Clinical trial NCT03163446
Conditions: Staphylococcus Aureus Bacteremia Staphylococcus Aureus Endocarditis
Keywords: Staphylococcus aureus bacteremia staphylococcal endocarditis
Sponsor: ContraFect
Start date: 2017-05-23; Completion date: 2019-03-07
Enrollment: 121 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety, tolerability, efficacy and pharmacokinetics (PK) of CF-301 in addition to background standard of care (SOC) antibacterial therapy for the treatment of Staphylococcus aureus (S. aureus) bloodstream infections (bacteremia), including endocarditis in adults. Patients will be randomized to receive a single intravenous dose of CF-301 or placebo in addition to SOC antibacterial therapy. Patients will be prescribed standard of care antibiotics selected by the investigators based on their professional experience, practice guidelines and local antibiotic susceptibility information for the treatment of S. aureus bacteremia.

CF-301 is a lysin and member of a new class of targeted protein-based antimicrobials that has demonstrated activity against S. aureus in laboratory (in vitro) and animal studies, alone and in addition to conventional antibiotics.

Detailed description:

Arms: arm 1: Patients will receive a single IV infusion of CF-301 in addition to standard of care (SOC) antibacterial therapy selected by the investigator. arm 2: Patients will receive a single IV infusion of placebo in addition to standard of care (SOC) antibacterial therapy selected by the investigator.
Interventions: intervention 1: CF-301 intervention 2: Placebo
Intervention descriptions: intervention 1: CF-301, 0.25 mg/kg, given as a single 2 hour iv infusion intervention 2: Placebo, given as a single 2 hour iv infusion

Protocol documents:
Prot_SAP_000.pdf: 
Protocol CF-301-102-4 
Protocol Amendment #4 
June 22, 2018 
1 
Clinical Trial Protocol 
CF-301 
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 
Protocol Number CF-301-102-4 
Protocol Amendment #4 
Sponsor: 
ContraFect Corporation 
28 Wells Ave 
Yonkers, NY 10701 
Original Protocol Date: August 29, 2016 
Country-Specific Protocol Amendment #1 for the United States Date: August 17, 2017 
Country-Specific Protocol Amendment #2 for the United States Date: December 14, 2017 
Administrative Amendment #1 for Latin America Date: October 3, 2017 
Country-Specific Protocol Amendment #2 for Latin America Date: December 14, 2017 
Country-Specific Protocol Amendment #1 for the EU Date: August 31, 2017 
Country-Specific Protocol Amendment #2 for the EU Date: December 18, 2017 
Country-Specific Protocol Amendment #1 for Israel Date: June 23, 2017 
Country-Specific Protocol Amendment #2 for Israel Date: December 19, 2017 
Protocol Amendment #3 Date: April 3, 2018 
Protocol Amendment #4 Date: June 22, 2018 
IND number: 113473 
EudraCT number: 2016-003059-31 
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 NCT03163446


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
2 
 
 
  
 
Summary of Changes 
The primary purpose of this Protocol Amendment is to refine the criteria/risk factors in inclusion 
criterion #4 to better enable enrollment of patients with severe complicated bacteremia in 
accordance with recommendations of both the Data Safety Monitoring Board (DSMB) and 
Adjudication Committee.  Consistent with this objective, the exclusion criteria were updated to 
allow enrollment of patients with osteomyelitis, nosocomial pneumonia due to S. aureus, 
implantable cardioverter defibrillators, permanent pacemakers, prosthetic cardiac values, cardiac 
value support rings, and other implantable cardiac devices (see revisions to exclusion criteria #6, 
7, 9, 11, 12 for all changes). 
In addition, the protocol was updated to add an assessment of re-infection by the site investigator 
and the independent Adjudication Committee between Test-of-Cure (TOC) and Day 180 for 
patients who meet the definition of response at TOC.  The protocol was also revised to collect 
serious adverse events (SAEs) through the Day 180 visit. 
The table below describes the changes that were made from the prior version of the protocol: 
Section(s) 
Brief Description of Changes 
2, 4, 8.3, 11.3, 12.16, 
15.4 
• 
Added an assessment of re-infection by the site investigator and 
Adjudication Committee between TOC and Day 180 for patients who meet 
the definition of response at TOC. 
2, 9.1, 9.4, 11.1 
• 
Added suggested treatment duration for osteomyelitis of 42 to 84 days of 
standard-of-care antibacterial therapy.  Added expected core study 
duration (through TOC) of 10 to 16 weeks for patients with osteomyelitis. 
2, 10.1 
• 
Clarified that the inclusion criteria must be met at the time of Screening 
(i.e., within 24 hours of randomization), unless otherwise noted, in order 
for the patient to be eligible for enrollment. 
• 
Revised inclusion criterion #3 to require at least two signs and symptoms 
of infection. 
• 
Revised the criteria/risk factors in inclusion criterion #4 to better enable 
enrollment of patients with severe complicated bacteremia. 
2, 10.2 
• 
Updated exclusion #6 to exclude patients with presence of a prosthetic 
cardiac valve, cardiac valve support ring, or other implantable cardiac 
devices (e.g., left ventricular assist device [LVAD]) only if the patient is 
scheduled for surgical removal of the prosthetic valve, ring, or implantable 
device during the 24 hours after randomization.  Patients with implantable 
cardioverter defibrillators and permanent pacemakers are eligible for 
enrollment, and patients with prosthetic cardiac values, cardiac value 
support rings, or other implantable cardiac devices who are NOT 
scheduled for surgery during the 24 hours after randomization are eligible 
for enrollment. 
• 
Updated exclusion #7 to exclude endocarditis with severe aortic or mitral 
valve regurgitation on TEE or TTE, or any paravalvular abscess, with 
scheduled surgery for endocarditis. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
3 
 
 
  
 
• 
Updated exclusion #9 so that osteomyelitis is NOT an exclusion. 
• 
Updated exclusion #10 to specify that ideal weight should be used in the 
creatinine clearance calculation by Cockcroft-Gault in patients with 
BMI ≥ 30 kg/m2. 
• 
Updated exclusion #11 to exclude community acquired pneumonia, and 
nosocomial pneumonia due to pathogens other than S. aureus.  Patients 
with nosocomial pneumonia due to S. aureus are eligible for enrollment. 
• 
Updated exclusion #12 to exclude patients not expected to survive through 
Day 14 of the study due to underlying disease (e.g., end-stage cancer). 
2, 4, 10.3.2, 11.3, 
12.14 
• 
Added an assessment of vital status (whether the patient is alive or dead, 
or last known alive date) at Day 180 or when a patient is deemed to be lost 
to follow-up.  The patient’s vital status should be determined using 
available sources (e.g., the patient’s relatives, hospital records, and/or 
public records) as permissible based on local laws and regulations. 
2, 4, 11.3, 14.2 
• 
Updated SAE reporting procedures to collect all SAEs occurring during 
the long-term follow-up period through Day 180. 
2, 4, 11.3, 12.16 
• 
Expanded the visit window around the Day 180 visit to ±14 days. 
2, 12.16 
• 
Added the following reason for non-response to the clinical outcome 
assessment: >12 weeks of SOC antibacterial therapy for S. aureus BSI 
and/or related infection (e.g., osteomyelitis). 
4, 11.2.1, 12.2, 
12.13.2 
• 
Updated the creatinine clearance calculation by Cockcroft-Gault to include 
the use of ideal body weight in patients with BMI ≥ 30 kg/m2. 
4, 11.2, 11.3, 12.12 
• 
Clarified that all blood cultures performed during the study (from the 
qualifying blood culture through to Day 180), including blood cultures that 
are positive or negative for S. aureus, should be entered in the eCRF, with 
all S. aureus isolates sent to the central lab. 
14.11 
• 
Made minor clarifications to SAE reporting procedures. 
23.1 (Appendix 1) 
• 
Revised definition of complicated bacteremia to be consistent with the 
changes made to the inclusion criteria. 
Various 
• 
Made minor editorial changes throughout the document for clarity and 
consistency. 
 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
4 
 
 
  
 
SPONSOR SIGNATURE PAGE 
Protocol CF-301-102-4 
Protocol Amendment #4 
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 
 
 
Sponsor’s Approval 
 
 
 
Alena Jandourek, M.D. 
Executive Director 
Clinical Development and Medical Affairs 
ContraFect Corporation 
 
Date 
 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
5 
 
 
  
 
INVESTIGATOR’S AGREEMENT 
Protocol CF-301-102-4 
Protocol Amendment #4 
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 
 
I, the undersigned, have received and reviewed the CF-301-102 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 
 
 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
6 
 
 
  
 
1. 
CONTACT INFORMATION 
Table 1: 
Contact Information 
Role in Study 
Name 
Contact Information 
Sponsor Responsible 
Physician/Medical 
Lead 
Alena Jandourek, M.D. 
Executive Director, 
Clinical Development and 
Medical Affairs 
ContraFect Corporation 
28 Wells Ave, Yonkers, NY 10701 
Telephone: 914 207 2300 (Office) 
                  206 384 0182 (Mobile) 
Email: AJandourek@contrafect.com 
Sponsor Project 
Manager 
Nancy Capra 
Executive Director, Project 
Management 
ContraFect Corporation 
28 Wells Ave, Yonkers, NY 10701 
Telephone: 215-760-3490 
Email: NCapra@contrafect.com 
Sponsor Clinical 
Operations Lead, 
Global 
Susan Ermlich 
Clinical Operations 
Consultant 
ContraFect Corporation 
28 Wells Ave, Yonkers, NY 10701 
Telephone: 215-796-0950 
Email: SErmlich@contrafect.com 
Sponsor Clinical 
Operations Lead, US 
Joy Lipka 
Clinical Operations 
Consultant 
ContraFect Corporation 
28 Wells Ave, Yonkers, NY 10701 
Telephone: 215-872-3791 
Email: JLipka@contrafect.com 
Sponsor Clinical 
Operations Lead, 
Latin America 
Maureen Chapnick 
Clinical Operations 
Consultant 
ContraFect Corporation 
28 Wells Ave, Yonkers, NY 10701 
Telephone: 908-868-4719 
Email: MChapnick@contrafect.com 
CRO Project Manager, 
US 
Kimberly Lumpkin 
Clinical Trial Manager 
SynteractHCR 
5759 Fleet Street, Suite 100 
Carlsbad, CA 92008 
Telephone: 760 277 5220 
Email: Kimberly.Lumpkin@synteractHCR.com 
CRO Project Manager, 
Latin America 
Veronica Prado 
Project Manager 
CIDAL 
4 Avenida 21-63 zona 14, Guatemala City, Guatemala 
Telephone (+502) 2375 8300 
International Calls: (1-786) 314-7083 
Email: vprado@cidal.net 
CRO Project Manager, 
Europe, Russia, and 
Israel 
Ute Doerge-Baischew 
Global Project Manager 
PSI CRO Deutschland GmbH 
PSI Pharma Support 
Behringstr. 7 | 82152 Planegg/Munich | Germany 
Telephone: +49 151 5514 6051 
Email: ute.doerge-baischew@psi-cro.com 
Lead Study Medical 
Monitor and US 
Medical Monitor 
Alena Jandourek, M.D. 
Executive Director, 
Clinical Development and 
Medical Affairs 
 
ContraFect Corporation 
28 Wells Ave, Yonkers, NY 10701 
Telephone: 914-207-2300 (Office) 
                  206-384-0182 (Mobile) 
Email: AJandourek@contrafect.com 
Medical Monitor, 
Latin America 
Jacobo Sabbaj, MD, FACP, 
FIDSA 
Advisor and Consultant 
CIDAL 
4 Avenida 21-63 zona 14, Guatemala City, Guatemala 
Telephone (+502) 2375-8300 
International Calls: (1-732) 428-5502 or  
                                (1-786) 338-9580 
Email: jsabbaj@cidal.net 
Contact Information continued on the next page 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
7 
 
 
  
 
Table 1: Contact Information (continued) 
Role in Study 
Name 
Contact Information 
Medical Monitor, 
Europe 
Liga Ulmane, M.D. 
Medical Affairs Manager 
PSI CRO Latvia SIA 
21 Kr. Valdemara, Riga, LV 1010, Latvia 
Telephone: +37129492424 
Email: Liga.Ulmane@psi-cro.com 
Medical Monitor, 
Backup 
John Riefler, M.D. 
Director of Medical 
Monitoring & Consulting 
PSI Pharma Support America Inc. 
875 First Avenue, King of Prussia, PA 19404 
Telephone: 267-464-2520, x 2120 
Email: John.Riefler@psi-cro.com 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
8 
 
 
  
 
2. 
SYNOPSIS 
Name of Sponsor/Company: ContraFect Corporation 
Investigational Product: CF-301 
Active Ingredient: C1149H1768N324O357S3 
Title of Study: 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 
Protocol number:  CF-301-102-4 (Protocol Amendment #4) 
Phase of development: 2 
Study centers:  Up to approximately 100 study centers will participate in this global study 
Objectives: 
Primary: 
• 
To describe the safety and tolerability of CF-301 vs. placebo in addition to standard-of-care 
(SOC) antibacterial therapy for the treatment of patients with Staphylococcus aureus bloodstream 
infections (BSIs) including endocarditis. 
• 
To estimate clinical outcome at Day 14 after CF-301/placebo administration. 
• 
To describe the pharmacokinetic (PK) parameters of CF-301. 
Secondary: 
• 
To estimate clinical outcome at Day 7 after CF-301/placebo administration, at the end of SOC 
antibacterial therapy (EOT), and at test-of-cure (TOC) 28 days after the EOT. 
• 
To estimate microbiological response at Days 7 and 14 after CF-301/placebo administration. 
• 
To estimate microbiological outcome at EOT and at TOC. 
Exploratory: 
• 
To describe the time to clearance of S. aureus bacteremia (defined as blood cultures negative for 
2 consecutive days). 
• 
To describe the time to defervesence (defined as the highest oral temperature equivalent on day of 
assessment < 38.0°C [< 100.4°F]). 
• 
To describe all-cause mortality. 
• 
To explore the relationship between CF-301 exposures and safety and efficacy endpoints. 
• 
To describe post-dose immunologic response to CF-301. 
• 
To explore the relationship between baseline and post-dose immunologic parameters and safety 
and efficacy endpoints. 
• 
To describe clinical and microbiological outcomes in the subset of patients with 
methicillin-resistant S. aureus (MRSA) infections. 
• 
To describe clinical and microbiological outcomes by diagnosis. 
• 
To describe relapse and re-infection rates. 
• 
To describe changes in cardiac valve vegetations, valvular function, and cardiac tissue in patients 
with endocarditis. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
9 
 
 
  
 
• 
To describe the occurrence of clinical evidence of septic emboli and metastatic S. aureus 
infections. 
• 
To explore health resource utilization, including total length of hospital stay, days in the intensive 
care unit (ICU), 30-day readmission for S. aureus BSI/endocarditis, and surgery for treatment of 
S. aureus BSI/endocarditis. 
Study Design: 
This is a randomized, multicenter, multinational, double-blind, study to evaluate the safety, 
tolerability, efficacy, and PK of CF-301 vs. placebo in addition to SOC antibacterial therapy for the 
treatment of adult patients with S. aureus BSI including endocarditis.  Patients who meet all screening 
criteria and have blood culture positive for S. aureus determined by rapid diagnostic or conventional 
method or Gram stain showing Gram-positive cocci in clusters plus positive tube coagulase test from 
blood culture specimens collected within 72 hours prior to randomization are eligible for the study. 
Approximately 115 patients will be randomized in a 3:2 ratio to one of two treatment groups: 
• 
Group 1: CF-301 in addition to SOC antibacterial therapy (70 patients) 
• 
Group 2: Placebo in addition to SOC antibacterial therapy (45 patients) 
Patients who are randomized will receive a single dose of CF-301 or placebo over a 2-hour infusion 
in addition to appropriate SOC antibacterial therapy. 
Standard-of-care antibacterial therapy will be selected by the investigator based on standard practice 
at the site, treatment guidelines (Liu et al., 2011; Baddour et al., 2015), and other local guidelines.  
Standard-of-care agents include daptomycin and vancomycin for MRSA and semi-synthetic 
penicillins (e.g., nafcillin, oxacillin, cloxicillin, flucloxacillin) and first-generation cephalosporins 
(e.g., cefazolin) for methicillin-susceptible S. aureus (MSSA).  If susceptibility is not known at the 
time of randomization, the patient should 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, SOC may be changed at the investigator’s discretion based on 
susceptibility results to one of the SOC options described above.  Standard-of-care should be 
administered at the doses and durations specified in the manufacturer’s prescribing information, 
treatment guidelines (Liu et al., 2011; Baddour et al., 2015), other local guidelines, and clinical 
practice.  The suggested duration of SOC treatment is 28 to 42 days for complicated bacteremia 
and/or endocarditis and 42 to 84 days for osteomyelitis.  Patients with known or suspected 
uncomplicated bacteremia are not eligible for the study; however, if a randomized patient is 
subsequently determined to have uncomplicated bacteremia, the suggested duration of SOC treatment 
is approximately 14 days.  The investigator will determine diagnosis at screening and during the study 
to determine treatment duration. 
An overall clinical assessment, including a detailed evaluation of signs and symptoms of S. aureus 
BSI, will occur at screening.  Intravenous catheters known or suspected to be infected must be 
removed or changed and replaced at a different site as soon as possible within 72 hours after 
randomization.  In patients with central venous catheters (CVCs), ultrasounds to evaluate clots in the 
vein are recommended within 48 hours after randomization.  Two aerobic blood cultures preferably 
from 2 different sites will be collected at screening at least 30 minutes apart and as close to the start of 
study drug dosing as possible, and at least one aerobic blood culture will be collected daily during the 
study until negative for 2 consecutive days and at Days 7 and 14 after CF-301/placebo administration.  
Additional blood cultures will be performed as clinically indicated.  Blood cultures should be 
collected from a peripheral venipuncture site when possible. 
Physical examinations will be performed at screening, daily through Day 7 and on Day 14 after 
CF-301/placebo administration, at EOT, and at TOC.  The physical examinations will include a close 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
10 
 
 
  
 
evaluation for any new areas of pain or signs of metastases; new signs should trigger diagnostic 
testing for metastatic foci. 
All patients should have a transthoracic echocardiogram (TTE) within 3 days of randomization.  All 
efforts should be made to perform this TTE before administration of study drug.  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 and the TTE within 3 days of randomization 
does not need to be performed.  Patients with endocarditis should have a follow-up TTE between 
Days 7 and 14; where possible, a transesophageal echocardiogram (TEE) should also be performed 
(Baddour et al., 2015; Habib et al., 2010; Habib et al., 2015).  TEEs are strongly recommended in 
patients with body mass index (BMI) > 30 kg/m2.  The site will provide all echocardiograms to the 
central echocardiography laboratory. 
Safety monitoring will include adverse event (AE) monitoring, physical examinations, vital sign 
measurements, 12-lead electrocardiograms (ECGs), clinical safety laboratory tests, and 
immunological monitoring.  Safety monitoring will be performed during the core study from 
screening through TOC, and a long-term follow-up will occur at Day 180 after CF-301/placebo 
administration.  An independent Data Safety Monitoring Board (DSMB) will review unblinded safety 
data throughout the core study as defined in the DSMB charter. 
Blood samples for PK will be collected as described in the “Pharmacokinetics” section below. 
Clinical response will be assessed by the investigator.  The Adjudication Committee will assess 
clinical response at predefined intervals.  The efficacy analysis of clinical response will be based on 
the Adjudication Committee’s assessment. 
Number of patients (planned): Approximately 115 patients with S. aureus BSI will be randomized 
(3:2) to receive a single dose of CF-301 or placebo. 
A sample size of approximately 70 patients in the CF-301 treatment group and 45 patients in the 
placebo group will provide at least 80% power to detect a treatment difference of 25% in clinical 
response rate at Day 14 after CF-301/placebo, based on expected clinical improvement or response 
rates of 60% and 85% in the placebo and CF-301 treatment groups, respectively, using a two-sided 
target alpha level of 0.05 and Fisher’s exact test. 
Inclusion Criteria: 
The following inclusion criteria must be met at the time of Screening (i.e., within 24 hours of 
randomization), unless otherwise noted below, in order for the patient to be eligible for enrollment: 
1. Male or female, 18 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 
positive tube coagulase test from blood culture specimens. (Note: the 72-hour time period starts at 
the time the specimen is collected for blood culture). 
3. At least two of the following signs or symptoms: 
a. Shortness of breath 
b. Sweating 
c. Fatigue 
d. Confusion 
e. Pain associated with metastatic foci 
f. Fever (oral temperature equivalent ≥ 38.0°C [≥ 100.4°F]) 
g. Leukocytosis (white blood cell [WBC] count > 10,000/µL), leukopenia (WBC < 4000/µL), or 
bandemia (> 10% immature neutrophils [bands] regardless of total peripheral WBC) 
h. Tachycardia (heart rate > 100 bpm) 
i. 
Tachypnea (respiratory rate > 20 breaths/min) 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
11 
 
 
  
 
j. 
Hypotension (systolic blood pressure < 90 mmHg) 
4. Patients must have: 
a. Known or suspected right- and/or left-sided endocarditis by Modified Duke Criteria (see 
protocol appendix) 
and/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. Signs or symptoms of catheter-related infection with clots in the vein at the catheter site 
seen on ultrasound 
iii. Signs or symptoms of metastatic foci of S. aureus infection (e.g., deep tissue abscess, 
septic pulmonary emboli) or hematogenous seeding (e.g., septic arthritis) confirmed by 
physical examination, imaging, or culture 
iv. S. aureus isolated from sterile body site other than blood 
v. Persistent fever (oral temperature equivalent ≥ 38.0°C [≥ 100.4°F]) at 72 hours or more 
after the initial blood culture 
vi. Skin examination findings suggesting the presence of acute systemic infection (e.g., 
presence of ecchymosis, infarcts, petechiae, pustules, or vasculitis) 
vii. Met criteria for severe sepsis or septic shock during the time of diagnosis/presumptive 
diagnosis of bacteremia 
 
Severe sepsis defined as documented or presumed infection associated with 
either organ dysfunction, hypoperfusion, or hypotension (systolic blood 
pressure < 90 mm Hg or a decrease of > 4 mm Hg from baseline systolic 
measure in the absence of other causes of hypotension) AND the presence of 
systemic inflammatory response syndrome (SIRS), defined by at least 2 of 
the following: 
• 
Temperature (oral, rectal, tympanic, or core) > 38.5°C (> 101.3°F) or 
< 35.0°C (< 95.0°F) 
• 
Heart rate > 90 beats/minute 
• 
Respiratory rate > 20 breaths/minute or partial pressure of arterial 
carbon dioxide (PaCO2) < 32 mmHg or on a ventilator 
• 
Leukocytosis (> 12,000 WBC/µL), leukopenia (< 4000 WBC/µL), or 
bandemia (> 10% immature neutrophils [bands] regardless of total 
peripheral WBC) 
 
Septic shock defined as persistent hypotension and perfusion abnormalities 
despite adequate fluid resuscitation or organ function not capable of 
maintaining homeostasis 
viii. Significantly immunocompromised: 
 
AIDS (HIV positive with an AIDS-defining condition or a CD4 count 
< 200 cells/mm³) 
 
Severe leukopenia defined as ANC <500 cells/mL for ≥ 3 days in the 7 days 
prior to the qualifying blood culture 
 
Post organ-transplantation including autologous bone marrow transplantation 
 
On treatment for active graft vs. host disease 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
12 
 
 
  
 
 
On immunosuppressive therapy (e.g., ≥ 15 mg of prednisone or equivalent 
for more than 5 days, biologics such as infliximab, monoclonal antibodies 
such as daclizumab, methotrexate, cyclophosphamide, or similar agents) 
 
On chemotherapy treatment 
or  
c. At least one of the following risk factors: 
i. 
Preexisting valvular heart disease 
ii. 
Surgery within the previous 30 days that puts the patient at risk for nosocomial 
bacteremia (e.g., orthopedic, cardiothoracic, or intraabdominal surgery) 
iii. 
Extravascular foreign material (Note: removal of extravascular foreign material 
known or suspected to be infected is required within 72 hours after randomization) 
iv. 
Hemodialysis 
5. Patient is not pregnant or breastfeeding and meets one of the following criteria: 
a. A female patient who is not of reproductive potential is eligible without requiring the use of 
contraception.  This includes females 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 and male patients of reproductive 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 should 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.  If the patient is not able to provide 
informed consent, he/she can be enrolled according to local regulatory requirements. 
Exclusion Criteria: 
1. Patient previously received CF-301. 
2. Treatment with any potentially effective (anti-staphylococcal) systemic antibiotic for more than 
72 hours within 7 days before randomization. 
EXCEPTION: Documented resistance to the prior systemic antibacterial therapy. 
3. Treatment with dalbavancin or oritavancin for the current infection. 
Note: patients who are receiving teicoplanin, linezolid, telavancin, ceftaroline fosamil, and/or 
sulfamethoxazole/trimethoprim are eligible for the study provided that treatment is switched to an 
appropriate SOC antibacterial agent (SOC agents include daptomycin and vancomycin for MRSA 
and semi-synthetic penicillins [e.g., nafcillin, oxacillin, cloxicillin, flucloxacillin] and 
first-generation cephalosporins [e.g., cefazolin] for MSSA. 
4. MRSA isolate is known or suspected to have intermediate susceptibility or resistance to 
vancomycin or daptomycin. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
13 
 
 
  
 
5. Presence of any removable infection source (e.g., intravascular line, abscess, dialysis graft) that 
will not be removed or debrided within 72 hours after randomization. 
6. Presence of an infected prosthetic joint, or presence of a prosthetic cardiac valve, cardiac valve 
support ring, or other implantable cardiac device (e.g., left ventricular assist device [LVAD]) if 
the patient is scheduled for surgical removal of the prosthetic valve, ring, or implantable device 
during the 24 hours after randomization.  Note: patients with implantable cardioverter 
defibrillators and permanent pacemakers are eligible for enrollment, and patients with prosthetic 
cardiac values, cardiac value support rings, or other implantable cardiac devices who are NOT 
scheduled for surgery during the 24 hours after randomization are eligible for enrollment. 
7. Endocarditis with severe aortic or mitral valve regurgitation on TEE or TTE, or any paravalvular 
abscess, with scheduled surgery for endocarditis. 
8. Known or suspected brain abscess. 
9. Known or suspected meningitis.  Note: Evidence of metastatic complications related to the 
primary infection such as septic arthritis and septic pulmonary infarcts are permitted. 
10. Asplenia in patients with creatinine clearance < 60 mL/min by Cockcroft-Gault using ideal body 
weight in patients with BMI ≥ 30 kg/m2 or on dialysis. 
11. Community acquired pneumonia, nosocomial pneumonia due to pathogens other than S. aureus, 
or known polymicrobial bacteremia (i.e., more than one pathogen in the blood).  Note: patients 
with nosocomial pneumonia due to S. aureus are eligible for enrollment. 
12. Patient is not expected to survive through Day 14 of the study due to underlying disease 
(e.g., end-stage cancer). 
13. Patient participated or plans to participate in an interventional investigational drug, device, or 
diagnostic trial within 30 days or 5 half-lives of investigational drug, whichever is longer, prior to 
or during the study. 
14. Other comorbid condition or laboratory abnormality that would, in opinion of investigator, pose 
safety risk for patient to participate or pose risk to patient’s ability to complete the study. 
15. Patient is employed by the sponsor or investigational site or is a first degree relative of a person 
employed by the sponsor or investigational site.  Patient is institutionalized by administrative or 
court order. 
Investigational product, dosage and mode of administration: 
• 
CF-301 will be administered at a dose of 0.25 mg/kg, with a maximum dose of 30 mg for patients 
who weigh ≥ 120 kg. 
• 
Patients with creatinine clearance of < 60 mL/min (including patients on dialysis) will receive a 
dose of 0.12 mg/kg, with a maximum dose of 15 mg for patients in this subset who weigh 
≥ 125 kg.  In patients on hemodialysis, CF-301/placebo will be administered either ≥ 8 hours 
prior to hemodialysis or ≥ 4 hours after the end of hemodialysis. 
• 
Patients who are > 50 years of age will receive a dose of 0.12 mg/kg, with a maximum dose of 
15 mg for patients in this subset who weigh ≥ 125 kg. 
If analyses by the DSMB support further dose reductions or dose increases up to 0.4 mg/kg based on 
accrued PK exposure data in specific patient demographic groups, these will be described in 
Administrative Amendments or Clarification Letters to the protocol.  If the accrued PK data suggest 
the need for an increase in dose above the 0.4 mg/kg dose defined in the original protocol, then a 
protocol amendment will be issued. 
CF-301 will be provided as a sterile injectable solution in 10 mL vials.  Each vial will contain 4.0 mL 
of CF-301 (10 mg/mL).  CF-301 will be diluted as specified in the Pharmacy Manual and 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
14 
 
 
  
 
administered as a 2-hour IV infusion using an IV set with an in-line filter (0.2 or 0.22 µm) with 
corresponding pump. 
Reference therapy, dosage and mode of administration: Placebo (vehicle control) will be provided 
as a sterile injectable solution in 10 mL vials.  Each vial will contain 4.0 mL of placebo.  Placebo will 
be administered diluted as specified in the Pharmacy Manual and administered as a 2-hour IV 
infusion using an IV set with an in-line filter (0.2 or 0.22 µm) with corresponding pump. 
Duration of treatment:  Patients will receive a single dose of CF-301 or placebo in addition to SOC 
antibacterial therapy.  The duration of SOC will generally be from 28 to 84 days based on the 
patient’s diagnosis (28 to 42 days for complicated bacteremia/endocarditis and 42 to 84 days for 
osteomyelitis), the investigator’s discretion, treatment guidelines, and standard practice. 
Duration of study (for each patient):  Each patient is expected to complete the core study (through 
TOC) in approximately 6 to 10 weeks, including screening, randomization, an estimated duration of 
approximately 28 to 42 days SOC, EOT visit, and TOC at 28-days after the end of SOC treatment.  
Patients with osteomyelitis are expected to complete the core study (through TOC) in approximately 
10 to 16 weeks, since estimated duration of SOC is 42 to 84 days. 
The study includes a long-term follow-up visit at Day 180 after CF-301/placebo administration for 
collection of an immunogenicity sample and assessment of SAEs and re-infection.  The ability of the 
patient to return for the Day 180 visit is not required for enrollment in the study, but the visit is highly 
encouraged.  With the long-term follow-up through Day 180 after CF 301/placebo administration, the 
total study duration is approximately 25 weeks. 
Criteria for evaluation: 
Safety and Immunogenicity: 
Adverse events will be monitored during the core study, from the time of consent through TOC.  
Patients must be directly observed during CF-301/placebo infusion, and vital signs (blood pressure, 
respiratory rate, and heart rate) will be performed approximately every 30 to 40 minutes during the 
infusion and at approximately 30 to 40 minutes after the infusion.  In patients who have clinical signs 
and symptoms of allergic reactions to CF-301, the infusion should 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.  If a patient experiences signs and symptoms consistent with anaphylaxis (Simons, et al., 
2011), blood samples for serum tryptase and CF-301-specific IgE will be collected as soon as possible 
within 2 hours.  If the serum tryptase sample is positive or equivocal, the sample may also be tested 
for β-tryptase. Another blood sample for serum tryptase will be collected 2 weeks later. 
Safety laboratory tests (biochemistry, hematology, coagulation, and urinalysis) will be performed at 
randomization (pre-dose), at approximately 2 to 4 hours after the start of CF-301/placebo infusion 
(for the first 17 patients randomized), on Day 2, weekly during SOC, at EOT, and at TOC.  Safety 
laboratory tests will be performed by a central laboratory. 
A 12-lead ECG will be performed at screening, at approximately 2 to 4 hours after the start of 
CF-301/placebo infusion (for the first 17 patients randomized), on Day 2, at EOT, and at TOC. 
Physical examination will be performed at screening, daily through Day 7 and on Day 14 after 
CF-301/placebo administration, at EOT, and at TOC.  Complete physical examinations will be 
performed at screening, Day 14, EOT, and TOC.  The physical examinations performed daily through 
Day 7 will be targeted physical examinations to evaluate for complications of BSI and will include 
assessments of head, eye, ear, nose, throat (HEENT), lungs, heart, skin for any evidence of emboli, 
and palpation for signs of pain.  Pain on physical examinations should trigger diagnostic testing for 
metastatic foci. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
15 
 
 
  
 
Vital signs will be performed at screening, approximately every 30 to 40 minutes during 
CF-301/placebo infusion and at approximately 30 to 40 minutes after the infusion, daily during SOC 
for inpatients (and at weekly scheduled visits for patients who are discharged [i.e., at the Day 7 and 
Day 14 visits, and weekly thereafter]), at EOT, and at TOC.  Vital signs will include blood pressure, 
respiratory rate, and heart rate during infusion and blood pressure, respiratory rate, heart rate, and 
temperature at all other time points. 
Blood samples will be collected for CF 301-specific anti-drug antibody (ADA) and IgE at 
randomization (pre-dose), Day 14, at EOT, at TOC, and on Day 180 after CF 301/placebo 
administration.  All testing will be performed at central laboratories, as described in the laboratory 
manual. 
If the patient agrees in the informed consent to have blood stored for optional future research (e.g., 
cytokine and chemokine assays and/or biomarker evaluation), 2 samples (1 serum and 1 plasma) will 
be collected at randomization (pre-dose), 12 to 24 hours after CF-301/placebo dosing, on Day 7, and 
at EOT and TOC.  Note: future use samples will NOT be collected from patients in Israel. 
An independent DSMB will review accruing safety, tolerability, immunogenicity, and PK data in an 
unblinded manner throughout the study, as detailed in the DSMB charter.  The Sponsor and study 
staff will remain blinded throughout the study.  The DSMB will conduct an initial unblinded review 
of safety, tolerability, and PK data after approximately 17 patients have PK data available 
(approximately 10 patients on CF-301 and approximately 7 patients on placebo).  The DSMB will 
also assess whether the PK target for the 0.25 mg/kg dose has been attained as predicted from the 
population PK data from the Phase 1 study.  If the mean exposure to CF-301 is significantly lower 
(e.g., by > 25%) or higher than the mean exposure in healthy volunteers in Study CF-301-101 dosed 
at 0.25 mg/kg (i.e., the target safe and efficacious exposure), then to achieve the planned exposure 
target the DSMB may recommend dose adjustment.  Enrollment will not be halted during the conduct 
of this review. 
After completion of the core study, all serious adverse events (SAEs) will be collected during the 
long-term follow-up through Day 180. 
Vital status (whether the patient is alive or dead, or last known alive date) will be obtained at Day 180 
or when a patient is deemed to be lost to follow-up.  The patient’s vital status should be determined 
using available sources (e.g., the patient’s relatives, hospital records, and/or public records) as 
permissible based on local laws and regulations. 
Efficacy: 
Signs and symptoms of S. aureus BSI/endocarditis will be evaluated at screening, daily during SOC 
for inpatients (and at weekly scheduled visits for patients who are discharged [i.e., at the Day 7 and 
Day 14 visits, and weekly thereafter]), at EOT, and at TOC. 
Two aerobic blood cultures preferably from 2 different sites will be collected at screening at least 
30 minutes apart and as close to the start of study drug dosing as possible, and at least one aerobic 
blood culture will be collected daily during the study until negative for 2 consecutive days and at 
Days 7 and 14 after CF-301/placebo administration.  Additional blood cultures will be performed as 
clinically indicated.  Blood cultures should be collected from a peripheral venipuncture site when 
possible. 
In patients with CVCs, ultrasounds to evaluate clots in the vein are recommended within 48 hours 
after randomization. 
Physical examinations will be performed at the time points described above under the “Safety” 
subsection and will include a close evaluation for any new areas of pain or signs of metastases; new 
signs should trigger diagnostic testing for metastatic foci.  Metastatic foci identified through Day 7 
post-randomization are considered related to the patient’s baseline S. aureus infection; new metastatic 
foci identified after Day 7 post-randomization are considered progression of the S. aureus infection. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
16 
 
 
  
 
All patients should have a TTE within 3 days of randomization.  All efforts should be made to 
perform this echocardiogram before administration of study drug.  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 and the echocardiogram within 3 days of 
randomization does not need to be performed.  Patients with endocarditis should have a follow-up 
TTE between Days 7 and 14; where possible, a TEE should also be performed (Baddour et al., 2015; 
Habib et al., 2010; Habib et al., 2015).  TEEs are strongly recommended in patients with 
BMI > 30 kg/m2.  The site will provide all echocardiograms to the central echocardiography 
laboratory. 
Clinical and microbiological outcome will be assessed at Days 7 and 14 after CF-301/placebo 
administration, at EOT, and at TOC. 
Clinical outcome will be assessed by the investigator and the independent Adjudication Committee.  
The signs and symptoms evaluated for clinical outcome assessments are presence of shortness of 
breath, sweating, fatigue, confusion, pain associated with metastatic foci, fever, leukocytosis, 
leukopenia, bandemia, tachycardia, tachypnea, and hypotension. 
Re-infection will be assessed at Day 180 after CF-301/placebo administration for patients who meet 
the definition of response at TOC.  Re-infection will be assessed by the investigator and the 
independent Adjudication Committee. 
Definitions for clinical outcomes and re-infection are provided in Table 1 and Table 2, respectively. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
17 
 
 
  
 
Table 1: Clinical Outcome Definitions at Day 7 (± 1 day), Day 14 (± 1 day), EOT (+ 2 days), and 
at TOC (±4 days) 
Clinical 
Outcome 
Definition 
Improvement 
(Days 7 and 14 
only) 
• 
Improvement in all attributable signs and symptoms of S. aureus BSI which were 
present at baselinea, 
• 
No new, worsening, or persistent signs and symptoms attributable to S. aureus BSI, 
• 
No development of a new foci of S. aureus infection after Day 7b 
• 
SOC for S. aureus BSI is ongoing with no need toc: 
 
add a SOC antibacterial agent due to persistent or worsening S. aureus BSI,  
 
switch to a different SOC antibacterial agent due to persistent or worsening 
S. aureus BSI, or 
 
increase SOC dose due to persistent or worsening S. aureus BSI, 
• 
No further surgery or medical intervention for S. aureus BSI is necessary, and 
• 
The patient is alive. 
Responsed 
• 
Complete resolution of attributable signs and symptoms of S. aureus BSI which were 
present at baseline, 
• 
No new signs and symptoms attributable to S. aureus BSI, 
• 
No development of a new foci of S. aureus infection after Day 7b 
• 
No further antibacterial therapy for S. aureus BSI is necessary, 
• 
No further surgery or medical intervention for S. aureus BSI is necessary, and 
• 
The patient is alive. 
Non-responsed 
• 
Persistence, worsening, or recurrence of attributable signs and symptoms of S. aureus 
BSI which were present at baseline, 
• 
New signs and symptoms attributable to S. aureus BSI, 
• 
Development of a new foci of S. aureus infection after Day 7b, 
• 
Complications of S. aureus BSI, 
• 
SOC for S. aureus BSI was changed toc: 
 
add a SOC antibacterial agent due to persistence, worsening, or recurrence of 
S. aureus BSI, 
 
switch to a different SOC antibacterial agent due to persistence, worsening, or 
recurrence of S. aureus BSI, or 
 
increase the dose of SOC due to persistence, worsening, or recurrence of 
S. aureus BSI, 
• 
>12 weeks of SOC antibacterial therapy for S. aureus BSI and/or related infection 
(e.g., osteomyelitis), 
• 
Further surgery or medical intervention for S. aureus BSI is necessary (e.g., valvular 
surgery for progressive S. aureus BSI), or 
• 
Death due to any cause. 
Indeterminate 
Study data are not available for the evaluation of efficacy for any reason including: 
• 
Lost to follow up 
• 
Withdrawal of consent 
• 
Extenuating circumstances that preclude the classification of clinical response 
a. 
Symptoms will be assessed as absent, mild, moderate, and severe.  All symptoms present at baseline must improve by 
one category (e.g., from moderate to mild) in order for a patient to be considered as having improvement. 
b. 
Does not apply at Day 7 assessment.  Metastatic foci identified through Day 7 post-randomization are considered 
baseline; new metastatic foci identified after Day 7 post-randomization are considered progression of the S. aureus 
infection. 
c. 
Per protocol, patients may be treated empirically and SOC may be changed once susceptibly data become available, as 
described in the “Study Design” section.  A change in SOC based on susceptibility data from the blood culture 
collected within 72 hours prior to randomization does not count as “non-response”. 
d. 
At Test-of-Cure, response = cure and non-response = failure. 
 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
18 
 
 
  
 
Table 2: Clinical Re-Infection Definitions at Day 180 (±14 days) 
Clinical 
Outcomea 
Definition 
No re-infection 
Between TOC and Day 180, the patient did not have S. aureus BSI/endocarditis or 
S. aureus infection at any body site (this includes infections that the investigator 
considers to be relapses as well as those that the investigator considers to be new 
S. aureus infections). 
Re-infection 
Between TOC and Day 180, the patient had S. aureus BSI/endocarditis and/or developed 
a S. aureus infection at any body site documented by a positive culture for S. aureus (this 
includes infections that the investigator considers to be relapses as well as those that the 
investigator considers to be new S. aureus infections). 
Indeterminate 
Study data are not available for the evaluation of efficacy for any reason including: 
• 
Lost to follow up 
• 
Withdrawal of consent 
• 
Extenuating circumstances that preclude the classification of clinical response 
a. 
Patients who meet the definition of response at TOC will be assessed for re-infection. 
 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
19 
 
 
  
 
Definitions for microbiological response (Days 7 and 14) and microbiological outcome (End of SOC 
and TOC) are provided in Table 3 and Table 4, respectively. 
Table 3: Microbiological Response Definitions at Day 7 (± 1 day) and Day 14 (± 1 day) 
Microbiological 
Response 
Definitions 
Clearance of bacteremia  
Blood cultures collected on or prior to assessment were negative for S. aureus 
on 2 consecutive days.   
Ongoing bacteremia 
Blood cultures collected on or prior to assessment continue to be positive for 
S. aureus 
Indeterminate 
Study data are not available for the evaluation of efficacy for any reason 
including: 
• 
Lost to follow up 
• 
Withdrawal of consent 
• 
Extenuating circumstances that preclude the classification of 
microbiological response 
 
Table 4: Microbiological Outcome Definitions at EOT (+ 2 days) and at TOC (±4 days) 
Microbiological 
Outcome 
Definitions 
Eradication  
Blood cultures were negative for S. aureus on 2 consecutive days. 
Presumptive Eradication  
Follow-up blood cultures were not done and the patient has responded clinically, 
as defined in Table 1. 
Persistence  
Blood cultures continue to be positive for S. aureus 
Presumed Persistence 
Follow-up blood cultures were not done and the patient has not responded 
clinically, as defined in Table 1. 
Relapse 
Patient was previously classified as having “clearance of bacteremia”, 
“eradication”, or “presumptive eradication”, and subsequently a blood culture 
was positive for S. aureus. 
Indeterminate 
Study data are not available for the evaluation of efficacy for any reason 
including: 
• 
Lost to follow up 
• 
Withdrawal of consent 
• 
Extenuating circumstances that preclude the classification of 
microbiological response 
 
 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
20 
 
 
  
 
Pharmacokinetics (PK): 
Blood samples will be collected for PK assessment of CF-301 in 3 subsets of patients as listed below.  
Pharmacokinetic samples will be collected from patients in both the CF-301 group and the placebo 
group to maintain the blind. 
• 
PK Subset 1:  A minimum of approximately 17 patients and up to approximately 34 patients 
(30%) will give serial PK samples at the following time points:  pre-dose, 0.5 (30 minutes), 
1.5 (1 hour 30 minutes), 2, 2.25 (2 hours 15 minutes), 3, 4, 8, 14, 24, and 48 hours after the 
start of study drug infusion.  The sponsor will determine if additional patients will give serial 
PK samples in Subset 1 based on ongoing review of accrued PK data, and the number of 
patients giving limited PK samples (Subsets 2 and 3 below) will be reduced accordingly.  
Note: PK Subset 1 will not be conducted in Israel. 
• 
PK Subset 2: Approximately 40 patients (35%) will give limited PK samples at the following 
time points:  2.25 (2 hours 15 minutes), 3, 8, and 24 hours after the start of study drug 
infusion. 
• 
PK Subset 3: Approximately 40 patients (35%) will give limited PK samples at the following 
time points:  2.25 (2 hours 15 minutes), 4, 8, and 24 hours after the start of study drug 
infusion. 
Permitted time windows are as follows: 
• 
± 10 minutes around the samples at 0.5 and 1.5 hours after the start of infusion 
• 
˗ 10 minutes before the sample at the end of infusion (the sample is to be drawn before the 
infusion is complete and can be obtained up to 10 minutes before the end of the infusion.  
Note that if the sample is drawn after the infusion is complete in error, it is still to be 
collected and the exact clock time should be recorded). 
• 
± 10 minutes around the samples at 2.25, 3, and 4 hours after the start of infusion 
• 
± 1 hour around the sample at 8 hours after the start of infusion 
• 
± 2 hours around the samples at 14 and 24 hours after the start of infusion. 
• 
± 4 hours around the sample at 48 hours after the start of infusion. 
PK parameters of CF-301 will be assessed from patients with serial PK sampling, including 
maximum plasma concentrations (Cmax), time to Cmax (Tmax), elimination half-life (T1/2), clearance 
(CL), volume of distribution (Vz), and area under the curve (AUC0-t and AUC0-∞). 
Pharmacodynamics (PD): 
The pharmacokinetic/pharmacodynamic (PK/PD) parameters include AUC0-24hr/minimum inhibitory 
concentration (MIC), Cmax/MIC, and %Time > MIC over a 24-hour period.  PK/PD parameters will be 
calculated for patients who have MICs available. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
21 
 
 
  
 
Statistical methods: 
A Statistical Analysis Plan (SAP) will be prepared and finalized before database lock and analyses of 
data.  Summary data will be tabulated and presented by treatment group. 
Safety: 
Safety will be evaluated by presenting summaries of treatment emergent AEs (TEAEs), clinical 
laboratory evaluations (biochemistry, hematology, coagulation, and urinalysis), vital signs (blood 
pressure, respiratory rate, heart rate, and temperature) and ECGs.  Abnormal physical examination 
results will be recorded as AEs.  A treatment emergent AE is one that occurs on or after the first dose 
of study drug through TOC. 
Adverse events will be coded using the Medical Dictionary of Regulatory Activities.  The incidence 
of TEAEs will be presented by system organ class (SOC) and preferred term (PT), by SOC, PT and 
relationship to study drug, and by SOC, PT and severity.  Serious AEs and TEAEs that lead to 
discontinuation of the study drug will also be presented by SOC and PT.  Descriptive statistics for 
clinical laboratory, vital signs and ECG parameters, including change from baseline, will be presented 
by time point collected and for the overall most abnormal post-baseline value.  Incidences of 
potentially clinically significant clinical laboratory results, vital signs and ECG parameters, as defined 
in the SAP, will also be summarized by time point collected and the overall most abnormal post-
baseline value. 
Efficacy: 
The primary efficacy outcome is clinical improvement or response at Day 14 after CF-301/placebo 
administration in the microbiological intent-to-treat (mITT) population.  The number and percentage 
of patients with an improvement/response, no response, and indeterminate will be determined by 
treatment group.  Exact 2-sided 95% confidence intervals for the point estimates of the clinical 
improvement/response rates in each treatment group will be determined using the Clopper-Pearson 
method.  The clinical improvement/response rate will be compared between the treatment groups 
using Fisher's exact test.  Statistical significance will be based on a two-sided alpha level of 0.05. 
The number and percentage of patients with a clinical outcome of improvement/response, no 
response, and indeterminate will be determined by treatment group at Day 7 after CF-301/placebo 
administration, at EOT, and at TOC in the mITT population.  Exact 2-sided 95% confidence intervals 
for the point estimates of the clinical improvement/response rates in each treatment group will be 
determined using the Clopper-Pearson method.  Statistical comparisons between the treatment groups 
will be conducted using Fisher's exact test and p-values will be provided as explorative statistics. 
The number and percentage of patients with a microbiological response of clearance of bacteremia, 
ongoing bacteremia, and indeterminate will be determined by treatment group at Days 7 and 14 after 
CF-301/placebo administration in the mITT population.  The number and percentage of patients with 
a microbiological outcome of eradication/presumptive eradication, persistence/presumptive 
persistence, and indeterminate will be determined by treatment group at EOT and TOC in the mITT 
population.  Exact 2-sided 95% confidence intervals for the point estimates of the clearance of 
bacteremia or microbiological eradication/presumptive eradication rates in each treatment group will 
be determined using the Clopper-Pearson method.  Statistical comparisons between the treatment 
groups will be conducted using Fisher's exact test and p-values will be provided as explorative 
statistics. 
Kaplan-Meier methods will be utilized to determine the time to clearance of bacteremia in the mITT 
population.  Time to clearance of bacteremia will be defined as the date/time from study drug 
administration to the date/time of the first negative blood culture of the two negative blood cultures 
taken on 2 consecutive days.  Patients whose SOC for BSI was changed by adding a SOC 
antibacterial agent, switching to a different SOC antibacterial agent, or increasing the dose of SOC 
due to persistence, worsening, or recurrence of S. aureus BSI, died prior to clearance of bacteremia or 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
22 
 
 
  
 
withdrew from the study will be censored at the date/time of the SOC change, death or study 
withdrawal, respectively. 
Pharmacokinetics: 
Data collected from Subset 1 will be used to determine the following PK parameters:  Cmax, Tmax, T1/2, 
CL, Vz, AUC0-t, and AUC0-∞.  These values along with the listings for plasma concentrations from all 
3 subsets (Subsets 1 to 3) will be reported in the Clinical Study Report (CSR). 
All PK data collected in this study (Subsets 1, 2, and 3) will be pooled with the PK data collected 
from the previous Phase 1 study (Protocol CF-301-101) to update the previously developed 
population PK model; this will be reported in a separate report, which will include the target 
attainment analysis.  The population PK and target attainment analyses will be described in a separate 
analysis plan. 
Pharmacodynamics: 
PK/PD analysis will be conducted to determine the AUC0-24hr/MIC, Cmax/MIC, and %Time > MIC 
ratios.  PK/PD parameters of CF-301 will be calculated for patients who have MICs available.  
Exposure response will be evaluated for efficacy and safety endpoints and will be detailed in a 
separate analysis plan (as described above in the Pharmacokinetics section). 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
23 
 
 
  
 
3. 
STUDY SCHEMATIC 
 
Abbreviations:  EOT = End of standard-of-care antibacterial therapy; Pbo = placebo; SOC = standard-of-care antibacterial therapy; 
TOC = test-of-cure visit 28 days after the EOT. 
 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
24 
 
 
  
 
4. 
SCHEDULE OF ASSESSMENT / STUDY FLOW CHART 
Core Study 
 
Immunogenicity 
Follow-Up 
Day 180  
Post CF-301/Pbo 
(±14 days)c 
Study Procedures 
Screening  
Day -1  
(≤ 24 hours of 
randomization)a 
Treatment (CF-301/Placebo + SOC) 
EOT 
(within 2 days 
after last 
dose of SOC) 
TOC 
28 Days 
Post EOT 
(±4 days)c 
Randomization/ 
Dosing 
Day 1a 
Day 2 
Subsequent 
days of SOCb 
Informed consent 
X 
 
 
 
 
 
 
I/E criteria 
X 
 
 
 
 
 
 
Medical history & risk factorsd 
X 
 
 
 
 
 
 
Apache II scoree 
 
X 
 
 
 
 
 
Diagnosisf 
X 
 
 
Day 7 
 
 
 
Safety labsg 
X 
X 
X 
Weekly 
X 
X 
 
12-Lead ECGh 
X 
X 
X 
 
X 
X 
 
Physical exami 
X 
X 
X 
Daily to D7, D14 
X 
X 
 
Weight and height 
X 
 
 
 
 
 
 
Vital signsj 
X 
X 
X 
Daily 
X 
X 
 
Symptoms of infectionk 
X 
X 
X 
Daily 
X 
X 
 
Blood culturesl 
X 
Daily until negative for 2 days, at D7 & D14, and as clinically indicated 
Pregnancy testm 
X 
X 
 
 
X 
X 
 
Remove/change IV cathetern 
 
Within 72 h after randomization 
 
 
 
Echocardiographyo 
 
X 
 
X 
 
 
 
Ultrasound of CVC sitep 
 
Within 48 h after rand. 
 
 
 
 
PK samplesq 
 
X 
X 
 
 
 
 
CF-301 ADA & IgEr 
 
X 
 
Day 14 
X 
X 
X 
Serum tryptases 
 
 
 
 
 
 
 
Optional future researcht 
 
X 
X 
Day 7 
X 
X 
 
CF-301 or placebo dosingu 
 
X 
 
 
 
 
 
AE assessmentv 
X 
X 
X 
X 
X 
X 
SAEs 
Prior/concomitant medsw 
X 
X 
X 
X 
X 
X 
 
Outcome assessment 
 
 
 
Days 7 & 14 
X 
X 
Xx 
Vital status 
 
 
 
 
 
 
Xy 
Abbreviations: ADA = anti-drug antibody; AE = adverse event; BSI = bloodstream infection; CRF = case report form; DR = drug related; EOT = end of standard-of-
care treatment; FSH = follicle stimulating hormone; h = hour; HEENT = head, eyes, ears, nose, throat; I/E = inclusion/exclusion; Pbo = placebo; PE = physical 
examination; PK = pharmacokinetic; rand. = randomization; SOC = standard-of-care; TEE = transesophageal echocardiogram; TTE = transthoracic 
echocardiogram; TOC = test of cure. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
25 
 
 
  
 
a. 
Patients should be randomized as soon as possible after confirmation of study eligibility.  However, to provide flexibility, screening assessments may be 
performed within 24 hours before randomization. Dosing should occur as soon as possible after randomization and within 24 hours of randomization. 
b. 
When a specific “Day” or “D” is noted (e.g., Day 7, D7), the days are relative to CF-301/placebo administration unless otherwise noted.  There is a ±1-day 
window around the procedures performed on Days 7 and 14. 
c. 
The core study ends at TOC performed 28 days after the end of SOC.  A long-term follow-up visit occurs at Day 180 after CF-301/placebo for collection of an 
immunogenicity sample and assessment of SAEs and re-infection.  The ability of the patient to return for the Day 180 visit is not required for enrollment in the 
study, but the visit is highly encouraged. 
d. 
Medical history for 1 year prior to screening. 
e. 
Certain components of the Apache II score will be determined locally (including oxygenation, Glasgow Coma Scale, and chronic health points) and other 
components will be obtained from central laboratory data. 
f. 
The investigator will determine diagnosis at screening and on Day 7 to determine treatment duration. 
g. 
Local Laboratory:  Limited safety laboratory tests may need to be performed locally at screening for study eligibility determination (e.g., serum creatinine to 
calculate creatinine clearance by Cockcroft-Gault formula using ideal body weight in patients with BMI ≥ 30 kg/m2 (Section 12.2) to determine the dose of 
study drug, FSH as applicable).  If local laboratory results are available within the 72 hours prior to screening, these may be used to support eligibility.  Central 
Laboratory:  Samples for safety laboratory tests (biochemistry, hematology, coagulation, and urinalysis) collected at randomization (pre-dose), at 
approximately 2 to 4 hours after the start of CF-301/placebo infusion (for the first 17 patients randomized), on Day 2, weekly during SOC, at EOT, and at TOC.  
Samples are sent to a central lab. 
h. 
12-lead ECG at screening, at approximately 2 to 4 hours after the start of CF-301/placebo infusion (for the first 17 patients randomized), on Day 2, at EOT, 
and at TOC. 
i. 
PE at screening, daily through Day 7 and on Day 14, at EOT, and at TOC.  Complete PEs will be performed at screening, Day 14, EOT, and TOC and include 
evaluation of the HEENT, neck, lungs, heart, chest, abdomen, extremities, neurological status, skin for any evidence of emboli, palpation for signs of pain, and 
any other notable conditions.  Targeted PEs will be performed daily through Day 7 and include evaluation for complications of BSI, HEENT, lungs, heart, skin 
for any evidence of emboli, and palpation for signs of pain.  Pain on PEs should trigger diagnostic testing for metastatic foci. 
j. 
Vital signs at screening, approximately every 30 to 40 minutes during CF 301/placebo infusion and at approximately 30 to 40 minutes after the infusion, daily 
during SOC for inpatients (and at weekly scheduled visits for patients who are discharged [i.e., at the Day 7 and Day 14 visits, and weekly thereafter]), at EOT, 
and at TOC.  Vital signs will include blood pressure, respiratory rate, and heart rate during/after infusion and blood pressure, respiratory rate, heart rate, and 
temperature at all other time points.  If more than one measurement is taken on a given day, record the highest value for temperature and most abnormal 
value for other vital signs in the CRF. 
k. 
Symptoms of infection at screening, daily during SOC for inpatients (and at weekly scheduled visits for patients who are discharged [i.e., at the Day 7 and 
Day 14 visits, and weekly thereafter]), at EOT, and at TOC. 
l. 
For study eligibility, patients have blood culture positive for S. aureus by rapid diagnostic or conventional method or Gram stain showing Gram-positive cocci 
in clusters plus positive tube coagulase test from blood culture collected within 72 hours prior to randomization; this qualifying blood culture will be collected in 
the eCRF.  Additionally, two aerobic blood cultures preferably from 2 different sites will be collected at screening at least 30 minutes apart and as close to the 
start of study drug dosing as possible, and at least one aerobic blood culture daily during the study until negative for 2 consecutive days and at Days 7 and 14 
and as clinically indicated.  Blood cultures should be collected from a peripheral venipuncture site when possible.  All blood cultures performed during the 
study (from the qualifying blood culture through to Day 180), including blood cultures that are positive or negative for S. aureus, should be entered in the 
eCRF.  S. aureus isolates, including the isolate from the qualifying blood culture, are sent to the central lab. 
m. For females of reproductive potential only: Urine or serum pregnancy test performed locally at screening for eligibility determination; blood sample collected for 
serum pregnancy test performed by the central lab at randomization, EOT, and TOC. 
n. 
IV catheters known or suspected to be infected must be removed or changed as soon as possible within 72 hours after randomization. 
o. 
All patients should have a TTE within 3 days of randomization.  All efforts should be made to perform this TTE before administration of study drug.  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 and the TTE within 3 days of randomization does not need to be performed.  Patients with endocarditis should have a follow-up TTE between 
Days 7 and 14; where possible, a TEE should also be performed.  TEEs are strongly recommended in patients with BMI > 30 kg/m2.  The site will provide all 
echocardiograms to the central echocardiography laboratory. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
26 
 
 
  
 
p. 
In patients with central venous catheters (CVCs), ultrasounds to evaluate clots in the vein are recommended within 48 hours after randomization. 
q. 
PK Subset 1: pre-dose, 0.5 (30 minutes), 1.5 (1 hour 30 minutes), 2, 2.25 (2 hours 15 minutes), 3, 4, 8, 14, 24, and 48 hours after the start of study drug 
infusion.  Note: PK Subset 1 will not be conducted in Israel. 
PK Subset 2: 2.25 (2 hours 15 minutes), 3, 8, and 24 hours after the start of study drug infusion. 
PK Subset 3: 2.25 (2 hours 15 minutes), 4, 8, and 24 hours after the start of study drug infusion. 
r. 
Blood samples for CF 301-specific ADA and IgE at randomization (pre-dose), Day 14, EOT, TOC, and Day 180; samples are sent to the central lab. 
s. 
If a patient experiences signs and symptoms consistent with anaphylaxis (Simons, et al., 2011; Section 11.2.3.1), blood samples for serum tryptase and CF-301-
specific IgE will be collected as soon as possible within 2 hours.  If the serum tryptase sample is positive or equivocal, the sample may also be tested for 
β-tryptase.  Another blood sample for serum tryptase will be collected 2 weeks later.  Samples are sent to a central lab. 
t. 
If patient consents to optional future research, two samples (1 serum and 1 plasma) for cytokine and IgE will be collected at randomization (pre-dose), 12 to 
24 hours after dosing, on Day 7, and at EOT and TOC.  Samples are sent to a central lab.  Note: future use samples will NOT be collected in Israel. 
u. 
Patients must be directly observed during CF-301/placebo infusion, and vital signs (blood pressure, respiratory rate, and heart rate) will be performed during/after 
infusion as described above.  CF-301 will be administered at a dose of 0.25 mg/kg, with a maximum dose of 30 mg for patients who weigh ≥ 120 kg.  Patients 
with creatinine clearance of < 60 mL/min (including patients on dialysis) will receive 0.12 mg/kg, with a maximum dose of 15 mg for patients in this subset who 
weigh ≥ 125 kg.  In patients on hemodialysis, CF-301/placebo will be administered either ≥ 8 hours prior to hemodialysis or ≥ 4 hours after end of hemodialysis.  
Patients who are > 50 years of age will receive a dose of 0.12 mg/kg, with a maximum dose of 15 mg for patients in this subset who weigh ≥ 125 kg. 
v. 
AEs will be collected from the time of consent through TOC.  After completion of the core study, all SAEs will be collected during the long-term follow-up through 
Day 180.  For patients who are unable to return for the Day 180 visit, this information may be obtained via phone or email. 
w. All medications taken within 28 days before randomization and through the EOT will be recorded, and only antibacterial medications or medications to treat AEs 
will be recorded after EOT through TOC. 
x. 
Re-infection between TOC and Day 180 will be assessed for patients who meet the definition of response at TOC. 
y. 
Vital status (whether the patient is alive or dead, or last known alive date) will be obtained at Day 180 or when a patient is deemed to be lost to follow-up.  The 
patient’s vital status should be determined using available sources (e.g., the patient’s relatives, hospital records, and/or public records) as permissible based on 
local laws and regulations. 
 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
27 
 
 
  
 
5. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
CONTACT INFORMATION ......................................................................................6 
2. 
SYNOPSIS ...................................................................................................................8 
3. 
STUDY SCHEMATIC ...............................................................................................23 
4. 
SCHEDULE OF ASSESSMENT / STUDY FLOW CHART ...................................24 
5. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............27 
6. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................32 
7. 
INTRODUCTION ......................................................................................................34 
7.1. 
Background .................................................................................................................34 
7.1.1. 
Summary .....................................................................................................................34 
7.1.2. 
Overview of S. aureus Blood Stream Infections .........................................................34 
7.1.3. 
Current Treatments and Drug Resistance ...................................................................35 
7.1.4. 
CF-301 for the Treatment of S. aureus .......................................................................36 
7.1.5. 
Preclinical Studies ......................................................................................................37 
7.1.6. 
Clinical Studies ...........................................................................................................40 
7.2. 
Risks and Benefits ......................................................................................................41 
7.3. 
Population to be Studied .............................................................................................43 
7.4. 
Rationale for Route and Dose .....................................................................................43 
7.5. 
Rationale for Inclusion of Patients with Renal Impairment .......................................44 
7.6. 
Statement of Compliance ............................................................................................45 
8. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................46 
8.1. 
Primary Objective .......................................................................................................46 
8.2. 
Secondary Objectives .................................................................................................46 
8.3. 
Exploratory Objectives ...............................................................................................46 
9. 
INVESTIGATIONAL PLAN .....................................................................................47 
9.1. 
Overall Study Design ..................................................................................................47 
9.2. 
Number of Patients .....................................................................................................48 
9.3. 
Treatment Assignment ................................................................................................49 
9.4. 
Dosing and Dose Adjustment Criteria ........................................................................49 
10. 
SELECTION AND DISCONTINUATION OF PATIENTS .....................................51 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
28 
 
 
  
 
10.1. 
Inclusion Criteria ........................................................................................................51 
10.2. 
Exclusion Criteria .......................................................................................................53 
10.3. 
Discontinuation Criteria..............................................................................................55 
10.3.1. 
Discontinuation from Study Drug ..............................................................................55 
10.3.2. 
Discontinuation from the Study ..................................................................................55 
10.4. 
Replacement of Patients .............................................................................................56 
10.5. 
Rescreening of Patients...............................................................................................56 
10.6. 
Criteria for Study Termination ...................................................................................56 
11. 
SCHEDULE OF OBSERVATIONS ..........................................................................57 
11.1. 
Study Duration ............................................................................................................57 
11.2. 
Core Study ..................................................................................................................57 
11.2.1. 
Screening ....................................................................................................................57 
11.2.2. 
Randomization ............................................................................................................58 
11.2.3. 
Study Drug ..................................................................................................................59 
11.2.3.1. 
Allergic Reactions / Anaphylaxis ...............................................................................59 
11.2.4. 
Standard-of-Care Antibacterial Therapy ....................................................................60 
11.2.5. 
End of Standard-of-Care .............................................................................................61 
11.2.6. 
Test-of-Cure ................................................................................................................62 
11.3. 
Immunogenicity Follow-up ........................................................................................63 
12. 
STUDY ASSESSMENTS ..........................................................................................64 
12.1. 
Informed Consent .......................................................................................................64 
12.2. 
Cockcroft-Gault ..........................................................................................................65 
12.3. 
Medical History ..........................................................................................................65 
12.4. 
Diagnosis ....................................................................................................................65 
12.5. 
Apache II score ...........................................................................................................65 
12.6. 
Physical Examination .................................................................................................65 
12.7. 
12-Lead Electrocardiogram ........................................................................................66 
12.8. 
Echocardiogram ..........................................................................................................66 
12.9. 
Vital Signs ..................................................................................................................66 
12.10. 
Symptoms of Infection ...............................................................................................66 
12.11. 
Management of IV Catheters ......................................................................................67 
12.12. 
Blood Cultures ............................................................................................................67 
12.13. 
Laboratory Testing......................................................................................................68 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
29 
 
 
  
 
12.13.1. 
Central Laboratory ......................................................................................................68 
12.13.2. 
Local Laboratory ........................................................................................................68 
12.14. 
Vital Status..................................................................................................................69 
12.15. 
Contraception ..............................................................................................................69 
12.16. 
Efficacy Outcome Assessments ..................................................................................69 
12.17. 
Pharmacokinetic Assessments ....................................................................................73 
12.18. 
Pharmacodynamic Assessments .................................................................................73 
12.19. 
DSMB .........................................................................................................................74 
12.20. 
Adjudication Committee .............................................................................................74 
13. 
TREATMENT OF PATIENTS ..................................................................................75 
13.1. 
Description of Study Drugs ........................................................................................75 
13.2. 
Dosage and Dose Regimen .........................................................................................75 
13.3. 
Study Drug Preparation and Administration ..............................................................76 
13.4. 
Storage/Stability .........................................................................................................76 
13.5. 
Drug Accountability ...................................................................................................76 
13.6. 
Prior and Concomitant Medications ...........................................................................77 
13.7. 
Prohibited Medications ...............................................................................................77 
13.8. 
Treatment Compliance ................................................................................................77 
13.9. 
Randomization and Blinding ......................................................................................77 
14. 
ADVERSE AND SERIOUS ADVERSE EVENTS ...................................................79 
14.1. 
Definition of Adverse Events .....................................................................................79 
14.1.1. 
Adverse Event (AE) ....................................................................................................79 
14.1.2. 
Serious Adverse Event (SAE) ....................................................................................79 
14.2. 
Timeframe for Collecting Adverse Events .................................................................79 
14.3. 
Relationship to Study Drug ........................................................................................79 
14.4. 
Study Endpoints ..........................................................................................................80 
14.5. 
Grading of Adverse Events .........................................................................................80 
14.6. 
Events of Clinical Interest ..........................................................................................80 
14.7. 
Overdose .....................................................................................................................80 
14.8. 
Pregnancy ...................................................................................................................80 
14.9. 
Unexpected Adverse Event .........................................................................................81 
14.10. 
Suspected Unexpected Adverse Drug Reaction (SUSAR) .........................................81 
14.11. 
SAE Reporting ............................................................................................................81 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
30 
 
 
  
 
14.12. 
AE and SAE Follow-up ..............................................................................................81 
15. 
STATISTICS ..............................................................................................................82 
15.1. 
Analysis Populations ..................................................................................................82 
15.2. 
Patient Population and Characteristics .......................................................................82 
15.3. 
Safety Analysis ...........................................................................................................82 
15.4. 
Efficacy Analysis ........................................................................................................83 
15.5. 
Pharmacokinetic Analysis ..........................................................................................84 
15.6. 
Pharmacodynamics Analysis ......................................................................................84 
15.7. 
Handling of Missing Data ...........................................................................................85 
16. 
DATA MANAGEMENT ...........................................................................................86 
16.1. 
Data Collection ...........................................................................................................86 
16.2. 
Access to Source Documents ......................................................................................86 
17. 
ADMINISTRATIVE ..................................................................................................87 
17.1. 
Statement of Good Clinical Practices .........................................................................87 
17.2. 
Protocol Adherence ....................................................................................................87 
17.3. 
Study Termination ......................................................................................................87 
18. 
QUALITY CONTROL AND ASSURANCE ............................................................88 
18.1. 
Sponsor Audits............................................................................................................88 
18.2. 
Inspection by Regulatory Authorities .........................................................................88 
19. 
ETHICS ......................................................................................................................89 
19.1. 
Institutional Review Board or Independent Ethics Committee ..................................89 
19.2. 
Informed Consent .......................................................................................................89 
19.3. 
Data Privacy................................................................................................................90 
20. 
RECORD KEEPING/RETENTION OF RECORDS .................................................91 
20.1. 
Confidentiality ............................................................................................................91 
21. 
USE OF STUDY RESULTS ......................................................................................92 
22. 
LIST OF REFERENCES ............................................................................................93 
23. 
APPENDICES ............................................................................................................96 
23.1. 
Appendix 1: Diagnosis Definitions ............................................................................96 
23.2. 
Appendix 2: Apache II score ......................................................................................98 
23.3. 
Appendix 3: Microbiological Sample Collection and Processing ............................100 
23.4. 
Appendix 4: Central Laboratory Testing ..................................................................102 
 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
31 
 
 
  
 
LIST OF TABLES 
Table 1: 
Contact Information ......................................................................................................6 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................32 
Table 3: 
Phase 1 Pharmacokinetic Parameters for CF-301 (Study CF-301-101) .....................41 
Table 4: 
Clinical Criteria for Diagnosing Anaphylaxis ............................................................60 
Table 5: 
Clinical Outcome Definitions at Day 7 (± 1 day), Day 14 (± 1 day), EOT 
(+ 2 days), and at TOC (±4 days) ...............................................................................70 
Table 6: 
Clinical Re-Infection Definitions at Day 180 (±14 days) ...........................................71 
Table 7: 
Microbiological Response Definitions at Day 7 (± 1 day) and Day 14 (± 1 
day) .............................................................................................................................72 
Table 8: 
Microbiological Outcome Definitions at EOT (+ 2 days) and at TOC 
(±4 days) .....................................................................................................................72 
Table 9: 
CF-301 Description ....................................................................................................75 
Table 10: Placebo Description ....................................................................................................75 
 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
32 
 
 
  
 
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 
ADA 
Anti-drug antibody 
AE 
Adverse event 
Apache II 
Acute Physiology and Chronic Health Evaluation II Score 
AR 
Authorized representative 
AUC0-∞ 
Area under the concentration-time curve to infinity 
AUC0-t 
Area under the concentration time curve 
BAT 
Basophil activation test 
BSI 
Blood stream infection 
CF-301 
Bacteriophage-derived lysin 
CFR 
Case Fatality Rate 
CL 
Clearance 
Cmax 
Maximum plasma concentration 
CRF 
Case report form 
CRO 
Contract Research Organization 
CVC 
Central Venous Catheter 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
Echo 
Echocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOT 
End of treatment 
FSH 
Follicle stimulating hormone 
GM 
Geometric Mean 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HIV 
Human immunodeficiency virus 
ICD 
Implantable Cardioverter Defibrillator 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
33 
 
 
  
 
Abbreviation or Specialist Term 
Explanation 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IRB 
Institutional Review Board 
IWRS 
Interactive web response system 
LAR 
Legally authorized representative 
LR 
Legal representative 
MIC 
Minimum inhibitory concentration 
MRSA 
Methicillin resistant S. aureus 
MSSA 
Methicillin susceptible S. aureus 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PK/PD 
Pharmacokinetic/pharmacodynamic 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SIRS 
Systemic Inflammatory Response Syndrome 
SOC 
Standard-of-care (antibacterial agent) or system organ class (for 
statistical analysis) 
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 
Vz 
Volume of distribution 
VISA 
Vancomycin intermediate S. aureus 
VRSA 
Vancomycin resistant S. aureus 
WBC 
White blood cell 
WHO 
World Health Organization 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
34 
 
 
  
 
7. 
INTRODUCTION 
7.1. 
Background 
7.1.1. 
Summary 
CF-301, a recombinantly-produced bacteriophage-derived lysin, is the first of a new class of 
highly targeted, protein-based therapies to enter clinical development.  Lysins are a new class 
of antimicrobials consistent of bacteriophage-derived cell-wall hydrolases.  CF-301 represents 
a novel, highly potent and targeted therapeutic for Staphylococcus aureus (S. aureus) blood 
steam infections (BSIs) to augment conventional antibiotics which are the current standard of 
care. 
S. aureus, a virulent pathogen in humans, is a leading cause of bacteremia and 
endocarditis.  S. aureus BSIs including endocarditis are associated with substantial 
morbidity and mortality.  For example, in 2011, the United States Centers for Disease 
Control (CDC) estimated that there were 80,461 serious methicillin-resistant S. aureus 
(MRSA) infection cases in the United States, all of which required hospitalization, 
resulting in up to 11,285 deaths (Dantes 2013).  S. aureus BSI is often associated with 
complications, including metastatic bone and soft tissue infections, endocarditis, and 
recurrent infections.  Complicated S. aureus BSI requires extended duration treatment with 
antibiotic therapy, 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, standard-of-care (SOC) antibiotics are unable to penetrate.  The availability of 
a new, highly effective treatment of S. aureus BSI remains an area of high unmet medical 
need due to the high degree of morbidity and mortality, potentially lengthy treatment burden, 
and the increasing prevalence of multidrug resistant strains. 
In in vitro experiments, CF-301 exhibits potent activity against all strains of S. aureus, 
including those that demonstrate resistance to currently available therapies such as 
vancomycin, daptomycin, and linezolid.  In vitro and in vivo studies have demonstrated 
CF-301 to have a very rapid onset of bactericidal action and synergistic effect when 
administered in combination with SOC antibiotic treatments for S. aureus BSI (e.g. 
daptomycin).  Importantly, while biofilm formation limits the efficacy of SOC antibiotics in 
the treatment of complicated S. aureus bacteremia (including endocarditis), CF-301 
demonstrates potent ability to clear biofilms in in vivo and in vitro models.  In vitro, CF-301 
exhibits low potential to develop resistance and can reduce the propensity for the 
development of resistance to SOC antibiotics when co-administered. 
ContraFect considers these nonclinical data to be highly predictive of human response, and as 
such, considers CF-301 to offer significant potential to improve patient outcomes when 
administered in combination with SOC antibiotics for the treatment of S. aureus bacteremia. 
7.1.2. 
Overview of S. aureus Blood Stream Infections 
S. aureus is a leading cause of bacteremia 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., endocarditis; Fowler et al, 2003). Intravenous drug 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
35 
 
 
  
 
users and patients with human immunodeficiency virus (HIV) and renal insufficiency, 
especially those requiring hemodialysis, are particularly at risk for developing S. aureus 
infections.  Approximately 20% of patients with S. aureus BSI develop metastatic 
complications such as infective endocarditis.  The incidence of infective endocarditis in the 
setting of S. aureus BSI has been estimated to be 10-15% (Fowler et al, 2003; Chang et al, 
2003; Valente et al, 2005), although incidence as high as 21% has been reported (Chang et al, 
2003).  Risk factors for infective endocarditis 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 et al, 2003; 
El-Ahdhab et al, 2005; Hill et al, 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, 21% versus 14%; systemic emboli, 27% versus 18%; persistent 
bacteremia, 17% versus 5 %; and in-hospital mortality, 22% versus 14%, respectively) 
(Fowler et al, 2005).  The likelihood of developing complications depends on several factors 
including the infecting pathogen, duration of illness prior to therapy, and underlying 
comorbidities.  Symptomatic cerebrovascular complications occur in up to 35% of patients 
(Ruttman et al, 2006; Snygg-Martin et al, 2008; García-Cabrera et al, 2013). Silent 
cerebrovascular complications (including ischemia and microhemorrhage) may occur in up 
to 80% of patients (Snygg-Martin et al, 2008; Cooper et al, 2009).  The in-hospital mortality 
rate for infective endocarditis is estimated to be 18 to 23% and the six-month mortality rate 
has been estimated to be between 22 to 27% (Wallace et al, 2002; Chu et al, 2004; Hasbun et 
al, 2003; Hill et al, 2007; Wang et al, 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 intravascular catheters and/or surgical drainage of 
abscess if present; López-Cortès et al, 2013).  Empiric treatment with antibiotic therapy that 
has activity against both MRSA and methicillin-susceptible S. aureus (MSSA) is generally 
indicated when blood cultures with Gram-positive cocci are observed (Kim et al, 2008; 
McConeghy et al, 2013).  Treatment failure is fairly common in patients with S. aureus 
BSI, particularly among those patients with infection due to MRSA (Lodise et al, 2008).  
Drug-resistance, toxicity related to high dose/long duration therapy, and biofilm formation 
that cannot be cleared by standard of care antibiotics contribute to treatment failure.  
Despite the availability of conventional antibiotic treatments, the 30-day all-cause mortality 
of S. aureus BSI has been estimated to be between 20-40% (Anantha et al, 2014; Van Hal et 
al, 2012). 
The threat of antibiotic resistance among bloodstream S. aureus isolates, and in particular, 
the increasing prevalence of methicillin resistance and the emergence of multi-drug 
resistance are of concern.  Among 24,000 nosocomial bloodstream infections in the United 
States between 1995 and 2002, the proportion of MRSA isolates increased from 22% to 
57% (Wisplinghoff et al, 2004).  Mortality associated with MRSA bacteremia has been 
reported to be higher than mortality associated with MSSA bacteremia (Shurland et al, 2007; 
Cosgrove et al, 2003).  Both the CDC and the World Health Organization (WHO) regard 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
36 
 
 
  
 
antibiotic resistance as one of the greatest threats to human health worldwide, with S. aureus 
bloodstream infections, especially MRSA, categorized as a “serious threat” by the CDC. 
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., MRSA with vancomycin minimum 
inhibitory concentration [MIC] >1.5 μg/mL), intermediate vancomycin resistance (VISA), and 
high-level vancomycin resistance (VRSA) are associated with worse clinical outcomes 
(Bayer, 2013).  Use of daptomycin, an alternative to vancomycin, has grown over the past 
decade.  Risk factors for the emergence of daptomycin resistance include previous 
exposure to vancomycin, infection with a MRSA strain with a vancomycin MIC of 2 μg/mL 
or greater, and treatment with insufficient doses of vancomycin (Moise et al, 2008; Rose et 
al, 2007; Fowler et al, 2006). 
As noted by Fowler et al (2005), while the introduction of penicillin to treat S. aureus 
BSI drastically decreased the case fatality rate (CFR) of S. aureus BSI from ~80% in the pre-
antibiotic era, CFRs reported over recent decades have plateaued in the ~15-50% range 
(Fowler et al, 2005).  This continued high mortality rate may be, at least in part, reflective of 
a relative plateau in antibiotic efficacy.  Hence, there is a medical need for novel, highly 
effective, targeted new treatments for S. aureus BSI, with limited propensity for resistance 
and with the potential for synergistic efficacy and reduced resistance when used in 
combination with existing agents.  A treatment that would target all forms of S. aureus BSI 
would offer advantages over a treatment specific for specific strains (e.g., MRSA) by 
potentially enabling faster initiation of treatment, without the need to first determine the 
susceptibility of the S. aureus strain.  Thus, a therapeutic agent, such as CF-301 would afford 
the opportunity to address a wider range of resistant strains quickly, potentially helping to 
prevent or slow the spread of resistant strains. 
7.1.4. 
CF-301 for the Treatment of S. aureus 
CF-301, a novel, targeted, antibacterial therapy for the treatment of S. aureus BSI, 
represents the first of a new field of protein-based therapies called bacteriophage-derived 
lysins.  In nature, lysins are highly specific enzymes produced by bacteriophages that digest 
the bacterial cell wall to allow phage progeny release.  CF-301 is a purified recombinant 
lysin that is fundamentally distinct from conventional antibiotics.  When added externally to 
S. aureus bacteria, CF-301 creates immediate lysis upon contact with the cell wall, 
causing log-fold death of the target bacterium.  Whereas most conventional antibiotics 
target a broad spectrum of bacteria, including pathogenic and normal flora, lysins are highly 
targeted to specific bacterial species.  CF-301 specifically targets staphylococci, including 
MSSA and MRSA as well as strains that are non-susceptible to vancomycin and daptomycin.  
The highly targeted nature of CF-301 reduces the potential for biological toxicity associated 
with negative effects of broad-spectrum antibiotics on the human microbiome including the 
killing of beneficial normal flora. 
CF-301 is distinct from current standard of care antibiotics due to: (1) its novel mechanism 
of action; (2) bactericidal activity against antibiotic-resistant S. aureus; (3) rapid onset of 
antibacterial activity both in vitro and in vivo; (4) narrow lytic spectrum of action; (5) potent 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
37 
 
 
  
 
activity against biofilms; (6) synergistic activity with standard of care antibiotics (oxacillin, 
vancomycin, and daptomycin; (7) low  propensity to  develop bacterial resistance; and (8) 
ability to protect against the emergence of resistance to standard of care antibiotic therapies 
when used in combination.  CF-301 activity has been evaluated in multiple preclinical 
disease models that indicate its ability to address the limitations of these current standard 
of care antibiotics against S. aureus. 
Full details of the background and development of CF-301 are available in the Investigator's 
Brochure. 
7.1.5. 
Preclinical Studies 
The efficacy of CF-301 was tested in two murine S. aureus bacteremia models. CF-301 was 
administered as a single or multiple doses, either alone or in combination with SOC antibiotics 
(daptomycin, vancomycin or oxacillin).  Results from these studies demonstrated that: 
• CF-301 was effective in mouse bacteremia and neutropenic thigh infection models either as a 
single-agent or in combination with daptomycin, vancomycin, or oxacillin. In a rat endocarditis 
model, CF-301 was effective in combination with daptomycin. 
• CF-301 performed synergistically against S. aureus isolates in combination with daptomycin, 
vancomycin, and oxacillin, and significantly improves the clearance of bacterial burden in 
tissues and the survival of mice in models of S. aureus bacteremia (including infections with a 
biofilm component), compared with antibiotic monotherapy. 
• CF-301 demonstrated in vivo activity against S. aureus biofilm in a mouse S. aureus infected 
catheter implant model alone and in combination with daptomycin. 
• AUC/MIC is the PK-PD index most predictive of efficacy in the murine neutropenic thigh 
infection model. AUC/MIC values >1.5 and >0.5 are supportive of efficacy as a single-agent 
and in combination with daptomycin, vancomycin, and oxacillin. 
Using the mouse neutropenic thigh infection model, AUC/MIC was determined to be the PK/PD 
index most predictive of efficacy of CF-301 administered either alone or in combination with 
daptomycin, vancomycin or oxacillin.  
• The minimal AUC/MIC ratios required to achieve bactericidal efficacy for CF-301 as a 
single-agent was ≥1.5 and CF-301 in combination with daptomycin was ≥0.3 and with 
vancomycin or oxacillin was ≥0.5.  In the mouse neutropenic thigh infection model with a 
catheter biofilm implant, a similar AUC/MIC value of ≥ 0.5 was determined to be correlated 
with efficacy. 
Target Attainment analysis utilizing population PK modeling for the purpose of supporting 
CF-301 dose selection for Phase 2 clinical evaluation was performed and demonstrates that in 
patients with S. aureus BSIs, doses of 0.25 mg/kg and 0.4 mg/kg, given as a 2-hour infusion (in 
the presence of SOC antibacterial therapy (e.g., daptomycin), are predicted to be efficacious. 
Nonclinical studies have been conducted to support clinical development: (1.) Pharmacokinetic 
and distribution studies; (2.) Safety pharmacology studies were conducted under GLP in rats and 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
38 
 
 
  
 
dogs to assess the effects of CF-301 on the central nervous system (CNS) as well as 
cardiovascular or respiratory function; (3.) single-dose and repeat-dose GLP toxicology studies 
conducted in rats and dogs; (2) genotoxicity study (Ames); (4.) special toxicity studies; and (5.) 
exploratory studies to determine the key PK parameter (AUC or Cmax) most correlated with 
toxicity.  The proposed route of administration and dosing regimen in human clinical trials is a 
single 2-hour IV infusion.  Therefore, the GLP in vivo rat and dog nonclinical toxicology studies 
utilized 2-hour IV infusions.  The rat was identified as the more sensitive toxicity species.  A 
summary of these studies is provided below. 
• CF-301 is a therapeutic protein, which like other proteins undergoes catabolism by multiple 
tissues to small peptides and individual amino acids, without the need for metabolic enzymes, 
such as cytochromes and are not actively transported across membranes. Therefore, the 
potential for drug-drug interactions with CF-301 is low. Further, because CF-301 undergoes 
catabolism in multiple organ, excretion in urine is not a route of elimination and was not found 
and is not expected in humans. 
• The half-life of CF-301 was short (< 1 hour in rats and 1.2-2.93 hours in dogs) and clearance 
was higher than the GFR in both species.  CF-301 distributed over total body water in both rats 
and dogs, indicating that CF-301 is distributed outside of the vascular space. There was no 
accumulation of CF-301 following 7 consecutive days of IV QD dosing via 2-hour infusion.  
• CF-301 has no direct pharmacological effects on the 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 three 
doses administered one week apart and was shown to be secondary to ADA formation.  A 
similar response was not observed after a single administration, even at a high dose.  
• Following single doses of CF-301 in rats up to 25 mg/kg, anti-CF-301 antibodies were 
detected 14 days after dosing, with increasing numbers of positive samples identified with 
increasing doses.  Following 7 daily repeated doses of up to 50 mg/kg/day in rats and dogs, 
titers of anti-CF-301 antibodies were detectable in a few animals on Day 8 (following last 
dose) and increased in incidence and titer by days 15 and 29 post dose, but the presence of 
anti-CF-301 antibodies did not affect the clearance of or exposure to CF-301. The results 
were consistent with a typical immune response with regard to the timeline of appearance of 
ADA.   
• Data from a GLP single-dose rat toxicity study.  The following key observations were made: 
o Perivascular/adventitial findings surrounding the pulmonary arteries, the primary 
toxicological observation following a single 2-hour IV infusion, occurred at a low 
incidence and minimal severity at 10 and 25 mg/kg and resolved during a 14-day recovery 
period. 
o The no observed effect level (NOEL) was 2.5 mg/kg following a single dose in the rat (the 
most sensitive species) and translates to a human dose of 0.4 mg/kg. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
39 
 
 
  
 
o The no observed adverse effect level (NOAEL) was 25 mg/kg following a single dose in 
the rat. 
• In 7-day GLP repeat-dose toxicity studies, dose-dependent adventitial findings in both rats 
and dogs were the dose-limiting toxicity observations.  Compared to a single dose of CF-301 
where the adventitial finding was of low incidence, minimal severity, and reversible at dose 
of ≤ 25 mg/kg, following repeated doses of CF-301, the adventitial finding increased in 
incidence, severity, and tissue distribution in medium to larger blood vessels of multiple 
tissues. There was evidence of reversibility of the lesions as well as progression to chronicity 
of the lesions at higher doses of ≥ 10 mg/kg/day in rats and dogs, following a 21 days post-
infusion treatment-free recovery period. 
• A series of special toxicity studies was conducted and demonstrated that:   
o Enzymatically-active CF-301 produced the adventitial vascular reactions whereas 
enzymatically-inactive CF-301 did not; and 
o CF-301 produced signs and symptoms of hypersensitization response in 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).  See information on clinical immunogenicity in Sections 7.1.6 and 7.2 and the IB. 
• A series of exploratory studies in the rat was 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. The 
goal of these investigations was to support the dose rationale for the Phase 2 clinical study by 
correlating the observation of arterial adventitial findings with either Cmax or AUC 
experimentally and by an unbiased Neural Network modeling. Overall, the exploratory 
studies and Neural Network analyses concluded that AUC is the PK parameter most 
associated with an observation of an arterial adventitial/ perivascular finding in the 
pulmonary arteries.  
• The exposure limit at the stopping rules for the first in human Phase 1 study was based on the 
NOEL dose of 2.5 mg/kg in the rat that showed a Cmax value of 1940 ng/mL. The associated 
AUC0-24 was 2520 ng•h/mL. These values were derived from a single rat TK study with only 
18 rats. Along with the FIH Phase 1 study, several more toxicology studies were conducted 
that brought up the total number of rats to 270 and dogs to 78. Cross-species PK modeling of 
the totality if the TK data was performed to better define the exposure levels at the Cmax and 
AUC at the rat NOEL dose of 2.5 mg/kg: 
o Based on this collective analysis, the predicted mean AUC0-24 was 3596 ng•h/mL and the 
predicted mean Cmax was 1754 ng/mL following a single 2.5 mg/kg 2-hour infusion of 
CF-301 (the rat NOEL dose). 
In summary, the efficacy and safety of CF-301 has been evaluated nonclinical. Based on data 
from standard mouse models of efficacy, target attainment simulations were performed. These 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
40 
 
 
  
 
showed that in patients with S. aureus BSIs, doses of 0.25 mg/kg and 0.4 mg/kg, given as a 
2-hour infusion (in the presence of SOC antibacterial therapy (e.g., daptomycin, vancomycin, or 
oxacillin), are predicted to be efficacious.  The toxicity of CF-301 has been characterized and the 
dose-responsiveness evaluated.  Based on the current understanding of the nature of the 
adventitial findings and the absence of any clinical signs, body weight changes, clinical 
pathology changes or other parameters that could be easily monitored, the proposed clinical 
doses have been shown to provide exposure below the predicted Cmax and AUC values at the rat 
NOEL dose of 2.5 mg/kg. 
Additional detail on the preclinical studies can be found in the CF-301 Investigator’s Brochure. 
7.1.6. 
Clinical Studies 
CF-301 has been evaluated in one Phase 1 clinical study, CF-301-101, which was a double-blind, 
randomized, study to evaluate the safety, tolerability, and pharmacokinetics (PK) of single, 
escalating IV doses of CF-301 in healthy male and female subjects.  Pre-defined stopping rules 
were included in the protocol and an independent Data Safety Monitoring Board (DSMB) 
reviewed safety and PK data at pre-specified time points 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 CF-301-specific antidrug antibody [ADA], 
CF-301-specific immunoglobulin E [IgE], and ex vivo CF-301-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 active drug CF-301 
(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.   
CF-301 was generally safe and well tolerated during study CF-301-101.  There were no deaths, 
no serious adverse events (SAEs), and no discontinuations due to adverse events (AEs) during 
the study.  There were no infusion reactions or adverse events of hypersensitivity related to 
CF-301 reported.  A total of 5 non-serious AEs were reported by 4 subjects:  2 subjects who 
received CF-301 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 treatment emergent adverse event (TEAE) 
(headache in the CF-301 group) was considered related to study drug.  The number of TEAEs 
observed in the placebo and CF-301 groups was similar and the incidence of AEs among 
subjects who received CF-301 was not dose-dependent. 
Pharmacokinetic parameters of CF-301 are summarized in Table 3.  After IV infusion of CF-301, 
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 (GM) t½ ranged from 
4.37 to 6.58 hours for the first 3 cohorts, independent of dose, and was 11.3 hours for the 
1 subject in Cohort 4 with individual subject values ranging from 4.33 to 14.7 hours across the 
4 cohorts with no apparent relationship to dose. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
41 
 
 
  
 
Table 3: 
Phase 1 Pharmacokinetic Parameters for CF-301 (Study CF-301-101) 
 
Abbreviations: λz = 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%) dosed with 
CF-301 developed CF-301-specific ADA (7 by Day 28 and 2 by Day 90).  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 CF-301 were reported.  No 
subjects tested positive for CF-301-specific basophil activation test (BAT).  Consideration of this 
single, transient low-level signal for CF-301-reactive IgE, along with the lack of any signal from 
the CF‑301-specific BAT, suggests a low risk for allergic-type hypersensitivity.  
In conclusion, CF-301 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 CF-301 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% of subjects developed 
CF-301-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 CF-301 
in urine. 
Additional detail on Study CF-301-101 can be found in the CF-301 Investigator’s Brochure. 
7.2. 
Risks and Benefits 
Pre-clinical pharmacology and toxicity studies (Section 7.1.5) indicate that a single dose of 
CF-301 at 0.25mg/kg administered to patients with S. aureus BSIs including endocarditis is 
anticipated to be an efficacious dose with exposures well below the levels which were associated 
with toxicity in animal models.  Animal infection model results are considered to be highly 
predictive of human efficacy in antibacterials.  Furthermore, the Phase 1, single ascending dose 
clinical study of CF-301 demonstrated CF-301 to be well tolerated, with no adverse clinical 
safety signals, with a linear PK profile at the intended dose for use in this Phase 2 (0.25 mg/kg). 
The Phase 2 study will evaluate the safety, tolerability, efficacy and PK of CF-301 in addition to 
SOC antibacterial therapy in patients with complicated S. aureus BSIs (bacteremia) including 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
42 
 
 
  
 
endocarditis.  As previously described (Sections 7.1.2 and 7.1.3), S. aureus BSIs including 
endocarditis are highly morbid conditions, which result in substantial morbidity and mortality 
despite currently available, SOC antistaphylococcal antibiotics.  An important objective of the 
Phase 2 study is to evaluate whether CF-301 in addition to SOC antibacterial therapy improves 
clinical outcomes in these patients compared to SOC alone.  As such, all patients in this study 
will be treated with SOC antibacterial therapy for S. aureus BSI or endocarditis based on current 
guidelines.  The therapeutic benefits and side effects of SOC antibacterial agents are documented 
in the prescribing information and published literature. 
Patients will be randomized to receive a single dose of CF-301 or placebo in addition to SOC 
antibacterial therapy, and no patients in the study will be treated with the experimental therapy, 
CF-301, alone.  Together with the favorable safety and tolerability profile in Phase 1, a single 
dose of CF-301 may provide additional clinical benefit over and above the benefit of SOC 
treatment, which allows for a positive benefit/risk ratio. 
Since this is the first time that CF-301 will be studied in patients with S. aureus BSIs, a rigorous 
safety monitoring plan has been put in place.  All patients will be dosed in a hospital setting and 
all patients will be closely monitored for safety and tolerability by repeated assessment of AEs, 
physical examinations, vital signs, 12 lead electrocardiograms (ECGs), clinical safety laboratory 
tests, and immunological tests.  Patients will be directly observed during CF-301/placebo 
infusion, and vital signs (blood pressure, respiratory rate, and heart rate) will be performed 
approximately every 30 to 40 minutes during the infusion and at approximately 30 to 40 minutes 
after the infusion.  An independent DSMB will review unblinded safety data throughout the 
study as defined in the DSMB charter. 
As CF-301 is a protein-based therapeutic, and therefore hypersensitivity is possible, patients will 
be monitored closely for immunologic responses to CF-301 both clinically and by laboratory 
measurement of CF-301- specific ADA and CF-301-specific IgE.  Importantly, in the Phase 1 
study, no hypersensitivity related to CF-301 was observed.  Furthermore, the incidence and 
magnitude of pre-existing (pre-dose) CF-301-specitic-IgE in CF-301-naïve healthy subjects and 
patients with S. aureus bacteremia has been evaluated and found to be low.  Taken together, this 
provides strong evidence to support the conclusion that the risk of immediate, IgE-mediated, 
allergic reaction to CF-301 in the present Phase 2 study is low. 
Although some CF-301-naïve healthy subjects and patients with S. aureus bacteremia have been 
found to have measurable pre-existing (pre-dose) CF-301-specific ADAs, the clinical relevance 
of these findings is unknown.  The current study consists of only a single dose of CF-301.  
Patients will be dosed in a hospital setting and directly observed during CF-301/placebo infusion, 
and vital signs (blood pressure, respiratory rate, and heart rate) will be performed approximately 
every 30 to 40 minutes during the infusion and at approximately 30 to 40 minutes after the 
infusion.  In patients who have clinical signs and symptoms of allergic reactions to CF-301, the 
infusion should 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 (Section 11.2.3).  Treatments for acute allergic 
hypersensitivity reactions should be provided in accordance with standard medical practice. 
Overall, based on risk/benefit analysis, the Sponsor considers the current study to be appropriate 
in the planned population. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
43 
 
 
  
 
7.3. 
Population to be Studied 
Adult patients with S. aureus BSI including endocarditis will be included in this study. 
7.4. 
Rationale for Route and Dose 
CF-301 will be administered by IV infusion over 2 hours and is not expected to be orally 
bioavailable. 
CF-301 was shown to be effective as a single dose when given in combination with SOC 
antibacterial therapy in eradicating S. aureus in the neutropenic murine thigh infection models 
(standard models for assessing anti-infective drug PK/PD parameters [Louie et al., 2001]) as well 
as in other in vitro and in vivo models of activity.  A population PK analysis was performed on 
the data from the CF-301-101 study in humans, which was also supported by allometric scaling 
of the animal PK data extrapolated to humans.  The simulations predict that the majority of 
patients in Study CF-301-102 who would receive a single dose of 0.25 mg/kg CF-301 as a 
2-hour IV infusion in combination with SOC antibacterial therapy are expected to achieve 
AUC/MIC ratios that are equal to or greater than the efficacious AUC/MIC ratios of 0.5 (i.e., the 
ratio established in a neutropenic thigh model to be efficacious when CF-301 was given with 
daptomycin).  PK/PD modeling of the available animal and human data support a target 
efficacious dose in humans to be between 0.1 to 0.2 mg/kg.  Therefore, a single dose of 
0.25 mg/kg CF-301 administered as a 2-hour infusion in combination with SOC antibacterial 
therapy is anticipated to achieve the desired AUC/MIC ratio of 0.5 or greater in >80% of patients 
for isolates with an MIC of ≤ 2 µg/ml. 
The GLP single-dose toxicity study in rats (Study CF-301-054) established a 2.5 mg/kg dose 
given as a 2-hour IV infusion in rats as the NOEL.  Initially at the IND application, the only 
available TK/toxicity data was from Study CF-301-052 which was a single daily dose in 72 rats 
that determined an AUC0-inf of 2270 ng•h/mL and a Cmax of 1900 ng/mL associated with this 
NOEL dose of 2.5 mg/kg.  Additional TK and toxicity studies have been performed in order to 
refine the understanding of the critical Cmax and AUC exposures associated with adventitial 
findings that were observed in pulmonary arteries of rats following single 2-hour IV infusion at 
doses above the NOEL dose. 
Cross-species population PK modeling on pooled data from available TK and toxicity studies in 
both the rats (n=27) and dogs (n=78).  The analysis support that a CF-301 NOEL dose of 
2.5 mg/kg in rats is associated with an AUC0-24 of 3600 ng•h/mL and a Cmax of 1750 ng/mL.  
Further, interrogation of all rat and dog toxicity data by both conventional statistical analysis and 
Neural Network analysis indicate that total dose and AUC exposures are the most relevant 
predictors of an adventitial reaction observation in rats administered a 2-hour IV infusion of 
CF-301 at doses above the 2.5 mg/kg NOEL.  Neural Network analysis provides a method for 
analyzing data with minimal assumption about the nature and type of relationships between 
variables and allow inclusion of all available variables in one analysis without the need for user 
selection and provide an additional level assessment compared to conventional statistical 
analysis. 
The population PK modeling data (animal and human) support that a single dose of CF-301 
≤ 0.4 mg/kg administered as a 2-hour IV infusion would not exceed the AUC and Cmax limits 
associated with NOEL dose of 2.5 mg/kg 2-hour infusion in rats and would, therefore, be 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
44 
 
 
  
 
expected to be well tolerated and not associated with adverse clinical effects.  Single doses of 
CF-301 at 0.25 mg/kg and 0.4 mg/kg administered as 2-hour IV infusions were assessed in study 
CF-301-101 and were well tolerated, although the 0.4 mg/kg dose was only administered to one 
subject.  Interpretive criteria indicate that the majority of contemporary clinical S. aureus isolates 
have an MIC < 2 µg/ml, and are predicted to be susceptible to CF-301 at 0.25 mg/kg and 
0.4 mg/kg doses in humans. 
From a benefit/risk perspective, the selected dose of 0.25 mg/kg for the current study is expected 
to maintain AUC/MIC ratios of > 0.5, which is well above the expected efficacious threshold 
established in animal efficacy studies, and is expected to result in exposures in humans (AUC 
and Cmax) that are approximately two-fold lower than the exposures associated with the NOEL in 
rats. 
Therefore, based on the safety, efficacy, and PK results of study CF-301-101 and cross-species 
population PK modeling, the clinical efficacy and safety of the CF-301 0.25 mg/kg dose in the 
current study is predicted to be efficacious by PK/PD target attainment modeling and is predicted 
to be well within the safety limit of exposure based on PK/TK modeling. 
The modeling of the data described in the paragraphs above demonstrates that a single dose of 
0.25 mg/kg in humans may be needed to achieve target AUC:MIC ratios of ≥ 0.5 in > 80% 
patients for isolates with an MIC of > 2 μg/mL.  Modeling of the PK data supports that a single 
dose of 0.4 mg/kg of CF-301 administered as a 2-hour IV infusion would not exceed the 
modeled AUC0-24 of 3600 ng•h/mL or Cmax 1750 ng/mL exposure limits associated with the 
NOEL dose of 2.5 mg/kg established in the rat following a 2-hour IV infusion, as described 
above. 
Following a review of the 0.25 mg/kg dose data from the Phase 2 study by the DSMB (based on 
predefined criteria described in a DSMB charter), if the observed AUC0-24 turn out to be 
significantly lower (by >25%) or higher than the target AUCs predicted from the study 
CF-301-101, the DSMB may recommend that the dose of CF-301 may be adjusted in order to 
achieve exposure targets. 
7.5. 
Rationale for Inclusion of Patients with Renal Impairment 
Patients with renal insufficiency are at high risk for infection with complicated S. aureus BSI; 
therefore, it is anticipated that patients with renal insufficiency may derive benefit from a new 
therapeutic agent that may provide additional benefit above SOC alone.  Therefore, patients with 
renal insufficiency are an important patient population in which to study the safety, efficacy, and 
PK of CF-301 on a background on SOC antibacterial therapy. 
CF-301 is a recombinant protein with a molecular mass of approximate 26 kDa.  Measurement of 
CF-301 levels in urine of healthy subjects in Study CF-301-101 determined a negligible amount 
(<0.1% the dose) of CF-301 excreted in urine.  The lack of urinary excretion of CF-301 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 CF-301 in mice, IV administration of 
131-I-CF-301, resulted in detection of CF-301 in multiple tissues (CF-301-023).  The kidneys had 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
45 
 
 
  
 
the highest level of CF-301, followed by the liver, spleen, stomach, lung, and blood that was 
rapidly decreased in the level of CF-301 in the majority of organs, including the kidney, 
suggesting rapid clearance of CF-301 from the blood and catabolism by multiple tissues. This is 
consistent with normal catabolism of protein and peptides (Meibohm and Zhou, 2012; Czock et 
al, 2012; Maack, 1979; Meier et al, 2004; lshimitsu et al, 1994).  Furthermore, literature reviews 
reveal that even in subjects with severe renal impairment, the capacity for catabolism of peptides 
and small proteins (e.g., < 60 kDa), remains substantial (>50% remaining capacity). 
Based on the collective CF-301 nonclinical and clinical data and published literature, the main 
route of elimination for CF-301 is understood to be catabolism and not urinary excretion. Also, 
even patients with severe renal impairment, retain substantial capacity for protein catabolism 
(Meibohm and Zhou, 2012; Czock et al, 2012; Maack, 1979; Meier et al, 2004; lshimitsu et al, 
1994). Thus, CF-301 dosing in patients with mild and moderate renal impairment (defined as 
creatinine clearance 30 to 80 mL/min) was not expected to substantially impact CF-301 plasma 
levels. 
Given the single-dose administration paradigm of CF-301, and the potential benefit of CF-301 to 
patients with renal insufficiency who are at risk for complicated S. aureus BSIs, inclusion of 
patients with mild or moderate renal insufficiency including patients undergoing dialysis was 
initially planned at a single-dose level of 0.25 mg/kg.  Based on the DSMB’s review of PK 
exposure data, patients with creatinine clearance < 60 mL/min (including patients on dialysis) 
will receive a dose of 0.12 mg/kg.  In view of the spleen’s role as a major organ for CF-301 
catabolism, subjects with creatinine clearance <30 mL/min who are asplenic were excluded from 
the study under prior versions of the protocol and subjects with creatinine clearance <60 mL/min 
who are asplenic will be excluded under this amendment.  Enrollment and subsequent tolerability 
and clinical outcome of these patients will be closely monitored as a component of DSMB 
activities, as described in the DSMB charter.  In patients on hemodialysis, CF-301/placebo will 
be administered either ≥ 8 hours prior to dialysis or ≥ 4 hours after end of dialysis. 
As patients with renal insufficiency and S. aureus BSIs may benefit from treatment with CF-301, 
this approach will allow for obtaining data in a patient population with severe renal disease, 
safeguard the safety of patients in this study, and allow for continued evaluation of CF-301 in 
this important population. 
7.6. 
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. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
46 
 
 
  
 
8. 
TRIAL OBJECTIVES AND PURPOSE 
8.1. 
Primary Objective 
• To describe the safety and tolerability of CF-301 vs. placebo in addition to SOC antibacterial 
therapy for the treatment of patients with S. aureus BSIs including endocarditis. 
• To estimate clinical outcome at Day 14 after CF 301/placebo administration. 
• To describe the PK parameters of CF-301. 
8.2. 
Secondary Objectives 
• To estimate clinical outcome at Day 7 after CF 301/placebo administration, at the end of 
SOC antibacterial therapy (EOT), and at test-of-cure (TOC) 28 days after the EOT. 
• To estimate microbiological response at Days 7 and 14 after CF-301/placebo administration. 
• To estimate microbiological outcome at EOT and at TOC. 
8.3. 
Exploratory Objectives 
• To describe the time to clearance of S. aureus bacteremia (defined as blood cultures negative 
for 2 consecutive days). 
• To describe the time to defervesence (defined as the highest oral temperature equivalent on 
day of assessment < 38.0°C [< 100.4°F]). 
• To describe all-cause mortality. 
• To explore the relationship between CF-301 exposures and safety and efficacy endpoints. 
• To describe post-dose immunologic response to CF-301. 
• To explore the relationship between baseline and post-dose immunologic parameters and 
safety and efficacy endpoints. 
• To describe clinical and microbiological outcomes in the subset of patients with MRSA 
infections. 
• To describe clinical and microbiological outcomes by diagnosis. 
• To describe relapse and reinfection rates. 
• To describe changes in cardiac valve vegetations, valvular function, and cardiac tissue in 
patients with endocarditis. 
• To describe the occurrence of clinical evidence of septic emboli and metastatic S. aureus 
infections. 
• To explore health resource utilization, including total length of hospital stay, days in the 
intensive care unit (ICU), 30-day readmission for S. aureus BSI/endocarditis, and surgery for 
treatment of S. aureus BSI/endocarditis 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
47 
 
 
  
 
9. 
INVESTIGATIONAL PLAN 
9.1. 
Overall Study Design 
This is a randomized, multicenter, multinational, double-blind, study to evaluate the safety, 
tolerability, efficacy, and PK of CF-301 vs. placebo in addition to SOC antibacterial therapy for 
the treatment of adult patients with S. aureus BSI including endocarditis.  Patients who meet all 
screening criteria and have blood culture positive for S. aureus determined by rapid diagnostic or 
conventional method or Gram stain showing Gram-positive cocci in clusters plus positive tube 
coagulase test from blood culture specimens collected within 72 hours prior to randomization are 
eligible for the study. 
Approximately 115 patients will be randomized in a 3:2 ratio to one of two treatment groups: 
• Group 1: CF-301 in addition to SOC antibacterial therapy (70 patients) 
• Group 2: Placebo in addition to SOC antibacterial therapy (45 patients) 
Patients who are randomized will receive a single dose of CF-301 or placebo (at the doses 
described in Section 9.4) over a 2-hour infusion in addition to appropriate SOC antibacterial 
therapy. 
Standard-of-care antibacterial therapy will be selected by the investigator based on standard 
practice at the site, treatment guidelines (Liu et al., 2011; Baddour et al., 2015), and other local 
guidelines.  Standard-of-care agents include daptomycin and vancomycin for MRSA and 
semi-synthetic penicillins (e.g., nafcillin, oxacillin, cloxicillin, flucloxacillin) and first-generation 
cephalosporins (e.g., cefazolin) for MSSA.  If susceptibility is not known at the time of 
randomization, the patient should 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, SOC may be changed at the investigator’s discretion based on 
susceptibility results to one of the SOC options described above.  Standard-of-care should be 
administered at the doses and durations specified in the manufacturer’s prescribing information, 
treatment guidelines (Liu et al., 2011; Baddour et al., 2015), other local guidelines, and clinical 
practice.  The suggested duration of SOC treatment is 28 to 42 days for complicated bacteremia 
and/or endocarditis and 42 to 84 days for osteomyelitis.  Patients with known or suspected 
uncomplicated bacteremia are not eligible for the study; however, if a randomized patient is 
subsequently determined to have uncomplicated bacteremia, the suggested duration of SOC 
treatment is approximately 14 days.  The investigator will determine diagnosis at screening and 
during the study to determine treatment duration. 
An overall clinical assessment, including a detailed evaluation of signs and symptoms of 
S. aureus BSI, will occur at screening.  Intravenous catheters known or suspected to be infected 
must be removed or changed and replaced at a different site as soon as possible within 72 hours 
after randomization.  In patients with central venous catheters (CVCs), ultrasounds to evaluate 
clots in the vein are recommended within 48 hours after randomization.  Two aerobic blood 
cultures preferably from 2 different sites will be collected at screening at least 30 minutes apart 
and as close to the start of study drug dosing as possible, and at least one aerobic blood culture 
will be collected daily during the study until negative for 2 consecutive days and at Days 7 and 
14 after CF-301/placebo administration.  Additional blood cultures will be performed as 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
48 
 
 
  
 
clinically indicated.  Blood cultures should be collected from a peripheral venipuncture site when 
possible. 
Physical examinations will be performed at screening, daily through Day 7 and on Day 14 after 
CF-301/placebo administration, at EOT, and at TOC.  The physical examinations will include a 
close evaluation for any new areas of pain or signs of metastases; new signs should trigger 
diagnostic testing for metastatic foci. 
All patients should have a transthoracic echocardiogram (TTE) within 3 days of randomization.  
All efforts should be made to perform this TTE before administration of study drug.  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 and the TTE within 
3 days of randomization does not need to be performed.  Patients with endocarditis should have a 
follow-up TTE between Days 7 and 14; where possible, a transesophageal echocardiogram 
(TEE) should also be performed (Baddour et al., 2015; Habib et al., 2010; Habib et al., 2015).  
TEEs are strongly recommended in patients with body mass index (BMI) > 30.  The site will 
provide all echocardiograms to the central echocardiography laboratory. 
Safety monitoring will include AE monitoring, physical examinations, vital sign measurements, 
12-lead ECGs, clinical safety laboratory tests, and immunological monitoring.  Safety 
monitoring will be performed during the core study from screening through TOC, and a 
long-term follow-up will occur at Day 180 after CF-301/placebo administration.  An independent 
DSMB will review unblinded safety data throughout the core study as defined in the DSMB 
charter. 
Blood samples for PK will be collected. 
Clinical response will be assessed by the investigator.  The Adjudication Committee will assess 
clinical response at predefined intervals.  The efficacy analysis of clinical response will be based 
on the Adjudication Committee’s assessment. 
9.2. 
Number of Patients 
Approximately 115 patients with S. aureus BSI will be randomized (3:2) to receive a single dose 
of CF-301 or placebo. 
In a study of Staphylococcus aureus bacteremia and endocarditis, 61.7% and 60.9% of patients 
receiving daptomycin and standard of care therapy in the modified intent to treat population, 
respectively, were considered a clinical success at the end of therapy (Fowler et al., 2006).  The 
median duration of therapy was 14 days for the daptomycin group and 15 days for the standard 
of care group.  Thus, it is reasonable to assume an expected clinical improvement or response 
rate of 60% in placebo group. 
A sample size of approximately 70 patients in the CF-301 treatment group and 45 patients in the 
placebo group will provide at least 80% power to detect a treatment difference of 25% in clinical 
response rate at Day 14 after CF-301/placebo, based on expected clinical improvement or 
response rates of 60% and 85% in the placebo and CF-301 treatment groups, respectively, using 
a two-sided target alpha level of 0.05 and Fisher’s exact test. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
49 
 
 
  
 
9.3. 
Treatment Assignment 
Approximately 115 patients will be randomized in a 3:2 ratio to one of two treatment groups: 
• Group 1: CF-301 (70 patients) 
• Group 2: Placebo (45 patients) 
9.4. 
Dosing and Dose Adjustment Criteria 
Study Drug 
CF-301 and placebo will be provided as sterile injectable solutions in 10 mL vials.  Each vial of 
CF-301 will contain 4.0 mL of CF-301 (10 mg/mL).  Placebo (vehicle control) is similar in 
appearance to CF-301, but does not contain the active ingredient.  CF-301 and placebo will be 
diluted as specified in the Pharmacy Manual and administered as a 2-hour IV infusion. 
The dosing scheme is as follows: 
• CF-301 will be administered at a dose of 0.25 mg/kg, with a maximum dose of 30 mg for 
patients who weigh ≥ 120 kg. 
• Patients with creatinine clearance of < 60 mL/min (including patients on dialysis) will 
receive a dose of 0.12 mg/kg, with a maximum dose of 15 mg for patients in this subset who 
weigh ≥ 125 kg.  In patients on hemodialysis, CF-301/placebo will be administered either 
≥ 8 hours prior to hemodialysis or ≥ 4 hours after the end of hemodialysis. 
• Patients who are > 50 years of age will receive a dose of 0.12 mg/kg, with a maximum dose 
of 15 mg for patients in this subset who weigh ≥ 125 kg. 
If analyses by the DSMB support further dose reductions or dose increases up to 0.4 mg/kg 
based on accrued PK exposure data in specific patient demographic groups, these will be 
described in Administrative Amendments or Clarification Letters to the protocol.  If the accrued 
PK data suggest the need for an increase in dose above the 0.4 mg/kg dose defined in the original 
protocol, then a protocol amendment will be issued. 
Patients must be directly observed during CF-301/placebo infusion, and vital signs (blood 
pressure, respiratory rate, and heart rate) will be performed approximately every 30 to 
40 minutes during the infusion and at approximately 30 to 40 minutes after the infusion.  In 
patients who have clinical signs and symptoms of allergic reactions to CF-301, the infusion 
should 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.  If a patient 
experiences signs and symptoms consistent with anaphylaxis (Simons, et al., 2011; Table 4), 
blood samples for serum tryptase and CF-301-specific IgE will be collected as soon as possible 
within 2 hours.  If the serum tryptase sample is positive or equivocal, the sample may also be 
tested for β-tryptase.  Another blood sample for serum tryptase will be collected 2 weeks later. 
Standard-of-Care Antibacterial Therapy 
Standard-of-care antibacterial therapy will be selected by the investigator based on standard 
practice at the site, treatment guidelines (Liu et al., 2011; Baddour et al., 2015), and other local 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
50 
 
 
  
 
guidelines.  Standard-of-care agents include daptomycin and vancomycin for MRSA and 
semi-synthetic penicillins (e.g., nafcillin, oxacillin, cloxicillin, flucloxacillin) and first-generation 
cephalosporins (e.g., cefazolin) for MSSA.  Note: patients who are receiving teicoplanin, 
linezolid, telavancin, ceftaroline fosamil, and/or sulfamethoxazole/trimethoprim are eligible for 
the study provided that treatment is switched to a SOC agent. 
If susceptibility is not known at the time of randomization, the patient should 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, SOC may be 
changed at the investigator’s discretion based on susceptibility results to one of the SOC options 
described above. 
Standard-of-care should be administered at the doses and durations specified in the 
manufacturer’s prescribing information, treatment guidelines (Liu et al., 2011; Baddour et al., 
2015), other local guidelines, and clinical practice. 
The suggested duration of SOC treatment is 28 to 42 days for complicated bacteremia and/or 
endocarditis and 42 to 84 days for osteomyelitis.  Patients with known or suspected 
uncomplicated bacteremia are not eligible for the study; however, if a randomized patient is 
subsequently determined to have uncomplicated bacteremia, the suggested duration of SOC 
treatment is approximately14 days.  The investigator will determine diagnosis at screening and 
during the study to determine treatment duration. 
Recommended doses for SOC antibacterial agents are as follows: 
• 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 being 10 to 20 µg/mL.  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 collected in the 
CRF.  Since red man syndrome is a known side effect of vancomycin, do not administer 
vancomycin at the same time as study drug.  Study drug should be administered either 
prior to the start of vancomycin infusion or a minimum of 2 hours after vancomycin 
infusion is complete. 
• Daptomycin: 6 to 8 mg/kg once daily 
The manufacturer’s prescribing information for the SOC antibacterial agents should be 
referenced for full dosing information. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
51 
 
 
  
 
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 24 hours of 
randomization), unless otherwise noted below, in order for the patient to be eligible for 
enrollment: 
1. Male or female, 18 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 plus positive coagulase test from blood culture specimens.  A list of acceptable rapid 
diagnostic tests is provided in Section 23.3. (Note: the 72-hour time period starts at the time 
the specimen is collected for blood culture). 
3. At least two of the following signs or symptoms: 
a. Shortness of breath 
b. Sweating 
c. Fatigue 
d. Confusion 
e. Pain associated with metastatic foci 
f. Fever (oral temperature equivalent ≥ 38.0°C [≥ 100.4°F]) 
g. Leukocytosis (white blood cell [WBC] count > 10,000/µL), leukopenia (WBC 
< 4000/µL), or bandemia (> 10% immature neutrophils [bands] regardless of total 
peripheral WBC) 
h. Tachycardia (heart rate > 100 bpm) 
i. Tachypnea (respiratory rate > 20 breaths/min) 
j. Hypotension (systolic blood pressure < 90 mmHg) 
4. Patients must have: 
a. Known or suspected right- and/or left-sided endocarditis by Modified Duke Criteria 
(Section 23.1) 
and/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. Signs or symptoms of catheter-related infection with clots in the vein at the 
catheter site seen on ultrasound 
iii. Signs or symptoms of metastatic foci of S. aureus infection (e.g., deep tissue 
abscess, septic pulmonary emboli) or hematogenous seeding (e.g., septic 
arthritis) confirmed by physical examination, imaging, or culture 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
52 
 
 
  
 
iv. S. aureus isolated from sterile body site other than blood 
v. Persistent fever (oral temperature equivalent ≥ 38.0°C [≥ 100.4°F]) at 
72 hours or more after the initial blood culture 
vi. Skin examination findings suggesting the presence of acute systemic infection 
(e.g., presence of ecchymosis, infarcts, petechiae, pustules, or vasculitis) 
vii. Met criteria for severe sepsis or septic shock during the time of 
diagnosis/presumptive diagnosis of bacteremia 
 Severe sepsis defined as a documented or presumed infection 
associated with either organ dysfunction, hypoperfusion, or 
hypotension (systolic blood pressure < 90 mm Hg or a decrease of 
> 4 mm Hg from baseline systolic measure in the absence of other 
causes of hypotension) AND the presence of systemic inflammatory 
response syndrome (SIRS), defined by at least 2 of the following: 
• 
Temperature (oral, rectal, tympanic, or core) > 38.5°C (> 
101.3°F) or < 35.0°C (< 95.0°F) 
• 
Heart rate > 90 beats/minute 
• 
Respiratory rate > 20 breaths/minute or partial pressure of 
arterial carbon dioxide (PaCO2) < 32 mmHg or on a ventilator 
• 
Leukocytosis (> 12,000 WBC/µL), leukopenia (< 4000 
WBC/µL), or bandemia (> 10% immature neutrophils [bands] 
regardless of total peripheral WBC) 
 Septic shock defined as persistent hypotension and perfusion 
abnormalities despite adequate fluid resuscitation or organ function not 
capable of maintaining homeostasis 
viii. Significantly immunocompromised: 
 AIDS (HIV positive with an AIDS-defining condition or a CD4 count 
< 200 cells/mm³) 
 Severe leukopenia defined as ANC <500 cells/mL for ≥ 3 days in the 
7 days prior to the qualifying blood culture 
 Post organ-transplantation including autologous bone marrow 
transplantation 
 On treatment for active graft vs. host disease 
 On immunosuppressive therapy (e.g., ≥ 15 mg of prednisone or 
equivalent for more than 5 days, biologics such as infliximab, 
monoclonal antibodies such as daclizumab, methotrexate, 
cyclophosphamide, or similar agents) 
 On chemotherapy treatment 
or  
c. At least one of the following risk factors: 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
53 
 
 
  
 
i. Preexisting valvular heart disease 
ii. Surgery within the previous 30 days that puts the patient at risk for 
nosocomial bacteremia (e.g., orthopedic, cardiothoracic, or intraabdominal 
surgery) 
iii. Extravascular foreign material (Note: removal of extravascular foreign 
material known or suspected to be infected is required within 72 hours after 
randomization) 
iv. Hemodialysis 
5. Patient is not pregnant or breastfeeding and meets one of the following criteria: 
a. A female patient who is not of reproductive potential is eligible without requiring the 
use of contraception.  This includes females 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 and male patients of reproductive 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 should 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.  If the patient is not able to provide 
informed consent, he/she can be enrolled according to local regulatory requirements (see 
Section 12.1). 
10.2. 
Exclusion Criteria 
1. Patient previously received CF-301. 
2. Treatment with any potentially effective (anti-staphylococcal) systemic antibiotic for more 
than 72 hours within 7 days before randomization. 
EXCEPTION: Documented resistance to the prior systemic antibacterial therapy. 
3. Treatment with dalbavancin or oritavancin for the current infection. 
Note: patients who are receiving teicoplanin, linezolid, telavancin, ceftaroline fosamil, and/or 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
54 
 
 
  
 
sulfamethoxazole/trimethoprim are eligible for the study provided that treatment is switched 
to an appropriate SOC antibacterial agent (SOC agents include daptomycin and vancomycin 
for MRSA and semi-synthetic penicillins [e.g., nafcillin, oxacillin, cloxicillin, flucloxacillin] 
and first-generation cephalosporins [e.g., cefazolin] for MSSA. 
4. MRSA isolate is known or suspected to have intermediate susceptibility or resistance to 
vancomycin or daptomycin. 
5. Presence of any removable infection source (e.g., intravascular line, abscess, dialysis graft) 
that will not be removed or debrided within 72 hours after randomization. 
6. Presence of an infected prosthetic joint, or presence of a prosthetic cardiac valve, cardiac 
valve support ring, or other implantable cardiac device (e.g., left ventricular assist device 
[LVAD]) if the patient is scheduled for surgical removal of the prosthetic valve, ring, or 
implantable device during the 24 hours after randomization.  Note: patients with implantable 
cardioverter defibrillators and permanent pacemakers are eligible for enrollment, and patients 
with prosthetic cardiac values, cardiac value support rings, or other implantable cardiac 
devices who are NOT scheduled for surgery during the 24 hours after randomization are 
eligible for enrollment. 
7. Endocarditis with severe aortic or mitral valve regurgitation on TEE or TTE, or any 
paravalvular abscess, with scheduled surgery for endocarditis. 
8. Known or suspected brain abscess. 
9. Known or suspected meningitis.  Note: Evidence of metastatic complications related to the 
primary infection such as septic arthritis and septic pulmonary infarcts are permitted. 
10. Asplenia in patients with creatinine clearance < 60 mL/min by Cockcroft-Gault using ideal 
body weight in patients with BMI ≥ 30 kg/m2 (Section 12.2) or on dialysis. 
11. Community acquired pneumonia, nosocomial pneumonia due to pathogens other than 
S. aureus, or known polymicrobial bacteremia (i.e., more than one pathogen in the blood).  
Note: patients with nosocomial pneumonia due to S. aureus are eligible for enrollment. 
12. Patient is not expected to survive through Day 14 of the study due to underlying disease 
(e.g., end-stage cancer). 
13. Patient participated or plans to participate in an interventional investigational drug, device, or 
diagnostic trial within 30 days or 5 half-lives of investigational drug, whichever is longer, 
prior to or during the study. 
14. Other comorbid condition or laboratory abnormality that would, in opinion of investigator, 
pose safety risk for patient to participate or pose risk to patient’s ability to complete the 
study. 
15. Patient is employed by the sponsor or investigational site or is a first degree relative of a 
person employed by the sponsor or investigational site.  Patient is institutionalized by 
administrative or court order. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
55 
 
 
  
 
10.3. 
Discontinuation Criteria 
10.3.1. 
Discontinuation from Study Drug 
Any AE that results in stopping of the study drug infusion is considered an event of clinical 
interest and must be reported within 24 hours (Section 14.6).  Reasons for study drug 
discontinuation include any of the following: 
• Patient is unable or unwilling to complete the study drug infusion 
• Patient withdraws informed consent at any time during study drug infusion 
• Clinical signs and symptoms of allergic reaction or anaphylaxis to CF-301 (see 
Section 11.2.3 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 PI and/or Sponsor 
• 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 from study drug (i.e., have the infusion stopped before the full dose is 
administered) should continue to participate in study visits unless consent was withdrawn. 
10.3.2. 
Discontinuation from the Study 
Reasons for discontinuation during the core study or during the long-term follow-up include any 
of the following: 
• Patient is unable or unwilling to adhere to the protocol 
• Patient is unable to return for the long-term follow-up (Day 180 only) 
• Patient withdraws informed consent 
• AE (whether or not related to study drug) that precludes further participation in the study 
in the judgment of the Investigator and/or Sponsor 
• Patient lost to follow-up [Note: vital status (whether the patient is alive or dead, or last 
known alive date) will be obtained when a patient is deemed to be lost to follow-up 
(Section 12.14)]. 
• The Investigator considers that it is in the patient’s best interest not to continue 
participation in the study 
• Other medical reason, at the discretion of the Investigator and/or the Medical Monitor 
The reasons for withdraw from the core study and during the long-term follow-up will be 
collected separately on the CRF.  The ability of the patient to return for the Day 180 visit is not 
required for enrollment in the study, but the visit is highly encouraged; patients who are unable 
to return for the visit should be contacted by phone or email (Section 11.3).  If a patient 
completes the core study, but does not return for the long-term follow-up, he/she will be 
considered as having completed the core study. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
56 
 
 
  
 
Patients are encouraged to remain in the study for follow up assessments.  Sites should contact 
the sponsor in advance if the investigator is considering withdrawing the patient from the study.  
Patients who are withdrawn from the core study or during the long-term follow-up will not 
participate in further study visits, but any AEs should be followed to resolution, as described in 
Section 14.11. 
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. 
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. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
57 
 
 
  
 
11. 
SCHEDULE OF OBSERVATIONS 
The study flow chart is provided in Section 3 and a study schematic is provided in Section 3.  
The study procedures performed at each visit are described in the subsections below. 
11.1. 
Study Duration 
Patients will receive a single dose of CF-301 or placebo in addition to SOC antibacterial therapy.  
The duration of SOC will generally be from 28 to 84 days based on the patient’s diagnosis (28 to 
42 days for complicated bacteremia/endocarditis and 42 to 84 days for osteomyelitis), the 
investigator’s discretion, treatment guidelines, and standard practice. 
Each patient is expected to complete the core study (through TOC) in approximately 6 to 
10 weeks, including screening, randomization, an estimated duration of approximately 28 to 
42 days SOC, EOT visit, and TOC at 28-days after the end of SOC treatment. Patients with 
osteomyelitis are expected to complete the core study (through TOC) in approximately 10 to 
16 weeks, since estimated duration of SOC is 42 to 84 days. 
The study includes a long-term follow-up visit at Day 180 after CF-301/placebo administration 
for collection of an immunogenicity sample and assessment of SAEs and re-infection.  The 
ability of the patient to return for the Day 180 visit is not required for enrollment in the study, but 
the visit is highly encouraged.  With the long-term follow-up through Day 180 after 
CF-301/placebo administration, the total study duration is approximately 25 weeks. 
11.2. 
Core Study 
11.2.1. 
Screening 
Patients will be screened to determine whether or not they meet the eligibility criteria for the 
study.  Patients should be randomized as soon as possible after confirmation of study eligibility.  
However, to provide flexibility, screening assessments may be performed within 24 hours before 
randomization.  For the purposes of the visit schedule, screening is considered Day ˗1. 
The qualifying blood culture collected within 72 hours prior to randomization that supports study 
eligibility will be collected in the eCRF and the isolate will be sent to the central laboratory 
whenever possible (Section 12.12).  In addition, two aerobic blood cultures are collected at 
screening, as described below. 
If local laboratory test results from the patient’s routine care are available from the 72 hours 
before screening, these may be used to support study eligibility determination (Section 12.13). 
If the patient had an echocardiogram performed prior to enrollment in the study for the current 
infection, this will be provided to the central echocardiography laboratory (Section 12.8). 
The following procedures will be performed at the time of Screening: 
• Informed consent (see Section 12.1) 
• Review of inclusion/exclusion criteria 
• Medical history for the prior 1 year 
• Risk factors for complicated S. aureus BSI 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
58 
 
 
  
 
• Diagnosis 
• Local laboratory testing, if needed for eligibility determination (see Section 12.13), and to 
determine serum creatinine to calculate creatinine clearance by Cockcroft-Gault formula using 
ideal weight for patients with BMI ≥ 30 kg/m2 (Section 12.2) to determine the dose of study 
drug. 
• 12-lead ECG 
• Complete physical examination (Section 12.6), including body weight and height. 
• Vital signs (blood pressure, respiratory rate, heart rate, and temperature).  If more than one 
measurement is taken on the day assessment, the highest value for temperature and most 
abnormal value for other vital signs should be recorded in the eCRF. 
• Symptoms attributable to S. aureus BSI/endocarditis 
• Two aerobic blood cultures preferably from 2 different sites will be collected at least 
30 minutes apart and as close to the start of study drug dosing as possible (collected via 
peripheral venipuncture when possible).  Results of all blood cultures (including blood cultures 
that are positive or negative for S. aureus) will be entered in the eCRF and S. aureus isolates 
will be sent to the central laboratory (Section 12.12) 
• Urine or serum β-hCG pregnancy test for women of reproductive potential only (performed 
locally study eligibility; see Section 12.13 and Inclusion Criteria in Section 10.1) 
• AE assessment from the time informed consent is obtained 
• Medication review 
11.2.2. 
Randomization 
Patients who are screened and determined to be eligible for the study will be randomized via an 
interactive web response system (IWRS).  For the purposes of the visit structure, the day of 
CF-301/placebo dosing considered Day 1 of the study.  Dosing should occur as soon as possible 
after randomization and within 24 hours of randomization.  The following procedures will be 
performed on the day of randomization: 
• Collect components of Apache II score.  Certain components of the Apache II score will be 
performed locally and collected on the CRF (including oxygenation, Glasgow Coma Scale, 
and chronic health points) and other components will be obtained from central laboratory data. 
• Blood and urine samples for clinical safety laboratory tests pre-dose and approximately 2 to 
4 hours after the start of CF-301/placebo infusion (for the first 17 patients randomized). (sent 
to the central laboratory; see Section 12.13) 
• Blood sample for serum pregnancy test for women of reproductive potential only (sent to the 
central laboratory; see Section 12.13). 
• 12-lead ECG at approximately 2 to 4 hours after the start of CF-301/placebo infusion (for the 
first 17 patients randomized) 
• Targeted physical examination (Section 12.6).  Note: if the physical examination at screening 
was performed within 3 hours of randomization, it does not need to be repeated. 
• Vital signs: 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
59 
 
 
  
 
• Temperature.  If more than one measurement is taken on the day of randomization, the 
highest temperature should be recorded in the eCRF. 
• Blood pressure, respiratory rate, and heart rate approximately every 30 to 40 minutes 
during the infusion and at approximately 30 to 40 minutes after the infusion. 
• Symptoms attributable to S. aureus BSI/endocarditis 
• An aerobic blood culture collected prior to CF-301/placebo dosing (collected via peripheral 
venipuncture when possible).  All blood culture (including blood cultures that are positive or 
negative for S. aureus) will be entered in the eCRF and S. aureus isolates will be sent to the 
central laboratory (Section 12.12) 
• Intravenous catheters known or suspected to be infected must be removed or changed and 
replaced at a different site as soon as possible within 72 hours after randomization 
• All patients should have a TTE within 3 days of randomization.  All efforts should be made to 
perform this TTE before administration of study drug.  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 and the TTE within 3 days of randomization does 
not need to be performed.  TEEs are strongly recommended in patients with BMI > 30 kg/m2.  
The site will provide all echocardiograms to the central echocardiography laboratory. 
• Ultrasounds to evaluate clots in the vein are recommended within 48 hours after randomization 
in patients with CVCs. 
• Blood samples for PK at the time points described in Section 12.16. 
• Blood samples for immunogenicity samples (ADA, IgE) and optional future research collected 
pre-dose (to be sent to the central laboratory (Section 12.13).  Note: future use samples will 
NOT be collected from patients in Israel. 
• CF-301/placebo dosing.  Patients must be directly observed during CF-301/placebo infusion 
(see Section 11.2.3). 
• AE assessment 
• Medication review 
11.2.3. 
Study Drug 
Patients will receive a single dose of study drug (CF-301 or placebo) as described in Section 9.4. 
11.2.3.1. Allergic Reactions / Anaphylaxis 
Patients must be directly observed during CF-301/placebo infusion, and vital signs (blood 
pressure, respiratory rate, and heart rate) will be performed approximately every 30 to 
40 minutes during the infusion and at approximately 30 to 40 minutes after the infusion.  In 
patients who have clinical signs and symptoms of allergic reactions to CF-301, the infusion 
should 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. 
If a patient experiences signs and symptoms consistent with anaphylaxis as described in Table 4, 
blood samples for serum tryptase and CF-301-specific IgE will be collected as soon as possible 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
60 
 
 
  
 
within 2 hours.  If the serum tryptase sample is positive or equivocal, the sample may also be 
tested for β-tryptase. Another blood sample for serum tryptase will be collected 2 weeks later.  
Collection of these samples is important to further support the diagnosis of anaphylaxis.  
Anaphylaxis should be reported as an SAE (see Section 14). 
Table 4: 
Clinical Criteria for Diagnosing Anaphylaxis 
Anaphylaxis is highly likely when any one of the following three 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 ONE 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 allergena 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, et al., 2011 
a. 
Or other trigger, for example, immunologic but IgE-independent, or non-immunologic (direct) mast cell activation. 
11.2.4. 
Standard-of-Care Antibacterial Therapy 
Standard-of-care antibacterial therapy will be administered as described in Section 9.4. 
The eCRF will collect information on the entire course of SOC antibacterial treatment for the 
patient’s current episode of S. aureus BSI/endocarditis, including SOC received prior to patient’s 
entry in the study. 
For the purposes of the visit schedule, the day of CF-301/placebo dosing is considered Day 1 of 
the study and each subsequent day during SOC is considered a sequential study day (i.e., Day 2, 
Day 3, Day 4, etc.). 
There is a ±1-day window around the procedures performed on Days 7 and 14. 
The following procedures will be performed during SOC: 
• Diagnosis assessment on Day 7 
• Blood and urine samples for clinical safety laboratory tests on Day 2 and weekly during SOC 
(sent to the central laboratory; see Section 12.13) 
• 12-lead ECG on Day 2 
• Targeted physical examinations (Section 12.6) daily through Day 7. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
61 
 
 
  
 
• Vital signs (blood pressure, respiratory rate, heart rate, and temperature) daily for inpatients 
(and at weekly scheduled visits for patients who are discharged [i.e., at the Day 7 and Day 14 
visits, and weekly thereafter]).  If more than one measurement is taken on a given day, the 
highest value for temperature and most abnormal value for other vital signs should be recorded 
in the eCRF. 
• Symptoms attributable to S. aureus BSI/endocarditis assessed daily for inpatients (and at 
weekly scheduled visits for patients who are discharged [i.e., at the Day 7 and Day 14 visits, 
and weekly thereafter]). 
• An aerobic blood culture collected daily until negative for 2 consecutive days and at Days 7 
and 14 after CF-301/placebo administration.  Additional blood cultures will be performed as 
clinically indicated.  Blood cultures should be collected from a peripheral venipuncture site 
when possible.  Results of all blood cultures (including blood cultures that are positive or 
negative for S. aureus) will be entered in the eCRF and S. aureus isolates will be sent to the 
central laboratory (Section 12.12) 
• If not done at randomization, intravenous catheters known or suspected to be infected must be 
removed or changed and replaced at a different site as soon as possible within 72 hours after 
randomization 
• If not done at randomization, all patients should have a TTE within 3 days of randomization.  
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 and the TTE 
within 3 days of randomization does not need to be performed.  TEEs are strongly 
recommended in patients with BMI > 30 kg/m2.  The site will provide all echocardiograms to 
the central echocardiography laboratory. 
• If not done at randomization, ultrasounds to evaluate clots in the vein are recommended within 
48 hours after randomization in patients with CVCs. 
• Blood samples for PK at the time points described in Section 12.16. 
• Blood samples for immunogenicity samples (CF-301 ADA & IgE) on Day 14 (to be sent to 
the central laboratory (Section 12.13). 
• Blood samples for optional future research on Day 2 and Day 7 (to be sent to the central 
laboratory (Section 12.13).  Note: future use samples will NOT be collected from patients in 
Israel. 
• AE assessment daily 
• Medication review daily 
• Clinical outcome assessment on Day 7 and Day 14 (Section 12.15) 
11.2.5. 
End of Standard-of-Care 
A visit will be performed on or within 2 days after the end of SOC.  For the purposes of the visit 
schedule, this visit is termed the “EOT” visit. 
The following procedures will be performed at the EOT: 
• Blood and urine samples for clinical safety laboratory tests (sent to the central laboratory; see 
Section 12.13) 
• 12-lead ECG 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
62 
 
 
  
 
• Complete physical examination (Section 12.6) 
• Vital signs (blood pressure, respiratory rate, heart rate, and temperature).  If more than one 
measurement is taken on the day assessment, the highest value for temperature and most 
abnormal value for other vital signs should be recorded in the eCRF. 
• Symptoms attributable to S. aureus BSI/endocarditis. 
• Blood cultures as clinically indicated.  Blood cultures should be collected from a peripheral 
venipuncture site when possible.  Results of all blood cultures (including blood cultures that 
are positive or negative for S. aureus) will be entered in the eCRF and S. aureus isolates will 
be sent to the central laboratory (Section 12.12). 
• Blood sample for serum pregnancy test for women of reproductive potential only (sent to the 
central laboratory; see Section 12.13). 
• Blood samples for immunogenicity samples (CF-301 ADA & IgE) (to be sent to the central 
laboratory (Section 12.13). 
• Blood samples for optional future research.  Note: future use samples will NOT be collected 
from patients in Israel. 
• AE assessment 
• Medication review 
• Clinical outcome assessment (Section 12.15) 
Every attempt must be made to ensure the patient returns for the EOT visit, 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 the EOT visit, 
the site must contact the medical monitor to discuss whether the EOT visit may be conducted 
over the phone in order to facilitate collection of as much data as possible for the investigator to 
make the assessment of clinical outcome at EOT.  In the event the EOT visit is conducted over the 
phone, the site should collect information on signs/symptoms of infection, SOC antibacterial 
therapy, concomitant medications, and AEs.  The investigator should make an assessment of 
clinical outcome based on the data collected.  If the patient is at another facility (e.g., nursing 
home, another hospital), the site should obtain medical records from that facility whenever 
possible. 
11.2.6. 
Test-of-Cure 
A test-of-cure visit will be performed 28 days (± 4 days) after the last day of SOC antibacterial 
therapy.  For the purposes of the visit schedule, this visit is termed the “TOC” visit. The 
procedures to be performed at TOC are the same as the EOT procedures, listed above in 
Section 11.2.5. 
Every attempt must be made to ensure the patient returns for the TOC visit, 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 the TOC visit, 
the site must contact the medical monitor to discuss whether the TOC visit may be conducted 
over the phone in order to facilitate collection of as much data as possible for the investigator to 
make the assessment of clinical outcome at TOC.  In the event the TOC visit is conducted over 
the phone, the site should collect information on signs/symptoms of infection, SOC antibacterial 
therapy, concomitant medications, and AEs.  The investigator should make an assessment of 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
63 
 
 
  
 
clinical outcome based on the data collected.  If the patient is at another facility (e.g., nursing 
home, another hospital), the site should obtain medical records from that facility whenever 
possible. 
11.3. 
Immunogenicity Follow-up 
The study includes a long-term follow-up visit at Day 180 (± 14 days) after CF-301/placebo 
administration for collection of an immunogenicity sample and assessment of SAEs and 
re-infection.  The ability of the patient to return for the Day 180 visit is not required for 
enrollment in the study, but the visit is highly encouraged and the site may offer support for the 
patient to facilitate return for the visit (e.g., reimbursement of travel expenses).   
The following procedures will be performed at the Day 180 visit: 
• Blood samples for CF-301 ADA & IgE will be collected and sent to the central 
laboratory (Section 12.13). 
• Re-infection between TOC and Day 180 will be assessed by the investigator for patients 
who meet the definition of response at TOC (Section 12.15; Table 6). 
• Blood cultures should be performed between TOC and Day 180 as clinically indicated.  
Results of all blood cultures (including blood cultures that are positive or negative for S. 
aureus) will be entered in the eCRF and S. aureus isolates will be sent to the central 
laboratory (Section 12.12). 
• All SAEs will be collected through Day 180. 
• Vital status (whether the patient is alive or dead, or last known alive date) will be 
obtained when a patient is deemed to be lost to follow-up and for all patients at Day 180.  
The patient’s vital status should be determined using available sources (e.g., the patient’s 
relatives, hospital records, and/or public records) as permissible based on local laws and 
regulations. 
For patients who are unable to return for the visit, relapse, SAE information, and vital status may 
be obtained via phone or email. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
64 
 
 
  
 
12. 
STUDY ASSESSMENTS 
12.1. 
Informed Consent 
Fully informed consent will be obtained before any study specific procedures are performed.  
The content and process of obtaining informed consent must be in accordance with all applicable 
ethical and regulatory requirements. 
It is anticipated, by the very nature of the study that some patients who will be eligible for this 
protocol will not be able to give fully informed consent themselves due to various reasons 
including sedation, unconscious state, etc.  Therefore, in a situation where a patient is unable to 
provide consent for him/herself, informed consent will be obtained by using one of the following 
possible options, which must comply with an individual country’s local laws and ethics 
committees regulating the enrollment of incapacitated adults into clinical trials. 
This process must be expedited to ensure that securing a representative’s consent does not lead to 
delays that may result in increased risk or delayed medical treatment to the patient. 
Therefore, the following will be applied as long as local laws allow: 
• Consent from a legal (LR) or authorized (AR) or legally authorized representative (LAR) or 
next of kin or legally appointed individual in person or judge or specifically appointed lawyer 
for this purpose as required by local regulations; 
• In extreme and urgent circumstances when emergent action is required to save the life of the 
person concerned, restore good health or alleviate suffering, it is understood that the 
presumed will of the patient will be determined by a physician and documented based on 
his/her knowledge of the study subject. The physician will follow the process required by 
local regulations and ethics committee for enrolment of this patient.  Note: under the FDA 
regulations, the type of consent described in this bullet is only allowed when the research is 
reviewed under the exception from informed consent as emergency research (21 CFR 50.24).  
Therefore, for enrollment at sites in the United States, informed consent should be given by 
the patient or a LAR. 
When consent is obtained remotely (by fax, scanned copy, etc.) according to local regulations via 
a LR / LAR / AR / next of kin / legally appointed individual, an original signature must be 
obtained at the earliest opportunity. 
Patients enrolled in the study on the basis of consent by a LR / LAR / AR / next of kin / legally 
appointed individual / independent physician or by a physician will be given the opportunity to 
provide written confirmatory consent when and if they become able to do so and if the local 
regulations allow and/or require this.  If the subject declines to confirm consent, he/she will be 
withdrawn from the study at the point where he/she declines consent. 
In addition, where local regulatory and ethics committees allow, advance consent may be 
obtained prior to study entry in an attempt to obtain personal consent from the patient 
themselves. 
Should a patient who is enrolled in the study on the basis of advance consent subsequently 
become unable to make medical decisions for him/herself, then the patient's legally acceptable 
next of kin / LAR / LR / AR should be informed of the patient's participation in the trial.  


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
65 
 
 
  
 
The above guidelines apply to all areas of the protocol where Informed Consent is referenced. 
12.2. 
Cockcroft-Gault 
Estimated creatinine clearance is calculated by Cockcroft-Gault formula as follows:  
 
In patients with BMI < 30 kg/m2: 
Estimated creatinine clearance = [(140 - age) x weight in kg]/[72 x serum creatinine in 
mg/dL] [x 0.85 if female]. 
In patients with BMI ≥ 30 kg/m2: 
Estimated creatinine clearance = [(140 - age) x ideal body weight in kg]/[72 x serum 
creatinine in mg/dL] [x 0.85 if female]. 
o For height in inches: Ideal body weight = 2.3 kg x each inch over 5 feet + W 
o For height in cm: Ideal body weight = 0.9 kilograms × (height (cm) − 152) + W 
W = 50 kg for males; 45.5 kg for females 
12.3. 
Medical History 
A complete medical history for 1 year prior to screening will be recorded for each patient.  
Medical history will include previous and current medical diagnoses and major surgical 
procedures. 
12.4. 
Diagnosis 
The investigator will determine diagnosis at screening and during the study to determine 
treatment duration.  Diagnosis definitions are provided in Section 23.1). 
12.5. 
Apache II score 
Certain components of the Apache II score will be determined locally (including oxygenation, 
Glasgow Coma Scale, and chronic health points) on the day of randomization and collected on 
the eCRF and other components will be obtained from central laboratory data. 
12.6. 
Physical Examination 
Physical examination will be performed at screening, daily through Day 7 and on Day 14 after 
CF-301/placebo administration, at EOT, and at TOC.   
Complete physical examinations will be performed at screening, Day 14, EOT, and TOC.  
Complete physical examinations include, but are not limited to, evaluation of the head, eyes, 
ears, nose, throat (HEENT), neck, lungs, heart, chest, abdomen, extremities, neurological status, 
skin for any evidence of emboli, palpation for signs of pain, and any other notable conditions. 
Weight and height will be measured at screening.  If it is not possible to measure weight and 
height at screening, a recently available historical weight and height can be used. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
66 
 
 
  
 
Targeted physical examinations will be performed daily through Day 7.  Targeted physical 
examinations include evaluation for complications of BSI, HEENT, lungs, heart, skin for any 
evidence of emboli, and palpation for signs of pain. 
Pain on physical examinations should trigger diagnostic testing for metastatic foci. 
12.7. 
12-Lead Electrocardiogram 
A 12-lead ECG will be performed at screening, at approximately 2 to 4 hours after the start of 
CF-301/placebo infusion (for the first 17 patients randomized), on Day 2, at EOT, and at TOC. 
Heart rate, PR interval, QRS, QT, QTcB, and QTCF values will be recorded on the eCRF.  Any 
clinically relevant abnormality will be recorded as an adverse event and will be followed to 
resolution/satisfaction. 
12.8. 
Echocardiogram 
All patients should have a TTE within 3 days of randomization.  All efforts should be made to 
perform this TTE before administration of study drug.  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 and the TTE within 3 days of randomization does not 
need to be performed.  Patients with endocarditis should have a follow-up TTE between Days 7 
and 14; where possible, a TEE should also be performed (Baddour et al., 2015; Habib et al., 
2010; Habib et al., 2015).  TEEs are strongly recommended in patients with BMI > 30 kg/m2.  
The site will provide all echocardiograms to the central echocardiography laboratory.  The 
central echocardiography laboratory will review the echocardiograms for diagnostic evaluation 
of valvular function and other parameters. 
12.9. 
Vital Signs 
Vital signs will be performed at screening, approximately every 30 to 40 minutes during 
CF-301/placebo infusion and at approximately 30 to 40 minutes after the infusion, daily during 
SOC for inpatients (and at weekly scheduled visits for patients who are discharged [i.e., at the 
Day 7 and Day 14 visits, and weekly thereafter]), at EOT, and at TOC.  Vital signs will include 
blood pressure, respiratory rate, and heart rate during infusion and blood pressure, respiratory 
rate, heart rate, and temperature at all other time points.  If more than one measurement is taken 
on the day assessment, the highest value for temperature and most abnormal value for other vital 
signs should be recorded in the eCRF. 
12.10. 
Symptoms of Infection 
The investigator will assess symptoms (shortness of breath, sweating, fatigue, confusion, and 
pain associated with metastatic foci) at screening, daily during SOC for inpatients (and at weekly 
scheduled visits for patients who are discharged [i.e., at the Day 7 and Day 14 visits, and weekly 
thereafter]), at EOT, and at TOC.  The investigator will determine if symptoms are attributable to 
S. aureus BSI/endocarditis.  The investigator will assess symptoms as follows: 
Absent 
 
Mild 
Awareness of sign or symptom, but easily tolerated 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
67 
 
 
  
 
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 
12.11. 
Management of IV Catheters 
Intravenous catheters known or suspected to be infected must be removed or changed and 
replaced at a different site as soon as possible within 72 hours after randomization.  In patients 
with CVCs, ultrasounds to evaluate clots in the vein are recommended within 48 hours after 
randomization 
12.12. 
Blood Cultures 
For study eligibility, patients must have blood culture positive for S. aureus determined by rapid 
diagnostic or conventional method or Gram stain showing Gram-positive cocci in clusters plus 
positive tube coagulase test from blood culture specimens collected within 72 hours prior to 
randomization.  The site microbiological laboratory is encouraged to use an FDA-cleared or 
CE-IVD certified rapid diagnostic test to identify S. aureus if it is available at the site 
(Section 23.3). 
The qualifying blood culture collected within 72 hours prior to randomization that supports study 
eligibility will be collected in the eCRF.  Wherever possible, the isolate from the initial positive 
culture for S. aureus should be retained and sent for confirmation of identification and 
susceptibility testing at the central microbiology laboratory. 
Two aerobic blood cultures preferably from 2 different sites will be collected at screening at least 
30 minutes apart and as close to the start of study drug dosing as possible, and at least one 
aerobic blood culture will be collected daily during the study until negative for 2 consecutive 
days and at Days 7 and 14 after CF-301/placebo administration.  Additional blood cultures will 
be performed as clinically indicated.  Blood cultures should be collected from a peripheral 
venipuncture site when possible.  Results from all blood cultures performed during the study 
(from the qualifying blood culture through to Day 180), including blood cultures that are positive 
or negative for S. aureus, should be entered in the eCRF.  S. aureus isolates, including the isolate 
from the qualifying blood culture, are sent to the central lab. 
The study site’s local microbiology laboratory will perform identification and in vitro 
susceptibility testing to SOC antibiotics according to local practices.  The investigator should 
ensure that all S. aureus isolates obtained from all cultures performed during the study period 
(and wherever possible, the isolate from the initial positive culture for S. aureus) are sent to the 
central microbiology laboratory, as described in Section 23.3 and the laboratory manual.  The 
central microbiology laboratory will repeat the identification and perform in vitro susceptibility 
testing of isolates in batches for the purposes of the final study analysis; the central microbiology 
laboratory will not be providing ‘real-time’ results.  Further evaluation to identify the potential 
mechanism of resistance may be performed. 
The use of FDA-cleared or CE-IVD certified rapid diagnostic tests to identify S. aureus may be 
employed to reduce the amount of prior empiric antibacterial therapy being administered to 
potential study patients.  Patients may be enrolled based on a positive result from a rapid 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
68 
 
 
  
 
diagnostic test, but confirmation of S. aureus by conventional methods will be the required 
objective measure for S. aureus in the study analyses for efficacy.  Patients who are enrolled 
based on a positive rapid diagnostic test, but have negative result for S. aureus or missing blood 
culture at screening should continue to be followed in the study for safety assessments. 
12.13. 
Laboratory Testing 
12.13.1. 
Central Laboratory 
The laboratory tests that will be performed by the central safety laboratory are presented in 
Section 23.4.  The details for sample collection, preparation, and shipping to the central 
laboratory will be provided in a separate laboratory manual.  The following samples will be 
collected for sending to the central laboratory: 
• Blood and urine samples will be collected for safety laboratory tests (biochemistry, 
hematology, coagulation, and urinalysis) at randomization (pre-dose), at approximately 
2 to 4 hours after the start of CF-301/placebo infusion (for the first 17 patients 
randomized), on Day 2, weekly during SOC, at EOT, and at TOC. 
• Blood samples for serum pregnancy testing will be collected at randomization, EOT, and 
TOC (female patients of reproductive potential).  The pregnancy test that qualifies the 
patient for study eligibility is performed locally, as described under Section 12.13.2. 
• Blood samples will be collected for CF 301-specific anti-drug antibody (ADA) and IgE at 
randomization (pre-dose), Day 14, at EOT, at TOC, and on Day 180 after CF 301/placebo 
administration. 
• If a patient experiences signs and symptoms consistent with anaphylaxis (Simons, et al., 
2011; Section 11.2.3.1), blood samples for serum tryptase and CF-301-specific IgE will 
be collected as soon as possible within 2 hours.  If the serum tryptase sample is positive 
or equivocal, the sample may also be tested for β-tryptase. Another blood sample for 
serum tryptase will be collected 2 weeks later. 
• If the patient agrees in the informed consent to have blood stored for optional future 
research (e.g., cytokine and chemokine assays and/or biomarker evaluation), 2 samples 
(1 serum and 1 plasma) will be collected at randomization (pre-dose), 12 to 24 hours after 
CF-301/placebo dosing, on Day 7, and at EOT and TOC.  Note: future use samples will 
NOT be collected from patients in Israel. 
12.13.2. 
Local Laboratory 
Limited safety laboratory tests may need to be performed by the site’s local laboratory at 
screening so that timely results are available for study eligibility determination.  If laboratory 
safety results are already available within the 72 hours prior to screening from standard-of-
care/routine testing, these results may be used to support eligibility determination.  The 
laboratory tests that are required to be available locally for eligibility determination are those that 
are part of the inclusion/exclusion criteria, as follows: 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
69 
 
 
  
 
• Serum creatinine to calculate creatinine clearance by Cockcroft-Gault formula using 
ideal body weight in patients with BMI ≥ 30 kg/m2 (Section 12.2) to determine the dose 
of study drug 
• Urine or serum pregnancy test (for women of reproductive potential; see inclusion 
criteria) 
• FSH (to confirm postmenopausal status as applicable; see inclusion criteria) 
Other safety laboratory tests may be performed locally at the investigator’s discretion to assess 
the patient in general for study eligibility.  During the study, additional clinical laboratory safety 
testing should be performed at the site’s local laboratory per the site’s standard of care for 
routine clinical management of the patient. 
12.14. 
Vital Status 
Vital status (whether the patient is alive or dead, or last known alive date) will be obtained at 
Day 180 or when a patient is deemed to be lost to follow-up.  The patient’s vital status should be 
determined using available sources (e.g., the patient’s relatives, hospital records, and/or public 
records) as permissible based on local laws and regulations. 
12.15. 
Contraception 
Contraception requirements are described in the Inclusion Criteria (Section 10.1). 
The manufacturer’s prescribing information for the SOC antibacterial agents should be 
referenced for information related to pregnancy and contraception. 
12.16. 
Efficacy Outcome Assessments 
Clinical and microbiological outcome will be assessed at Days 7 and 14 after CF-301/placebo 
administration, at EOT, and at TOC. 
Clinical Outcome:  Clinical outcome will be assessed by the investigator and the independent 
Adjudication Committee and will be based on the definitions in Table 5.  The signs and 
symptoms evaluated for clinical outcome assessments are presence of shortness of breath, 
sweating, fatigue, confusion, pain associated with metastatic foci, fever, leukocytosis, 
leukopenia, bandemia, tachycardia, tachypnea, and hypotension. 
Re-infection will be assessed at Day 180 after CF-301/placebo administration for patients who 
meet the definition of response at TOC (Table 5).  Re-infection will be assessed by the 
investigator and the independent Adjudication Committee.  The definition of re-infection is 
provided in Table 6. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
70 
 
 
  
 
Table 5: 
Clinical Outcome Definitions at Day 7 (± 1 day), Day 14 (± 1 day), EOT 
(+ 2 days), and at TOC (±4 days) 
Clinical 
Outcome 
Definition 
Improvement 
(Days 7 and 14 
only) 
• 
Improvement in all attributable signs and symptoms of S. aureus BSI which were 
present at baselinea, 
• 
No new, worsening, or persistent signs and symptoms attributable to S. aureus BSI, 
• 
No development of a new foci of S. aureus infection after Day 7b 
• 
SOC for S. aureus BSI is ongoing with no need toc: 
 
add a SOC antibacterial agent due to persistent or worsening S. aureus BSI,  
 
switch to a different SOC antibacterial agent due to persistent or worsening S. 
aureus BSI, or 
 
increase SOC dose due to persistent or worsening S. aureus BSI, 
• 
No surgery or medical intervention for S. aureus BSI is necessary, and 
• 
The patient is alive. 
Responsed 
• 
Complete resolution of attributable signs and symptoms of S. aureus BSI which 
were present at baseline, 
• 
No new signs and symptoms attributable to S. aureus BSI, 
• 
No development of a new foci of S. aureus infection after Day 7b 
• 
No further antibacterial therapy for S. aureus BSI is necessary, 
• 
No further surgery or medical intervention for S. aureus BSI is necessary, and 
• 
The patient is alive. 
Non-responsed 
• 
Persistence, worsening, or recurrence of attributable signs and symptoms of 
S. aureus BSI which were present at baseline, 
• 
New signs and symptoms attributable to S. aureus BSI, 
• 
Development of a new foci of S. aureus infection after Day 7b, 
• 
Complications of S. aureus BSI, 
• 
SOC for S. aureus BSI was changed toc: 
 
add a SOC antibacterial agent due to persistence, worsening, or recurrence of S. 
aureus BSI, 
 
switch to a different SOC antibacterial agent due to persistence, worsening, or 
recurrence of S. aureus BSI, or 
 
increase the dose of SOC due to persistence, worsening, or recurrence of 
S. aureus BSI, 
• 
>12 weeks of SOC antibacterial therapy for S. aureus BSI and/or related infection 
(e.g., osteomyelitis), 
• 
Surgery or medical intervention for S. aureus BSI is necessary (e.g., valvular 
surgery for progressive S. aureus BSI), or 
• 
Death due to any cause. 
Indeterminate 
Study data are not available for the evaluation of efficacy for any reason including: 
• 
Lost to follow up 
• 
Withdrawal of consent 
• 
Extenuating circumstances that preclude the classification of clinical response 
a. 
Symptoms will be assessed as absent, mild, moderate, and severe.  All symptoms present at baseline must improve by one 
category (e.g., from moderate to mild) in order for a patient to be considered as having improvement. 
b. 
Does not apply at Day 7 assessment.  Metastatic foci identified through Day 7 post-randomization are considered baseline; 
new metastatic foci identified after Day 7 post-randomization are considered progression of the S. aureus infection. 
c. 
Per protocol, patients may be treated empirically and SOC may be changed once susceptibly data become available, as 
described in the “Study Design” section.  A change in SOC based on susceptibility data from the blood culture collected 
within 72 hours prior to randomization does not count as “non-response”. 
d. 
At Test-of-Cure, response = cure and non-response = failure. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
71 
 
 
  
 
Table 6: 
Clinical Re-Infection Definitions at Day 180 (±14 days) 
Clinical 
Outcomea 
Definition 
No re-infection 
Between TOC and Day 180, the patient did not have S. aureus BSI/endocarditis or S. aureus 
infection at any body site (this includes infections that the investigator considers to be 
relapses as well as those that the investigator considers to be new S. aureus infections). 
Re-infection 
Between TOC and Day 180, the patient had S. aureus BSI/endocarditis and/or developed a S. 
aureus infection at any body site documented by a positive culture for S. aureus (this 
includes infections that the investigator considers to be relapses as well as those that the 
investigator considers to be new S. aureus infections). 
Indeterminate 
Study data are not available for the evaluation of efficacy for any reason including: 
• 
Lost to follow up 
• 
Withdrawal of consent 
• 
Extenuating circumstances that preclude the classification of clinical response 
a. 
Patients who meet the definition of response at TOC will be assessed for re-infection. 
 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
72 
 
 
  
 
Microbiological Response/Outcome:  Definitions for microbiological response (Days 7 and 14) 
and microbiological outcome (End of SOC and TOC) are provided in Table 7 and Table 8, 
respectively.  Microbiological outcome will be determined programmatically based on the data 
from the central microbiology laboratory.  In the event an isolate is not sent to the central 
microbiology laboratory then the local laboratory data collected on the case report form (CRF) 
will be used. 
Table 7: 
Microbiological Response Definitions at Day 7 (± 1 day) and Day 14 (± 1 day) 
Microbiological 
Response 
Definitions 
Clearance of bacteremia  Blood cultures collected on or prior to assessment were negative for 
S. aureus on 2 consecutive days.   
Ongoing bacteremia 
Blood cultures collected on or prior to assessment continue to be positive 
for S. aureus 
Indeterminate 
Study data are not available for the evaluation of efficacy for any reason 
including: 
• 
Lost to follow up 
• 
Withdrawal of consent 
• 
Extenuating circumstances that preclude the classification of 
microbiological response 
 
Table 8: 
Microbiological Outcome Definitions at EOT (+ 2 days) and at TOC 
(±4 days) 
Microbiological 
Outcome 
Definitions 
Eradication  
Blood cultures were negative for S. aureus on 2 consecutive days. 
Presumptive Eradication  Follow-up blood cultures were not done and the patient has responded 
clinically, as defined in Table 5. 
Persistence  
Blood cultures continue to be positive for S. aureus. 
Presumed Persistence 
Follow-up blood cultures were not done and the patient has not responded 
clinically, as defined in Table 5. 
Relapse 
Patient was previously classified as having “clearance of bacteremia”, 
“eradication”, or “presumptive eradication”, and subsequently a blood 
culture was positive for S. aureus. 
Indeterminate 
Study data are not available for the evaluation of efficacy for any reason 
including: 
• 
Lost to follow up 
• 
Withdrawal of consent 
• 
Extenuating circumstances that preclude the classification of 
microbiological response 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
73 
 
 
  
 
12.17. 
Pharmacokinetic Assessments 
Blood samples will be collected for PK assessment of CF-301 in 3 subsets of patients as listed 
below.  Pharmacokinetic samples will be collected from patients in both the CF-301 group and 
the placebo group to maintain the blind.  Blood samples for PK may be collected by peripheral 
venipuncture or from a central IV catheter.  For samples < 3 hours after start of infusion, the 
sample must be collected from a different site than the site of infusion.  The specific details 
pertaining to sample collection, processing, and shipping are provided in the laboratory manual. 
• PK Subset 1:  A minimum of approximately 17 patients and up to approximately 
34 patients (30%) will give serial PK samples at the following time points:  pre-dose, 
0.5 (30 minutes), 1.5 (1 hour 30 minutes), 2, 2.25 (2 hours 15 minutes), 3, 4, 8, 14, 24, 
and 48 hours after the start of study drug infusion.  The sponsor will determine if 
additional patients will give serial PK samples in Subset 1 based on ongoing review of 
accrued PK data, and the number of patients giving limited PK samples (Subsets 2 and 3 
below) will be reduced accordingly.  Note: PK Subset 1 will not be conducted in Israel. 
• PK Subset 2:  Approximately 40 patients (35%) will have limited PK samples collected 
at the following time points:  2.25 (2 hours 15 minutes), 3, 8, and 24 hours after the start 
of study drug infusion. 
• PK Subset 3:  Approximately 40 patients (35%) will have limited PK samples collected 
at the following time points:  2.25 (2 hours 15 minutes), 4, 8, and 24 hours after the start 
of study drug infusion. 
Permitted time windows are as follows: 
• ± 10 minutes around the samples at 0.5 and 1.5 hours after the start of infusion 
• ˗ 10 minutes before the sample at the end of infusion (the sample is to be drawn before 
the infusion is complete and can be obtained up to 10 minutes before the end of the 
infusion.  Note that if the sample is drawn after the infusion is complete in error, it is still 
to be collected and the exact clock time should be recorded). 
• ± 10 minutes around the samples at 2.25, 3, and 4 hours after the start of infusion 
• ± 1 hour around the sample at 8 hours after the start of infusion 
• ± 2 hours around the samples at 14 and 24 hours after the start of infusion. 
• ± 4 hours around the sample at 48 hours after the start of infusion. 
PK parameters of CF-301 will be assessed from patients with serial PK sampling, including 
maximum plasma concentrations (Cmax), time to Cmax (Tmax), elimination half-life (T1/2), 
clearance (CL), volume of distribution (Vz), and area under the curve (AUC0-t and AUC0-∞). 
12.18. 
Pharmacodynamic Assessments 
The PK/PD parameters include AUC0-24hr/minimum inhibitory concentration (MIC), Cmax/MIC, 
and %Time > MIC over a 24-hour period.  PK/PD parameters will be calculated for patients who 
have MICs available. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
74 
 
 
  
 
12.19. 
DSMB 
An independent DSMB will review accruing safety, tolerability, immunogenicity, and PK data in 
an unblinded manner throughout the study, as detailed in the DSMB charter.  The Sponsor and 
study staff will remain blinded throughout the study.  The DSMB will conduct an initial 
unblinded review of safety, tolerability, and PK data after approximately 17 patients have PK 
data available (approximately 10 patients on CF-301 and approximately 7 patients on placebo).  
After the first approximately 17 patients have received the CF-301 0.25 mg/kg or placebo single 
2-hour infusion and have PK data available, the DSMB will assess the exposures in this initial 
group of patients, as detailed in the DSMB Charter.  If the mean exposure to CF-301 is 
significantly lower (e.g., by > 25%) or higher than the mean exposure in healthy volunteers in 
Study CF-301-101 dosed at 0.25 mg/kg (i.e., the target safe and efficacious exposure), then the 
DSMB may recommend dose adjustment of CF-301 to achieve the planned exposure target that 
was established to be safe and is expected to be efficacious (refer to Section 7.1.5 for toxicology 
data and animal PK/PD data).  Additional DSMB reviews are described in the DSMB charter.  
Enrollment will not be halted during the conduct of DSMB reviews.  No formal efficacy analyses 
will be conducted at the time of these reviews; however, descriptive summary tables of key 
efficacy endpoints may be provided to support assessment of benefit/risk.  If analyses by the 
DSMB support further dose reductions or dose increases up to 0.4 mg/kg based on accrued PK 
exposure data in specific patient demographic groups, these will be described in Administrative 
Amendments or Clarification Letters to the protocol.  If the accrued PK data suggest the need for 
an increase in dose above the 0.4 mg/kg dose defined in the original protocol, then a protocol 
amendment will be issued. 
12.20. 
Adjudication Committee 
An independent blinded Adjudication Committee will adjudicate the Day 7 diagnosis, and this 
adjudicated diagnosis will be considered the final diagnosis to be used for the analysis.  In 
addition, clinical response and re-infection will be assessed by the Adjudication Committee at 
predefined intervals.  The efficacy analysis of clinical response and re-infection will be based on 
the Adjudication Committee’s assessment.  The role of the Adjudication Committee and 
procedures for adjudication are described in the Adjudication Committee Charter. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
75 
 
 
  
 
13. 
TREATMENT OF PATIENTS 
13.1. 
Description of Study Drugs 
CF-301 will be provided as a sterile injectable solution in 10 mL vials.  Each vial will contain 
4.0 mL of CF-301 (10 mg/mL), as described in Table 9.  Study drug will be labeled in 
accordance with regulatory requirements. 
Table 9: 
CF-301 Description 
Product Name: 
CF-301 
Chemical Name 
C1149H1768N324O357S3 
Dosage Form: 
Sterile injectable solution 
Unit Dose: 
4.0 mL (10 mg/mL) in 10 mL vials; 
0.25 mg/kg dose and 0.12 mg/kg dose (See Section 9.4) 
Route of Administration: 
Intravenous infusion over 2 hours 
Physical Description: 
Clear colorless solution 
Manufacturer: 
Emergent BioSolutions 
 
Material 
Function of Component 
CF-301 
Active Ingredient 
Water for Injection 
Solvent 
L-Histidine 
Buffer 
D-Sorbitol 
Stabilizer 
Placebo will be provided as a sterile injectable solution in 10 mL vials. Each vial will contain 
4.0 mL of placebo.  The composition of the placebo is shown in Table 10.  The placebo 
formulation is equivalent to the drug product formation minus the active pharmaceutical 
ingredient (CF-301).  Placebo is similar in appearance to CF-301. 
Table 10: 
Placebo Description 
Material 
Function of Component 
Water for Injection 
Solvent 
L-Histidine 
Buffer 
D-Sorbitol 
Stabilizer 
13.2. 
Dosage and Dose Regimen 
The dosage and dose regimen for study drug and SOC is described in Section 9.4. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
76 
 
 
  
 
13.3. 
Study Drug Preparation and Administration 
 
The CF-301 or placebo study drug will be prepared by a pharmacist or study staff designated by 
the Investigator.  CF-301 and placebo are similar in appearance, but the CF-301 study drug 
and/or prepared infusion may contain small visible particles.  Therefore, the pharmacist/study 
staff responsible for preparing study drug will not be involved in any other study procedures or 
assessments.  Measures will be put into place (e.g., covering the infusion bag) to ensure the study 
staff administering the study drug are not unblinded.  Additional details are provided in a 
separate Pharmacy Manual. 
The specified dose and volume of CF-301 or placebo will be calculated for individual patients 
and diluted as specified in the Pharmacy Manual.  The patient’s weight at screening will be used 
to calculate the mg/kg dose of study drug.  If it is not possible to measure weight at screening, a 
recently available historical weight can be used. 
The IV infusion will be administered over 2 hours using an IV set with an in-line filter (0.2 or 
0.22 µm) with corresponding pump, as described in the Pharmacy Manual. 
Detailed instructions for study drug preparation and administration are provided in the Pharmacy 
Manual. 
13.4. 
Storage/Stability 
The CF-301 formulation must be stored at -20 (±5)°C in a controlled temperature monitored and 
locked area. 
The CF-301 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 some of the 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 the Study Monitor and open to inspection at any time by any 
applicable regulatory authorities. 
The Investigator or designee will be expected to collect and retain all used, unused, and partially 
used containers of study drug until the end of the study.  The Investigator or designee must 
maintain records that document: 
• investigational product delivery to the study site 
• the inventory at the site 
• use by each patient, including injection vials from each supply dispensed 
These records should include dates, quantities, batch/serial numbers (if available), and the unique 
code numbers (if available) assigned to the investigational product and study patients. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
77 
 
 
  
 
The investigational product must be used only in accordance with the protocol.  The Investigator 
will also maintain records adequately documenting that the patients were provided the study drug 
specified. 
Completed accountability records will be archived by the site.  At the completion of the study, 
the Investigator or designee will oversee shipment of any remaining study drug back to 
ContraFect or ContraFect’s designee or destruction according to institutional standard operating 
procedures.  If local procedures mandate site destruction of investigational supply, prior written 
approval must be obtained from ContraFect.  If drug is destroyed locally, a certificate of 
destruction will be provided to ContraFect or designee. 
13.6. 
Prior and Concomitant Medications 
All medications taken within 28 days before randomization and through the EOT will be 
recorded, and only antibacterial medications or medications to treat adverse events will be 
recorded after EOT through TOC. 
13.7. 
Prohibited Medications 
Patients who received treatment with dalbavancin or oritavancin for the current infection are 
excluded from the study.  Note: patients who are receiving teicoplanin, linezolid, telavancin, 
ceftaroline fosamil, and/or sulfamethoxazole/trimethoprim are eligible for the study provided 
that treatment is switched to an appropriate SOC antibacterial agent (SOC agents include 
daptomycin and vancomycin for MRSA and semi-synthetic penicillins [e.g., nafcillin, oxacillin, 
cloxicillin, flucloxacillin] and first-generation cephalosporins [e.g., cefazolin] for MSSA. 
Patients who participated or plan to participate in an interventional investigational drug, device, 
or diagnostic trial within 30 days prior to or during the study are excluded from the study.  In 
addition, patients who previously received CF-301 are excluded. 
All medications for the health and welfare of the patient are permitted. 
The manufacturer’s prescribing information for the SOC antibacterial therapy should be 
consulted for information regarding any concomitant medication restrictions. 
13.8. 
Treatment Compliance 
Study drug (CF-301 or placebo) will be administered to hospitalized patients by study site 
personnel. 
13.9. 
Randomization and Blinding 
Patients will be assigned to receive CF-301 or placebo in a 3:2 ratio via the IWRS.  Patients 
randomized into the study will be assigned the treatment corresponding to the next available 
number in the computer-generated randomization schedule.  A patient is considered randomized 
when the IWRS randomization transaction is recorded regardless of whether the patient actually 
receives study drug. 
This is a double-blind study.  Study site personnel will be blinded to treatment group. A 
pharmacist not associated with the operational conduct of the study will prepare the study 
medication for infusion, as described in Section 13.3. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
78 
 
 
  
 
An independent DSMB will review data in an unblinded manner, as described in Section 12.18 
and the DSMB charter.  The Sponsor, study staff, and Adjudication Committee will be blinded to 
treatment group. 
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, may the PI unblind a patient’s treatment 
assignment.  Prior to any unblinding, the PI 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 PI must notify the Sponsor if the blind is broken for any reason and the PI was 
unable to contact the Sponsor prior to unblinding.  The PI will record in source documentation 
the date and reason for revealing the blinded treatment assignment for that patient. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
79 
 
 
  
 
14. 
ADVERSE AND SERIOUS ADVERSE EVENTS 
14.1. 
Definition of Adverse Events 
14.1.1. 
Adverse Event (AE) 
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 adverse event 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: the clinical outcome of the disease under study 
is collected as an efficacy endpoint and an outcome of non-response is not an AE. 
• 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 
14.1.2. 
Serious Adverse Event (SAE) 
A serious adverse event 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 in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• 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. 
14.2. 
Timeframe for Collecting Adverse Events 
All AEs and SAEs will be collected during the core study, from the time of consent through 
TOC.  After completion of the core study, all SAEs will be collected during the long-term 
follow-up through Day 180.  For patients who are unable to return for the Day 180 visit, this 
information may be obtained via phone or email. 
14.3. 
Relationship to Study Drug 
The Investigator must make the determination of relationship to the investigational product for 
each AE (unrelated or related).  The Investigator should decide whether, in his or her medical 
judgment, there is a reasonable possibility that the event may have been caused by the 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
80 
 
 
  
 
investigational product.  If no valid reason exists for suggesting a relationship, then the AE 
should be classified as “unrelated.”  If there is any valid reason, even if undetermined, for 
suspecting a possible cause-and-effect relationship between the investigational product and the 
occurrence of the AE, then the AE should be considered “related.” 
14.4. 
Study Endpoints 
Study endpoints of efficacy non-response would not ordinarily be reported as AEs.  Serious AEs 
with an outcome of death which are a component of a study endpoint (e.g., all-cause mortality) 
must be reported as SAEs. 
14.5. 
Grading of Adverse Events 
The severity (or intensity) of each AE will be assessed 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 14.1.2 above).  Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations. 
14.6. 
Events of Clinical Interest 
Any AE that results in stopping of the study drug infusion is considered an event of clinical 
interest and must be reported within 24 hours. 
14.7. 
Overdose 
An overdose occurs if a patient has taken, accidentally or intentionally, study drug in a dose 
exceeding that prescribed by the protocol.  An overdose (and any associated AE) must be 
reported within 24 hours of the site becoming aware of the overdose. 
14.8. 
Pregnancy 
Female patients who become pregnant during the core study should be immediately discontinued 
from the study and followed to determine the outcome of the pregnancy.  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 should notify the 
sponsor.  At the completion of the pregnancy, the investigator will document the outcome of the 
pregnancy.  If the outcome of the pregnancy meets the criteria for immediate classification as an 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
81 
 
 
  
 
SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly), the investigator should follow the procedures for reporting an SAE. 
14.9. 
Unexpected Adverse Event 
An AE is considered “unexpected” if the nature of the AE is not consistent with what is listed in 
the Investigator’s Brochure (IB).  Reports which add significant information on specificity or 
severity of a known, already documented serious adverse drug reaction constitute unexpected 
events.   
EXAMPLES:  hepatic necrosis would be unexpected (by virtue of greater severity) if the IB 
referred only to elevated hepatic enzymes or hepatitis.  Similarly, cerebral thromboembolism and 
cerebral vasculitis would be unexpected (by virtue of greater specificity) if the investigator’s 
brochure listed only cerebral vascular accidents. 
14.10. 
Suspected Unexpected Adverse Drug Reaction (SUSAR) 
An AE associated with the use of the study drug which is serious, unexpected, and study drug 
related. 
14.11. 
SAE Reporting 
All SAEs must be reported within 24 hours of the site becoming aware of the SAE.  SAEs are 
reported through the electronic data capture (EDC) system or backup paper SAE report form.  
The SAE report should provide as much of the required information as is available at the time.  
The following minimum information is required for reporting an SAE: patient identification, 
reporting source, causality, and an event outcome. 
Other procedural and contact details on SAE reporting will be described in the SAE completion 
guidelines which will be available to the Investigator.  Any event that is serious, study drug 
related, and unexpected as assessed by the medical monitor or the sponsor will be submitted to 
the regulatory authorities and in accordance with national regulatory laws and regulations.  The 
Investigator will be responsible for reporting all SAEs that require reporting to the local IRB/IEC 
in accordance with its regulations and guidelines. 
Investigators will be notified of all unexpected, serious, drug-related events (7/15 Day Safety 
Reports) that occur during the clinical trial.  Each site is responsible for notifying its IRB or IEC 
of these additional SAEs. 
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, 
stabilization occurs (the investigator does not expect any further improvement or worsening of 
the event), or the event is otherwise explained, regardless of whether the patient is still 
participating in the study.  All appropriate therapeutic measures should be undertaken and 
recorded.  Where appropriate, medical tests and examinations will be performed to document 
resolution of the event(s). 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
82 
 
 
  
 
15. 
STATISTICS 
A Statistical Analysis Plan (SAP) will be prepared and finalized before database lock and 
unblinding of the Core Study, and analyses of data.  Descriptive statistics, including the numbers 
and percentages for categorical variables, and the numbers, means, standard deviations (SD), 
medians, minimums, and maximums for continuous variables will be provided by treatment 
group.  Exploratory analyses may also be performed.  Listings of individual patient’s data will be 
produced. 
15.1. 
Analysis Populations 
The analysis populations are: 
• The Intent-to-Treat (ITT) Population includes all randomized patients regardless of whether 
or not the patient received study drug (CF-301 or placebo). 
• The Safety Population includes all patients who receive any amount of study drug (CF-301 or 
placebo). 
• The Microbiological Intent-to-Treat (mITT) Population includes all patients who: 
1. Had documented S. aureus BSI and/or endocarditis based on a blood culture collected 
within 72 hours of randomization and  
2. Received any amount of study drug. 
The mITT population is the primary analysis population for the efficacy analyses. 
• The Clinically Evaluable (CE) Population includes all patients who: 
1. Have confirmed clinical diagnosis of S. aureus BSI and/or endocarditis 
2. Received adequate course of antibacterial therapy, as defined in SAP. 
3. Have sufficient information to determine clinical outcome at the visit (i.e., not 
indeterminate). 
4. Have no additional confounding factors, as described in the SAP. 
• The Microbiologically Evaluable (ME) Population includes all patients who are in the mITT 
and CE Population and: 
1. For Day 7 and Day 14 only: Had a culture performed at the visit. 
• The PK Population includes all randomized patients who provide PK samples. 
15.2. 
Patient Population and Characteristics 
Enrollment, protocol deviations, and discontinuations from the study drug and the study will be 
summarized by treatment group.  Demographics, medical and surgical history, baseline 
assessment of signs and symptoms of S. aureus BSI/endocarditis, BSI risk factors, diagnosis, 
APACHE II score, microbiological assessment and study drug administration will be 
summarized by treatment group. 
15.3. 
Safety Analysis 
Safety will be evaluated by presenting summaries of treatment emergent AEs (TEAEs), clinical 
laboratory evaluations (biochemistry, hematology, coagulation, and urinalysis), vital signs (blood 
pressure, respiratory rate, heart rate, and temperature) and ECGs.  Abnormal physical 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
83 
 
 
  
 
examination results will be recorded as AEs.  A treatment emergent AE is one that occurs on or 
after the first dose of study drug through TOC.  Safety analyses will be conducted in the Safety 
Population and subjects will be analyzed according to the treatment actually received. 
Adverse events will be coded using the Medical Dictionary of Regulatory Activities.  The 
incidence of TEAEs will be presented by system organ class (SOC) and preferred term (PT), by 
SOC, PT and relationship to study drug, and by SOC, PT and severity.  Serious AEs and TEAEs 
that lead to discontinuation of the study drug will also be presented by SOC and PT. 
Descriptive statistics for clinical laboratory, vital signs and ECG parameters, including change 
from baseline, will be presented by time point collected and for the overall most abnormal post-
baseline value.  Incidences of potentially clinically significant (meeting predefined criteria 
specified in the SAP) clinical laboratory results, vital signs and ECG parameters will also be 
summarized by time point collected and the overall most abnormal post-baseline value. 
15.4. 
Efficacy Analysis 
For all efficacy analyses, patient data will be summarized in the group to which the patient was 
randomized.  The primary efficacy outcome is clinical improvement or response at Day 14 after 
CF-301/placebo administration in the mITT Population.  The number and percentage of patients 
with an improvement/response, no response, and indeterminate will be determined by treatment 
group.  Exact 2-sided 95% confidence intervals for the point estimates of the clinical 
improvement/response rates in each treatment group will be determined using the Clopper-
Pearson method.  The clinical improvement/response rate will be compared between the 
treatment groups using Fisher's exact test.  Statistical significance will be based on a two-sided 
alpha level of 0.05. 
The number and percentage of patients with a clinical outcome of improvement/response, no 
response, and indeterminate will be determined by treatment group at Day 7 after 
CF-301/placebo administration, at EOT, and at TOC in the mITT Population.  Exact 2-sided 
95% confidence intervals for the point estimates of the clinical improvement/response rates in 
each treatment group will be determined using the Clopper-Pearson method.  Statistical 
comparisons between the treatment groups will be conducted using Fisher's exact test and 
p-values will be provided as explorative statistics. 
The number and percentage of patients with a microbiological response of clearance of 
bacteremia, ongoing bacteremia, and indeterminate will be determined by treatment group at 
Days 7 and 14 after CF-301/placebo administration in the mITT Population.  The number and 
percentage of patients with a microbiological outcome of eradication/presumptive eradication, 
persistence/presumptive persistence, and indeterminate will be determined by treatment group at 
EOT and TOC in the mITT Population.  Exact 2-sided 95% confidence intervals for the point 
estimates of the clearance of bacteremia or microbiological eradication/presumptive eradication 
rates in each treatment group will be determined using the Clopper-Pearson method.  Statistical 
comparisons between the treatment groups will be conducted using Fisher's exact test and 
p-values will be provided as explorative statistics. 
Additional exploratory efficacy analyses will be conducted to support the efficacy findings for 
the primary and secondary outcomes.  Kaplan-Meier methods will be utilized to determine the 
time to clearance of bacteremia and time to defervesence in the mITT Population.  Time to 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
84 
 
 
  
 
clearance of bacteremia will be defined as the date/time from study drug administration to the 
date/time of the first negative blood culture of the two negative blood cultures taken on 
2 consecutive days.  Time to defervesence will be determined only in those patients who had a 
fever at baseline and will be defined as the date/time from study drug administration to the 
date/time of the first oral temperature equivalent < 38.0°C (< 100.4°F) using the highest 
temperature value on a given day.  For both time to clearance of bacteremia and time to 
defervesence, patients whose SOC for BSI was changed by adding a SOC antibacterial agent, 
switching to a different SOC antibacterial agent, or increasing the dose of SOC due to 
persistence, worsening, or recurrence of S. aureus BSI, died prior to clearance of 
bacteremia/defervesence or withdrew from the study prior to clearance of 
bacteremia/defervesence will be censored at the date/time of the SOC change, death or study 
withdrawal, respectively.  
All-cause mortality through TOC in the ITT Population and microbiological relapse at EOT, 
TOC, and Day 180 in the mITT Population will be summarized by treatment group. Exact 
2-sided 95% confidence intervals for the point estimates of all-cause mortality and 
microbiological relapse in each treatment group will be determined using the Clopper-Pearson 
method.   
Clinical improvement (Day 7 and Day 14), clinical response (EOT and TOC), clearance of 
bacteremia (Day 7 and Day 14) and microbiological eradication/presumed eradication (EOT and 
TOC) will be summarized separately for patients with MSSA and MRSA in the mITT 
population. Exact 2-sided 95% confidence intervals for the point estimates will be determined 
using the Clopper-Pearson method. 
Additional exploratory analyses will be described in the SAP. 
15.5. 
Pharmacokinetic Analysis 
Data collected from Subset 1 will be used to determine the following PK parameters:  Cmax, Tmax, 
T1/2, CL, Vz, AUC0-t, and AUC0-∞.  These values along with the listings for plasma 
concentrations from all 3 subsets (Subsets 1 to 3) will be reported in the Clinical Study Report 
(CSR). 
All PK data collected in this study (Subsets 1, 2, and 3) will be pooled with the PK data collected 
from the previous Phase 1 study (Protocol CF-301-101) to update the previously developed 
population PK model; this will be reported in a separate report, which will include the target 
attainment analysis.  The population PK and target attainment analyses will be described in a 
separate analysis plan. 
15.6. 
Pharmacodynamics Analysis 
PK/PD analysis will be conducted to determine the AUC0-24hr/MIC, Cmax/MIC, and %Time > 
MIC ratios.  PK/PD parameters of CF-301 will be calculated for patients who have MICs 
available.  Exposure response will be evaluated for efficacy and safety endpoints and will be 
detailed in a separate analysis plan (as described above in the Section 15.5). 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
85 
 
 
  
 
15.7. 
Handling of Missing Data 
For the primary and secondary efficacy outcomes, patients with missing data are assigned a 
response of indeterminate.  In the mITT population, indeterminate outcomes are included in the 
denominator for the calculation of the outcome rate.  Thus, a response of indeterminate is 
analyzed the same as a response of non-response or failure for the clinical outcome or ongoing 
bacteremia or persistence/presumed persistence for microbiological outcome. 
Handling of other missing data will be described in the SAP.   


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
86 
 
 
  
 
16. 
DATA MANAGEMENT 
16.1. 
Data Collection 
The investigative site will be provided electronic case report forms (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 should be consistent with the 
source documents or the discrepancies should be explained. 
The Investigator will be responsible for reviewing all data and eCRF entries and will verify that 
the information is true and correct. 
Patient data should be entered into the eCRF and be ready for review as soon as possible, but no 
later than 5 days after each visit/time point. 
16.2. 
Access to Source Documents 
Qualified representatives of ContraFect designees (“Study Monitors”) 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 CRFs 
• 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 CRFs and office, hospital, and 
laboratory records supporting the participation of each patient in the study.  The CRFs and other 
documentation supporting the study must be kept up-to-date by the Investigator and the 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’s 
requirements. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
87 
 
 
  
 
17. 
ADMINISTRATIVE 
17.1. 
Statement of Good Clinical Practices 
This trial will be conducted in adherence to the study protocol, Good Clinical Practices (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 in 
and 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 is to notify the IRB/IEC in 
writing of the study’s completion or early termination, and send a copy of the notification to 
ContraFect or CRO and retain one copy for the site study regulatory file, called the On Site 
Study File (OSF). 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
88 
 
 
  
 
18. 
QUALITY CONTROL AND ASSURANCE 
18.1. 
Sponsor Audits 
During the study, individuals from ContraFect’s Quality Assurance department and/or their 
authorized representatives 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 to arrange a 
convenient time for this visit.  The Investigator and staff are expected to cooperate with the 
auditors and allow access to all patient records supporting the CRFs 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 CRFs and other study-related documents.  The Investigator must immediately notify 
ContraFect when contacted by any regulatory authority for purposes of conducting an inspection. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
89 
 
 
  
 
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 the ICH E6 GCP, 
and/or local laws, whichever provides the greatest level of protection for the study participants.  
The protocol and any information supplied to the patient to obtain informed consent, including 
written ICF(s), patient recruitment procedures (e.g., advertisements), and written information to 
be provided to patients (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, 
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 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. 
When 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 submit a final report to the 
IRB/IEC and to ContraFect. 
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. 
19.2. 
Informed Consent 
Preparation of the informed consent form (ICF) is the responsibility of the Investigator and 
ContraFect or designee and must include all elements required by the 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. 
A master study-specific template will be used to prepare the ICF.  ContraFect or designee must 
review and approve all changes to site-specific ICFs. 
The ICF must include a statement that ContraFect or designee and regulatory authorities have 
direct access to patient records.  Prior to the beginning of the study, the Investigator must have 
the IRB/IECs written approval/favorable opinion of the written ICF and any other information to 
be provided to the patient. 
Before undergoing screening, each patient must consent in writing to study participation.  If the 
patient is not able to provide informed consent, he/she can be enrolled according to local 
regulatory requirements (Section 12.1).  The patient (or representative) will sign and date the 
ICF.  The person rendering consent will also sign and date the ICF as the person who obtained 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
90 
 
 
  
 
the consent of the patient.  The original signed ICF will be retained with the study center’s 
records.  Each patient will receive a copy of his or her signed ICF. 
19.3. 
Data Privacy 
Applicable data privacy laws and regulations must be adhered to.  The Investigator and 
ContraFect are responsible for ensuring that sensitive information is handled in accordance with 
local requirements (e.g., Health Insurance Portability and Accountability Act [HIPAA]). 
Appropriate consent and authorizations for use and disclosure and/or transfer (if applicable) of 
protected information must be obtained. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
91 
 
 
  
 
20. 
RECORD KEEPING/RETENTION OF RECORDS 
The Investigator must ensure that all records pertaining to the conduct of the clinical study, ICFs, 
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 CRF 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 will retain the original CRF 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 records will be kept in 
a locked file cabinet.  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 local data protection laws. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
92 
 
 
  
 
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.  If necessary, the 
authorities will be notified of the Investigator’s name, address, qualifications, and extent of 
involvement. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
93 
 
 
  
 
22. 
LIST OF REFERENCES 
Anantha RV, Jegatheswaran J, Pepe DL, et al. Risk factors for mortality among patients with 
Staphylococcus aureus bacteremia: a single-centre retrospective cohort study. CMAJ Open 2014; 
2:E352. 
Baddour LM, Wilson WR, Bayer AS, et al. Infective Endocarditis in Adults: Diagnosis, 
Antimicrobial Therapy, and Management of Complications, a Scientific Statement for Healthcare 
Professionals From the American Heart Association. Circulation. 2015;132:1435-86. 
Bayer AS, Schneider T, and Sahl H-G. Mechanisms of daptomycin resistance in Staphylococcus 
aureus: role of the cell membrane and cell wall. Ann N Y Acad Sci. 2013 Jan; 1277 (1): 139-158. 
Centers for Disease Control (CDC). Antibiotic resistance threats in the United States: 2013.  
http://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf. Accessed 21 Dec 2015. 
Chang FY, MacDonald BB, Peacock JE Jr, et al. A prospective multicenter study of Staphylococcus 
aureus bacteremia: incidence of endocarditis, risk factors for mortality, and clinical impact of 
methicillin resistance. Medicine (Baltimore) 2003; 82:322. 
Chu VH, Cabell CH, Benjamin DK Jr, et al. Early predictors of in-hospital death in infective 
endocarditis. Circulation 2004; 109:1745. 
Cooper HA, Thompson EC, Laureno R, et al. Subclinical brain embolization in left-sided infective 
endocarditis: results from the evaluation by MRI of the brains of patients with left- sided intracardiac 
solid masses (EMBOLISM) pilot study. Circulation 2009; 120:585. 
Cosgrove S, Sakoulas G, Perencevich EN et al. Comparison of Mortality Associated with 
Methicillin-Resistant and Methicillin- Susceptible Staphylococcus aureus Bacteremia: A Meta-
analysis. Clin Infect Disease 2003 Jan 1;36: 56-59. 
Czock D, Frieder K, and Seidling HM. Pharmacokinetic predictions for patients with renal 
impairment: focus on peptides and protein drugs. Br J Clin Pharmacol. 2012 Jul;74(1):66-74.  
Dantes R, Mu Y, Belflower R et al. National Burden of Invasive Methicillin-Resistant 
Staphylococcus aureus Infections, United States, 2011. JAMA Intern Med. 2013;173(21):1970-1978. 
El-Ahdhab F, Benjamin DK Jr, Wang A, et al. Risk of endocarditis among patients with prosthetic 
valves and Staphylococcus aureus bacteremia. Am J Med 2005; 118:225. 
Finkelman, F. D. Anaphylaxis: lessons from mouse models. The Journal of Allergy and Clinical 
Immunology, 2007;120(3), 506–15. 
Fowler VG, Jr., Boucher HW, Corey GR, Abrutyn E, Karchmer AW, Rupp ME, et al. Daptomycin 
versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J 
Med 2006;355(7):653-65. 
Fowler VG, Jr., Miro JM, Hoen B, Cabell CH, Abrutyn E, Rubinstein E, et al. Staphylococcus aureus 
endocarditis: a consequence of medical progress. JAMA. 2005;293(24):3012-21. 
Fowler VG Jr, Justice A, Moore C, et al. Risk factors for hematogenous complications of 
intravascular catheter-associated Staphylococcus aureus bacteremia. Clin Infect Dis 2005; 40:695. 
Fowler VG Jr, Olsen MK, Corey GR, et al. Clinical identifiers of complicated Staphylococcus aureus 
bacteremia. Arch Intern Med 2003; 163:2066. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
94 
 
 
  
 
García-Cabrera E, Fernández-Hidalgo N, Almirante B, et al. Neurological complications of infective 
endocarditis: risk factors, outcome, and impact of cardiac surgery: a multicenter observational study. 
Circulation 2013; 127:2272. 
Habib G, Badano G, Tribouilloy C, Vilacosta I, Zamorano JL. Recommendations for the practice of 
echocardiography in infective endocarditis. European Journal of Echocardiography 2010; 11:202–
219. 
Habib G, Lancellotti P, Antunes MJ, et al. The Task Force for the Management of Infective 
Endocarditis of the European Society of Cardiology (ESC). European Heart Journal 2015; 36:3075–
3123. 
Hasbun R, Vikram HR, Barakat LA, et al. Complicated left-sided native valve endocarditis in adults: 
risk classification for mortality. JAMA 2003; 289:1933. 
Hill EE, Herijgers P, Claus P, et al. Infective endocarditis: changing epidemiology and predictors of 
6-month mortality: a prospective cohort study. Eur Heart J 2007; 28:196. 
Ishimitsu T, Nishikimi T, Saito Y et al. Plasma Levels of Adrenomedullin, a Newly Identified 
Hypotensive Peptide, in Patients with Hypertension and Renal Failure. J Clin Invest. 1994 
Nov;94(5): 2158–61.  
Khatib R, Johnson LB, Fakih MG, et al. Persistence in Staphylococcus aureus bacteremia: Incidence, 
characteristics of patients and outcome. Scandinavian Journal of Infectious Diseases. Published 
online 2006 Jul;38:1, 7-14. 
Kim SH, Kim KH, Kim HB, et al. Outcome of vancomycin treatment in patients with methicillin-
susceptible Staphylococcus aureus bacteremia. Antimicrob Agents Chemother 2008; 52:192. 
Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease 
classification system" Critical Care Medicine. 1985;13(10);818–29. 
Liu C, Bayer A, Cosgrove SE et al. IDSA Guidelines: Clinical Practice Guidelines by the Infectious 
Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus Aureus 
Infections in Adults and Children. Clinical Infectious Diseases; 2011;1-38. 
Lodise TP, Graves J, Evans A, et al. Relationship between vancomycin MIC and failure among 
patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin. 
Antimicrob Agents Chemother 2008; 52:3315. 
López -Cortés LE, Del Toro MD, Gálvez-Acebal J, et al. Impact of an evidence-based bundle 
intervention in the quality-of-care management and outcome of Staphylococcus aureus bacteremia. 
Clin Infect Dis 2013; 57:1225. 
Louie A, Kaw P, Liu W, et al. 2001 Pharmacodynamics of Daptomycin in a Murine Thigh Modelof 
Staphylococcus aureus Infection. Antimicrobial Agents And Chemotherapy; Mar. 2001;45(3):845–
51. 
Maack T, Johnson V, Kau ST et al. Renal filtration, transport, and metabolism of low-molecular 
weight proteins: A review. Kidney International; 1979;16: 251-70. 
McConeghy KW, Bleasdale SC, Rodvold KA. The empirical combination of vancomycin and a β-
lactam for Staphylococcal bacteremia. Clin Infect Dis 2013; 57:1760. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
95 
 
 
  
 
Meibohm B and Zhou H. Characterizing the Impact of Renal Impairment on the Clinical 
Pharmacology of Biologics. Journal of Clinical Pharmacology; Jan 2012;52:0091-2700. 
Meier JJ, Nauck MA, Kranz D et al. Secretion, Degradation, and Elimination of Glucagon-Like 
Peptide 1 and Gastric Inhibitory Polypeptide in Patients with Chronic Renal Insufficiency and 
Healthy Control Subjects. Diabetes. 2004 Mar;53(3):654-62. 
Moise PA, Smyth DS, El-Fawal N, et al. Microbiological effects of prior vancomycin use in patients 
with methicillin-resistant Staphylococcus aureus bacteraemia. J Antimicrob Chemother 2008; 61:85. 
Rose WE, Rybak MJ, Kaatz GW. Evaluation of daptomycin treatment of Staphylococcus aureus 
bacterial endocarditis: an in vitro and in vivo simulation using historical and current dosing 
strategies. J Antimicrob Chemother 2007; 60:334. 
Ruttmann E, Willeit J, Ulmer H, et al. Neurological outcome of septic cardioembolic stroke after 
infective endocarditis. Stroke 2006; 37:2094. 
Simons FER, Ardusso LRF, Bilo MB, El-Gamal YM, Ledford DK, Ring J, et al. World Allergy 
Organization Anaphylaxis Guidelines: Summary. J Allergy Clin Immunol. 2011;127(3):587–93. e1-
e20. 
Snygg-Martin U, Gustafsson L, Rosengren L, et al. Cerebrovascular complications in patients with 
left-sided infective endocarditis are common: a prospective study using magnetic resonance imaging 
and neurochemical brain damage markers. Clin Infect Dis 2008; 47:23. 
Valente AM, Jain R, Scheurer M, et al. Frequency of infective endocarditis among infants and 
children with Staphylococcus aureus bacteremia. Pediatrics 2005; 115:e15. 
van Hal SJ, Jensen SO, Vaska VL, et al. Predictors of mortality in Staphylococcus aureus 
Bacteremia. Clin Microbiol Rev 2012; 25:362. 
Wallace SM, Walton BI, Kharbanda RK, et al. Mortality from infective endocarditis: clinical 
predictors of outcome. Heart 2002; 88:53. 
Wang A, Athan E, Pappas PA, et al. Contemporary clinical profile and outcome of prosthetic valve 
endocarditis. JAMA. 2007;297(12):1354-1361. 
Wisplinghoff H, Bischoff T, Tallent SM, et al. Nosocomial bloodstream infections in US hospitals: 
analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 2004; 
39:309. 
World Health Organization. Antimicrobial resistance: global report on surveillance. 2014.  
http://apps.who.int/iris/bitstream/10665/112642/1/9789241564748_eng.pdf. Accessed 21 Dec 2015. 
 
 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
96 
 
 
  
 
23. 
APPENDICES 
23.1. 
Appendix 1: Diagnosis Definitions 
The investigator will determine diagnosis at screening and on Day 7 to determine SOC treatment 
duration.  An independent blinded Adjudication Committee will adjudicate the Day 7 diagnosis, 
and this adjudicated diagnosis will be considered the final diagnosis to be used for the analysis.  
The diagnosis definitions that will be used by the investigator and Adjudication Committee are 
provided in the table below. 
Diagnosis 
Definition 
S. aureus 
endocarditis 
Definite or possible endocarditis based on the Modified Duke Criteria (Li, et al. 
2000), as defined below. 
 
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 for endocarditis:  
a. S. aureus (in the absence of a primary focus) identified from 2 separate 
blood cultures 
b. Microorganisms consistent with endocarditis 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 infective endocarditis 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 endocarditis, such as predisposing heart condition, or 
intravenous drug use 
2. Fever, defined as oral temperature equivalent > 38.0°C (> 100.4°F) 
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 
 
Left-sided endocarditis: involvement of mitral and/or aortic valve 
Right-sided endocarditis: involvement of pulmonic and/or tricuspid value 
Left- and right-sided endocarditis: involvement of mitral and/or aortic valve AND 
pulmonic and/or tricuspid value 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
97 
 
 
  
 
Complicated 
S. aureus BSI 
• 
Patient did not have endocarditis based on the Modified Duke Criteria; and 
• 
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 
Signs or symptoms of catheter-related infection with clots in the vein at the 
catheter site seen on ultrasound 
o 
Signs or symptoms of metastatic foci of infection (e.g., deep tissue abscess, 
septic pulmonary emboli) or hematogenous seeding (e.g., septic arthritis) 
confirmed by physical examination, imaging, or culture 
o 
S. aureus isolated from sterile body site other than blood  
o 
Persistent fever (oral temperature equivalent ≥ 38.0°C [≥ 100.4°F]) at 
72 hours or more after the initial blood culture 
o 
Skin examination findings suggesting the presence of acute systemic 
infection (e.g., presence of ecchymosis, infarcts, petechiae, pustules, or 
vasculitis) 
o 
Met criteria for severe sepsis or septic shock during the time of 
diagnosis/presumptive diagnosis of bacteremia 
 
Severe sepsis defined as a documented or presumed infection 
associated with either organ dysfunction, hypoperfusion, or 
hypotension (systolic blood pressure < 90 mm Hg or a decrease of 
> 4 mm Hg from baseline systolic measure in the absence of other 
causes of hypotension) AND the presence of SIRS (defined in 
Section 10.1) 
 
Septic shock defined as persistent hypotension and perfusion 
abnormalities despite adequate fluid resuscitation or organ function 
not capable of maintaining homeostasis 
o 
Significantly immunocompromised: 
 
AIDS (HIV positive with an AIDS-defining condition or a CD4 
count < 200 cells/mm³) 
 
Severe leukopenia defined as ANC <500 cells/mL for > 3 days in 
the 7 days prior to the qualifying blood culture 
 
Post organ-transplantation including autologous bone marrow 
transplantation 
 
On treatment for active graft vs. host disease 
 
On immunosuppressive therapy (e.g., ≥ 15 mg of prednisone or 
equivalent for more than 5 days, biologics such as infliximab, 
monoclonal antibodies such as daclizumab, methotrexate, 
cyclophosphamide, or similar agents) 
 
On chemotherapy treatment 
Uncomplicated 
S. aureus BSIa 
• 
Patient did not have endocarditis 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 
a 
Patients with known or suspected uncomplicated S. aureus BSI are not eligible for the study.  The definition is included here 
in the event that patients are determined to have this diagnosis post-randomization. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
98 
 
 
  
 
23.2. 
Appendix 2: Apache II score 
Certain components of the Apache II score will be determined locally (including oxygenation, Glasgow Coma Scale, and chronic 
health points) and other components will be obtained from central laboratory data. 
Apache II Score Form 
HIGH ABNORMAL RANGE 
LOW ABNORMAL RANGE 
PHYSIOLOGIC VARIABLE 
+4  
+3 
+2 
+1 
0 
+1 
+2 
+3 
+4 
1 
Temperature rectal (oC)a 
>=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 
130-139 
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 
Hematocrit (%) 
>=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 
a 
The method of temperature collection will be recorded in the eCRF and will be converted in programming to rectal temperature equivalent for Apache II score calculation. 
 
Table continued on next page 
 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
99 
 
 
  
 
Apache II Score Form 
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 
  
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 =  
Source:  Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system" Critical Care 
Medicine. 1985;13(10);818–29. 
 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
100 
 
 
  
 
23.3. 
Appendix 3: Microbiological Sample Collection and Processing 
Patients who meet all screening criteria and have blood culture positive for S. aureus determined 
by rapid diagnostic or conventional method or Gram stain showing Gram-positive cocci in 
clusters plus positive tube coagulase test from blood culture specimens collected within 72 hours 
prior to randomization are eligible for the study. 
Two aerobic blood cultures preferably from 2 different sites will be collected at screening at least 
30 minutes apart and as close to the start of study drug dosing as possible, and at least one 
aerobic blood culture will be collected daily during the study until negative for 2 consecutive 
days and at Days 7 and 14 after CF-301/placebo administration.  Additional blood cultures will 
be performed as clinically indicated.  Cultures should be taken from a peripheral venipuncture 
site when possible using proper skin decontamination. 
Blood samples must be transported to the local microbiology laboratory as soon as possible and 
incubated within less than 24 hours of collection.  Each set (taken from different peripheral 
venipunctures) should be processed separately. 
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 labs are encouraged to utilize the direct tube 
coagulase test when available.  Patients may be enrolled if their Gram stain shows Gram-positive 
cocci in clusters and the direct tube coagulase test is positive after 4 hours of incubation. 
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, as listed in the table 
below. 
FDA cleared and CE-IVD Certified Rapid Diagnostic Tests for Detection of S. aureus 
Directly from Positive Blood Cultures 
Manufacturer 
Test Name 
Alere 
BinaxNOW S.aureus 
Biofire Diagnostics (BioMerieux Company) 
Film Array System and BCID Panel 
AdvanDX (OpGen Company) 
PNA QuickFISH and mecA XpressFISH 
Nanosphere 
Verigene 
Cepheid 
GeneXpert 
Miacom-MetaSystems 
hemoFISH Masterpanel 
Blood must be directly inoculated on non-selective agar medium (e.g. tryptic soy agar + 5% 
sheep blood) to confirm organism identification and purity.  Organisms must be isolated in pure 
culture and identified according to the local laboratory’s standard operating procedures.  Only 
S. aureus strains will be sent to the designated central microbiology laboratory for confirmation 
of identification and standardized susceptibility testing. 
Results of Gram stain, organism identification, and rapid diagnostic testing will be recorded on 
the CRF. 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
101 
 
 
  
 
Susceptibility Testing 
Susceptibility testing of S. aureus should 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 should test 
susceptibilities to daptomycin, vancomycin, and oxacillin or cefoxitin (CLSI recommended 
surrogate for oxacillin to detect MRSA). 
Results of susceptibility testing will be recorded on the CRF. 
Archiving and Shipment of Isolates 
All S. aureus strains will be stored frozen at -70°C in duplicate (in a non-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 central 
microbiology laboratory manual.  Backup isolates will remain in storage at the site until 
notification from ContraFect.  The sites local microbiology laboratory must maintain a shipment 
tracking log for each subject.  This log should contain the subject number, specimen collection 
date/time, local lab accession number, genus/species and date of shipment. 
 
 


Protocol CF-301-102-4 
Protocol Amendment #4 
 
June 22, 2018 
 
102 
 
 
  
 
23.4. 
Appendix 4: Central Laboratory Testing 
The following laboratory tests will be performed by central laboratories.  Only those laboratory 
tests required for eligibility screening will be performed by the local safety laboratory as 
described in Section 12.13. 
Hematology 
Serum 
Chemistry 
Coagulation 
Profile 
Urinalysis 
Immunologic 
Tests 
Pregnancy 
Exploratory 
Testing 
Pharmaco-
kinetics 
Hematocrit 
Albumin 
Prothrombin time 
(PT)/international 
normalized ratio 
(INR) 
Color and 
appearance 
CF-301-specific 
anti- drug 
antibody (ADA) 
Serum 
pregnancy 
test 
Future 
researchc 
PK 
samples for 
Subsets 1, 
2, and 3d 
Hemoglobin 
Alkaline 
phosphatase 
aPTT (activated 
partial 
thromboplastin 
time) 
pH and 
Specific 
Gravity 
CF-301-specific 
IgE 
 
 
 
Mean 
corpuscular 
hemoglobin 
(MCH) 
Alanine 
aminotransferase 
(ALT) 
 
Bilirubin 
Serum tryptase (in 
event of 
anaphylaxis; 
(Section 
11.2.3.1)b  
 
 
 
Mean 
corpuscular 
hemoglobin 
concentration 
(MCHC) 
Aspartate 
aminotransferase 
(AST) 
 
Glucose 
 
 
 
 
Mean 
corpuscular 
volume 
(MCV) 
Bicarbonate 
 
Ketones 
 
 
 
 
Platelet count 
Bilirubin – total, 
direct, indirect 
 
Leukocytesa 
 
 
 
 
Red blood cell 
(RBC) 
distribution 
width 
Blood urea 
nitrogen (BUN) 
 
Nitrite 
 
 
 
 
RBC count 
Calcium 
 
Protein 
 
 
 
 
White blood 
cell (WBC) 
count 
Chloride 
 
Urobilinoge
n 
 
 
 
 
WBC 
differential (% 
and absolute) 
Creatinine 
 
 
 
 
 
 
Basophils 
Gamma-glutamyl 
transferase (GGT) 
 
 
 
 
 
 
Eosinophils 
Glucose 
 
 
 
 
 
 
Lymphocytes 
Lactate 
dehydrogenase 
 
 
 
 
 
 
Monocytes 
Phosphorus 
 
 
 
 
 
 
Neutrophils 
Potassium 
 
 
 
 
 
 
Immature 
neutrophils 
Sodium 
 
 
 
 
 
 
 
Total protein 
 
 
 
 
 
 
a. 
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, lukocyte esterase, nitrite. 
b. 
If the serum tryptase sample is positive or equivocal, the sample may also be tested for β-tryptase. 
c. 
Optional future research (e.g., cytokine and chemokine assays and/or biomarker evaluation).  Note: future use samples will 
NOT be collected from patients in Israel. 
d. 
PK Subset 1 will not be conducted in Israel.