.4)
14/19 (73.7)
3/14 (21.4) 
22/28 (78.6)
19/26 (73.1)
p-value3
0.0646
0.0049 
0.7540
 
 
 
 
Abbreviations: BSI= blood stream infection; IE=infective endocarditis; L-IE=left-sided infective endocarditis; 
MRSA=methicillin-resistant S. aureus; MSSA=methicillin-sensitive S. aureus; R-IE=right-sided infective endocarditis; 
SoCA=standard-of-care antibiotics. 
Notes: Clinical responder=clinical outcome of improvement or response. 
Denominator is all patients in the mITT population with noted diagnosis at time point within each treatment group. 
1. 
One patient in the SoCA alone group had both MRSA and MSSA and was counted in both subgroups. 
2. 
One patient in the exebacase + SoCA group with MRSA had both R-IE and L-IE and is counted under L-IE. 
3. 
P-value is based on Fisher's exact test. 
 
Secondary efficacy analyses included clinical outcome at Day 7, at the end of treatment with 
SoCA (EOT), and at test-of-cure (TOC) (28 days after EOT). Responder rates at Day 7, EOT, 
and TOC were similar between treatment groups, but when patients with L-IE were excluded, 
results for the secondary efficacy endpoints were supportive of the primary efficacy endpoint. 
In patients with BSI/R-IE (excluding L-IE), responder rates at Day 7, EOT, and TOC were 
exebacase + SoCA group, r
and 
SoCA alone group, respectively. 
exebacase + SoCA group 
were responders at Day 
31
SoCA alone group, respectively. The trend observed at Day 7, EOT, and TOC was 
supportive of the 42.8 percentage point higher clinical responder rate at Day 14 among MRSA 
patients in the exebacase + SoCA group compared with the SoCA alone group. In the MSSA 
subgroup, the responder rates at Day 7, EOT, and TOC were similar between treatment groups; 
as described above, the MSSA results were affected by the difference in the number of patients 
with left-sided endocarditis between treatment groups. 


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An exploratory analysis of health resource utilization in patients with MRSA enrolled in the US 
showed that, in patients who were alive at the time of discharge, the median length of stay was 
lower in the exebacase + SoCA group compared with the SoCA alone group (6 days and 10 days, 
respectively), and the 30-day all-
exebacase 
+ SoCA and SoCA alone groups, respectively. 
An exploratory analysis of 30-day all-cause mortality was performed. The 30-day all-cause 
 patients) in the exebacase + SoCA group 
(6 of 47 patients) in the SoCA alone group. In the MRSA subgroup, the 30-day all-cause 
 patients) in the exebacase + SoCA 
(4 of 16 patients) in the SoCA alone group (ad hoc p value=0.0556) [Fowler 2020]. 
An ad hoc analysis of time to resolution of symptoms was performed. A total of 86 patients 
(53 in the exebacase + SoCA group and 33 in SoCA alone group) had at least one symptom 
attributable to S. aureus BSI/IE present at screening
in 
the exebacase + SoCA group 
in the SoCA alone group. The median time to symptom 
resolution was 3 days in the exebacase + SoCA group and 6 days in SoCA alone group. Median 
time to symptom resolution in the MRSA subgroup was 3 and 7 days in the exebacase + SoCA 
group and SoCA alone group, respectively, and 3 and 5 days in the exebacase + SoCA group and 
SoCA alone group in the MSSA subgroup, respectively [Cassino 2021]. 
Pharmacokinetics: 
Based on a population PK model of the 72 patients that received exebacase, the median Cmax and 
AUC0-24 were estimated to be 1056 ng/mL and 3108 ng*hr/mL, respectively. All patients 
achieved the efficacy target of AUC/MIC 0.5.
Safety: 
As expected in a critically ill, hospitalized study population, a similarly high percentage of 
patients in both treatment groups 
exebacase + SoCA and SoCA alone groups, respectively) and through 
exebacase + SoCA and SoCA alone groups, respectively), as shown in Table 6. 
The incidence of TEAEs within approximately 7 days of administration of the single dose of 
study drug (on Day 1) was similar between treatment 
exebacase + SoCA and SoCA alone groups, respectively). 
There were no TEAEs of hypersensitivity related to exebacase, and no patients had an AE of 
clinical interest defined as a TEAE that resulted in stopping of the study drug infusion 
(i.e., withdrawal of study drug). 


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Treatment-emergent AEs that the Investigator considered to be related to study drug occurred in 
he exebacase + SoCA group 
SoCA alone 
group. All of these TEAEs were non-serious, except for 1 SAE of splenic artery thrombosis, 
which occurred 30 days after exebacase dosing and was not considered related to study drug by 
the Sponsor. 
Serious TEAEs also occurred in a similar percentage of patients in the exebacase + SoCA and 
SoCA alone groups 
 
 
A total of 7 patients (9.7
exebacase + SoCA group and 6 patients (12.8
SoCA 
alone group died through Day 30. In the MRSA subgroup, 
exebacase + SoCA group 
SoCA alone group died through 
Day 30 (ad hoc p-value=0.0556). 
exebacase + SoCA group 
SoCA alone group died through TOC, which is equivalent to 
60-day mortality since the last death occurred on Day 58. A total of 17 
9 
exebacase + SoCA and SoCA alone groups, respectively, died through 
Day 180. The higher number of patients with L-IE and comorbidities (diabetes, renal 
impairment, hemodialysis, hypertension, and >1 baseline cardiac diagnosis) in the 
exebacase + SoCA group may have contributed to the higher percentage of deaths in the 
exebacase + SoCA group through TOC and Day 180. In patients with BSI/R-IE 
(excluding L-IE), a similar percentage of patients died in the exebacase + SoCA and SoCA alone 
groups 
 
respectively). 
A population PK model was developed from the data collected in the Phase 2 study to assess the 
probabilities of a relationship between exebacase exposures and safety parameters. The model 
showed no significant relationship between the exposures of exebacase (Cmax and AUC0-24) and 
death, any SAE, SAE in cardiac disorders system organ class (SOC), or TEAEs in key SOCs of 
interest (cardiac disorders, infections and infestations, gastrointestinal disorders, or respiratory, 
thoracic and mediastinal disorders). 


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Table 6: 
Phase 2 Study: Overview of Adverse Events (Safety Population)
Parameter 
Exebacase+ SoCA
(N=72) 
n (%)
SoCA Alone
(N=47) 
n (%) 
Number of patients with: 
 
TEAE through Day 7
48 (66.7)
30 (63.8)
TEAE through TOC
64 (88.9)
40 (85.1)
TEAE through Day 180
67 (93.1)
40 (85.1)
 
Serious TEAE through TOC
34 (47.2)
23 (48.9)
Serious TEAE through Day 180
45 (62.5)
28 (59.6)
 
TEAE related to study drug
8 (11.1)
4 (8.5)
Serious TEAE related to study drug
1 (1.4)
0
 
TEAE leading to study drug interruption or withdrawal1
1 (1.4)
0
Serious TEAE leading to study drug interruption or withdrawal
0
0
 
Death through Day 30
7 (9.7)
6 (12.8) 
Death through TOC2
14 (19.4)
7 (14.9) 
Death through Day 180
17 (23.6)
9 (19.1) 
Abbreviations: eCRF=electronic case report form; SoCA=standard-of-care antibiotics; TEAE=treatment-emergent adverse event; 
TOC=test-of-cure. 
Note: Denominator is all patients in the safety population within each treatment group. 
1. 
There were no TEAEs leading to study drug discontinuation/withdrawal. One patient in the exebacase + SoCA group had 
non-serious TEAEs (arterial hypertension and shakiness) that resulted in study drug interruption; the study drug infusion 
was subsequently resumed, both TEAEs resolved, and the patient received the full dose. 
2. 
The last death through TOC occurred on Day 58; thus, death through TOC is equivalent to 60-day mortality. 
Immunogenicity:
exebacase + SoCA and SoCA alone groups, 
respectively, were positive for exebacase-specific ADA. This is consistent with prior estimates of 
pre-existing ADA in the Phase 1 study, a validation study, and a study evaluating pre-existing 
ADA in the serum of patients with S. aureus bacteremia from an established repository. 
Among patients dosed with exebacase, pre-existing exebacase-specific ADA did not appear to 
affect efficacy outcomes or the incidence of TEAEs: clinical responder rates at Day 14 were 
similar in patients who were ADA-positive and ADA-
respectively), and the rates of TEAEs were similar in patients who were ADA-positive and 
ADA-
 
Of baseline ADA-negative patients with at least 1 post-dose ADA sample, 37 of 52 patients 
exebacase + SoCA group developed treatment-emergent ADA. These results are 
consistent with data from the Phase 1 study (Study CF-301-101) in which 69.3
received exebacase developed treatment-emergent ADA. In the SoCA alone group, 
8 of 32 
-emergent exebacase-specific ADA. The etiology of 
this observation is unclear but suggests that something other than study drug triggers ADA 
(e.g., potentially related to exposure to phage material in the setting of S. aureus infection). 


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exebacase + SoCA group was positive for exebacase-specific IgE at 
baseline. In this patient, IgE was not increased post-dose, and there were no TEAEs of 
hypersensitivity or immune-related TEAEs reported. Of baseline IgE-negative patients with at 
least 1 post-dose IgE sample, 6 of 65 patients (9.2
exebacase + SoCA group developed 
treatment-emergent IgE compared with no patients in the SoCA alone group. The treatment-
emergent IgE responses were generally of low magnitude and transient, which is consistent with 
Phase 1 (Study CF-301-101), suggesting that a single dose of exebacase is not sensitizing for 
Type I hypersensitivity. 
In conclusion, the Phase 2 study established proof-of-concept for exebacase and the emerging 
new field of direct lytic agents as potential therapeutics. The results of the Phase 2 study support 
the further evaluation of exebacase in a definitive Phase 3 study designed to examine efficacy 
and safety in patients with BSI/R-IE including a focus on MRSA. Exebacase was generally safe 
and well tolerated, with AEs consistent with the critically ill patient population with severe, 
potentially life-threatening S. aureus BSI including R-IE and L-IE and underlying comorbid 
conditions. There were no TEAEs of hypersensitivity to exebacase or immune-related events 
reported during the study, despite the presence of exebacase-specific ADA at baseline in 
-existing ADA did not appear to affect efficacy 
or safety outcomes in the study. Importantly, exebacase did not appear to be sensitizing for 
allergic hypersensitivity given low incidence of treatment-emergent IgE, which was of low 
magnitude and transient. Additional detail on the clinical studies can be found in the 
Investigator’s Brochure. 
7.1.7. 
Compassionate Use/Expanded Access 
Exebacase has also been administered to 15 patients with prosthetic joint infections and 
7 patients under expanded access. The youngest patient dosed with exebacase was 5 months old
[Moorthy 2021]. 
Prosthetic Joint Infections 
Exebacase has been arthroscopically administered to a total of 15 successive individual named 
patients with coagulase negative Staphylococci (CoNS) prosthetic joint infections (PJIs) in the 
setting of a lysin-debridement, (systemic antistaphylococcal) antibiotics, and implant retention 
(DAIR) procedure at the reference regional center (CROIAc) at Hopital de la Croix-Rousse in 
Lyon, France under individual Autorisation Temporaire D'utilisation (ATU) from the French 
Health Authority, Agence Nationale de Sécurité du Médicament et des Produits de Santé 
(ANSM). Twelve of these patients had PJIs of the knee; three patients had a PJIs of the hip. 
All patients underwent the arthroscopic DAIR procedure performed with local arthroscopic 
administration of exebacase to the affected joint. Exebacase has been well tolerated after 
intraarticular (IA) administration with no local tissue effects seen at the joint and no systemic 
effects attributed to IA administration of exebacase. No serious adverse reactions to exebacase 
were reported for any of the patients treated under ATU. 


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Four of these patients with relapsing, multidrug-resistant Staphylococcus epidermidis PJI of the 
knee were recently described [Ferry 2021]. These patients with relapsing infections had 
experienced iterative relapses, in some cases while on suppressive antibiotic therapy, after open 
DAIR. The “Lysin-DAIR procedure” was proposed based on the potent bacteriolytic and 
anti-biofilm activity, as compassionate treatment, followed by suppressive tedizolid as salvage 
therapy. After >1 year of follow up (respectively 14 and 16 months), two of the four patients 
who had a septic arthritis picture at presentation had a favorable clinical response, whereas the 
other two patients who had a fistula at the time of presentation had a less favorable outcome.
Compassionate Use/Expanded Access
As of December 18, 2021, 7 patients have received exebacase under compassionate use. 
All 7 patients had S. aureus bacteremia, which the treating physicians were not able to clear with 
standard of care antistaphylococcal antibiotics. All patients received treatment with exebacase 
under Emergency IND requested by the treating physician and approved by the US FDA. 
Exebacase was intravenously administered using the same dosing paradigm as in the Phase 3 
study. All patients tolerated exebacase well, and there were no serious adverse drug reactions 
reported for any of these patients who were dosed under compassionate use.
7.2. 
Benefits and Risks 
The Phase 3 study will evaluate the efficacy and safety of exebacase in addition to SoCA 
compared with SoCA alone in adult and adolescent patients with complicated S. aureus BSI 
including R-IE (excluding patients with L-IE) with a focus on patients with MRSA. As 
previously described (Sections 7.1.2 and 7.1.3), S. aureus BSIs including IE are highly morbid 
conditions, which result in substantial morbidity and mortality despite currently available SoCA. 
The main objective of the Phase 3 study is to evaluate whether exebacase in addition to SoCA 
improves clinical outcomes in these patients compared to SoCA alone. As such, all patients in 
this study will be treated with SoCA therapy for S. aureus BSI or R-IE based on current 
guidelines. The therapeutic benefits and side effects of SoCA are well documented in the 
prescribing information and published literature. 
Patients will be randomized to receive a single dose of exebacase or placebo in addition to 
SoCA. No patients in the study will be treated with the experimental therapy, exebacase, alone. 
Together with the efficacy results in Phase 2, and the favorable safety and tolerability profile in 
Phase 1 and Phase 2 (described in Section 7.1.6), a single dose of exebacase may provide 
additional clinical benefit over and above the benefit of SoCA alone, which allows for a positive 
benefit-to-risk ratio. 
A rigorous safety monitoring plan has been put in place for the Phase 3 study. All patients will 
be dosed in a hospital setting and all patients will be closely monitored by repeated assessment of 
AEs, physical examinations, vital signs, and clinical safety laboratory tests. Although no patients 
in the Phase 1 or Phase 2 studies experienced hypersensitivity reactions to exebacase during or 
after infusion, and no patients discontinued study drug administration, patients must be observed 


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during exebacase/placebo infusion by someone from the clinical care team or research team with 
patient care experience as described in Section 9.4.1.1, and vital signs will be measured 
approximately 30 to 40 minutes after the start of infusion and as clinically indicated during the 
infusion. An independent DSMB will review accruing safety and tolerability data in an 
unblinded manner throughout the study, as described in the DSMB charter. All fatal SAEs and 
suspected unexpected serious adverse reactions (SUSARs) will be provided to the DSMB on an 
ongoing basis. The DSMB will also review results from a futility analysis of the primary efficacy 
parameter in the MRSA population in the mITT analysis set when approximately 
have primary (Day 14) adjudicated clinical outcome data available. The DSMB will monitor the 
overall safety of patients in order to minimize unacceptable risk to patients. As a result, the 
DSMB may recommend changes to study conduct on the basis of emerging safety information to 
protect the safety and welfare of clinical study patients. Enrollment will continue during the 
DSMB reviews. 
Overall, based on the benefit-to-risk analysis, the Sponsor considers the current study to be 
appropriate in the planned study population. 
7.3. 
Population to be Studied 
Adult and adolescent patients with complicated S. aureus BSI including R-IE will be included in 
this study. 
7.4. 
Rationale for Route and Dose 
In the Phase 1 study (Study CF-301-101), single escalating doses of exebacase (0.04, 0.12, 0.25, 
or 0.4 mg/kg) were administered over 2-hour infusion. In the Phase 2 study (Study CF-301-102), 
a single dose of exebacase was administered over 2-hour infusion at a dose of 0.25 mg/kg based 
on target attainment, with a dose adjustment to 0.12 mg/kg for patients with CrCl <60 mL/min 
and patients >50 years of age. 
A population PK model was developed using the data from the Phase 2 study in patients with 
complicated S. aureus BSI/IE. The population PK model showed that CrCl was a statistically 
significant and clinically relevant covariate affecting the PK of exebacase. Age was also 
statistically significant, but not a clinically meaningful predictor of exebacase exposures 
(
 effect on AUC0-24 or Cmax). For a given dose, compared with patients with normal renal 
function, patients with mild renal impairment are expected to have 
max and up 
AUC0-24; patients with moderate renal impairment are expected to have up to 
 higher Cmax and up to 
AUC0-24; patients with severe renal impairment are 
 higher Cmax and up to 2-fold higher AUC0-24; and patients with 
end-stage renal disease (ESRD) 
 higher Cmax and up to 3-fold 
higher AUC0-24. 


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The Phase 1 and Phase 2 studies of exebacase (Studies CF-301-101 and CF-301-102) were both 
performed with weight-based dosing (i.e., mg/kg) commonly used for IV dosing. Monte Carlo 
simulations performed on the population PK model showed that weight-based dosing would 
introduce a significant systematic bias in exposures, regardless of renal function group, and also 
increase the range of exposures. Weight-based dosing would result in a situation where patients 
with higher body weight would be expected to achieve significantly higher exposures than the 
target value and patients with lower body weight would be expected to achieve significantly 
lower exposures than the target value, rather than ensuring similar exposures across individuals, 
which is the intent of a weight-based dosing. A simulation of a scenario for administration of 
fixed dose that achieves the same average exposure as in Phase 2 resulted in no 
weight-dependent increase in exposure. Therefore, selection of the doses to be used in the 
Phase 3 study focused on the fixed dosing scenarios. 
Modeling data identified 3 categories for dosing based on renal function: 1) patients with normal 
renal function (CrCl 90 mL/min) and mild renal impairment (
60 to <90 mL/min); 
2) patients with moderate (
30 to <60 mL/min) and severe (CrCl 15 to <30 mL/min) renal 
impairment; 3) patients with ESRD (CrCl <15 mL/min) including patients who require dialysis. 
Simulations were performed for a series of fixed doses of exebacase ranging from 5 to 24 mg for 
each of the renal impairment groups described above. The doses for the Phase 3 study were 
selected to match the median AUC0-24 of 3108 ng*hr/mL, which is the median exposure 
determined by population PK analysis of the 72 patients that received exebacase in the Phase 2 
study. 
Based on the simulations, the following dosing scheme was selected for the Phase 3 study: 
For patients with normal renal function or mild renal impairment 
, 
an exebacase dose of 18 mg administered as approximately a 2-hour IV infusion would result 
in Cmax and AUC0-24 values of 1254 ng/hr and 3026 ng*hr/mL, respectively. 
 For patients with moderate or severe renal impairment (CrCl of 15 to <60 mL/min), 
an exebacase dose of 12 mg administered as approximately a 2-hour IV infusion would result 
in Cmax and AUC0-24 values of 1107 ng/hr and 3099 ng*hr/mL, respectively. 
 For patients with ESRD (CrCl <15 mL/min), including those on dialysis, an exebacase dose 
of 8 mg administered as approximately a 2-hour IV infusion would result in Cmax and 
AUC0-24 values of 910 ng/hr and 3109 ng*hr/mL, respectively. In patients receiving 
 hours before the start of 
 
For the dosing regimen described above, approximately all patients would be expected to achieve 
efficacy targets associated with AUC/MIC
0.5 for isolates that have an exebacase 
MIC 2 g/mL. The fixed-dose scheme above is expected to result in similar exposures in 
patients regardless of their body weight or renal function status and achieve the average exposure 
target of approximately 3108 ng*hr/mL. 


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7.5. 
Rationale for Inclusion of Adolescent Patients 
To date, exebacase has not been evaluated in adolescent patients. It is anticipated that, as with 
adults, adolescent patients with S. aureus BSI including R-IE may derive benefit from a new 
therapeutic agent that may provide additional benefit above SoCA alone. Therefore, adolescent 
patients are an important patient population in which to study the safety, efficacy, and PK of 
exebacase in addition to SoCA. 
Literature specific to adolescents with S. aureus BSI is limited, since most literature summarizes 
data across all pediatric age groups (some of which also includes neonates), and many studies are 
at single hospitals or groups of hospitals within a specific country or region. Among different 
hospitals or regions, the incidence of S. aureus bacteremia among pediatrics, including 
adolescents, ranges from 3.7 to 14.4 per 100,000 population [Oestergaard 2018, McMullan 2016, 
Mejer 2012, Vanderkooi 2011]. The rate of S. aureus bacteremia among hospitalized pediatric 
patients, including adolescents, ranges from approximately 1.5 to 3.5 per 1000 hospital 
admissions [Klieger 2015, Cobos-Carrascosa 2015, Burke 2009]. In one study, definitive IE 
occurred 
pediatric patients with S. aureus bacteremia, including adolescents 
[Valente 2004], which is similar to the incidence of IE in adult patients with S. aureus 
bacteremia [Fowler 2003, Chang 2003]. 
Risk factors for S. aureus bacteremia in pediatric patients, including adolescents, are similar to 
those of adults and include dialysis, plasmapheresis, organ transplantation, cancer, 
immunodeficiency, previous hospitalization, and presence of a central venous catheter (CVC) 
[Oestergaard 2018, Burke 2009]. Diabetes, a risk factor in adults, is increasingly diagnosed at 
younger ages, and adolescent obesity is likely to increase the incidence of diabetes in adolescents 
[Twig 2020]. Risk factors for S. aureus IE in pediatric patients, including adolescents, include 
presence of congenital heart disease and/or multiple positive blood cultures [Valente 2004]. 
Mortality due to S. aureus bacteremia in pediatric patients, including adolescents, ranges from 
 for hospital-onset infections a
-onset 
infections [McMullan 2016, Klieger 2015]. 
Guidelines regarding selection of antibiotics for treatment of MRSA S. aureus bacteremia and IE 
in pediatrics include those antibiotics also recommended for adults, and the recommended 
duration of antibiotics is similar in adults and pediatric patients [Liu 2011]. 
Adult PK data for exebacase was assessed in a population PK model with a range of body 
weights in adults. Exposure in adults showed no significant effect of weight on the PK of 
exebacase. According to CDC Growth Charts, in an age range of 12.0 to 17.99 years, mean body 
weight ranges from 42.07 to 67.87 kg for males and 44.89 to 59.81 for females [CDC 2002]. 
the 
age range of 12.0 to 17.99 years. This difference, along with the knowledge that population PK 
in adults did not indicate any clinically relevant body weight effect on the PK of exebacase, 
suggests patients 12 to <18 years of age are likely to have exposures comparable to adults at a 


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given dose. In addition, the metabolism of exebacase (a peptide) in adults and adolescents is
expected to be similar since adults and adolescents have similar capacity for catabolism of 
peptides. The collective data indicates adolescents receiving the same dose of exebacase as 
adults are not expected to have substantially different exposure than adults. 
Adolescent patients with S. aureus BSI/R-IE may derive benefit from exebacase. A favorable 
benefit-to-risk ratio was demonstrated in adults with S. aureus BSI/R-IE in the Phase 2 study, 
and exposures are expected to be similar between adults and adolescents. Therefore, adolescents 
12 to <18 years of age with S. aureus BSI/R-IE are being enrolled in this study to allow initial 
assessment of safety, PK, and efficacy in this age group. 
7.6. 
Rationale for Inclusion of Patients with Renal Impairment 
Patients with renal impairment, particularly those with ESRD receiving dialysis, are at high risk 
for infections with S. aureus, including complicated BSI/R-IE; therefore, it is anticipated that 
patients with renal impairment may derive benefit from a new therapeutic agent that may provide 
additional benefit above SoCA alone. Therefore, patients with renal insufficiency are an 
important patient population in which to study the safety, efficacy, and PK of exebacase in 
addition to SoCA. 
Patients with renal impairment and on hemodialysis were included in the Phase 2 study 
(Study CF-301-102). Among patients that received exebacase in the Phase 2 study, there were 
5 patients 
 
had mild, moderate, 
and severe renal impairment, respectively, and 21 
hemodialysis. 
Exebacase is a therapeutic protein with a molecular mass of approximate 26 kDa. Measurement 
of exebacase levels in urine of healthy subjects in the Phase 1 study (Study CF-301-101) 
determi
of the dose) of exebacase excreted in urine. The lack of 
urinary excretion of exebacase is consistent with the expected route of elimination of 
endogenous and biotechnology-derived proteins via tissue catabolism resulting in degradation to 
small peptides and individual amino acids (S6R1). 
In a biodistribution study of Iodine-131 radio-labeled exebacase in mice, IV administration of 
131-I-exebacase resulted in detection of exebacase in multiple tissues. The kidneys had the 
highest level of exebacase, followed by the liver, spleen, stomach, lung, and blood. Over time 
there was a significant decrease in the level of exebacase in the majority of organs, including the 
kidney, suggesting rapid clearance of exebacase from the blood and catabolism by multiple 
tissues. This is consistent with normal catabolism of protein and peptides. Furthermore, literature 
reviews reveal that even in subjects with severe renal impairment, the capacity for catabolism of 
[Meibohm 2012, Czock 2012, Maack 1979, Meier 2004, Ishimitsu 1994]. Based on the collective 
nonclinical and clinical data for exebacase and published literature, the main route of elimination 
for exebacase is understood to be catabolism and not urinary excretion. 


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In view of the spleen’s role as a major organ for exebacase catabolism, patients with 
both asplenia and CrCl <60 mL/min (including those on dialysis) are excluded due to the risk for 
reduced ability to catabolize exebacase.
As described in Section 7.4, the doses for the Phase 3 study were selected such that the 
exposures in the Phase 3 study are expected to match the exposures observed in the Phase 2 
study regardless of patient renal status or body weight.
As described in Section 7.2, an independent DSMB will review accruing safety and tolerability 
data in an unblinded manner throughout the study. The DSMB will monitor the overall safety of 
patients in order to minimize unacceptable risk to patients. As a result, the DSMB may 
recommend changes to study conduct on the basis of emerging safety information to protect the 
safety and welfare of clinical study patients.
Patients with renal impairment, particularly those on hemodialysis, are at particular risk for 
S. aureus BSI with associated poor outcomes. As patients with renal impairment and S. aureus 
BSI may benefit from treatment with exebacase, this approach will allow for obtaining data in a 
patient population with renal impairment, safeguard the safety of patients in this study, and allow 
for continued evaluation of exebacase in this important population. 
7.7. 
Statement of Compliance 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
the ethical principles of the Declaration of Helsinki, and applicable regulatory and Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC) requirements.
8. 
TRIAL OBJECTIVES AND PURPOSE 
8.1. 
Primary Objectives 
 Efficacy: To determine if exebacase in addition to SoCA is superior to SoCA alone for 
clinical responder rate at Day 14 in patients with MRSA BSI, including IE (i.e., the MRSA 
population) in the microbiological intent-to-treat (mITT) analysis set 
 Safety: To determine the safety and tolerability of exebacase in addition to SoCA compared 
with SoCA alone in the safety analysis set 
8.2. 
Secondary Objectives 
 To determine if exebacase in addition to SoCA is superior to SoCA alone for clinical 
responder rate at Day 14 in all patients with S. aureus (i.e., the overall population) in the 
mITT analysis set 
 To determine if exebacase in addition to SoCA is superior to SoCA alone for 30-day survival 
in the MRSA population in the mITT analysis set 


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 To determine if exebacase in addition to SoCA is superior to SoCA alone for clinical 
responder rate at Day 60 in the MRSA population in the mITT analysis set
 To determine if exebacase in addition to SoCA is superior to SoCA alone for clinical 
responder rate at Day 60 in the overall population in the mITT analysis set
To determine clinical responder rate at Day 60 in the overall R-IE and MRSA R-IE 
populations in the mITT analysis set
8.3. 
Additional Objectives 
 To determine the survival time through Day 60 in the overall and MRSA populations in the 
mITT analysis set 
To determine clinical responder rate at Day 14 in the overall R-IE and MRSA R-IE 
populations in the mITT analysis set 
 To determine clinical responder rate at Day 30 in the overall and MRSA populations, 
and overall R-IE and MRSA R-IE populations in the mITT analysis set 
 To determine clinical responder rate at Day 14 by source of S. aureus infection in the overall 
and MRSA populations in the mITT analysis set 
 To evaluate bacteremia clearance rate at Days 4 and 7 in the overall and MRSA populations 
in the mITT analysis set 
 To describe post-dose immunologic response (anti-drug antibody to exebacase) in the safety 
analysis set. 
 To describe the relationship between baseline and post-dose immunologic parameters and 
efficacy and safety endpoints in the mITT and safety analysis sets, respectively 
 To evaluate impact of exebacase on health resource utilization in the mITT analysis set 
 To characterize the PK parameters of exebacase in the study population in the PK analysis 
set 
9. 
INVESTIGATIONAL PLAN 
9.1. 
Overall Study Design 
This is a randomized, multicenter, double-blind, placebo-controlled study to evaluate the efficacy 
and safety of exebacase in addition to SoCA compared with SoCA alone for the treatment of 
adult and adolescent patients with S. aureus BSI including R-IE (excluding patients with L-IE). 
Patients who meet all screening criteria and have blood culture positive for S. aureus determined 
by rapid diagnostic or conventional methods, or Gram stain showing Gram-positive cocci in 
clusters plus either positive tube coagulase test or positive latex slide agglutination test from 


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blood culture specimens collected within approximately 72 hours before randomization are 
eligible for the study. 
Approximately 348 patients will be randomly assigned in a 2:1 ratio to receive a single dose of 
exebacase (232 patients) or placebo (116 patients). Patients will receive exebacase or placebo as 
soon as possible after randomization. The randomization will be stratified by poorly controlled 
diabetes (yes or no) as defined below and susceptibility of the S. aureus isolate (MRSA, MSSA, 
or unknown). For stratification, poorly controlled diabetes is defined as a hemoglobin A1C 
(HgA1C) 
A HgA1C test is not 
required for patients with no medical history of diabetes and no suspicion of diabetes during the 
screening period. These patients will be stratified to “no” for poorly controlled diabetes. 
A HgA1C test should be performed in patients with medical history of diabetes or suspicion of 
diabetes during screening for whom a HgA1C test result within the approximately 90 days prior 
to randomization is not available. If a HgA1C is unavailable and testing cannot be performed for 
these patients prior to randomization, contact the Medical Monitor to determine how the patient 
should be stratified based on available clinical information. All efforts will be made to obtain 
susceptibility results from blood cultures before randomization to enable stratification by MRSA 
or MSSA. If a blood culture was performed for the current S. aureus infection prior to the 
qualifying blood culture, susceptibility results from the prior blood culture may be used. If the 
patient has a concomitant S. aureus infection at another body site from which susceptibility 
results are available (e.g., skin, abscess), the susceptibility results from this other culture may be 
used. If the patient is known to be colonized with MRSA, MRSA may be selected for the 
stratification factor. 
Patients will receive SoCA selected by the Investigator/Sub-Investigator (or other delegated 
medically qualified person listed on the FDA Form 1572 and trained on the protocol) based on 
recommendations in the protocol. These are based on authoritative treatment guidelines 
[Liu 2011, Baddour 2015] and include daptomycin or vancomycin for MRSA and semi-synthetic 
penicillins (e.g., nafcillin, oxacillin, cloxacillin, flucloxacillin) and first-generation 
cephalosporins (e.g., cefazolin) for MSSA. Daptomycin or vancomycin may be used for patients 
with MSSA with a known history of beta-lactam allergy or other reason that beta-lactam cannot 
be used. The duration of SoCA will generally be from 2 to 8 weeks (14 to 56 days). If a longer 
duration of treatment with SoCA is anticipated, this must be discussed prior to randomization 
with the Medical Monitor. Long-term oral antibiotic suppression therapy (e.g., for osteomyelitis), 
is not considered to be SoCA for S. aureus BSI/IE and would be considered a “concomitant 
medication”. Treatment with oral step-down antibiotics is not permitted, except in adolescents. 
The SoCA will be administered as specified in the manufacturer’s prescribing information. 
All efforts will be made to determine the source of S. aureus BSI/IE (e.g., full physical 
examination, imaging as needed, cultures of other infected body sites or catheters that may be 
considered the source), preferably during screening or within 1 week after randomization. 
The resolution of the source of S. aureus BSI/IE will be evaluated at Days 7, 14, 30, and 60. 


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Patients will be evaluated for signs and symptoms attributable to S. aureus BSI/IE and metastatic 
foci (e.g., deep tissue abscess, septic arthritis, etc.) and septic emboli (e.g., to the brain, lung, 
etc.) during screening and at the Day 7, 14, 30, and 60 visits. Additionally, if SoCA is changed 
after study drug dosing due to lack of clinical response, signs and symptoms will be assessed on 
the day of the SoCA change. The Investigator/Sub-Investigator (or other delegated medically 
qualified person listed on the FDA Form 1572 and trained on the protocol) will assess whether 
each sign or symptom is attributable to S. aureus BSI/IE or provide an alternative attribution and 
will assess the symptom severity per the definitions described in Table 9. Some symptoms may 
be considered ‘medically not evaluable’ due to certain medical circumstances or treatments, such 
as a patient in a medically induced coma or after surgery to remove a metastatic focus. 
Every effort should be made to perform study visits “in person”, including physical 
examinations, assessment of signs and symptoms, and evaluation of metastatic foci/septic emboli 
by the Investigator/Sub-Investigator (or other delegated medically qualified person listed on the 
FDA Form 1572 and trained on the protocol), and preferably by the same person at all visits. If it 
is not feasible to evaluate the patient “in person” at study visits, the signs and symptoms should 
be evaluated during the telephone/telehealth visits by detailed questioning and a complete 
medical review of systems. Medical records may be used to supplement the telephone/telehealth 
evaluation for physical examination, signs and symptoms, and metastatic foci/septic emboli 
(see Sections 12.10, 12.13, and 12.12, respectively). In rare instances in which it is not feasible 
to conduct study visits “in person” or by telephone/telehealth, medical records alone may be used 
after contacting the Medical Monitor or designee. The Investigator/Sub-Investigator 
(or other delegated medically qualified person listed on the FDA Form 1572 and trained on the 
protocol) must review, sign, and date the physical exam, sign and symptom, and metastatic 
foci/septic emboli data extracted from the medical record and recorded in the site’s source 
documents. 
Diagnostic testing will be performed as clinically indicated to assess metastatic foci or septic 
emboli (e.g., imaging, aspiration, and/or cultures). Metastatic foci identified through Day 7 are 
considered part of the patient’s baseline S. aureus BSI/IE; new metastatic foci identified after 
Day 7 or new septic emboli after study drug dosing are considered complications of S. aureus 
BSI/IE for the purpose of assessing clinical outcome. New septic emboli are defined as an acute 
presentation of septic emboli after dosing and are a reason for failure for clinical outcome; 
septic emboli that are incidentally found on imaging are considered part of the patient’s baseline 
S. aureus BSI/IE if found before Day 7. 
Intravenous catheters known or suspected to be infected must be removed, and as clinically 
needed replaced, preferably at a different site, as soon as possible within approximately 72 hours 
after randomization. Other hemodialysis access types (i.e., arteriovenous [AV] fistulas or AV 
grafts) that are known or suspected to be infected will be evaluated for removal/replacement, 
if clinically feasible. If removal is not feasible based on standard medical practice, the patient 
should be discussed with the Medical Monitor prior to enrollment. In patients with CVCs, 


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ultrasounds to evaluate clots in the vein should be performed within approximately 48 hours after 
randomization, unless the clot in the vein has been detected within this timeframe via other 
method (e.g., imaging such as CT scan or MRI or direct visualization during surgery). 
In addition to the study-qualifying blood culture from specimens collected within approximately 
72 hours before randomization (described earlier in this section), 1 aerobic blood culture will be 
collected during screening (or after randomization and before dosing), collected via peripheral 
venipuncture when possible. One aerobic blood culture will be collected daily during the study 
until 2 consecutive negative cultures followed out to negative for at least 48 hours on 2 different 
days are obtained after exebacase/placebo administration (Note: blood cultures may be collected 
every other day for adolescents). Additional blood cultures will be performed as clinically 
indicated. Other (non-blood) cultures should be performed to determine the source of S. aureus
BSI/IE and evaluate metastatic foci, and as clinically indicated during the study.
Complete physical examinations and review of body systems will be performed during screening 
and on Days 7, 14, 30, and 60 for visits performed “in person” by the Investigator/ 
Sub-Investigator (or other delegated medically qualified person listed on the FDA Form 1572 
and trained on the protocol). A physical examination is not required for visits performed 
remotely by telephone/telehealth; however, a complete medical review of body systems will be 
performed during the telephone/telehealth visit and medical record data may be used to 
supplement these visits (e.g., sign and symptom evaluation and physical exam findings) to assess 
the patient’s clinical status, primary source of infection, and the status of any pre-existing or 
presence of new metastatic foci; the findings will be entered in the electronic case report forms 
(eCRF) (Section 11.5.1). The physical examinations will include a close evaluation for any new 
areas of pain or other signs or symptoms of metastatic foci of infection or septic emboli; 
new signs or symptoms (e.g., pain, shortness of breath) will trigger diagnostic testing for 
metastatic foci or septic emboli (e.g., imaging, aspiration, and/or cultures). The physical 
examination will also include an evaluation of the primary source of S. aureus BSI/IE. 
Additional physical examinations will be performed as clinically indicated. 
transesophageal echocardiogram (TEE) within 3 days before or after randomization. All efforts 
will be made to perform the TTE or TEE before randomization. Where possible, a TEE will be 
performed [Baddour 2015, Habib 2010, Habib 2015] and is recommended in patients with body 
mass index (BMI) >30 kg/m2; the TEE may be performed within 3 days before or after 
randomization unless the TEE is performed due to clinical suspicion of L-IE. In patients that 
have clinical findings suggestive of L-IE (new murmur, worsening cardiac function, and/or 
peripheral or central nervous embolic phenomenon), a TEE will be performed before 
randomization to rule out mitral and/or aortic valve vegetation(s) or the patient will be excluded 
from the study per exclusion criterion #2 (Section 10.2). In cases where there is an alternative 
cause of new heart failure or cerebral emboli, a patient with a negative TTE for L-IE may be 
discussed with the Medical Monitor for potential enrollment. In patients with persistent 


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S. aureus 
), 
an echocardiogram will be performed before randomization to rule out L-IE. A TTE may be 
performed with permission of the Medical Monitor. If this echocardiogram is not performed or 
L-IE is not ruled out by this echocardiogram, the patient should not be randomized. 
In adolescents (12 to <18 years of age), echocardiograms (TTE or TEE) will be performed as 
clinically indicated taking into consideration risk factors for endocarditis (e.g., structurally 
abnormal heart [including pacemakers]), clinical features suggestive of endocarditis 
(e.g., new murmur) or persistent bacteremia [McMullan 2020], described in Section 12.14. If the 
patient had an echocardiogram performed prior to the study that was intended to evaluate the 
current infection, an additional TTE or TEE is not required unless as indicated above, but should 
. Follow-up 
echocardiograms will be performed as clinically indicated. Images from all echocardiograms 
through the Day 60 visit will be provided to the central echocardiography laboratory as directed 
by the Sponsor. 
Safety monitoring will include AE monitoring, physical examinations, vital sign measurements, 
clinical safety laboratory tests, and 12-lead electrocardiograms (ECG). Safety monitoring will be 
performed from screening through the last follow-up visit (Day 60). An independent DSMB will 
review unblinded safety data throughout the study as defined in the DSMB charter. All fatal 
SAEs and SUSARs will be provided to the DSMB on an ongoing basis allowing the DSMB to 
monitor fatal and unexpected serious events in a timely manner. 
Blood samples for PK and immunogenicity (exebacase-specific ADA and IgE) will be collected. 
Samples for ADA testing will be collected during screening and on any day between the Day 30 
and Day 60 visit windows (i.e., between Day 26 and Day 67). The sample for IgE testing will be 
collected during screening and will be stored at the site unless the patient later develops clinical 
signs or symptoms of a potential allergic reaction that may be attributed to study drug. 
If a patient has clinical signs or symptoms of a potential allergic reaction that may be attributed 
to study drug (Section 9.4.1.1), a blood sample for IgE will be collected as soon as possible 
within 2 hours of the event, if feasible, and both this sample and the IgE sample at screening will 
be sent to a central laboratory for testing.
Clinical outcome will be assessed by the Investigator/Sub-Investigator (or other delegated 
medically qualified person listed on the FDA Form 1572 and trained on the protocol). 
An independent blinded clinical endpoint AC will determine study eligibility, final diagnosis, 
primary source of BSI/IE, adequacy of source control, and clinical outcome on Days 14, 30, 
and 60. The adjudicated diagnosis, source, and clinical outcomes will be used for the analysis. 


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Visits Performed Remotely by Telephone/Telehealth, Use of Medical Records, and Use of 
Mobile Health Nursing Services 
Telephone/telehealth visits may be performed under the circumstances described in 
Section 11.5.1. During the telephone/telehealth visit, information on the following will be 
collected: any AEs that may have occurred since the last visit and outcome of any ongoing AEs, 
thorough medical review of body systems to assess signs and symptoms of S. aureus BSI/IE, 
outcome of pre-existing or presence of new metastatic foci, outcome of primary source of 
infection, SoCA and reasons for any changes in SoCA, concomitant medications, 
surgeries/procedures, vital status, and clinical outcome. Medical records* may be used to 
supplement information obtained during the telephone/telehealth visit.
In rare instances in which it is not feasible to conduct study visits “in person” or by 
telephone/telehealth, medical records* alone may be used for physical examinations, 
signs/symptoms, and metastatic foci/septic emboli assessments after contacting the 
Medical Monitor or designee.
* When medical records are used alone or to supplement information collected during the 
telephone/telehealth visit, the physical examinations, signs/symptoms, and metastatic 
foci/septic emboli assessments extracted from the medical record will be recorded in the site’s 
source documents and entered in the relevant eCRFs. The Investigator/ Sub-Investigator 
(or other delegated medically qualified person listed on the FDA Form 1572 and trained on the 
protocol) is expected to review, sign, and date the assessments extracted from the medical 
record and recorded in the site’s source documents. Symptom severity assessments must be 
made in accordance with Table 9. The eCRFs will be verified by the site monitor using these 
source documents. 
Local laboratory, vital signs, and ECG data obtained in conjunction with the Day 7, 14, 30, or 
60 visits may be used for the study if available (including using data from medical records of 
another hospital, skilled nursing facility or other similar institution). 
Mobile health services, specifically contracted for the study, may be used to supplement 
telephone/telehealth visits to perform study visit procedures, such as collecting laboratory 
samples, evaluating vital signs, and/or obtaining a 12-lead ECG, after approval by the 
Medical Monitor or designee, as described in Section 11.5.1.
9.2. 
Number of Patients 
Approximately 348 patients will be randomly assigned to receive a single dose of exebacase or 
placebo. The sample size calculation is provided in Section 15.3. 
9.3. 
Treatment Assignment 
Patients will be randomly assigned in a 2:1 ratio to receive a single dose of exebacase 
(approximately 232 patients) or placebo (approximately 116 patients). 


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9.4. 
Dosing and Dose Adjustment Criteria 
9.4.1.
Study Drug 
Patients will receive a single infusion of exebacase or placebo as soon as possible after 
randomization. Exebacase and placebo will be diluted and administered as approximately a 
2-hour IV infusion, as specified in the Pharmacy Manual. 
The dosing scheme is as follows: 
 Patients with normal renal function or mild renal impairment (CrCl* 
 will be 
administered a dose of 18 mg of exebacase. 
 Patients with moderate or severe renal impairment (CrCl* of 15 to <60 mL/min) will be 
administered a dose of 12 mg of exebacase. 
 Patients with ESRD (CrCl* <15 mL/min), including those on hemodialysis, will be 
administered a dose of 8 mg of exebacase. In patients receiving hemodialysis, study drug will 
 hours before the start of 
hemodialysis. 
*Note: CrCl will be calculated by Cockcroft-Gault formula (provided in Section 12.8.1.1)
using ideal body weight 
2 and serum creatinine result obtained 
locally as close to the start of study drug dosing as possible (but not more than approximately 
24 hours before the start of study drug dosing; see Section 12.8.1). 
The study drugs are described in additional detail in Section 13.
9.4.1.1. 
Observation During Study Drug for Potential Allergic Reactions/Anaphylaxis
Patients must be observed during exebacase/placebo infusion by someone from the clinical care 
team or research team with patient care experience, and vital signs (blood pressure, respiratory 
rate, and heart rate, and temperature) will be performed approximately 30 to 40 minutes after the 
start of infusion and as clinically indicated during the infusion.
While not observed in the Phase 1 or Phase 2 studies, if a patient has clinical signs and 
symptoms of a potential allergic reaction that may be attributed to study drug, the following must 
be done: 
 The infusion must be stopped immediately and vital signs checked; if hypotension or oxygen 
desaturation are present with or without skin flushing, hives, or rash, epinephrine should be 
administered immediately intramuscularly. Additional treatments for sequelae of suspected 
anaphylactic reaction should be provided in accordance with standard medical practice. 
 A blood sample for exebacase-specific IgE will be collected as soon as possible within 
2 hours of the event, if feasible, and both this sample and the IgE sample at screening will be 
sent to a central laboratory for testing. 


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The clinical criteria for diagnosing anaphylaxis are described in Table 7 [Simons 2011]. 
Anaphylaxis will be reported as an SAE (see Section 14). 
Table 7: 
Clinical Criteria for Diagnosing Anaphylaxis 
Anaphylaxis is highly likely when any one of the following 2 criteria is fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both 
(e.g., generalized urticaria, itching or flushing, swollen lips-tongue-uvula), AND at least 1 of the following: 
a. 
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow 
[PEF], hypoxemia) 
b. Reduced blood pressure or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], 
syncope, incontinence) 
OR 
2. Two or more of the following that occur rapidly after exposure to a likely allergen1 for that patient 
(minutes to several hours)
a. 
Involvement of the skin-mucosal tissue (e.g., generalized urticaria, itch-flush, swollen lips-tongue-uvula) 
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) 
c. 
Reduced blood pressure or associated symptoms (e.g., hypotonia [collapse], syncope, incontinence) 
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
Source: Simons 2011 
1. 
Or other trigger, for example, immunologic but IgE-independent, or non-immunologic (direct) mast cell activation. 
9.4.2.
Standard-of-Care Antibiotics (SoCA)
The SoCA will be selected by the Investigator/Sub-Investigator (or other delegated medically 
qualified person listed on the FDA Form 1572 and trained on the protocol) based on 
recommendations in the protocol. These are based on authoritative treatment guidelines 
[Liu 2011, Baddour 2015] and include daptomycin or vancomycin for MRSA and semi-synthetic 
penicillins (e.g., nafcillin, oxacillin, cloxacillin, flucloxacillin) and first-generation 
cephalosporins (e.g., cefazolin) for MSSA. Daptomycin or vancomycin may be used for patients 
with MSSA with a known history of beta-lactam allergy or other reason that beta-lactam cannot 
be used. The known allergy will be documented in the eCRF. 
Antibiotics other than those listed above should not be used instead of or in addition to SoCA to 
treat the S. aureus BSI/IE on a routine basis; if a non-protocol recommended antibiotic needs to 
be added, the medical reason for doing so (e.g., lack of clinical response, intolerance, etc.) should 
be documented in the eCRF. If a patient is transferred to another facility (e.g., skilled nursing 
facility or rehabilitation) that results in a change to SoCA (e.g., the SoCA is not available for use 
on the formulary at the facility), the reason for change in the eCRF should reflect this. 
Note: Patients who are receiving teicoplanin, linezolid, telavancin, beta-lactam/beta-lactam 
inhibitors (e.g., piperacillin-tazobactam), carbapenems, fourth- or fifth-generation cephalosporins 
(e.g., cefepime, ceftaroline fosamil), and/or sulfamethoxazole/trimethoprim are eligible for the 
study provided that treatment is switched to a protocol-specified appropriate SoCA, as described 
above. Patients with persistent S. aureus bacteremia for which treatment with ceftaroline fosamil 
or other non-protocol-recommended antibiotic (e.g., rifampin, gentamicin, other beta lactam) 


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was instituted prior to randomization due to lack of response or intolerance (i.e., added to or 
switched from a protocol-recommended SoCA) may remain on the non-protocol-recommended 
antibiotic after randomization, if approved by the Medical Monitor. 
Vancomycin or daptomycin used in combination with beta-lactams has not been shown to offer 
benefit and may increase the risk of kidney injury [Tong 2020]; therefore, this combination 
should not routinely be used in this study as first-line therapy. 
If susceptibility is not known at the time of randomization, the patient will be treated empirically 
based on local susceptibility patterns and local guidelines and practice; if prevalence of MRSA is 
high, empiric treatment with either daptomycin or vancomycin is recommended until 
susceptibility results become available. Once susceptibility data are available, SoCA may be 
changed at the Investigator’s/Sub-Investigator’s (or other delegated medically qualified person 
listed on the FDA Form 1572 and trained on the protocol) discretion based on susceptibility 
results to one of the SoCA options described above. 
The duration of SoCA will generally be from 2 to 8 weeks (14 to 56 days). If a longer duration of 
treatment with SoCA is anticipated, this must be discussed prior to randomization with the 
Medical Monitor. Long-term oral antibiotic suppression therapy (e.g., for osteomyelitis), is not 
considered to be SoCA for S. aureus BSI/IE and would be considered a “concomitant 
medication”. Treatment with oral step-down antibiotics is not permitted, except in adolescents. 
The SoCA will be administered as specified in the manufacturer’s prescribing information.
Recommended doses for SoCA in adult patients are listed below. Doses for adolescent patients 
and patients with renal impairment should be guided by prescribing information and local 
guidelines. 
 Nafcillin or equivalent: 12 g every 24 hours divided into 4 to 6 infusions daily 
 Cefazolin: 6 g every 24 hours divided into 3 infusions daily 
 Vancomycin: 30 mg/kg every 24 hours divided into every 12-hour (q12h) dosing with 
vancomycin trough levels of 10 to 20 µg/mL or to attain an AUC of 400 to 600 mg*h/L 
(assuming an MIC of 1 mg/L) [Ryback 2020]. 
 Vancomycin dosing should be adjusted based on trough levels. It is recommended that 
trough levels are repeated after adjustment of vancomycin dosing. Vancomycin trough 
levels will be recorded in the eCRF. 
 Study drug should not be infused at the same time as SoCA treatment and, if possible, 
any other medications. Since there are known potential side effects of vancomycin 
(e.g., erythematous, pruritic rash on the face, neck and upper body, and other symptoms), 
study drug should be administered either prior to the start of vancomycin infusion or a 
minimum of 1 hour after vancomycin infusion is complete. 
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The manufacturer’s prescribing information for SoCA should be referenced for full dosing 
information. 
Note: If a patient is put on long-term antibiotic suppression therapy (for example, in a patient 
with osteomyelitis), the suppression therapy is NOT considered part of SoCA. 
10. 
SELECTION AND DISCONTINUATION OF PATIENTS 
10.1. 
Inclusion Criteria 
The following inclusion criteria must be met at the time of screening (i.e., within approximately 
24 hours before randomization), unless otherwise noted below, in order for the patient to be 
eligible for enrollment:
1. Male or female, 12 years of age or older.
2. Within 72 hours* before randomization, blood culture positive for S. aureus determined by 
rapid diagnostic test or conventional method, or Gram stain showing Gram-positive cocci in 
clusters and either positive tube coagulase test or positive latex slide agglutination test from 
blood culture specimens.
Note: The 72-hour* time period starts at the time the specimen is collected for blood culture.
Any S. aureus-positive blood culture collected within the 72 hours* before randomization
can be used to support enrollment of the patient. 
*There is an approximately +1-hour window to randomize the patient after the 72-hour 
window (i.e., approximately 73 hours) to account for any technical issues with 
randomization. If the patient is randomized within the approximately +1-hour window, 
please inform the Medical Monitor or designee. 
3. At least two of the following signs or symptoms attributable to S. aureus BSI/IE within 
approximately 24 hours before randomization. If more than one measurement is taken within 
the approximately 24 hours before randomization, the most abnormal value is used for 
inclusion.
a. Shortness of breath 
b. Sweating
c.
Chills and/or rigors
d. Fatigue
e.
Confusion 
f. Pain associated with metastatic foci 
g. 
(oral 
 


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h. Leukocytosis (white blood cell [WBC] count >10,000/µL) [CTCAE 2017],
leukopenia (WBC <4000/µL), or bandemia (>10
regardless of total peripheral WBC) 
i. Tachycardia (heart rate >100 bpm) 
j. Tachypnea (respiratory rate >20 breaths/min) 
k. Hypotension (systolic blood pressure <90 mmHg) 
4. Patient must have: 
a. Known or suspected R-IE (involvement of pulmonic and/or tricuspid valve[s]) based on 
Modified Duke Criteria (defined in Table 8)
or 
b. Known or suspected complicated S. aureus BSI, demonstrated as one or more of the 
following: 
i. Blood culture positive for S. aureus on more than one day 
ii. Clots in the vein at or near the catheter site seen on ultrasound or other method 
(e.g., MRI, echocardiogram, surgery) 
iii. Signs or symptoms of metastatic foci of S. aureus infection (e.g., splenic abscess, 
deep tissue abscess not associated with open wound or other local source of 
infection, septic pulmonary emboli) or hematogenous seeding (e.g., of the renal 
system evidenced by S. aureus bacteriuria [in absence of other source such as 
indwelling ureteral catheter], septic arthritis, osteomyelitis) confirmed by physical 
examination, imaging, and/or culture (Sections 12.10 and 12.12)
Note: Patients who present with acute osteomyelitis as the first manifestation of 
S aureus BSI (e.g., adolescents) may be enrolled even if original source of infection 
is not known.
iv.
more 
v. Met criteria for sepsis or septic shock using the Sequential (sepsis-related) 
Organ Failure Assessment (SOFA) score (definition in Section 23.1 [adapted from 
Singer 2016]) during the time of diagnosis/presumptive diagnosis of BSI. 
If the SOFA score is the only criteria for complicated S. aureus BSI that is met, 
contact the Medical Monitor prior to randomization.


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vi. Significantly immunocompromised:
AIDS (HIV positive with an AIDS-defining condition or a CD4 count of
approximately 200 cells/mm³ within approximately 90 days)
Severe leukopenia defined as absolute neutrophil count (ANC) of
approximately 500 cells/mL in the 7 days prior to the qualifying blood
culture or during the screening window
Post organ transplantation including autologous bone marrow or stem cell
transplantation and on immunosuppressive therapy for the organ transplant
around the time of presentation with the S. aureus BSI/IE
On treatment for active graft vs. host disease
On immunosuppressive therapy, such as:

Biologics such as infliximab, monoclonal antibodies such as
daclizumab, methotrexate, cyclophosphamide, or similar agents.
A list of similar agents is in Appendix 4 in Section 23.4.

Patients who have taken 10 mg of prednisone or equivalent for 5 days
or more.
On myelosuppressive chemotherapy or immunotherapy
Advanced cirrhosis
or 
c.
At least one of the following risk factors for complicated S. aureus BSI:
i.
Preexisting right-sided valvular heart disease
ii.
Surgery (e.g., orthopedic, cardiothoracic, or intraabdominal surgery) within the
previous 30 days that puts the patient at risk for nosocomial bacteremia
iii.
Extravascular foreign material. Note: Catheters including ports, AV fistulas and
related dialysis access points are considered intravascular foreign material.
iv.
Hemodialysis
5. Patient is not pregnant or breastfeeding and meets one of the following criteria:
a.
A female patient who is not of childbearing potential is eligible without requiring the use
of contraception. This includes female patients who have not undergone menarche or
who are documented to be surgically sterile (e.g., hysterectomy, or removal of both
ovaries, or tubal ligation) or postmenopausal (i.e., amenorrhea >1 year and follicle
stimulating hormone [FSH] >40 mIU/mL) with a negative pregnancy test. FSH and
pregnancy testing is not required in postmenopausal females with amenorrhea for
>2 years.


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b. Female patients of childbearing potential and male patients with partners of childbearing 
potential must agree to remain abstinent* or use 2 methods of contraception and refrain 
from donating sperm (male patients) from screening through 30 days after receiving the 
study drug. 
* Abstinence is defined as refraining from heterosexual intercourse from screening 
through 30 days after receiving the study drug; the Investigator/Sub-Investigator 
(or other delegated medically qualified person listed on the FDA Form 1572 and 
trained on the protocol) will consider whether abstinence is consistent with the 
preferred and usual lifestyle of the patient. 
Acceptable methods of contraception include either: 
 Hormonal contraception (injection, implant, pill, patch, or vaginal ring) and a condom 
or diaphragm with spermicide, or 
 Intrauterine device (IUD) and a condom or diaphragm 
c. A male patient who is not of reproductive potential is eligible without requiring the use of 
contraception. This includes males who have undergone a successful vasectomy, 
defined as (1) microscopic documentation of azoospermia, or (2) a vasectomy more than 
2 years ago with no resultant pregnancy despite sexual activity post vasectomy. 
6. Willing and able to provide written informed consent or assent. If the patient is not able to 
provide written informed consent or assent, written informed consent may be provided by the 
patient¶s legally acceptable representative as permissible based on local laws and regulations. 
For patients 12 to <18 years of age, written informed consent from the patient¶s 
parent/guardian or other legally acceptable representative will be obtained according to the 
site¶s IRB requirements. For emancipated minors, written informed consent will be obtained 
according to the site¶s IRB requirements. 
10.2. 
Exclusion Criteria 
1. Patient previously received exebacase. 
2. Known or suspected left-sided IE (involvement of mitral and/or aortic valve[s]) based on 
Modified Duke Criteria (defined in Table 8). 
Note: In adult patients that have clinical findings suggestive of L-IE (new murmur, 
worsening cardiac function, and/or peripheral or central nervous embolic phenomenon), 
a TEE will be performed before randomization to rule out mitral and/or aortic valve 
vegetation(s) or the patient will be excluded from the study. In cases where there is an 
alternative cause of new heart failure or cerebral emboli, a patient with a negative TTE for 
L-IE may be discussed with the Medical Monitor for potential enrollment. In patients with 
persistent bacteremia for 3 days (i.e., blood cultures positive for S. aureus for 3 days), 
an echocardiogram will be performed before randomization to rule out L-IE. A TTE may be 
performed with permission from the Medical Monitor. If this echocardiogram is not 


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performed or L-IE is not ruled out by this echocardiogram, the patient should not be 
randomized. In adolescents (12 to <18 years of age), echocardiograms (TTE or TEE) will be 
performed as clinically indicated taking into consideration risk factors for endocarditis 
(e.g., structurally abnormal heart [including pacemakers]), clinical features suggestive of 
endocarditis (e.g., new murmur), or persistent bacteremia [McMullan 2020]. 
3. Treatment with any potentially effective systemic anti-staphylococcal antibiotic for more 
than 72 hours* within 7 days before randomization. 
Exception: Documented S. aureus resistance to the prior systemic antibiotics and/or 
persistent S. aureus-positive blood cultures while on the systemic antibiotics. 
*There is an approximately +1-hour window to randomize the patient after the 72-hour 
window (i.e., approximately 73 hours) to account for any technical issues with 
randomization. If the patient is randomized within the approximately +1-hour window, 
please inform the Medical Monitor or designee. 
4. Current or planned treatment within the 14 days following randomization with dalbavancin 
or oritavancin. 
Notes: 
 Patients who are receiving teicoplanin, linezolid, telavancin, beta-lactam/beta-lactam 
inhibitors (e.g., piperacillin-tazobactam), carbapenems, fourth- or fifth-generation 
cephalosporins (e.g., cefepime, ceftaroline fosamil), and/or 
sulfamethoxazole/trimethoprim are eligible for the study provided that treatment is 
switched to a protocol-specified appropriate SoCA (appropriate SoCA includes 
daptomycin and vancomycin for MRSA and semi-synthetic penicillins [e.g., nafcillin, 
oxacillin, cloxacillin, flucloxacillin] and first-generation cephalosporins [e.g., cefazolin] 
for MSSA.  
 Daptomycin or vancomycin may be used for patients with MSSA with a known history of 
beta-lactam allergy or other reason that beta-lactam cannot be used. 
 Patients with persistent S. aureus bacteremia for which treatment with ceftaroline fosamil 
or other non-protocol-recommended antibiotic (e.g., rifampin, gentamicin, other beta 
lactam) was instituted prior to randomization due to lack of response or intolerance 
(i.e., added to or switched from a protocol-recommended SoCA) may remain on the 
non-protocol-recommended antibiotic after randomization, if approved by the Medical 
Monitor. 
 Vancomycin or daptomycin used in combination with beta-lactams has not been shown to 
offer benefit and may increase the risk of kidney injury [Tong 2020]; therefore, this 
combination should not routinely be used in this study as first-line therapy. 
5. Removed (Protocol Amendment 4). 


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6. Presence of any removable or surgically managed infection source (e.g., intravascular 
catheter, abscess) that will not be removed or debrided based upon standard medical practice 
within approximately 72 hours after randomization 
Note: Other hemodialysis access types (i.e., AV fistulas or AV grafts) and surgically 
managed infection sources that are known or suspected to be infected will be evaluated for 
removal/replacement, if clinically feasible. If removal/debridement is not feasible based on 
standard medical practice, the patient should be discussed with the Medical Monitor for 
potential enrollment. 
7. Presence of prosthetic valve or cardiac valve support ring, or presence of known or suspected 
infected hardware* (orthopedic), prosthetic joint*, or cardiac device (e.g., implantable 
cardioverter defibrillator [ICD], permanent pacemaker). Note: Patients who have S. aureus 
bacteremia after the removal of infected hardware or cardiac device may be included in the 
study. 
*Patients with planned surgery for known or suspected infected non-cardiac hardware or 
prosthetic joint may be enrolled if surgical removal is planned within 5 days after 
randomization, with approval of the Medical Monitor. 
8. Removed (Protocol Amendment 5). 
9. Patient with BOTH asplenia and CrCl <60 mL/min including those on dialysis 
(risk for reduced ability to catabolize exebacase). Note: CrCl will be calculated by 
Cockcroft-Gault formula (provided in Section 12.8.1.1) using ideal body weight in patients 
with BMI 30 kg/m2 and serum creatinine result obtained locally (see Section 12.8.1). 
10. Patient receiving continuous renal replacement therapy (CRRT) within 4 hours prior to 
dosing and/or within 8 hours after dosing. 
11. Known polymicrobial BSI (i.e., more than one pathogen in the blood). Note: Culture results 
that include organisms that are considered contaminants do not exclude the patient. 
12. Patient with known, ongoing systemic infection caused by other bacterial pathogen(s) 
(i.e., other than S. aureus) and/or fungal pathogen(s) and/or patient who has a known positive 
coronavirus disease 2019 (COVID-19) diagnostic test at the time of screening. Patients who 
previously had COVID-19 and are COVID-19-negative by diagnostic test are eligible for 
enrollment. Note: COVID-19 testing should be performed as clinically indicated in 
accordance with local standard medical practice. 
13. Patient is not expected to survive through Day 14 of the study due to underlying comorbidity 
(e.g., terminal end-stage cancer) and/or patient has an Acute Physiology and Chronic Health 
Evaluation II (APACHE II) score of >30. 
14. Patient participated or plans to participate in another interventional investigational drug, 
device, or diagnostic trial involving administration of an investigational agent within 30 days 
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Note: Patients who have received agents under FDA Emergency Use Authorization (EUA) 
for COVID-19 prevention (e.g., vaccines or Evusheld or similar agents) or for COVID-19 
treatment under FDA EAU are not excluded. 
15. Other comorbid condition or laboratory abnormality that would, in the opinion of the 
Investigator/Sub-Investigator (or other delegated medically qualified person listed on the 
FDA Form 1572 and trained on the protocol), pose a safety risk for the patient to participate 
or pose a risk to the patient¶s ability to complete the study. 
16. Patient is employed by the Sponsor or a member of the investigational site study team 
(i.e., on the Delegation of Authority Log) or is a first degree relative of a person employed by 
the Sponsor or a member of the investigational site study team (i.e., on the Delegation of 
Authority Log). Patient is institutionalized by administrative or court order. 
17. Patient is not willing or able to comply with the protocol requirements. 
10.3. 
Discontinuation Criteria 
10.3.1. 
Discontinuation of Study Drug 
Reasons for discontinuation (i.e., withdrawal) of study drug will be recorded in the eCRF and 
include the following: 
 Patient is unable or unwilling to complete the study drug infusion 
 Patient (or the patient¶s legally acceptable representative/parent/guardian) withdraws 
informed consent/assent at any time during study drug infusion 
 Clinical signs and symptoms of allergic reaction or anaphylaxis to study drug 
(see Section 9.4.1.1 for procedures to be performed in the event of anaphylaxis) 
 AE (whether or not related to study drug) that precludes further infusion of study drug in the 
judgment of the Investigator and/or Sponsor. Note: Any AE that results in discontinuation 
(i.e., withdrawal) of the study drug infusion is considered an adverse event of clinical interest 
(AECI) and must be reported within 24 hours (Section 14.9). 
 The Investigator considers that it is in the patient¶s best interest not to continue the study 
drug infusion 
 Other medical reason, at the discretion of the Investigator and/or the Medical Monitor 
Patients who discontinue study drug will continue to participate in study visits unless 
consent/assent is withdrawn (see the next section; Section 10.3.2). 


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10.3.2. 
Discontinuation from the Study 
Reasons for study discontinuation will be recorded in the eCRF and include the following: 
 Patient is unable or unwilling to adhere to the protocol 
 Patient (or the patient¶s legally acceptable representative/parent/guardian) withdraws 
informed consent/assent 
 AE (whether or not related to study drug) that precludes further participation in the study in 
the judgment of the Investigator and/or Sponsor. Note: Since death due to any cause is a 
component of the clinical failure definition for efficacy (as defined in Table 10 in 
Section 12.18), patients who die during the study will be treated as having completed the 
study. 
 Patient is lost to follow-up 
The Investigator considers that it is in the patient¶s best interest not to continue participation 
in the study. The Investigator will contact the Sponsor in advance if the Investigator is 
considering withdrawing the patient from the study. 
 Other medical reason, at the discretion of the Investigator and/or the Medical Monitor 
Patients who discontinue the study will not participate in further study visits, but AEs will be 
followed as described in Section 14.12 unless informed consent/assent is withdrawn. 
In addition, vital status (whether the patient is alive or dead, or last known date alive if vital 
status is unknown) will be obtained at Days 14, 30, and 60 for all patients, including patients that 
discontinue the study or withdraw consent/assent (as described in the informed consent/assent 
form). All efforts must be made to obtain vital status on all patients through Day 60. Vital status 
data are important for both the safety analysis (to have an accurate accounting of patients who 
died) and the efficacy analysis (³death due to any cause´ is a reason for failure for clinical 
outcome). The patient¶s vital status will be determined using available sources (e.g., the patient, 
patient¶s contacts, hospital and other medical records, and public records, such as social media, 
obituaries, social security death index), as described in the informed consent/assent form and 
FDA guidance (see Section 12.17). 
10.4. 
Replacement of Patients 
Patients who withdraw from study drug and/or the study will not be replaced. 
10.5. 
Rescreening of Patients 
Patients not fulfilling the entry criteria and not randomized may be rescreened for participation if 
their eligibility characteristics have changed. Screening procedures that fall within the screening 
window do not need to be repeated. 


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10.6. 
Criteria for Study Termination 
The end of the study will occur when the last patient completes the study (last patient last visit) 
or discontinues from the study.
Although the Sponsor has every intention of completing the study, the Sponsor reserves the right 
to discontinue the study at any time for clinical or administrative reasons or if required by 
regulatory authorities.
11. 
SCHEDULE OF OBSERVATIONS 
The study schematic and schedule of assessments are provided in Sections 3 and 4, respectively. 
The study procedures/assessments performed at each visit are described in the subsections that 
follow. 
11.1. 
Study Duration 
Patients will receive a single dose of exebacase or placebo in addition to SoCA. The duration of 
SoCA will generally be from 2 to 8 weeks (14 to 56 days). If a longer duration of treatment with 
SoCA is anticipated, this must be discussed prior to randomization with the Medical Monitor.
Long-term oral antibiotic suppression therapy (e.g., for osteomyelitis), is not considered to be 
SoCA for S. aureus BSI/IE and would be considered a “concomitant medication”. The duration 
of the study for each patient will be approximately 60 days (±7 days). 
11.2. 
Visit Windows 
Visit windows are as follows: 
Day 7 (±1 day) 
Day 14 (±1 day) 
Day 30 (±4 days) 
Day 60 (±7 days) 
11.3. 
Screening 
Patients will be screened to determine whether or not they meet the eligibility criteria for the 
study. Patients will be randomized as soon as possible after confirmation of study eligibility. 
However, to provide flexibility, screening assessments may be performed within approximately 
24 hours before randomization, unless otherwise noted. The following assessments/procedures 
will be performed during screening: 
 Informed consent/assent (see Section 12.1).
 Review of inclusion/exclusion criteria (see Sections 10.1, 10.2, and 12.2). 


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 The qSOFA score will be determined for all patients (see Section 12.2.2). In patients that 
have at least 2 criteria of qSOFA, a SOFA score will be performed (see Section 23.1) to 
determine whether the patient meets the criteria for sepsis and/or septic shock per the 
inclusion criteria. 
 Baseline APACHE II score will be calculated for all patients (see Sections 12.2.3 
and 23.2). Patients with APACHE II score of >30 are excluded from the study. 
 Medical history for 1 year prior to screening, including relevant previous and current medical 
diagnoses and major surgical procedures (Section 12.4). 
 Diagnosis determined by the Investigator/Sub-Investigator (or other delegated medically 
qualified person listed on the FDA Form 1572 and trained on the protocol) based on the 
definitions in Section 12.5. 
 Risk factors for complicated S. aureus BSI (see Section 12.6). 
 Make all efforts to determine the source of S. aureus BSI/IE (e.g., full physical examination, 
imaging as needed, cultures of other infected body sites or catheters that may be considered 
the source) preferably during screening (Section 12.7). 
 Limited laboratory tests may need to be performed by the site’s local laboratory during 
screening so that timely results are available for study eligibility determination, stratification, 
and to determine the dose of study drug (based on CrCl). The specific laboratory tests that 
are required to be available locally are described in Section 12.8.1.
 Blood and urine samples for clinical safety laboratory tests will be collected during screening 
(for patients who meet eligibility criteria and are expected to be randomized) or after 
randomization and before dosing; samples will be sent to the central laboratory for testing 
(see Section 12.8.2.1). If a blood or urine sample for safety laboratory testing by the central 
laboratory is not able to be obtained at a given timepoint/visit, the local laboratory results 
may be entered into the eCRF for that timepoint/visit, if feasible. For adolescents, 
local clinical laboratory results during the screening window (or after randomization and 
before dosing) can substitute for central safety laboratory tests and will be entered into the 
eCRF. 
 For females of childbearing potential only: urine or serum pregnancy test performed locally 
during screening for eligibility determination. Blood sample for serum pregnancy test will be 
collected for women of childbearing potential during screening (for patients who meet 
eligibility criteria and are expected to be randomized); samples will be sent to the central 
laboratory for testing (see Section 12.8.2.2). 


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 Blood samples for immunogenicity: 
 Blood sample for exebacase-specific ADA testing will be collected during screening 
(for patients who meet eligibility criteria and are expected to be randomized) or after 
randomization and before dosing; the ADA sample will be sent to the central laboratory 
for testing (Section 12.8.2.3).
Blood samples for exebacase-specific IgE testing will be collected during screening 
(for patients who meet eligibility criteria and are expected to be randomized) or after 
randomization and before dosing and retained at the site. If a patient has clinical signs or 
symptoms of a potential allergic reaction that may be attributed to study drug 
(Section 9.4.1.1), a blood sample for exebacase-specific IgE will be collected as soon as 
possible within 2 hours of the event, if feasible, and both this sample and the IgE sample 
at screening will be sent to a central laboratory for testing (Section 12.8.2.3).
 Blood sample for PK: the pre-dose sample will be collected during screening (for patients 
who meet eligibility criteria and are expected to be randomized or after randomization and 
before dosing); samples will be sent to the central laboratory for testing (Section 12.8.2.4). 
 Blood cultures, as follows: 
 The “qualifying” blood culture from specimens collected within approximately 72 hours 
before randomization (per the inclusion criteria in Section 10.1) will be recorded in the 
eCRF and the S. aureus isolate should be sent to the central laboratory. The site will 
make all efforts to work with the local microbiology laboratory to ensure that, wherever 
possible, the S. aureus isolate from the qualifying blood culture is retained and sent to the 
central laboratory. 
 Note: Since susceptibility of the S. aureus isolate is a stratification factor 
(Section 12.3), the site will make all efforts to work with the local microbiology 
laboratory to ensure that susceptibility results from blood cultures are obtained before 
randomization to enable stratification by MRSA or MSSA. If a blood culture was 
performed for the current S. aureus infection prior to the qualifying blood culture, 
susceptibility results from the prior blood culture may be used. If the patient has a 
concomitant S. aureus infection at another body site from which susceptibility results 
are available (e.g., skin, abscess), the susceptibility results from this other culture may 
be used. If the patient is known to be colonized with MRSA, MRSA may be selected 
for the stratification factor. 
 In addition to the study-qualifying blood culture from specimens collected within 
approximately 72 hours before randomization, 1 aerobic blood culture will be collected 
during screening (or after randomization and before dosing), collected via peripheral 
venipuncture when possible. 


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 Results of all blood cultures performed (from the initial S. aureus-positive culture) will 
be entered in the eCRF (whether positive or negative for S. aureus). 
 All S. aureus isolates, including from cultures collected pre-study, should be sent to the 
central laboratory (see Section 12.8.2.5). 
 Other (non-blood) cultures should be performed to determine the source of S. aureus BSI/IE 
(Section 12.7) and evaluate metastatic foci (Section 12.12). Results of other (non-blood) 
cultures (whether positive or negative for S. aureus) will be entered in the eCRF, and all 
S. aureus isolates, including from cultures collected pre-study, should be sent to the central 
laboratory (Section 12.8.2.6). 
 12-lead ECG at screening or after randomization and before dosing (Section 12.9). 
 Complete physical examination, including body weight and height (see Section 12.10). 
 Vital signs (blood pressure, respiratory rate, heart rate, and temperature) (Section 12.11). 
 If more than one vital sign measurement is taken within the approximately 24 hours prior 
to randomization, the most abnormal value will be recorded in the eCRF. 
 Metastatic foci and septic emboli evaluation will be evaluated; diagnostic testing to assess 
metastatic foci or septic emboli (e.g., imaging, aspiration, and/or cultures) will be performed 
as clinically indicated (see Section 12.12). 
 Signs and symptoms attributable to S. aureus BSI/IE. Select symptoms will also be evaluated 
at pre-BSI/IE. Pre-BSI/IE is the patient’s “usual state of health” before the BSI/IE started. 
The specific signs and symptoms assessed by the Investigator/Sub-Investigator 
(or other delegated medically qualified person listed on the FDA Form 1572 and trained on 
the protocol) are described in Section 12.13.
Medication review (see Sections 13.6 and 13.7).
AE assessment from the time informed consent/assent is obtained (see Section 14).
11.4. 
Day 1: Study Drug Dosing 
For the purpose of the visit structure, the day of exebacase/placebo dosing is considered Day 1 of 
the study. The following assessments/procedures will be performed on the day of dosing: 
 Randomization: patients who are screened and determined to be eligible for the study will be 
randomly assigned to exebacase or placebo via an Interactive Response Technology (IRT) 
system. 
 The randomization will be stratified by poorly controlled diabetes (yes or no) defined 
below and susceptibility of the S. aureus isolate (MRSA, MSSA, or unknown) will be 
entered into the IRT system. For stratification, poorly controlled diabetes is defined as a 
 A HgA1C test is not 


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required for patients with no medical history of diabetes and no suspicion of diabetes 
during the screening period. These patients will be stratified to “no” for poorly controlled 
diabetes. A HgA1C test should be performed in patients with medical history of diabetes 
or suspicion of diabetes during screening for whom a HgA1C test result within the 
approximately 90 days prior to randomization is not available. If a HgA1C is unavailable 
and testing cannot be performed for these patients prior to randomization, contact the 
Medical Monitor to determine how the patient should be stratified based on available 
clinical information. All efforts will be made to obtain susceptibility results from blood 
cultures before randomization to enable stratification by MRSA or MSSA. If a blood 
culture was performed for the current S. aureus infection prior to the qualifying blood 
culture, susceptibility results from the prior blood culture may be used. If the patient has 
a concomitant S. aureus infection at another body site from which susceptibility results 
are available (e.g., skin, abscess), the susceptibility results from this other culture may be 
used. If the patient is known to be colonized with MRSA, MRSA may be selected for the 
stratification factor (Section 12.8.2.5).
 CrCl will be entered into the IRT system and the system will provide the dose of study 
drug (Section 9.4). Serum creatinine to calculate CrCl will be performed as close to the 
start of study drug dosing as possible (but not more than approximately 24 hours before 
the start of study drug dosing; Section 12.8.1). The Cockcroft-Gault formula for 
2 and serum 
creatinine result obtained locally is provided in Section 12.8.1.1. 
 The IRT system will also provide the PK group (described in more detail later in this 
section). 
 Study drug dosing: Exebacase/placebo dosing will occur as soon as possible after 
randomization. Study drug dosing is described in Sections 9.4.1, 13, and the 
Pharmacy Manual.
 Patients must be observed during the study drug infusion by someone from the clinical 
care team or research team with patient care experience (Section 9.4.1.1). 
If a patient has clinical signs or symptoms of a potential allergic reaction that may be 
attributed to study drug (Section 9.4.1.1), a blood sample for exebacase-specific IgE will 
be collected as soon as possible within 2 hours of the event, if feasible, and both this 
sample and the IgE sample collected at screening will be sent to the central laboratory for 
testing (Section 12.8.2.3).
 If not already done during screening (as preferred; Section 11.3 above), make all efforts to 
determine the source of S. aureus BSI/IE (e.g., full physical examination, imaging as needed, 
cultures of other infected body sites or catheters that may be considered the source) within 
1 week after randomization (Section 12.7). 


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 Blood and urine samples for clinical safety laboratory tests will be collected approximately 
24 hours post-dose (Day 2) and sent to the central laboratory for testing 
(see Section 12.8.2.1). If a blood or urine sample for safety laboratory testing by the central 
laboratory is not able to be obtained at a given timepoint/visit, the local laboratory results 
may be entered into the eCRF for that timepoint/visit, if feasible. For adolescents, local 
clinical laboratory results from during the approximately 24 hours post-dose (Day 2) can 
substitute for central safety laboratory tests and will be entered into the eCRF. 
 All patients will be assigned to one of two PK sampling schemes and blood samples will be 
collected at 3 timepoints as listed below, and sent to the central laboratory for measurement 
of exebacase (Section 12.8.2.4). The IRT system will also provide the PK group. 
 PK Group 1: pre-dose (collected during screening for patients who meet eligibility 
criteria and are expected to be randomized or after randomization and before dosing), 
within 5 to 25 minutes after the end of infusion, and between 3 to 5 hours after the end of 
infusion. 
 PK Group 2: pre-dose (collected during screening for patients who meet eligibility 
criteria and are expected to be randomized or after randomization and before dosing), 
within 5 to 25 minutes after the end of infusion, and between 8 to 12 hours after the end 
of infusion. 
 Blood culture: One aerobic blood culture will be collected daily during the study until 
2 consecutive negative cultures followed out to negative for at least 48 hours on 2 different 
days are obtained after exebacase/placebo administration (collected via peripheral 
venipuncture when possible). Note: blood cultures may be collected every other day for 
adolescents. 
 Results of all blood cultures (whether positive or negative for S. aureus) will be entered 
in the eCRF. 
 All S. aureus isolates will be sent to the central laboratory (Section 12.8.2.5). 
 Other (non-blood) cultures should be performed to determine the source of S. aureus BSI/IE 
(Section 12.7) and evaluate metastatic foci (Section 12.12), and as clinically indicated during 
the study. Results of other (non-blood) cultures (whether positive or negative for S. aureus) 
will be entered in the eCRF, and all S. aureus isolates will be sent to the central laboratory 
(Section 12.8.2.6). 
 Vital signs (blood pressure, respiratory rate, heart rate, and temperature) will be performed 
approximately 30 to 40 minutes after the start of infusion and as clinically indicated during 
the infusion (Section 12.11). 
 Metastatic foci and septic emboli evaluation will be evaluated; diagnostic testing to assess 
metastatic foci or septic emboli (e.g., imaging, aspiration, and/or cultures) will be performed 
as clinically indicated (see Section 12.12). 


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 Signs and symptoms attributable to S. aureus BSI/IE. The specific signs and symptoms 
assessed by the Investigator/Sub-Investigator (or other delegated medically qualified person 
listed on the FDA Form 1572 and trained on the protocol) are described in Section 12.13. 
 Echocardiography: 
 
randomization. All efforts will be made to perform the TTE or TEE before 
randomization. 
o Where possible, a TEE will be performed and is recommended in patients with 
BMI >30 kg/m2; the TEE may be performed within 3 days before or after 
randomization unless the TEE is performed due to clinical suspicion of L-IE
(see below). 
o
In patients that have clinical findings suggestive of L-IE (new murmur, worsening 
cardiac function, and/or peripheral or central nervous embolic phenomenon), a TEE 
will be performed before randomization to rule out mitral and/or aortic valve 
vegetation(s) or the patient will be excluded from the study per exclusion criterion #2 
(Section 10.2). In cases where there is an alternative cause of new heart failure or 
cerebral emboli, a patient with a negative TTE for L-IE may be discussed with the 
Medical Monitor for potential enrollment. 
o 
S. aureus 
), an echocardiogram will be performed before randomization to 
rule out L-IE. A TTE may be used performed with permission of the 
Medical Monitor. If this echocardiogram is not performed or L-IE is not ruled out by 
this echocardiogram, the patient should not be randomized. 
 In adolescents (12 to <18 years of age), echocardiograms (TTE or TEE) will be 
performed as clinically indicated taking into consideration risk factors for endocarditis, 
(e.g., structurally abnormal heart [including pacemakers]), clinical features suggestive of 
endocarditis (e.g., new murmur), or persistent bacteremia [McMullan 2020], described in 
Section 12.14. 
 If the patient had an echocardiogram performed prior to the study that was intended to 
evaluate the current infection, it will be sent to the central echocardiography laboratory as 
directed by the Sponsor and an additional TTE or TEE is not required unless as indicated 
randomization. 
 The results of all echocardiograms will be entered in the eCRF. Images from all 
echocardiograms will be provided to the central echocardiography laboratory as directed 
by the Sponsor. 


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 If not already done prior to the study, intravenous catheters known or suspected to be 
infected must be removed, and as clinically needed replaced, preferably at a different site, 
as soon as possible within approximately 72 hours after randomization (Section 12.15).
Other hemodialysis access types (i.e., AV fistulas or AV grafts) that are known or suspected 
to be infected will be evaluated for removal/replacement, if clinically feasible. 
If removal/debridement is not feasible based on standard medical practice, the patient should 
be discussed with the Medical Monitor for potential enrollment. 
 In patients with CVCs, ultrasounds to evaluate clots in the vein should be performed within 
approximately 48 hours after randomization, unless the clot in the vein has been detected 
within this timeframe via other method (e.g., imaging such as CT scan or MRI or direct 
visualization during surgery) (Section 12.16). 
 Medication review (see Sections 13.6 and 13.7). 
 AE assessment (see Section 14). 
11.5. 
Days 7, 14, 30, 60, and Daily Assessments 
Study visits are performed on Days 7, 14, 30, and 60 after study drug dosing. Visit windows are 
as follows: Day 7 (±1 day), Day 14 (±1 day), Day 30 (±4 days), Day 60 (±7 days). In addition, 
some study assessments/procedures are performed daily. The following assessments/procedures 
will be performed at the timepoints noted below:
 The duration of SoCA will generally be from 2 to 8 weeks (14 to 56 days). If a longer 
duration of treatment with SoCA is anticipated, this must be discussed prior to randomization 
with the Medical Monitor. Long-term oral antibiotic suppression therapy 
(e.g., for osteomyelitis), is not considered to be SoCA for S. aureus BSI/IE and would be 
considered a “concomitant medication” as described in Section 9.4.2.
 The eCRF will collect information on the entire course of SoCA for the patient’s current 
episode of S. aureus BSI/IE, including SoCA received prior to the patient’s entry in the 
study. 
 Diagnosis determined by the Investigator/Sub-Investigator (or other delegated medically 
qualified person listed on the FDA Form 1572 and trained on the protocol) on Day 7 based 
on the definitions in Section 12.5. 
If not already done during screening (as preferred; Section 11.3 above), make all efforts to 
determine the source of S. aureus BSI/IE (e.g., full physical examination, imaging as needed, 
cultures of other infected body sites or catheters that may be considered the source) 
within 1 week after randomization (Section 12.7). The resolution of the source of S. aureus 
BSI/IE will be evaluated at Days 7, 14, 30, and 60. 


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 Blood and urine samples for clinical safety laboratory tests will be collected on 
Day 14 for adults* and Day 30 and sent to the central laboratory (see Section 12.8.2.1).  
*The collection of Day 14 samples is not required for adolescents. Results from local clinical 
laboratory testing completed within the Day 14 visit window should be entered into the 
eCRF if available and feasible. For all patients, if a blood or urine sample for safety 
laboratory testing by the central laboratory is not able to be obtained at a given 
timepoint/visit, the local laboratory results may be entered into the eCRF for that 
timepoint/visit, if feasible. If a blood or urine sample for safety laboratory testing by the 
central laboratory or local laboratory results are not able to be obtained at the Day 30 visit, 
samples may be collected between the Day 30 and 60 visits when collecting the blood 
sample(s) for exebacase-specific ADA and pregnancy testing (if applicable). 
For adolescents, the results of local clinical laboratory testing during the screening window 
and at all other timepoints corresponding to the protocol can substitute for central safety 
laboratory tests and will be entered into the eCRF; samples for ADA and IgE must be 
collected at the timepoints specified in the protocol and sent to the central laboratory. 
 Blood sample for serum pregnancy test will be collected between the Days 30 and 60 visits
for women of childbearing potential only and sent to the central laboratory for testing 
(see Section 12.8.2.2). 
 Blood cultures: One aerobic blood culture will be collected daily during the study until 
2 consecutive negative cultures followed out to negative for at least 48 hours on 2 different 
days are obtained after exebacase/placebo administration (via peripheral venipuncture when 
possible). Additional blood cultures will be performed as clinically indicated. 
Note: blood cultures may be collected every other day for adolescents. 
 Results of all blood cultures (whether positive or negative for S. aureus) will be entered 
in the eCRF. 
 All S. aureus isolates will be sent to the central laboratory (Section 12.8.2.5). 
 Other (non-blood) cultures should be performed to determine the source of S. aureus BSI/IE 
(Section 12.7) and evaluate metastatic foci (Section 12.12), and as clinically indicated during 
the study. Results of other (non-blood) cultures (whether positive or negative for S. aureus) 
will be entered in the eCRF, and all S. aureus isolates will be sent to the central laboratory 
(Section 12.8.2.6). 
 12-lead ECG on Day 14 (see Section 12.9). 
 Complete physical examination on Days 7, 14, 30, and 60 (see Section 12.10). 
 Vital signs (blood pressure, respiratory rate, heart rate, and temperature) will be performed at 
the Day 7, 14, 30, and 60 visits for visits performed “in person” or may be obtained via the 
study-specific mobile health service, if feasible (Section 12.11). 


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 If more than one vital sign measurement is taken on the same day, the most abnormal 
value will be recorded in the eCRF. 
 Metastatic foci and septic emboli evaluation will be evaluated at the Day 7, 14, 30, 
and 60 visits; diagnostic testing to assess metastatic foci or septic emboli 
(e.g., imaging, aspiration, and/or cultures) will be performed as clinically indicated 
(see Section 12.12). Note: For the assessment of clinical outcome (Section 12.18), metastatic 
foci identified through Day 7 are considered part of the patient’s baseline S. aureus BSI/IE; 
new metastatic foci identified after Day 7 or new septic emboli after study drug dosing are 
considered complications of S. aureus BSI/IE for the purpose of assessing clinical outcome. 
New septic emboli are defined as an acute presentation of septic emboli after dosing and are 
a reason for failure for clinical outcome; septic emboli that are incidentally found on imaging 
are considered part of the patient’s baseline S. aureus BSI/IE if found before Day 7. 
 Signs and symptoms attributable to S. aureus BSI/IE will be evaluated at the Day 7, 14, 30, 
and 60 visits. Additionally, if SoCA is changed after study drug dosing due to lack of clinical 
response, signs and symptoms will be assessed on the day of the SoCA change. The specific 
signs and symptoms assessed by the Investigator/Sub-Investigator (or other delegated 
medically qualified person listed on the FDA Form 1572 and trained on the protocol) are 
described in Section 12.13. 
Echocardiography: 
 If the echocardiogram was not already done before randomization (as preferred and 
required for certain patients; see Section 11.4 above), a TTE or TEE will be performed 
within 3 days after randomization for adult patients. In adolescents (12 to <18 years 
of age), echocardiograms will be performed as clinically indicated (Section 12.14). 
 Follow-up echocardiograms will be performed as clinically indicated. 
 The results of all echocardiograms performed through the Day 60 visit will be entered in 
the eCRF. Images from all echocardiograms through the Day 60 visit will be provided to 
the central echocardiography laboratory as directed by the Sponsor (see Section 12.14). 
If not already done, IV catheters known or suspected to be infected must be removed, and as 
clinically needed replaced, preferably at a different site, as soon as possible within 
approximately 72 hours after randomization. Other hemodialysis access types 
(i.e., AV fistulas or AV grafts) that are known or suspected to be infected will be evaluated 
for removal/replacement, if clinically feasible. If removal/debridement is not feasible based 
on standard medical practice, the patient should be discussed with the Medical Monitor for 
potential enrollment (Section 12.15).


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 If not already done, in patients with CVCs, ultrasounds to evaluate clots in the vein should be 
performed within approximately 48 hours after randomization, unless the clot in the vein 
has been detected within this timeframe via other method (e.g., imaging such as CT scan or 
MRI or direct visualization during surgery) (Section 12.16). 
 Blood samples for exebacase-specific ADA will be collected on any day between the 
Day 30 and Day 60 visit windows (i.e., between Day 26 and Day 67) and sent to the 
central laboratory for testing (Section 12.8.2.3). 
 Ongoing medication review through the Day 60 visit (Sections 13.6 and 13.7). 
 Ongoing AE assessment through the Day 60 visit (Section 14).
 Clinical outcome will be assessed by the Investigator/Sub-Investigator (or other delegated 
medically qualified person listed on the FDA Form 1572 and trained on the protocol) at 
Days 14, 30, and 60. The clinical outcome definitions are in Section 12.18. 
 Vital status (whether the patient is alive or dead, or last known date alive if vital status is 
unknown) will be obtained at Days 14, 30, and 60 for all patients, including patients that 
discontinue the study or withdraw consent/assent (as described in the informed 
consent/assent form). The patient’s vital status will be determined using available sources 
(e.g., the patient, patient’s contacts, hospital and other medical records, and public records, 
such as social media, obituaries, social security death index), as described in the informed 
consent/assent form and FDA guidance (see Section 12.17). 
 Health resource utilization information will be collected through Day 60 (Section 12.20). 
11.5.1. 
Visits Performed Remotely by Telephone/Telehealth, Use of Medical Records,
and Use of Mobile Health Services 
Every attempt must be made to ensure the patient returns for study visits, including offering 
support to the patient to facilitate return for the visit (e.g., reimbursement of travel expenses). 
If extenuating circumstances prevent the patient from returning to the study site for a visit, 
the site must contact the Medical Monitor or designee* to discuss whether a visit may be 
conducted by telephone or other telehealth technology (e.g., videoconference) in order to 
facilitate collection of as much data as possible for the Investigator/Sub-Investigator 
(or other delegated medically qualified person listed on the FDA Form 1572 and trained on the 
protocol) to assess clinical outcome. It will be recorded in the eCRF that the visit was conducted 
by telephone/telehealth. The information to be collected during a telephone/telehealth visit is 
listed subsequently in this section. 
* For patients that have travel restrictions due to COVID-19, the Day 30 or Day 60 visit may 
be conducted by telephone/telehealth without Medical Monitor pre-approval. The reason 
for the telephone/telehealth visit (i.e., COVID-19) will be documented in the eCRF. 
All efforts should be made to collect laboratory samples, if feasible. 


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The following information will be collected during the telephone/telehealth visit and entered in 
the eCRFs: any AEs that may have occurred since the last visit and outcome of any ongoing 
AEs, thorough medical review of body systems to assess signs and symptoms of S. aureus
BSI/IE, outcome of pre-existing or presence of new metastatic foci, outcome of primary source 
of infection, SoCA and reasons for any changes in SoCA, concomitant medications, 
surgeries/procedures, vital status, and clinical outcome. 
Medical records* may be used to supplement information obtained during the 
telephone/telehealth visit. If the patient is at another facility (e.g., nursing home, another 
hospital), the site will obtain medical records from that facility whenever possible.
In rare instances in which it is not feasible to conduct study visits “in person” or by 
telephone/telehealth, medical records* alone may be used for physical examinations, 
signs/symptoms, and metastatic foci/septic emboli assessments after contacting the 
Medical Monitor or designee. 
* When medical records are used alone or to supplement information collected during the 
telephone/telehealth visit, the physical examinations, signs/symptoms, and metastatic 
foci/septic emboli assessments extracted from the medical record will be recorded in the 
site’s source documents and entered in the relevant eCRFs. The Investigator/ 
Sub-Investigator (or other delegated medically qualified person listed on the 
FDA Form 1572 and trained on the protocol) is expected to review, sign, and date the 
assessments extracted from the medical record and recorded in the site’s source 
documents. Symptom severity assessments must be made in accordance with Table 9.
The eCRFs will be verified by the site monitor using these source documents.
Mobile health services, specifically contracted for the study, may be used to supplement 
telephone/telehealth visits to perform study visit procedures, such as collecting laboratory 
samples, evaluating vital signs, and/or obtaining a 12-lead ECG, after approval by the 
Medical Monitor or designee.
Mobile health services may include: 
 Day 14: Collection of laboratory samples, evaluation of vital signs, and performance of a 
12-lead ECG. 
 Day 30: Collection of laboratory samples and evaluation of vital signs.
 Day 30 to Day 60: Samples for exebacase-specific ADA and pregnancy testing may be 
collected between the Day 30 and Day 60 visit windows (i.e., between Day 26 to Day 67).
If a blood or urine sample for safety laboratory testing by the central laboratory or local 
laboratory results are not able to be obtained at the Day 30 visit, samples may be collected on 
any day between the Day 30 and 60 visit windows (i.e., between Day 26 and Day 67) when 
collecting the blood sample(s) for exebacase-specific ADA and pregnancy test (if applicable). 


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Alternatively, local laboratory, vital signs, and ECG data obtained in conjunction with the Day 7, 
14, 30, or 60 visits may be used for the study if available (including using data from medical 
records of another hospital, skilled nursing facility or other similar institution). 
12. 
STUDY ASSESSMENTS 
The study schematic and schedule of assessments are provided in Sections 3 and 4, respectively. 
The study procedures/assessments performed at each visit are described in the subsections under 
Section 11. The individual procedures/assessments are described in detail in the subsections that 
follow. 
12.1. 
Informed Consent/Assent 
Each patient must provide written informed consent or assent before any study-specific 
assessment or procedures are performed. Some patients who will be eligible for the study may
not be able to give written informed consent or assent themselves due to reasons such as 
sedation, unconscious state, etc. Therefore, in a situation where a patient is unable to provide 
written informed consent or assent for themselves, written informed consent may be provided by 
the patient’s legally acceptable representative, as permissible based on local laws and 
regulations. In such cases, if the patient regains the ability to supply informed consent or assent 
themselves, they should be reconsented/assented. For patients 12 to <18 years of age, 
written informed consent from the patient’s parent/guardian or other legally acceptable 
representative will be obtained according to the site’s IRB requirements. For emancipated 
minors, written informed consent will be obtained according to the site’s IRB requirements. 
The informed consent process is described in Section 19.2. 
12.2. 
Inclusion/Exclusion Criteria Review 
The inclusion and exclusion criteria described in Sections 10.1 and 10.2, respectively, will be 
reviewed to determine whether the patient is eligible for the study. For patients who are not 
eligible, the specific inclusion criteria not met, exclusion criteria met, and/or other reasons for 
screen failure will be entered in the IRT system. Study eligibility will be adjudicated by the AC
(Section 12.23). 
12.2.1. 
Contraception Requirements 
Contraception requirements are described in the inclusion criteria (Section 10.1). 
The manufacturer’s prescribing information for SoCA will be referenced for information related 
to pregnancy and contraception. 


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12.2.2. 
Quick SOFA and SOFA Scores 
Sepsis and/or septic shock based on the SOFA score are criteria for complicated S. aureus BSI 
according to the inclusion criterion #4 (Section 10.1) and the diagnosis definition in Table 8 
(Section 12.5). During screening, the quick SOFA (qSOFA) score will be determined for all 
patients. The qSOFA score is used to rapidly identify patients as being more likely to have poor 
outcomes typical of sepsis [Singer 2016], and is defined as having at least 2 of the following 
clinical criteria: r
, altered mental status, and/or systolic blood pressure 
. In patients that have at least 2 of these clinical criteria, a SOFA score will be 
performed to determine whether the patient meets the criteria for sepsis and/or septic shock. 
The SOFA score will be determined according to the criteria described in the Appendix 1 
(Section 23.1). If arterial blood gas (ABG) data is not available from testing performed as part of 
clinical care, oxygen saturation (SpO2) may be used to determine the SOFA score by converting 
to partial pressure of oxygen (PaO2) (see Oxygen Conversion Table; Table 14) and the fraction 
of inspired oxygen (FiO2) may be estimated using the Estimated FiO2 Table (Table 15) provided 
in Section 23.3, Appendix 3. 
12.2.3. 
APACHE II Score 
Baseline APACHE II score will be calculated for all patients. Per exclusion criterion #15 
(Section 10.2), patients with APACHE II score of >30 are excluded from the study. 
The APACHE II score form is provided in the appendix (Section 23.2, Appendix 2). If ABG data 
is not available from testing performed as part of clinical care, SpO2 may be used to determine 
the APACHE II score by converting to PaO2 (see Oxygen Conversion Table; Table 14) and the 
FiO2 may be estimated using the Estimated FiO2 Table (Table 15) provided in Section 23.3, 
Appendix 3, and serum bicarbonate may be used for pH. 
12.3. 
Randomization 
Patients who are screened and determined to be eligible for the study will be randomly assigned 
to receive exebacase or placebo in a 2:1 ratio via the IRT system. Randomized patients will be 
assigned the treatment corresponding to the next available randomization number in the 
respective stratum from the computer-generated randomization schedule. A patient is considered 
randomized when a randomization transaction is recorded in the IRT. Study drug dosing will 
occur as soon as possible after randomization (Section 9.4.1). 
The randomization will be stratified by poorly controlled diabetes (yes or no) as defined below 
and susceptibility of the S. aureus isolate (MRSA, MSSA, or unknown) will be entered into the 
IRT system. For stratification, poorly controlled diabetes is defined as a 
approximately 90 days before randomization. A HgA1C test is not required for patients with no 
medical history of diabetes and no suspicion of diabetes during the screening period. 
These patients will be stratified to “no” for poorly controlled diabetes. A HgA1C test should be 
performed in patients with medical history of diabetes or suspicion of diabetes during screening 
for whom a HgA1C test result within the approximately 90 days prior to randomization is not 


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available. If a HgA1C is unavailable and testing cannot be performed for these patients prior to 
randomization, contact the Medical Monitor to determine how the patient should be stratified 
based on available clinical information. All efforts will be made to obtain susceptibility results 
from blood cultures before randomization to enable stratification by MRSA or MSSA. If a blood 
culture was performed for the current S. aureus infection prior to the qualifying blood culture, 
susceptibility results from the prior blood culture may be used. If the patient has a concomitant 
S. aureus infection at another body site from which susceptibility results are available 
(e.g., skin, abscess), the susceptibility results from this other culture may be used. If the patient is 
known to be colonized with MRSA, MRSA may be selected for the stratification factor 
(Section 12.8.2.5). 
Creatinine clearance value will be entered into the IRT system and the system will provide the 
dose of study drug based on the CrCl value (Section 9.4.1). Serum creatinine to calculate CrCl 
will be performed as close to the start of study drug dosing as possible (but not more than 
approximately 24 hours before the start of study drug dosing; Section 12.8.1). 
The Cockcroft-Gault formula for calculating CrCl using ideal body weight in patients with 
BMI 
 kg/m2 and serum creatinine result obtained locally is provided in Section 12.8.1.1. 
The IRT system will also provide the PK group (Section 12.8.2.4). 
12.4. 
Medical History 
Medical history for 1 year prior to screening will be recorded in the eCRF. Medical history will 
include relevant previous and current medical diagnoses and major surgical procedures.
The current episode of S. aureus BSI/IE (the disease under study) should not be recorded on the 
Medical History eCRF since this is collected separately (i.e., on the Diagnosis eCRF). 
12.5. 
Diagnosis 
The Investigator/Sub-Investigator (or other delegated medically qualified person listed on the 
FDA Form 1572 and trained on the protocol) will determine diagnosis during screening and on 
Day 7. Final diagnosis will be adjudicated by the AC (Section 12.23). This adjudicated final 
diagnosis will be used for the analysis. The diagnosis definitions that will be used by the 
Investigator/Sub-Investigator (or other delegated medically qualified person listed on the 
FDA Form 1572 and trained on the protocol) and AC are provided in Table 8.


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Table 8: 
Diagnosis Definitions 
Diagnosis
Definition
S. aureus R-IE
Definite or possible R-IE based on the Modified Duke Criteria [adapted from 
Li 2000], as defined below, with involvement of pulmonic and/or tricuspid valve(s). 
1. Definite diagnosis: presence of 2 major, 1 major and 3 minor, or 5 minor criteria, 
or 
2. Possible diagnosis:1 major criterion and 1 minor criterion, or 3 minor criteria 
Major and minor criteria are as follows: 
A. Major clinical criteria: 
1. Blood cultures positive: 
a. S. aureus (in the absence of a primary focus) identified from 2 separate 
blood cultures 
b. S. aureus identified from persistently positive blood cultures 
(at least 2 positive cultures of blood samples drawn >12 hours apart, or 
positive results of all of 3 or a majority of 4 or more separate blood 
cultures [with first and last samples drawn at least 1 hour apart]) 
2. Evidence of endocardial involvement: 
a. Echocardiogram positive for IE with pendulum-like intracardiac mass on 
valve or supporting structures, or in the path of regurgitant jets 
b. New valvular regurgitation (worsening or changing of preexisting 
murmur not a sufficient criterion) when confirmed by echocardiogram 
B. Minor clinical criteria: 
1. Predisposition to IE, such as predisposing heart condition, or intravenous 
drug use 
2. 
 
3. Vascular phenomena, such as conjunctival hemorrhage, and Janeway’s 
lesions 
4. Immunologic phenomena, such as glomerulonephritis, Osler’s nodes, 
Roth’s spots, and rheumatoid factor 
5. Microbiologic evidence: positive blood cultures for S. aureus but with no 
major clinical criterion met or serologic evidence of active infection 
Table continued on next page 


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Table 8: 
Diagnosis Definitions (Continued)
Diagnosis 
Definition 
Complicated 
S. aureus BSI 
 
Patient did not have IE based on the Modified Duke Criteria, S. aureus was 
isolated from blood culture; and patient had one or more of the following: 
o Blood culture positive for S. aureus on more than one day 
o Clots in the vein at or near the catheter site seen on ultrasound or other 
method (e.g., MRI, echocardiogram, surgery) 
o Signs or symptoms of metastatic foci of infection (e.g., splenic abscess, 
deep tissue abscess not associated with open wound or other local source of 
infection, septic pulmonary emboli) or hematogenous seeding 
(e.g., of the renal system evidenced by S. aureus bacteriuria [in absence of 
other source such as indwelling ureteral catheter], septic arthritis, 
osteomyelitis) confirmed by physical examination, imaging, and/or culture 
Note: Patients who present with acute osteomyelitis as the first manifestation 
of S aureus BSI (e.g., adolescents) may be enrolled even if original source of 
infection is not known. 
o Persistent fever (oral temperature equivalent 38.0°C [ 100.4°F]) for 
72 hours or more 
o Met criteria for sepsis or septic shock using the SOFA score (definition in  
Section 23 [adapted from Singer 2016]) during the time of 
diagnosis/presumptive diagnosis of BSI 
o Significantly immunocompromised: 
 
AIDS (HIV positive with an AIDS-defining condition or a CD4 count of 
approximately 200 cells/mm³ within approximately 90 days) 
 
Severe leukopenia defined as ANC of approximately 500 cells/mL in 
the 7 days prior to the qualifying blood culture or during the screening 
window 
 
Post organ transplantation including autologous bone marrow or stem 
cell transplantation and on immunosuppressive therapy for the organ 
transplant around the time of presentation with the S. aureus BSI/IE 
 
On treatment for active graft vs. host disease 
 
On immunosuppressive therapy, such as: 
 
Biologics such as infliximab, monoclonal antibodies such as 
daclizumab, methotrexate, cyclophosphamide, or similar agents. 
A list of similar agents is in Appendix 4 in Section 23.4. 
 
Patients who have taken 10 mg of prednisone or equivalent for 
5 days or more. 
 
On myelosuppressive chemotherapy or immunotherapy 
 
Advanced cirrhosis 
Table continued on next page 


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Table 8: 
Diagnosis Definitions (Continued) 
S. aureus
L-IE1 
Definite or possible L-IE based on the Modified Duke Criteria, with involvement 
of mitral and/or aortic valve(s) 
S. aureus L-IE 
and R-IE1
Definite or possible L-IE and R-IE based on the Modified Duke Criteria, 
with involvement of mitral and/or aortic valve(s) and pulmonic and/or 
tricuspid valve(s). 
Uncomplicated 
S. aureus BSI1
Patient did not have IE based on the Modified Duke Criteria; and
 
S. aureus was isolated from blood culture; and 
Patient did not meet criteria for complicated S. aureus BSI 
Abbreviations: BSI=bloodstream infection; IE=infective endocarditis; L-IE=left-sided infective endocarditis; R-IE=right-sided 
infective endocarditis 
1. 
Patients with known or suspected L-IE or uncomplicated S. aureus BSI are not eligible for the study. The diagnosis 
definitions are included here in the event that patients are determined to have these diagnoses post-randomization. If patients 
with L-IE or uncomplicated S. aureus BSI are enrolled, they will continue in the study and be followed for safety and 
efficacy.  
12.6. 
Risk Factors 
The following risk factors for complicated S. aureus BSI, as described in the inclusion criteria 
(Section 10.1), will be recorded in the eCRF: 
 Preexisting right-sided valvular heart disease
 Surgery within the previous 30 days that puts the patient at risk for nosocomial bacteremia 
(e.g., orthopedic, cardiothoracic, or intraabdominal surgery)
 Extravascular foreign material. Note: Catheters including ports, AV fistulas and related 
dialysis access points are considered intravascular foreign material.
 Hemodialysis
12.7. 
Source of S. aureus Infection 
All efforts will be made to determine the source of S. aureus BSI/IE (e.g., full physical 
examination, imaging as needed, cultures of other infected body sites or catheters that may be 
considered the source), preferably during screening or within 1 week after randomization. 
The source of S. aureus BSI/IE will be recorded in the eCRF. The resolution of the source of 
S. aureus BSI/IE will be evaluated at Days 7, 14, 30, and 60. 
The primary source of BSI/IE and adequacy of source control will be adjudicated by the AC.
12.8. 
Laboratory Tests 
12.8.1.
Laboratory Tests Performed by the Local Laboratory 
The central laboratory will not be providing ‘real-time’ results; therefore, limited laboratory tests 
may need to be performed by the site’s local laboratory during screening so that timely results 
are available for study eligibility determination, stratification, and to determine the dose of study 
drug (based on CrCl using ideal body weight; see below). If local laboratory results are already 


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available within the approximately 72 hours prior to screening from standard-of-care/routine 
testing, these results may be used to support eligibility determination, unless otherwise specified 
below in underlined text. The laboratory tests that are required to be available locally are as 
follows: 
 Serum creatinine to calculate CrCl will be performed as close to the start of study drug 
dosing as possible (but not more than approximately 24 hours before the start of study drug 
dosing). CrCl is used for eligibility determination (in patients who are asplenic; see exclusion 
criterion #11 in Section 10.2) and to determine the dose of study drug (see Section 9.4.1). 
Therefore, is important to use the serum creatinine result obtained closest to the start of study 
drug dosing to determine CrCl to guide dosing. The Cockcroft-Gault formula for calculating 
CrCl using serum creatinine result and ideal body
2 is 
provided in Section 12.8.1.1.
If a HgA1C value is not already available approximately 90 days before randomization in 
patients with medical history of diabetes or suspicion of diabetes during screening, a HgA1C 
will be performed to determine if diabetes is poorly controlled (since poorly controlled 
diabetes, defined as a H
within approximately 90 days before randomization, 
is a stratification factor; see Section 12.3). If a HgA1C testing cannot be performed for 
patients with diabetes prior to randomization, contact the Medical Monitor to determine how 
the patient should be stratified based on available clinical information. A HgA1C test is not 
required for patients with no medical history of diabetes and no suspicion of diabetes during 
the screening period. These patients will be stratified to “no” poorly controlled diabetes.
 
-hCG pregnancy test (for women of childbearing potential; see inclusion 
criteria in Sections 10.1 and 12.8.2.2) 
 FSH (to confirm postmenopausal status as applicable; see inclusion criteria in Section 10.1) 
 Laboratory tests for SOFA score as needed (see Sections 12.2.2 and 23.1) 
 Laboratory tests for APACHE II score (see Sections 12.2.3 and 23.2) 
 Other safety laboratory tests may be performed locally at the Investigator’s/ 
Sub-Investigator’s (or other delegated medically qualified person listed on the 
FDA Form 1572 and trained on the protocol) discretion to assess the patient in general for 
study eligibility or during the study per the site’s standard-of-care for routine clinical 
management of the patient. 
Note: If a blood or urine sample for safety laboratory testing by the central laboratory is not able 
to be obtained at a given timepoint/visit, the local laboratory results may be entered in the eCRF 
for that timepoint/visit, if feasible. For adolescents, the results of local clinical laboratory testing 
during the screening window and at all other timepoints corresponding to the protocol can 
substitute for central safety laboratory tests and will be entered into the eCRF; samples for 


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ADA and IgE must be collected at the timepoints specified in the protocol and sent to the central 
laboratory. 
12.8.1.1. Estimated Creatinine Clearance by Cockcroft-Gault 
Estimated CrCl will be calculated for eligibility determination (in patients who are asplenic; 
see exclusion criterion #11 in Section 10.2) and to determine the dose of study drug 
(see Section 9.4.1) using the serum creatinine result obtained locally as close to the start of study 
drug dosing as possible (but not more than approximately 24 hours before the start of study drug 
dosing), as described above in Section 12.8.1. Estimated CrCl is calculated by Cockcroft-Gault 
formula as follows: 
In Patients with BMI <30 kg/m2: 
Estimated CrCl = [(140 – age) x weight in kg]/[72 x serum creatinine in mg/dL] 
[x 0.85 if female]. 
In Patients with 
 kg/m2: 
Estimated CrCl = [(140 – age) x ideal body weight in kg]/[72 x serum creatinine in mg/dL] 
[x 0.85 if female]. 
 For height in inches: Ideal body weight = 2.3 kg x each inch over 5 feet + W 
 
W
W = 50 kg for males; 45.5 kg for females 
12.8.2. 
Laboratory Sample Collection for Sending to Central Laboratory
The following subsections describe the laboratory samples that will be collected and sent to the 
central laboratory. The details for sample collection, preparation, and shipping to the central
laboratory will be provided in a separate laboratory manual.
12.8.2.1. Samples for Safety Laboratory Testing
Blood and urine samples for safety laboratory tests (biochemistry, hematology, coagulation, 
and urinalysis) will be collected during screening (for patients who meet eligibility criteria and 
are expected to be randomized) or after randomization and before dosing, approximately 
24 hours after study drug administration (Day 2), on Day14 for adults*, and on Day 30; the 
samples will be sent to a central laboratory for testing. *The collection of Day 14 samples is not 
required for adolescents. Results from local clinical laboratory testing completed within the 
Day 14 visit window should be entered into the eCRF if available and feasible. 
Note: For all patients, if a blood or urine sample for safety laboratory testing by the central 
laboratory is not able to be obtained at a given timepoint/visit, the local laboratory results may be 
entered into the eCRF for that timepoint/visit, if feasible. If a blood or urine sample for safety 
laboratory testing by the central laboratory or local laboratory results are not able to be obtained 


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at the Day 30 visit, samples may be collected on any day between the Day 30 and 60 visit 
windows (i.e., between Day 26 and Day 67) when collecting the blood sample(s) for 
exebacase-specific ADA and pregnancy test (if applicable). 
Note: For adolescents, the results of local clinical laboratory testing during the screening window 
and at all other timepoints corresponding to the protocol can substitute for central safety 
laboratory tests and will be entered into the eCRF; samples for ADA and IgE must be collected 
at the timepoints specified in the protocol and sent to the central laboratory. 
12.8.2.2. Samples for Pregnancy Testing
For females of childbearing potential only, blood samples for serum pregnancy test will be 
collected during screening (for patients who meet eligibility criteria and are expected to be 
randomized) and between the Days 30 and 60 visits and sent to the central laboratory for testing.
(Note: A urine or serum pregnancy test will be done locally as part of screening for eligibility; 
Section 12.8.1).
12.8.2.3. Samples for Immunogenicity
Blood samples for exebacase-specific ADA will be collected during screening (for patients who 
meet eligibility criteria and are expected to be randomized) or after randomization and before 
dosing and on any day between the Day 30 and Day 60 visit windows (i.e., between Day 26 and 
Day 67); samples are sent to the central laboratory for testing. 
Blood samples for exebacase-specific IgE testing will be collected during screening 
(for patients who meet eligibility criteria and are expected to be randomized) and retained at the 
site. If a patient has treatment-emergent clinical signs or symptoms of a potential allergic 
reaction that may be attributed to study drug (Section 9.4.1.1), a blood sample for 
exebacase-specific IgE will be collected as soon as possible within 2 hours of the event, 
if feasible, and both this sample and the IgE sample at screening will be sent to a central 
laboratory for testing. 
12.8.2.4. Samples for Pharmacokinetics
All patients will be assigned to one of two PK sampling schemes and blood samples will be 
collected at 3 timepoints as listed below, and sent to the central laboratory for measurement of 
exebacase:
 PK Group 1: pre-dose (collected during screening for patients who meet eligibility criteria 
and are expected to be randomized or after randomization and before dosing), within 
5 to 25 minutes after the end of infusion, and between 3 to 5 hours after the end of infusion. 
 PK Group 2: pre-dose (collected during screening for patients who meet eligibility criteria 
and are expected to be randomized or after randomization and before dosing), within 
5 to 25 minutes after the end of infusion, and between 8 to 12 hours after the end of infusion. 


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The actual time of PK sample collection, actual time of start and end of infusion, actual rate of 
volume and rate of infusion, and dosing information will be recorded. 
12.8.2.5. Blood Cultures 
Blood cultures will be collected from a peripheral venipuncture site when possible. The study 
site’s local microbiology laboratory will perform identification and in vitro susceptibility testing 
to SoCA according to local practices. The results of all blood cultures (whether positive or 
negative for S. aureus) performed (from the initial S. aureus-positive blood culture collected
pre-study through the Day 60 visit) will be entered in the eCRF. The S. aureus isolates from all 
blood cultures (from the initial S. aureus-positive blood culture collected pre-study through the 
Day 60 visit) should be sent to the central laboratory. If two blood cultures are drawn at the same 
timepoint, only one S. aureus isolate from the blood cultures will be sent to the central 
laboratory. Blood cultures will be performed at the following timepoints: 
 Qualifying blood culture: The “qualifying” blood culture from specimens collected within 
approximately 72 hours before randomization (per the inclusion criteria in Section 10.1) will 
be recorded in the eCRF and the S. aureus isolate should be sent to the central laboratory. 
The site will make all efforts to work with the local microbiology laboratory to ensure that, 
wherever possible, the S. aureus isolate from the qualifying blood culture is retained and sent 
to the central laboratory. 
 Note: Since susceptibility of the S. aureus isolate is a stratification factor (Section 12.3), 
the site will make all efforts to work with the local microbiology laboratory to ensure that 
susceptibility results from blood cultures are obtained before randomization to enable 
stratification by MRSA or MSSA. If a blood culture was performed for the current
S. aureus infection prior to the qualifying blood culture, susceptibility results from the 
prior blood culture may be used. If the patient has a concomitant S. aureus infection at 
another body site from which susceptibility results are available (e.g., skin, abscess), 
the susceptibility results from this other culture may be used. If the patient is known to be 
colonized with MRSA, MRSA may be selected for the stratification factor. 
 Screening: One aerobic blood culture will be collected during screening (or after 
randomization and before dosing). 
 Daily: One aerobic blood culture will be collected daily during the study until 2 consecutive 
negative cultures followed out to negative for at least 48 hours on 2 different days are 
obtained after exebacase/placebo administration. Note: blood cultures may be collected every 
other day for adolescents. 
 Additional blood cultures will be performed as clinically indicated.


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12.8.2.5.1. Microbiological Sample Collection and Processing 
The details for microbiological sample collection, processing, and shipping to the central 
laboratory will be provided in a separate Laboratory Manual. 
Blood samples must be transported to the local microbiology laboratory as soon as possible and 
incubated within less than 24 hours of collection.
Organism Identification 
When growth is present in the blood culture bottle, a Gram stain must be performed. 
Gram-positive cocci in clusters are indicative of a presumptive staphylococcal infection. For this 
study, rapid identification and differentiation of S. aureus from coagulase-negative staphylococci 
is critical to patient enrollment. Local microbiology laboratories are encouraged to utilize the 
direct tube coagulase test, when available, to identify S. aureus. Patients may be enrolled if their 
Gram stain shows Gram-positive cocci in clusters and either the direct tube coagulase test is 
positive after 4 hours of incubation indicating S. aureus or latex slide agglutination test is 
positive.
Additionally, patients may be enrolled based on rapid diagnostic test results if an FDA-cleared or 
CE-IVD certified rapid diagnostic for S. aureus is available at the site. Examples of rapid 
diagnostic tests are listed in the table below. 
Examples of FDA cleared and CE-IVD Certified Rapid Diagnostic Tests for Detection of 
S. aureus Directly from Positive Blood Cultures
Manufacturer 
Test Name 
Alere (Abbott) 
BinaxNOW S. aureus 
Biofire Diagnostics (BioMerieux Company) 
Film Array System and BCID Panel 
AdvanDX (OpGen Company) 
PNA QuickFISH and mecA XpressFISH 
Luminex 
Verigene 
Cepheid 
GeneXpert 
Miacom-MetaSystems 
hemoFISH Masterpanel 
GenMark 
ePlex 
Accelerate Diagnostics 
PhenoTest 
Organisms must be isolated in pure culture and identified according to the local laboratory’s 
standard operating procedures. Patients who have a negative result for S. aureus on blood culture 
or have a missing blood culture(s) will continue to be followed in the study. Only S. aureus 
strains will be sent to the central microbiology laboratory for confirmation of identification and 
standardized susceptibility testing. The local laboratory results of Gram stain, organism 
identification, and rapid diagnostic testing will be recorded in the eCRF. 


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Diagnostic Testing 
Laboratories routinely using and clinical reporting the results of FDA-approved assays for the 
detection of mec A or mecA/C genes should record the results of the diagnostic test in the eCRF. 
Susceptibility Testing 
Susceptibility testing of S. aureus will be performed according to the local laboratory’s standard 
operating procedures and in accordance with the guidelines of the Clinical and Laboratory 
Standards Institute (CLSI) and/or European Committee on Antimicrobial Susceptibility Testing 
(EUCAST). At a minimum, the local laboratory will test susceptibilities to daptomycin, 
vancomycin, and oxacillin or cefoxitin (CLSI recommended surrogate for oxacillin to detect 
MRSA). The results of susceptibility testing will be recorded in the eCRF.
Archiving and Shipment of Isolates
All S. aureus strains will be stored frozen at -
-automatic defrost freezer) at the 
site’s local microbiology laboratory as backup samples. The S. aureus isolates will be shipped to 
the designated central microbiology laboratory as directed in a separate microbiology laboratory 
manual. Backup isolates must be stored at the site until notification from ContraFect or designee 
that they can be discarded. 
Testing at the Central Laboratory 
The central microbiology laboratory will repeat the identification and perform in vitro 
susceptibility testing of isolates; the central laboratory results will be used for the analysis. 
Further evaluation to identify the potential mechanism of resistance may be performed. 
12.8.2.6. Other (Non-Blood) Cultures
“Other” cultures (i.e., cultures from catheter tips or body sites or body fluids other than blood) 
will be performed to determine the source of S. aureus BSI/IE (Section 12.7) and evaluate 
metastatic foci (Section 12.12), and as clinically indicated during the study. The results of all 
other (non-blood) cultures (whether positive or negative for S. aureus) collected pre-study 
through the Day 60 visit will be recorded in the eCRF. S. aureus isolates from all other 
(non-blood) cultures collected pre-study through the Day 60 visit should be sent to the central 
laboratory. 
12.8.3. 
Laboratory Tests Performed by the Central Laboratory(ies) 
The central laboratory(ies) will not be providing ‘real-time’ results; therefore, limited laboratory 
tests may be performed locally to assess the patient for study eligibility/determine study drug 
dose, during the study per the site’s standard-of-care for routine clinical management of the 
patient, or for adolescent patients (as described in Section 12.8.1).


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The following laboratory tests will be performed at the central laboratory(ies): 
 Biochemistry: albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), bicarbonate, bilirubin (total, direct, indirect), blood urea nitrogen 
(BUN), calcium, chloride, creatinine, gamma-glutamyl transferase (GGT), glucose, lactate 
dehydrogenase, phosphorus, potassium, sodium, total protein. (Timepoints for sample 
collection are described in Section 12.8.2.1). 
 Hematology: hematocrit, hemoglobin, mean corpuscular hemoglobin (MCH), mean 
corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), 
platelet count, red blood cell (RBC) distribution width, RBC count, WBC count, 
WBC differential (% and absolute), basophils, eosinophils, lymphocytes, monocytes, 
neutrophils, immature neutrophils. (Timepoints for sample collection are described in 
Section 12.8.2.1). 
 Coagulation: Prothrombin time (PT)/international normalized ratio (INR), activated partial 
thromboplastin time (aPTT). (Timepoints for sample collection are described in 
Section 12.8.2.1). 
 Urinalysis: color and appearance, pH and specific gravity, bilirubin, glucose, ketones, 
leukocytes*, nitrite, protein, urobilinogen. *Leukocytes will only be resulted in the event that 
the macroscopic analysis flags positive (abnormal) for the following results and will reflex to 
a technologist microscopic review: protein, blood, leukocyte esterase, nitrite. (Timepoints for 
sample collection are described in Section 12.8.2.1). 
 Pregnancy: serum -hCG. (Timepoints for sample collection are described in 
Section 12.8.2.2). 
 Immunogenicity: exebacase-specific ADA and IgE. (Timepoints for sample collection are 
described in Section 12.8.2.3). 
 Pharmacokinetics: blood levels of exebacase. (Timepoints for sample collection are 
described in Section 12.8.2.4). 
 Microbiology: identification and susceptibility of S. aureus isolates from blood cultures and 
other cultures. Further evaluation to identify the potential mechanism of resistance may be 
performed. (Timepoints for sample collection are described in Sections 12.8.2.5 and 
12.8.2.6). 
12.9. 
12-Lead Electrocardiogram 
A 12-lead ECG will be performed during screening (or after randomization and before dosing) 
and on Day 14. Additional 12-lead ECGs will be performed as clinically indicated. Heart rate, 
PR interval, QRS, QT, QTcB, and QTCF values, if available, will be recorded in the eCRF. 
Any clinically relevant abnormality on the screening ECG will be recorded as medical history; 
any clinically relevant abnormality on the Day 14 ECG will be recorded as an AE. 


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12.10. 
Physical Examination and Weight/Height 
Complete physical examinations and review of body systems will be performed during screening 
and at the Day 7, 14, 30, and 60 visits. Additional physical examinations will be performed as 
clinically indicated. The complete physical examinations will include evaluation of general, 
head, eye, ear, nose, and throat (HEENT), cardiovascular, skin for any evidence of emboli, 
musculoskeletal, respiratory, gastrointestinal, neurological systems, and signs of pain. 
The physical examinations will include a close evaluation for any new or worsening signs or 
symptoms (e.g., pain, shortness of breath) of suspected new metastatic foci of infection or 
suspected septic emboli. Diagnostic testing (e.g., imaging, aspiration, and/or cultures) will be 
performed as clinically indicated to confirm suspected new metastatic foci or septic emboli. 
The physical examination will also include an evaluation of the primary source of S. aureus
BSI/IE. Weight and height will be measured during screening. If it is not possible to measure 
weight and height during screening, a recently available historical weight and height will be 
used. Physical examination findings and weight/height will be recorded on the relevant eCRFs.
Every effort should be made to perform study visits “in person” by the Investigator/ 
Sub-Investigator (or other delegated medically qualified person listed on the FDA Form 1572 
and trained on the protocol). If it is not feasible to evaluate the patient “in person” at study visits,
telephone/telehealth visits may be performed under the circumstances described in 
Section 11.5.1. A physical examination/vital signs are not required for visits performed remotely 
by telephone/telehealth; however, a complete medical review of body systems will be performed 
during the telephone/telehealth visit and medical records* may be used to supplement these 
telephone/telehealth visits (e.g., sign and symptom evaluation and physical exam findings) to 
assess the patient’s clinical status, primary source of infection, and the status of any pre-existing 
or presence of new metastatic foci. The findings will be entered into the relevant eCRFs. 
In rare instances in which it is not feasible to conduct study visits “in person” or by 
telephone/telehealth, medical records* alone may be used for physical examination assessments 
after contacting the Medical Monitor or designee. 
* When medical records are used alone or to supplement information collected during the 
telephone/telehealth visit, the physical examination assessments extracted from the 
medical record will be recorded in the site’s source documents and entered in the relevant 
eCRFs. The Investigator/Sub-Investigator (or other delegated medically qualified person 
listed on the FDA Form 1572 and trained on the protocol) is expected to review, sign, 
and date the physical examination assessments extracted from the medical record and 
recorded in the site’s source documents. The eCRFs will be verified by the site monitor 
using these source documents. 


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12.11. 
Vital Signs 
Vital signs (blood pressure, respiratory rate, heart rate, and temperature) will be performed 
during screening, approximately 30 to 40 minutes after the start of infusion and as clinically 
indicated during the infusion, and at the Day 7, 14, 30, and 60 visits for visits performed 
“in person” or may be obtained via the study-specific mobile health service (Section 11.5.1). If it 
is not possible to perform vital signs “in person” or via the study-specific mobile health service, 
medical records may be used. The vital sign assessments extracted from the medical record will 
be recorded in the site’s source documents and entered in the relevant eCRFs, and will be used to 
support the assessment of signs/symptoms as described in Section 12.13. 
At screening, if more than one measurement is taken within the approximately 24 hours before 
randomization, the most abnormal value is recorded in the eCRF. At Days 7, 14, 30, and 60, 
if more than one measurement is taken on a given day, the most abnormal value will be recorded 
in the eCRF. 
12.12. 
Metastatic Foci and Septic Emboli 
Patients will be evaluated for existing and new metastatic foci (e.g., deep tissue abscess, 
septic arthritis, etc.) and septic emboli (e.g., to the brain, lung, etc.) during screening. Presence of 
new or worsening of existing metastatic foci/septic emboli will be evaluated at the Day 7, 14, 30, 
and 60 visits. Diagnostic testing will be performed as clinically indicated to assess metastatic 
foci or septic emboli (e.g., imaging, aspiration, and/or cultures). For non-blood sites of S. aureus
infection, the Investigator/Sub-Investigator (or other delegated medically qualified person listed 
on the FDA Form 1572 and trained on the protocol) will determine whether this is the source of 
S. aureus BSI/IE (Section 12.7) or a metastatic focus (Section 12.12). 
Every effort should be made to perform study visits “in person”, by the Investigator/ 
Sub-Investigator (or other delegated medically qualified person listed on the FDA Form 1572 
and trained on the protocol), and preferably by the same person at all visits. If it is not feasible to 
evaluate the patient “in person” at study visits, telephone/telehealth visits may be performed 
under the circumstances described in Section 11.5.1. Metastatic foci/septic emboli should be 
evaluated during the telephone/telehealth visits by detailed questioning and a complete medical 
review of systems. Medical records* may be used to supplement the telephone/telehealth 
evaluation for metastatic foci/septic emboli. 
In rare instances in which it is not feasible to conduct study visits “in person” or by 
telephone/telehealth, medical records* alone may be used for metastatic foci/septic emboli 
assessments after contacting the Medical Monitor or designee. 
* When medical records are used alone or to supplement information collected during the 
telephone/telehealth visit, the metastatic foci/septic emboli assessments extracted from the 
medical record will be recorded in the site’s source documents and entered in the relevant 
eCRFs. The Investigator/Sub-Investigator (or other delegated medically qualified person 


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listed on the FDA Form 1572 and trained on the protocol) is expected to review, sign, 
and date the metastatic foci/septic emboli assessments extracted from the medical record 
and recorded in the site’s source documents. The eCRFs will be verified by the site 
monitor using these source documents. 
The Investigator/Sub-Investigator (or other delegated medically qualified person listed on the 
FDA Form 1572 and trained on the protocol) and the AC will consider the development of new 
metastatic foci or septic emboli, and timing for metastatic foci (i.e., before/on Day 7 or after 
Day 7), when evaluating clinical outcome (Section 12.18). Metastatic foci identified through 
Day 7 are considered part of the patient’s baseline S. aureus BSI/IE; new metastatic foci 
identified after Day 7 or new septic emboli after study drug dosing are considered complications 
of S. aureus BSI/IE for the purpose of assessing clinical outcome. New septic emboli are defined 
as an acute presentation of septic emboli after dosing and are a reason for failure for clinical 
outcome; septic emboli that are incidentally found on imaging are considered part of the patient’s 
baseline S. aureus BSI/IE if found before Day 7. 
12.13. 
Signs and Symptoms of Infection 
Signs and symptoms will be evaluated during screening and at the Day 7, 14, 30, and 60 visits. 
Additionally, if SoCA is changed after study drug dosing due to lack of clinical response, signs 
and symptoms will be assessed on the day of the SoCA change and entered into the eCRF. The 
Investigator/Sub-Investigator (or other delegated medically qualified person listed on the 1572 
and trained on the protocol) will assess whether each sign or symptom is attributable to S. aureus
BSI/IE or provide an alternative attribution and will assess the symptom severity per the 
definitions in Table 9. 
Per inclusion criterion 3, each patient is required to have at least 2 signs or symptoms attributable 
to S. aureus BSI/IE at screening (within approximately 24 hours before randomization) in order 
to be enrolled in the study. If more than one measurement is taken within the approximately 
24 hours before randomization, the most abnormal value is used for inclusion. The signs and 
symptoms that will be assessed at each visit are described in the inclusion criteria (Section 10.1) 
and include: 
 Shortness of breath 
 Sweating 
 Chills and/or rigors 
 Fatigue 
 Confusion 
 Pain associated with metastatic foci 
 
hypothermia (oral temperature 
 


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 Leukocytosis (white blood cell [WBC] count >10,000/µL) [CTCAE 2017], leukopenia 
(WBC 
peripheral WBC) 
 Tachycardia (heart rate >100 bpm)
Tachypnea (respiratory rate >20 breaths/min)
 Hypotension (systolic blood pressure <90 mmHg) 
Leukocytosis, leukopenia, or bandemia are assessed when blood tests are performed as part of 
standard medical practice. 
Select symptoms (shortness of breath, fatigue, confusion) will also be evaluated at pre-BSI/IE. 
Pre-BSI/IE is the patient’s “usual state of health” before the BSI/IE started. Pre-BSI/IE is 
established by asking the patient or legally acceptable representative about these symptoms and 
severity (using Table 9) prior to onset of the BSI/IE. The medical record may also be used. 
The Investigator/Sub-Investigator (or other delegated medically qualified person listed on the 
1572 and trained on the protocol) will assess the severity of specific symptoms attributable to 
S. aureus as absent, mild, moderate, or severe, as defined in Table 9. The definition of “absent” 
for shortness of breath, fatigue, and confusion takes into account the pre-BSI (i.e., absent is 
defined as return to pre-BSI or absence). Symptoms of sweating and chills/rigors and signs 
attributable to S. aureus will be assessed as present or absent. Some symptoms may be 
considered ‘medically not evaluable’ due to certain medical circumstances or treatments, such as 
a patient in a medically induced coma or after surgery to remove a metastatic focus. 
The Investigator/Sub-Investigator (or other delegated medically qualified person listed on the 
FDA Form 1572 and trained on the protocol) and the AC will assess the resolution of or 
persistence, worsening, or recurrence of signs and symptoms attributable to S. aureus BSI/IE 
which were present at screening, or any new signs or symptoms attributable to S. aureus BSI/IE, 
when evaluating clinical outcome, according to the clinical outcome definitions in Table 10 in 
Section 12.18. All signs and symptoms attributable to S. aureus that were present at screening 
must be absent or improve by 2 grades (i.e., from severe to mild) in order to be considered as 
resolved. Symptoms attributable to S. aureus that were present at screening and only improve by 
1 grade (i.e., from severe to moderate or from moderate to mild) are considered persistent. 


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Table 9: 
Severity Definitions for Symptoms Attributable to S. aureus 
Symptom
Absent 
Mild 
Moderate 
Severe 
Shortness of 
breath 
(SOB)1
Resolution 
(to pre-BSI/IE) or 
absence of SOB 
SOB with moderate 
exertion 
(e.g., climbing stairs) 
SOB with minimal 
exertion (e.g., normal/ 
routine activities 
(e.g., walking on flat 
surface, performing 
usual daily activities 
[i.e., instrumental 
ADL]) 
SOB at rest and/or 
requiring oxygen 
(or increase in oxygen 
requirement in 
patients who required 
oxygen pre-BSI/IE); 
limits ability to 
perform self-care 
ADL
Fatigue1 
Resolution 
(to pre-BSI/IE) or 
absence of fatigue 
Transient, relieved by 
rest; does not interfere 
with usual activities 
Frequent, interferes 
with usual daily 
activities 
(i.e., instrumental 
ADL)
Fatigue not relieved 
by rest; limits ability 
to perform self-care 
ADL 
Confusion1,2
Resolution 
(to pre-BSI/IE) or 
absence of confusion 
(e.g., disorientation) 
Transient confusion 
(e.g., mild 
disorientation that 
does not interfere with 
usual activities). 
Moderate 
disorientation; 
interferes with ability 
to do usual activities 
(i.e., instrumental 
ADL)
Severe, continuous 
confusion state 
(e.g., delirium) 
disorientation limiting 
ability to perform 
self-care ADL
Pain assoc. 
with 
metastatic 
foci
Absence of pain from 
metastatic foci 
Transient mild pain; 
does not interfere with 
usual activities or 
sleep 
Frequent pain; 
interferes with usual 
activities or sleep 
Constant pain 
interferes with usual 
activities or sleep 
and/or ability to 
perform self-care 
ADL
Reference: Adapted from NIH Common Terminology Criteria for Adverse Events (CTCAE) 
Abbreviation: ADL=activities of daily living; assoc.=associated; BSI=blood-stream infection; IE=infective endocarditis; 
SOB=shortness of breath 
Note: Some symptoms may be considered ‘medically not evaluable’ due to certain medical circumstances or treatments, such as a 
patient in a medically induced coma or after surgery to remove a metastatic focus. 
1. 
A pre-BSI/IE assessment will be done for shortness of breath, fatigue, and confusion. Pre-BSI/IE is the patient’s “usual state 
of health” before the BSI/IE started. 
2. 
Confusion is defined as a disorder characterized by a lack of clear and orderly thought and behavior. Confusion may include 
disorientation, illusions, movement changes, inattentiveness, agitation, and/or hallucinations. 
Every effort should be made to perform study visits “in person” by the Investigator/ 
Sub-Investigator (or other delegated medically qualified person listed on the 1572 and trained on 
the protocol), and preferably by the same person at all visits. If it is not feasible to evaluate the 
patient “in person” at study visits, telephone/telehealth visits may be performed under the 
circumstances described in Section 11.5.1. Signs and symptoms should be evaluated during the 
telephone/telehealth visits by detailed questioning and a complete medical review of systems. 
Medical records* may be used to supplement the telephone/telehealth evaluation for signs and 
symptoms. 
In rare instances in which it is not feasible to conduct study visits “in person” or by 
telephone/telehealth, medical records* alone may be used for signs/symptoms assessments after 
contacting the Medical Monitor or designee. 


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* When medical records are used alone or to supplement information collected during the 
telephone/telehealth visit, the signs/symptoms assessments extracted from the medical 
record will be recorded in the site’s source documents and entered in the relevant eCRFs.
The Investigator/Sub-Investigator (or other delegated medically qualified person listed on 
the FDA Form 1572 and trained on the protocol) is expected to review, sign, and date the 
signs/symptoms assessments extracted from the medical record and recorded in the site’s 
source documents. The eCRFs will be verified by the site monitor using these source 
documents. 
It is understood that symptoms that are not present may not be specifically documented as 
“absent” in the medical record. The Investigator/Sub-Investigator (or other delegated 
medically qualified person listed on the FDA Form 1572 and trained on the protocol) will 
use their medical judgement in evaluating physical examination, signs/symptoms, and 
metastatic foci/septic emboli data extracted from the medical record to determine whether 
symptoms not specifically mentioned in the medical record can be considered to be absent 
with a reasonable degree of medical certainty. If so, such symptoms should be recorded in 
the source document as “absent”. If this is not the case, and the Investigator/
Sub-Investigator (or other delegated medically qualified person listed on the 
FDA Form 1572 and trained on the protocol) cannot make the determination that a 
symptom not specifically mentioned in the medical record is absent 
(e.g., due to insufficient information in the medical record), the symptom should then be 
recorded as “not assessed”.
For example, if the Investigator/Sub-Investigator (or other delegated medically qualified 
person listed on the FDA Form 1572 and trained on the protocol) reviews the progress 
notes, nursing notes, consult notes, and other parts of the medical record, and there is no 
specific mention of a symptom, for example sweating, and there is no reasonable medical 
reason to expect that the patient had sweating attributable to the S. aureus BSI
(e.g., blood cultures are negative and patient’s condition is clinically improved), 
the Investigator/Sub-Investigator (or other delegated medically qualified person listed on 
the FDA Form 1572 and trained on the protocol) may assess the symptom as “absent” 
based on their medical review of the medical record. The Investigator/Sub-Investigator 
(or other delegated medically qualified person listed on the FDA Form 1572 and trained 
on the protocol) will make a notation of their medical assessment in the source document. 


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12.14. 
Echocardiography 
Echocardiograms will be performed as follows: 
 All adu
randomization. All efforts will be made to perform the TTE or TEE before randomization.
 Where possible, a TEE will be performed [Baddour 2015, Habib 2010, Habib 2015] and 
is recommended in patients with BMI >30 kg/m2; the TEE may be performed within 
3 days before or after randomization unless the TEE is performed due to clinical 
suspicion of L-IE (see below). 
 In patients that have clinical findings suggestive of L-IE (new murmur, worsening 
cardiac function, and/or peripheral or central nervous embolic phenomenon), a TEE will 
be performed before randomization to rule out mitral and/or aortic valve vegetation(s) or 
the patient will be excluded from the study per exclusion criterion #2 (Section 10.2). 
In cases where there is an alternative cause of new heart failure or cerebral emboli, a 
patient with a negative TTE for L-IE may be discussed with the Medical Monitor for 
potential enrollment. 
 
S. aureus
will be performed before randomization to 
rule out L-IE. A TTE may be performed with permission of the Medical Monitor. If this 
echocardiogram is not performed or L-IE is not ruled out by this echocardiogram, 
the patient should not be randomized. 
 In adolescents (12 to <18 years of age), echocardiograms (TTE or TEE) will be performed as 
clinically indicated taking into consideration risk factors for endocarditis (e.g., structurally 
abnormal heart [including pacemakers]), clinical features suggestive of endocarditis 
(e.g., new murmur), or persistent bacteremia [McMullan 2020]. 
 If the patient had an echocardiogram performed prior to the study that was intended to 
evaluate the current infection, it will be sent to the central echocardiography laboratory as 
directed by the Sponsor and an additional TTE or TEE is not required unless as indicated 
above
randomization. 
 Follow-up echocardiograms will be performed as clinically indicated.
The results of all echocardiograms from the initial echocardiogram performed to evaluate the 
current infection through the Day 60 visit will be entered in the eCRF. The images from all 
echocardiograms from the initial echocardiogram performed to evaluate the current infection 
through the Day 60 visit will be provided to the central echocardiography laboratory as directed 
by the Sponsor. In addition, the results of any prior echocardiograms that are part of the patient’s 
medical history (i.e., from the 1 year prior to screening) will be recorded in the eCRF. 


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12.15. 
Management of IV Catheters 
If not already done prior to the study, intravenous catheters known or suspected to be infected 
must be removed, and as clinically needed replaced, preferably at a different site, as soon as 
possible within approximately 72 hours after randomization. Other hemodialysis access types 
(i.e., AV fistulas or AV grafts) that are known or suspected to be infected will be evaluated for 
removal/replacement, if clinically feasible. If removal/debridement is not feasible based on 
standard medical practice, the patient should be discussed with the Medical Monitor for potential 
enrollment. As described in Section 12.8.2.6, cultures from catheter tips will be performed to 
determine the source of S. aureus BSI/IE and as clinically indicated.
12.16. 
Ultrasounds of Central Venous Catheter Site 
In patients with CVCs, ultrasounds to evaluate clots in the vein should be performed within 
approximately 48 hours after randomization, unless the clot in the vein has been detected within 
this timeframe via other method (e.g., imaging such as CT scan or MRI or direct visualization 
during surgery). 
12.17. 
Vital Status 
Vital status (whether the patient is alive or dead, or last known date alive if vital status is 
unknown) will be obtained at Days 14, 30, and 60 for all patients, including patients that 
discontinue the study or withdraw consent/assent (as described in the informed consent/assent 
form). All efforts must be made to obtain vital status on all patients through Day 60. Vital status 
data are important for both the safety analysis (to have an accurate accounting of patients who 
died) and the efficacy analysis (“death due to any cause” is a reason for failure for clinical 
outcome). The patient’s vital status will be determined using available sources (e.g., the patient, 
patient’s contacts, hospital and other medical records, and public records, such as social media, 
obituaries, social security death index), as described in the informed consent/assent form and 
FDA guidance described below. 
The FDA issued a guidance entitled “Data retention when subjects withdraw from 
FDA-regulated clinical trials” [FDA 2008], in which FDA provided the following policy: 
“Following are key points regarding FDA’s policy on the withdrawal of subjects from a clinical 
investigation, whether the subject elects to discontinue further interventions or the clinical 
Investigator terminates the subject’s participation in further interventions: 
 According to FDA regulations, when a subject withdraws from a study, the data collected on 
the subject to the point of withdrawal remains part of the study database and may not be 
removed. 
 An Investigator may ask a subject who is withdrawing whether the subject wishes to provide 
continued follow-up and further data collection subsequent to their withdrawal from the 
interventional portion of the study. Under this circumstance, the discussion with the subject 
would distinguish between study-related interventions and continued follow-up of associated 


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clinical outcome information, such as medical course or laboratory results obtained through 
non-invasive chart review, and address the maintenance of privacy and confidentiality of the 
subject’s information. 
 If a subject withdraws from the interventional portion of the study, but agrees to continued 
follow-up of associated clinical outcome information as described in the previous bullet, 
the Investigator must obtain the subject’s informed consent for this limited participation in 
the study (assuming such a situation was not described in the original informed consent 
form). In accordance with FDA regulations, IRB approval of informed consent documents 
would be required (21 CFR 50.25, 56.109(b), 312.60, 312.66, 812.100). 
 If a subject withdraws from the interventional portion of a study and does not consent to 
continued follow-up of associated clinical outcome information, the Investigator must not 
access for purposes related to the study the subject’s medical record or other confidential 
records requiring the subject’s consent. However, an Investigator may review study data 
related to the subject collected prior to the subject’s withdrawal from the study, and may 
consult public records, such as those establishing survival status.” 
12.18. 
Clinical Outcome 
Clinical outcome will be assessed by the Investigator/Sub-Investigator (or other delegated 
medically qualified person listed on the FDA Form 1572 and trained on the protocol) and the AC 
at Days 14, 30, and 60 according to the definitions in Table 10. The signs and symptoms 
attributable to S. aureus BSI/IE that are evaluated for clinical outcome assessments are described 
in Section 12.12.


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Table 10: 
Clinical Outcome Definitions at Days 14, 30, and 60 
Clinical Outcome 
Definition
Responder
All of the following criteria are met: 
 
Resolution of signs and symptoms attributable to S. aureus BSI/IE which were present 
at screening1, 
 
No new signs or symptoms attributable to S. aureus BSI/IE, 
 
No complications of S. aureus BSI/IE, including: 
 
No development of a new metastatic focus of S. aureus infection (e.g., deep tissue 
abscess, septic arthritis) after Day 72, 
 
No development of new septic emboli (e.g., to the brain, lung, etc.) after study 
drug dosing3, 
 
No change in the SoCA after study drug dosing due to persistence, worsening, or 
recurrence or new signs/symptoms of S. aureus BSI/IE4, 
 
Blood culture(s) negative for S. aureus by Day145, and 
The patient is alive.
Failure
At least 1 of the following criteria is met: 
 
Persistence, worsening, or recurrence of signs or symptoms attributable to S. aureus 
BSI/IE which were present at screening,1 
 
New signs or symptoms attributable to S. aureus BSI/IE, 
 
Complications of S. aureus BSI/IE, including: 
 
Development of a new metastatic focus of S. aureus infection (e.g., deep tissue 
abscess, septic arthritis) after Day 72, 
 
Development of new septic emboli (e.g., to the brain, lung, etc.) after study drug 
dosing3, 
 
SoCA was changed after study drug dosing due to persistence, worsening, or 
recurrence or new signs/symptoms of S. aureus BSI/IE4, 
 
Failure to clear blood cultures by Day145, or 
Death due to any cause. 
Indeterminate 
The patient is not available for the evaluation of clinical outcome for any reason including:
 
Lost to follow-up 
 
Withdrawal of consent/assent 
Other reason for not performing assessment
Note: Visit windows are as follows: Day 14 (±1 day), Day 30 (±4 days), Day 60 (±7 days). 
1. 
Specific symptoms attributable to S. aureus will be assessed as absent, mild, moderate, and severe according to the 
definitions in Table 9. Sweating and chills/rigors and signs attributable to S. aureus will be assessed as present or absent. 
All signs and symptoms attributable to S. aureus that were present at screening must be absent or improve by 2 grades 
(i.e., from severe to mild) in order to be considered as resolved. Symptoms attributable to S. aureus that were present at 
screening and only improve by 1 grade (i.e., from severe to moderate or from moderate to mild) are considered persistence. 
2. 
Metastatic foci identified through Day 7 are considered part of the patient’s baseline S. aureus BSI/IE; new metastatic foci 
identified after Day 7 are considered complications of S. aureus BSI/IE for the purpose of assessing clinical outcome. 
3. 
New septic emboli are defined as an acute presentation of septic emboli after dosing and are a reason for failure for clinical 
outcome; septic emboli that are incidentally found on imaging are considered part of the patient’s baseline S. aureus BSI/IE 
if found before Day 7. 
4. 
Patients may be treated empirically and SoCA may be changed after susceptibility data become available. A change in 
SoCA based on susceptibility data from the blood culture collected within approximately 72 hours before randomization 
does not count as “failure”. 
5. 
Failure to attain negative blood cultures on or before Day 14. Only applies to Day 14 assessment. 


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12.19. 
Microbiological Outcome 
Microbiological outcome will be determined programmatically at Days 4 and 7 according to the 
definitions in Table 11. 
Table 11: 
Microbiological Outcome Definitions at Days 4 and 7
Microbiological Outcome
Definitions
Clearance of bacteremia1
Two consecutive blood cultures collected on 2 different days on or prior to 
assessment were negative for S. aureus. 
Ongoing bacteremia1
Blood culture on the day of assessment or the most recent blood culture prior to 
the day of assessment was positive for S. aureus. 
If the patient does not meet the criteria for clearance or ongoing bacteremia, including because follow-up blood 
cultures were not done, microbiological outcome is presumed from clinical outcome as follows: 
Presumed clearance of 
bacteremia1
The patient is a responder at Day 14 (per the adjudicated clinical outcome, 
as defined in Table 10). 
Presumed ongoing 
bacteremia1
The patient is a failure at Day 14 (per the adjudicated clinical outcome, as defined 
in Table 10). 
Indeterminate 
The patient is indeterminate for clinical outcome at Day 14 (per the adjudicated 
clinical outcome, as defined in Table 10). 
1.
For the analysis, clearance of bacteremia will include both clearance and presumed clearance of bacteremia, and ongoing 
bacteremia will include both ongoing and presumed ongoing bacteremia. 
12.20. 
Health Resource Utilization 
Health resource utilization information will be collected through Day 60. 
The hospital admission and discharge dates for the initial hospitalization, and whether the 
admission was for S. aureus BSI/IE, will be entered on the eCRF. For patients who die while in 
the hospital, the date of death should be entered as the hospital discharge date. The admission
and discharge dates will be used for determining the hospital length-of-stay and in-hospital 
mortality. Additionally, information on intensive care unit (ICU) admission(s) and discharge(s) 
during the initial hospital admission will be entered in the eCRF for determining the ICU 
length-of-stay. 
The location to which the patient is discharged (e.g., home, nursing home and skilled nursing 
facility/long-term acute care, rehabilitation, palliative care/hospice) and whether the patient is 
receiving SoCA in an outpatient facility or via home health care will also be collected in the 
eCRF. 
The eCRF will collect hospital readmissions for any cause and for S. aureus BSI/IE or 
complication of S. aureus BSI/IE (e.g., metastatic foci, septic emboli) through Day 60. 


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12.21. 
Discharge Summaries 
Redacted discharge summaries from the initial hospitalization when the patient started in the 
study will be collected; if discharge summaries are not able to be provided, a patient narrative 
will be provided by the Investigator/Sub-Investigator (or other delegated medically qualified 
person listed on the FDA Form 1572 and trained on the protocol) (this narrative will be collected 
in the Investigator’s Narrative eCRF). 
Discharge summaries and autopsy reports will be collected for SAEs, when feasible/applicable. 
An Investigator’s narrative of the SAE will be entered into the SAE eCRF. 
12.22. 
DSMB 
An independent DSMB will review accruing safety and tolerability data in an unblinded manner 
throughout the study. All fatal SAEs and SUSARs will be provided to the DSMB on an ongoing
basis allowing the DSMB to monitor fatal and unexpected serious events in a timely manner. 
The DSMB will also review results from a futility analysis of the primary efficacy parameter in 
the MRSA population in the mITT analysis set when approximately 
primary (Day 14) adjudicated clinical outcome data available. Details of the roles and 
responsibilities of the DSMB, timing of data reviews, and the futility stopping threshold will be 
documented in the DSMB charter. The Sponsor and study staff will remain blinded throughout 
the study. The DSMB will monitor the overall safety of patients in order to minimize 
unacceptable risk to patients. As a result, the DSMB may recommend changes to study conduct 
on the basis of emerging safety information to protect the safety and welfare of clinical study 
patients. Enrollment will continue during the DSMB reviews. 
12.23. 
Adjudication Committee 
An independent, blinded clinical endpoint AC will adjudicate study eligibility, diagnosis, 
primary source of BSI/IE, adequacy of source control, and clinical outcomes at Days 14, 30, and 
60. The adjudicated diagnosis and primary source of BSI/IE will be considered the final 
diagnosis and the primary source of BSI/IE to be used for the analysis. The efficacy analysis of 
clinical outcome will be based on the AC’s assessment. The role of the AC and procedures for 
adjudication will be described in the AC charter. 
13. 
TREATMENT OF PATIENTS 
13.1. 
Description of Study Drugs 
The study drugs, exebacase and placebo, are described in Table 12. Exebacase and placebo will 
be provided as frozen, sterile, injectable solution for dilution. The placebo formulation is 
equivalent to the drug product formulation minus the active pharmaceutical ingredient 
(exebacase). Placebo is similar in appearance to exebacase. Study drug will be labeled in 
accordance with regulatory requirements. Additional information is provided in the 
Pharmacy Manual.


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Table 12: 
Description of Study Drugs (Exebacase and Placebo) 
Study Drug 
Exebacase 
Placebo 
Dosage form 
Sterile injectable solution for dilution 
Sterile injectable solution for dilution 
Route of administration 
Intravenous infusion over 
approximately 2 hours 
Intravenous infusion over 
approximately 2 hours 
Physical description 
Frozen solution 
Frozen solution 
Manufacturer 
Emergent BioSolutions, 
Pantheon (Thermo Fisher Scientific) 
Emergent BioSolutions, 
Pantheon (Thermo Fisher Scientific) 
Ingredients (function) 
Exebacase (Active Ingredient) 
Water for injection (Solvent) 
L-Histidine (Buffer) 
D-Sorbitol (Stabilizer) 
Water for injection (Solvent) 
L-Histidine (Buffer) 
D-Sorbitol (Stabilizer) 
13.2. 
Dosage and Dose Regimen 
Patients will receive a single infusion of exebacase or placebo as soon as possible after 
randomization. Study drug will be diluted and administered as approximately a 2-hour 
IV infusion, as specified in the Pharmacy Manual. 
The dosing scheme is as follows: 
 Patients with normal renal function or mild renal impairment (CrCl* 
 will be 
administered a dose of 18 mg of exebacase. 
 Patients with moderate or severe renal impairment (CrCl* of 15 to <60 mL/min) will be 
administered a dose of 12 mg of exebacase. 
Patients with ESRD (CrCl* <15 mL/min), including those on hemodialysis, will be 
administered a dose of 8 mg of exebacase. In patients receiving hemodialysis, study drug will 
 
hours after the end of 
hemodialysis. 
*Note: CrCl will be calculated by Cockcroft-Gault formula (provided in Section 12.8.1.1) 
using ideal body weight in patients wi
2 and serum creatinine result obtained 
locally as close to the start of study drug dosing as possible (but not more than approximately 
24 hours before the start of study drug dosing; see Section 12.8.1). 
13.3. 
Study Drug Preparation and Administration 
Detailed instructions for study drug preparation and administration are provided in the 
Pharmacy Manual.


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13.4. 
Storage/Stability 
The exebacase formulation must be stored at -20 (±5)
 in a controlled temperature monitored 
and locked area. The exebacase formulation will be monitored for stability at 
International Conference on Harmonisation (ICH) storage conditions.
13.5. 
Drug Accountability 
Responsibility for drug accountability at the study site rests with the Investigator; however, 
the Investigator may assign drug accountability duties to an appropriate qualified pharmacist or
designee. Inventory and accountability records must be maintained and must be readily available 
for inspection by ContraFect or designee and open to inspection at any time by applicable 
regulatory authorities. 
The Investigator or designee will be expected to collect and retain all used, unused, and partially 
used containers of study drug as described in the Pharmacy Manual. The Investigator or designee 
must maintain drug accountability records that document: 
 Investigational product delivery to the study site 
 The inventory at the site 
 Use by each patient, including vial dispensed 
These records will include dates, quantities, batch/serial numbers (if available), and the unique 
code numbers (if available) assigned to the investigational product and study patients. 
The investigational product must be used only in accordance with the protocol. The Investigator 
or designee will also maintain records adequately documenting that the patients were provided 
the study drug specified. 
After the completion of the study and final monitoring of drug accountability by ContraFect or 
designee, the Investigator or designee will oversee shipment of any remaining study drug back to 
the drug supply vendor or designee or destruction according to institutional standard operating 
procedures with pre-approval by ContraFect or designee. If drug is destroyed locally, 
a certificate of destruction will be provided to ContraFect or designee and maintained in the 
study files. 
13.6. 
Prior and Concomitant Medications 
Medications taken within 28 days before randomization through the Day 60 visit will be 
recorded in the eCRF as described in the CRF Completion Guidelines (CCGs). 


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13.7. 
Prohibited Medications 
Patients on the following medications are excluded as described in the exclusion criteria 
(Section 10.2): 
 Patients who received treatment or are planned to receive treatment within the 14 days 
following randomization with dalbavancin or oritavancin are excluded from the study.  
Note: Patients who are receiving teicoplanin, linezolid, telavancin, beta-lactam/beta-lactam 
inhibitors (e.g., piperacillin-tazobactam), carbapenems, fourth- or fifth-generation 
cephalosporins (e.g., cefepime, ceftaroline fosamil), and/or sulfamethoxazole/trimethoprim 
are eligible for the study provided that treatment is switched to a protocol-specified 
appropriate SoCA (appropriate SoCA includes daptomycin and vancomycin for MRSA and 
semi synthetic penicillins [e.g., nafcillin, oxacillin, cloxacillin, flucloxacillin] and first 
generation cephalosporins [e.g., cefazolin] for MSSA. Daptomycin or vancomycin may be 
used for patients with MSSA with a known history of beta-lactam allergy or other reason that 
beta-lactam cannot be used. 
 Patients with persistent S. aureus bacteremia for which treatment with ceftaroline fosamil or 
other non-protocol-recommended antibiotic (e.g., rifampin, gentamicin, other beta lactam) 
was instituted prior to randomization due to lack of response or intolerance (i.e., added to or 
switched from a protocol-recommended SoCA) may remain on the non-protocol 
recommended antibiotic after randomization, if approved by the Medical Monitor 
 Vancomycin or daptomycin used in combination with beta-lactams has not been shown to 
offer benefit and may increase the risk of kidney injury [Tong 2020]; therefore, 
this combination should not routinely be used in this study as first-line therapy. 
 Patients who previously received exebacase are excluded. 
 Patients who participated or plan to participate in another interventional investigational drug, 
device, or diagnostic trial involving administration of an investigational agent within 30 days 
prior to or during the study are excluded from the study. Note: Patients who have received 
agents under FDA Emergency Use Authorization (EUA) for COVID-19 prevention 
(e.g., vaccines or Evusheld or similar agents) or for COVID-19 treatment under FDA EAU 
are not excluded. 
Treatment with oral step-down antibiotics for the S. aureus BSI/IE is not permitted, except in 
adolescents. 
The manufacturer’s prescribing information for SoCA will be consulted for information 
regarding any concomitant medication restrictions.
13.8. 
Treatment Compliance 
Study drug will be administered to hospitalized patients by study site personnel.


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13.9. 
Randomization and Blinding 
Randomization: 
Patients will be assigned to receive exebacase or placebo in a 2:1 ratio via the IRT system.  
The randomization will be stratified by poorly controlled diabetes (yes or no) as defined below 
and susceptibility of the S. aureus isolate (MRSA, MSSA, or unknown). For stratification, 
poorly controlled diabetes is defined as a 
ely 90 days before 
randomization. A HgA1C test is not required for patients with no medical history of diabetes and 
no suspicion of diabetes during the screening period. These patients will be stratified to “no” for 
poorly controlled diabetes. A HgA1C test should be performed in patients with medical history 
of diabetes or suspicion of diabetes during screening for whom a HgA1C test result within the 
approximately 90 days prior to randomization is not available. If a HgA1C is unavailable and 
testing cannot be performed for these patients prior to randomization, contact the 
Medical Monitor to determine how the patient should be stratified based on available clinical 
information. All efforts will be made to obtain susceptibility results from blood cultures before 
randomization to enable stratification by MRSA or MSSA. If a blood culture was performed for 
the current S. aureus infection prior to the qualifying blood culture, susceptibility results from 
the prior blood culture may be used. If the patient has a concomitant S. aureus infection at 
another body site from which susceptibility results are available (e.g., skin, abscess), 
the susceptibility results from this other culture may be used. If the patient is known to be 
colonized with MRSA, MRSA may be selected for the stratification factor (Section 12.8.2.5). 
Patients randomized into the study will be assigned the treatment corresponding to the next 
available number in the respective stratum from the computer-generated randomization schedule. 
A patient is considered randomized when the IRT randomization transaction is recorded 
regardless of whether the patient actually receives study drug. 
Blinding: 
This is a double-blind study. The Investigator, study site personnel, and patients will be blinded 
to treatment group and will not make any effort to determine which study drug treatment is being 
received (except in the case of emergency unblinding by the Investigator/Sub-Investigator or 
other delegated medically qualified person listed on the FDA Form 1572 and trained on the 
protocol). A pharmacist or study staff member not associated with the operational conduct of the 
study will prepare the study medication for infusion, as described in the Pharmacy Manual. 
An independent DSMB will review data in an unblinded manner, as described in Section 12.22 
and the DSMB charter. An independent unblinded statistician will provide unblinded data to the 
DSMB for the interim analyses of safety and futility as detailed in the DSMB Charter. 
The Sponsor, study staff, and AC will be blinded to treatment group. The blinded PK staff 
responsible for study drug concentration assessment will not be involved in any other study 
procedures or assessments. 


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Emergency Unblinding: 
The Investigator/Sub-Investigator (or other delegated medically qualified person listed on the 
FDA Form 1572 and trained on the protocol) may unblind a patient’s treatment assignment only 
in the case of an emergency, when knowledge of the study drug is essential for the clinical 
management or welfare of a specific patient. Prior to any unblinding, the Investigator/ 
Sub-Investigator (or other delegated medically qualified person listed on the FDA Form 1572 
and trained on the protocol) is strongly advised to discuss options with the Medical Monitor or 
appropriate Sponsor study personnel. As soon as possible and without revealing the patient’s 
study treatment assignment (unless important to the safety of patients in the study), 
the Investigator/Sub-Investigator (or other delegated medically qualified person listed on the 
FDA Form 1572 and trained on the protocol) must notify the Sponsor if the blind is broken for 
any reason and the Investigator/Sub-Investigator (or other delegated medically qualified person 
listed on the FDA Form 1572 and trained on the protocol) was unable to contact the Sponsor 
prior to unblinding. The Investigator/Sub-Investigator (or other delegated medically qualified 
person listed on the FDA Form 1572 and trained on the protocol) will record in source 
documentation the date and reason for revealing the blinded treatment assignment for that 
patient. The Investigator/Sub-Investigator (or other delegated medically qualified person listed 
on the FDA Form 1572 and trained on the protocol) will be responsible for reporting the 
emergency unblinding to the local IRB/IEC in accordance with its regulations and guidelines. 
Unblinding in the setting of a SUSAR is detailed in a separate Safety Management Plan and 
Unblinding Plan. 
14. 
ADVERSE AND SERIOUS ADVERSE EVENTS 
14.1. 
Timeframe for Collecting Adverse Events 
All AEs and SAE will be collected from the time of consent/assent through the Day 60 visit. 
14.2. 
Reporting of Serious Adverse Events 
All SAEs will be reported within 24 hours of the site becoming aware of the SAE. SAEs will be 
reported through the electronic data capture (EDC) system or on the backup paper SAE report 
form. The SAE report will provide as much of the required information as is available at the 
time. The following minimum information is required for reporting an SAE:  
 SAE description, 
 Patient identification, 
 Reporter/site, 
 Investigator causality assessment. 
Additional procedural and contact details on SAE reporting will be provided separately to the 
Investigator. 


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Follow-up of SAEs is described in Section 14.12. 
14.3. 
Definition of Adverse Event 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign, symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product.
Examples of AEs are as follows: 
 Changes in the general condition of the patient* 
 Subjective symptoms offered by or elicited from the patient* 
 Objective signs observed by the Investigator or other study personnel* 
 All diseases that occur after the start of the study including a change in severity or frequency 
of preexisting disease* 
* Note: Manifestations of the disease under study or clinical outcome of failure for the disease 
under study should not be reported as AEs except if the event results in re-admission to the 
hospital and/or death (see Section 14.5 for additional details).
Hospitalization refers to an overnight admission into the hospital for the purpose of investigating 
and/or treating an acute illness or other AE. Hospitalizations not intended to treat an acute illness 
or AE, such as hospitalizations for social reasons, should not be reported as SAEs. 
Planned hospital admissions and/or surgical operations for an elective procedure or an illness or 
disease that existed at screening and did not aggravate during the study should not be reported as 
SAEs. These elective procedures should be recorded in the Surgery and Other Procedures eCRF 
and these pre-existing illnesses or diseases should be recorded in the Medical History eCRF.
All clinically relevant new abnormalities in laboratory values or clinically relevant physical 
findings that occur during the study. Note: Laboratory values that are abnormal but not of 
clinical significance are not to be reported as AEs. 
14.4. 
Definition of Serious Adverse Event 
A SAE is an AE that fulfills one or more of the following: 
 Results in death 
 Is immediately life-threatening (i.e., an event in which the patient was at risk of death at the 
time of the event) 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity 


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 Is a congenital abnormality or birth defect 
 It is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
Note: Manifestations of the disease under study or clinical outcome of failure for the disease 
under study should not be reported as SAEs except if the event results in re-admission to the 
hospital and/or death (see Section 14.5 for additional details).
Hospitalization refers to an overnight admission into the hospital for the purpose of investigating 
and/or treating an acute illness or other AE. Hospitalizations not intended to treat an acute illness 
or AE, such as hospitalizations for social reasons, should not be reported as SAEs. 
Planned hospital admissions and/or surgical operations for an elective procedure or an illness or 
disease that existed at screening and did not aggravate during the study should not be reported as 
SAEs. These elective procedures should be recorded in the Surgery and Other Procedures eCRF 
and these pre-existing illnesses or diseases should be recorded in the Medical History eCRF.
14.5. 
Study Endpoints 
Study endpoints refer to outcomes that the Sponsor is measuring to evaluate clinical efficacy. 
Clinical outcome of the disease under study is collected as an efficacy endpoint, and a clinical 
outcome of “failure” or individual components of the clinical failure definition (as defined in 
Table 10 in Section 12.18) or other manifestations of the disease under study that do not meet the 
clinical failure definition (e.g., metastatic foci of S. aureus through Day 7) will not be reported as 
AEs or SAEs, except if the event: 
 Results in re-admission to the hospital, and/or
 Results in death 
For example:
 Recurrence of S. aureus BSI or IE will be reported as an SAE only if it results in 
re-admission to the hospital and/or results in death. 
 Development of a new metastatic focus of S. aureus BSI/IE will be reported as an SAE only 
if it results in re-admission to the hospital and/or results in death.
Information on the individual components of clinical failure definition and other manifestations 
of the disease under study are collected on other eCRFs (e.g., eCRFs to collect signs/symptoms 
of BSI/IE, metastatic foci/septic emboli, cultures, clinical outcome, etc.). 
14.6. 
Pre-Existing Conditions 
Planned hospital admissions and/or surgical operations for an elective procedure or an illness or 
disease that existed at screening and did not aggravate during the study should not be reported as 
SAEs. These elective procedures should be recorded in the Surgery and Other Procedure eCRF 
and these pre-existing illnesses or diseases should be recorded in the Medical History eCRF. 


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14.7. 
Relationship to Study Drug 
The Investigator/Sub-Investigator (or other delegated medically qualified person listed on the 
FDA Form 1572 and trained on the protocol) must make the determination of relationship to the 
investigational product for each AE (unrelated or unrelated) and record the assessment on the 
SAE eCRF or paper backup SAE form.
Related: Based on the Investigator’s/Sub-Investigator’s (or other delegated medically qualified 
person listed on the FDA Form 1572 and trained on the protocol) medical judgment, there is a 
reasonable medical possibility that the event may have been caused by the investigational 
product. There is evidence to suggest a causal relationship between the investigational product 
and the AE.
Unrelated: Based on the Investigator’s/Sub-Investigator’s (or other delegated medically qualified 
person listed on the FDA Form 1572 and trained on the protocol) medical judgment, there is no 
medically plausible reason that suggests a relationship between the event and the investigational 
product. 
14.8. 
Grading of Adverse Events 
The severity (or intensity) of each AE will be assessed by the Investigator/Sub-Investigator 
(or other delegated medically qualified person listed on the FDA Form 1572 and trained on the 
protocol) according to the following scale: 
 Mild: Awareness of sign or symptom, but easily tolerated 
 Moderate: Interferes with normal activities and may require minimal intervention 
 Severe: Incapacitating, with inability to work or perform normal activities and/or requires 
significant medical intervention 
Clarification of the Difference in Meaning Between “Severe” and “Serious” 
The term “severe” is often used to describe the intensity (severity) of a specific event 
(as in mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 
“serious”, which is based on the outcome or action criteria usually associated with events that 
pose a threat to life or functioning (as defined in Section 14.4 above). Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations. 


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14.9. 
Adverse Events of Clinical Interest 
An AECI is an AE (serious or non-serious) of scientific and medical interest specific to the 
sponsor’s product or program. Ongoing monitoring and rapid communication to the sponsor is 
requested as such an event might warrant further investigation in order to further characterize it.
An AECI in this study is any AE that results in discontinuation (i.e., withdrawal) of the study 
drug infusion and must be reported within 24 hours through the EDC system on the SAE eCRF 
or backup paper SAE form, as described in Section 14.2. 
14.10. 
Overdose 
An overdose is defined as the receipt of more than one dose of study drug by a patient during this 
study. If an overdose is associated with an SAE, the SAE must be reported within 24 hours of the 
site becoming aware of the SAE, as described in Section 14.2. The actual dose of study drug 
administered will be recorded in the Study Drug Administration eCRF. 
14.11. 
Pregnancy 
Female patients who become pregnant during the study will be followed to determine the 
outcome of the pregnancy. Since this is a single-dose study, female patients who become 
pregnant during the study after study drug dosing may remain in the study to complete 
subsequent study visits and assessment of efficacy endpoints. The pregnancy must be reported to 
the Sponsor within 24 hours of the site becoming aware of the pregnancy. If the pregnancy ends 
for any reason before the anticipated date, the Investigator/Sub-Investigator (or other delegated 
medically qualified person listed on the FDA Form 1572 and trained on the protocol) will notify 
the Sponsor. At the completion of the pregnancy, the Investigator/Sub-Investigator 
(or other delegated medically qualified person listed on the FDA Form 1572 and trained on the 
protocol) will document the outcome of the pregnancy. If the outcome of the pregnancy meets 
the criteria for immediate classification as an SAE (i.e., postpartum complication, spontaneous 
abortion, stillbirth, neonatal death, or congenital anomaly), the Investigator/Sub-Investigator 
(or other delegated medically qualified person listed on the FDA Form 1572 and trained on the 
protocol) will follow the procedures for reporting an SAE.
14.12. 
AE and SAE Follow-up 
All AEs and SAEs will be followed to resolution (the patient’s health has returned to his or her 
baseline status or all variables have returned to normal), or until an outcome is reached, 
or until deemed to be stable by the Investigator/Sub-Investigator or other delegated medically 
qualified person listed on the FDA Form 1572 and trained on the protocol, or the event is 
otherwise explained, regardless of whether the patient is still participating in the study. 
All appropriate therapeutic measures will be undertaken and recorded. Where appropriate, 
medical tests and examinations will be performed to document resolution of the event(s).


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Any updated information on a SAE will be submitted within 24 hours of receipt of the 
information. Supporting documents (discharge summaries, imaging reports, culture reports, 
autopsy reports, etc.) will be provided for all SAEs. For SAEs that result in death, the 
Investigator/Sub-Investigator (or other delegated medically qualified person listed on the 
FDA Form 1572 and trained on the protocol) will provide a copy of any post-mortem findings 
including histopathology. 
The Investigator/Sub-Investigator (or other delegated medically qualified person listed on the 
FDA Form 1572 and trained on the protocol) will provide a narrative for the SAE, which is 
entered in the SAE eCRF. 
14.13. 
Regulatory Reporting Requirements for SAEs 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. 
The Sponsor will comply with country-specific regulatory requirements for safety reporting to 
the regulatory authority, IRBs/IECs, and investigators. 
A SAE may qualify for expedited reporting to regulatory authorities if it is determined to be a 
SUSAR. A SUSAR is an AE associated with the use of the study drug which is serious, 
unexpected, and study-drug related. Expectedness of SAEs is determined by the Sponsor based 
on the Reference Safety Information of the Investigator’s Brochure.
The Sponsor or its designee is responsible for submitting expedited safety reports to the
appropriate regulatory agency for all confirmed SUSARs in accordance with national regulatory 
laws and regulations. In the case of a fatal or life-threatening SUSAR, the Sponsor or its 
designee notifies the appropriate regulatory agency as soon as possible but in no case later than 
7 calendar days after the Sponsor’s initial receipt of the information. For a non-fatal, 
non-life-threatening SUSAR, the report is to be submitted no later than 15 calendar days after the 
Sponsor is made aware of the event. 
Investigators will be notified of all serious, unexpected, drug-related events (7/15 Day Safety 
Reports) that occur during the clinical trial. Each site is responsible for notifying its IRB/IEC of 
these SAEs in accordance with its regulations and guidelines.
14.14. 
Expectedness Determination 
An AE is considered “unexpected” if the nature of the AE is not consistent with what is listed in 
the Reference Safety Information of the Investigator’s Brochure. Reports that add significant 
information on specificity or severity of a known, already documented serious adverse drug 
reaction constitute unexpected events. The Sponsor will be responsible for determining whether 
a SAE is expected or unexpected for the purpose of regulatory reporting. 


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15. 
STATISTICS 
A Statistical Analysis Plan (SAP) will be prepared and finalized before the interim analysis for 
futility. Any changes to the SAP after it has been signed but prior to final database lock and 
unblinding will be documented in an amendment. Descriptive statistics, including numbers and 
percentages for categorical variables, and numbers, means, standard deviations, medians, 
minimums, and maximums for continuous variables will be provided by treatment group.
Treatment groups will be referred to as “exebacase + SoCA” and “SoCA alone” for patients 
randomly assigned to exebacase and placebo, respectively. Additional analyses may also be 
performed. Listings of individual patient data will be produced. 
15.1. 
Populations 
Three populations will be used for presentation and analysis of the data: the overall population 
which includes patients with MRSA and/or MSSA, the MRSA population, and the MSSA 
population. If a patient has both MRSA and MSSA, the patient will be included in the MRSA 
population. The determination of MRSA and MSSA will be based on the central laboratory 
determination of genus and species and susceptibility results based on cefoxitin disk diffusion 
unless no central result is available. In this case, the local laboratory susceptibility result will be 
used, and MRSA will be defined as the S. aureus isolate that is resistant to cefoxitin or in the 
absence of a cefoxitin susceptibility result, is resistant to oxacillin. 
15.2. 
Analysis Sets 
The analysis sets are as follows: 
 Intent-to-treat (ITT) analysis set: all randomized patients 
 Safety analysis set: all randomized patients who receive any amount of study drug 
 Microbiological ITT (mITT) analysis set: all randomized patients who receive any amount of 
study drug and had documented S. aureus BSI/IE based on a blood culture prior to 
administration of study drug. Determination of S. aureus is based on the central laboratory 
determination of genus and species unless no central result is available. In this case, the local 
laboratory result will be used. 
 Per-Protocol (PP) analysis set: all randomized patients who have no confounding factors 
(as defined in the SAP) potentially affecting the evaluation of efficacy 
 PK analysis set: all randomized patients receiving exebacase with PK samples valid for 
exebacase assay 
15.3. 
Sample Size 
The study is designed to have sufficient power for the primary efficacy outcome in patients with 
MRSA (clinical outcome at Day 14 in the mITT analysis set) and the first two secondary efficacy 
outcomes (clinical outcome at Day 14 in the overall population in the mITT analysis set and 
30-day all-cause mortality in the MRSA population in the mITT analysis set). Based on data 


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(exebacase + SoCA group) 
(SoCA alone group) 
30-day all-cause mortality rate in the MRSA population with no censoring (i.e., all patients are 
 randomization ratio, and a 2-sided alpha of 0.05, 
a total of 135 patients are required in the mITT analysis set in the MRSA population 
(90 and 45 patients in the exebacase + SoCA and SoCA alone groups, respectively) based on the 
log rank test. A total of 135 
cal responder rate in the 
exebacase +SoCA group at Day 
SoCA alone group, using a 2-sided alpha of 
have MRSA, a sample size of 339 patients (226 and 113 patients in the exebacase + SoCA and 
SoCA alone groups
+ SoCA 
the SoCA alone group using a 2-sided alpha of 0.05 and a 
Fisher's exact test. Table 13 provides a summary of the sample size calculations. 
Table 13: 
Sample Size Calculations (2:1 Randomization Ratio, 2-sided Alpha=0.05) 
Primary Outcome 
Clinical Responder  
Day 14 
(MRSA Population) 
Secondary Outcome 
Clinical Responder  
Day 14 
(Overall Population) 
Secondary Outcome 
30-Day All-Cause 
Mortality 
(MRSA Population) 
Exebacase +  
SoCA 
SoCA 
Alone 
Exebacase +  
SoCA 
SoCA  
Alone 
Exebacase + 
 SoCA 
SoCA  
Alone 
Outcome Rate 
 
 
 
 
 
 
Power 
 
 
 
Sample Size 
(mITT analysis set) 
90 
45 
226 
113 
90 
45 
If 
a total of 348 patients will be required.
15.4. 
Patient Population and Characteristics 
Patient enrollment, protocol deviations, and discontinuations from the study drug and the study 
will be summarized by treatment group. The number and percentage of patients who 
discontinued the study due to a coronavirus-related reason, such as unwillingness to attend study 
visits and development of COVID-19, will also be presented. Demographics, medical and 
surgical history, baseline assessment of signs and symptoms attributable to S. aureus BSI/IE, 
risk factors for complicated S. aureus BSI, diagnosis, source of S. aureus BSI/IE, APACHE II 
score, microbiological assessment, and study drug administration will be summarized by 
treatment group. 


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15.5. 
Efficacy Analyses 
For efficacy analyses, patient data will be analyzed in the treatment group and stratum 
(unless otherwise specified) to which the patient was randomized.
For analysis of clinical outcome, once a patient is assessed as a clinical failure due to any of the 
reasons listed below, the patient is considered a clinical failure for all subsequent visits through 
Day 60 (i.e., the failure is carried forward): 
 Complications of S. aureus BSI/IE, including:
 Development of a new metastatic focus of S. aureus infection (e.g., deep tissue abscess, 
septic arthritis) after Day 7,
Development of new septic emboli (e.g., to the brain, lung, etc.) after study drug dosing,
SoCA for S. aureus BSI/IE was changed after study drug dosing due to persistence, 
worsening, or recurrence or new signs/symptoms of S. aureus BSI/IE, or
 Death due to any cause.
The other reasons for failure (persistence, worsening, or recurrence of signs or symptoms 
attributable to S. aureus BSI/IE which were present at screening, new signs or symptoms 
attributable to S. aureus BSI/IE, and failure to clear blood cultures by Day14) do not carry 
forward to subsequent visits. 
15.5.1.
Primary Efficacy Analyses
The primary efficacy outcome is clinical responder rate at Day 14 in patients with MRSA in the 
mITT analysis set as assessed by the AC. The determination of MRSA (and MSSA) will be 
based on the central laboratory susceptibility results unless no central result is available. In this 
case, the local laboratory susceptibility result will be used. Estimand attributes and intercurrent 
events of interest are described in the SAP. The number and percentage of patients classified as 
responder, failure, and indeterminate will be determined by treatment group.
The null and alternative hypotheses are the following:
 
H1: P1 – P2 
0 
Where: 
P1 = the primary efficacy outcome in the exebacase + SoCA group 
P2 = the primary efficacy outcome in the SoCA alone group 
The clinical responder rate will be compared between the treatment groups using Fisher's exact 
test. Statistical significance and rejection of the null hypothesis will be based on a 2-sided 
alpha=0.05. A summary of the reasons for failure and indeterminate (including a separate reason 
for a missed visit due to coronavirus) will also be provided. 


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Additional analyses of the primary efficacy outcome in patients with MRSA will be conducted. 
Clinical outcome at Day 14 will be assessed separately across the randomization stratification 
factor of poorly controlled diabetes (yes or no). For each subgroup, the number and percentage 
of patients classified as responder, failure, and indeterminate will be determined by treatment 
group in the mITT analysis set. Other subgroup analyses, including age ( 65 and <65 years; 
if the number of adolescents is not too small, a subgroup of adolescents will be defined as 
12 to <18 years of age; age groups of elderly patients will also be examined depending on the 
number of elderly patients enrolled, final diagnosis (and the final diagnosis categories of 
BSI/R-IE and complicated BSI/R-IE), SoCA received, and renal function category, will be 
conducted for exploratory purposes. Additional subgroups of interest will be defined in the SAP. 
If the number of adolescents is small, primary efficacy results will be provided only in a listing. 
The primary efficacy outcome will also be assessed in the PP analysis set. 
Sensitivity analyses of the primary outcome will also be conducted. The first sensitivity analysis 
will calculate an adjusted p-value (for the randomization stratification factor of poorly controlled 
diabetes) using the Cochran-Mantel-Haenszel methodology. The second sensitivity analysis will 
use multiple imputation methods, as detailed in the SAP, for patients with an indeterminate 
outcome at Day 14. 
15.5.2. 
Secondary Efficacy Analyses 
Key secondary efficacy outcomes include clinical outcome at Day 14 in the overall population in 
the mITT analysis set as assessed by the AC, survival through Day 30 in the MRSA population 
in the mITT analysis set, and clinical outcome at Day 60 in the MRSA and overall populations in 
the mITT analysis set as assessed by the AC. 
To control for the inflation of the overall type I error rate, a hierarchical testing procedure will be 
used. If statistical significance is declared for the primary efficacy outcome, testing will be done 
for the secondary efficacy outcomes in the order listed below. Testing will proceed to the next 
secondary outcome only if statistical significance (2-sided alpha=0.05) is declared for the 
preceding secondary outcome being tested. 
 Clinical responder rate at Day 14 in the overall population (MRSA and MSSA) in the 
mITT analysis set. The number and percentage of patients classified as responder, failure, 
and indeterminate will be determined by treatment group. The clinical responder rate will be 
compared between the treatment groups using Fisher's exact test. A summary of the reasons 
for failure and indeterminate (including a separate reason for a missed visit due to 
coronavirus) will also be provided. 
 30-day survival in the MRSA population in the mITT analysis set. Time to death through 
Day 30 will be analyzed using Kaplan-Meier methods. Patients who are lost to follow-up 
prior to Day 30 or have not died by Day 30 will be censored at the date last known alive on 
or prior to Day 30. Survival curves will be provided. The median, 25th and 75th percentiles, 


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and the probability of survival at Day 30 will be determined by treatment group. Differences 
between treatment groups will be determined using the log-rank test. 
 Clinical responder rate at Day 60 in the MRSA population in the mITT analysis set. 
The number and percentage of patients classified as responder, failure, and indeterminate will 
be determined by treatment group. The clinical responder rate will be compared between the 
treatment groups using Fisher's exact test. A summary of the reasons for failure and 
indeterminate (including a separate reason for a missed visit due to coronavirus) will also be 
provided. 
 Clinical responder rate at Day 60 in the overall population (MRSA and MSSA) in the 
mITT analysis set. The number and percentage of patients classified as responder, failure, 
and indeterminate will be determined by treatment group. The clinical responder rate will be 
compared between the treatment groups using Fisher's exact test. A summary of the reasons 
for failure and indeterminate (including a separate reason for a missed visit due to 
coronavirus) will also be provided. 
Additional analyses of the key secondary efficacy outcomes will be conducted. Clinical outcome 
at Day 14 in the overall population and Day 60 in the MRSA and overall populations will be 
assessed separately across the randomization stratification factor of poorly controlled diabetes 
(yes or no). For each subgroup, the number and percentage of patients classified as responder, 
failure, and indeterminate will be determined by treatment group in the mITT analysis set. 
Other subgroup analyses, as detailed above for the primary efficacy outcome will be conducted 
for exploratory purposes. If the number of adolescents is small, secondary efficacy results will be 
provided only in a listing. The key secondary efficacy outcomes will also be assessed in the 
PP analysis set. 
Sensitivity analyses of the key secondary outcomes will also be conducted. If the outcome is 
found to be statistically significant, a sensitivity analysis will calculate an adjusted p-value 
(for the randomization stratification factors) using the Cochran-Mantel-Haenszel methodology
(for clinical outcome at Day 14 and 60) or a stratified log-rank test (for 30-day survival). 
In addition, sensitivity analyses will use multiple imputation methods for missing data, as 
detailed in the SAP, for patients with an indeterminate response at Day 14 and Day 60. 
Clinical response at Day 60 in patients with R-IE will be summarized in the mITT analysis set in 
the overall population and in patients with MRSA. The number and percentage of patients 
classified as responder, failure, and indeterminate will be determined by treatment group. 


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15.5.3. 
Additional Efficacy Analyses 
Analyses of additional efficacy outcomes will be conducted to support the findings of the 
primary and secondary efficacy outcomes. 
 Survival time (mITT analysis set) through Day 60 in the overall, MRSA and MSSA 
populations: Survival time will be analyzed using Kaplan-Meier methods. Patients who do 
not die by Day 60 or who are lost to follow-up will be censored at date last known alive. 
Survival curves will be provided. The median, 25th and 75th percentiles, and the probability of 
survival at Day 14, Day 30 and Day 60 will be determined by treatment group.
 Clinical responder rate at Day 14 in the overall R-IE and MRSA R-IE (based on final 
diagnosis by the AC) populations (mITT analysis set): The number and percentage of 
patients classified as responder, failure, and indeterminate will be determined by treatment 
group. 
 Clinical responder rate at Day 30 in the overall and MRSA populations, and overall R-IE and 
MRSA R-IE populations (mITT analysis set): The number and percentage of patients 
classified as responder, failure, and indeterminate will be determined by treatment group.
 Clinical responder rate at Day 14 by source of S. aureus infection as determined by the AC in 
the overall and MRSA populations (mITT analysis set): The number and percentage of 
patients classified as responder, failure, and indeterminate will be determined by treatment 
group and source of infection in the overall and MRSA populations.
Bacteremia on Day 4 and Day 7 in the overall, MRSA and MSSA populations
(mITT analysis set): The number and percentage of patients classified with clearance of 
bacteremia/presumed clearance of bacteremia, ongoing bacteremia/presumed ongoing 
bacteremia, and indeterminate by Day 4 and Day 7 will be determined by treatment group in 
the overall and MRSA populations. 
 Clinical responder rate at Day 14, Day 30, and Day 60 in the MSSA population 
(mITT analysis set): The number and percentage of patients classified as responder, failure, 
and indeterminate will be determined by treatment group. 
15.6. 
Safety Analyses 
All safety analyses will be conducted in the safety analysis set and will be summarized by study 
drug actually received.
Safety will be evaluated by presenting summaries of treatment-emergent AEs (TEAEs), 
clinical laboratory evaluations (biochemistry, hematology, and coagulation), vital signs 
(blood pressure, respiratory rate, heart rate, and temperature), and ECG parameters. A TEAE is 
one that occurs on or after the administration of study drug through the Day 60 visit 
(Day 60 ± 7 days). 


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Adverse events will be coded using the Medical Dictionary of Regulatory Activities (MedDRA). 
Deaths obtained only through vital status information will be coded as “Death NOS” and 
analyzed as an AE/SAE with outcome of fatal. An overall summary of AEs will be provided by 
treatment group. The incidence of TEAEs will be presented by system organ class (SOC) and 
preferred term (PT) through Day 7 and Day 60, by SOC, PT and relationship to study drug, and 
by SOC, PT and severity. Serious adverse events, SAEs with an outcome of death, and TEAEs 
that lead to discontinuation of the study drug will also be presented by SOC and PT. Depending 
on the number of adolescents (age 12 to <18 years) randomized, the overall summary of AEs and 
TEAEs by SOC and PT, and/or listings of AEs will be provided for this subgroup. 
Descriptive statistics for clinical laboratory results, vital signs, and ECG parameters, including 
change from baseline, will be presented by timepoint collected and for the overall most abnormal 
post-baseline value (clinical laboratory results and vital signs only). Incidences of potentially 
clinically significant clinical laboratory results, vital signs, and ECG parameters, as defined in 
the SAP, will also be summarized by timepoint collected and the overall most abnormal 
post-baseline value (clinical laboratory results and vital signs only). Urinalysis results will be 
presented in a listing. 
15.7. 
Interim Analysis 
Interim analyses of safety data (unblinded) will be provided to the DSMB throughout the study 
as defined in the DSMB charter. A futility analysis of the primary efficacy outcome in the 
MRSA population based on Day 14 clinical outcome data from approximately 
in 
the MRSA population in the mITT analysis set will also be reviewed by the DSMB. The futility 
analysis will be based on conditional power and the threshold for stopping the study due to 
futility will be provided in the SAP and DSMB charter. The futility boundary is non-binding. 
15.8. 
Immunogenicity Analysis 
ADA results will be defined as positive and negative based on the confirmatory cut-off point. 
ADA-positive samples will be further classified as neutralizing (i.e., inhibiting exebacase 
activity) or non-neutralizing (i.e., having no effect on activity). Baseline and Day 30-60 ADA 
results will be summarized by result in a shift table and for ADA positive patients, the number 
and percentage with neutralizing or non-neutralizing ADA will be provided. The number and 
percentage of patients who had treatment-boosted ADA (defined as increased ADA titers in 
patients who were positive at baseline) will be summarized. TEAEs by baseline ADA result and 
clinical outcome at Day 14 by baseline ADA result will also be summarized. IgE results will be 
presented in a listing. 


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15.9. 
Health Resource Utilization Analysis 
The following with be evaluated in the mITT analysis set for patients enrolled in the US for the 
overall, MRSA and MSSA population: 
 In-hospital mortality: defined as death during the initial hospitalization for S. aureus BSI/IE
through Day 60 
 Hospital length-of-stay (post-study drug administration): for patients that were discharged 
alive, the length-of-stay from the date of study drug administration to the date of discharge
from the initial hospitalization 
 ICU length-of-stay (post-study drug administration): for patients that were discharged from 
the initial hospitalization alive, the total number of days in the ICU from the date of study 
drug administration to the date of discharge from the initial hospitalization 
 Discharged location: where the patient was discharged to from the hospital 
(e.g., home, nursing home and skilled nursing facility/long-term acute care, rehabilitation, 
palliative care/hospice) 
 Outpatient therapy and home health care: whether or not SoCA was received in an outpatient 
facility or via home health care, and the number of days that SoCA was received as an 
outpatient 
 30-day all-cause readmissions: for patients that were discharged alive, readmission for any 
cause within 30 days of discharge from the initial hospitalization
30-day readmissions for S. aureus BSI/IE or complication of S. aureus BSI/IE: for patients 
that were discharged alive, readmission for S. aureus BSI/IE or complication of S. aureus
BSI/IE (e.g., metastatic foci, septic emboli) within 30 days of discharge from the initial 
hospitalization 
Insurance type: private insurance, Medicare, Medicare, other
15.10. 
Pharmacokinetic Analysis 
All PK data, dosing, and covariate information collected in this study will be pooled with the 
data collected from the prior studies to update the previously developed population PK model.
The population PK analysis will be described in a separate SAP and a separate report. 
The relationship between PK parameters of exebacase (AUC and Cmax), derivative parameters 
(such as parameter over MIC), and clinical outcome and ADA will be examined. 
The relationship between PK parameters and most frequent or most clinically significant AEs 
may be explored.


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15.11. 
Handling of Missing Data 
For the primary and secondary efficacy outcomes (with the exception of 30-day survival), 
patients with missing data are assigned a clinical outcome of indeterminate. In the mITT analysis 
set, indeterminate outcomes are included in the denominator for the calculation of the responder
rate. Thus, a clinical outcome of indeterminate is analyzed the same as a clinical outcome of 
failure. Sensitivity analyses will be conducted where missing data are imputed using a multiple 
imputation analysis. For the secondary outcome of 30-day survival, patients who are lost to 
follow-up prior to Day 30 will be censored at the last known date alive on or prior to Day 30. 
Handling of other missing data will be described in the SAP. 
16. 
DATA MANAGEMENT 
16.1. 
Data Collection 
The investigative site will be provided eCRFs in which to record all the protocol-specified data 
for each patient in this study. Entries made in the eCRF must be verifiable against source 
documents. Data reported in the eCRF will be consistent with the source documents or the 
discrepancies will be explained. 
The Investigator/Sub-Investigator (or other delegated medically qualified person listed on the 
FDA Form 1572 and trained on the protocol) will be responsible for reviewing all data and eCRF 
entries and will verify that the information is true and correct. 
Patient data will be entered into the eCRF and be ready for review as soon as possible, as 
outlined in the eCRF completion guidelines.
16.2. 
Access to Source Documents 
Study Monitors who are representatives of ContraFect or designee will monitor the study 
according to a predetermined Monitoring Plan. Monitoring visits provide ContraFect with the 
opportunity to: 
 Evaluate the progress of the study 
 Verify the accuracy and completeness of eCRFs 
 Assure that all protocol requirements, applicable laws and/or regulations, and Investigator’s 
obligations are being fulfilled 
 Resolve any inconsistencies in the study records. 
The Investigator must allow the Study Monitors to periodically review, at mutually convenient 
times during the study and after the study has been completed, all eCRFs and office, hospital, 
and laboratory records supporting the participation of each patient in the study. The eCRFs and 
other documentation supporting the study must be kept up-to-date by the Investigator and the 


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research staff at the investigative site. These study materials must be available for review by the 
Study Monitor, and/or other qualified representatives of ContraFect, at each monitoring visit.
The Study Monitor will review the various records of the study (eCRFs, patient medical and 
laboratory records, and other pertinent data). The Study Monitor will verify the eCRF data 
against original source documentation for accuracy and completeness. The study monitor will 
identify data discrepancies and collaborate with the Investigator and research staff to resolve the 
discrepancies in a timely manner. Protocol deviations will also be identified and recorded. 
The Study Monitor will ensure that each issue identified during a monitoring visit is 
appropriately documented, reported, and resolved in a timely manner in accordance with the 
Monitoring Plan. 
17. 
ADMINISTRATIVE 
17.1. 
Statement of Good Clinical Practices 
This trial will be conducted in adherence to the study protocol, GCP as defined in Title 21 of the 
US Code of Federal Regulations Parts 50, 54 56, 312, and Part 11 as well as ICH E6: 
Guideline for Good Clinical Practice (ICH E6 GCP) consolidated guidelines and applicable 
regulatory requirements (http://www.fda.gov/cder/guidance/index.htm). 
17.2. 
Protocol Adherence 
The Investigator must adhere to the protocol as described in this document. The Investigator is 
responsible for enrolling patients who have met the protocol inclusion and exclusion criteria. 
The IRB/IEC responsible for overseeing the conduct of the study must be notified of all changes 
to the protocol and any deviations from the protocol that may increase risk to the patient and/or 
that may adversely affect the rights of the patient or validity of the investigation. 
17.3. 
Study Termination 
ContraFect reserves the right to terminate the study. The Investigator must notify the IRB/IEC in 
writing of the study’s completion or early termination, send a copy of the notification to 
ContraFect or designee, and retain a copy for the site’s study file. 
18. 
QUALITY CONTROL AND ASSURANCE 
18.1. 
Sponsor Audits 
Individuals from ContraFect’s Quality Assurance department or designee may visit the 
Investigator’s site to conduct an audit of the study. The purpose of this visit will be to determine 
the Investigator’s adherence to the protocol, applicable regulations, and ContraFect’s procedures, 
in addition to assessing the accuracy of the study data. Prior to initiating this audit, the 
Investigator will be contacted by ContraFect or designee to arrange a convenient time for this 


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visit. The Investigator and staff are expected to cooperate with the auditor(s) and allow access to 
all patient records supporting the eCRFs and other study-related documents. 
18.2. 
Inspection by Regulatory Authorities 
During the investigational product’s development program, a regulatory authority may visit the 
Investigator to conduct an inspection of the study and the site. The Investigator and staff are 
expected to cooperate with the inspectors and allow access to all source documents supporting 
the eCRFs and other study-related documents. The Investigator must immediately notify 
ContraFect when contacted by any regulatory authority for purposes of conducting an inspection. 
19. 
ETHICS 
19.1. 
Institutional Review Board or Independent Ethics Committee 
It is the responsibility of the Investigator to assure that all aspects of the ethics review are 
conducted in accordance with the Declaration of Helsinki as described in ICH E6 GCP, 
and/or local laws, whichever provides the greatest level of protection for the study participants. 
Any information supplied to the patient, such as written informed consent/assent form(s) and 
written information to be provided to patients (e.g., information leaflets), must be reviewed and 
approved by a qualified IRB/IEC prior to enrollment of participants in the study. Prior to 
initiation of the study at a site, ContraFect must receive documentation of the IRB/IEC approval, 
which specifically identifies the study/protocol, and a list of the committee members. 
Amendments to the protocol and revisions to the informed consent/assent must also be submitted 
to and, if required, approved by the IRB/IEC. 
Investigators must submit progress reports to the IRB/IEC in accordance with the IRB/IEC 
requirements. If applicable, annual re-approval of the study must be obtained. Copies of progress 
reports and annual re-approvals must be sent to ContraFect. 
If ContraFect provides the Investigator with a safety report, the Investigator must promptly 
forward a copy to the IRB/IEC in accordance with its regulations and guidelines. 
After completion or termination of the study, the Investigator must notify the IRB/IEC in writing 
of the study’s completion or early termination, send a copy of the notification to ContraFect or 
designee, and retain a copy for the site’s study file. 
The Investigator, as part of the records retention requirements for the study, must maintain 
documentation of all submissions, correspondence, and approvals to and from the IRB/IEC. 
The Investigator is responsible for conducting the study in accordance with the protocol, all 
applicable laws, regulations, and GCP according to ICH guidelines. 


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19.2. 
Informed Consent/Assent 
Preparation of the informed consent and assent forms is the responsibility of the Investigator and 
ContraFect or designee and must include all elements required by ICH, GCP, and applicable 
regulatory requirements, and must adhere to GCP and to the ethical principles that have their 
origin in the Declaration of Helsinki. 
Master study-specific informed consent and assent templates will be used to prepare the 
site-specific informed consent and assent forms. ContraFect or designee must review and 
approve all changes to site-specific informed consent and assent forms. 
The informed consent and assent forms must include a statement that ContraFect or designee and 
regulatory authorities have direct access to patient records. Prior to initiation of the study at a 
site, the Investigator must have the IRB/IECs written approval/favorable opinion of the written 
informed consent and assent forms and any other information to be provided to the patient. 
Some patients who will be eligible for this protocol may not be able to give written informed 
consent or assent themselves due to reasons such as sedation, unconscious state, etc. Therefore, 
in a situation where a patient is unable to provide written informed consent or assent for 
themselves, written informed consent may be provided by the patient’s legally acceptable 
representative, as permissible based on local laws and regulations. In such cases, if the patient 
regains the ability to supply informed consent themselves, they should be reconsented/assented. 
For patients 12 to <18 years of age, written informed consent from the patient’s parent/guardian 
or other legally acceptable representative will be obtained according to the site’s IRB 
requirements. For emancipated minors, written informed consent will be obtained according to 
the site’s IRB requirements. 
Each patient (or the patient’s legally acceptable representative/parent/guardian) must provide 
written informed consent or assent before any study-specific assessment or procedures are 
performed and must provide written informed consent or assent on the supplemental consent 
form before medical health services are provided. The patient (or the patient’s legally acceptable 
representative/parent/guardian) will sign and date the informed consent or assent form. 
The person rendering consent or assent will also sign and date the informed consent or assent 
form as the person who obtained the consent or assent of the patient. The original signed 
informed consent or assent form will be retained with the site’s study file. Each patient will be 
provided a copy of his or her signed informed consent or assent form. 
19.3. 
Data Privacy 
Applicable data privacy laws and regulations must be adhered to. The study site, Investigator, 
and ContraFect and their respective designees are responsible for ensuring that the protected 
health information (as defined under applicable laws) of all patients enrolled in the study is 
handled in accordance with the US Health Insurance Portability and Accountability Act of 1996 
(“HIPAA”) Privacy and Security Rules, 45 C.F.R. Parts 160-164, the Health Information 


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Technology for Economic and Clinical Health Act (HITECH), P.L. No. 111-005, Part I, 
Title XIII, Subpart D, 13401-13409, the California Consumer Privacy Act (“CCPA”), and any 
other applicable state and local privacy laws (collectively referred to as the “Applicable Data 
Privacy Laws”).
Appropriate informed consent/assent and authorizations for use and disclosure and/or transfer 
(if applicable) of protected health information must be obtained from all patients enrolled in the 
study. 
20. 
RECORD KEEPING/RETENTION OF RECORDS 
The Investigator must ensure that all records pertaining to the conduct of the clinical study, 
informed consent/assent forms, drug accountability records, source documents, and other study 
documentation are adequately maintained for a period 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. 
The Investigator must not destroy any records associated with the study without receiving 
approval from ContraFect. The Investigator must notify ContraFect in the event of accidental 
loss or destruction of any study records. If the Investigator leaves the institution where the study 
was conducted, ContraFect must be contacted to arrange alternative record storage options. 
Whenever possible, an original recording of an observation must be retained as the source 
document. However, a photocopy of a record is acceptable provided it is legible and is a verified 
copy of the original document. 
All eCRF data entered by the site (including audit trail), as well as computer hardware and 
software (for accessing the data), will be maintained or made available at the site in compliance 
with applicable record retention regulations. ContraFect or designee will retain the original eCRF 
data and audit trail. 
20.1. 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records that leave the site will be 
identified only by a coded number to maintain patient confidentiality. All computer entry and 
networking programs will be performed with coded numbers only. Clinical information will not 
be released without written permission of the patient, except as necessary for monitoring by the 
IRB/IEC, regulatory authorities, or the Sponsor or designees. The patients will be informed that 
representatives of ContraFect, IRB/IEC, or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for 
inspection will be handled in strictest confidence and in accordance with all applicable data 
protection laws. 


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21. 
USE OF STUDY RESULTS 
By signing the study protocol, the Investigator and his or her institution agree that the results of 
the study may be used by ContraFect for the purposes of national and international registration, 
publication, and information for medical and pharmaceutical professionals. As required, 
the authorities will be notified of the Investigator’s name, address, qualifications, and extent of 
involvement. 
22. 
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23.
APPENDICES
23.1. 
Appendix 1: Sequential (Sepsis-Related) Organ Failure Assessment Score (SOFA)
In patients that meet the qSOFA score (as described in Section 12.2.2), a SOFA score will be performed to determine whether the 
patient meets the criteria for sepsis and/or septic shock. Sepsis and/or septic shock based on the SOFA score are criteria for 
complicated S. aureus BSI according to the inclusion criterion #4 (Section 10.1) and the diagnosis definition in Table 8 (Section 12.5). 
If the SOFA score is the only criteria for complicated S. aureus BSI that is met according to inclusion criterion #4, contact the Medical 
Monitor prior to randomization. The SOFA score is determined according to the definitions and table below [adapted from 
Singer 2016]: 
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Organ dysfunction can
be identified as an acute change in total SOFA score of 2 points consequent to the infection. The baseline SOFA score can be
assumed to be 0 in patients not known to have preexisting organ dysfunction. A SOFA score of 2 points reflects an overall
mortality risk of approximately 10% in a general hospital population with suspected infection.
Septic shock is a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to
substantially increase mortality. Patients with septic shock can be identified with a clinical construct of sepsis with persisting
hypotension requiring vasopressors to maintain MAP 65 mmHg and having a serum lactate level >2 mmol/L (18 mg/dL) despite
adequate volume resuscitation. With these criteria, hospital mortality is in excess of 40%.
System 
Score 
0
1
2
3
4
Respiration: PaO2/FiO2, mmHg (kPa) 
400 (53.3) 
<400 (53.3) 
<300 (40) 
<200 (26.7) with 
respiratory support  
<100 (13.3) with 
respiratory support 
Coagulation: Platelets, x103/µL 
150
<150
<100
<50
<20
Liver: Bilirubin, mg/dl (µmol/L) 
<1.2 (20) 
1.2-1.9 (20-32) 
2.0-5.9 (33-101) 
6.0-11.9 (102-204) 
>12.0 (204)
Cardiovascular
MAP 70 mmHg 
MAP <70 mmHg 
Dopamine 
<5 or dobutamine 
(any dose)1 
Dopamine 5.1-15 or 
epinephrine 0.1 or 
norepinephrine 0.11 
Dopamine >15 or 
epinephrine >0.1 or 
norepinephrine >0.11 
CNS: Glasgow Coma Score 
15 
13-14
10-12
6-9
<6 
Renal: Creatinine, mg/dL (µmol/L) 
<1.2 (110) 
1.2-1.9 (110-170) 
2.0-3.4 (171-299) 
3.5-4.9 (300-440) 
>5.0 (440)
Renal: Urine output, mL/d
<500
<200
Reference: Adapted from Singer 2016 
Abbreviations: FiO2=fraction of inspired oxygen; MAP=mean arterial pressure; PaO2=partial pressure of oxygen 
1.
Catecholamine doses given as µg/kg/min for at least 1 hour


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23.2. 
Appendix 2: APACHE II Score 
APACHE II Score Form 
 
PHYSIOLOGIC VARIABLE
HIGH ABNORMAL RANGE 
LOW ABNORMAL RANGE 
+4  
+3
+2
+1 
0 
+1
+2
+3
+4
1 
Temperature core ( C) 
>=41 
39-40.9 
 
38.5-38.9 
36.0-38.4 
34-35.9 
32-33.9 
30-31.9 
<=29.9 
2 
Mean arterial pressure = 
(2 x diastolic + systolic)/3 
>=160 
130-159 
110-129 
 
70-109 
50-69 
 
<=49 
3 
Heart rate (ventricular response)
>=180 
140-179 
110-139 
70-109 
55-69 
40-54 
<=39
4 
Respiratory rate (non-ventilated or 
ventilated) 
>=50 
35-49 
25-34 
12-24 
10-11 
6-9 
<5 
5 
Oxygenation 
A-aDO2 or PaO2(mmHg)
a) FiO2>0.5:record A-aDO2
>=500 
350-499 
200-349 
<200 
b) FiO2<0.5:record only PaO2 
>70 
61-70 
55-60 
<55 
6 
Arterial pH
If no ABGs see Serum HCO3 below* 
>=7.7 
7.6-7.69 
7.5-7.59 
7.33-7.49
7.25-7.32 
7.15-7.24
<7.15
7 
Serum Sodium
>=180 
160-179 
155-159 
150-154 
130-149 
120-129 
111-119 
<=110
8 
Serum Potassium
>=7 
6-6.9 
5.5-5.9 
3.5-5.4 
3-3.4 
2.5-2.9
<2.5 
9 
Serum Creatinine (mg/dL)
Double point for acute renal failure 
>=3.5 
2-3.4 
1.5-1.9
0.6-1.4
<0.6 
10 
>=60
50-59.9 
46-49.9 
30-45.9 
20-29.9 
<20 
11 
White Blood Count 
>=40 
20-39.9 
15-19.9 
3-14.9 
1-2.9 
<1 
12 
Glasgow Coma Scale (see next page)
(Score = 15 minus actual GCS) 
15 minus the GCS =
A 
Total Acute Physiology Score (APS)
Sum of the 12 individual variable points =
* 
Serum HCO3(venous-mmol/L)
>=52 
41-51.9 
32-40.9 
22-31.9 
18-21.9 
15-17.9 
<15 
Reference: Adapted from Knaus 1985


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APACHE II Score Form (Continued)
Glasgow Coma Scale (Circle appropriate response) 
B   Age Points 
C  
Chronic Health Points 
APACHE II 
Score  
(sum of A+B+C)
Eyes open
4 - spontaneously 
3 - to verbal 
2 - to painful stimuli 
1 - no response 
 
Motor response 
6 - to verbal command 
5 - localizes to pain 
4 - withdraws to pain 
3 - decorticate 
2 - decerebrate 
1 - no response 
verbal - nonintubated
5 - oriented and conversant 
4 - disoriented and talks 
3 - inappropriate words 
2 - incomprehensible sounds 
1 - no response 
 
verbal - intubated 
5 - seems able to talk 
3 - questionable ability to talk 
1 - generally unresponsive 
Age
<44 
45-54 
55-64 
65-74 
>75 
 
Points
0 
2 
3 
5 
6  
If any of the 5 CHE categories below is answered with 
yes, give +5 points for non-operative or emergency 
postoperative patients or +2 points for elective 
postoperative patients. 
A APS points 
(from prior page) 
+ B Age points 
+ C Chronic 
Health Points 
__________ 
= Total 
APACHE II score 
Liver 
- Cirrhosis with PHT or 
encephalopathy
Age Points =
Cardiovascular
- Class IV angina or at rest or with 
minimal self-care activities 
Pulmonary 
- Chronic hypoxemia or hypercapnia or 
polycythaemia of PHT >40 mmHg
Kidney
- Chronic peritoneal or haemodialysis
Immune
- Immune compromised host
Chronic Health Points = 
Reference: Adapted from Knaus 1985 


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23.3. 
Appendix 3: Oxygen Conversion Tables 
Table 14:
Oxygen Saturation (SpO2) to Partial Pressure of Oxygen (PaO2)
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
Table 15:
Estimation of FiO2 
 
FiO2 should be decimal (e.g., 0.21) when determining PaO2/FiO2 ratio. 
Method
O2 flow (L/min)
Estimated FiO2 (%)
Nasal Cannula
1
24
2 
27
3 
30
4 
33
5 
36
6 
40
 
 
NasopharyngealCatheter
4
40
5 
50
6 
60
 
 
Face Mask
5 
40
6-7
50
7-8
60
 
 
Face Mask with Reservoir
6
60
7 
70
80


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23.4. 
Appendix 4: Common Categories of Immunosuppressive and 
Myelosuppressive Agents 
Inclusion criterion 4.b.vi describes the criterion for complicated S. aureus BSI of 
“On immunosuppressive therapy, such as:
 Biologics such as infliximab, monoclonal antibodies such as daclizumab, methotrexate, 
cyclophosphamide, or similar agents.
 Patients 
” 
This section describes the “similar agents” that meet the criterion of immunosuppressive therapy 
(listed below). This is not an all-inclusive list of all immunosuppressive therapies. Please contact 
the Medical Monitor if you have questions regarding these immunosuppressive therapies or if a 
patient is on a potential immunosuppressive therapy that is not listed. Immunosuppressive 
therapy includes, but is not limited to, the following medications: 
Medications:
 Methotrexate (Rheumatrex, Trexall) at any dose 
 Leflunomide (Arava) / Teriflunomide (Aubagio) at any dose
 Cyclophosphamide (Cyotxan) at any dose
 Cyclosporine A at any dose (not including ophthalmic formulation (Restatis)) 
 Tacrolimus (FK506) at any dose (not including ophthalmic formulation (Protopic))
 Azathioprine at any dose 
 Mycophenolate Mofetil (Cellcept) at any dose 
 Sirolimus (Rapamycin, Rapamune) at any dose 
 Everolimus (Certican) at any dose 
 Temsirolimus (Torisel) at any dose
 Gusperimus at any dose 
 Thalidomide at any dose 
 Apremilast (Otezla): PDE-4 inhibitor 
Biologics: 
 Anti-tumor Necrosis Factors (TNR Agents)
Etanercept (Enbrel)
 Afelimomab (Fab 2)
 Infliximab (Remicade)
 Certolizumab (Cimzia)
Golimumab (Simponi) 
 IL-1 Receptor Antagonist (IL-1RA) - Kineret (Anakinra) 


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 CTLA-4 Fusion Protein 
 Abatacept (Orencia) 
 Alefacept (Amevive) 
Belatacept (Nulojix)
 Anti-CD20 
 Rituximab (Rituxan/MabThera) 
 Obinutuzumab (Gazyva) 
 Ocrelizumab (Ocrevus) 
 Ofatumumab (Arzerra) 
 Anti-CD52 - Alemtuzumab (Campath)
 Anti-Interleukin Antibodies
Daclizumab (Anti-Tac, Zenapax)
Basiliximab (Simulect)
Anti-IL6 - Tocilizumab (Actemra/RoActemra) 
 Anti-IL 12/13 - Ustekinumab (Stelara) 
 Anti-BAFF (B-cell activating factor) - Belimumab 
 Integrin Inhibitor - Natalizumab (Tysarbi) 
 Anti-CTLA 4 – Ipilimumab 
 Ixekizumab (Taltz) or other Anti- IL 17 or Anti-IL 23 antibodies 
 Other Interleukins 
 Aldesleukin (Proleukin) 
 Canakinumab (Ilaris) 
 Oprelvekin (Neumega) 
 Anti-PDL1 - Avelumab (Bavencio) 
 Other Selective Immunosuppressants 
 Muromonab or OKT-3 
 Efalizumab (Raptiva) - anti-CD11a 
 Fingolimod (Gilenza) - sphingosine 1-phosphatge receptor modulator 
Eculizumab (Soliris): anti-complement protein C5
Tofacitinib (Xeljanz): JAK-STAT inhibitor