Conditions: Acinetobacter Baumannii-calcoaceticus Complex Hospital-acquired Bacterial Pneumonia Ventilator-associated Bacterial Pneumonia Bacteremia Colistin Resistant ABC
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 207
Healthy volunteers: no

Brief summary:
This is a 2-part study, with Part A being the randomized, controlled portion of the study in patients with ABC hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), or bacteremia. Part B is the single-group portion of the study and includes ABC infections that are resistant to or have failed colistin or polymyxin B treatment, as detailed in the inclusion criteria.

Detailed description:

Arms:
arm 1: Part A was the pivotal, assessor-blind, randomized, comparative portion of the study in patients with documented ABC hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), ventilated pneumonia (VP), or bacteremia.

Part A - Group 1 (experimental): 1.0 g sulbactam/1.0 g durlobactam IV infused over 3 hours every 6 hours (q6h) plus 1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h arm 2: Part A - Group 2 (control group): 2.5 mg/kg colistin IV infused over 30 minutes every 12 hours (after an initial loading dose of colistin 2.5 to 5 mg/kg) plus 1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h. arm 3: Part B (Group 3) was the open-label, supportive portion of the study that included patients known to have HABP, VABP, VP, and/or bacteremia infections associated with ABC organisms resistant to colistin or polymyxin B, who failed a colistin or polymyxin B regimen prior to study entry or were on acute renal replacement therapy, and patients with infections due to colistin- or polymyxin B-resistant ABC with sources of infection other than HABP, VABP, VP, and/or bacteremia.

Part B - Group 3: 1.0 g ETX2514/1.0 g sulbactam IV infused over 3 hours q6h plus 1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h.

Interventions: intervention 1: Sulbactam intervention 2: Durlobactam intervention 3: Colistin intervention 4: Imipenem/Cilastatin 500 mg/500 mg
Intervention descriptions: intervention 1: 1.0 g sulbactam IV infused over 3 hours every 6 hours (q6h). intervention 2: 1.0 g durlobactam IV infused over 3 hours every 6 hours (q6h).

Sulbactam-Durlobactam: Treatment for 7 days up to 14 days if clinically indicated. intervention 3: Treatment for 7 days up to 14 days if clinically indicated. intervention 4: 1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h. Treatment for 7 days up to 14 days if clinically indicated.

Protocol document:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
A Randomized, Active-Controlled Study to Evaluate the Efficacy 
and Safety of Intravenous Sulbactam-ETX2514 in the Treatment of 
Patients With Infections Caused by Acinetobacter 
baumannii-calcoaceticus Complex 
Investigational Product: Sulbactam-ETX2514 (ETX2514SUL) 
Protocol Number: CS2514-2017-0004 
EudraCT Number: 2018-002526-23 
 
 
Entasis Therapeutics 
Gatehouse Park BioHub 
35 Gatehouse Drive 
Waltham, MA 02451 
United States 
Telephone: +1-781-810-0120 
Fax: +1-781-810-0122 
 
 
 
Version Number: 4.0 
Original Protocol: 10 December 2018 
Amendment 1: 29 April 2019 
Amendment 2: 14 January 2020 
Amendment 3: 17 December 2020 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Entasis Therapeutics except to the extent that disclosure would be required by law and 
for the purpose of evaluating and/or conducting a clinical study for Entasis Therapeutics. You 
are allowed to disclose the contents of this document only to your Institutional Review Board or 
Independent Ethics Committee and study personnel directly involved with conducting this 
protocol. Persons to whom the information is disclosed must be informed that the information is 
confidential and proprietary to Entasis Therapeutics and that it may not be further disclosed to 
third parties. 


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SIGNATURE PAGE 
STUDY TITLE: A Randomized, Active-Controlled Study to Evaluate the Efficacy and 
Safety of Intravenous Sulbactam-ETX2514 in the Treatment of Patients With Infections 
Caused by Acinetobacter baumannii-calcoaceticus Complex 
 
I, the undersigned, have read this protocol and agree that it contains all necessary information 
required to conduct the study. 
Signature 
 
 
 
 
 
 
 
Date 
 
Steven LaRosa, MD 
Vice President, Clinical Development 
Entasis Therapeutics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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INVESTIGATOR AGREEMENT 
By signing below I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by Entasis Therapeutics to study personnel under my supervision. I will discuss this material with 
them to ensure they are fully informed about the study product and study procedures. I will let 
them know that this information is confidential and proprietary to Entasis Therapeutics and that it 
may not be further disclosed to third parties. I understand that the study may be terminated or 
enrollment suspended at any time by Entasis Therapeutics, with or without cause, or by me if it 
becomes necessary to protect the best interests of the study patients. 
I agree to conduct this study in full accordance with Food and Drug Administration Regulations, 
Institutional Review Board/Ethic Committee Regulations and International Council for 
Harmonisation Guidelines for Good Clinical Practices. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 
  


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SYNOPSIS 
TITLE: A Randomized, Active-Controlled Study to Evaluate the Efficacy and Safety of 
Intravenous Sulbactam-ETX2514 in the Treatment of Patients With Infections Caused by 
Acinetobacter baumannii-calcoaceticus Complex 
PROTOCOL NUMBER: CS2514-2017-0004 
INVESTIGATIONAL PRODUCT: Sulbactam-ETX2514 (ETX2514SUL) 
PHASE: 3 
INDICATION(S): Treatment of serious infections caused by Acinetobacter baumannii
(A. baumannii)-calcoaceticus complex (ABC) 
OBJECTIVES: 
This is a 2-part study, with Part A being the randomized, controlled portion of the study in patients 
with ABC hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial 
pneumonia (VABP), ventilated pneumonia (VP), or bacteremia. Part B is the single-group portion 
of the study and includes ABC infections that are resistant to or have failed colistin or polymyxin B 
treatment, as detailed in the inclusion criteria. 
The primary objectives of this study are the following: 
 To compare the efficacy of ETX2514SUL plus imipenem/cilastatin to colistin plus 
imipenem/cilastatin in patients with carbapenem-resistant ABC (CRABC) infections in Part A; 
and 
 To compare the incidence of nephrotoxicity, as measured by the Risk–Injury–Failure–Loss–
End-stage renal disease (RIFLE) criteria, of ETX2514SUL to colistin in patients with ABC 
infections in Part A. 
The secondary objectives of this study are the following: 
 To compare the efficacy of ETX2514SUL plus imipenem/cilastatin to colistin plus 
imipenem/cilastatin in all randomized patients in Part A; 
 To evaluate the efficacy of ETX2514SUL plus imipenem/cilastatin in patients with colistin- or 
polymyxin B-resistant ABC infections in Part B;  
 To estimate the efficacy of ETX2514SUL plus imipenem/cilastatin for each primary infection 
site;  
 To evaluate and compare the safety of ETX2514SUL and colistin; 
 To describe the overall safety profile of ETX2514SUL; and 
 To determine the systemic exposure of ETX2514 and sulbactam in a small cohort of severely 
ill patients administered ETX2514SUL in Part A. 
 


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The exploratory objectives of this study are the following: 
 To evaluate the efficacy of ETX2514SUL in relation to pharmacokinetics (PK) exposure; 
 To evaluate the efficacy of ETX2514SUL in relation to minimum inhibitory concentration 
(MIC) distribution of ETX2514SUL; 
 To evaluate the efficacy of ETX2514SUL in relation to total duration of treatment received; 
and 
 To compare the resource utilization of patients receiving ETX2514SUL plus 
imipenem/cilastatin to patients receiving colistin plus imipenem/cilastatin. 
POPULATION: 
The population for this study is male and female patients 18 years of age with documented ABC 
infections. 
INCLUSION CRITERIA: 
General Inclusion Criteria: 
Patients who meet all of the following general inclusion criteria, in addition to the specific inclusion 
criteria listed below for Parts A and B, will be eligible to participate in the study: 
1. A signed informed consent form; 
Note: If a study patient is unable to provide informed consent due to their medical condition, 
the patient’s legally authorized representative may consent on behalf of the study patient, or 
the decision can be made according to the procedure permitted by local law and institutional 
Standard Operating Procedures. 
2. Male or female 18 years of age; 
3. A confirmed diagnosis of a serious infection and the expectation, in the judgment of the 
Investigator, that the patient’s infection will require treatment with intravenous (IV) antibiotics;
4. A known infection caused by ABC (bacteremia, HABP, VABP, VP, complicated urinary tract 
infection [cUTI] or acute pyelonephritis [AP], or surgical or post-traumatic wound infections) 
as either a single pathogen or member of a polymicrobial infection based on evidence from 
culture or, if available, rapid diagnostic test from a sample collected within 72 hours prior to 
randomization (HABP/VABP/VP patients), AND 1 of the following: 
a. Has received no more than 48 hours of potentially effective (ie, Gram negative 
coverage) antimicrobial therapy prior to the first dose of study drug; OR 
b. Is clinically failing prior treatment regimens (ie, clinical deterioration or failure to 
improve after at least 48 hours of antibiotic treatment); 
Note: Rapid testing of respiratory specimens utilizing Biofire® FilmArray® 2.0 Pneumonia 
Panel (BPP) technology should be used to enable early identification of ABC pneumonia. 
Patients can be randomized based on the results of the BPP rapid test while awaiting results of 
cultures from the local laboratory. However, if the respiratory sample does not grow ABC in 
the local microbiology laboratory culture, these patients will be withdrawn from the study drug 
treatment. 


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Note: Isolation of ABC from pleural effusion (empyema) is allowed, if concurrent pulmonary 
infiltrate is confirmed. 
5. Acute Physiology and Chronic Health Evaluation (APACHE) II score between 10 and 30, 
inclusive, OR Sequential Organ Failure Assessment (SOFA) score between 7 and 11, inclusive, 
at the time of diagnosis of infection. Patients who are not being treated in an intensive care unit 
and cannot have an APACHE II or SOFA score performed should have a quick SOFA (qSOFA) 
score 2 for enrollment; 
6. Expectation, in the judgment of the Investigator, that the patient will benefit from effective 
antibiotic therapy and appropriate supportive care for the anticipated duration of the study; and
7. Women of childbearing potential (ie, not post-menopausal or surgically sterilized) must have 
a negative highly sensitive urine or serum pregnancy test before randomization. Participating 
women of childbearing potential must be willing to consistently use one highly effective 
method of contraception (ie, condom, combined oral contraceptive, implant, injectable, 
indwelling intrauterine device, or a vasectomized partner) from Screening until at least 30 days 
after administration of the last dose of study drug. 
Part A-Specific Inclusion Criteria: 
In addition to the general inclusion criteria above, patients may enroll in Part A if they meet the 
criteria below. All patients must be categorized in 1 infection type that is judged to be the primary 
infection by the Investigator: 
1. Diagnosed with HABP, VABP, VP, and/or bacteremia, defined as: 
HABP With ABC in Sputum/Respiratory Sample 
All of the following: 
AND signs or symptoms evidenced 
by at least 2 of the following: 
AND at least 1 of the 
following: 
 
Onset of symptoms >48 hours 
after admission or 7 days after 
discharge from an inpatient 
acute or chronic care facility 
(eg, LTAC, rehabilitation 
center, hospital, or skilled 
nursing home); OR 
 
Admission from LTAC or 
rehabilitation center, or 
admission from home <7 days 
after discharge from an LTAC 
or rehabilitation center; AND 
 
New or evolving infiltrate on 
chest X-ray, MRI, CT scan, or 
ultrasound obtained within 
48 hours prior to randomization. 
Note: If an ultrasound is 
performed, a confirmatory 
X-ray or CT scan should be 
performed within 24 hours. 
 
A new onset of cough (or 
worsening of baseline cough); 
 
Auscultatory findings consistent 
with pneumonia/pulmonary 
consolidation (eg, rales, dullness 
on percussion, bronchial breath 
sounds, or egophony); 
 
Dyspnea, tachypnea, or 
respiratory rate 
>25 breaths/minute; OR 
 
Hypoxemia (oxygen saturation 
<90% or pO2 <60 mmHg while 
breathing room air, or worsening 
of the oxygen saturation/FiO2); 
OR the following ALONE: 
 
New onset need for mechanical 
ventilation. 
 
Fever [1] (oral or tympanic 
temperature 38°C 
[100.4°F] or rectal/core 
temperature 38.3°C 
[100.9°F]) OR 
hypothermia (rectal/core 
temperature <35°C 
[<95°F]); 
 
Elevated total peripheral 
WBC count (>10,000/mm3); 
 
>15% immature neutrophils 
(bands) regardless of total 
peripheral WBC count; OR 
 
Leukopenia (total WBC 
count <4500/mm3). 
1. 
Evidence of fever within 24 hours of the Screening Visit is acceptable if observed and documented by a healthcare 
provider. 
ABC = Acinetobacter baumannii-calcoaceticus complex; CT = computed tomography; FiO2 = fraction of inspired oxygen; 
HABP = hospital-acquired bacterial pneumonia; LTAC = long-term acute care; MRI = magnetic resonance imaging; 
pO2 = partial pressure of oxygen; WBC = white blood cell.
 


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VABP With ABC in Sputum/Respiratory Sample 
All of the following: 
AND signs or symptoms evidenced 
by at least 2 of the following: 
AND at least 1 of the following: 
 
Onset of symptoms >48 hours 
after receiving ventilator 
support via an endotracheal (or 
nasotracheal) tube;  
 
Requires ventilator support; 
AND 
 
New or evolving infiltrate on 
chest X-ray, MRI, CT scan, or 
ultrasound obtained within 
48 hours prior to 
randomization. Note: If an 
ultrasound is performed, a 
confirmatory X-ray or CT scan 
should be performed within 
24 hours. 
 
Auscultatory findings consistent 
with pneumonia/pulmonary 
consolidation (eg, rales, dullness 
on percussion, bronchial breath 
sounds, or egophony); 
 
An acute change in the ventilator 
support system to enhance 
oxygenation, as determined by a 
worsening oxygen 
saturation/FiO2 ratio; 
 
Increased suctioning; OR 
 
Tracheal aspirate change to 
purulence. 
 
Fever [1] (oral or tympanic 
temperature 38°C 
[100.4°F] or rectal/core 
temperature 38.3°C 
[100.9°F]) OR hypothermia 
(rectal/core temperature 
<35°C [<95°F]); 
 
Elevated total peripheral 
WBC count (>10,000/mm3); 
 
>15% immature neutrophils 
(bands) regardless of total 
peripheral WBC count; OR 
 
Leukopenia (total WBC 
<4500/mm3). 
1. 
Evidence of fever within 24 hours of the Screening Visit is acceptable if observed and documented by a healthcare 
provider. 
ABC = Acinetobacter baumannii-calcoaceticus complex; CT = computed tomography; FiO2 = fraction of inspired oxygen; 
MRI = magnetic resonance imaging; VABP = ventilator-associated bacterial pneumonia; WBC = white blood cell. 
Ventilated Pneumonia With ABC in Respiratory Sample 
All of the following: 
AND signs or symptoms evidenced 
by at least 2 of the following: 
AND at least 1 of the following: 
 
Requires ventilator 
support; AND 
 
New or evolving infiltrate 
on chest X-ray, MRI, CT 
scan, or ultrasound 
obtained within 48 hours 
prior to randomization. 
Note: If an ultrasound is 
performed, a confirmatory 
X-ray or CT scan should 
be performed within 
24 hours. 
 
Auscultatory findings consistent 
with pneumonia/pulmonary 
consolidation (eg, rales, dullness 
on percussion, bronchial breath 
sounds, or egophony); 
 
An acute change in the ventilator 
support system to enhance 
oxygenation; 
 
Increased suctioning; OR 
 
Tracheal aspirate change to 
purulence. 
 
Fever [1] (oral or tympanic 
temperature 38°C [100.4°F] 
or rectal/core temperature 
38.3°C [100.9°F]) OR 
hypothermia (rectal/core 
temperature <35°C [<95°F]); 
 
Elevated total peripheral WBC 
count (>10,000/mm3); 
 
>15% immature neutrophils 
(bands) regardless of total 
peripheral WBC count; OR 
 
Leukopenia (total WBC count 
<4500/mm3). 
1. 
Evidence of fever within 24 hours of the Screening Visit is acceptable if observed and documented by a healthcare 
provider. 
ABC = Acinetobacter baumannii-calcoaceticus complex; CT = computed tomography; MRI = magnetic resonance imaging; 
WBC = white blood cell. 
 


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Bacteremia With ABC 
All of the following: 
AND at least 1 of the following: 
 
Isolation of ABC from at least 1 blood culture collected 
from a peripheral vein OR newly placed intravenous line. 
 
Fever [1] (oral or tympanic temperature 
38°C [100.4°F] or rectal/core temperature 
38.3°C [100.9°F]) OR hypothermia 
(rectal/core temperature <35°C [<95°F]); 
 
Elevated total peripheral WBC count 
(>10,000/mm3); 
 
>15% immature neutrophils (bands) 
regardless of total peripheral WBC count; 
 
Leukopenia (total WBC count <4500/mm3);  
 
Tachycardia >100 bpm; 
 
Tachypnea >25 breaths/minute; OR 

Hypotension, systolic <90 mmHg.
1. 
Evidence of fever within 24 hours of the Screening Visit is acceptable if observed and documented by a healthcare 
provider. 
ABC = Acinetobacter baumannii-calcoaceticus complex; bpm = beats per minute; WBC = white blood cell. 
Part B-Specific Inclusion Criteria: 
Part B will include patients with the following ABC infections: HABP, VABP, VP, or bacteremia 
who do not qualify for Part A, and cUTI/AP or surgical or post-traumatic wound infections.  
1. Patients with HABP, VABP, VP, or bacteremia should be considered for enrollment in Part B 
if they meet ANY of the following criteria (a, b, c, OR d), in addition to the general inclusion 
criteria above: 
a. Has an infection caused by ABC organisms known to be resistant to colistin or 
polymyxin B (defined as MIC 4 mg/L by a non-agar based method); 
For known colistin- or polymyxin B-resistant infections, the following must be satisfied: 
o Has a known resistant infection based on evidence from culture and susceptibility 
testing by a non-agar based method within 72 hours prior to randomization, alone or 
as a single organism of a polymicrobial infection; AND has received no more than 
48 hours of an antimicrobial agent to which the ABC is susceptible prior to the first 
dose of study drug; 
OR 
o Has documented clinical evidence of failure (ie, clinical deterioration or failure to 
improve that is attributable to ABC infection) after at least 48 hours of treatment with 
colistin or polymyxin B; OR 
b. Has known intolerance to colistin;  
Note: Patients whom the Investigator feels may have a potential intolerance to colistin can 
be enrolled in Part B on a case-by-case basis after discussion with the Medical Monitor; 
OR 
c. Has myasthenia gravis or another neuromuscular syndrome(s) that contraindicates colistin 
and is not ventilated;  


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Note: Ventilated patients with myasthenia gravis or other neuromuscular syndromes 
where, in the opinion of the Investigator, colistin administration is reasonable are 
permitted for consideration for the study; OR 
d. Has acute kidney injury and is receiving renal replacement therapy at study entry; 
2. Patients diagnosed with cUTI, AP, or surgical or post-traumatic wound infections may enroll 
in Part B if they meet the general inclusion criteria as well as either a, b, c, d, OR e in addition 
to the indication requirements for f: 
a. Has an infection caused by ABC organisms known to be resistant to colistin or 
polymyxin B (defined as MIC 4 mg/L by a non-agar based method); OR 
b. Has known intolerance to colistin;  
Note: Patients whom the Investigator feels may have a potential intolerance to colistin can 
be enrolled in Part B on a case-by-case basis after discussion with the Medical Monitor; 
OR 
c. Has myasthenia gravis or another neuromuscular syndrome(s) that contraindicates 
colistin; OR 
d. Has acute kidney injury and is receiving renal replacement therapy at study entry; OR 
e. Has documented clinical evidence of failure (ie, clinical deterioration or failure to 
improve) after at least 48 hours of treatment with a polymyxin-based regimen; AND 
f. Is diagnosed with cUTI, AP, or surgical or post-traumatic wound infection, defined as: 
cUTI With ABC 
At least 1 of the following: 
AND at least 2 of the following signs 
and symptoms: 
AND at least 1 of 
the following: 
 
Indwelling urinary catheter or 
intermittent bladder catheterization; 
 
Neurogenic bladder with presence or 
history of urine residual volume of 
100 mL; 
 
Obstructive uropathy (eg, nephrolithiasis, 
tumor, fibrosis) that is expected to be 
medically or surgically treated within 
48 hours post-randomization; 
 
Azotemia due to intrinsic renal disease; 
OR 
 
Urinary retention in men due to 
previously diagnosed benign 
hypertrophy. 
 
Chills, rigors, or fever [1] (oral or 
tympanic temperature 38°C 
[100.4°F] or rectal/core 
temperature 38.3°C [100.9°F]); 
 
Elevated WBC count 
(>10,000/mm3) or left shift 
(>15% immature PMNs); 
 
Nausea or vomiting; 
 
Dysuria, increased urinary 
frequency, or urinary urgency; OR 
 
Lower abdominal pain or pelvic 
pain. 
 
Positive LCE on 
urinalysis; 
 
WBC count 
10 cells/mm3 
in unspun urine; 
OR 
 
WBC count 
10 cells/hpf in 
urine sediment. 
1. 
Evidence of fever within 24 hours of the Screening Visit is acceptable if observed and documented by a healthcare 
provider. 
ABC = Acinetobacter baumannii-calcoaceticus complex; cUTI = complicated urinary tract infection; hpf = high-power 
field; LCE = leukocyte esterase; PMN = polymorphonuclear leukocyte; WBC = white blood cell. 


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AP With ABC 
Presence of an ascending tract infection including at least 2 of the 
following signs or symptoms: 
AND at least 1 of the 
following: 
 
Chills, rigors, or fever [1] (oral or tympanic temperature 38°C 
[100.4°F] or rectal/core temperature 38.3°C [100.9°F]); 
 
Elevated WBC count (>10,000/mm3) or left shift (>15% immature 
PMNs); 
 
Nausea or vomiting; 
 
Dysuria, increased urinary frequency, or urinary urgency;  
 
Flank pain; OR 
 
Costovertebral angle tenderness on physical examination.
 
Positive LCE on 
urinalysis; 
 
WBC count 10 cells/mm3 
in unspun urine; OR 
 
WBC count 10 cells/hpf 
in urine sediment. 
1. 
Evidence of fever within 24 hours of the Screening Visit is acceptable if observed and documented by a healthcare 
provider. 
ABC = Acinetobacter baumannii-calcoaceticus complex; AP = acute pyelonephritis; hpf = high-power field; 
LCE = leukocyte esterase; PMN = polymorphonuclear leukocyte; WBC = white blood cell.
Surgical Wound Infection With ABC 
Superficial SSI meeting all of the following criteria: 
AND at least 1 of the following 
regional or systemic signs of 
infection: 
 
Follows clean surgery (elective, not emergency, nontraumatic, 
primarily closed, no acute inflammation; no break in technique; 
respiratory, gastrointestinal, biliary, and genitourinary tracts not 
entered); 
 
Involves only the skin or subcutaneous tissue around the incision, 
does not involve fascia; 
 
Occurs within 30 days after procedure; 
 
Original surgical incision 3 cm; AND 
 
Purulent drainage (spontaneous or therapeutic) that is positive for 
ABC by culture with surrounding erythema, edema, and/or 
induration extending at least 5 cm in the shortest distance from the 
peripheral margin of the wound and with a minimum total lesion 
surface area of 75 cm2. 
 
Lymph node tenderness and 
increase in volume or palpable 
proximal to the primary ABSSSI; 
 
Fever [1] (oral or tympanic 
temperature 38°C [100.4°F] or 
rectal/core temperature 38.3°C 
[100.9°F]) OR hypothermia 
(rectal/core temperature <35°C 
[<95°F]); 
 
WBC count 10,000/mm3 or 
<4000/mm3; OR 
 
>15% immature neutrophils. 
1. 
Evidence of fever within 24 hours of the Screening Visit is acceptable if observed and documented by a healthcare 
provider. 
ABC = Acinetobacter baumannii-calcoaceticus complex; ABSSSI = acute bacterial skin and skin structure infection; 
SSI = surgical site infection; WBC = white blood cell.
 
 


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EXCLUSION CRITERIA: 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Presence of suspected or confirmed deep-seated infection (eg, lung abscess in patients with 
pneumonia, skin abscess, or decubitus ulcer) that is not planned on being drained or debrided 
within 24 hours after randomization; 
Note: Patients with an empyema who will have drainage within 24 hours of Screening and who 
are expected to be able to be treated with 14 or fewer days of antibiotics are allowed. 
2. Evidence of active concurrent pneumonia requiring additional antimicrobial treatment caused 
by Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Mycoplasma 
pneumoniae, Chlamydia pneumoniae, Legionella pneumophila, respiratory syncytial virus, 
influenza and parainfluenza viruses, Middle East respiratory syndrome coronavirus, 
mycobacteria, aspergillus, mucormycosis, etc; 
Note: If these organisms are identified but it is deemed by the Investigator that no treatment is 
warranted and their presence does not significantly change the prognosis of the patient, then 
the patient may be considered for this study. 
3. Pulmonary disease that precludes evaluation of a therapeutic response (such as lung cancer 
resulting in bronchial obstruction or on the same side as the pneumonia, active tuberculosis, 
cystic fibrosis, granulomatous disease, fungal pulmonary infection, lung abscess, pleural 
empyema, post obstructive pneumonia, or COVID-19 infection without clinical improvement);
Note: Patients with an empyema who will have drainage within 24 hours of Screening and who 
are expected to be able to be treated with 14 or fewer days of antibiotics are allowed. 
4. Presence of suspected or confirmed deep seated bacterial infections such as bacterial Gram 
negative osteomyelitis, endocarditis, or meningitis requiring prolonged therapy, as determined 
by history and/or physical examination; 
5. Acute infective endocarditis due to Gram positive bacteria that require urgent/emergent 
indication of surgery (ie, heart failure because of valvular insufficiency or septic shock), or 
Post-Traumatic Wound Infection With ABC 
Post-traumatic wound (including 
penetrating trauma) characterized by 
the following within 24 hours of 
Screening: 
AND at least 1 of the following regional or systemic signs of 
infection: 
 
Purulent drainage (spontaneous or 
therapeutic) that is positive for ABC 
by culture with surrounding 
erythema, edema, and/or induration 
extending at least 5 cm in the shortest 
distance from the peripheral margin 
of the wound and with a minimum 
total lesion surface area of 75 cm2. 
 
Lymph node tenderness and increase in volume or palpable 
proximal to the primary ABSSSI; 
 
Fever [1] (oral or tympanic temperature 38°C [100.4°F] or 
rectal/core temperature 38.3°C [100.9°F]) OR hypothermia 
(rectal/core temperature <35°C [<95°F]); 
 
WBC count 10,000/mm3 or <4000/mm3; OR 
 
>15% immature neutrophils. 
1. 
Evidence of fever within 24 hours of the Screening Visit is acceptable if observed and documented by a healthcare 
provider. 
ABC = Acinetobacter baumannii-calcoaceticus complex; ABSSSI = acute bacterial skin and skin structure infection; 
WBC = white blood cell. 


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patients in whom surgery is contraindicated due to prohibitive risk for surgery due to 
comorbidities; 
6. Irremovable implantable device or line thought to be the potential source of ABC infection; 
7. Sustained shock with persisting hypotension requiring vasopressors to maintain mean arterial 
pressure (MAP) 60 mmHg; 
Note: Patients who can maintain MAP 60 mmHg on a reasonable dose of pressors or are 
weaning off of pressors may be considered. Patients who require more than the maximal dose 
of 2 vasopressors to maintain MAP 60 mmHg are ineligible. If vasopressors are weaned to 
below these levels, patient enrollment can be reconsidered. 
8. For patients to be enrolled with the primary indication of HABP, VABP, or VP, any of the 
following conditions: 
a. Diagnosis of ventilator-associated tracheobronchitis; or 
b. Inability to provide proper respiratory specimens for culture. Respiratory samples from 
expectorated or induced sputum should show <10 squamous epithelial cells and 
>25 polymorphonuclear neutrophils per 100 field; 
9. For patients to be enrolled with the primary indication of cUTI or AP, any of the following 
urologic conditions: 
a. Likely to receive ongoing antibacterial drug prophylaxis after treatment of cUTI 
(eg, patients with vesico-uretal reflux); 
b. Suspected or confirmed prostatitis; 
c. Requirement for bladder irrigation with antibiotics or for antibiotics to be administered 
directly via urinary catheter; 
d. Previous or planned cystectomy or ileal loop surgery; 
e. Uncomplicated urinary tract infection (eg, female patients with urinary frequency, 
urgency, or pain or discomfort without systemic symptoms or signs of infection); 
f. Complete, permanent obstruction of the urinary tract; 
g. Suspected or confirmed perinephric or renal corticomedullary abscess; 
h. Polycystic kidney disease; or 
i. Any recent history of trauma to the pelvis or urinary tract; 
10. Pregnant or breastfeeding women; 
11. APACHE II score >30 and SOFA score >11 at the time of diagnosis of infection; 
Note: A qSOFA score must be calculated for all patients without an APACHE II score. 
Glasgow coma score for APACHE II calculation should be the best response prior to initiation 
of sedation/neuromuscular blockade, even if sedation has been in use for >24 hours. 
12. Receiving peritoneal dialysis;  
13. Requirement for temporary or acute onset treatment with antiseizure medication that, in the 
opinion of the Investigator, would prohibit the patient from complying with the protocol. 
Patients at risk of seizure or requiring prophylactic antiseizure medications during the study 


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can be considered for enrollment at the discretion of the Investigator. Patients with a history of 
epilepsy or who are on stable treatment (ie, no recurrent episodes in the past 30 days) and no 
history of imipenem-associated seizures may be considered for enrollment in the study; 
14. Requirement for continuing treatment with probenecid, methotrexate, ganciclovir, valproic 
acid, or divalproex sodium during the study; 
15. Evidence of significant hepatic disease or dysfunction, including known acute viral hepatitis, 
hepatic cirrhosis, hepatic failure, chronic ascites, or hepatic encephalopathy; 
16. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3  upper limit of 
normal (ULN) AND total bilirubin >2  ULN at Screening; 
Note: Patients with AST or ALT up to 5  ULN are eligible if these elevations are acute and 
are documented as being directly related to the infectious process being treated. 
17. Requirement at the time of randomization for any reason, or likely to require during the 
patient’s participation in the study (from randomization through the Late Follow-up [LFU]
Visit), for additional systemic Gram negative antimicrobial therapy; 
18. Requirement for inhaled antibiotics; 
19. Known history of human immunodeficiency virus infection and known recent CD4 count 
<200/mm3 within the last year or presence of significant immunologic disease or dysfunction, 
as determined by a current diagnosis of an Acquired Immune Deficiency Syndrome-defining 
illness; 
20. Presence of neutropenia (absolute neutrophil count <500/mm3) obtained from a local laboratory 
at Screening; 
21. A QT interval corrected using Fridericia’s formula 480 msec; 
22. History of significant hypersensitivity or allergic reaction to any β-lactam (BL), any 
contraindication to the use of cilastatin based on local approved prescribing information 
(eg, Summary of Medicinal Product Characteristics), any contraindication to the excipients 
used in the respective formulations, or any contraindication to the use of BL antibiotics; 
23. Participation in a clinical study involving investigational medication or an investigational 
device within the last 30 days or 5 half-lives, whichever is longer, prior to Day 1; 
24. Any condition that, in the opinion of the Investigator, would compromise the safety of the 
patient or the quality of the data or require greater than 14 days of treatment with antibiotics; 
25. Unable or unwilling, in the opinion of the Investigator, to comply with the protocol;  
26. Has previously received ETX2514 in this study; or 
27. For Part A only, patients with an infection known to be resistant to colistin or polymyxin B
(defined as MIC 4 mg/L by a non-agar based method), with a known intolerance to colistin, 
or taking any drug that prevents them from receiving colistin. 
STUDY DESIGN AND DURATION: 
This study is a randomized, active-controlled study to evaluate the safety and efficacy of IV 
ETX2514SUL in patients with ABC infections. Patients providing informed consent and meeting 


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all study eligibility criteria will be enrolled in the study and have pretreatment blood and infection 
site-specific samples obtained and submitted to the local laboratory.  
The study will be enrolled in 2 parallel parts, with the PK data from the first approximately 
30 patients in Part A (with only 15 patients dosed with ETX2514SUL) reviewed prior to initiating 
enrollment in Part B: 
a. Part A will be the pivotal, assessor-blind, randomized, comparative portion of the study in 
patients with documented ABC HABP, VABP, VP, or bacteremia. While study drugs will not 
be masked due to logistical reasons, every attempt will be made to maintain the blind for 
patients, all staff at the site, and the Sponsor or its designees, except for the treatment physician 
and other immediate healthcare providers. In Part A, patients will be randomized 1:1 to 1 of 
the following treatment groups: 
o Group 1: 1.0 g ETX2514/1.0 g sulbactam IV infused over 3 hours every 6 hours (q6h) plus 
1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h; or 
o Group 2: 2.5 mg/kg colistin IV infused over 30 minutes every 12 hours (q12h) plus 1.0 g 
imipenem/1.0 g cilastatin IV infused over 1 hour q6h. 
Patients will be enrolled until there are 120 patients in the CRABC Microbiologically Modified 
Intent-to-Treat (m-MITT) Population in Part A, as determined by the central microbiology 
laboratory. Approximately 200 patients are expected to be enrolled in Part A, assuming 
approximately 60% of patients will have CRABC (see the statistical methods for complete 
details). The HABP/VABP/VP patients who are randomized to Part A based on a positive 
screening of a respiratory sample for ABC by the BPP, but who subsequently do not have 
growth of ABC in their respiratory sample culture processed by the local microbiology 
laboratory, will be withdrawn from the study drug treatment. 
Randomization will be stratified by indication (HABP/VABP/VP versus bacteremia), severity 
of illness (based on APACHE II [10 to 19 versus 20 to 30], SOFA [7 to 9 versus 10], or 
qSOFA [2 versus 3] score at Screening), and geography (China Mainland versus Rest of 
World). In the situation where a patient has more than one score reported, the scores will be 
used in the following order: APACHE, SOFA, and qSOFA. 
Enrollment of HABP, VP, and bacteremia patients will be limited to a total of no more than 
40% of patients in Part A, regardless of resistance. 
b. Part B will be the open-label, supportive portion of the study that will include patients known 
to have HABP, VABP, VP, and/or bacteremia infections associated with ABC organisms that 
are known to be resistant to colistin or polymyxin B, those failing a colistin or polymyxin B
regimen prior to study entry or are on acute renal replacement therapy, and patients with 
infections due to colistin- or polymyxin B-resistant ABC with sources of infection other than 
HABP, VABP, VP, and/or bacteremia, as detailed in the inclusion criteria. 
Any patient who has a qualifying ABC infection and meets study inclusion criteria but has 
a contraindication to colistin due to underlying conditions, intolerance, or evidence of 
failing colistin or polymyxin B therapy prior to study entry, and/or has a colistin- or 
polymyxin B-resistant ABC infection cannot be enrolled in Part A but can be considered for 
enrollment in Part B (see the inclusion and exclusion criteria for details).  
Patients with ABC infections who are not otherwise eligible for Part A are expected to be 
enrolled in Part B. Patient enrollment in Part B will continue until Part A enrollment in the 


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CRABC m-MITT Population is complete. In Part B, patients will receive the following 
treatment: 
o Group 3: 1.0 g ETX2514/1.0 g sulbactam IV infused over 3 hours q6h plus 1.0 g 
imipenem/1.0 g cilastatin IV infused over 1 hour q6h. 
Transfer from Part A to Part B: Since Part A will be the first time patients in intensive care are 
receiving ETX2514SUL, PK in the first approximately 30 patients must be verified prior to 
initiating Part B to ensure the treatment planned in Part B is optimal for the targeted patient 
population. Patients randomized to either group of Part A can only be transferred to Part B, once 
Part B is open for enrollment, if the ABC identified from the baseline culture is subsequently 
determined to be resistant to colistin or polymyxin B by the local microbiology laboratory. If Part B 
is not yet open for enrollment in a given country and a patient in Part A has a baseline culture 
determined to be colistin- or polymyxin B-resistant but is responding to therapy, the patient may 
remain in Part A at the discretion of the Investigator. A patient in Part A whose culture is 
determined to be colistin- or polymyxin B-resistant and who has not shown improvement or whose 
condition has worsened will be withdrawn from the study drug treatment. All such cases must be 
discussed with the Medical Monitor. 
Any organism isolated from the blood or infection site-specific cultures will be identified by genus 
and species by the local laboratory. Organisms will be cultured and quantified (urine and 
bronchoalveolar lavage only) at the local laboratory, and susceptibility of the organism(s) will be 
performed per local laboratory standards. Isolates of pathogens cultured at the local laboratory are 
to be sent to the central laboratory for confirmation of identification and susceptibility testing.  
No dosing regimen changes, other than those specified in the protocol for renal insufficiency or for 
patients on imipenem who develop a seizure that is thought to be directly related to imipenem, can 
occur without discussion with the Medical Monitor. Patients with cultures growing organisms with 
evidence of carbapenem resistance should remain on their assigned treatment regimen; treatment 
regimen changes can occur after 5 days after discussion with the Medical Monitor. If changes to 
the regimen are needed due to unsatisfactory clinical response, patients should be classified as 
clinical failures and discontinued from study drug. All patients should receive at least 48 hours of 
IV study drug (ie, 8 doses of ETX2514SUL plus 8 doses of imipenem/cilastatin or 4 doses of 
colistin plus 8 doses of imipenem/cilastatin in patients without dose adjustments) before the 
Investigator considers the patient to be a clinical failure and discontinues the patient from study 
drug therapy. 
Note: Patients who experience focal tremors, myoclonus, or seizures at any point during the study 
should be evaluated neurologically, placed on anticonvulsant therapy (if not already instituted), 
and the dose of imipenem/cilastatin should be evaluated to determine whether it should be 
decreased or discontinued.  
Day 1 is defined as the first day of study drug administration. The subsequent study days are 
defined by the number of treatment days thereafter. Treatment days should constitute 24 hours of 
treatment. For those patients with no dose adjustments, the duration of antibiotic treatment with 
study drug therapy will be 28 doses of ETX2514SUL plus 28 doses of imipenem/cilastatin or 
14 doses of colistin plus 28 doses of imipenem/cilastatin (ie, treatment for 7 days for those without 
dose adjustments), with a prolongation of therapy up to 14 days if clinically indicated. Refer to the 
Pharmacy Manual for specifics on dosing for all patients. 


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The overall study design is shown in the figure below.  
*Part B: Part B will be the open-label, supportive portion of the study that will include patients known to have HABP, VABP, 
VP, and/or bacteremia infections associated with ABC organisms that are known to be resistant to colistin or polymyxin B, those 
failing a colistin or polymyxin B regimen prior to study entry or are on acute renal replacement therapy, and patients with 
infections due to colistin- or polymyxin B-resistant ABC with sources of infection other than HABP, VABP, VP, and/or 
bacteremia. The total number of patients enrolled in Part B may be adjusted based on the number needed to be enrolled in Part A 
to achieve the number needed to be treated in the CRABC m-MITT Population. 
ABC = Acinetobacter baumannii-calcoaceticus complex; APACHE = Acute Physiologic Assessment and Chronic Health 
Evaluation; CRABC = Carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex; cUTI = complicated urinary tract 
infection; ETX2514SUL = sulbactam-ETX2514; HABP = hospital-acquired bacterial pneumonia; IMI = imipenem/cilastatin; 
LFU = Late Follow-up; m-MITT = Microbiologically Modified Intent-to-Treat; q6h = every 6 hours; q12h = every 12 hours; 
TOC = Test of Cure; VABP = ventilator-associated bacterial pneumonia; VP = ventilated pneumonia. 
Patients who have early discontinuation of study drug dosing should perform all End of Treatment 
(EOT) Visit procedures and should be followed through the LFU Visit for safety assessments, even 
if the reason for discontinuation is clinical failure. 
In Part A, clinical outcome assessments will be performed by a blinded assessor, in addition to the 
unblinded Investigator. Whenever possible, the same blinded assessor should complete all clinical 
outcome assessments for a study patient. If there is a discrepancy between the assessment of the
blinded assessor and unblinded Investigator, the assessment from the blinded assessor will be used. 
If there is a missing assessment from either the blinded assessor or unblinded Investigator, the 
other available assessment will be used. An adjudication committee may be organized for endpoint 
adjudication should it be deemed necessary as determined by the Data Safety Monitoring 
Board (DSMB). In such a case, a charter will be developed that describes their activities. 
Intense PK sampling will be performed on the first approximately 30 patients randomized in 
Part A. The purpose of the intense PK sampling is to ensure that exposures observed in this severely 
ill cohort are comparable to those observed thus far in prior clinical studies. The PK samples will 
be collected for both treatment groups in Part A to keep the study data blinded. Pharmacokinetic 
assessment of the initial 15 patients on ETX2514SUL in Part A will be performed by an 


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independent PK assessor, prior to the opening of enrollment in Part B. To explore the PK profile 
of the ETX2514SUL combination in Chinese patients with severe infection, the intense PK sample 
will also be collected from the first approximately 20 patients randomized in Part A at China 
Mainland sites. All other patients enrolled in the study (Parts A and B) will have samples collected 
for sparse PK analysis, which will be used to better inform the population PK model. 
Patients will be enrolled in the study for approximately 28 days, with a maximum duration of 
32 days. Screening laboratory analytes can be performed as standard of care up to 48 hours prior 
to randomization on Day 1, with the exception of local laboratory serum creatinine determination, 
which must be obtained at the local laboratory within 24 hours of the first dose of study drug. The 
Treatment Period begins on Day 1, and study drug will be administered for 7 days (ie, 28 doses of 
ETX2514SUL plus 28 doses of imipenem/cilastatin or 14 doses of colistin plus 28 doses of 
imipenem/cilastatin for those without dose adjustments) with a prolongation of therapy of up to 
14 days if clinically indicated. The EOT Visit will be completed on the final dosing day or the 
following day. The Test of Cure (TOC) Visit will be completed 7 days (2 days) after the 
EOT Visit for all patients. The LFU Visit will be completed 14 days (2 days) after the EOT Visit
for all patients. For patients with an LFU Visit occurring before Day 28, a telephone call to assess 
survival will be made on Day 28 or anytime thereafter. Every attempt must be made to record 
survival status at Day 28 or anytime thereafter for all randomized patients (including 
HABP/VABP/VP patients who are randomized to Part A based on a positive BPP rapid test, but 
who subsequently do not have growth of ABC in their respiratory sample culture), regardless of 
their status of treatment, as long as the patient has not withdrawn consent from participation in the 
study. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
In Part A, the following study drugs will be administered in a 1:1 randomized manner: 
 Group 1 (experimental group): 1.0 g ETX2514/1.0 g sulbactam IV infused over 3 hours q6h 
plus 1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h; or 
 Group 2 (control group): 2.5 mg/kg colistin IV infused over 30 minutes q12h (after an initial 
loading dose of colistin 2.5 to 5 mg/kg) plus 1.0 g imipenem/1.0 g cilastatin IV infused over 
1 hour q6h. 
In Part B, the following study drugs will be administered: 
 Group 3 (experimental group): 1.0 g ETX2514/1.0 g sulbactam IV infused over 3 hours q6h 
plus 1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h. 
EFFICACY VARIABLES:  
The primary efficacy endpoint for the study is 28-day all-cause mortality in the CRABC m-MITT 
Population in Part A. 
The secondary efficacy endpoints for Part A and Part B include the following: 
 28-day all-cause mortality in the Intent-to-Treat (ITT) Population; 
 Clinical cure at TOC in the CRABC m-MITT Population; 
 Clinical cure at TOC in the m-MITT, Clinical Evaluable (CE), Microbiologic Evaluable (ME), 
and CRABC ME Populations; 


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 Clinical cure at Day 5, Day 7, EOT, and LFU in the m-MITT, CRABC m-MITT, CE, ME, and 
CRABC ME Populations; 
 Microbiological favorable assessment at Day 5, Day 7, EOT, TOC, and LFU in the m-MITT, 
CRABC m-MITT, ME, and CRABC ME Populations; 
 14-day all-cause mortality in the CRABC m-MITT and m-MITT Populations;  
 28-day all-cause mortality in the m-MITT and CRABC ME Populations; and 
 PK exposure of ETX2514 and sulbactam in the PK Population. 
The exploratory efficacy endpoints include the following: 
 Clinical cure based on PK exposure; 
 Clinical cure based on MIC distribution of ETX2514SUL;  
 Clinical cure based on baseline resistance to ETX2514SUL, carbapenems, or colistin;  
 Number of days in the intensive care unit; 
 Number of patients transferred to the intensive care unit; 
 For patients with VABP, VP, or ventilated HABP, number of days on ventilators;  
 Number of days in the hospital; and 
 Number of days on study drug treatment. 
Outcome Definitions: 
Clinical Outcome: 
Clinical outcome will be used to determine a response of clinical success for all patients. Based on 
the assessment of signs and symptoms, the unblinded Investigator will choose 1 of the following 
clinical outcomes at the Day 5, Day 7, EOT Visit, TOC Visit, LFU Visit, and ET Visit, if 
applicable. In Part A, in addition to the unblinded Investigator, a blinded assessor will also 
determine clinical outcome. If there is a discrepancy between the assessment of the blinded 
assessor and unblinded Investigator, the assessment from the blinded assessor will be used. If there 
is a missing assessment from either the blinded assessor or unblinded Investigator, the other 
available assessment will be used. An adjudication committee may be organized for endpoint 
adjudication should it be deemed necessary by the DSMB. In such a case, a charter will be 
developed that describes their activities. 
Clinical cure: complete resolution or significant improvement of signs and symptoms that were 
present at baseline and no new symptoms, such that no additional Gram negative antimicrobial 
therapy is warranted. 
Clinical failure: symptoms present at study entry have not significantly improved or completely 
resolved, or new symptoms have developed and require the initiation of a non-study Gram negative 
antibacterial drug therapy, death, or intolerance to study drug leading to discontinuation from the 
study treatment. 
Clinical indeterminate: determination cannot be made because of missing data or the patient is lost 
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Microbiologic Outcome: 
Microbiologic outcome for bacteremia, complicated urinary tract infection, or acute 
pyelonephritis: 
For patients with bacteremia, cUTI, or AP, per-patient microbiological response will be determined 
programmatically as 1 of the following outcomes based on the results of blood and/or urine cultures 
at the Day 5, Day 7, EOT, TOC, and LFU Visits. A microbiological favorable assessment will 
include eradication and presumed eradications, as detailed below. 
Microbiologic eradication: 
 For patients with cUTI or AP: the baseline strain of ABC is reduced to <103 colony-forming 
units (CFU)/mL on urine culture and negative on repeat blood culture (if positive at baseline);
or 
 For patients with bacteremia: absence of the baseline strain of ABC on culture. 
Microbiologic presumed eradication: no culture was done, and the patient meets clinical criteria 
for clinical cure. 
Microbiologic persistence: 
 For patients with cUTI or AP: the demonstration that the urine culture grew 103 CFU/mL of 
the baseline strain of ABC identified at study entry and/or a blood culture demonstrates the 
same baseline pathogen(s); or 
 For patients with bacteremia: presence of the baseline strain of ABC on repeat culture. 
Patients who are a persistence at EOT will be considered a persistence at TOC. 
Microbiologic presumed persistence: no culture was done, and the patient meets clinical criteria 
for clinical failure. 
Microbiologic indeterminate: if clinically indicated (for cUTI and bacteremia only), no follow-up 
culture is available, the culture cannot be interpreted for any reason, or the culture is considered 
contaminated.  
Microbiologic recurrence:  
 For patients with cUTI or AP: the demonstration that the urine culture grew 103 CFU/mL of 
the baseline strain of ABC identified at study entry at any time after documented eradication at 
the TOC Visit up to and including the LFU Visit; or  
 For patients with bacteremia: a positive blood culture for ABC at any time after documented 
eradication at the TOC Visit up to and including the LFU Visit. 
Microbiologic outcome for hospital-acquired bacterial pneumonia, ventilator-associated bacterial 
pneumonia, ventilated pneumonia, or surgical or post-traumatic wound infections: 
Microbiologic presumed eradication: no culture was done, and the patient meets clinical criteria 
for clinical cure. For patients with HABP/VABP/VP or surgical or post-traumatic wound 
infections, where repeat culture samples may not be indicated, presumed eradication based on 
clinical improvement will be inferred. 


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Microbiologic presumed persistence: no culture was done, and the patient meets clinical criteria 
for clinical failure. 
SAFETY VARIABLES: 
The safety parameters include the incidence, severity, causality, and seriousness of 
treatment-emergent adverse events (TEAEs) and adverse events of special interest, including 
nephrotoxicity as measured by RIFLE criteria, and the evaluation of changes from baseline in 
safety laboratory test results, electrocardiograms (ECGs), vital signs, physical examinations, and 
chest X-ray/radiology/ultrasound and mechanical ventilator assessments for patients with HABP, 
VABP, or VP. Newly emergent infections that appear after baseline will be reported as adverse 
events and summarized separately. 
STATISTICAL ANALYSES: 
This study is designed to estimate treatment efficacy of ABC infections with a pivotal component 
in Part A.  
Continuous variables will be summarized using the number of non-missing observations, 
arithmetic mean, standard deviation, median, minimum, and maximum values as descriptive 
statistics. Categorical variables will be summarized by using the frequency count and the 
percentage of patients in each category as descriptive statistics.  
All comparisons in Part A will be for ETX2514SUL plus imipenem/cilastatin versus colistin plus 
imipenem/cilastatin. The efficacy endpoints for Part B will be summarized descriptively only and 
will be used to supplement results in Part A. Listings of individual patient data will be produced. 
The ITT Population will include all patients randomized to study drug treatment (ETX2514SUL 
plus imipenem/cilastatin or colistin plus imipenem/cilastatin) in Part A or enrolled in Part B, 
regardless of whether the patient actually receives study drug. 
The Modified ITT (MITT) Population will include patients in Parts A and B who meet ITT criteria 
and receive any amount of study drug. The MITT Population will be considered the Safety 
Population. Patients with HABP/VABP/VP who were randomized to Part A on the basis of a BPP 
rapid test result but were subsequently withdrawn due to a lack of a culture growing ABC will be 
counted in the MITT and Safety Populations.  
The m-MITT Population will include patients who meet MITT criteria and have an ABC organism 
isolated as the qualifying culture specimen, as confirmed by the central and/or local microbiology 
laboratory. If an isolate for testing at the central laboratory is not available, the local laboratory 
data can be used to confirm the presence of ABC organism, as long as the local laboratory uses 
modern methods of diagnosis such as molecular-based tests, matrix-assisted laser 
desorption/ionization time-of-flight mass spectrometry, Vitek, Phoenix, etc (ie, not conventional 
biochemical or manual phenotypic methods). Patients with HABP/VABP/VP who are enrolled 
based upon a positive BPP rapid test for ABC, but subsequently are found to have respiratory 
sample cultures that do not grow ABC (by the local laboratory), will be withdrawn from the study
drug treatment. These patients will not be included in the m-MITT Population but will remain in 
the MITT Population. 
The CRABC m-MITT Population will include patients who meet m-MITT criteria and 
have a baseline ABC organism that is confirmed to be carbapenem-resistant (MIC to 
imipenem/meropenem 8 mg/L) by the central laboratory or by the local laboratory if the central


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laboratory is not able to identify the isolate for any reason. Patients will be excluded from the 
CRABC m-MITT Population if they have isolates that are deemed by the central laboratory to be 
resistant to ETX2514SUL (MIC >4 mg/L) or colistin (MIC 4 mg/L), if their blood culture or 
respiratory samples are collected more than 72 hours prior to randomization, if they are transferred 
from Part A to Part B, or if they are enrolled with infections other than ABC pneumonia or 
bloodstream infection (ie, ABC infections other than HABP, VABP, VP, and bacteremia). A 
sensitivity analysis for the primary efficacy endpoint will be performed for patients whose eligible 
culture is >48 hours from the first dose of study drug, as well as for all patients with and without 
evidence of non-susceptibility to colistin and ETX2514SUL at baseline. 
The CE Population will include patients who meet m-MITT criteria and meet evaluability criteria 
(meet key inclusion criteria, do not have key exclusion criteria, received at least 72 hours of study 
drug [ie, 12 doses of ETX2514SUL plus 12 doses of imipenem/cilastatin or 6 doses of colistin plus 
12 doses of imipenem/cilastatin in patients without dose adjustments] to be a clinical cure, received 
at least 48 hours of study drug [ie, 8 doses of ETX2514SUL plus 8 doses of imipenem/cilastatin or 
4 doses of colistin plus 8 doses of imipenem/cilastatin in patients without dose adjustments] to be 
a clinical failure, received 80% of anticipated doses, and did not have a clinical response of 
indeterminate at the TOC Visit). 
The ME Population will include patients who meet m-MITT criteria and CE criteria and have an 
appropriately collected culture specimen and interpretable culture result when specimen collection 
is clinically indicated at the TOC Visit. 
The CRABC ME Population will include patients who meet ME criteria and who have a baseline 
ABC organism that is confirmed to be carbapenem-resistant (and susceptible to ETX2514SUL for 
Parts A and B and susceptible to colistin for Part A). 
The PK Population will include patients who receive any amount of study drug and have evaluable
PK data. 
Efficacy: 
The primary efficacy endpoint for the study is 28-day all-cause mortality in the CRABC m-MITT 
Population in Part A. Patients in the CRABC m-MITT Population who discontinue study drug 
prematurely in Part A for any reason will be included in the assessment of 28-day all-cause 
mortality, provided consent has not been withdrawn.  
A sensitivity analysis for the primary efficacy endpoint will be performed for patients whose 
eligible culture is >48 hours from the first dose of study drug, as well as for all patients with and 
without evidence of non-susceptibility to colistin and ETX2514SUL at baseline. 
The non-inferiority assessment will be based on the 2-sided 95% confidence intervals (CIs) for the 
difference ([ETX2514SUL + imipenem/cilastatin] – [colistin + imipenem/cilastatin]) in 28-day 
all-cause mortality rates between the treatment groups. Non-inferiority will be concluded if the 
upper limit of the 2-sided 95% CI is less than +20%.  
If non-inferiority is achieved, a test of superiority will be performed. 
The analysis of the primary efficacy endpoint 28-day all-cause mortality will also be performed in 
the ITT Population. 
The number and percentage of patients in each response category for the secondary efficacy 
endpoints will be summarized by treatment group for the populations defined earlier. Two-sided 


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95% CIs for the difference in outcome rates between the treatment groups in Part A will be 
provided.  
Part B data will be analyzed separately from Part A using descriptive statistics. 
Further subgroup analyses will be conducted, and details of the analysis will be described in the 
Statistical Analysis Plan (SAP). 
Exploratory endpoint analysis will be described in the SAP. Exploratory endpoints for health 
resource utilization difference between treatment groups (such as length of ventilation, intensive 
care unit stay, hospitalization, additional antibiotic use, etc) will be reported separately. Efficacy 
analysis for patients with HABP/VABP/VP who are identified as positive for ABC by BPP 
molecular methodology will be explored. 
Pharmacokinetics: 
Descriptive statistics will be provided for PK concentration data and PK parameters. All PK 
analyses will be performed using the PK Population.  
For the intense PK group, PK samples will be obtained from the first approximately 30 patients 
randomized in Part A. The PK samples will be collected for both treatment groups in Part A to 
keep the study data blinded. The PK samples obtained from the ETX2514SUL group will be 
analyzed for ETX2514 and sulbactam concentrations using a validated assay by a central 
bioanalytical laboratory. Pharmacokinetic assessment of the initial 15 patients on ETX2514SUL 
in Part A will be performed by an independent PK assessor, prior to the opening of enrollment in 
Part B. The independent PK assessor will conduct sequential PK analysis from patients as they are 
enrolled. An initial aggregate assessment of PK parameters will be done after enrollment of the 
first 8 HABP/VABP/VP patients randomized to ETX2514SUL. The independent PK assessor will 
report results to the DSMB, relative to concentrations projected in the population PK model, once 
data from all 15 patients on ETX2514SUL is available. However, if the preliminary analysis of the 
first 8 patients with HABP/VABP/VP on ETX2514SUL reveals evidence of inadequate exposure
this will be escalated to the DSMB. 
The intense PK sampling will also be performed on the first approximately 20 patients randomized 
in Part A from China Mainland sites. The PK samples obtained from patients who have received 
the ETX2514SUL treatment will be analyzed for ETX2514 and sulbactam concentrations, which 
will be applied to build the population PK model combined with data from the sparse PK group. 
For the sparse PK group, PK samples will be obtained from all other patients enrolled in the study 
(Parts A and B), which will be used to better inform the population PK model. 
Analysis of the PK data and incorporation into the population PK analysis and 
PK/pharmacodynamic model will be described in a separate PK Analysis Plan. 
Safety: 
All patients who receive any amount of study drug (MITT Population) will be included in the 
safety analyses. Patients who received the wrong study drug for their entire course of treatment 
will be analyzed in the group based on the drug received. 
A primary analysis of safety will be performed for Part A to assess the proportion of patients with 
nephrotoxicity, as measured by the RIFLE criteria based on the Safety and CE Populations. 


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Overall safety will be assessed for Part A and Part B in the Safety Population. The number and 
percentage of patients in each treatment group reporting at least 1 occurrence of a TEAE for each 
unique system organ class and preferred term will be tabulated. A TEAE is defined as an adverse 
event occurring on or after the administration of the first dose of study drug. Treatment-emergent 
adverse events will also be tabulated by treatment group, severity, and the relationship to study 
drug as assessed by the Investigator. The number and percentage of patients in each treatment 
group reporting at least 1 occurrence of a treatment-emergent serious adverse event will be 
tabulated. The number and percentage of patients (in each treatment group) prematurely 
discontinuing study drug treatment due to a TEAE will be tabulated by system organ class and 
preferred term. Adverse events of special interest in Part A will be summarized for all patients by 
treatment. 
Safety laboratory data will be presented by descriptive statistics of the post-baseline value and the 
change from baseline, as well as the number and percentage of patients with potentially clinically 
significant laboratory values. Descriptive statistics of vital signs and ECG parameters and the 
change from baseline will also be presented. An outlier analysis of the ECG parameters will be 
conducted. 
SAMPLE SIZE DETERMINATION: 
Patients will be enrolled until there are 120 patients in the CRABC m-MITT Population in Part A. 
The study will have 80% power to demonstrate non-inferiority between Group 1 and Group 2 using 
a 20% non-inferiority margin and a 2-sided 95% CI. This assumes a mortality rate in the 
comparator group (Group 2) of 41% and in the ETX2514SUL group (Group 1) of 36%. To have 
120 patients in the CRABC m-MITT Population, Part A will need to enroll approximately 
200 patients, assuming 60% of ABC clinical isolates are carbapenem-resistant. Patient enrollment 
in Part B (Group 3) will continue until Part A enrollment in the CRABC m-MITT Population is 
complete. Rates of carbapenem resistance among isolates from Part A patients will be monitored 
by the unblinded data manager/designee at the Clinical Research Organization on an ongoing basis. 
SITES: Approximately 100 global sites. 
SPONSOR: 
Entasis Therapeutics 
Gatehouse Park BioHub 
35 Gatehouse Drive 
Waltham, MA 02451 
United States 
Telephone: +1-781-810-0120 
Fax: +1-781-810-0122 


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TABLE OF CONTENTS 
Signature Page ................................................................................................................................ 2 
Investigator Agreement ................................................................................................................... 3 
Synopsis .......................................................................................................................................... 4 
Table of Contents .......................................................................................................................... 24 
List of Tables ................................................................................................................................ 29 
List of Figures ............................................................................................................................... 30 
List of Abbreviations and Definition of Terms............................................................................. 31 
1  Introduction and Background Information ............................................................................. 33 
1.1 
Nonclinical Experience With ETX2514 ....................................................................... 34 
1.2 
Clinical Experience With ETX2514 ............................................................................. 34 
1.3 
Rationale ........................................................................................................................ 36 
1.4 
Risk/Benefit ................................................................................................................... 37 
2  Study Objectives ..................................................................................................................... 40 
2.1 
Primary Objectives ........................................................................................................ 40 
2.2 
Secondary Objectives .................................................................................................... 40 
2.3 
Exploratory Objectives .................................................................................................. 40 
3  Study Description.................................................................................................................... 41 
3.1 
Summary of Study Design ............................................................................................ 41 
3.2 
Study Indication ............................................................................................................ 44 
4  Selection and Withdrawal of Patients ..................................................................................... 45 
4.1 
Inclusion Criteria ........................................................................................................... 45 
4.1.1  General Inclusion Criteria ................................................................................. 45 
4.1.2  Part A-Specific Inclusion Criteria ..................................................................... 46 
4.1.3  Part B-Specific Inclusion Criteria ..................................................................... 48 
4.2 
Exclusion Criteria .......................................................................................................... 51 
4.3 
Withdrawal and Discontinuation Criteria ..................................................................... 54 
5  Study Treatments .................................................................................................................... 56 
5.1 
Treatment Groups .......................................................................................................... 56 
5.2 
Rationale for Dosing ..................................................................................................... 56 
5.3 
Dosing in Patients With Renal Insufficiency ................................................................ 57 
5.4 
Randomization and Blinding ......................................................................................... 57 


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5.4.1  Unblinded Investigator ...................................................................................... 58 
5.4.2  Blinded Assessor ............................................................................................... 58 
5.5 
Drug Supplies ................................................................................................................ 59 
5.5.1  Formulation and Packaging ............................................................................... 59 
5.5.2  Study Drug Preparation and Dispensing ........................................................... 59 
5.5.3  Study Drug Administration ............................................................................... 60 
5.5.4  Treatment Compliance ...................................................................................... 60 
5.5.5  Storage and Accountability ............................................................................... 60 
5.6 
Prior and Concomitant Medications and/or Procedures ................................................ 60 
5.6.1  Excluded Medications and/or Procedures ......................................................... 60 
5.6.2  Restricted Medications and/or Procedures ........................................................ 61 
5.6.3  Allowed Medications and/or Procedures .......................................................... 61 
5.6.4  Documentation of Prior and Concomitant Medication Use .............................. 62 
6  Study Procedures .................................................................................................................... 63 
6.1 
Informed Consent .......................................................................................................... 63 
6.2 
Screening Visit (-48 Hours to Day 1) ............................................................................ 63 
6.3 
Treatment Period – Day 1 Through End of Treatment ................................................. 65 
6.3.1  Day 1 ................................................................................................................. 65 
6.3.2  Day 2 ................................................................................................................. 66 
6.3.3  Day 3 ................................................................................................................. 66 
6.3.4  Day 4 ................................................................................................................. 67 
6.3.5  Day 5 ................................................................................................................. 68 
6.3.6  Day 6 ................................................................................................................. 69 
6.3.7  Day 7 to Day 14 and End of Treatment Visit .................................................... 69 
6.4 
Test of Cure Visit .......................................................................................................... 70 
6.5 
Late Follow-Up and Day 28 Visit ................................................................................. 71 
6.6 
Early Termination Visit/Withdrawal Procedures .......................................................... 71 
7  Efficacy Assessments .............................................................................................................. 73 
7.1 
Primary Efficacy Endpoint ............................................................................................ 73 
7.2 
Secondary Efficacy Endpoints ...................................................................................... 73 
7.3 
Other Efficacy Endpoints .............................................................................................. 73 
7.4 
Assessment of 28-Day Survival .................................................................................... 73 
7.5 
Assessment of Clinical Signs and Symptoms ............................................................... 74 


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7.6 
Clinical Outcome ........................................................................................................... 75 
7.7 
Microbiologic Assessments ........................................................................................... 76 
7.7.1  Respiratory Tract Specimens ............................................................................ 77 
7.7.2  Blood Specimens ............................................................................................... 78 
7.7.3  Urine Specimens ............................................................................................... 78 
7.7.4  Surgical or Post-Traumatic Wound Specimens................................................. 79 
7.8 
Microbiologic Outcome ................................................................................................ 79 
7.8.1  Microbiologic Outcome for Bacteremia, Complicated Urinary Tract Infection, 
or Acute Pyelonephritis ..................................................................................... 79 
7.8.2  Microbiologic Outcome for Hospital-Acquired Bacterial Pneumonia, 
Ventilator-Associated Bacterial Pneumonia, Ventilated Pneumonia, or 
Surgical or Post-Traumatic Wound Infections .................................................. 80 
7.9 
Pharmacokinetic Assessments ....................................................................................... 80 
7.9.1  Intense Pharmacokinetic Sampling ................................................................... 80 
7.9.2  Sparse Pharmacokinetic Sampling .................................................................... 81 
8  Safety Assessments ................................................................................................................. 83 
8.1 
Adverse Events .............................................................................................................. 83 
8.1.1  Adverse Drug Reaction ..................................................................................... 83 
8.1.2  Unexpected Adverse Drug Reaction ................................................................. 84 
8.1.3  Assessment of Adverse Events by the Investigator .......................................... 84 
8.1.4  Adverse Events of Special Interest .................................................................... 85 
8.2 
Serious Adverse Events ................................................................................................. 85 
8.3 
Serious Adverse Event Reporting − Procedures for Investigators ................................ 86 
8.4 
Pregnancy Reporting ..................................................................................................... 87 
8.5 
Expedited Reporting ...................................................................................................... 87 
8.6 
Clinical Laboratory Evaluations .................................................................................... 88 
8.7 
Vital Signs ..................................................................................................................... 88 
8.8 
Medical/Surgical History Assessments ......................................................................... 89 
8.9 
Electrocardiograms ........................................................................................................ 89 
8.10  Physical Examinations .................................................................................................. 89 
8.11  Chest X-Ray/Radiology/Ultrasound ............................................................................. 90 
8.12  Mechanical Ventilator Assessments .............................................................................. 90 
8.13  Safety Monitoring and Assessment of Abnormal Liver Function Tests ....................... 90 
9  Statistics .................................................................................................................................. 93 


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9.1 
Analysis Populations ..................................................................................................... 93 
9.2 
Statistical Methods ........................................................................................................ 94 
9.2.1  Patient Population and Characteristics .............................................................. 94 
9.2.2  Analysis of Efficacy .......................................................................................... 94 
9.2.2.1  Primary efficacy analysis .................................................................... 94 
9.2.2.2  Secondary efficacy analysis ................................................................ 95 
9.2.2.3  Exploratory efficacy analysis .............................................................. 95 
9.2.3  Pharmacokinetic Analysis ................................................................................. 95 
9.2.4  Analysis of Safety ............................................................................................. 96 
9.2.5  Sample Size Determination ............................................................................... 96 
9.3 
Data Safety Monitoring Board ...................................................................................... 97 
10  Data Management and Record Keeping ................................................................................. 98 
10.1  Data Management ......................................................................................................... 98 
10.1.1  Data Handling ................................................................................................... 98 
10.1.2  Computer Systems ............................................................................................. 98 
10.1.3  Data Entry ......................................................................................................... 98 
10.1.4  Medical Information Coding ............................................................................. 98 
10.1.5  Data Validation ................................................................................................. 98 
10.2  Record Keeping ............................................................................................................. 98 
11  Investigator Requirements and Quality Control ..................................................................... 99 
11.1  Ethical Conduct of the Study ........................................................................................ 99 
11.2  Institutional Review Board/Independent Ethics Committee ......................................... 99 
11.3  Informed Consent .......................................................................................................... 99 
11.4  Patient Card ................................................................................................................... 99 
11.5  Study Monitoring Requirements ................................................................................. 100 
11.6  Disclosure of Data ....................................................................................................... 100 
11.7  Retention of Records ................................................................................................... 100 
11.8  Publication Policy ....................................................................................................... 101 
11.9  Financial Disclosure .................................................................................................... 101 
11.10 Insurance and Indemnity ............................................................................................. 101 
11.11 Legal Aspects .............................................................................................................. 101 
12  Study Administrative Information ........................................................................................ 102 
12.1  Protocol Amendments ................................................................................................. 102 


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12.2  End of Study ................................................................................................................ 102 
12.3  Address List ................................................................................................................. 102 
12.3.1  Sponsor ............................................................................................................ 102 
12.3.2  Contract Research Organization ...................................................................... 102 
12.3.3  Serious Adverse Event Reporting ................................................................... 102 
12.3.4  Biological Specimens ...................................................................................... 103 
13  References ............................................................................................................................. 104 
Appendix A: Schedule of Procedures (Parts A & B) .................................................................. 106 
Appendix B: Central Clinical Laboratory Analytes .................................................................... 109 


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LIST OF TABLES 
Table 1. 
Study Drug Dose Adjustments by Renal Function ..................................................... 57 
Table 2. 
Unit Conversion Guidance .......................................................................................... 59 
Table 3. 
Signs and Symptoms for Presenting Indications ........................................................ 75 
Table 4. 
Sampling Times for Intense Pharmacokinetic Assessments ....................................... 81 
Table 5. 
Sampling Times for Sparse Pharmacokinetic Assessments ........................................ 81 
Table 6. 
Definition of RIFLE Criteria ...................................................................................... 85 
Table 7. 
28-Day All-Cause Mortality Rates in the CRABC m-MITT Population Required to 
Demonstrate Non-Inferiority and Superiority ............................................................. 97 


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LIST OF FIGURES 
Figure 1.  Study Design ............................................................................................................... 43 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
A. baumannii 
Acinetobacter baumannii 
ABC 
Acinetobacter baumannii-calcoaceticus complex 
ALT 
Alanine aminotransferase 
AP 
Acute pyelonephritis 
APACHE 
Acute Physiology and Chronic Health Evaluation 
AST 
Aspartate aminotransferase 
BAL 
Bronchoalveolar lavage 
BL 
β-lactam 
BLI 
β-lactamase inhibitor 
BPP 
Biofire® FilmArray® 2.0 Pneumonia Panel 
CBA 
Colistin base activity 
C. difficile 
Clostridium difficile 
CE 
Clinical Evaluable 
CFR 
Code of Federal Regulations 
CFU 
Colony-forming units 
CI 
Confidence interval 
CLSI 
Clinical and Laboratory Standards Institute 
CMS 
Colistimethate sodium 
COVID-19 
Coronavirus Disease 2019 
CRA 
Clinical research associate 
CRABC 
Carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex
CT 
Computed tomography 
CTA 
Clinical trial authorization 
cUTI 
Complicated urinary tract infection 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
EOT 
End of Treatment 
ET 
Early Termination 
ETX2514SUL 
Sulbactam-ETX2514 
FDA 
Food and Drug Administration 
FiO2 
Fraction of inspired oxygen 
GCP 
Good Clinical Practice 
HABP 
Hospital-acquired bacterial pneumonia 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 


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Abbreviation 
Definition 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
IU 
International unit 
IV 
Intravenous(ly) 
LFT 
Liver function test 
LFU 
Late Follow-up 
MAP 
Mean arterial pressure 
MDR 
Multi-drug resistant 
ME 
Microbiologic Evaluable 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
Minimum inhibitory concentration 
MITT 
Modified Intent-to-Treat 
MIU 
Million international unit 
m-MITT 
Microbiologically Modified Intent-to-Treat 
MRI 
Magnetic resonance imaging 
P. carinii 
Pneumocystis carinii 
PD 
Pharmacodynamic  
PEEP 
Positive end-expiratory pressure 
PK 
Pharmacokinetic(s) 
q6h 
Every 6 hours 
q12h 
Every 12 hours 
qSOFA 
Quick Sequential Organ Failure Assessment 
QTcF 
QT interval corrected using Fridericia’s formula 
RIFLE 
Risk–Injury–Failure–Loss–End-stage renal disease 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOFA 
Sequential Organ Failure Assessment 
TEAE 
Treatment-emergent adverse event 
TOC 
Test of Cure 
ULN 
Upper limit of normal 
US 
United States 
VABP 
Ventilator-associated bacterial pneumonia 
VP 
Ventilated pneumonia 
WBC 
White blood cell 
WHO 
World Health Organization 
XDR 
Extremely drug resistant 
 


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1 
INTRODUCTION AND BACKGROUND INFORMATION  
There is a significant unmet medical need to identify new agents to treat Acinetobacter baumannii 
(A. baumannii)-calcoaceticus complex (ABC) infections. Sulbactam-ETX2514 (ETX2514SUL) 
is a novel bactericidal β-lactam (BL)/β-lactamase inhibitor (BLI) combination, which is being 
developed for the treatment of infections caused by ABC, including multi-drug resistant (MDR) 
and carbapenem-resistant ABC (CRABC) isolates. 
Acinetobacter baumannii, a non-fermenting Gram negative bacterial species, is increasingly being 
recognized as an important cause of severe infections, particularly in compromised hospital 
patients. It is a significant public health concern and is classified as a “serious threat” pathogen in 
the recent United States (US) Centers for Disease Control and Prevention “Antibiotic Resistance 
Threats in the United States” report1 and is ranked as “critical” on the World Health Organization 
(WHO) global priority list of antibiotic-resistant bacteria to guide research, discovery, and 
development of new antibiotics. 2 Acinetobacter baumannii causes severe infections that are 
associated with high mortality. Approximately 2% of healthcare-associated infections are caused 
by A. baumannii.3 Patients on mechanical ventilators and those with central line-catheters have the 
highest proportion of infections caused by A. baumannii. Serious infections caused by 
A. baumannii, including hospital-acquired bacterial pneumonia (HABP)/ventilator-associated 
bacterial pneumonia (VABP), ventilated pneumonia (VP), complicated urinary tract 
infection (cUTI), bacteremia, and wound infections, are estimated to occur in 70,000 patients to 
90,000 patients in the United States per year, of which approximately 63% are caused by MDR 
isolates.4 Multi-drug resistance in A. baumannii is an evolving problem, with some countries in 
Europe reporting carbapenem resistance rates >50%.5 Mortality associated with bacteremia and 
pneumonia caused by A. baumannii ranges from 30% to 50%.6,7 The risk of death associated with 
infections caused by A. baumannii isolates resistant to carbapenems is even higher,1,7 and MDR 
A. baumannii is an evolving global problem. While most reports focus on A. baumannii as the 
etiological agent of these infections, several very closely related Acinetobacter species that are 
genotypically distinct but phenotypically indistinguishable from A. baumannii also cause human 
disease. Therefore, this group is referred to as the “Acinetobacter baumannii-calcoaceticus 
complex”.8 
In the early 1960s to 1970s, infections due to A. baumannii were managed effectively with BL 
antibiotics, as the rates of resistance to available antimicrobial classes were low.9,10 However, by 
the end of the 1970s, resistance to aminoglycosides and BL antibiotics had been reported. In the 
1980s, carbapenems such as imipenem became the drug of choice for treatment of A. baumannii 
infections; widespread carbapenem resistance, however, has now been observed in many 
countries.1,10 
In the late 1990s to 2000s, the in vitro activity and clinical effectiveness of sulbactam against 
A. baumannii were demonstrated.9 There has been a steady decline, however, in the in vitro 
susceptibility of A. baumannii to sulbactam. Presently, the majority of A. baumannii isolates are 
MDR, defined as non-susceptible to at least 3 or more antimicrobial categories, and many are 
extremely drug resistant (XDR), defined as non-susceptibility to at least 1 agent in all but 2 or 
fewer antimicrobial categories. 11  For example, data from the Healthcare Safety Network 
summarizing healthcare-associated infections reported that approximately 60% to 70% of 
A. baumannii isolates causing pneumonia or bacteremia were resistant to carbapenems and were 
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ETX2514 is a novel, rationally designed diazabicyclooctenone BLI. It is a potent inhibitor of 
Classes A and C β-lactamases and a broad-spectrum inhibitor of Class D β-lactamases. ETX2514 
has no activity against Class B β-lactamases. ETX2514 is not a BL. It displays a covalent, 
reversible mechanism of inhibition through β-lactamase active-site serine carbamoylation. 
ETX2514 exhibits intrinsic activity against some Enterobacteriaceae but has no significant 
clinical activity against A. baumannii. 
Sulbactam is a penicillin derivative and is used widely as an inhibitor of β-lactamases. Although 
sulbactam is available as a standalone product in a small number of countries (eg, Combactam™, 
Germany), the vast majority of human use is in combination with BL (eg, Unasyn™, 
ampicillin/sulbactam). Unasyn is approved by regulatory authorities in the United States, Europe, 
and the Asia-Pacific region. 
Entasis Therapeutics is developing ETX2514SUL for the treatment of serious infections caused 
by A. baumannii. The dose of sulbactam, 1 g once every 6 hours (q6h) (maximum daily dose in 
patients with normal renal clearance of 4 g), that will be used in combination with ETX2514 is the 
highest dose approved for human use. 
1.1 
Nonclinical Experience With ETX2514 
Nonclinical data are provided in more detail in the Investigator’s Brochure. 
The nonclinical safety program for ETX2514 includes toxicology studies up to 14 days duration 
in rats and dogs, safety pharmacology, and genetic toxicity. These studies demonstrate that 
ETX2514 was generally well tolerated and was not associated with target organ toxicity when 
administered in doses up to 2000 mg/kg. ETX2514 did not exhibit high protein binding, and in 
vitro data did not indicate significant drug-drug interactions via cytochrome P450 pathways or 
interactions with hepatic or renal transporters. ETX2514 was largely excreted unchanged in the 
urine. Reproductive toxicology studies are currently ongoing. 
1.2 
Clinical Experience With ETX2514 
A summary of clinical experience is provided in greater detail in the Investigator’s Brochure. 
ETX2514 has been evaluated both alone and in combination with sulbactam and/or 
imipenem/cilastatin in a Phase 1 first-in-human study. This study evaluated single ascending doses 
and multiple ascending doses of ETX2514 to fully characterize the safety and pharmacokinetics 
(PK) profile of ETX2514. In addition, this study evaluated if there was any clinically significant 
drug-drug interaction between sulbactam, ETX2514, and imipenem/cilastatin. 
Additionally, a Phase 1 study evaluated lung penetration by ETX2514 and sulbactam in 30 healthy 
volunteers. Administration of single doses of ETX2514SUL was also studied in patients with mild, 
moderate, or severe renal insufficiency, as well as in hemodialysis patients.  
A Phase 2 study in patients with cUTI or acute pyelonephritis (AP) has been completed. The 
primary objective of this study was to assess the safety of ETX2514SUL in moderately ill 
hospitalized patients. Study CS2514-2514-2017-0003 was conducted at 20 sites in 4 countries 
(Belarus, Bulgaria, Russia, and Ukraine). This study was a double-blind, randomized, 
placebo-controlled study to evaluate the safety and efficacy of intravenous (IV) ETX2514SUL in 
patients with cUTIs or AP who were otherwise relatively healthy. Patients providing informed 
consent and meeting all study eligibility criteria were enrolled and had a pretreatment urine and 
blood sample obtained and submitted to the local laboratory. Eighty patients were randomized in 


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a 2:1 ratio (53 patients randomized into the ETX2514SUL group and 27 patients randomized into 
the placebo group) to receive either 1 g ETX2514/1 g sulbactam IV (infused over 3 hours) or 
matching placebo q6h, respectively. All patients received background therapy with 
500 mg/500 mg IV imipenem/cilastatin q6h (infused over 30 minutes). Therapy was continued for 
7 days, with the option to increase for up to 14 days if bacteremia was present.  
Key findings from the above studies are summarized below: 
 ETX2514 demonstrated linear PK and had no evidence of accumulation. 
 ETX2514 did not interact with sulbactam and/or imipenem/cilastatin. 
 ETX2514 was predominantly excreted renally and dose adjustments were necessary for 
patients with moderate or severe renal insufficiency including dialysis. Similarly, higher doses 
are recommended for patients with augmented renal clearance or receiving continuous renal 
replacement therapy. 
 ETX2514SUL demonstrated good penetration of the lung epithelium. 
Efficacy results: 
 ETX2514SUL when dosed with imipenem/cilastatin showed comparable efficacy to 
placebo + imipenem/cilastatin in treatment of hospitalized patients with cUTI or AP. Among 
patients with imipenem nonsusceptible infections, imipenem combined with ETX2514SUL 
was able to successfully treat 3 out of 3 infections. 
Safety and tolerability results: 
 ETX2514 was generally safe and well tolerated when given alone or with sulbactam and/or 
imipenem/cilastatin. 
 To date, there have been no serious adverse drug reactions or deaths in clinical studies. 
 The most common adverse events reported were headache and infusion site reactions, 
including phlebitis and vascular pain at the infusion site. 
 Mild reductions in total white blood cell (WBC) and absolute neutrophil counts have been 
observed with multiple doses of ETX2514, although no events of leukopenia or neutropenia 
have been observed. 
 Asymptomatic, transient increases in hepatic enzymes (unaccompanied by increases in 
bilirubin) have been observed with ETX2514SUL, and these are thought to be related to known 
effects of sulbactam. 
 Mild to moderate allergic reactions including urticaria have been observed at rates <1% with 
ETX2514SUL. 
 No clinically significant changes in vital signs or electrocardiogram (ECG) parameters have 
been observed in patients treated with ETX2514SUL. Transient increases in systolic blood 
pressure within normal ranges were observed in healthy elderly subjects dosed with 
ETX2514SUL. 
 ETX2514, at the studied doses, had no clinically relevant effects on studied ECG parameters 
in a thorough QT study conducted in healthy volunteers. 


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1.3 
Rationale 
Entasis Therapeutics is developing ETX2514SUL for the treatment of serious infections caused 
by ABC, particularly those that are resistant to carbapenems. The dose of sulbactam, 1.0 g q6h 
(maximum daily dose in patients with normal renal clearance of 4 g), that will be used in 
combination with ETX2514 is the highest dose approved for human use, often in combination with 
ampicillin or cefoperazone. 
ETX2514 is a novel diazabicyclooctenone BLI with a spectrum of activity that encompasses 
clinically important β-lactamases of Ambler Class A and C and broad-spectrum inhibition of 
Class D β-lactamases. ETX2514 is not a BL. ETX2514 has greater potency than comparator BLIs, 
including clavulanic acid, tazobactam, and avibactam against all Class A, C, and D enzymes tested. 
ETX2514 does not inhibit the Class B New Delhi Metallo-β-lactamase 1.  
Sulbactam is classified as a BLI but also has intrinsic antibacterial activity against A. baumannii 
due to its inhibition of Penicillin Binding Protein 3, a transpeptidase that is essential for the final 
step of bacterial peptidoglycan synthesis.12 Although no breakpoint for A. baumannii has been 
established by the European Committee on Antimicrobial Susceptibility Testing or Clinical and 
Laboratory Standards Institute (CLSI) for sulbactam alone, sulbactam is used in combination with 
ampicillin (in a 2:1 ampicillin:sulbactam ratio) in therapy for A. baumannii. The CLSI has 
established breakpoints of 8/4 (ampicillin/sulbactam) mg/L for this agent for Acinetobacter 
species. Because the activity of ampicillin/sulbactam versus A. baumannii can be attributed to the 
sulbactam 
component 
alone, 
the 
CLSI-defined 
susceptible 
breakpoint 
of 
8/4 (ampicillin/sulbactam) mg/L that applies to the combination suggests a susceptible breakpoint 
of 4 mg/L for sulbactam alone in A. baumannii.  
The addition of ETX2514 to sulbactam in vitro restores the activity of sulbactam such that the 
minimum inhibitory concentration (MIC) to inhibit 90% of growth versus a collection of recent 
A. baumannii clinical isolates shifts from >32 mg/L to 2 mg/L in the presence of ETX2514 (held 
constant at 4 mg/L). In vitro experiments supported a susceptibility-testing paradigm of holding 
the concentration of ETX2514 constant at 4 mg/L while varying the sulbactam concentration in 
2-fold increments. This activity of sulbactam-ETX2514 was consistent across A. baumannii 
isolates from different geographic regions and infection types and did not change in subsets of 
meropenem-resistant, colistin-resistant, or MDR isolates, nor did it change over time (a total of 
3611 isolates collected from 2011 to 2018 were tested). A detailed assessment of human dose 
projection of sulbactam-ETX2514 was performed utilizing PK parameters from human Phase 1 
and Phase 2 data, lung penetration data, PK/pharmacodynamic (PD) targets, and current MIC 
distribution versus A. baumannii. A preliminary probability of target attainment was completed. 
The result of these analyses suggested a 3-hour infusion of 1.0 g sulbactam/1.0 g ETX2514 
administered 4 times a day is predicted to be effective to treat patients infected with A. baumannii 
with MICs 4 mg/L. Complete details of this assessment can be found in the Investigator’s 
Brochure. 
Current treatment guidelines (Infectious Diseases Society of America/American Thoracic Society) 
for the treatment of HABP/VABP/VP due to A. baumannii recommend the use of carbapenems or 
ampicillin/sulbactam as first-line agents as long as the isolates are sensitive to these drugs. 
However, in the event of carbapenem resistance, the current recommended regimens are to use 
polymyxins such as colistin to treat these infections. This study utilizes a combination of colistin 
and imipenem as the comparator. The combination of a carbapenem with a polymyxin has been 
shown to have increased activity in vitro against A. baumannii.13 The selection of the comparator 


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for this study is challenging. The possibility of utilizing “best-available care” as the comparator 
was considered, but it was determined that this was not a satisfactory option because of the size of 
the study and the potential to confound assessment of comparative efficacy. On a world-wide basis, 
including Europe, the majority of ABC isolates are MDR. Common regimens that are utilized 
include colistin either alone or plus a carbapenem and tigecycline plus 1 or more agents. It is of 
interest that tigecycline is not indicated for treatment of patients with pneumonia in Europe or for 
the treatment of HABP/VABP/VP in the United States. 
Based on these considerations, this study will use colistin plus imipenem/cilastatin as the 
comparator. Imipenem/cilastatin is indicated for the treatment of HABP/VABP/VP and is widely 
used in this indication. Part A will enroll patients prior to the availability of antibiotic sensitivities, 
and it is anticipated that approximately 40% of ABC infections could be sensitive to carbapenem. 
Imipenem/cilastatin would be the drug of choice in this population. For those patients with 
CRABC infection, colistin would be the drug of choice. Although recent data14 suggest that the 
addition of a carbapenem to colistin may not be synergistic in the treatment of CRABC infections, 
there was no suggestion of a negative effect of this combination. Moreover, discontinuation of 
imipenem/cilastatin in these patients after randomization will result in unblinding of treatment 
assignment. Lastly, assessment of efficacy of the combination of ETX2514 with both sulbactam 
and imipenem/cilastatin in the treatment of CRABC infections would entail not discontinuing the 
carbapenem in the investigational treatment group. Hence, all patients in this study will receive 
imipenem/cilastatin regardless of the carbapenem sensitivity of the ABC infection. 
This is a Phase 3, randomized, active-controlled pivotal study to evaluate the efficacy and safety 
of IV ETX2514SUL plus imipenem/cilastatin compared to colistin plus imipenem/cilastatin in the 
treatment of patients with ABC infections. In Part A, all patients will receive imipenem/cilastatin 
as the best treatment option for HABP, VABP, VP, and/or bacteremia caused by ABC. In addition, 
the experimental group will receive ETX2514SUL, while the comparator group will receive 
colistin, both agents targeting drug-resistant ABC. These combinations of drugs should provide all 
patients with the best treatment options for ABC infections, while anticipating a high rate of drug 
resistant ABC infections.  
Part B will be the open-label, supportive portion of the study that will include patients known to 
have HABP, VABP, VP, and/or bacteremia infections associated with ABC organisms that are 
known to be resistant to colistin or polymyxin B, those failing a colistin or polymyxin B regimen 
prior to study entry or are on acute renal replacement therapy, and patients with infections due to 
colistin- or polymyxin B-resistant ABC with sources of infection other than HABP, VABP, VP, 
and/or bacteremia. The goal is to gather preliminary efficacy and safety data in the setting of these 
other infections and provide a salvage option for XDR strains of ABC infections; hence, Part B 
will not be pivotal and will not have a comparator. The objective of Part B will be to estimate 
efficacy of the combination of sulbactam and ETX2514 against colistin- or polymyxin B-resistant 
ABC infecting various sites, as supporting evidence for Part A results. Safety of ETX2514SUL 
will be assessed as a whole in Part A and Part B. 
1.4 
Risk/Benefit 
No unique contraindications have been determined for ETX2514. Contraindications to the use of 
sulbactam include a history of hypersensitivity or allergic reactions to sulbactam or any 
cephalosporin, penicillin, or carbapenem. 


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ETX2514 was well tolerated in repeat dose animal toxicology studies; no specific safety signals 
were observed that require special monitoring in human subjects. Reductions in absolute 
neutrophil count and monocytes were reported in the dog repeat dose toxicity studies and will be 
monitored by routine hematology assessments in human subjects. 
Studies in healthy adult and elderly subjects and in patients with renal impairment or cUTI have 
revealed no serious adverse drug reactions or deaths to date, and the withdrawal rate due to adverse 
events has been low (1%). Adverse events have generally been mild to moderate in severity. The 
most common treatment-emergent adverse events (TEAEs) in both healthy elderly subjects and in 
patients have included injection site reactions/pain and headache; the less common TEAEs in 
patients were nausea, diarrhea, and vomiting. Overall, ETX2514SUL has been well tolerated, and 
only 1 drug-unrelated serious adverse event (SAE) has been reported to date. Doses of 
ETX2514SUL must be adjusted in patients with impaired renal function. Mild decreases from 
baseline in mean WBC and neutrophil counts have been observed in subjects receiving ETX2514 
alone or multiple doses of ETX2514 with imipenem/cilastatin. Mild increases in alanine 
aminotransferase (ALT) were observed with administration of ETX2514SUL with 
imipenem/cilastatin. These findings were not considered clinically significant since mean values 
remained within the reference range at all time points. However, WBC counts and hepatic function 
will be monitored closely in ongoing clinical studies. No clinically significant changes in vital 
signs or ECG parameters have been observed in patients treated with ETX2514SUL with or 
without imipenem/cilastatin. 
Although sulbactam is available as a standalone product in a small number of countries 
(eg, Combactam, Germany), the vast majority of human use is in combination with BLs 
(eg, Unasyn, combination of ampicillin/sulbactam). The clinical safety of sulbactam has been 
established by nearly 30 years of experience with Unasyn. Based on the product label, Unasyn is 
generally safe and well tolerated. The dose of sulbactam that will be used in combination with 
ETX2514 is the highest dose approved for human use (1.0 g q6h, maximum daily dose in patients 
with normal renal clearance of 4.0 g).15 The most frequently reported adverse events reported with 
Unasyn are nausea, vomiting, diarrhea, pain at the injection site, and skin rash. Hepatic 
dysfunction, including hepatitis and cholestatic jaundice, has been associated with the use of 
sulbactam. Hepatic toxicity is usually reversible; however, deaths have been reported. Routine 
monitoring of liver function will be conducted at baseline and during and after administration of 
ETX2514SUL. 
Dose adjustments are necessary for severe renal insufficiency and hemodialysis patients. It is 
expected that the combination of ETX2514SUL with imipenem/cilastatin will have high levels of 
penetration in the lung and, hence, should show good efficacy in treatment of patients with 
ABC pneumonia. Reproductive studies for ETX2514 have not yet been completed, so precautions 
against exposure in pregnant women and avoidance of pregnancy of participants in this study are 
necessary. Allergic and hypersensitivity reactions are a potential risk, as with all antimicrobials, 
and patients with serious known allergies to BLs will not be enrolled in the study. 
Colistin is now used routinely for Gram negative infections that are resistant to carbapenems, based 
on treatment guidelines in most countries with high prevalence of such infections. The risk of 
nephrotoxicity and neurotoxicity are well described in the colistin label and the literature. Dosing 
of colistin in this trial is weight-based and will be adjusted based on daily calculations of estimated 
glomerular filtration rate (eGFR). Patients will be monitored for worsening renal function and 


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signs of neurotoxicity. Patients with contraindications for colistin treatment may be considered for 
enrollment in Part B of the study. 
Imipenem/cilastatin is indicated for a broad variety of infections and has been approved for use 
for many years for the treatment of serious infections, including those caused by ABC. Key risks, 
including hypersensitivity and seizures, are well documented in the literature. Dose adjustments 
for renal insufficiency are being implemented in the dosing of patients in this protocol as a key 
risk mitigation. Drugs that are contraindicated with the use of imipenem/cilastatin are not allowed 
for use in this protocol. 


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2 
STUDY OBJECTIVES 
This is a 2-part study, with Part A being the randomized, controlled portion of the study in patients 
with ABC HABP, VABP, VP, or bacteremia. Part B is the single-group portion of the study and 
includes ABC infections that are resistant to or have failed colistin or polymyxin B treatment, as 
detailed in the inclusion criteria. 
2.1 
Primary Objectives 
The primary objectives of this study are the following: 
 To compare the efficacy of ETX2514SUL plus imipenem/cilastatin to colistin plus 
imipenem/cilastatin in patients with CRABC infections in Part A; and 
 To 
compare 
the 
incidence 
of 
nephrotoxicity, 
as 
measured 
by 
the 
Risk–Injury–Failure–Loss–End-stage renal disease (RIFLE) criteria, of ETX2514SUL to 
colistin in patients with ABC infections in Part A. 
2.2 
Secondary Objectives 
The secondary objectives of this study are the following: 
 To compare the efficacy of ETX2514SUL plus imipenem/cilastatin to colistin plus 
imipenem/cilastatin in all randomized patients in Part A;  
 To evaluate the efficacy of ETX2514SUL plus imipenem/cilastatin in patients with colistin- or 
polymyxin B-resistant ABC infections in Part B;  
 To estimate the efficacy of ETX2514SUL plus imipenem/cilastatin for each primary infection 
site;  
 To evaluate and compare the safety of ETX2514SUL and colistin; 
 To describe the overall safety profile of ETX2514SUL; and 
 To determine the systemic exposure of ETX2514 and sulbactam in a small cohort of severely 
ill patients administered ETX2514SUL in Part A. 
2.3 
Exploratory Objectives 
The exploratory objectives of this study are the following: 
 To evaluate the efficacy of ETX2514SUL in relation to PK exposure; 
 To evaluate the efficacy of ETX2514SUL in relation to MIC distribution of ETX2514SUL; 
 To evaluate the efficacy of ETX2514SUL in relation to total duration of treatment received; 
and 
 To compare the resource utilization of patients receiving ETX2514SUL plus 
imipenem/cilastatin to patients receiving colistin plus imipenem/cilastatin. 


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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This study is a randomized, active-controlled study to evaluate the safety and efficacy of IV 
ETX2514SUL in patients with ABC infections. Patients providing informed consent and meeting 
all study eligibility criteria will be enrolled in the study and have pretreatment blood and infection 
site-specific samples obtained and submitted to the local laboratory.  
The study will be enrolled in 2 parallel parts, with the PK data from the first approximately 
30 patients in Part A (with only 15 patients dosed with ETX2514SUL) reviewed prior to initiating 
enrollment in Part B: 
a. Part A will be the pivotal, assessor-blind, randomized, comparative portion of the study in 
patients with documented ABC HABP, VABP, VP, or bacteremia. While study drugs will not 
be masked due to logistical reasons, every attempt will be made to maintain the blind for 
patients, all staff at the site, and the Sponsor or its designees, except for the treatment physician 
and other immediate healthcare providers (see Section 5.4). In Part A, patients will be 
randomized 1:1 to 1 of the following treatment groups: 
o Group 1: 1.0 g ETX2514/1.0 g sulbactam IV infused over 3 hours q6h plus 1.0 g 
imipenem/1.0 g cilastatin IV infused over 1 hour q6h; or 
o Group 2: 2.5 mg/kg colistin IV infused over 30 minutes every 12 hours (q12h) plus 1.0 g 
imipenem/1.0 g cilastatin IV infused over 1 hour q6h. 
Patients will be enrolled until there are 120 patients in the CRABC Microbiologically Modified 
Intent-to-Treat (m-MITT) Population in Part A, as determined by the central microbiology 
laboratory. Approximately 200 patients are expected to be enrolled in Part A, assuming 
approximately 60% of patients will have CRABC (see Section 9 for complete details). The 
HABP/VABP/VP patients who are randomized to Part A based on a positive screening of a 
respiratory sample for ABC by the Biofire FilmArray 2.0 Pneumonia Panel (BPP), but who 
subsequently do not have growth of ABC in their respiratory sample culture processed by the 
local microbiology laboratory, will be withdrawn from the study drug treatment. 
Randomization will be stratified by indication (HABP/VABP/VP versus bacteremia), severity 
of illness (based on Acute Physiology and Chronic Health Evaluation [APACHE] II [10 to 
19 versus 20 to 30], Sequential Organ Failure Assessment [SOFA] [7 to 9 versus 10], or quick 
SOFA [qSOFA] [2 versus 3] score at Screening), and geography (China Mainland versus Rest 
of World). In the situation where a patient has more than one score reported, the scores will be 
used in the following order: APACHE, SOFA, and qSOFA. 
Enrollment of HABP, VP, and bacteremia patients will be limited to a total of no more than 
40% of patients in Part A, regardless of resistance. 
b. Part B will be the open-label, supportive portion of the study that will include patients known 
to have HABP, VABP, VP, and/or bacteremia infections associated with ABC organisms that 
are known to be resistant to colistin or polymyxin B, those failing a colistin or polymyxin B 
regimen prior to study entry or are on acute renal replacement therapy, and patients with 
infections due to colistin- or polymyxin B-resistant ABC with sources of infection other than 
HABP, VABP, VP, and/or bacteremia, as detailed in Section 4.1.3.  


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Any patient who has a qualifying ABC infection and meets study inclusion criteria but has a 
contraindication to colistin due to underlying conditions, intolerance, or evidence of 
failing colistin or polymyxin B therapy prior to study entry, and/or has a colistin- or 
polymyxin B-resistant ABC infection cannot be enrolled in Part A but can be considered for 
enrollment in Part B (see Section 4 for details). 
Patients with ABC infections who are not otherwise eligible for Part A are expected to be 
enrolled in Part B. Patient enrollment in Part B will continue until Part A enrollment in the 
CRABC m-MITT Population is complete. In Part B, patients will receive the following 
treatment: 
o Group 3: 1.0 g ETX2514/1.0 g sulbactam IV infused over 3 hours q6h plus 1.0 g 
imipenem/1.0 g cilastatin IV infused over 1 hour q6h. 
Transfer from Part A to Part B: Since Part A will be the first time patients in intensive care are 
receiving ETX2514SUL, PK in the first approximately 30 patients must be verified prior to 
initiating Part B to ensure the treatment planned in Part B is optimal for the targeted patient 
population. Patients randomized to either group of Part A can only be transferred to Part B, once 
Part B is open for enrollment, if the ABC identified from the baseline culture is subsequently 
determined to be resistant to colistin or polymyxin B by the local microbiology laboratory. If 
Part B is not yet open for enrollment in a given country and a patient in Part A has a baseline 
culture determined to be colistin- or polymyxin B-resistant but is responding to therapy, the patient 
may remain in Part A at the discretion of the Investigator. A patient in Part A whose culture is 
determined to be colistin- or polymyxin B-resistant and who has not shown improvement or whose 
condition has worsened will be withdrawn from the study drug treatment. All such cases must be 
discussed with the Medical Monitor. 
Any organism isolated from the blood or infection site-specific cultures will be identified by genus 
and species by the local laboratory. Organisms will be cultured and quantified (urine and 
bronchoalveolar lavage [BAL] only) at the local laboratory, and susceptibility of the organism(s) 
will be performed per local laboratory standards. Isolates of pathogens cultured at the local 
laboratory are to be sent to the central laboratory for confirmation of identification and 
susceptibility testing.  
No dosing regimen changes, other than those specified in the protocol for renal insufficiency (see 
Section 5.3) or for patients on imipenem who develop a seizure that is thought to be directly related 
to imipenem, can occur without discussion with the Medical Monitor. Patients with cultures 
growing organisms with evidence of carbapenem resistance should remain on their assigned 
treatment regimen; treatment regimen changes can occur after 5 days after discussion with the 
Medical Monitor. If changes to the regimen are needed due to unsatisfactory clinical response, 
patients should be classified as clinical failures and discontinued from study drug. All patients 
should receive at least 48 hours of IV study drug (ie, 8 doses of ETX2514SUL plus 8 doses of 
imipenem/cilastatin or 4 doses of colistin plus 8 doses of imipenem/cilastatin in patients without 
dose adjustments) before the Investigator considers the patient to be a clinical failure and 
discontinues the patient from study drug therapy.  
Note: Patients who experience focal tremors, myoclonus, or seizures at any point during the study 
should be evaluated neurologically, placed on anticonvulsant therapy (if not already instituted), 
and the dose of imipenem/cilastatin should be evaluated to determine whether it should be 
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Day 1 is defined as the first day of study drug administration. The subsequent study days are 
defined by the number of treatment days thereafter. Treatment days should constitute 24 hours of 
treatment. For those patients with no dose adjustments, the duration of antibiotic treatment with 
study drug therapy will be 28 doses of ETX2514SUL plus 28 doses of imipenem/cilastatin or 
14 doses of colistin plus 28 doses of imipenem/cilastatin (ie, treatment for 7 days for those without 
dose adjustments), with a prolongation of therapy up to 14 days if clinically indicated. Refer to the 
Pharmacy Manual for specifics on dosing for all patients. 
The overall study design is shown in Figure 1. 
Figure 1. Study Design 
 
*Part B: Part B will be the open-label, supportive portion of the study that will include patients known to have HABP, VABP, 
VP, and/or bacteremia infections associated with ABC organisms that are known to be resistant to colistin or polymyxin B, those 
failing a colistin or polymyxin B regimen prior to study entry or are on acute renal replacement therapy, and patients with 
infections due to colistin- or polymyxin B-resistant ABC with sources of infection other than HABP, VABP, VP, and/or 
bacteremia. The total number of patients enrolled in Part B may be adjusted based on the number needed to be enrolled in Part A 
to achieve the number needed to be treated in the CRABC m-MITT Population. 
ABC = Acinetobacter baumannii-calcoaceticus complex; APACHE = Acute Physiologic Assessment and Chronic Health 
Evaluation; CRABC = Carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex; cUTI = complicated urinary tract 
infection; ETX2514SUL = sulbactam-ETX2514; HABP = hospital-acquired bacterial pneumonia; IMI = imipenem/cilastatin; 
LFU = Late Follow-up; m-MITT = Microbiologically Modified Intent-to-Treat; q6h = every 6 hours; q12h = every 12 hours; 
TOC = Test of Cure; VABP = ventilator-associated bacterial pneumonia; VP = ventilated pneumonia. 
Patients who have early discontinuation of study drug dosing should perform all End of Treatment 
(EOT) Visit procedures and should be followed through the Late Follow-up (LFU) Visit for safety 
assessments, even if the reason for discontinuation is clinical failure. 
In Part A, clinical outcome assessments will be performed by a blinded assessor, in addition to the 
unblinded Investigator. Whenever possible, the same blinded assessor should complete all clinical 
outcome assessments for a study patient. If there is a discrepancy between the assessment of the 
blinded assessor and unblinded Investigator, the assessment from the blinded assessor will be used. 
If there is a missing assessment from either the blinded assessor or unblinded Investigator, the 


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other available assessment will be used. An adjudication committee may be organized for endpoint 
adjudication should it be deemed necessary as determined by the Data Safety Monitoring Board 
(DSMB). In such a case, a charter will be developed that describes their activities. 
Intense PK sampling will be performed on the first approximately 30 patients randomized in 
Part A. The purpose of the intense PK sampling is to ensure that exposures observed in this 
severely ill cohort are comparable to those observed thus far in prior clinical studies. The PK 
samples will be collected for both treatment groups in Part A to keep the study data blinded. 
Pharmacokinetic assessment of the initial 15 patients on ETX2514SUL in Part A will be performed 
by an independent PK assessor, prior to the opening of enrollment in Part B. To explore the PK 
profile of the ETX2514SUL combination in Chinese patients with severe infection, the intense PK 
sample will also be collected from the first approximately 20 patients randomized in Part A at 
China Mainland sites. All other patients enrolled in the study (Parts A and B) will have samples 
collected for sparse PK analysis, which will be used to better inform the population PK model.  
Patients will be enrolled in the study for approximately 28 days, with a maximum duration of 
32 days. Screening laboratory analytes can be performed as standard of care up to 48 hours prior 
to randomization on Day 1, with the exception of local laboratory serum creatinine determination, 
which must be obtained at the local laboratory within 24 hours of the first dose of study drug. The 
Treatment Period begins on Day 1, and study drug will be administered for 7 days (ie, 28 doses of 
ETX2514SUL plus 28 doses of imipenem/cilastatin or 14 doses of colistin plus 28 doses of 
imipenem/cilastatin for those without dose adjustments) with a prolongation of therapy of up to 
14 days if clinically indicated. The EOT Visit will be completed on the final dosing day or the 
following day. The Test of Cure (TOC) Visit will be completed 7 days (2 days) after the EOT 
Visit for all patients. The LFU Visit will be completed 14 days (2 days) after the EOT Visit for 
all patients. For patients with an LFU Visit occurring before Day 28, a telephone call to assess 
survival will be made on Day 28 or anytime thereafter. Every attempt must be made to record 
survival status at Day 28 or anytime thereafter for all randomized patients (including 
HABP/VABP/VP patients who are randomized to Part A based on a positive BPP rapid test, but 
who subsequently do not have growth of ABC in their respiratory sample culture), regardless of 
their status of treatment, as long as the patient has not withdrawn consent from participation in the 
study. 
3.2 
Study Indication 
ETX2514SUL is indicated for the treatment of serious infections caused by ABC. 


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4 
SELECTION AND WITHDRAWAL OF PATIENTS  
4.1 
Inclusion Criteria 
4.1.1 
General Inclusion Criteria 
Patients who meet all of the following general inclusion criteria, in addition to the specific 
inclusion criteria listed below for Parts A and B, will be eligible to participate in the study: 
1. A signed informed consent form (ICF); 
Note: If a study patient is unable to provide informed consent due to their medical condition, 
the patient’s legally authorized representative may consent on behalf of the study patient, or 
the decision can be made according to the procedure permitted by local law and institutional 
Standard Operating Procedures in compliance with Section 6.1. 
2. Male or female 18 years of age; 
3. A confirmed diagnosis of a serious infection and the expectation, in the judgment of the 
Investigator, that the patient’s infection will require treatment with IV antibiotics; 
4. A known infection caused by ABC (bacteremia, HABP, VABP, VP, cUTI or AP, or surgical 
or post-traumatic wound infections) as either a single pathogen or member of a polymicrobial 
infection based on evidence from culture or, if available, rapid diagnostic test from a sample 
collected within 72 hours prior to randomization (HABP/VABP/VP patients), AND 1 of the 
following: 
a. Has received no more than 48 hours of potentially effective (ie, Gram negative 
coverage) antimicrobial therapy prior to the first dose of study drug; OR 
b. Is clinically failing prior treatment regimens (ie, clinical deterioration or failure to 
improve after at least 48 hours of antibiotic treatment); 
Note: Rapid testing of respiratory specimens utilizing BPP technology (see Section 7.7) should 
be used to enable early identification of ABC pneumonia. Patients can be randomized based 
on the results of the BPP rapid test while awaiting results of cultures from the local laboratory. 
However, if the respiratory sample does not grow ABC in the local microbiology laboratory 
culture, these patients will be withdrawn from the study drug treatment. 
Note: Isolation of ABC from pleural effusion (empyema) is allowed, if concurrent pulmonary 
infiltrate is confirmed. 
5. APACHE II score between 10 and 30, inclusive, OR SOFA score between 7 and 11, inclusive, 
at the time of diagnosis of infection. Patients who are not being treated in an intensive care unit 
and cannot have an APACHE II or SOFA score performed should have a qSOFA score 2 for 
enrollment; 
6. Expectation, in the judgment of the Investigator, that the patient will benefit from effective 
antibiotic therapy and appropriate supportive care for the anticipated duration of the study; and 


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7. Women of childbearing potential (ie, not post-menopausal or surgically sterilized) must have 
a negative highly sensitive urine or serum pregnancy test before randomization. Participating 
women of childbearing potential must be willing to consistently use one highly effective 
method of contraception (ie, condom, combined oral contraceptive, implant, injectable, 
indwelling intrauterine device, or a vasectomized partner) from Screening until at least 30 days 
after administration of the last dose of study drug. 
4.1.2 
Part A-Specific Inclusion Criteria 
In addition to those general inclusion criteria listed in Section 4.1.1, patients may enroll in Part A 
if they meet the criteria below. All patients must be categorized in 1 infection type that is judged 
to be the primary infection by the Investigator: 
1. Diagnosed with HABP, VABP, VP, and/or bacteremia, defined as: 
HABP With ABC in Sputum/Respiratory Sample 
All of the following: 
AND signs or symptoms evidenced 
by at least 2 of the following: 
AND at least 1 of the 
following: 
 
Onset of symptoms >48 hours 
after admission or 7 days after 
discharge from an inpatient acute 
or chronic care facility 
(eg, LTAC, rehabilitation center, 
hospital, or skilled nursing 
home); OR 
 
Admission from LTAC or 
rehabilitation center, or 
admission from home <7 days 
after discharge from an LTAC or 
rehabilitation center; AND 
 
New or evolving infiltrate on 
chest X-ray, MRI, CT scan, or 
ultrasound obtained within 
48 hours prior to randomization. 
Note: If an ultrasound is 
performed, a confirmatory X-ray 
or CT scan should be performed 
within 24 hours. 
 
A new onset of cough (or 
worsening of baseline cough); 
 
Auscultatory findings consistent 
with pneumonia/pulmonary 
consolidation (eg, rales, dullness 
on percussion, bronchial breath 
sounds, or egophony); 
 
Dyspnea, tachypnea, or 
respiratory rate 
>25 breaths/minute; OR 
 
Hypoxemia (oxygen saturation 
<90% or pO2 <60 mmHg while 
breathing room air, or worsening 
of the oxygen saturation/ FiO2); 
OR the following ALONE: 
 
New onset need for mechanical 
ventilation. 
 
Fever [1] (oral or tympanic 
temperature 38°C 
[100.4°F] or rectal/core 
temperature 38.3°C 
[100.9°F]) OR 
hypothermia (rectal/core 
temperature <35°C 
[<95°F]); 
 
Elevated total peripheral 
WBC count 
(>10,000/mm3); 
 
>15% immature 
neutrophils (bands) 
regardless of total 
peripheral WBC count; 
OR 
 
Leukopenia (total WBC 
count <4500/mm3). 
1. 
Evidence of fever within 24 hours of the Screening Visit is acceptable if observed and documented by a healthcare 
provider. 
ABC = Acinetobacter baumannii-calcoaceticus complex; CT = computed tomography; FiO2 = fraction of inspired oxygen; 
HABP = hospital-acquired bacterial pneumonia; LTAC = long-term acute care; MRI = magnetic resonance imaging; 
pO2 = partial pressure of oxygen; WBC = white blood cell.
 
 
 


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VABP With ABC in Sputum/Respiratory Sample 
All of the following: 
AND signs or symptoms evidenced 
by at least 2 of the following: 
AND at least 1 of the 
following: 
 
Onset of symptoms >48 hours 
after receiving ventilator support 
via an endotracheal (or 
nasotracheal) tube;  
 
Requires ventilator support; 
AND 
 
New or evolving infiltrate on 
chest X-ray, MRI, CT scan, or 
ultrasound obtained within 
48 hours prior to randomization. 
Note: If an ultrasound is 
performed, a confirmatory X-ray 
or CT scan should be performed 
within 24 hours. 
 
Auscultatory findings consistent 
with pneumonia/pulmonary 
consolidation (eg, rales, dullness 
on percussion, bronchial breath 
sounds, or egophony); 
 
An acute change in the ventilator 
support system to enhance 
oxygenation, as determined by a 
worsening oxygen saturation/FiO2 
ratio; 
 
Increased suctioning; OR 
 
Tracheal aspirate change to 
purulence. 
 
Fever [1] (oral or tympanic 
temperature 38°C 
[100.4°F] or rectal/core 
temperature 38.3°C 
[100.9°F]) OR 
hypothermia (rectal/core 
temperature <35°C 
[<95°F]); 
 
Elevated total peripheral 
WBC count 
(>10,000/mm3); 
 
>15% immature 
neutrophils (bands) 
regardless of total 
peripheral WBC count; 
OR 
 
Leukopenia (total WBC 
<4500/mm3). 
1. 
Evidence of fever within 24 hours of the Screening Visit is acceptable if observed and documented by a healthcare 
provider. 
ABC = Acinetobacter baumannii-calcoaceticus complex; CT = computed tomography; FiO2 = fraction of inspired oxygen; 
MRI = magnetic resonance imaging; VABP = ventilator-associated bacterial pneumonia; WBC = white blood cell. 
 
Ventilated Pneumonia With ABC in Respiratory Sample 
All of the following: 
AND signs or symptoms evidenced 
by at least 2 of the following: 
AND at least 1 of the 
following: 
 
Requires ventilator support; 
AND 
 
New or evolving infiltrate on 
chest X-ray, MRI, CT scan, or 
ultrasound obtained within 
48 hours prior to randomization. 
Note: If an ultrasound is 
performed, a confirmatory X-ray 
or CT scan should be performed 
within 24 hours. 
 
Auscultatory findings consistent 
with pneumonia/pulmonary 
consolidation (eg, rales, dullness 
on percussion, bronchial breath 
sounds, or egophony); 
 
An acute change in the ventilator 
support system to enhance 
oxygenation; 
 
Increased suctioning; OR 
 
Tracheal aspirate change to 
purulence. 
 
Fever [1] (oral or tympanic 
temperature 38°C 
[100.4°F] or rectal/core 
temperature 38.3°C 
[100.9°F]) OR 
hypothermia (rectal/core 
temperature <35°C 
[<95°F]); 
 
Elevated total peripheral 
WBC count 
(>10,000/mm3); 
 
>15% immature 
neutrophils (bands) 
regardless of total 
peripheral WBC count; 
OR 
 
Leukopenia (total WBC 
count <4500/mm3).
1. 
Evidence of fever within 24 hours of the Screening Visit is acceptable if observed and documented by a healthcare 
provider. 
ABC = Acinetobacter baumannii-calcoaceticus complex; CT = computed tomography; MRI = magnetic resonance imaging; 
WBC = white blood cell. 
 


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4.1.3 
Part B-Specific Inclusion Criteria 
Part B will include patients with the following ABC infections: HABP, VABP, VP, or bacteremia 
who do not qualify for Part A, and cUTI/AP or surgical or post-traumatic wound infections.  
1. Patients with HABP, VABP, VP, or bacteremia should be considered for enrollment in Part B 
if they meet ANY of the following criteria (a, b, c, OR d), in addition to the general inclusion 
criteria listed in Section 4.1.1: 
a. Has an infection caused by ABC organisms known to be resistant to colistin or 
polymyxin B (defined as MIC 4 mg/L by a non-agar based method); 
For known colistin- or polymyxin B-resistant infections, the following must be 
satisfied: 
o Has a known resistant infection based on evidence from culture and susceptibility 
testing by a non-agar based method within 72 hours prior to randomization, alone 
or as a single organism of a polymicrobial infection; AND has received no more 
than 48 hours of an antimicrobial agent to which the ABC is susceptible prior to 
the first dose of study drug; 
OR 
o Has documented clinical evidence of failure (ie, clinical deterioration or failure to 
improve that is attributable to ABC infection) after at least 48 hours of treatment 
with colistin or polymyxin B; OR 
Bacteremia With ABC 
All of the following: 
AND at least 1 of the following: 
 
Isolation of ABC from at least 1 blood culture collected from a 
peripheral vein OR newly placed intravenous line. 
 
Fever [1] (oral or tympanic 
temperature 38°C 
[100.4°F] or rectal/core 
temperature 38.3°C 
[100.9°F]) OR hypothermia 
(rectal/core temperature 
<35°C [<95°F]); 
 
Elevated total peripheral 
WBC count (>10,000/mm3); 
 
>15% immature neutrophils 
(bands) regardless of total 
peripheral WBC count; 
 
Leukopenia (total WBC count 
<4500/mm3);  
 
Tachycardia >100 bpm; 
 
Tachypnea 
>25 breaths/minute; OR 
 
Hypotension, systolic 
<90 mmHg. 
1. 
Evidence of fever within 24 hours of the Screening Visit is acceptable if observed and documented by a healthcare 
provider. 
ABC = Acinetobacter baumannii-calcoaceticus complex; bpm = beats per minute; WBC = white blood cell. 


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b. Has known intolerance to colistin;  
Note: Patients whom the Investigator feels may have a potential intolerance to colistin 
can be enrolled in Part B on a case-by-case basis after discussion with the Medical 
Monitor; OR 
c. Has myasthenia gravis or another neuromuscular syndrome(s) that contraindicates 
colistin and is not ventilated;  
Note: Ventilated patients with myasthenia gravis or other neuromuscular syndromes 
where, in the opinion of the Investigator, colistin administration is reasonable are 
permitted for consideration for the study; OR 
d. Has acute kidney injury and is receiving renal replacement therapy at study entry; 
2. Patients diagnosed with cUTI, AP, or surgical or post-traumatic wound infections may enroll 
in Part B if they meet the general inclusion criteria listed in Section 4.1.1 as well as either a, 
b, c, d, OR e in addition to the indication requirements for f: 
a. Has an infection caused by ABC organisms known to be resistant to colistin or 
polymyxin B (defined as MIC 4 mg/L by a non-agar based method); OR 
b. Has known intolerance to colistin;  
Note: Patients whom the Investigator feels may have a potential intolerance to colistin 
can be enrolled in Part B on a case-by-case basis after discussion with the Medical 
Monitor; OR 
c. Has myasthenia gravis or another neuromuscular syndrome(s) that contraindicates 
colistin; OR 
d. Has acute kidney injury and is receiving renal replacement therapy at study entry; OR 
e. Has documented clinical evidence of failure (ie, clinical deterioration or failure to 
improve) after at least 48 hours of treatment with a polymyxin-based regimen; AND 
f. Is diagnosed with cUTI, AP, or surgical or post-traumatic wound infection, defined as: 
 
 


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cUTI With ABC 
At least 1 of the following: 
AND at least 2 of the following signs 
and symptoms: 
AND at least 1 of 
the following: 
 
Indwelling urinary catheter or intermittent 
bladder catheterization; 
 
Neurogenic bladder with presence or 
history of urine residual volume of 
100 mL; 
 
Obstructive uropathy (eg, nephrolithiasis, 
tumor, fibrosis) that is expected to be 
medically or surgically treated within 
48 hours post-randomization; 
 
Azotemia due to intrinsic renal disease; 
OR 
 
Urinary retention in men due to 
previously diagnosed benign 
hypertrophy. 
 
Chills, rigors, or fever [1] (oral or 
tympanic temperature 38°C 
[100.4°F] or rectal/core 
temperature 38.3°C [100.9°F]); 
 
Elevated WBC count 
(>10,000/mm3) or left shift 
(>15% immature PMNs); 
 
Nausea or vomiting; 
 
Dysuria, increased urinary 
frequency, or urinary urgency; OR 
 
Lower abdominal pain or pelvic 
pain. 
 
Positive LCE on 
urinalysis; 
 
WBC count 
10 cells/mm3 in 
unspun urine; 
OR 
 
WBC count 
10 cells/hpf in 
urine sediment. 
1. 
Evidence of fever within 24 hours of the Screening Visit is acceptable if observed and documented by a healthcare 
provider. 
ABC = Acinetobacter baumannii-calcoaceticus complex; cUTI = complicated urinary tract infection; hpf = high-power field; 
LCE = leukocyte esterase; PMN = polymorphonuclear leukocyte; WBC = white blood cell.
 
 
AP With ABC 
Presence of an ascending tract infection including at least 2 of the following 
signs or symptoms: 
AND at least 1 of the 
following: 
 
Chills, rigors, or fever [1] (oral or tympanic temperature 38°C [100.4°F] 
or rectal/core temperature 38.3°C [100.9°F]); 
 
Elevated WBC count (>10,000/mm3) or left shift (>15% immature PMNs); 
 
Nausea or vomiting; 
 
Dysuria, increased urinary frequency, or urinary urgency;  
 
Flank pain; OR 
 
Costovertebral angle tenderness on physical examination.
 
Positive LCE on 
urinalysis; 
 
WBC count 
10 cells/mm3 in unspun 
urine; OR 
 
WBC count 10 cells/hpf 
in urine sediment. 
1. 
Evidence of fever within 24 hours of the Screening Visit is acceptable if observed and documented by a healthcare 
provider. 
ABC = Acinetobacter baumannii-calcoaceticus complex; AP = acute pyelonephritis; hpf = high-power field; LCE = leukocyte 
esterase; PMN = polymorphonuclear leukocyte; WBC = white blood cell.
 
 


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Surgical Wound Infection With ABC 
Superficial SSI meeting all of the following criteria: 
AND at least 1 of the following 
regional or systemic signs of 
infection: 
 
Follows clean surgery (elective, not emergency, nontraumatic, 
primarily closed, no acute inflammation; no break in technique; 
respiratory, gastrointestinal, biliary, and genitourinary tracts not 
entered); 
 
Involves only the skin or subcutaneous tissue around the incision, 
does not involve fascia; 
 
Occurs within 30 days after procedure; 
 
Original surgical incision 3 cm; AND 
 
Purulent drainage (spontaneous or therapeutic) that is positive for 
ABC by culture with surrounding erythema, edema, and/or 
induration extending at least 5 cm in the shortest distance from the 
peripheral margin of the wound and with a minimum total lesion 
surface area of 75 cm2. 
 
Lymph node tenderness and 
increase in volume or palpable 
proximal to the primary ABSSSI; 
 
Fever [1] (oral or tympanic 
temperature 38°C [100.4°F] or 
rectal/core temperature 38.3°C 
[100.9°F]) OR hypothermia 
(rectal/core temperature <35°C 
[<95°F]); 
 
WBC count 10,000/mm3 or 
<4000/mm3; OR 
 
>15% immature neutrophils. 
1. 
Evidence of fever within 24 hours of the Screening Visit is acceptable if observed and documented by a healthcare 
provider. 
ABC = Acinetobacter baumannii-calcoaceticus complex; ABSSSI = acute bacterial skin and skin structure infection; 
SSI = surgical site infection; WBC = white blood cell.
 
Post-Traumatic Wound Infection With ABC 
Post-traumatic wound (including 
penetrating trauma) characterized by 
the following within 24 hours of 
Screening: 
AND at least 1 of the following regional or systemic signs of 
infection: 
 
Purulent drainage (spontaneous or 
therapeutic) that is positive for ABC 
by culture with surrounding erythema, 
edema, and/or induration extending at 
least 5 cm in the shortest distance 
from the peripheral margin of the 
wound and with a minimum total 
lesion surface area of 75 cm2. 
 
Lymph node tenderness and increase in volume or palpable 
proximal to the primary ABSSSI; 
 
Fever [1] (oral or tympanic temperature 38°C [100.4°F] or 
rectal/core temperature 38.3°C [100.9°F]) OR hypothermia 
(rectal/core temperature <35°C [<95°F]); 
 
WBC count 10,000/mm3 or <4000/mm3; OR 
 
>15% immature neutrophils. 
1. 
Evidence of fever within 24 hours of the Screening Visit is acceptable if observed and documented by a healthcare 
provider. 
ABC = Acinetobacter baumannii-calcoaceticus complex; ABSSSI = acute bacterial skin and skin structure infection; 
WBC = white blood cell. 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Presence of suspected or confirmed deep-seated infection (eg, lung abscess in patients with 
pneumonia, skin abscess, or decubitus ulcer) that is not planned on being drained or debrided 
within 24 hours after randomization; 
Note: Patients with an empyema who will have drainage within 24 hours of Screening and who 
are expected to be able to be treated with 14 or fewer days of antibiotics are allowed. 
2. Evidence of active concurrent pneumonia requiring additional antimicrobial treatment caused 
by Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Mycoplasma 
pneumoniae, Chlamydia pneumoniae, Legionella pneumophila, respiratory syncytial virus, 


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influenza and parainfluenza viruses, Middle East respiratory syndrome coronavirus, 
mycobacteria, aspergillus, mucormycosis, etc; 
Note: If these organisms are identified but it is deemed by the Investigator that no treatment is 
warranted and their presence does not significantly change the prognosis of the patient, then 
the patient may be considered for this study. 
3. Pulmonary disease that precludes evaluation of a therapeutic response (such as lung cancer 
resulting in bronchial obstruction or on the same side as the pneumonia, active tuberculosis, 
cystic fibrosis, granulomatous disease, fungal pulmonary infection, lung abscess, pleural 
empyema, post obstructive pneumonia, or COVID-19 infection without clinical improvement); 
Note: Patients with an empyema who will have drainage within 24 hours of Screening and who 
are expected to be able to be treated with 14 or fewer days of antibiotics are allowed. 
4. Presence of suspected or confirmed deep seated bacterial infections such as bacterial Gram 
negative osteomyelitis, endocarditis, or meningitis requiring prolonged therapy, as determined 
by history and/or physical examination; 
5. Acute infective endocarditis due to Gram positive bacteria that require urgent/emergent 
indication of surgery (ie, heart failure because of valvular insufficiency or septic shock), or 
patients in whom surgery is contraindicated due to prohibitive risk for surgery due to 
comorbidities; 
6. Irremovable implantable device or line thought to be the potential source of ABC infection; 
7. Sustained shock with persisting hypotension requiring vasopressors to maintain mean arterial 
pressure (MAP) 60 mmHg; 
Note: Patients who can maintain MAP 60 mmHg on a reasonable dose of pressors or are 
weaning off of pressors may be considered. Patients who require more than the maximal dose 
of 2 vasopressors to maintain MAP 60 mmHg are ineligible. If vasopressors are weaned to 
below these levels, patient enrollment can be reconsidered. 
8. For patients to be enrolled with the primary indication of HABP, VABP, or VP, any of the 
following conditions: 
a. Diagnosis of ventilator-associated tracheobronchitis; or 
b. Inability to provide proper respiratory specimens for culture. Respiratory samples from 
expectorated or induced sputum should show <10 squamous epithelial cells and 
>25 polymorphonuclear neutrophils per 100 field; 
9. For patients to be enrolled with the primary indication of cUTI or AP, any of the following 
urologic conditions: 
a. Likely to receive ongoing antibacterial drug prophylaxis after treatment of cUTI 
(eg, patients with vesico-uretal reflux); 
b. Suspected or confirmed prostatitis; 
c. Requirement for bladder irrigation with antibiotics or for antibiotics to be administered 
directly via urinary catheter; 
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e. Uncomplicated urinary tract infection (eg, female patients with urinary frequency, 
urgency, or pain or discomfort without systemic symptoms or signs of infection); 
f. Complete, permanent obstruction of the urinary tract; 
g. Suspected or confirmed perinephric or renal corticomedullary abscess; 
h. Polycystic kidney disease; or 
i. Any recent history of trauma to the pelvis or urinary tract; 
10. Pregnant or breastfeeding women; 
11. APACHE II score >30 and SOFA score >11 at the time of diagnosis of infection; 
Note: A qSOFA score must be calculated for all patients without an APACHE II score. 
Glasgow coma score for APACHE II calculation should be the best response prior to initiation 
of sedation/neuromuscular blockade, even if sedation has been in use for >24 hours. 
12. Receiving peritoneal dialysis;  
13. Requirement for temporary or acute onset treatment with antiseizure medication that, in the 
opinion of the Investigator, would prohibit the patient from complying with the protocol. 
Patients at risk of seizure or requiring prophylactic antiseizure medications during the study 
can be considered for enrollment at the discretion of the Investigator. Patients with a history 
of epilepsy or who are on stable treatment (ie, no recurrent episodes in the past 30 days) and 
no history of imipenem-associated seizures may be considered for enrollment in the study; 
14. Requirement for continuing treatment with probenecid, methotrexate, ganciclovir, valproic 
acid, or divalproex sodium during the study; 
15. Evidence of significant hepatic disease or dysfunction, including known acute viral hepatitis, 
hepatic cirrhosis, hepatic failure, chronic ascites, or hepatic encephalopathy; 
16. Aspartate aminotransferase (AST) or ALT >3  upper limit of normal (ULN) AND total 
bilirubin >2  ULN at Screening; 
Note: Patients with AST or ALT up to 5  ULN are eligible if these elevations are acute and 
are documented as being directly related to the infectious process being treated. 
17. Requirement at the time of randomization for any reason, or likely to require during the 
patient’s participation in the study (from randomization through the LFU Visit), for additional 
systemic Gram negative antimicrobial therapy. See Section 5.6.3 for a list of antibiotics that 
are allowed to treat mixed or concurrent infections; 
18. Requirement for inhaled antibiotics; 
19. Known history of human immunodeficiency virus infection and known recent CD4 count 
<200/mm3 within the last year or presence of significant immunologic disease or dysfunction, 
as determined by a current diagnosis of an Acquired Immune Deficiency Syndrome-defining 
illness; 
20. Presence of neutropenia (absolute neutrophil count <500/mm3) obtained from a local 
laboratory at Screening; 
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22. History of significant hypersensitivity or allergic reaction to any BL, any contraindication to 
the use of cilastatin based on local approved prescribing information (eg, Summary of 
Medicinal Product Characteristics), any contraindication to the excipients used in the 
respective formulations, or any contraindication to the use of BL antibiotics; 
23. Participation in a clinical study involving investigational medication or an investigational 
device within the last 30 days or 5 half-lives, whichever is longer, prior to Day 1; 
24. Any condition that, in the opinion of the Investigator, would compromise the safety of the 
patient or the quality of the data or require greater than 14 days of treatment with antibiotics; 
25. Unable or unwilling, in the opinion of the Investigator, to comply with the protocol;  
26. Has previously received ETX2514 in this study; or 
27. For Part A only, patients with an infection known to be resistant to colistin or polymyxin B 
(defined as MIC 4 mg/L by a non-agar based method), with a known intolerance to colistin, 
or taking any drug that prevents them from receiving colistin. 
4.3 
Withdrawal and Discontinuation Criteria 
Participation of a patient in this clinical study may be withdrawn or study drug discontinued by 
the patient or Investigator for any of the following reasons: 
 The patient withdraws consent or requests discontinuation from the study for any reason; 
 Occurrence of any medical condition or circumstance that exposes the patient to substantial 
risk and/or does not allow the patient to adhere to the requirements of the protocol; 
 Any SAE, clinically significant adverse event, severe laboratory abnormality, intercurrent 
illness, or other medical condition which indicates to the Investigator that continued 
participation is not in the best interest of the patient; 
 Patient develops severe liver-related abnormalities, as detailed below: 
o ALT or AST >10  ULN; 
o ALT or AST >5  ULN for more than 2 weeks or progressively increasing transaminases 
despite clinical improvement of underlying infection;  
o Confirmed values of ALT or AST >3  ULN and total bilirubin >2  ULN or international 
normalized ratio >1.5 (for patients who are not on coumadin) without evidence of an 
alternative etiology; or 
o Confirmed values of ALT or AST >3  ULN along with signs or symptoms compatible 
with hepatitis or hypersensitivity (eg, fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, jaundice, fever, rash, or eosinophilia [>5%]); 
 Pregnancy; 
 Requirement of prohibited concomitant medications, including the need for antibiotics that 
have an overlapping Gram negative coverage other than study drugs; 
Note: Patients who require antibiotic prophylaxis due to immunosuppression (eg, 
trimethoprim-sulfamethoxazole for prophylaxis against Pneumocystis carinii [P. carinii] 
pneumonia) may participate in the study. 


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 Patients randomized to Part A based on a positive screening of a respiratory sample for ABC 
by BPP rapid test, but subsequently do not have growth of ABC in their respiratory sample 
culture processed by the local microbiology laboratory;  
 Patient failure to comply with protocol requirements or study-related procedures, including the 
need for treatment with study drug beyond 14 days; or  
 Termination of the study by the Sponsor or the regulatory authority. 
If a patient withdraws prematurely from the study due to the above criteria or any other reason 
other than withdrawal of consent to participate, study staff should make every effort to complete 
the full panel of assessments scheduled for the EOT Visit. The reason for patient withdrawal must 
be documented in the electronic case report form (eCRF). Even if a patient discontinues study drug 
and/or the patient is a clinical failure, he/she should remain enrolled in the study, as long as all 
assessments for the EOT Visit and follow-up visits can be completed. Reasons for discontinuation 
of study drug must be recorded in the eCRF. Every attempt must be made to record survival status 
at Day 28 or anytime thereafter for all randomized patients (including HABP/VABP/VP patients 
who are randomized to Part A based on a positive BPP rapid test, but who subsequently do not 
have growth of ABC in their respiratory sample culture), regardless of their status of treatment, 
as long as the patient has not withdrawn consent from participation in the study.  


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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
In Part A, the following study drugs will be administered in a 1:1 randomized manner: 
 Group 1 (experimental group): 1.0 g ETX2514/1.0 g sulbactam IV infused over 3 hours q6h 
plus 1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h; or 
 Group 2 (control group): 2.5 mg/kg colistin IV infused over 30 minutes q12h (after an initial 
loading dose of colistin 2.5 to 5 mg/kg) plus 1.0 g imipenem/1.0 g cilastatin IV infused over 
1 hour q6h. 
In Part B, the following study drugs will be administered: 
 Group 3 (experimental group): 1.0 g ETX2514/1.0 g sulbactam IV infused over 3 hours q6h 
plus 1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h. 
5.2 
Rationale for Dosing 
The doses of ETX2514 and sulbactam to be evaluated in this study have been selected based on 
Phase 1 and Phase 2 PK, safety, and efficacy data and extensive PK/PD modeling and probability 
of target attainment against CRABC in the lung. Data from these studies and details of the PK/PD 
modeling are provided in more detail in the Investigator’s Brochure. 
ETX2514 1.0 g was generally well tolerated in all of the clinical studies to date. Sulbactam 1.0 g 
was generally well tolerated in the Phase 2 study. The total daily dose of sulbactam being used in 
the current study is consistent with the US Product Circular for Unasyn, in which the maximum 
approved daily dose in patients with normal renal clearance for sulbactam is 4 g, which is 
equivalent to 1.0 g sulbactam q6h. 
The ETX2514SUL regimen of 1.0 g ETX2514/1.0 g sulbactam should be infused over 3 hours q6h 
given for 7 days to 14 days (28 doses to 56 doses), depending on the clinical response.  
Imipenem/cilastatin will be administered as a 1.0 g/1.0 g dose infused over 1 hour q6h given for 
the same duration as ETX2514SUL or colistin. 
Colistin will be administered at a daily dose of 5 mg/kg of colistin base activity (CBA) divided 
into 2 doses 12 hours apart. Doses will be adjusted to ideal body weight in obese patients. Patients 
who weigh <60 kg with normal renal function will receive a flat dose of 300 mg CBA or 
9 million international unit (MIU)/day. A single loading dose of 2.5 to 5 mg/kg (total dose not 
exceeding 300 mg CBA or 9 MIU and following local standard of care) given IV over 3 to 
6 minutes (or according to standard of care) will be administered on Day 1. Colistin infusions 
beyond the loading dose on Day 1 will begin 12 hours after the initial loading dose and will be 
infused over 30 minutes. Details on dosing for those patients who are on colistin prior to 
randomization into the study can be found in the Pharmacy Manual. 
Details of study drug preparation and administration can also be found in the Pharmacy Manual. 
No dosing regimen changes, other than those specified in the protocol for renal insufficiency (see 
Section 5.3) or for patients on imipenem who develop a seizure that is thought to be directly related 
to imipenem, can occur without discussion with the Medical Monitor. 


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5.3 
Dosing in Patients With Renal Insufficiency 
Estimated creatinine clearance will be determined daily while patients are receiving IV study drug. 
Principal Investigators will be responsible for testing estimated creatinine clearance daily at the 
local laboratory per institutional Standard Operating Procedures and must adjust doses of all 
medications as detailed in Table 1 in order to optimize efficacy and safety. Estimated creatinine 
clearance and dose adjustment data will be captured in source documents and in the eCRFs. 
Table 1 summarizes the recommended dosing regimens for patients with renal impairment.16,17 Of 
note, patients with estimated creatinine clearance <15 mL/min will only be dosed with 
imipenem/cilastatin as outlined in Table 1 if renal replacement therapy of acute hemodialysis is 
planned to be instituted within 48 hours of dosing.   
Table 1. 
Study Drug Dose Adjustments by Renal Function 
Estimated Creatinine 
Clearance, mL/min 
(Cockcroft-Gault) 
ETX2514SUL Dosage 
Regimen 
Colistin Dosage 
Regimen 
Imipenem/Cilastatin 
Dosage Regimen [1] 
130-200 (augmented renal 
clearance) 
1.5/1.5 g q6h 
2.5 mg/kg q12h 
1.0/1.0 g q6h 
90-129 (normal) 
1.0/1.0 g q6h
2.5 mg/kg q12h
1.0/1.0 g q6h
60-89 (mild renal 
impairment) 
1.0/1.0 g q6h
1.25 to 1.9 mg/kg q12h
0.75/0.75 g q8h
30-59 (moderate renal 
impairment) 
1.0/1.0 g q6h
1.25 mg/kg q12h or 
2.5 mg/kg once daily
0.5/0.5 g q6h
15-29 (severe renal 
impairment) 
1.0/1.0 g q8h
1.5 mg/kg q36h
0.5/0.5 g q12h
0-14 (severe renal 
impairment) [2] 
1.0/1.0 g q12h
1.5 mg/kg q36h
0.5/0.5 g q12h
Intermittent hemodialysis 
1.0/1.0 g q12h [4]
Non-dialysis day: CBA 
dose of 65 mg q12h. 
Dialysis day supplement: 
add 40 mg (for 3-hour 
IHD session) or 50 mg 
(for 4-hour IHD session) 
post-dialysis [3]
0.5/0.5 g q12h [4]
Continuous renal 
replacement therapy 
1.5/1.5 g q6h
220 mg q12h
1.0/1.0 g q8h to q12h, 
depending on 
ultrafiltration rate
1. 
Administer doses 0.5 g by IV infusion over 20 to 30 minutes. Administer doses >0.5 g by IV infusion over 40 to 
60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed. 
2. 
Patients with creatinine clearance 15 mL/min should not receive imipenem/cilastatin unless renal replacement therapy 
of acute hemodialysis is instituted within 48 hours of dosing. 
3. 
The dialysis session should occur toward the end of a colistimethate dosing interval, and the supplement to the baseline 
(non-dialysis) daily dose should be administered with the next regular dose, after the dialysis session has ended. 
4. 
The dialysis session should occur toward the end of a dosing interval, and the daily dose should be administered after the 
dialysis session has ended. 
CBA = colistin base activity; ETX2514SUL = sulbactam-ETX2514; IHD = intermittent hemodialysis; IV = intravenous; 
q6h = every 6 hours; q8h = every 8 hours; q12h = every 12 hours; q36h = every 36 hours.
5.4 
Randomization and Blinding 
Qualifying patients enrolling in Part A will be randomized in a 1:1 ratio to receive 1.0 g 
ETX2514/1.0 g sulbactam q6h plus 1.0 g imipenem/1.0 g cilastatin q6h or 2.5 mg/kg colistin q12h 
plus 1.0 g imipenem/1.0 g cilastatin q6h via the Interactive Response Technology (IRT) system. 
Patients enrolled in the study based on the positive BPP rapid test results but are found to not grow 


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ABC in respiratory specimen cultures by the local microbiology laboratory will be withdrawn from 
the study drug treatment as detailed in Section 4.3. 
Randomization in Part A will be stratified by indication (HABP/VABP/VP versus bacteremia), 
severity of illness (based on APACHE II [10 to 19 versus 20 to 30], SOFA [7 to 9 versus 10], or 
qSOFA [2 versus 3] score at Screening), and geography (China Mainland versus Rest of World). 
In the situation where a patient has more than one score reported, the scores will be used in the 
following order: APACHE, SOFA, and qSOFA. A quick reference guide will be provided that 
describes the IRT system and includes user instructions. Enrollment of HABP, VP, and bacteremia 
patients will be limited to a total of no more than 40% of patients in Part A, regardless of resistance. 
The study data will be collected and handled as if it were a blinded study. The blinded assessor 
(see Section 5.4.2), the Sponsor, and the Sponsor’s designees involved in medical and safety 
monitoring, data management, and other aspects of the study (eg, interpretation of the results) will 
be blinded to treatment assignment. Given the complexity of the regimens, the Principal 
Investigator, other care givers, the clinical research associate (CRA), and other site personnel 
(eg, study coordinators and pharmacy staff) will be unblinded (see Section 5.4.1). Patients will not 
be informed of their treatment assignment, and efforts will be made to keep patients naïve to their 
treatment throughout the course of the study. 
Part B is open-label and not randomized; all patients enrolling in Part B will receive 
1.0 g ETX2514/1.0 g sulbactam q6h plus 1.0 g imipenem/1.0 g cilastatin q6h. 
5.4.1 
Unblinded Investigator 
An unblinded Investigator at each site will evaluate criteria for clinical outcomes, conduct 
causality assessment for adverse events, and assess clinical signs and symptoms at study visits for 
patients in both Part A and Part B. For patients in Part A, a blinded assessor will also evaluate 
criteria for clinical outcomes, conduct causality assessment for adverse events, and assess clinical 
signs and symptoms at study visits. The unblinded Investigator must be a qualified physician, able 
to perform medical evaluations, and determine medical diagnoses (eg, Principal Investigator, 
sub-Investigator). For consistency, whenever possible, the same unblinded Investigator should 
complete all unblinded assessments for a study patient. If there is a discrepancy between the 
assessment of the blinded assessor and unblinded Investigator, the assessment from the blinded 
assessor will be used. If there is a missing assessment from either the blinded assessor or unblinded 
Investigator, the other available assessment will be used. An adjudication committee may be 
organized for endpoint adjudication should it be deemed necessary by the DSMB. In such a case, 
a charter will be developed that describes their activities. 
5.4.2 
Blinded Assessor 
Study data will be collected and handled as if it were a blinded study. 
For patients in Part A, each site will assign a blinded assessor, in addition to the unblinded 
Investigator, to evaluate criteria for clinical outcomes, conduct causality assessment for adverse 
events, and assess clinical signs and symptoms at study visits where an endpoint is evaluated (see 
Appendix A). A blinded assessor must be qualified to perform medical evaluations and determine 
medical diagnoses (eg, physician, physician’s assistant, or nurse practitioner [in the United 
States]). The blinded assessor may participate in the consenting process and Screening procedures, 
but once a patient is randomized the blinded assessor should have no other role in the study other 
than making blinded assessments. For consistency, whenever possible, the same blinded assessor 


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should complete all blinded assessments for a study patient. All efforts will be made to keep the 
blinded assessor blinded during the course of the study. The blinded assessor should not have 
access to sections in the patient’s medical record in which treatment group or dosing frequency 
are documented, should have no role in patient care or treatment, and should be restricted to limited 
sections of the patient’s chart in order to assess clinical outcomes. Data collection by the blinded 
assessor will be used for entry into the eCRF. 
5.5 
Drug Supplies 
5.5.1 
Formulation and Packaging 
ETX2514 sodium 500 mg is presented as a sterile lyophilized cake in a sterile 10 mL amber glass 
vial with a stopper, overseal, and clinical label. Two ETX2514 500 mg vials will be combined to 
generate the 1.0 g ETX2514 dose. 
Sulbactam sodium 1.0 g is presented as a sterile powder in a sterile 30 mL clear glass vial with a 
stopper, overseal, and clinical label.  
Commercially available imipenem/cilastatin and colistin will be provided. Each commercial 
material will have a clinical label. 
Imipenem/cilastatin is presented in fixed dose vials containing 0.5 g imipenem and 0.5 g cilastatin. 
Two vials will be combined to generate 1.0 g imipenem and 1.0 g cilastatin. 
Colistin is presented in vials containing colistimethate sodium (CMS). 
For non-US sites, CMS vials containing 2 MIU/vial powder for solution (equivalent to 
approximately 68 mg of CBA/vial based on microbiological standardization) will be used.  
For US sites, CMS equivalent to 150 mg of CBA/vial powder for solution (equivalent to 
approximately 400 mg or 4.5 MIU of CMS based on microbiological standardization) will be used. 
To avoid errors in dosing and administration, CMS will be referred to in terms of “international 
unit” (IU), “CBA”, or, simply, “colistin.” 
Table 2 provides a guide for conversion of IU values to mg of CBA. Greater details of dose 
calculations and conversion tables can be found in the Pharmacy Manual. 
Study drugs will be labeled according to the requirements of local law and legislation, as well as 
current Good Manufacturing Practice and Good Clinical Practice (GCP) guidelines. 
Table 2. 
Unit Conversion Guidance 
Colistin (IU) 
Colistin (mg of CBA) 
150,000 IU 
5 mg 
1 MIU 
34 mg 
4.5 MIU 
150 mg 
9 MIU 
300 mg 
CBA = colistin base activity; IU = international unit; MIU = million international unit. 
Source: Colistin summary of product characterization 
5.5.2 
Study Drug Preparation and Dispensing 
A pharmacist (or qualified designee) will prepare the study drug according to the requirements 
outlined in the Pharmacy Manual. The IV bags will be labeled with the date and time of study drug 
preparation and patient identification number and will be transferred to the study staff for 


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administration to the patient. Reconstituted study drug should be administered according to the 
requirements outlined in the Pharmacy Manual. 
5.5.3 
Study Drug Administration 
The pharmacist (or qualified designee) will be responsible for providing study personnel with 
study drug ready for IV infusion. Patients will receive treatment in accordance with the 
randomization schedule provided via the IRT system. Patients will receive randomized treatment 
administered as described in the Pharmacy Manual.  
Patients will receive all infusions by programmable infusion pump, or drip infusion in case of 
failure of the pump, while seated or partially reclined in bed. The times at which each infusion is 
started and stopped must be recorded. If a dose is interrupted for more than 10 minutes, the 
interruption and reason for interruption should be noted in the source documents. Any missed dose 
should also be noted in the source documents with the reason for the missed dose. For patients 
with normal renal function, study drug infusions will be administered q6h (15 minutes) for 
ETX2514SUL and imipenem/cilastatin and q12h (15 minutes) for colistin. Infusions that fall 
outside of the q6h (15 minutes) or q12h (15 minutes) dosing schedule will be considered 
protocol deviations. It is critical that administration and infusion time be captured in the eCRF 
based on actual time. Windows for administration and infusion should be used sparingly, and the 
patient should remain on schedule based on the q6h administration requirement. 
Dosing time is relative to the start of infusion. For additional information on study drug product 
dilution, infusion volumes, and dispensing instructions, refer to the Pharmacy Manual. 
5.5.4 
Treatment Compliance 
The infusion date and start and stop times will be recorded in the source documents and eCRFs. 
Treatment compliance will be calculated based on the number of doses received and expected as 
detailed in the Statistical Analysis Plan (SAP). 
5.5.5 
Storage and Accountability 
The pharmacist or designated study personnel will ensure that all study drugs are stored in a locked, 
secure area with limited access. Study drugs will be stored under recommended storage conditions 
per the label and in accordance with the Pharmacy Manual. 
The date and time of preparation of study drug will be recorded on the IV bags. Refer to the 
Pharmacy Manual for additional information. 
The Investigator is responsible for maintaining a current record of inventory/drug accountability. 
Vials may not be discarded until inventory and drug accountability are performed by the monitor. 
Study drugs must only be used for this protocol.  
5.6 
Prior and Concomitant Medications and/or Procedures 
5.6.1 
Excluded Medications and/or Procedures 
Treatment with any of the following concomitant medications or procedures is prohibited: 
 Probenecid; 
 Methotrexate; 


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 Ganciclovir; 
 Valproic acid or divalproex sodium; 
 Any additional or adjunctive non-study-specific Gram negative antibiotic therapy administered 
with the intention of treating HABP, VABP, VP, bacteremia, cUTI, AP, or other infection; 
and/or 
Note: Patients who require antibiotic prophylaxis due to immunosuppression (eg, 
trimethoprim-sulfamethoxazole for prophylaxis against P. carinii pneumonia) may participate 
in the study. 
 For patients with cUTI or AP, bladder irrigations with any antiseptic or antibiotic. 
5.6.2 
Restricted Medications and/or Procedures 
 For patients with surgical or post-traumatic wounds, topical antibiotics are prohibited. For all 
other patients, topical antibiotics are permitted; and 
 For patients with all indications being considered for Part A, curariform muscle relaxants (eg, 
tubocurarine) and other drugs, including ether, succinylcholine, gallamine, decamethonium, 
and sodium citrate, that potentiate the neuromuscular blocking effect should be used with 
extreme caution in patients being treated with colistin. 
5.6.3 
Allowed Medications and/or Procedures 
Unless specifically restricted per the protocol, medications and procedures for the management of 
the patient are permitted per standard of care. Patients who require antibiotic prophylaxis due to 
immunosuppression (eg, trimethoprim-sulfamethoxazole for prophylaxis against P. carinii 
pneumonia) may participate in the study. Additionally, treatment with any of the following 
concomitant antibiotics is allowed for treatment of Gram positive bacteria or Clostridium difficile 
(C. difficile) infections.  
Permitted medications include the following: 
 Agents with Gram positive only coverage, including the following: 
o Vancomycin; 
o Linezolid;  
o Daptomycin; 
o Oritavancin; 
o Tedizolid; and 
o Dalbavancin; 
 Agents for treatment of C. difficile infections, including the following:  
o Metronidazole;  
o Oral vancomycin;  
o Rifaximin; and 
o Fidaxomicin. 


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5.6.4 
Documentation of Prior and Concomitant Medication Use 
Reasonable effort will be made to determine all relevant treatments (including all antibiotics, 
prescription and non-prescription medications, herbal medications, vitamin supplements, 
supportive therapies, and non-pharmacologic treatments) received within 14 days before the first 
dose of study drug and during the study. The name, route of administration, dose, frequency, 
indication, and duration of the treatment will be recorded in the eCRF. The date and time of start 
and stop of any antibiotic therapy received within 14 days before the first dose of study drug and 
during the study will also be recorded. 
Patients cannot participate in any other investigational medication study while participating in this 
study or have taken any investigational product within 30 days or 5 half-lives, whichever is longer, 
prior to Day 1 in this study. 


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6 
STUDY PROCEDURES 
A detailed schedule of procedures is provided in Appendix A. 
6.1 
Informed Consent 
Informed consent must be obtained before any study procedures are performed. An ICF of limited 
scope may be signed prior to Screening to perform only BPP rapid testing of respiratory specimens. 
A comprehensive ICF, which will include all study procedures, will be signed at Screening. 
Patients will participate as much as possible in the informed consent procedure; however, as 
permitted by local law and institutional Standard Operating Procedures, in cases of a lack of 
decision-making capacity, informed consent on behalf of the patient may be provided by a legally 
authorized representative, independent physician, or consortium of independent physicians. These 
patients, upon return of their capacity, will be consented and allowed to make their own informed 
medical decisions.  
6.2 
Screening Visit (-48 Hours to Day 1) 
Screening can occur up to 48 hours before the first dose of study drug. All Screening procedures 
must be performed prior to randomization and the first dose of study drug (Day 1). All Screening 
laboratories will be performed at the local laboratory and may have been collected as standard of 
care within 48 hours prior to randomization, with the exception of serum creatinine determination, 
which must be obtained at the local laboratory within 24 hours before the first dose of study drug. 
The following procedures will be performed at Screening: 
 Obtain informed consent; 
 Review all inclusion and exclusion criteria; 
 Only for patients suspected to have HABP/VABP/VP, perform rapid testing of respiratory 
specimens using BPP to detect ABC infection as specified in Section 7.7.1 and the Laboratory 
Manual; 
o For patients who only signed the limited scope ICF (which only allows rapid testing on a 
respiratory sample): 
 If the BPP rapid test is negative or indeterminate for ABC, the patient should be screen 
failed; 
 If the BPP is indeterminate, the Investigator may opt to wait and repeat the test within 
24 hours before screen failing the patient;  
Note: The Investigator should review the local culture result from the respiratory 
sample once available. If the local culture result is positive for ABC, the patient may 
be re-screened under a new patient number, beginning with the main ICF and ensuring 
all eligibility criteria are met. 
o For patients who signed the main ICF (including all study procedures): 
 If the BPP rapid test result is negative for ABC, the patient should not be screen failed 
immediately, instead the Investigator should wait for the local culture result. In case 
the local culture result is positive for ABC, the Investigator should proceed with the 
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o Patients with suspected HABP/VABP/VP with a positive BPP rapid test for ABC of their 
respiratory specimen must meet all other enrollment criteria in order to be randomized. The 
respiratory specimen should be sent to the local laboratory for culture and susceptibility. If 
culture of the respiratory specimen by the local microbiology laboratory subsequently does 
not show growth with ABC, this patient must be withdrawn from the study treatment as 
they no longer meet eligibility criteria (see Section 4.3);  
 Obtain medical/surgical history; 
 Record prior and concomitant medications; 
 Obtain demographics, including sex, age, race, and ethnicity; 
 Perform a complete physical examination, including weight and height; 
 Calculate APACHE II, SOFA, or qSOFA score; 
Note: An APACHE II or SOFA score will be calculated prior to randomization for patients in 
Part A only. For patients who are not being treated in an intensive care unit and cannot have 
an APACHE II or SOFA score performed, and for all patients in Part B, a qSOFA score should 
be calculated.  
Note: An APACHE II, SOFA, or qSOFA score that was calculated as part of standard of care 
within 24 hours of Screening may be used and does not need to be repeated. 
 Obtain vital signs, including blood pressure, heart rate, and respiratory rate, and, for ventilated 
patients, oxygen therapy and respiratory settings including fraction of inspired oxygen (FiO2) 
and positive end-expiratory pressure (PEEP); 
 Perform/review chest X-ray, magnetic resonance imaging (MRI), computed tomography (CT) 
scan, or ultrasound within 72 hours of Screening (HABP, VABP, and VP patients only). For 
images obtained 48 hours prior to randomization, repeat imaging is required. Findings should 
be consistent with the screening image and diagnosis of pneumonia, in the Investigator’s 
judgment; otherwise, the patient is no longer eligible; 
Note: If an ultrasound is performed, a confirmatory X-ray or CT scan should be performed 
within 24 hours. 
 Assess clinical signs and symptoms (see Section 7.5); 
 Perform a highly sensitive urine or serum pregnancy test for women of childbearing potential 
only; 
 Collect blood samples for serum chemistry, serum creatinine, hematology, and baseline blood 
cultures; 
 Collect urine sample for urinalysis; 
 Collect infection site-specific culture specimens based on diagnosis. Cultures obtained within 
72 hours prior to randomization that are positive for ABC are acceptable for enrollment, but 
site-specific culture samples should be repeated within 24 hours prior to randomization (see 
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 Perform 12-lead ECG and consult the study Medical Monitor and local cardiologist in cases 
of clinically significant abnormal findings (eg, a QTcF 480 msec); and 
 Assess adverse events. 
6.3 
Treatment Period – Day 1 Through End of Treatment 
All patients will receive IV treatment for a minimum of 28 doses of ETX2514SUL plus 28 doses 
of imipenem/cilastatin or 14 doses of colistin plus 28 doses of imipenem/cilastatin (ie, 7 days of 
antibiotics for those without dose adjustments). Patients can receive up to 14 days of IV treatment 
if clinically indicated. Time of discontinuation of antibiotics will be determined on achievement 
of clinical cure (see Section 7.6). Additionally, at any time during the study, if a patient develops 
signs and symptoms of disease worsening, cultures from all appropriate sites should be collected 
and sent to the central laboratory. 
6.3.1 
Day 1 
The following procedures will be performed at Day 1: 
 Record concomitant medications; 
 Obtain vital signs, including blood pressure, heart rate, and respiratory rate, and, for ventilated 
patients, oxygen therapy and respiratory settings including FiO2 and PEEP; 
 Assess clinical signs and symptoms (see Section 7.5); 
 Collect predose blood samples for: 
o Serum chemistry; 
o Serum creatinine;  
o Hematology; and 
o Blood cultures in patients with bacteremia, if applicable; 
 Collect predose urine sample for urinalysis; 
 Calculate APACHE II, SOFA, or qSOFA score prior to randomization; 
Note: An APACHE II or SOFA score will be calculated prior to randomization for patients in 
Part A only. For patients who are not being treated in an intensive care unit and cannot have 
an APACHE II or SOFA score performed, and for all patients in Part B, a qSOFA score should 
be calculated. 
 Randomize patient to study drug via IRT; 
 Administer study drug; 
 For intense PK sampling, collect PK samples after the second infusion at the end of the infusion 
after the infusion pump is turned off (+15 minutes), 1.5 hours (15 minutes) after the end of 
the infusion, and immediately prior to the start of the next infusion;  


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 For sparse PK sampling, collect PK samples after the second infusion, immediately prior to 
the start of the next infusion. The patient should have received at least 2 infusions before this 
schedule is implemented; 
Note: When possible, PK samples should be collected after the second infusion on Day 1. If 
the second infusion happens during the night and it is not possible to collect the PK sample 
after the infusion, the same procedures could be done after the third infusion on Day 1. The 
PK sample should be taken after the patient received at least 2 infusions on Day 1. 
 Perform 12-lead ECG at the end of the first infusion of study drug for all patients, and consult 
the study Medical Monitor and local cardiologist in cases of clinically significant abnormal 
findings (eg, a QTcF 480 msec after the end of infusion and after the patient has been in a 
supine position for at least 10 minutes); and 
 Assess adverse events. 
6.3.2 
Day 2 
The following procedures will be performed at Day 2: 
 Record concomitant medications; 
 Perform a limited physical examination, if needed; 
 Obtain vital signs, including blood pressure, heart rate, and respiratory rate, and, for ventilated 
patients, oxygen therapy and respiratory settings including FiO2 and PEEP; 
 Assess clinical signs and symptoms (see Section 7.5); 
 Collect blood samples for:  
o Serum creatinine; and 
o Blood cultures in patients with bacteremia, if applicable; 
 Administer study drug; and 
 Assess adverse events. 
6.3.3 
Day 3 
The following procedures will be performed at Day 3: 
 Record concomitant medications; 
 Perform a complete physical examination, including weight; 
 Obtain vital signs, including blood pressure, heart rate, and respiratory rate, and, for ventilated 
patients, oxygen therapy and respiratory settings including FiO2 and PEEP; 
 Assess clinical signs and symptoms (see Section 7.5); 
 Collect blood sample for: 
o Serum chemistry; 
o Serum creatinine;  


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o Hematology; and  
o Blood cultures in patients with bacteremia, if applicable; 
 Collect urine sample for urinalysis; 
 Administer study drug;  
 For intense PK sampling, if PK samples will not be collected on Day 4, collect PK samples at 
the end of any infusion after the infusion pump is turned off (+15 minutes), and immediately 
prior to the start of the next infusion;  
 For sparse PK sampling, if PK samples will not be collected on Day 4, collect PK samples 
after the end of infusion, immediately prior to the start of the next infusion; 
Note: When possible, PK samples should be collected on Day 4. If collection on Day 4 is not 
possible, post-dose PK samples may be collected on Day 3 or Day 5 instead of Day 4, at the 
discretion of the Investigator. 
 If PK samples are collected, repeat 12-lead ECG as close as possible following the end of the 
infusion of study drug administration associated with the PK samples, if clinically indicated; 
and 
 Assess adverse events. 
6.3.4 
Day 4 
The following procedures will be performed at Day 4: 
 Record concomitant medications; 
 Perform a limited physical examination, if needed; 
 Obtain vital signs, including blood pressure, heart rate, and respiratory rate, and, for ventilated 
patients, oxygen therapy and respiratory settings including FiO2 and PEEP; 
 Assess clinical signs and symptoms (see Section 7.5); 
 Collect blood samples for:  
o Serum creatinine; and 
o Blood cultures in patients with bacteremia, if applicable; 
 Administer study drug;  
 For intense PK sampling, collect PK samples at the end of any infusion after the infusion pump 
is turned off (+15 minutes), and immediately prior to the start of the next infusion;  
 For sparse PK sampling, collect PK samples after the end of infusion, immediately prior to the 
start of the next infusion;  
Note: When possible, PK samples should be collected on Day 4. If collection on Day 4 is not 
possible, post-dose PK samples may be collected on Day 3 or Day 5 instead of Day 4, at the 
discretion of the Investigator. 


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 If PK samples are collected, repeat 12-lead ECG as close as possible following the end of the 
infusion of study drug administration associated with the PK samples, if clinically indicated; 
and 
 Assess adverse events. 
6.3.5 
Day 5 
The following procedures will be performed at Day 5: 
 Record concomitant medications; 
 Perform a complete physical examination, including weight; 
 Obtain vital signs, including blood pressure, heart rate, and respiratory rate, and, for ventilated 
patients, oxygen therapy and respiratory settings including FiO2 and PEEP; 
 Assess clinical signs and symptoms (see Section 7.5); 
 Assess clinical outcome. In Part A, clinical outcome will be assessed by the blinded assessor, 
in addition to the unblinded Investigator (see Section 7.6); 
 Collect blood sample for:  
o Serum chemistry; 
o Serum creatinine;  
o Hematology; and  
o Blood cultures in patients with bacteremia, if applicable; 
 Collect urine sample for urinalysis; 
 Collect infection site-specific cultures based on diagnosis if clinically indicated (see 
Section 7.7); 
 Administer study drug;  
 For intense PK sampling, if PK samples were not collected on either Day 3 or Day 4, collect 
PK samples at the end of any infusion after the infusion pump is turned off (+15 minutes), and 
immediately prior to the start of the next infusion; 
 For sparse PK sampling, if PK samples were not collected on either Day 3 or Day 4, collect 
PK samples after the end of infusion, immediately prior to the start of the next infusion; 
Note: When possible, PK samples should be collected on Day 4. If collection on Day 4 is not 
possible, post-dose PK samples may be collected on Day 3 or Day 5 instead of Day 4, at the 
discretion of the Investigator. 
 If PK samples are collected, repeat 12-lead ECG as close as possible following the end of the 
infusion of study drug administration associated with the PK samples, if clinically indicated; 
and 
 Assess adverse events. 


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6.3.6 
Day 6 
The following procedures will be performed at Day 6: 
 Record concomitant medications; 
 Perform a limited physical examination, if needed; 
 Obtain vital signs, including blood pressure, heart rate, and respiratory rate, and, for ventilated 
patients, oxygen therapy and respiratory settings including FiO2 and PEEP; 
 Assess clinical signs and symptoms (see Section 7.5); 
 Collect blood sample for: 
o Serum creatinine; and 
o Blood cultures in patients with bacteremia, if applicable; 
 Administer study drug; and 
 Assess adverse events. 
6.3.7 
Day 7 to Day 14 and End of Treatment Visit 
Patients will be treated with 28 doses of ETX2514SUL plus 28 doses of imipenem/cilastatin or 
14 doses of colistin plus 28 doses of imipenem/cilastatin (ie, 7 days for those without dose 
adjustments), with a prolongation of therapy up to 14 days if clinically indicated.  
If EOT occurs on Day 7, Day 7 study procedures may be considered the EOT Visit study 
procedures. If EOT occurs after Day 7, the EOT Visit activities should be completed within 
24 hours after the last dose of study drug. Day 7 to Day 14 study procedures are only required if 
the patient receives IV study drug treatment on Day 7 to Day 14. If EOT has already occurred, 
study procedures are not required to be performed.  
The following procedures will be performed at Day 7 to Day 14 and at the EOT Visit: 
 Record concomitant medications; 
 Perform a complete physical examination, including weight (Day 7 and EOT Visit only); 
 Perform a limited physical examination, if needed (Day 8 to Day 14 only); 
 Obtain vital signs, including blood pressure, heart rate, and respiratory rate, and, for ventilated 
patients, oxygen therapy and respiratory settings including FiO2 and PEEP; 
 Assess clinical signs and symptoms (see Section 7.5); 
 Assess clinical outcome. In Part A, clinical outcome will be assessed by the blinded assessor, 
in addition to the unblinded Investigator (see Section 7.6) (Day 7 and EOT Visit only); 
 Perform a highly sensitive urine or serum pregnancy test for women of childbearing potential 
only (EOT Visit only); 
 Collect blood sample for:  
o Serum chemistry (Day 7 and EOT Visit only);  
o Serum creatinine;  


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o Hematology (Day 7 and EOT Visit only); and  
o Blood cultures in patients with bacteremia, if applicable; 
 Collect urine sample for urinalysis (Day 7 and EOT Visit only);  
 Perform 12-lead ECG and consult the study Medical Monitor and local cardiologist in cases 
of clinically significant abnormal findings (eg, a QTcF 480 msec) (EOT Visit only); 
 Collect infection site-specific cultures based on diagnosis if clinically indicated (see 
Section 7.7) (Day 7 and EOT Visit only); 
 Administer study drug; and 
 Assess adverse events. 
6.4 
Test of Cure Visit  
The TOC Visit will occur 7 days (2 days) after the EOT Visit. 
The following procedures will be performed at the TOC Visit: 
 Record concomitant medications; 
 Perform a limited physical examination, if needed; 
 Obtain vital signs, including blood pressure, heart rate, and respiratory rate, and, for ventilated 
patients, oxygen therapy and respiratory settings including FiO2 and PEEP; 
 For patients with HABP, VABP, or VP, perform chest X-ray, MRI, or CT scan; 
 Assess clinical signs and symptoms (see Section 7.5);  
 Assess clinical outcome. In Part A, clinical outcome will be assessed by the blinded assessor, 
in addition to the unblinded Investigator (see Section 7.6); 
Note: If a patient is a clinical failure at EOT, the patient is automatically considered a failure 
at the TOC Visit and LFU Visit, and the assessment of clinical response by the Investigator 
should be listed as “failure at EOT or TOC.” 
 Collect blood samples for:  
o Serum chemistry; 
o Serum creatinine;  
o Hematology; and  
o Blood cultures in patients with bacteremia, if applicable; 
 Collect urine sample for urinalysis;  
 Collect infection site-specific cultures based on diagnosis if clinically indicated (see 
Section 7.7); and 
 Assess adverse events. 


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6.5 
Late Follow-Up and Day 28 Visit 
The LFU Visit will occur 14 days (2 days) following the EOT Visit. The LFU Visit should be 
performed as an in-person visit; however, if the patient is unable to attend the LFU Visit at the 
site, the patient may be contacted by telephone call for follow-up assessment of concomitant 
medications, clinical signs and symptoms, and adverse events. All patients who are alive and have 
not withdrawn consent for participation in the study must be contacted at Day 28 or anytime 
thereafter to assess survival if their LFU Visit is prior to Day 28.  
The following procedures will be performed at the LFU Visit: 
 Record concomitant medications; 
 Perform a limited physical examination, if needed; 
 Obtain vital signs, including blood pressure, heart rate, and respiratory rate, and, for ventilated 
patients, oxygen therapy and respiratory settings including FiO2 and PEEP; 
 Assess clinical signs and symptoms (see Section 7.5); 
 Assess clinical outcome. In Part A, clinical outcome will be assessed by the blinded assessor, 
in addition to the unblinded Investigator (see Section 7.6); 
Note: If a patient is a clinical failure at EOT, the patient is automatically considered a failure 
at the TOC Visit and LFU Visit, and the assessment of clinical response by the Investigator 
should be listed as “failure at EOT or TOC.” 
 Collect blood samples for: 
o Serum chemistry;  
o Serum creatinine;  
o Hematology; and  
o Blood cultures in patients with bacteremia, if applicable; 
 Collect urine sample for urinalysis;  
 Collect infection site-specific cultures based on diagnosis if clinically indicated (see 
Section 7.7); and 
 Assess adverse events. 
6.6 
Early Termination Visit/Withdrawal Procedures 
For patients who are withdrawn from the study prior to completion of study drug treatment or 
discontinue study drug prematurely, an Early Termination (ET) Visit should be completed at the 
time of study withdrawal or study drug discontinuation. Patients who discontinue study drug 
prematurely but are not withdrawn from the study should complete TOC and LFU Visits. Patients 
who are randomized to Part A based on a positive screening of a respiratory sample for ABC by 
BPP rapid test, but subsequently do not have growth of ABC in their respiratory sample culture 
processed by the local microbiology laboratory, will be considered withdrawn from the study drug 
treatment. For patients who are withdrawn from the study after the EOT Visit but prior to 
completion of the study, the next scheduled visit (either the TOC Visit or LFU Visit) should be 
completed at the time of study withdrawal. An assessment of all-cause mortality at Day 28 or 


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anytime thereafter must be made for all patients initially randomized to the study (including 
HABP/VABP/VP patients who are randomized to Part A based on a positive BPP rapid test, but 
who subsequently do not have growth of ABC in their respiratory sample culture), regardless of 
the duration of study drug received, as long as there has been no withdrawal of consent. See 
Section 4.3 for complete details on criteria for withdrawal and/or discontinuation. 
The following procedures will be performed at the ET Visit: 
 Record concomitant medications; 
 Perform a complete physical examination, including weight; 
 Obtain vital signs, including blood pressure, heart rate, and respiratory rate, and, for ventilated 
patients, oxygen therapy and respiratory settings including FiO2 and PEEP; 
 Assess clinical signs and symptoms (see Section 7.5); 
 Assess clinical outcome. In Part A, clinical outcome will be assessed by the blinded assessor, 
in addition to the unblinded Investigator (see Section 7.6); 
 Perform a highly sensitive urine or serum pregnancy test for women of childbearing potential 
only; 
 Collect blood sample for:  
o Serum chemistry;  
o Serum creatinine;  
o Hematology; and  
o Blood cultures in patients with bacteremia, if applicable; 
 Collect urine sample for urinalysis;  
 Perform 12-lead ECG and consult the study Medical Monitor and local cardiologist in cases 
of clinically significant abnormal findings (eg, a QTcF 480 msec); 
 Collect infection site-specific cultures based on diagnosis if clinically indicated (see 
Section 7.7); and 
 Assess adverse events. 


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7 
EFFICACY ASSESSMENTS 
7.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint for the study is 28-day all-cause mortality in the CRABC m-MITT 
Population in Part A. 
7.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints for Part A and Part B include the following: 
 28-day all-cause mortality in the Intent-to-Treat (ITT) Population; 
 Clinical cure at TOC in the CRABC m-MITT Population; 
 Clinical cure at TOC in the m-MITT, Clinical Evaluable (CE), Microbiologic Evaluable (ME), 
and CRABC ME Populations; 
 Clinical cure at Day 5, Day 7, EOT, and LFU in the m-MITT, CRABC m-MITT, CE, ME, and 
CRABC ME Populations; 
 Microbiological favorable assessment at Day 5, Day 7, EOT, TOC, and LFU in the m-MITT, 
CRABC m-MITT, ME, and CRABC ME Populations; 
 14-day all-cause mortality in the CRABC m-MITT and m-MITT Populations;  
 28-day all-cause mortality in the m-MITT and CRABC ME Populations; and 
 PK exposure of ETX2514 and sulbactam in the PK Population. 
7.3 
Other Efficacy Endpoints 
The exploratory efficacy endpoints include the following: 
 Clinical cure based on PK exposure; 
 Clinical cure based on MIC distribution of ETX2514SUL;  
 Clinical cure based on baseline resistance to ETX2514SUL, carbapenems, or colistin;  
 Number of days in the intensive care unit; 
 Number of patients transferred to the intensive care unit; 
 For patients with VABP, VP, or ventilated HABP, number of days on ventilators;  
 Number of days in the hospital; and 
 Number of days on study drug treatment. 
7.4 
Assessment of 28-Day Survival 
Every attempt must be made to record survival status at Day 28 or anytime thereafter for all 
randomized patients (including HABP/VABP/VP patients who are randomized to Part A based on 
a positive BPP rapid test, but who subsequently do not have growth of ABC in their respiratory 
sample culture), regardless of their status of treatment, as long as the patient has not withdrawn 
consent from participation in the study. An in-person assessment is preferred; however, this 
assessment may also be performed via a telephone call if an in-person visit is not possible.  


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For patients with an LFU Visit occurring before Day 28, a telephone call to assess survival will be 
made on Day 28 or anytime thereafter. 
7.5 
Assessment of Clinical Signs and Symptoms 
Clinical signs and symptoms of the presenting indication will be assessed at Screening, daily 
during IV treatment beginning on Day 1, at the EOT Visit, at the TOC Visit, at the LFU Visit, and 
at the ET Visit, if applicable, by the blinded assessor and the unblinded Investigator for Part A and 
by the unblinded Investigator for Part B. When possible, the same study personnel should complete 
the assessments at approximately the same time each day. Maximum daily temperature (defined 
as the maximum temperature reported on a single treatment day) will be recorded. Body 
temperature may be taken per the site’s preferred method, as specified in Table 3, and will be 
recorded in the appropriate eCRF. The same method of measuring a patient’s body temperature 
should be used throughout the study. 
Each sign and/or symptom of the presenting indication will be assigned a classification of absent, 
mild, moderate, or severe. Findings from the assessment of signs and symptoms will be captured 
on the appropriate eCRF and should not be documented as adverse events. The signs and symptoms 
by indication are presented in Table 3. 
 
 


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Table 3. 
Signs and Symptoms for Presenting Indications 
Presenting 
Indication 
Signs and Symptoms 
HABP/VABP/VP 
mechanically 
ventilated patients 
 
Rales; 
 
Dullness on percussion; 
 
Bronchial breath sounds; 
 
Egophony; 
 
Purulent secretion; and 
 
Fever [1] (oral or tympanic temperature 38°C 
[100.4°F] or rectal/core temperature 38.3°C 
[100.9°F]) OR hypothermia (rectal/core 
temperature <35°C [<95°F]). 
 
HABP/VABP/VP 
non-mechanically 
ventilated patients 
 
Cough; 
 
Rales; 
 
Dullness on percussion; 
 
Bronchial breath sounds; 
 
Egophony; 
 
Dyspnea; 
 
Respiratory rate >25 breaths/minute; and 
 
Fever [1] (oral or tympanic temperature 38°C 
[100.4°F] or rectal/core temperature 38.3°C 
[100.9°F]) OR hypothermia (rectal/core 
temperature <35°C [<95°F]). 
Bacteremia 
 
Heart rate >100 bpm; 
 
Respiratory rate 
>25 breaths/minute; 
 
Systolic blood pressure 
<90 mmHg; and
 
Fever [1] (oral or tympanic temperature 38°C 
[100.4°F] or rectal/core temperature 38.3°C 
[100.9°F]) OR hypothermia (rectal/core 
temperature <35°C [<95°F]). 
cUTI or AP 
 
Urinary frequency; 
 
Urinary urgency; 
 
Dysuria; 
 
Nausea; 
 
Vomiting; 
 
Abdominal pain; 
 
Supra-pubic pain or 
discomfort; 
 
Flank pain; 
 
Costovertebral angle tenderness on examination; 
and 
 
Fever [1] (oral or tympanic temperature 38°C 
[100.4°F] or rectal/core temperature 38.3°C 
[100.9°F]) OR hypothermia (rectal/core 
temperature <35°C [<95°F]). 
Surgical and 
post-traumatic 
wound infections 
 
Purulent drainage; 
 
Erythema; 
 
Warmth; 
 
Exudation; 
 
Odor; 
 
Pain; 
 
Leukocytosis; and 
 
Fever [1] (oral or tympanic temperature 38°C 
[100.4°F] or rectal/core temperature 38.3°C 
[100.9°F]) OR hypothermia (rectal/core 
temperature <35°C [<95°F]). 
1. 
Maximum daily temperature on a single treatment day will be recorded. Note: Axial temperature is not allowed. 
AP = acute pyelonephritis; bpm = beats per minute; cUTI = complicated urinary tract infection; HABP = hospital-acquired 
bacterial pneumonia; VABP = ventilator-associated bacterial pneumonia; VP = ventilated pneumonia. 
7.6 
Clinical Outcome 
Clinical outcome will be used to determine a response of clinical success for all patients. Based on 
the assessment of signs and symptoms, the unblinded Investigator will choose 1 of the following 
clinical outcomes at the Day 5, Day 7, EOT Visit, TOC Visit, LFU Visit, and ET Visit, if 
applicable. In Part A, in addition to the unblinded Investigator, a blinded assessor will also 
determine clinical outcome. If there is a discrepancy between the assessment of the blinded 
assessor and unblinded Investigator, the assessment from the blinded assessor will be used. If there 
is a missing assessment from either the blinded assessor or unblinded Investigator, the other 
available assessment will be used (see Section 5.4.1). An adjudication committee may be 
organized for endpoint adjudication should it be deemed necessary by the DSMB. In such a case, 
a charter will be developed that describes their activities. 


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Clinical cure: complete resolution or significant improvement of signs and symptoms that were 
present at baseline and no new symptoms, such that no additional Gram negative antimicrobial 
therapy is warranted. 
Clinical failure: symptoms present at study entry have not significantly improved or completely 
resolved, or new symptoms have developed and require the initiation of a non-study Gram negative 
antibacterial drug therapy, death, or intolerance to study drug leading to discontinuation from the 
study treatment. 
Clinical indeterminate: determination cannot be made because of missing data or the patient is lost 
to follow-up. 
7.7 
Microbiologic Assessments 
To assess the primary indication and follow-up of the primary indication, all specimens will be 
sent to the local laboratory for culture and susceptibility testing per institutional standards. Pure 
cultures of isolated pathogens will be shipped from the local laboratory to the central laboratory 
for confirmation of species identification, susceptibility testing, and possible molecular 
characterization, as detailed in the Microbiology Laboratory Manual. Definitions of resistance for 
purposes of this protocol are detailed in Section 9.1 and in the Microbiology Laboratory Manual. 
Rapid diagnosis of ABC HABP/VABP/VP will utilize the BPP to detect ABC in respiratory 
specimens. Details of the test and its use will be included in the Laboratory Manual. The test results 
will be recorded in the eCRF. 
All patients must have a specimen sample from the site of infection (ie, respiratory secretion, 
blood, urine, or wound) and 2 sets of blood culture samples from 2 separate venipuncture sites 
collected at Screening. Screening respiratory specimens for patients with suspected 
HABP/VABP/VP should be subjected to BPP rapid diagnostic testing as detailed above, where 
available, and submitted to the local microbiology laboratory for culture and susceptibility testing. 
In these cases, if the local microbiology laboratory culture does not grow ABC, the patient will be 
withdrawn from the study drug treatment. 
If the screening sample for culture that is growing ABC is taken per standard of care before the 
patient or patient’s legally authorized representative signs informed consent, that isolate may be 
used for baseline eligibility and sent to the central laboratory once consent is obtained, as long as 
the sample was collected within 72 hours prior to randomization. Additional samples for baseline 
culture should be collected again within 24 hours prior to randomization, at the time points 
specified in the Schedule of Procedures (Appendix A), and if clinically indicated. Patients who are 
failing their current treatment as evidenced by worsening clinical condition may enroll in the study, 
provided they meet all other requisites. However, additional samples must be taken from the site 
of infection within 24 hours prior to randomization and sent to the local laboratory for culture. 
The local laboratory will culture each sample for species identification, quantification (urine and 
BAL only), and susceptibility testing. Any organism isolated from the culture will be identified by 
genus and species by the local laboratory. Potential pathogen(s) cultured at the local laboratory, 
including species isolated from mixed infections with other Gram positive or Gram negative 
organisms, will be sent to a designated central laboratory for confirmation of species identification, 
susceptibility testing results, and potential molecular characterization. 
All organisms identified on culture at the local laboratory and the local laboratory assessment of 
susceptibility testing for each organism will be captured in the eCRF. 


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Enrollment in Part A can occur after ABC is identified in the blood and/or other respiratory tract 
specimens but prior to establishing the resistance profile. If local laboratory susceptibility testing 
reveals colistin resistance after a patient has been randomized to Part A, the patient must be 
transferred to Part B, regardless of the treatment group assignment in Part A, once Part B is open 
for enrollment. If Part B is not open for enrollment, patients will be withdrawn from the study drug 
treatment. 
Patients who are randomized to Part A based on a positive screening of a respiratory sample for 
ABC by BPP rapid test, but subsequently do not have growth of ABC in their respiratory sample 
culture processed by the local microbiology laboratory, will be withdrawn from the study drug 
treatment. The need for continued standard of care treatment should be assessed by the 
Investigator. 
When a patient’s culture grows Gram positive organisms but the patient is clinically improving, 
the patient may remain on study drug without additional Gram positive antibiotic coverage at the 
Investigator’s discretion. Patients who are not clinically improving or need adjustment in 
antimicrobial therapy that is not allowed per the protocol should be discontinued from study drug 
at the discretion of the Investigator, but should remain in the study to complete all study 
assessments. Additional cultures and all EOT procedures should be performed at the time of 
discontinuation and every attempt must be made to collect survival data at Day 28 or anytime 
thereafter. 
7.7.1 
Respiratory Tract Specimens 
For patients with HABP, VABP, or VP, the BPP rapid diagnostic testing at Screening should be 
conducted using BAL-like specimens (BAL or mini-BAL) or endotracheal aspirate by Protected 
Endotracheal Catheter specimens, as applicable. See the Laboratory Manual for further details.  
For patients with HABP, VABP, or VP that were diagnosed with a positive BPP rapid test of their 
respiratory specimen at Screening, respiratory specimens for culture and susceptibility testing must 
be collected again at Screening. All HABP/VABP/VP patients should have additional specimens 
collected on Day 5, Day 7, EOT, TOC, LFU, and ET Visits from the respective sites as clinically 
indicated.  
Acceptable specimens for culture and susceptibility testing should include at least 1 positive 
pretreatment sample (ie, sample obtained prior to study drug dosing) obtained by Protected 
Specimen Brush with BAL or mini-BAL, by non-bronchoscopic BAL, by Protected Endotracheal 
Catheter suction, or from culture of lung tissue or pleural fluid obtained prior to randomization 
and treatment. Non-ventilated patients may have specimens obtained via deep expectoration or 
expectorated/induced sputum or culture of pleural fluid or lung tissue.  
All respiratory specimens, even if positive by BPP rapid test for ABC, should be sent to the local 
microbiology laboratory for Gram stain (expectorated sputum only), culture and pathogen 
identification, susceptibility testing, and quantification (BAL only). 
To be adequate, respiratory samples from expectorated or induced sputum should show 
<10 squamous epithelial cells and >25 polymorphonuclear neutrophils per 100  field. Specimens 
should be cultured regardless of determination of adequacy. However, if the specimen is deemed 
to be inadequate, another respiratory sample should be collected and cultured.  
Gram stains will be conducted per institutional standards, and Gram stain data should be captured 
in source documents. Colony counts are not expected to be performed on expectorated or induced 


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sputum or endotracheal aspirate. If the sputum is cultured, isolates of all pathogens exhibiting 
significant growth identified by the site laboratory’s routine procedures should be sent to the 
central laboratory, even if the organisms are from a specimen that does not meet the specimen 
adequacy criteria described above. Culture-purified isolates of pathogens from respiratory samples 
will be sent to the central laboratory for confirmation of identification and susceptibility testing. 
7.7.2 
Blood Specimens 
Two sets of samples from 2 separate venipuncture sites are required for blood cultures in all 
patients. Each set of blood culture samples will be collected from a separate venipuncture site and 
will consist of 1 aerobic and 1 anaerobic blood culture bottle (an additional aerobic bottle is 
allowed if an anaerobic culture is not standard practice at the site). Each set of blood cultures 
should be collected by direct venipuncture from independent sites approximately 15 minutes to 
30 minutes apart. A positive blood culture for ABC within 72 hours prior to randomization can be 
used for enrollment of a patient as long as the sample was drawn from a peripheral vein or through 
a newly inserted catheter; however, 2 sets of blood cultures, as outlined above, must be repeated 
within 24 hours prior to randomization. For a patient to meet criteria for catheter-related 
bloodstream infection, please see the necessary sampling procedures described in Part A-Specific 
Inclusion Criterion 1 (Section 4.1.2). If Screening/baseline blood cultures are positive for ABC, 
repeat blood cultures should be obtained daily until negative or the patient is a treatment failure. 
To avoid unnecessary blood draws, the Investigator may wait until the result of the prior blood 
culture is known before performing the next blood culture. 
Additional blood cultures, including blood cultures taken during fever spikes (oral or tympanic 
temperature 38°C [100.4°F] or rectal/core temperature 38.3°C [100.9°F]), may also be 
collected at the Investigator’s discretion. 
Isolates of pathogens (eg, not considered to be a contaminant as outlined in the Microbiology 
Laboratory Manual) from each individual positive blood culture will be sent to the central 
laboratory. 
7.7.3 
Urine Specimens 
For patients with cUTI or AP, urine samples will be collected at Screening, Day 5, Day 7, EOT, 
TOC, LFU, and ET Visits by 1 of the following methods that minimizes the risk of bacterial 
contamination: 
 Clean-catch mid-stream; 
 Newly inserted Foley catheter (bag specimens are not permitted); 
 Bladder needle aspiration; 
 Suprapubic catheter; 
 Ureter aspiration; or 
 Nephrostomy tube. 
Urine cultures will be performed by the local laboratory. The local laboratory will culture each 
sample for species identification, quantification, and susceptibility testing. Any organism isolated 
from the urine will be identified by genus and species by the local laboratory. Culture-purified 
isolates of potential pathogens isolated at baseline and all post-baseline organisms culture-purified 


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at the local laboratory and not considered to be contaminants as outlined in the Microbiology 
Laboratory Manual will be sent to the central laboratory for confirmation of identification and 
susceptibility results. A urine sample taken to support diagnosis or to treat a medical condition 
within 48 hours prior to the first dose of study drug can be used for baseline microbiologic 
assessments if the organism(s) cultured was obtained and stored for shipment to the designated 
central laboratory. Otherwise, a repeat urine sample for baseline microbiologic assessments is 
required.  
Baseline urine cultures must grow 1 or 2 defined bacterial pathogens, each at 105 colony-forming 
units (CFU)/mL. If a patient grows 3 organisms in the urine, the urine culture will be considered 
contaminated unless 1 of the organisms also grows in a concurrently obtained blood culture. 
For post-baseline urine cultures, only those potential pathogens that grow at 103 CFU/mL and 
deemed not to be contaminants as outlined in the Microbiology Laboratory Manual will be 
culture-purified and sent to the central laboratory for confirmation of identification and 
susceptibility testing. 
7.7.4 
Surgical or Post-Traumatic Wound Specimens 
For patients with surgical or post-traumatic wound infections, an adequate clinical specimen for 
microbiologic evaluation will be collected at Screening, Day 5, Day 7, EOT, TOC, LFU, and ET 
Visits as long as clinically indicated (ie, as long as there is material to send for culture). Clinical 
specimens include pus from a wound or abscess and aspirate from the leading edge of cellulitis.  
All specimens should be sent to the local laboratory for Gram stain, species identification, and 
susceptibility testing. 
Isolates of potential pathogen(s) culture-purified at the local laboratory will be sent to the central 
laboratory for confirmation of identification and susceptibility testing results. 
7.8 
Microbiologic Outcome 
7.8.1 
Microbiologic Outcome for Bacteremia, Complicated Urinary Tract Infection, or 
Acute Pyelonephritis 
For patients with bacteremia, cUTI, or AP, per-patient microbiological response will be 
determined programmatically as 1 of the following outcomes based on the results of blood and/or 
urine cultures at the Day 5, Day 7, EOT, TOC, and LFU Visits. A microbiological favorable 
assessment will include eradication and presumed eradications, as detailed below. 
Microbiologic eradication: 
 For patients with cUTI or AP: the baseline strain of ABC is reduced to <103 CFU/mL on urine 
culture and negative on repeat blood culture (if positive at baseline); or 
 For patients with bacteremia: absence of the baseline strain of ABC on culture. 
Microbiologic presumed eradication: no culture was done, and the patient meets clinical criteria 
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Microbiologic persistence: 
 For patients with cUTI or AP: the demonstration that the urine culture grew 103 CFU/mL of 
the baseline strain of ABC identified at study entry and/or a blood culture demonstrates the 
same baseline pathogen(s); or 
 For patients with bacteremia: presence of the baseline strain of ABC on repeat culture. 
Patients who are a persistence at EOT will be considered a persistence at TOC. 
Microbiologic presumed persistence: no culture was done, and the patient meets clinical criteria 
for clinical failure. 
Microbiologic indeterminate: if clinically indicated (for cUTI and bacteremia only), no follow-up 
culture is available, the culture cannot be interpreted for any reason, or the culture is considered 
contaminated.  
Microbiologic recurrence:  
 For patients with cUTI or AP: the demonstration that the urine culture grew 103 CFU/mL of 
the baseline strain of ABC identified at study entry at any time after documented eradication 
at the TOC Visit up to and including the LFU Visit; or  
 For patients with bacteremia: a positive blood culture for ABC at any time after documented 
eradication at the TOC Visit up to and including the LFU Visit. 
7.8.2 
Microbiologic Outcome for Hospital-Acquired Bacterial Pneumonia, 
Ventilator-Associated Bacterial Pneumonia, Ventilated Pneumonia, or Surgical or 
Post-Traumatic Wound Infections 
Microbiologic presumed eradication: no culture was done, and the patient meets clinical criteria 
for clinical cure. For patients with HABP/VABP/VP or surgical or post-traumatic wound 
infections, where repeat culture samples may not be indicated, presumed eradication based on 
clinical improvement will be inferred. 
Microbiologic presumed persistence: no culture was done, and the patient meets clinical criteria 
for clinical failure. 
7.9 
Pharmacokinetic Assessments 
7.9.1 
Intense Pharmacokinetic Sampling 
The first approximately 30 patients randomized in Part A will have samples collected for intense 
PK analysis to ensure that exposures observed in this severely ill cohort are comparable to those 
observed thus far in prior clinical studies. Intense PK sampling will also be performed on the first 
approximately 20 patients randomized in Part A at sites in China Mainland.  
Samples for intense PK analysis will be collected on Day 1, preferably after the second infusion, 
as follows: 
 At the end of the infusion after the infusion pump is turned off (+15 minutes); 
 1.5 hours (15 minutes) after the end of infusion; and 
 Immediately prior to the start of the next infusion.  


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When possible, PK samples should be collected after the second infusion on Day 1. If the second 
infusion happens during the night and it is not possible to collect the PK sample after the infusion, 
the same procedures could be done after the third infusion on Day 1. The PK sample should be 
taken after the patient received at least 2 infusions on Day 1.  
Additional samples for intense PK analysis will be collected on Day 4 (1 day) as follows: 
 At the end of any infusion after the infusion pump is turned off (+15 minutes); and 
 Immediately prior to the start of the next infusion. 
Table 4 shows the sampling times for intense PK assessments. 
Table 4. 
Sampling Times for Intense Pharmacokinetic Assessments 
PK Sampling Time 
Day 1 [1] 
Day 4 (1 Day) 
End of infusion (+15 minutes) [2] 
X
X 
1.5 hours (15 minutes) after end of 
infusion  
X
 
Immediately prior to the start of the 
next infusion 
X
X  
1. 
PK sample should be taken preferably after the second infusion on Day 1. 
2. 
PK sample should be taken at the end of the infusion after the infusion pump is turned off. 
PK = pharmacokinetic. 
7.9.2 
Sparse Pharmacokinetic Sampling 
All other patients enrolled in the study (Parts A and B) will have samples collected for sparse PK 
analysis. Samples for sparse PK analysis will be collected on Day 1, preferably after the second 
infusion, and on Day 4 as follows: 
 On Day 1, immediately prior to the start of the next infusion; and 
 On Day 4 (1 day), immediately prior to the start of the next infusion. 
When possible, PK samples should be collected after the second infusion on Day 1. If the second 
infusion happens during the night and it is not possible to collect the PK sample after the infusion, 
the same procedures could be done after the third infusion on Day 1. The PK sample should be 
taken after the patient received at least 2 infusions on Day 1. Table 5 shows the sampling times for 
sparse PK assessments. 
Table 5. 
Sampling Times for Sparse Pharmacokinetic Assessments 
PK Sampling Time 
Day 1 [1] 
Day 4 (1 Day) 
Immediately prior to the start of the 
next infusion 
X
X 
1. 
PK sample should be taken preferably after the second infusion on Day 1. 
PK = pharmacokinetic. 
The PK samples will be collected for both treatment groups in Part A to keep the study data 
blinded. The PK samples obtained from the ETX2514SUL group will be analyzed for ETX2514 
and sulbactam concentrations using a validated assay by a central bioanalytical laboratory.  
The PK plasma samples will be used to estimate PK parameters using non-compartmental 
methods, such as area under the concentration-time curve, maximum plasma concentration, time 
to maximum plasma concentration, drug clearance, half-life, minimum plasma concentration, and 


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steady-state volume of distribution for ETX2514SUL. Population PK and PK/PD modeling will 
be performed and reported separately. The results will not be included in the clinical study report. 
Additional PK sampling may be performed as needed for patients with eGFR >130 mL/min/m2 
undergoing acute hemodialysis or renal replacement therapy utilizing the trough sampling 
approach. 
The actual PK sampling times will be captured on the eCRF. Actual dosing time will also be 
captured on the eCRF. Actual sampling time will be used for the PK calculations. 
See the Laboratory Manual for more details about PK sampling.  


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8 
SAFETY ASSESSMENTS 
8.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An adverse event can therefore be any unfavorable and/or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational medicinal product, whether or not related to the investigational medicinal 
product. All adverse events, including observed or volunteered problems, complaints, or 
symptoms, are to be recorded on the appropriate eCRF. 
Adverse events, which include clinical laboratory test variables, will be monitored and 
documented from the time of the main informed consent (not the limited scope ICF) until study 
participation is complete. This is to be understood that Investigators should report any adverse 
event occurring from the time the main ICF (including all study procedures) was signed. 
Investigators are not required to report adverse events occurring for patients who only signed the 
limited scope ICF (which only allows rapid testing on a respiratory sample). Patients should be 
instructed to report any adverse event that they experience to the Investigator. Beginning at 
enrollment, Investigators should make an assessment for adverse events at each visit and record 
the event on the appropriate adverse event eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate adverse event on the eCRF. 
Additionally, the condition that led to a medical or surgical procedure (eg, surgery, endoscopy, 
tooth extraction, or transfusion) should be recorded as an adverse event, not the procedure.  
Any medical condition already present at Screening should not be reported as an adverse event 
unless the medical condition or signs or symptoms present at baseline changes in severity or 
seriousness at any time during the study. In this case, it should be reported as an adverse event. 
Clinically significant abnormal laboratory or other examination (eg, ECG) findings that are 
detected during the study or are present at Screening and significantly worsen during the study 
should be reported as adverse events. The Investigator will exercise his or her medical and 
scientific judgment in deciding whether an abnormal laboratory finding or other abnormal 
assessment is clinically significant. Clinically significant abnormal laboratory values occurring 
during the clinical study will be followed until repeat tests return to normal, stabilize, or are no 
longer clinically significant. Any abnormal test that is determined to be an error does not require 
reporting as an adverse event. 
Newly emergent infections that appear after baseline will be reported as adverse events and 
summarized separately. Clinical failures should not be considered adverse events and should not 
be reported as such. 
8.1.1 
Adverse Drug Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Response” to a medicinal product means that a causal 


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relationship between a medicinal product and an adverse event is at least a reasonable possibility, 
ie, the relationship cannot be ruled out. 
8.1.2 
Unexpected Adverse Drug Reaction 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information. For ETX2514SUL, the reference 
safety information is included in the Investigator’s Brochure currently in force.  
8.1.3 
Assessment of Adverse Events by the Investigator 
The unblinded Investigator will assess the severity (intensity) of each adverse event as mild, 
moderate, or severe. In Part A, in addition to the unblinded Investigator, a blinded assessor will 
also be responsible for the causality assessment, and as detailed below. 
Assessment of severity: 
Mild – An event that is easily tolerated and generally not interfering with normal daily activities. 
Moderate – An event that is sufficiently discomforting to interfere with normal daily activities. 
Severe – An event that is incapacitating with inability to work or perform normal daily activities. 
Causality assessment: 
The relationship of an adverse event to the administration of the study drug is to be assessed by 
the blinded assessor and the unblinded Investigator for Part A and by the unblinded Investigator 
for Part B, according to the following definitions: 
No (unrelated, not related, no relation) – The time course between the administration of study drug 
and the occurrence or worsening of the adverse event rules out a causal relationship and another 
cause (concomitant drugs, therapies, complications, etc) is suspected. 
Yes (related) – The time course between the administration of study drug and the occurrence or 
worsening of the adverse event is consistent with a causal relationship and no other cause 
(concomitant drugs, therapies, complications, etc) can be identified. 
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal relationship. 
The following factors should also be considered: 
 The temporal sequence from study drug administration- 
o The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event. 
 Underlying, concomitant, intercurrent diseases- 
o Each report should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the patient may have. 
 Concomitant drug- 
o The other drugs the patient is taking or the treatment the patient receives should be 
examined to determine whether any of them might be recognized to cause the event in 
question. 


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 Known response pattern for this class of study drug- 
o Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect. 
 Exposure to physical and/or mental stresses- 
o The exposure to stress might induce adverse changes in the recipient and provide a logical 
and better explanation for the event. 
 The pharmacology and PK of the study drug- 
o The known PK properties (absorption, distribution, metabolism, and excretion) of the study 
drug should be considered. 
8.1.4 
Adverse Events of Special Interest 
Adverse events of special interest will be analyzed, summarized, and reported in the clinical study 
report. Statistical comparisons will be made between the investigational and control groups in 
Part A.  
Adverse events of special interest and their definitions include the following: 
 Allergic and hypersensitivity reactions: Severe and serious adverse drug reactions from the 
Medical Dictionary for Regulatory Activities (MedDRA) Standardized MedDRA Queries of 
allergy and hypersensitivity; 
 Nephrotoxicity: Using the RIFLE criteria for the duration of the study (see Table 6);18 and  
 Emergent infections and superinfections: All serious and severe events in the MedDRA system 
organ class of infections and infestations other than the indication infection (ie, ABC). 
Table 6. 
Definition of RIFLE Criteria 
Term 
Definition 
Risk (R) 
Increased creatinine level 1.5 or GFR decrease 25% 
Injury (I) 
Increased creatinine level 2 or GFR decrease 50%
Failure (F) 
Increased creatinine level 3, GFR decrease 75%, or 
creatinine level 4 mg/dL 
Loss (L) 
Persistent acute renal failure or complete loss of 
function for 4 weeks 
ESKD (E) 
ESKD for 3 months 
ESKD = end-stage kidney disease; GFR = glomerular filtration rate; RIFLE = Risk–Injury–Failure–Loss–End-stage renal 
disease. 
8.2 
Serious Adverse Events 
An adverse event or adverse reaction is considered serious if, in the view of either the Investigator 
or Sponsor, it results in any of the following outcomes: 
 Death; 
 A life-threatening adverse event; 
Note: An adverse event or adverse reaction is considered “life-threatening” if, in view of either 
the Investigator or Sponsor, its occurrence places the patient at immediate risk of death. It does 
not include an event that, had it occurred in a more severe form, might have caused death. 


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 Requires hospitalization or prolongation of existing hospitalizations; 
Note: Any hospital admission with at least 1 overnight stay will be considered an inpatient 
hospitalization. An emergency room visit without hospital admission will not be recorded as 
an SAE under this criterion, nor will hospitalization for a procedure scheduled or planned 
before signing of informed consent. However, unexpected complications and/or prolongation 
of hospitalization that occur during elective surgery should be recorded as adverse events and 
assessed for seriousness. Admission to the hospital for social or situational reasons (ie, no place 
to stay, live too far away to come for hospital visits) will not be considered inpatient 
hospitalizations. Adverse events recorded for a patient who is hospitalized for treatment of the 
underlying illness, do not necessarily meet serious criterion of hospitalization.  
 A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions; 
 A congenital anomaly/birth defect; or 
 An important medical event. 
Note: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to prevent 
1 of the outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalizations, or the development of 
drug dependency. 
8.3 
Serious Adverse Event Reporting − Procedures for Investigators 
Initial reports 
All SAEs occurring from the time of the main informed consent (not the limited scope ICF) or 
randomization until 30 days following the last administration of study drug must be reported to 
Medpace Clinical Safety within 24 hours of the knowledge of the occurrence (this refers to any 
adverse event that meets any of the aforementioned serious criteria). This is to be understood that 
Investigators should report any SAE occurring from the time the main ICF (including all study 
procedures) was signed. Investigators are not required to report SAEs occurring for patients who 
only signed the limited scope ICF (which only allows rapid testing on a respiratory sample). All 
SAEs that the Investigator considers related to study drug occurring after the 30-day follow-up 
period must be reported to the Sponsor. All SAEs should be reported as if it were a blinded study 
and without evidence of treatment assignment on the report. 
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study. When the form is completed, Medpace Safety personnel will be 
notified electronically and will retrieve the form. If the event meets serious criteria 
and it is not possible to access the EDC system, send an email to Medpace Safety at 
medpace-safetynotification@medpace.com or call the Medpace SAE reporting line (telephone 
number listed below), and fax the completed paper SAE form to Medpace (fax number listed 
below) within 24 hours of awareness. When the EDC system becomes available, the SAE 
information must be entered within 24 hours of the system becoming available.  


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Safety Contact Information: Medpace Clinical Safety 
Medpace SAE reporting line – US: 
Telephone: +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3 
Fax: +1-866-336-5320 or +1-513-579-0444 
E-mail: medpace-safetynotification@medpace.com 
Medpace SAE reporting line – Rest of World: 
Telephone: +49 89 89 55 718 44 
Fax: +49 89 89 55 718 104 
E-mail: medpace-safetynotification@medpace.com 
Follow-up reports 
The Investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the patient 
dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(eg, patient discharge summary or autopsy reports) to Medpace Clinical Safety via fax or e-mail. 
If it is not possible to access the EDC system, refer to the procedures outlined above for initial 
reporting of SAEs.  
8.4 
Pregnancy Reporting 
If the patient or partner of a patient participating in the study becomes pregnant during the study 
or within 120 days of discontinuing study drug, the Investigator should report the pregnancy to 
Medpace Clinical Safety within 24 hours of being notified. Medpace Clinical Safety will then 
forward the Exposure In Utero form to the Investigator for completion.  
A patient becoming pregnant while on study drug will immediately be withdrawn from the study 
and early study termination procedures will be performed. 
The patient or partner should be followed by the Investigator until completion of the pregnancy. 
If the pregnancy ends for any reason before the anticipated date, the Investigator should notify 
Medpace Clinical Safety. 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 SAE (ie, postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 
8.5 
Expedited Reporting 
The Sponsor will report all relevant information about suspected unexpected serious adverse 
reactions that are fatal or life-threatening as soon as possible to the Food and Drug Administration 
(FDA), applicable competent authorities in all the Member States concerned, and to the Central 
Ethics Committee, and in any case no later than 7 days after knowledge by the Sponsor of such a 
case, and that relevant follow-up information will subsequently be communicated within an 
additional 8 days.  
Given that all-cause mortality is the primary efficacy endpoint in the study, all death cases will not 
be automatically unblinded by the case processing team. Death cases, where there is a plausible 
cause of death that is related to study drug administration, will be treated as potential suspected 
unexpected serious adverse reactions and processed as such and reported as needed. The DSMB 


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will periodically monitor deaths in aggregate, analyzed by treatment group, as detailed in the 
DSMB charter. 
All other suspected unexpected serious adverse reactions will be reported to the FDA, applicable 
competent authorities concerned, and to the Central Ethics Committee concerned as soon as 
possible but within a maximum of 15 days of first knowledge by the Sponsor.  
The Sponsor will also inform all Investigators as required.  
8.6 
Clinical Laboratory Evaluations 
Standard clinical laboratory profiles for chemistry will be evaluated at Screening, Day 1, Day 3, 
Day 5, Day 7, the EOT Visit, the TOC Visit, the LFU Visit, and the ET Visit. Serum creatinine 
will be evaluated daily while the patient is receiving study drug and will be analyzed at the local 
laboratory to assess the need for dose adjustments. All Screening laboratories will be performed 
at the local laboratory and may have been collected as standard of care within 48 hours prior to 
randomization, with the exception of serum creatinine determination, which must be obtained at 
the local laboratory within 24 hours before the first dose of study drug. All other samples are to be 
sent to the central laboratory. The Day 5 safety chemistry panel will be performed at the local 
laboratory and sent to the central laboratory. 
Standard clinical laboratory profiles for hematology including complete blood count (with red 
blood cell count, total white blood cell count with differential counts, platelet count, hemoglobin, 
and hematocrit) will be performed at Screening, Day 1, Day 3, Day 5, Day 7, the EOT Visit, the 
TOC Visit, the LFU Visit, and the ET Visit.  
A urinalysis including urine dipstick analysis for leukocytes, nitrites, or a catalase test of the urine 
specimen, microscopic evaluation, specific gravity, and pH will be performed at Screening, Day 1, 
Day 3, Day 5, Day 7, the EOT Visit, the TOC Visit, the LFU Visit, and the ET Visit. 
A highly sensitive urine or serum pregnancy test will be performed at Screening, the EOT Visit, 
and the ET Visit for women of childbearing potential. 
See Appendix B for a list of central clinical laboratory analytes. 
Standard of care safety laboratory profiles should also be performed by the local laboratory. 
Abnormal values of laboratory parameters must be followed up to normalization or stabilization 
at the discretion of the Investigator. 
In China all sites will perform all laboratory tests at the local laboratory, following the timepoints 
outlined above. 
8.7 
Vital Signs 
Vital signs (including systolic and diastolic blood pressure, heart rate, respiratory rate, and, for 
ventilated patients, oxygen therapy and respiratory settings including FiO2 and PEEP) will be taken 
after at least 5 minutes in a seated or supine position. Vital signs will be recorded at Screening, all 
days that the patient receives study drug treatment, the EOT Visit, the TOC Visit, the LFU Visit, 
and the ET Visit. Vital signs should be collected at the same time as assessments of signs and 
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8.8 
Medical/Surgical History Assessments 
Medical and surgical history will be obtained and evaluated at Screening to confirm the patient’s 
eligibility to enroll in the study.   
8.9 
Electrocardiograms 
Twelve-lead ECGs will be performed for all patients at Screening, at the end of the first infusion 
of study drug on Day 1, at EOT, and at the ET Visit. If clinically indicated, the 12-lead ECGs will 
be repeated as close as possible following the end of the infusion of study drug on the day on which 
the post-dose PK samples are drawn (Day 4 [1 day]; day selected at the discretion of the 
Investigator). All 12-lead ECGs will be performed after the end of the infusion and after the patient 
has been in a supine position for at least 10 minutes. The value at Screening will be used for 
assessing the QTcF exclusion criterion. All 12-lead ECGs will be performed and read locally. The 
following ECG parameters will be recorded: 
 Heart rate; 
 QRS interval; 
 PR interval; 
 RR interval; 
 QT interval; and  
 QTc interval. 
All ECGs will be evaluated for the presence of abnormalities by a qualified local physician. The 
ECGs will be classified as 1 of the following: 
 Normal; 
 Having a not clinically significant abnormality; or 
 Having a clinically significant abnormality. 
An example of a clinically significant abnormality may be a corrected QTcF 480 msec. 
8.10 
Physical Examinations 
A complete physical examination will be performed at Screening, Day 3, Day 5, Day 7, at the 
EOT Visit, and at the ET Visit. A limited physical examination will be performed, if needed, at 
Day 2, Day 4, Day 6, Day 8 to Day 14 (if EOT has not already occurred), at the TOC Visit, and at 
the LFU Visit.  
A complete physical examination must include source documentation of weight, skin, head and 
neck, heart, lung, abdomen, extremities, back/flank/costovertebral angle tenderness, and 
neuromuscular assessments. Height will only be collected at Screening. Limited physical 
examinations are symptom-based. When clinically indicated, a prostate exam can be performed, 
at the discretion of the Investigator. 
Physical examinations may be performed at unscheduled time points if deemed necessary by the 
Investigator. 


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8.11 
Chest X-Ray/Radiology/Ultrasound 
Chest X-rays, MRIs, or CT scans will be performed in patients with HABP, VABP, or VP at 
Screening and the TOC Visit, and as clinically indicated to evaluate for the presence of infiltrates. 
Ultrasounds may also be performed for patients with HABP, VABP, or VP at Screening. If an 
ultrasound is performed, a confirmatory X-ray or CT scan should be performed within 24 hours. 
Imaging should be conducted per institutional guidelines and results recorded in the source 
documents and the eCRF. 
8.12 
Mechanical Ventilator Assessments 
Patients whose primary indication for enrollment into the study is HABP, VABP, or VP and who 
require mechanical ventilation support will be managed by the study Investigators per institutional 
guidelines. Data regarding mechanical ventilation settings will be captured in the source 
documents and the eCRFs. 
8.13 
Safety Monitoring and Assessment of Abnormal Liver Function Tests 
Management and discontinuation criteria for abnormal liver function tests (LFTs) have been 
designed to ensure patient safety and evaluate liver event etiology.19 Safety monitoring for LFTs 
will occur from randomization until 30 days following the last administration of study drug; 
however, any abnormal LFT will be monitored according to the Safety Monitoring Plan. 
Investigators should evaluate standard of care laboratory reports in addition to study laboratory 
reports when monitoring for LFTs. 
Abnormal liver chemistry criteria: 
The Investigator or sub-Investigator must review patient laboratory reports to identify if they meet 
the following criteria: 
 Moderate abnormality that happened after study drug administration: 
o AST or ALT >2 × baseline or evidence of progressively increasing levels despite 
improvement of underlying infection; or 
o Total bilirubin >2 × baseline or evidence of progressively increasing levels despite 
improvement of underlying infection. 
 Severe abnormality: 
o Confirmed values of AST or ALT >3 × ULN and total bilirubin >2 × ULN or evidence of 
acute hepatic insufficiency or failure, as evidenced by progression of Child-Pugh score to 
B or C; or 
o Persistently high values of AST or ALT > 5 × ULN for 14 days. 


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Action to be taken by Investigator: 
If any 1 of the abnormal liver chemistry criteria is met, the Investigator or sub-Investigator must 
do the following: 
 Obtain a detailed history of symptoms and prior or concurrent diseases. The Investigator 
should ensure that the medical history form captures any preexisting illness that may be 
relevant in assessing hepatic function; 
 Obtain a history of concomitant drug use (including over-the-counter/herbal/dietary 
supplements); 
 Obtain a history of exposure to environmental chemical agents; 
 Following the initial observed elevation, every effort should be made to have the patient 
reassessed within 24 hours to 48 hours. Repeat LFTs will be performed and sent to the central 
laboratory. Liver function tests may also be repeated via the local laboratory at the discretion 
of the Investigator; 
 Patients who have an Investigator-assessed, study drug-related elevation of their LFTs must be 
monitored 2 to 3 times per week until liver function chemistries (ALT, AST, alkaline 
phosphatase, and total bilirubin) completely return to normal range or return to the baseline 
level and associated clinical signs and symptoms return to baseline levels. If the elevation of 
LFTs is attributed to a non-study drug-related issue (eg, chronic hepatitis, chronic cholestasis, 
concomitant treatments, cardiovascular causes, etc), the patient should be monitored until the 
LFTs stabilize or return to the patient’s baseline level and associated clinical signs and 
symptoms return to baseline levels. The Investigator should contact the Medical Monitor to 
discuss additional management and follow-up of patients with elevation of LFTs; 
 The event must be reported to Medpace within 48 hours to 72 hours after its occurrence on a 
Liver Event Form; 
 Consider a consultation with a specialist such as a hepatologist; and 
 Consider performing liver imaging (ie, MRI, CT, or ultrasound). 
Hy’s Law definition:  
The definition of Hy’s Law is as follows: 
1. AST or ALT >3 × ULN; 
2. Total bilirubin >2 × ULN;  
3. No evidence of intra- or extra-hepatic bilirubin obstruction (elevated alkaline phosphatase) or 
Gilbert’s Syndrome; and 
4. No evidence of any other reason for increase in transaminases as noted above.  
If the first 3 criteria of Hy’s Law are met in a concurrent blood sample, the case must be 
reported as an SAE. 


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Criteria for study drug discontinuation (severe hepatic abnormalities): 
In the absence of an explanation for increased liver enzymes, the patient should be discontinued 
from the study drug. Discontinuation should be considered if: 
 ALT or AST >10 × ULN; 
 ALT or AST >5 × ULN for more than 2 weeks or progressively increasing transaminases 
despite clinical improvement of underlying infection; 
 AST or ALT >3 × ULN and total bilirubin >2  ULN or international normalized ratio >1.5 
(for patients who are not on coumadin);  
 AST or ALT >3 × ULN along with signs or symptoms compatible with hepatitis or 
hypersensitivity (eg, fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
jaundice, fever, rash, or eosinophilia [>5%]); or 
 Close monitoring for a patient with moderate hepatic laboratory test abnormality is not 
possible. 
Follow-up examination: 
If any abnormal liver chemistry criteria are met, the following assessments should be obtained at 
the LFU Visit and documented in a Liver Event Form: 
 Clinical symptoms course; 
 Concomitant medications: over-the-counter/herbal/dietary supplements (start and stop dates); 
 Alcohol use; 
 Risk 
factors 
for 
non-alcoholic 
steatohepatitis, 
such 
as 
diabetes, 
obesity, 
and 
hypertriglyceridemia; 
 Autoimmune hepatitis/cholangitis; 
 Wilson’s disease; and 
 Laboratory assessments. Based on the patient’s history, other testing may be appropriate, 
including: 
o Acute viral hepatitis (A, B, C, D, E, or other infectious agents); and 
o Other laboratory tests, including international normalized ratio and direct bilirubin. 


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9 
STATISTICS 
9.1 
Analysis Populations 
This study is designed to estimate treatment efficacy of ABC infections, with a pivotal component 
in Part A.  
The ITT Population will include all patients randomized to study drug treatment (ETX2514SUL 
plus imipenem/cilastatin or colistin plus imipenem/cilastatin) in Part A or enrolled in Part B, 
regardless of whether the patient actually receives study drug. 
The Modified ITT (MITT) Population will include patients in Parts A and B who meet ITT criteria 
and receive any amount of study drug. The MITT Population will be considered the Safety 
Population. Patients with HABP/VABP/VP who were randomized to Part A on the basis of a BPP 
rapid test result but were subsequently withdrawn due to a lack of a culture growing ABC will be 
counted in the MITT and Safety Populations.  
The m-MITT Population will include patients who meet MITT criteria and have an ABC organism 
isolated as the qualifying culture specimen, as confirmed by the central and/or local microbiology 
laboratory. If an isolate for testing at the central laboratory is not available, the local laboratory 
data can be used to confirm the presence of ABC organism, as long as the local laboratory uses 
modern methods of diagnosis such as molecular-based tests, matrix-assisted laser 
desorption/ionization time-of-flight mass spectrometry, Vitek, Phoenix, etc (ie, not conventional 
biochemical or manual phenotypic methods). Patients with HABP/VABP/VP who are enrolled 
based upon a positive BPP rapid test for ABC, but subsequently are found to have respiratory 
sample cultures that do not grow ABC (by the local laboratory), will be withdrawn from the study 
drug treatment as detailed in Section 4.3. These patients will not be included in the m-MITT 
Population but will remain in the MITT Population. 
The CRABC m-MITT Population will include patients who meet m-MITT criteria and 
have a baseline ABC organism that is confirmed to be carbapenem-resistant (MIC to 
imipenem/meropenem 8 mg/L) by the central laboratory or by the local laboratory if the central 
laboratory is not able to identify the isolate for any reason. Patients will be excluded from the 
CRABC m-MITT Population if they have isolates that are deemed by the central laboratory to be 
resistant to ETX2514SUL (MIC >4 mg/L) or colistin (MIC 4 mg/L), if their blood culture or 
respiratory samples are collected more than 72 hours prior to randomization, if they are transferred 
from Part A to Part B, or if they are enrolled with infections other than ABC pneumonia or 
bloodstream infection (ie, ABC infections other than HABP, VABP, VP, and bacteremia). A 
sensitivity analysis for the primary efficacy endpoint will be performed for patients whose eligible 
culture is >48 hours from the first dose of study drug, as well as for all patients with and without 
evidence of non-susceptibility to colistin and ETX2514SUL at baseline. 
The CE Population will include patients who meet m-MITT criteria and meet evaluability criteria 
(meet key inclusion criteria, do not have key exclusion criteria, received at least 72 hours of study 
drug [ie, 12 doses of ETX2514SUL plus 12 doses of imipenem/cilastatin or 6 doses of colistin plus 
12 doses of imipenem/cilastatin in patients without dose adjustments] to be a clinical cure, received 
at least 48 hours of study drug [ie, 8 doses of ETX2514SUL plus 8 doses of imipenem/cilastatin 
or 4 doses of colistin plus 8 doses of imipenem/cilastatin in patients without dose adjustments] to 
be a clinical failure, received 80% of anticipated doses, and did not have a clinical response of 
indeterminate at the TOC Visit). 


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The ME Population will include patients who meet m-MITT criteria and CE criteria and have an 
appropriately collected culture specimen and interpretable culture result when specimen collection 
is clinically indicated at the TOC Visit. 
The CRABC ME Population will include patients who meet ME criteria and who have a baseline 
ABC organism that is confirmed to be carbapenem-resistant (and susceptible to ETX2514SUL for 
Parts A and B and susceptible to colistin for Part A). 
The PK Population will include patients who receive any amount of study drug and have evaluable 
PK data. 
9.2 
Statistical Methods 
Continuous variables will be summarized using the number of non-missing observations, 
arithmetic mean, standard deviation, median, minimum, and maximum values as descriptive 
statistics. Categorical variables will be summarized by using the frequency count and the 
percentage of patients in each category as descriptive statistics.  
All comparisons in Part A will be for ETX2514SUL plus imipenem/cilastatin versus colistin plus 
imipenem/cilastatin. The efficacy endpoints for Part B will be summarized descriptively only and 
will be used to supplement results in Part A. Listings of individual patient data will be produced. 
A complete analysis of efficacy and safety data will be performed and detailed in the SAP.  
9.2.1 
Patient Population and Characteristics 
The number of patients randomized, treated, completed, and discontinued early from the study and 
the reasons for discontinuation will be summarized descriptively. In addition, reasons leading to 
study discontinuation will be summarized for each treatment group. The number and percentage 
of randomized patients included in each analysis population will also be presented. 
Summary statistics will be provided by treatment group for demographics (eg, age, gender, race, 
and ethnicity) and for baseline characteristics. 
9.2.2 
Analysis of Efficacy 
9.2.2.1 
Primary efficacy analysis 
The primary efficacy endpoint for the study is 28-day all-cause mortality in the CRABC m-MITT 
Population in Part A. Patients in the CRABC m-MITT Population who discontinue study drug 
prematurely in Part A for any reason will be included in the assessment of 28-day all-cause 
mortality, provided consent has not been withdrawn.  
A sensitivity analysis for the primary efficacy endpoint will be performed for patients whose 
eligible culture is >48 hours from the first dose of study drug, as well as for all patients with and 
without evidence of non-susceptibility to colistin and ETX2514SUL at baseline. Details of the 
sensitivity analysis will be described in the SAP. 
The non-inferiority assessment will be based on the 2-sided 95% confidence intervals (CIs) for the 
difference ([ETX2514SUL + imipenem/cilastatin] – [colistin + imipenem/cilastatin]) in 28-day 
all-cause mortality rates between the treatment groups. Non-inferiority will be concluded if the 
upper limit of the 2-sided 95% CI is less than +20%. 
If non-inferiority is achieved, a test of superiority will be performed. 


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The analysis of the primary efficacy endpoint 28-day all-cause mortality will also be performed in 
the ITT Population. 
9.2.2.2 
Secondary efficacy analysis 
The number and percentage of patients in each response category for the secondary efficacy 
endpoints will be summarized by treatment group for the populations defined earlier. Two-sided 
95% CIs for the difference in outcome rates between the treatment groups in Part A will be 
provided.  
Part B data will be analyzed separately from Part A using descriptive statistics. 
Further subgroup analyses will be conducted, and details of the analysis will be described in the 
SAP. 
9.2.2.3 
Exploratory efficacy analysis 
Exploratory endpoint analysis will be described in the SAP. Exploratory endpoints for health 
resource utilization difference between treatment groups (such as length of ventilation, intensive 
care unit stay, hospitalization, additional antibiotic use, etc) will be reported separately. Efficacy 
analysis for patients with HABP/VABP/VP who are identified as positive for ABC by BPP 
molecular methodology will be explored. 
9.2.3 
Pharmacokinetic Analysis 
Descriptive statistics will be provided for PK concentration data and PK parameters. All PK 
analyses will be performed using the PK Population. 
Intense pharmacokinetic group:  
Pharmacokinetic samples will be obtained from the first approximately 30 patients randomized in 
Part A on a schedule detailed in Section 7.9. The PK samples will be collected for both treatment 
groups in Part A to keep the study data blinded. The PK samples obtained from the ETX2514SUL 
group will be analyzed for ETX2514 and sulbactam concentrations using a validated assay by a 
central bioanalytical laboratory. Pharmacokinetic assessment of the initial 15 patients on 
ETX2514SUL in Part A will be performed by an independent PK assessor, prior to the opening of 
enrollment in Part B. The independent PK assessor will conduct sequential PK analysis from 
patients as they are enrolled. An initial aggregate assessment of PK parameters will be done after 
enrollment of the first 8 HABP/VABP/VP patients randomized to ETX2514SUL. The independent 
PK assessor will report results to the DSMB, relative to concentrations projected in the population 
PK model, once data from all 15 patients on ETX2514SUL is available. However, if the 
preliminary analysis of the first 8 patients with HABP/VABP/VP on ETX2514SUL reveals 
evidence of inadequate exposure this will be escalated to the DSMB. 
China Mainland intense pharmacokinetic group: 
The intense PK sampling will also be performed on the first approximately 20 patients randomized 
in Part A from China Mainland sites. The PK samples obtained from patients who have received 
the ETX2514SUL treatment will be analyzed for ETX2514 and sulbactam concentrations, which 
will be applied to build the population PK model combined with data from the sparse PK group. 


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Sparse pharmacokinetic group: 
All other patients enrolled in the study (Parts A and B) will have a sparse PK sampling, which will 
be used to better inform the population PK model. 
Analysis of the PK data and incorporation into the population PK analysis and PK/PD model will 
be described in a separate PK Analysis Plan. 
9.2.4 
Analysis of Safety 
All patients who receive any amount of study drug (MITT Population) will be included in the 
safety analyses. Patients who received the wrong study drug for their entire course of treatment 
will be analyzed in the group based on the drug received. 
A primary analysis of safety will be performed for Part A to assess the proportion of patients with 
nephrotoxicity, as measured by the RIFLE criteria based on the Safety and CE Populations. 
Overall safety will be assessed for Part A and Part B in the Safety Population. The number and 
percentage of patients in each treatment group reporting at least 1 occurrence of a TEAE for each 
unique system organ class and preferred term will be tabulated. A TEAE is defined as an adverse 
event occurring on or after the administration of the first dose of study drug. Treatment-emergent 
adverse events will also be tabulated by treatment group, severity, and the relationship to study 
drug as assessed by the Investigator. The number and percentage of patients in each treatment 
group reporting at least 1 occurrence of a treatment-emergent SAE will be tabulated. The number 
and percentage of patients (in each treatment group) prematurely discontinuing study drug 
treatment due to a TEAE will be tabulated by system organ class and preferred term. Adverse 
events of special interest in Part A will be summarized for all patients by treatment. 
Safety laboratory data will be presented by descriptive statistics of the post-baseline value and the 
change from baseline, as well as the number and percentage of patients with potentially clinically 
significant laboratory values. Descriptive statistics of vital signs and ECG parameters and the 
change from baseline will also be presented. An outlier analysis of the ECG parameters will be 
conducted. 
9.2.5 
Sample Size Determination 
Patients will be enrolled until there are 120 patients in the CRABC m-MITT Population in Part A. 
The study will have 80% power to demonstrate non-inferiority between Group 1 and Group 2 
using a 20% non-inferiority margin and a 2-sided 95% CI. This assumes a mortality rate in the 
comparator group (Group 2) of 41% and in the ETX2514SUL group (Group 1) of 36%. To have 
120 patients in the CRABC m-MITT Population, Part A will need to enroll approximately 
200 patients, assuming 60% of ABC clinical isolates are carbapenem-resistant. Patient enrollment 
in Part B (Group 3) will continue until Part A enrollment in the CRABC m-MITT Population is 
complete. Rates of carbapenem resistance among isolates from Part A patients will be monitored 
by the unblinded data manager/designee at the Clinical Research Organization on an ongoing 
basis.  
Table 7 demonstrates the mortality rates in the ETX2514SUL plus imipenem/cilastatin treatment 
group required to demonstrate non-inferiority or superiority with no less than 80% power in the 
CRABC m-MITT Population relative to various 28-day all-cause mortality rates in the colistin 
plus imipenem/cilastatin treatment group, given 120 patients in the CRABC m-MITT Population. 


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The sample size of 120 patients in the CRABC m-MITT Population was calculated based on a 
41% mortality rate in the colistin plus imipenem/cilastatin treatment group. 
Table 7. 
28-Day All-Cause Mortality Rates in the CRABC m-MITT Population Required 
to Demonstrate Non-Inferiority and Superiority 
ETX2514SUL+IMI 
Colistin+IMI 
95% CI for Treatment 
Difference [1] 
Power 
Test 
39% 
45% 
(-0.24, 0.12)
82%
Demonstrate NI
21% 
45% 
(-0.40, -0.08)
80%
Demonstrate superiority
35% 
40% 
(-0.22, 0.12)
80%
Demonstrate NI
17% 
40% 
(-0.39, -0.07)
80%
Demonstrate superiority
30% 
35% 
(-0.22, 0.12)
83%
Demonstrate NI
13% 
35% 
(-0.37, -0.07)
81%
Demonstrate superiority
26% 
30% 
(-0.20, 0.12)
83%
Demonstrate NI
9% 
30% 
(-0.35, -0.07)
83%
Demonstrate superiority
1. 
95% CIs for treatment difference ([ETX2514SUL + IMI] – [colistin + IMI]) were calculated using a normal 
approximation to the binomial distribution. 
CI = confidence interval; CRABC = Carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex; 
ETX2514SUL = sulbactam-ETX2514; IMI = imipenem/cilastatin; m-MITT = Microbiologically Modified Intent-to-Treat; 
NI = non-inferiority. 
9.3 
Data Safety Monitoring Board 
An independent DSMB will review the safety data periodically. The DSMB will also review SAEs 
and deaths on an ongoing basis. They will make recommendations to the Sponsor based on the 
safety data. The PK assessment report of data from the initial cohort of patients in Part A from the 
independent PK assessor will be submitted to the DSMB for its approval of continued enrollment 
and initiation of Part B. Further details regarding the DSMB guidelines will be described in the 
DSMB Charter. 


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10 
DATA MANAGEMENT AND RECORD KEEPING 
10.1 
Data Management 
10.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the CRA during monitoring visits. The 
CRAs will verify data recorded in the EDC system with source documents. All corrections or 
changes made to any study data must be appropriately tracked in an audit trail in the EDC system. 
An eCRF will be considered complete when all missing, incorrect, and/or inconsistent data have 
been accounted for. 
10.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
10.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure user name and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the US Code of Federal Regulations 
(21 CFR Part 11) and other appropriate international regulations. All passwords will be strictly 
confidential. 
10.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
 MedDRA (latest) for medical history and adverse events; and 
 WHO Drug Dictionary for prior and concomitant medications. 
10.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
10.2 
Record Keeping 
Records of patients, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data is defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are 
contained in source documents (original records or certified copies). These records will be retained 
in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records.  


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11 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
11.1 
Ethical Conduct of the Study 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve human subjects. Compliance with this 
standard provides public assurance that the rights, safety, and wellbeing of study patients are 
protected, consistent with the principles that have their origin in the Declaration of Helsinki, and 
that the clinical study data are credible. 
11.2 
Institutional Review Board/Independent Ethics Committee 
It is the responsibility of the Sponsor or their designee (ie, Medpace) to obtain the approval of the 
responsible ethics committees according to the national regulations.  
The study will only start in the respective sites once the respective committee’s written approval 
has been given. 
11.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the Institutional Review Board (IRB) prior to its use and must be in 
compliance with all International Council for Harmonisation (ICH) GCP, local regulatory 
requirements, and legal requirements.   
The Investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
patient has been informed of his/her rights to privacy. An ICF of limited scope may be signed prior 
to Screening to perform only BPP rapid testing of respiratory specimens. A comprehensive ICF, 
which will include all study procedures, will be signed at Screening. The Investigator will obtain 
written informed consent from each patient before any study-specific activity is performed and 
should document in the source documentation that consent was obtained prior to enrollment in the 
study. Patients will participate as much as possible in the informed consent procedure; however, 
as permitted by local law and institutional Standard Operating Procedures, in cases of a lack of 
decision-making capacity, informed consent on behalf of the patient may be provided by a legally 
authorized representative, independent physician, or consortium of independent physicians. These 
patients, upon return of their capacity, will be consented and allowed to make their own informed 
medical decisions.  
The original signed copy of the ICF must be maintained by the Investigator and is subject to 
inspection by a representative of the Sponsor, their representatives, auditors, the IRB, and/or 
regulatory agencies. A copy of the signed ICF will be given to the patient. 
11.4 
Patient Card  
On enrollment in the study, the patient will receive a patient card to be carried at all times. The 
patient card will state that the patient is participating in a clinical research study, type of treatment, 
and contact details in case of an SAE. 


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11.5 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, ICH GCP, Directive 2001/20/EC, applicable regulatory requirements, and the 
Declaration of Helsinki, and that valid data are entered into the eCRFs. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well organized, and easily retrievable data. 
Before the enrollment of any patient in this study, the Sponsor or their designee will review with 
the Investigator and site personnel the following documents: protocol, Investigator’s Brochure, 
eCRFs and procedures for their completion, informed consent process, and the procedure for 
reporting SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data are 
entered by the site, the CRA will review the data for safety information, completeness, accuracy, 
and logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
Investigators. The Investigator and his/her staff will be expected to cooperate with the monitor and 
provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log. 
11.6 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB as appropriate. Patients or their legal 
representatives may request their medical information be given to their personal physician or other 
appropriate medical personnel responsible for their welfare. 
Patient medical information obtained during the study is confidential and disclosure to third parties 
other than those noted above is prohibited. 
11.7 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating patients (sufficient information to link 
records, eg, eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE forms, 
source documents, and detailed records of treatment disposition. The records should be retained 
by the Investigator according to specifications in the ICH guidelines, local regulations, or as 
specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain 
written permission from the Sponsor before disposing of any records, even if retention 
requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor.   


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11.8 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved. 
11.9 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR Part 54. In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a period 
of 1 year after the completion of the study. 
11.10 
Insurance and Indemnity 
In accordance with the relevant national regulations, the Sponsor has taken out patient liability 
insurance for all patients who give their consent to the clinical study. This cover is designed for 
the event that a fatality, physical injury, or damage to health occurs during the clinical study’s 
execution. 
11.11 
Legal Aspects 
The clinical study will be submitted to the relevant national competent authorities in all 
participating countries to achieve a clinical trial authorization (CTA). 
The study will commence (ie, initiation of study centers) when the CTA and favorable Ethics 
opinion have been received.  


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12 
STUDY ADMINISTRATIVE INFORMATION 
12.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigators by Medpace or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB, unless immediate implementation of the change is necessary for patient safety. In this case, 
the situation must be documented and reported to the IRB within 5 working days. 
12.2 
End of Study 
End of Study in this study is defined as the last visit or last study-related contact (whichever comes 
last) of the last patient worldwide. 
12.3 
Address List 
12.3.1 
Sponsor 
Entasis Therapeutics 
Gatehouse Park BioHub 
35 Gatehouse Drive 
Waltham, MA 02451 
United States 
Telephone: +1-781-810-0120 
Fax: +1-781-810-0122 
12.3.2 
Contract Research Organization 
Medpace, Inc.  
5375 Medpace Way 
Cincinnati, OH 45227 
United States 
Telephone: +1-513-579-9911 
Fax: +1-513-579-0444 
12.3.3 
Serious Adverse Event Reporting 
Medpace Clinical Safety – US and Latin America 
5375 Medpace Way 
Cincinnati, OH 45227 
United States 
Telephone: +1-800-730-5779, ext. 12999 or +1-513-579-9911, ext. 12999 
Fax: +1-866-336-5320 or +1-513-579-0444 
E-mail: medpace-safetynotification@medpace.com 
 


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Medpace Clinical Safety – Rest of World 
Wallace House 
17-21 Maxwell Place 
Stirling 
FK8 1JU 
United Kingdom 
Telephone: +49 89 89 55 718 44 
Fax: +49 89 89 55 718 104 
E-mail: medpace-safetynotification@medpace.com 
12.3.4 
Biological Specimens 
Medpace Reference Laboratories, LLC 
5365 Medpace Way 
Cincinnati, OH 45227 
United States 
Telephone: +1-513-366-3270 
Fax: +1-513-366-3273 
 
International Health Management Associates, Inc. 
2122 Palmer Drive 
Schaumburg, IL 60173 
United States 
Telephone: +1-847-303-5003 
Fax: +1-847-303-5601 
 


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13 
REFERENCES 
1.  
Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United 
States, 2013. 2013. 
2.  
World Health Organization. Global priority list of antibiotic-resistant bacteria to guide 
research, discovery, and development of new antibiotics. 2017. 
3. 
Sievert DM, Ricks P, Edwards JR, et al. Antimicrobial-resistant pathogens associated 
with healthcare-associated infections: summary of data reported to the National 
Healthcare Safety Network at the Centers for Disease Control and Prevention, 
2009-2010. Infect Control Hosp Epidemiol. 2013;34(1):1-14. 
4. 
Stewart T, Dorfman K. Hospital-treated Gram-negative infections. Decision Resources 
Group. 2015. 
5. 
European Centre for Disease Prevention and Control. Summary of the latest data on 
antibiotic resistance in the European Union. 2016. 
6. 
Spellberg B, Bonomo RA. Combination therapy for extreme drug-resistant (XDR) 
Acinetobacter baumannii: ready for prime-time? Crit Care Med. 2015;43(6):1332-1334. 
7. 
Cheng A, Chuang YC, Sun HY, et al. Excess mortality associated with 
colistin-tigecycline compared with colistin-carbapenem combination therapy for 
extensively drug-resistant Acinetobacter baumannii bacteremia: a multicenter prospective 
observational study. Crit Care Med. 2015;43(6):1194-1204. 
8. 
Peleg AY, Seifert H, Paterson DL. Acinetobacter baumannii: emergence of a successful 
pathogen. Clin Microbiol Rev. 2008;21(3):538-582. 
9. 
Doi Y, Murray GL, Peleg AY. Acinetobacter baumannii: evolution of antimicrobial 
resistance – treatment options. Semin Respir Crit Care Med. 2015;36(1):85-98. 
10. 
Gonzalez-Villoria AM, Valverde-Garduno V. Antibiotic-resistant Acinetobacter 
baumannii increasing success remains a challenge as a nosocomial pathogen. J Pathog. 
2016:7318075. 
11. 
Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively 
drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim 
standard definitions for acquired resistance. Clin Microbiol Infect. 2012;18(3):268-281. 
12. 
Penwell WF, Shapiro AB, Giacobbe RA, et al. Molecular mechanisms of sulbactam 
antibacterial activity and resistance determinants in Acinetobacter baumannii. Antimicrob 
Agents Chemother. 2015;59(3):1680-1689. 
13. 
Zusman O, Avni T, Leibovici L, et al. Systematic review and meta-analysis of in vitro 
synergy of polymyxins and carbapenems. Antimicrob Agents Chemother. 
2013;57(10):5104-5111. 
14. 
Paul M, Daikos GL, Durante-Mangoni E, et al. Colistin alone versus colistin plus 
meropenem for treatment of severe infections caused by carbapenem-resistant 
Gram-negative bacteria: an open-label, randomised controlled trial. Lancet Infect Dis. 
2018;18(4):391-400. 
15. 
UNASYN® ampicillin sodium and sulbactam sodium injection, powder, for solution 
[package insert]. New York, NY. Pfizer, Inc. Revised June 2018. 
http://labeling.pfizer.com/ShowLabeling.aspx?id=617. 
16. 
Nation RL, Garonzik SM, Thamlikitkul V, et al. Dosing guidance for intravenous colistin 
in critically-ill patients. Clin Infect Dis. 2017;64(5):565-571.  
17. 
Trotman RL, Williamson JC, Shoemaker DM, et al. Antibiotic dosing in critically ill 
adult patients receiving continuous renal replacement therapy. Clin Infect Dis. 
2005;41(8):1159-1166. 
 
 


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105
 
18. 
Hartzell JD, Neff R, Ake J, et al. Nephrotoxicity associated with intravenous colistin 
(colistimethate sodium) treatment at a tertiary care medical center. Clin Infect Dis. 
2009;48(12):1724-1728. 
19.  
Food and Drug Administration. Guidance for industry drug-induced liver injury: 
premarketing clinical evaluation. 2009. 


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106
APPENDIX A: SCHEDULE OF PROCEDURES (PARTS A & B) 
Procedure [1] 
Screening 
Treatment Period 
TOC 
LFU 
ET [6] 
-48 Hours 
to Day 1 
[2] 
Day 1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 [3] 
Days 8 
to 14 
[3] 
EOT 
(+1 day) 
[3,4] 
EOT 
+7 (2) 
Days [5] 
EOT +14 
(2) 
Days and 
Day 28 
[5] 
Informed consent [7] 
X
 
Inclusion/exclusion criteria 
X
 
Medical/surgical history 
X
 
Prior/concomitant medications 
X [8]
X
X
X
X
X
X
X 
X
X
X
X
X
Demographics [9] 
X
 
Complete physical examination 
[10] 
X
X
X
X 
X
X
Limited physical examination [10] 
X
X
X
 
X
X
X
Vital signs [11] 
X
X
X
X
X
X
X
X 
X
X
X
X
X
Chest X-ray, MRI, CT scan, or 
ultrasound [12] 
X
 
X
 
Assess clinical signs/symptoms 
X
X
X
X
X
X
X
X 
X
X
X
X
X
Assess clinical outcome [13,14] 
X
X 
X
X [13]
X [13]
X
Rapid diagnostic test [15] 
X
 
APACHE II, SOFA, or qSOFA 
score [16] 
X [17]
X
 
 
Randomization [18] 
X
 
Pregnancy test [19] 
X
 
X
X
Serum chemistry [20] 
X
X [25]
X
X 
[22]
X 
X
X
X
X
Serum creatinine [21]  
X
X [25]
X
X
X
X
X
X 
X
X
X
X
X
Hematology [20,23] 
X
X [25]
X
X
X 
X
X
X
X
Urinalysis [20,24] 
X
X [25]
X
X
X 
X
X
X
X
12-lead ECG [26] 
X
X [27]
X [27]
 
X
X
Blood cultures [28] 
X
X [25]
X
X
X
X
X
X 
X
X
X
X
X
Infection site-specific cultures [29] 
X [30]
X
X 
X
X
X
X
Administer study drug [31] 
X
X
X
X
X
X
X 
X
X
Assessment of adverse events [32] 
X
X
X
X
X
X
X
X 
X
X
X
X
X
PK samples [33] 
X
X
 


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1. 
All the procedures for Part B will be the same as Part A, unless otherwise specified. 
2. 
Screening can occur up to 48 hours before the first dose of study drug. All Screening procedures must be performed prior to randomization and the first dose of study drug 
(Day 1). All Screening laboratories will be performed at the local laboratory and may have been collected as standard of care within 48 hours prior to randomization, with 
the exception of serum creatinine determination, which must be obtained at the local laboratory within 24 hours before the first dose of study drug. 
3. 
Day 7 to Day 14 study procedures are only required if the patient receives IV study drug treatment on Day 7 to Day 14. If EOT has already occurred, study procedures are 
not required to be performed. 
4. 
Patients will be treated for 28 doses of ETX2514SUL plus 28 doses of imipenem/cilastatin or 14 doses of colistin plus 28 doses of imipenem/cilastatin (ie, 7 days for those 
without dose adjustments), with a prolongation of therapy up to 14 days if clinically indicated. If EOT occurs on Day 7, Day 7 study procedures may be considered the 
EOT Visit study procedures. If EOT occurs after Day 7, the EOT Visit activities should be completed within 24 hours after the last dose of study drug.  
5. 
The TOC Visit must occur 7 days (2 days) after the EOT for all patients. The LFU Visit must occur 14 days (2 days) after the EOT for all patients. The LFU Visit 
should be performed as an in-person visit; however, if the patient is unable to attend the LFU Visit at the site, the patient may be contacted by telephone call for 
follow-up assessment of concomitant medications, clinical signs and symptoms, and adverse events. All patients who are alive and have not withdrawn consent 
for participation in the study must be contacted at Day 28 or anytime thereafter to assess survival if their LFU Visit is prior to Day 28. 
6. 
For patients who are withdrawn from the study prior to completion of study drug or discontinue study drug prematurely, complete an ET Visit at the time of study 
withdrawal or study drug discontinuation. Patients who discontinue study drug prematurely but are not withdrawn from the study should complete TOC and LFU Visits. 
For patients who are withdrawn from the study after the EOT Visit but prior to completion of the study, complete the next scheduled visit (either the TOC Visit or LFU 
Visit) at the time of study withdrawal. 
7. 
Informed consent must be obtained before any study procedures are performed. An ICF of limited scope may be signed prior to Screening to perform only BPP rapid 
testing of respiratory specimens. A comprehensive ICF, which will include all study procedures, will be signed at Screening. 
8. 
Reasonable effort will be made to determine all relevant treatments (including all antibiotics, prescription and non-prescription medications, herbal medications, vitamin 
supplements, supportive therapies, and non-pharmacologic treatments) received within 14 days before the first dose of study drug and during the study. 
9. 
Demographic data will be collected, including sex, age, race, and ethnicity. 
10. The Screening complete physical examination includes weight and height. A limited, symptom-based physical examination will be performed at the indicated visits. If a 
patient does not display symptoms, no limited physical examination needs to be performed. 
11. Vital signs include blood pressure, heart rate, and respiratory rate, and, for ventilated patients, oxygen therapy and respiratory settings including FiO2 and PEEP. 
12. For patients with HABP, VABP, or VP only. A chest X-ray, MRI, CT scan, or ultrasound done within 72 hours of Screening is acceptable. For images obtained 48 hours 
prior to randomization, repeat imaging is required. Note: If an ultrasound is performed, a confirmatory X-ray or CT scan must be performed within 24 hours. Findings 
should be consistent with the screening image and diagnosis of pneumonia, in the Investigator’s judgment; otherwise, the patient is no longer eligible. 
13. If a patient is a clinical failure at EOT, the patient is automatically considered a failure at the TOC and LFU Visits, and the assessment of clinical response by the 
Investigator should be listed as “failure at EOT or TOC.”  
14. In Part A, all clinical outcome assessments will be performed by a blinded assessor, in addition to the unblinded Investigator. 
15. A respiratory specimen for BPP rapid diagnostic testing should only be collected for patients suspected to have HABP, VABP, or VP. 
16. An APACHE II or SOFA score will be calculated at Screening and prior to randomization for patients in Part A only. For patients who are not being treated in an intensive 
care unit and cannot have an APACHE II or SOFA score performed, and for all patients in Part B, a qSOFA score should be calculated. 
17. An APACHE II, SOFA, or qSOFA score that was calculated as standard of care within 24 hours of Screening may be used and does not need to be repeated at Screening.   
18. Via IRT. 
19. A highly sensitive urine or serum pregnancy test will be performed at Screening, EOT Visit, and ET Visit for women of childbearing potential. 
20. Screening laboratories will be performed by the local laboratory within 48 hours of randomization. Subsequent laboratory samples will be collected, processed, and sent to 
the central laboratory for analysis. 
21. While the patient is receiving study drug, serum creatinine will be collected daily and analyzed at the local laboratory to assess the need for dose adjustments. Screening 
serum creatinine will be collected at the local laboratory within 24 hours before the first dose of study drug. 
22. The Day 5 safety chemistry panel will be performed at the local laboratory and sent to the central laboratory. 
23. Hematology includes complete blood count (with red blood cell count, total white blood cell count with differential counts, platelet count, hemoglobin, and hematocrit).  
24. Urinalysis includes urine dipstick analysis for leukocytes, nitrites, or a catalase test of the urine specimen, microscopic evaluation, specific gravity, and pH. 


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25. Predose. 
26. The 12-lead ECGs will be performed after the end of infusion, except for at Screening, and all 12-lead ECGs will be performed after the patient has been in a supine 
position for at least 10 minutes. Consult the Medical Monitor and local cardiologist in cases of clinically significant abnormal findings (eg, a QTcF 480 msec). 
27. The 12-lead ECG will be performed for all patients at the end of the first infusion of study drug on Day 1. If clinically indicated, the 12-lead ECGs will be repeated as 
close as possible following the end of the infusion of study drug administration on the day on which post-dose PK samples are drawn (Day 3, Day 4, or Day 5). The day on 
which the post-dose PK samples are drawn is at the discretion of the Investigator.  
28. Two sets of samples from 2 separate venipuncture sites are required for blood cultures in all patients. Each set of blood culture samples will be collected from a separate 
venipuncture site and will consist of 1 aerobic and 1 anaerobic blood culture bottle (an additional aerobic bottle is allowed if an anaerobic culture is not standard practice at 
the site). If Screening/baseline blood cultures are positive for ABC, repeat blood cultures should be obtained daily until negative or the patient is a treatment failure. To 
avoid unnecessary blood draws, the Investigator may wait until the result of the prior blood culture is known before performing the next blood culture. 
29. After screening, collect samples only as clinically indicated. To assess the primary indication and follow-up of the presenting indication, all specimens will be sent to the 
local laboratory for culture and susceptibility testing per institutional standards. Pure cultures of isolated pathogens will be shipped from the local laboratory to the central 
laboratory for confirmation of species identification, susceptibility testing, and possible molecular characterization.  
30. If the screening sample for culture that is growing ABC is taken per standard of care before the patient or patient’s legally authorized representative signs informed 
consent, that isolate may be used for baseline eligibility and sent to the central laboratory once consent is obtained, as long as the sample was collected within 72 hours 
prior to randomization. Additional samples for baseline culture should be collected again within 24 hours prior to randomization, at the specified time points and if 
clinically indicated.  
31. All patients will receive IV treatment for a minimum of 28 doses of ETX2514SUL plus 28 doses of imipenem/cilastatin or 14 doses of colistin plus 28 doses of 
imipenem/cilastatin (ie, 7 days for those without dose adjustments), as described in the protocol. For patients with normal renal function, study drug infusions will be 
administered q6h (15 minutes) for ETX2514SUL and imipenem/cilastatin and q12h (15 minutes) for colistin. 
32. Adverse events should be captured as described in the protocol. 
33. Intense PK samples will be collected for the first approximately 30 patients randomized in Part A, after the patient received at least 2 infusions on Day 1, at the end of the 
infusion after the infusion pump is turned off (+15 minutes), 1.5 hours (15 minutes) after the end of the infusion, and immediately prior to the start of the next infusion, 
and on Day 4 (1 day) at the end of the infusion after the infusion pump is turned off (+15 minutes), and immediately prior to the start of the next infusion. Sparse PK 
samples will be collected for all other patients enrolled in the study (Parts A and B) immediately prior to the start of the next infusion on Day 1 and Day 4 (1 day). The 
patient should have received at least 2 infusions before this schedule is implemented. In addition, the intense PK sampling will also be performed on the first 
approximately 20 patients randomized from China Mainland sites in Part A, following the same procedure as described above. 
ABC = Acinetobacter baumannii-calcoaceticus complex; APACHE = Acute Physiologic Assessment and Chronic Health Evaluation; BPP = Biofire FilmArray 2.0 
Pneumonia Panel; CT = computed tomography; ECG = electrocardiogram; EOT = End of Treatment; ET = Early Termination; ETX2514SUL = sulbactam-ETX2514; 
FiO2 = fraction of inspired oxygen; HABP = hospital-acquired bacterial pneumonia; ICF = informed consent form; IRT = interactive response technology; IV = intravenous; 
LFU = Late Follow-up; MRI = magnetic resonance imaging; PEEP = positive end-expiratory pressure; PK = pharmacokinetic; q6h = every 6 hours; q12h = every 12 hours; 
qSOFA = quick Sequential Organ Failure Assessment; QTcF = QT interval corrected using Fridericia’s formula; SOFA = Sequential Organ Failure Assessment; TOC = Test of 
Cure; VABP = ventilator-associated bacterial pneumonia; VP = ventilated pneumonia. 
 


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109
APPENDIX B: CENTRAL CLINICAL LABORATORY ANALYTES 
Standard Safety Chemistry Panel 
Alanine aminotransferase 
Albumin
Alkaline phosphatase
Amylase
Aspartate aminotransferase 
Bicarbonate
Blood urea/Blood urea nitrogen 
Calcium
Chloride 
Creatine kinase
Creatinine 
Estimated glomerular filtration rate 
Gamma-glutamyl transferase 
Glucose
Inorganic phosphorus 
Lactate dehydrogenase
Lipase 
Potassium
Sodium 
Total bilirubin
Total protein 
Uric acid
 
Hematology 
Basophils 
Eosinophils
Hematocrit 
Hemoglobin
Lymphocytes 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin concentration
Mean corpuscular volume 
Monocytes 
Neutrophils
Platelet count 
Red blood cell count
White blood cell count and differential [1]
1. Manual microscopic review is performed only if white blood cell count 
and/or differential values are out of reference range.
 
Urinalysis 
Bilirubin 
Blood
Catalase 
Glucose
Ketones 
Leukocyte esterase
Microscopic evaluation [1] 
Nitrite
pH 
Protein
Specific gravity 
Urobilinogen
1. Microscopic evaluation is performed only as needed based on positive 
dipstick test results. 
A highly sensitive urine or serum (beta human chorionic gonadotropin) pregnancy test will be 
performed for female patients of childbearing potential only. 
 
Screening Only 
All Screening laboratories will be performed at the local laboratory and may have been collected 
as standard of care within 48 hours prior to randomization, with the exception of serum creatinine 
determination, which must be obtained at the local laboratory within 24 hours before the first dose 
of study drug. All other samples are to be sent to the central laboratory. The Day 5 safety chemistry 
panel will be performed at the local laboratory and sent to the central laboratory. 

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan 
(SAP) 
 
A Randomized, Active-Controlled Study to Evaluate the 
Efficacy and Safety of Intravenous Sulbactam-ETX2514 in 
the Treatment of Patients With Infections Caused by 
Acinetobacter baumannii-calcoaceticus Complex 
 
 
Protocol Number: CS2514-2017-0004 
 
Version: 2.0, 22 June 2021 
 
 
Entasis Therapeutics 
Gatehouse Park BioHub 
35 Gatehouse Drive 
Waltham, MA 02451 
United States 
Telephone: +1-781-810-0120 
Fax: +1-781-810-0122 
 
 
Confidentiality Statement: 
The information in this document is confidential and is not to be disclosed without the written consent of 
Entasis Therapeutics except to the extent that disclosure would be required by law and for the purpose of 
evaluating and/or conducting a clinical study for Entasis Therapeutics. You are allowed to disclose the 
contents of this document only to your Institutional Review Board or Independent Ethics Committee and 
study personnel directly involved with conducting this protocol. Persons to whom the information is 
disclosed must be informed that the information is confidential and proprietary to Entasis Therapeutics 
and that it may not be further disclosed to third parties. 
 


SAP CS2514-2017-0004 
Version 2.0, 22 June 2021 
Page 2 of 37 
SAP APPROVAL FORM 
 
Document Title: 
Statistical Analysis Plan 
 
Protocol Number: 
CS2514-2017-0004 
 
Study Title: 
A Randomized, Active-Controlled Study to Evaluate the Efficacy and 
Safety of Intravenous Sulbactam-ETX2514 in the Treatment of Patients 
With Infections Caused by Acinetobacter baumannii-calcoaceticus 
Complex 
 
 
This Statistical Analysis Plan has been reviewed and approved by:  
 
 
 
Approved by: 
 
 
 
 
 
 
 
 
 
 
 
Ran Fu, PhD 
 
Date 
 
                    Biostatistician  
                                 Medpace Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                    Mei Chen, PhD 
 
                                                Date 
                                 Vice-President, Biostatistics 
                                 Medpace Inc. 
 
 
 
                           
 
 
 
 
 
 
 
 
______ 
  Brian S. Murphy, MD MPH FIDSA                                         Date 
  Vice-President, Infectious Diseases 
  Medpace Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______ 
                                  David Altarac, MD MPA 
                                                 Date 
   Chief Medical Officer 
   Entasis Therapeutics 
 
 
 
 
 
 
 
 
 
David Altarac MD
Electronically signed by:
David Altarac MD
Reason: Approved
Date: Jun 22, 2021 16:14
EDT
Mei Chen
Electronically signed by:
Mei Chen
Reason: Approved
Date: Jun 22, 2021 17:32
EDT
Electronically signed by:
Brian Murphy
Reason: Approved
Date: Jun 23, 2021 07:33
EDT
Ran Fu
Electronically signed by:
Ran Fu
Reason: Approved
Date: Jun 23, 2021 09:00
EDT


SAP CS2514-2017-0004 
Version 2.0, 22 June 2021 
Page 3 of 37 
TABLE OF CONTENTS 
 
SAP APPROVAL FORM..................................................................................................2 
TABLE OF CONTENTS ..................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................6 
1. 
INTRODUCTION ..........................................................................................8 
2. 
STUDY OBJECTIVES ..................................................................................8 
2.1. 
Primary Objectives ...........................................................................................8 
2.2. 
Secondary Objectives .......................................................................................8 
2.3. 
Exploratory Objectives .....................................................................................9 
3. 
STUDY DESIGN ............................................................................................9 
3.1. 
General Study Design .......................................................................................9 
3.2. 
Study Population .............................................................................................13 
3.3. 
Randomization and Blinding ..........................................................................13 
3.3.1. 
Unblinded Investigator ...................................................................................13 
3.3.2. 
Blinded Assessor ............................................................................................14 
3.4. 
Study Assessments..........................................................................................14 
4. 
SAMPLE SIZE JUSTIFICATION .............................................................18 
5. 
EFFICACY ENDPOINTS AND ASSESSMENT ......................................18 
5.1. 
Primary Efficacy Endpoint .............................................................................18 
5.2. 
Secondary Efficacy Endpoints ........................................................................18 
5.3. 
Other Efficacy Endpoints ...............................................................................18 
5.4. 
Assessment of 28-Day Survival ......................................................................19 
5.5. 
Efficacy Assessments .....................................................................................19 
5.5.1. 
Clinical Outcome ............................................................................................19 
5.5.2. 
Microbiologic Outcome ..................................................................................20 
5.5.2.1. 
Microbiologic Outcome for Bacteremia, Complicated Urinary Tract 
Infection, or Acute Pyelonephritis ..................................................................20 
5.5.2.2. 
Microbiologic Outcome for Hospital-Acquired Bacterial Pneumonia, 
Ventilator-Associated Bacterial Pneumonia, Ventilated Pneumonia, or 
Surgical or Post-Traumatic Wound Infections ...............................................21 
6. 
SAFETY ASSESSMENTS ...........................................................................21 
6.1. 
Adverse Events ...............................................................................................21 


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6.2. 
Laboratory Assessments .................................................................................21 
6.3. 
Vital Signs ......................................................................................................22 
6.4. 
Medical/Surgical History Assessments ..........................................................22 
6.5. 
Electrocardiograms .........................................................................................22 
6.6. 
Physical Examinations ....................................................................................23 
6.7. 
Chest X-Ray/Radiology ..................................................................................23 
6.8. 
Mechanical Ventilator Assessments ...............................................................23 
6.9. 
Safety Monitoring and Assessment of Abnormal Liver Function Tests (LFT)23 
6.10. 
Data Safety Monitoring Board (DSMB) .........................................................23 
7. 
PHARMACOKINETIC ASSESSMENTS .................................................23 
7.1. 
Intense Pharmacokinetic Sampling .................................................................24 
7.2. 
Sparse Pharmacokinetic Sampling .................................................................24 
8. 
ANALYSIS POPULATIONS ......................................................................24 
8.1. 
Intent-to-Treat Population (ITT) .....................................................................24 
8.2. 
Modified Intent-to-Treat Population (MITT) .................................................24 
8.3. 
Microbiologically Modified Intent-to-Treat Population (m-MITT) ...............24 
8.4. 
Carbapenem-resistant ABC m-MITT Population (CRABC m-MITT) ..........25 
8.5. 
Clinical Evaluable Population (CE) ................................................................25 
8.6. 
Microbiologic Evaluable Population (ME) ....................................................25 
8.7. 
Carbapenem-resistant ABC Microbiologic Evaluable Population (CRABC 
ME) .................................................................................................................25 
8.8. 
Pharmacokinetic (PK) Population ..................................................................26 
9. 
STATISTICAL ANALYSIS ........................................................................26 
9.1. 
General Statistical Considerations ..................................................................26 
9.1.1. 
General Analysis Approach ............................................................................26 
9.1.2. 
Handling of Withdrawals and Missing Data ..................................................26 
9.1.3. 
Baseline Definition .........................................................................................26 
9.2. 
Study Subjects ................................................................................................27 
9.2.1. 
Subject Disposition .........................................................................................27 
9.2.2. 
Protocol Deviations ........................................................................................27 
9.2.3. 
Demographic and Baseline Characteristics ....................................................28 
9.2.4. 
Baseline Pathogens .........................................................................................28 
9.2.5. 
Medical and Surgical History .........................................................................28 


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9.2.6. 
Prior and Concomitant Medications ...............................................................29 
9.2.7. 
Dosing and Treatment Exposure ....................................................................29 
9.3. 
Efficacy Analyses ...........................................................................................30 
9.3.1. 
Primary Efficacy Analyses .............................................................................30 
9.3.2. 
Secondary Efficacy Analyses .........................................................................31 
9.3.3. 
Exploratory Efficacy Analyses .......................................................................32 
9.3.4. 
Subgroup Analyses .........................................................................................32 
9.4. 
Safety Analyses ..............................................................................................33 
9.4.1. 
Adverse Events ...............................................................................................34 
9.4.2. 
Clinical Laboratory Evaluations .....................................................................35 
9.4.3. 
Vital Signs ......................................................................................................36 
9.4.4. 
Electrocardiograms (ECG) .............................................................................36 
9.4.5. 
Physical Examination .....................................................................................36 
9.5. 
Pharmacokinetic Analyses ..............................................................................36 
10. 
REFERENCES .............................................................................................37 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
ABC 
AE 
Acinetobacter baumannii-calcoaceticus complex 
Adverse event 
ALP 
ALT 
Alkaline phosphatase 
Alanine aminotransferase 
AP 
Acute pyelonephritis 
APACHE 
Acute Physiology and Chronic Health Evaluation 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic class 
BMI 
Body Mass Index 
BPP 
Biofire FilmArray Pneumonia Panel 
CE 
Clinical Evaluable 
CFU 
Colony-forming units 
CI 
COVID-19 
Confidence interval 
Coronavirus Disease 2019 
CRA 
Clinical research associate 
CRABC 
Carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex
CSR 
Clinical Study Report 
CT 
Computed tomography 
cUTI 
Complicated urinary tract infection 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOT 
ESKD 
End of Treatment 
End-stage kidney disease 
ET 
Early Termination 
ETX2514SUL 
Sulbactam-ETX2514 
FiO2 
Fraction of inspired oxygen 
GFR 
HABP 
Glomerular filtration rate 
Hospital-acquired bacterial pneumonia 
ICF 
Informed consent form 
ICU 
Intensive-care units 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
IV 
Intravenous(ly) 
LFT 
Liver function test 
LFU 
Late Follow-up 
LLN 
Lower limit of normal 


SAP CS2514-2017-0004 
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Abbreviation 
Definition 
ME 
Microbiologic Evaluable 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
Minimum inhibitory concentration 
MITT 
Modified Intent-to-Treat 
m-MITT 
Microbiologically Modified Intent-to-Treat 
MRI 
Magnetic resonance imaging 
PCS 
Potentially clinically significant 
PEEP 
Positive end-expiratory pressure 
PK 
Pharmacokinetic(s) 
q6h 
Every 6 hours 
q12h 
Every 12 hours 
qSOFA 
Quick Sequential Organ Failure Assessment 
QTcF 
QT interval corrected using Fridericia’s formula 
RIFLE 
Risk–Injury–Failure–Loss–End-stage renal disease 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
System organ class 
SOFA 
Sequential Organ Failure Assessment 
TEAE 
TESAE 
Treatment-emergent adverse event 
Treatment-emergent serious adverse event 
TOC 
Test of Cure 
ULN 
Upper limit of normal 
VABP 
VP 
Ventilator-associated bacterial pneumonia 
Ventilated pneumonia 
WHO 
World Health Organization 
 
 
 
 


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1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) is created based on Protocol CS2514-2017-0004 (version 4.0,  
17 December 2020) and describes in detail the statistical methodology and the statistical analyses 
to be conducted for the above-mentioned protocol. Any deviations from the SAP after database 
lock will be documented in the final Clinical Study Report (CSR). 
2. 
STUDY OBJECTIVES 
This is a 2-part study, with Part A being the randomized, controlled portion of the study in patients 
with Acinetobacter baumannii-calcoaceticus Complex (ABC) hospital-acquired bacterial 
pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), ventilated pneumonia 
(VP), or bacteremia. Part B is the single-group portion of the study and includes ABC infections 
that are resistant to or have failed colistin treatment or polymyxin B treatment, as detailed in the 
inclusion criteria. 
2.1. 
Primary Objectives 
The primary objectives of this study are the following: 
 To compare the efficacy of Sulbactam-ETX2514 (ETX2514SUL) plus imipenem/cilastatin to 
colistin plus imipenem/cilastatin in patients with carbapenem-resistant Acinetobacter 
baumannii-calcoaceticus complex (CRABC) infections in Part A; and 
 To compare the incidence of nephrotoxicity, as measured by the Risk-Injury-Failure-Loss-
End-stage renal disease (RIFLE) criteria, of ETX2514SUL to colistin in patients with ABC 
infections in Part A. 
2.2. 
Secondary Objectives 
The secondary objectives of this study are the following: 
 To compare the efficacy of ETX2514SUL plus imipenem/cilastatin to colistin plus 
imipenem/cilastatin in all randomized patients in Part A; 
 To evaluate the efficacy of ETX2514SUL plus imipenem/cilastatin in patients with colistin- or 
polymyxin B-resistant ABC infections in Part B;  
 To estimate the efficacy of ETX2514SUL plus imipenem/cilastatin for each primary infection 
site;  
 To evaluate and compare the safety of ETX2514SUL and colistin; 
 To describe the overall safety profile of ETX2514SUL; and 
 To determine the systemic exposure of ETX2514 and sulbactam in a small cohort of severely 
ill patients administered ETX2514SUL in Part A. 


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2.3. 
Exploratory Objectives 
The exploratory objectives of this study are the following: 
 To evaluate the efficacy of ETX2514SUL in relation to pharmacokinetics (PK) exposure; 
 To evaluate the efficacy of ETX2514SUL in relation to minimum inhibitory concentration 
(MIC) distribution of ETX2514SUL; 
 To evaluate the efficacy of ETX2514SUL in relation to total duration of treatment received; 
and 
 To compare the resource utilization of patients receiving ETX2514SUL plus 
imipenem/cilastatin to patients receiving colistin plus imipenem/cilastatin. 
3. 
STUDY DESIGN 
3.1. 
General Study Design  
This study is a randomized, active-controlled study to evaluate the safety and efficacy of IV 
ETX2514SUL in patients with ABC infections. Patients providing informed consent and meeting 
all study eligibility criteria will be enrolled in the study and have pretreatment blood and infection 
site-specific samples obtained and submitted to the local laboratory.  
The study will be enrolled in 2 parallel parts, with the PK data from the first approximately 
30 patients in Part A (with only 15 patients dosed with ETX2514SUL) reviewed prior to initiating 
enrollment in Part B: 
a. Part A will be the pivotal, assessor-blind, randomized, comparative portion of the study in 
patients with documented ABC HABP, VABP, VP, or bacteremia. While study drugs will not 
be masked due to logistical reasons, every attempt will be made to maintain the blind for 
patients, all staff at the site, and the Sponsor or its designees, except for the treatment physician 
and other immediate healthcare providers. In Part A, patients will be randomized 1:1 to 1 of 
the following treatment groups: 
o Group 1: 1.0 g ETX2514/1.0 g sulbactam IV infused over 3 hours every 6 hours (q6h) plus 
1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h; or 
o Group 2: 2.5 mg/kg colistin IV infused over 30 minutes every 12 hours (q12h) plus 1.0 g 
imipenem/1.0 g cilastatin IV infused over 1 hour q6h. 
Patients will be enrolled until there are at least 120 patients in the CRABC Microbiologically 
Modified Intent-to-Treat (m-MITT) Population in Part A, as determined by the central 
microbiology laboratory. Approximately 200 patients are expected to be enrolled in Part A, 
assuming approximately 60% of patients will have CRABC (see the statistical methods for 
complete details). The HABP/VABP/VP patients who are randomized to Part A based on a 
positive screening of a respiratory sample for ABC by the Biofire FilmArray Pneumonia Panel 
(BPP), but who subsequently do not have growth of ABC in their respiratory sample culture 
processed by the local microbiology laboratory, will be withdrawn from the study drug 
treatment. 


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Randomization will be stratified by indication (HABP/VABP/VP versus bacteremia), severity 
of illness (based on Acute Physiology and Chronic Health Evaluation [APACHE] II [10 to 19 
versus 20 to 30], Sequential Organ Failure Assessment [SOFA] [7 to 9 versus 10], or quick 
SOFA [qSOFA] [2 versus 3] score at Screening), and geography (China Mainland versus Rest 
of World). In the situation where a patient has more than one score reported, the scores will be 
used in the following order: APACHE, SOFA, and qSOFA. 
b. Part B will be the open-label, supportive portion of the study that will include patients known 
to have HABP, VABP, VP, and/or bacteremia infections associated with ABC organisms that 
are known to be resistant to colistin or polymyxin B, those failing a colistin or polymyxin B 
regimen prior to study entry or are on acute renal replacement therapy, and patients with 
infections due to colistin- or polymyxin B-resistant ABC with sources of infection other than 
HABP, VABP, VP, and/or bacteremia, as detailed in the inclusion criteria. 
Any patient who has a qualifying ABC infection and meets study inclusion criteria but has 
a contraindication to colistin due to underlying conditions, intolerance, or evidence of 
failing colistin or polymyxin B therapy prior to study entry, and/or has a colistin- or 
polymyxin B-resistant ABC infection cannot be enrolled in Part A but can be considered for 
enrollment in Part B (see the inclusion and exclusion criteria for details).  
Patients with ABC infections who are not otherwise eligible for Part A are expected to be 
enrolled in Part B. Patient enrollment in Part B will continue until Part A enrollment in the 
CRABC m-MITT Population is complete. In Part B, patients will receive the following 
treatment: 
o Group 3: 1.0 g ETX2514/1.0 g sulbactam IV infused over 3 hours q6h plus 1.0 g 
imipenem/1.0 g cilastatin IV infused over 1 hour q6h. 
Transfer from Part A to Part B: Since Part A will be the first time patients in intensive care are 
receiving ETX2514SUL, PK in the first approximately 30 patients must be verified prior to 
initiating Part B to ensure the treatment planned in Part B is optimal for the targeted patient 
population. Patients randomized to either group of Part A can only be transferred to Part B, once 
Part B is open for enrollment, if the ABC identified from the baseline culture is subsequently 
determined to be resistant to colistin or polymyxin B by the local microbiology laboratory. If Part 
B is not yet open for enrollment in a given country and a patient in Part A has a baseline culture 
determined to be colistin- or polymyxin B-resistant but is responding to therapy, the patient may 
remain in Part A at the discretion of the Investigator. A patient in Part A whose culture is 
determined to be colistin  or polymyxin B-resistant and who has not shown improvement or whose 
condition has worsened will be withdrawn from the study drug treatment. All such cases must be 
discussed with the Medical Monitor. 
Any organism isolated from the blood or infection site-specific cultures will be identified by genus 
and species by the local laboratory. Organisms will be cultured and quantified (urine and 
bronchoalveolar lavage only) at the local laboratory, and susceptibility of the organism(s) will be 
performed per local laboratory standards. Isolates of pathogens cultured at the local laboratory are 
to be sent to the central laboratory for confirmation of identification and susceptibility testing.  
No dosing regimen changes, other than those specified in the protocol for renal insufficiency or 
for patients on imipenem who develop a seizure that is thought to be directly related to imipenem, 
can occur without discussion with the Medical Monitor. Patients with cultures growing organisms 


SAP CS2514-2017-0004 
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with evidence of carbapenem resistance should remain on their assigned treatment regimen; 
treatment regimen changes can occur after 5 days after discussion with the Medical Monitor. If 
changes to the regimen are needed due to unsatisfactory clinical response, patients should be 
classified as clinical failures and discontinued from study drug. All patients should receive at least 
48 hours of IV study drug (ie, 8 doses of ETX2514SUL plus 8 doses of imipenem/cilastatin or 4 
doses of colistin plus 8 doses of imipenem/cilastatin in patients without dose adjustments) before 
the Investigator considers the patient to be a clinical failure and discontinues the patient from study 
drug therapy. 
Note: Patients who experience focal tremors, myoclonus, or seizures at any point during the study 
should be evaluated neurologically, placed on anticonvulsant therapy (if not already instituted), 
and the dose of imipenem/cilastatin should be evaluated to determine whether it should be 
decreased or discontinued.  
Day 1 is defined as the first day of study drug administration. The subsequent study days are 
defined by the number of treatment days thereafter. Treatment days should constitute 24 hours of 
treatment. For those patients with no dose adjustments, the duration of antibiotic treatment with 
study drug therapy will be 28 doses of ETX2514SUL plus 28 doses of imipenem/cilastatin or 
14 doses of colistin plus 28 doses of imipenem/cilastatin (ie, treatment for 7 days for those without 
dose adjustments), with a prolongation of therapy up to 14 days if clinically indicated. Refer to the 
Pharmacy Manual for specifics on dosing for all patients. 
The overall study design is shown in the figure below.  
Study Design 
 
*Part B:  Part B will be the open-label, supportive portion of the study that will include patients known to have HABP, VABP, 
VP, and/or bacteremia infections associated with ABC organisms that are known to be resistant to colistin or polymyxin B, those 
failing a colistin or polymyxin B regimen prior to study entry or are on acute renal replacement therapy, and patients with infections 
due to colistin  or polymyxin B-resistant ABC with sources of infection other than HABP, VABP, VP, and/or bacteremia. 


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ABC = Acinetobacter baumannii-calcoaceticus complex; APACHE = Acute Physiologic Assessment and Chronic Health 
Evaluation; CRABC = Carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex; cUTI = complicated urinary tract 
infection; ETX2514SUL = sulbactam-ETX2514; HABP = hospital-acquired bacterial pneumonia; IMI = imipenem/cilastatin; LFU 
= Late Follow-up; m MITT = Microbiologically Modified Intent-to-Treat; q6h = every 6 hours; q12h = every 12 hours; TOC = 
Test of Cure; VABP = ventilator-associated bacterial pneumonia; VP = ventilated pneumonia. 
Patients who have early discontinuation of study drug dosing should be assessed for all End of 
Treatment (EOT) Visit procedures and should be followed through the Late Follow-up (LFU) Visit 
for safety assessments, even if the reason for discontinuation is clinical failure. 
In Part A, clinical outcome assessments will be performed by a blinded assessor, in addition to the 
unblinded Investigator. Whenever possible, the same blinded assessor should complete all clinical 
outcome assessments for a study patient. If there is a discrepancy between the assessment of the 
blinded assessor and unblinded Investigator, the assessment from the blinded assessor will be used. 
If there is a missing assessment from either the blinded assessor or unblinded Investigator, the 
other available assessment will be used. An adjudication committee may be organized for endpoint 
adjudication should it be deemed necessary as determined by the Data Safety Monitoring 
Board (DSMB). In such a case, a charter will be developed that describes their activities. 
Intense PK sampling will be performed on the first approximately 30 patients randomized in 
Part A. The purpose of the intense PK sampling is to ensure that exposures observed in this 
severely ill cohort are comparable to those observed thus far in prior clinical studies. The PK 
samples will be collected for both treatment groups in Part A to keep the study data blinded. 
Pharmacokinetic assessment of the initial 15 patients on ETX2514SUL in Part A will be performed 
by an independent PK assessor, prior to the opening of enrollment in Part B. To explore the PK 
profile of the ETX2514SUL combination in Chinese patients with severe infection, the intense PK 
sample will also be collected from the first approximately 20 patients randomized in Part A at 
China Mainland sites. All other patients enrolled in the study (Parts A and B) will have samples 
collected for sparse PK analysis, which will be used to better inform the population PK model. 
Patients will be enrolled in the study for approximately 28 days, with a maximum duration of 
32 days. Screening laboratory analytes can be performed as standard of care up to 48 hours prior 
to randomization on Day 1, with the exception of local laboratory serum creatinine determination, 
which must be obtained at the local laboratory within 24 hours of the first dose of study drug. The 
Treatment Period begins on Day 1, and study drug will be administered for 7 days (ie, 28 doses of 
ETX2514SUL plus 28 doses of imipenem/cilastatin or 14 doses of colistin plus 28 doses of 
imipenem/cilastatin for those without dose adjustments) with a prolongation of therapy of up to 
14 days if clinically indicated. The EOT Visit will be completed on the final dosing day or the 
following day. The Test of Cure (TOC) Visit will be completed 7 days (2 days) after the 
EOT Visit for all patients. The LFU Visit will be completed 14 days (2 days) after the EOT Visit 
for all patients. For patients with an LFU Visit occurring before Day 28, a telephone call to assess 
survival will be made on Day 28 or anytime thereafter. Every attempt must be made to record 
survival status at Day 28 or anytime thereafter for all randomized patients (including 
HABP/VABP/VP patients who are randomized to Part A based on a positive BPP rapid test, but 
who subsequently do not have growth of ABC in their respiratory sample culture), regardless of 
their status of treatment, as long as the patient has not withdrawn consent from participation in the 
study. 


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3.2. 
Study Population 
The population for this study is male and female patients 18 years of age with documented ABC 
infections. Inclusion and exclusion criteria are listed in the protocol.  
3.3. 
Randomization and Blinding 
Qualifying patients enrolling in Part A will be randomized in a 1:1 ratio to receive 1.0 g 
ETX2514/1.0 g sulbactam q6h plus 1.0 g imipenem/1.0 g cilastatin q6h or 2.5 mg/kg colistin q12h 
plus 1.0 g imipenem/1.0 g cilastatin q6h via the Interactive Response Technology (IRT) system. 
Patients enrolled in the study based on the positive BPP rapid test results but are found to not grow 
ABC in respiratory specimen cultures by the local microbiology laboratory will be withdrawn from 
the study drug treatment as detailed in Protocol Section 4.3. 
Randomization in Part A will be stratified by indication (HABP/VABP/VP versus bacteremia), 
severity of illness (based on APACHE II [10 to 19 versus 20 to 30], SOFA [7 to 9 versus 10], or 
qSOFA [2 versus 3] score at Screening), and geography (China Mainland versus Rest of World). 
In the situation where a patient has more than one score reported, the scores will be used in the 
following order: APACHE, SOFA, and qSOFA. A quick reference guide will be provided that 
describes the IRT system and includes user instructions. 
The study data will be collected and handled as if it were a blinded study. The blinded assessor 
(see Section 3.3.2), the Sponsor, and the Sponsor’s designees involved in medical and safety 
monitoring, data management, and other aspects of the study (eg, interpretation of the results) will 
be blinded to treatment assignment. Given the complexity of the regimens, the Principal 
Investigator, other care givers, the clinical research associate (CRA), and other site personnel (eg, 
study coordinators and pharmacy staff) will be unblinded (see Section 3.3.1). Patients will not be 
informed of their treatment assignment, and efforts will be made to keep patients naïve to their 
treatment throughout the course of the study. 
Part B is open-label and not randomized; all patients enrolling in Part B will receive 1.0 g 
ETX2514/1.0 g sulbactam q6h plus 1.0 g imipenem/1.0 g cilastatin q6h. 
3.3.1. 
Unblinded Investigator 
An unblinded Investigator at each site will evaluate criteria for clinical outcomes, conduct 
causality assessment for adverse events, and assess clinical signs and symptoms at study visits for 
patients in both Part A and Part B. For patients in Part A, a blinded assessor will also evaluate 
criteria for clinical outcomes, conduct causality assessment for adverse events, and assess clinical 
signs and symptoms at study visits. The unblinded Investigator must be a qualified physician, able 
to perform medical evaluations, and determine medical diagnoses (eg, Principal Investigator, 
sub-Investigator). For consistency, whenever possible, the same unblinded Investigator should 
complete all unblinded assessments for a study patient. If there is a discrepancy between the 
assessment of the blinded assessor and unblinded Investigator, the assessment from the blinded 
assessor will be used. If there is a missing assessment from either the blinded assessor or unblinded 
Investigator, the other available assessment will be used. An adjudication committee may be 
organized for endpoint adjudication should it be deemed necessary by the DSMB. In such a case, 
a charter will be developed that describes their activities. 


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3.3.2. 
Blinded Assessor 
Study data will be collected and handled as if it were a blinded study. 
For patients in Part A, each site will assign a blinded assessor, in addition to the unblinded 
Investigator, to evaluate criteria for clinical outcomes, conduct causality assessment for adverse 
events, and assess clinical signs and symptoms at study visits where an endpoint is evaluated. A 
blinded assessor must be qualified to perform medical evaluations and determine medical 
diagnoses (eg, physician, physician’s assistant, or nurse practitioner [in the United States]). The 
blinded assessor may participate in the consenting process and Screening procedures, but once a 
patient is randomized the blinded assessor should have no other role in the study other than making 
blinded assessments. For consistency, whenever possible, the same blinded assessor should 
complete all blinded assessments for a study patient. All efforts will be made to keep the blinded 
assessor blinded during the course of the study. The blinded assessor should not have access to 
sections in the patient’s medical record in which treatment group or dosing frequency are 
documented, should have no role in patient care or treatment, and should be restricted to limited 
sections of the patient’s chart in order to assess clinical outcomes. Data collection by the blinded 
assessor will be used for entry into the electronic case report form (eCRF). 
3.4. 
Study Assessments 
Table 1 presents the visit schedule and procedures of the study to be conducted at each visit. 
 


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Table 1. 
Schedule of Procedures (Parts A & B) 
Procedure [1] 
Screening 
Treatment 
TOC 
LFU 
ET [6] 
-48 Hours 
to Day 1 
[2] 
Day 1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 [3] 
Days 8 
to 14 
[3] 
EOT 
(+1 day) 
[3,4] 
EOT 
+7 (2) 
Days [5] 
EOT +14 
(2) 
Days and 
Day 28 
[5] 
Informed consent [7] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X [8] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics [9] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical examination 
[10] 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Limited physical examination [10] 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Vital signs [11] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chest X-ray, MRI, CT scan, or 
ultrasound [12] 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Assess clinical signs/symptoms 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess clinical outcome [13,14] 
 
 
 
 
 
X 
 
X 
 
X 
X [13] 
X [13] 
X 
Rapid diagnostic test [15] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
APACHE II, SOFA, or qSOFA 
score [16] 
X [17] 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization [18] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test [19] 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Serum chemistry [20] 
X 
X [25] 
 
X 
 
X 
[22] 
 
X 
 
X 
X 
X 
X 
Serum creatinine [21]  
X 
X [25] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology [20,23] 
X 
X [25] 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Urinalysis [20,24] 
X 
X [25] 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
12-lead ECG [26] 
X 
X [27] 
 
X [27] 
 
 
 
X 
 
 
X 
Blood cultures [28] 
X 
X [25] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Infection site-specific cultures [29] 
X [30] 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
Administer study drug [31] 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Assessment of adverse events [32] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK samples [33] 
 
X 
 
X 
 
 
 
 
 
 
 


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1. 
All the procedures for Part B will be the same as Part A, unless otherwise specified. 
2. 
Screening can occur up to 48 hours before the first dose of study drug. All Screening procedures must be performed prior to randomization and the first dose of study drug 
(Day 1). All Screening laboratories will be performed at the local laboratory and may have been collected as standard of care within 48 hours prior to randomization, with 
the exception of serum creatinine determination, which must be obtained at the local laboratory within 24 hours before the first dose of study drug. 
3. 
Day 7 to Day 14 study procedures are only required if the patient receives IV study drug treatment on Day 7 to Day 14. If EOT has already occurred, study procedures are 
not required to be performed. 
4. 
Patients will be treated for 28 doses of ETX2514SUL plus 28 doses of imipenem/cilastatin or 14 doses of colistin plus 28 doses of imipenem/cilastatin (ie, 7 days for those 
without dose adjustments), with a prolongation of therapy up to 14 days if clinically indicated. If EOT occurs on Day 7, Day 7 study procedures may be considered the 
EOT Visit study procedures. If EOT occurs after Day 7, the EOT Visit activities should be completed within 24 hours after the last dose of study drug.  
5. 
The TOC Visit must occur 7 days (2 days) after the EOT for all patients. The LFU Visit must occur 14 days (2 days) after the EOT for all patients. The LFU Visit 
should be performed as an in-person visit; however, if the patient is unable to attend the LFU Visit at the site, the patient may be contacted by telephone call for 
follow-up assessment of concomitant medications, clinical signs and symptoms, and adverse events. All patients who are alive and have not withdrawn consent 
for participation in the study must be contacted at Day 28 or anytime thereafter to assess survival if their LFU Visit is prior to Day 28. 
6. 
For patients who are withdrawn from the study prior to completion of study drug or discontinue study drug prematurely, complete an ET Visit at the time of study 
withdrawal or study drug discontinuation. Patients who discontinue study drug prematurely but are not withdrawn from the study should complete TOC and LFU Visits. 
For patients who are withdrawn from the study after the EOT Visit but prior to completion of the study, complete the next scheduled visit (either the TOC Visit or LFU 
Visit) at the time of study withdrawal. 
7. 
Informed consent must be obtained before any study procedures are performed. An ICF of limited scope may be signed prior to Screening to perform only BPP rapid 
testing of respiratory specimens. A comprehensive ICF, which will include all study procedures, will be signed at Screening. 
8. 
Reasonable effort will be made to determine all relevant treatments (including all antibiotics, prescription and non-prescription medications, herbal medications, vitamin 
supplements, supportive therapies, and non-pharmacologic treatments) received within 14 days before the first dose of study drug and during the study. 
9. 
Demographic data will be collected, including sex, age, race, and ethnicity. 
10. The Screening complete physical examination includes weight and height. A limited, symptom-based physical examination will be performed at the indicated visits. If a 
patient does not display symptoms, no limited physical examination needs to be performed. 
11. Vital signs include blood pressure, heart rate, and respiratory rate, and, for ventilated patients, oxygen therapy and respiratory settings including FiO2 and PEEP. 
12. For patients with HABP, VABP, or VP only. A chest X-ray, MRI, CT scan, or ultrasound done within 72 hours of Screening is acceptable. For images obtained 48 hours 
prior to randomization, repeat imaging using the same technique is required. Note: If an ultrasound is performed, a confirmatory X-ray or CT scan must be performed 
within 24 hours. Findings should be consistent with the screening image and diagnosis of pneumonia, in the Investigator’s judgment; otherwise, the patient is no longer 
eligible. 
13. If a patient is a clinical failure at EOT, the patient is automatically considered a failure at the TOC and LFU Visits, and the assessment of clinical response by the 
Investigator should be listed as “failure at EOT or TOC.”  
14. In Part A, all clinical outcome assessments will be performed by a blinded assessor, in addition to the unblinded Investigator. 
15. A respiratory specimen for BPP rapid diagnostic testing should only be collected for patients suspected to have HABP, VABP, or VP. 
16. An APACHE II or SOFA score will be calculated at Screening and prior to randomization for patients in Part A only. For patients who are not being treated in an intensive 
care unit and cannot have an APACHE II or SOFA score performed, and for all patients in Part B, a qSOFA score should be calculated. 
17. An APACHE II, SOFA, or qSOFA score that was calculated as standard of care within 24 hours of Screening may be used and does not need to be repeated at Screening.   
18. Via IRT. 
19. A highly sensitive urine or serum pregnancy test will be performed at Screening, EOT Visit, and ET Visit for women of childbearing potential. 
20. Screening laboratories will be performed by the local laboratory within 48 hours of randomization. Subsequent laboratory samples will be collected, processed, and sent to 
the central laboratory for analysis. 
21. While the patient is receiving study drug, serum creatinine will be collected daily and analyzed at the local laboratory to assess the need for dose adjustments. Screening 
serum creatinine will be collected at the local laboratory within 24 hours before the first dose of study drug. 
22. The Day 5 safety chemistry panel will be performed at the local laboratory and sent to the central laboratory. 
23. Hematology includes complete blood count (with red blood cell count, total white blood cell count with differential counts, platelet count, hemoglobin, and hematocrit).  


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24. Urinalysis includes urine dipstick analysis for leukocytes, nitrites, or a catalase test of the urine specimen, microscopic evaluation, specific gravity, and pH.  
25. Predose. 
26. The 12-lead ECGs will be performed after the end of infusion, except for at Screening, and all 12-lead ECGs will be performed after the patient has been in a supine 
position for at least 10 minutes. Consult the Medical Monitor and local cardiologist in cases of clinically significant abnormal findings (eg, a QTcF 480 msec). 
27. The 12-lead ECG will be performed for all patients at the end of the first infusion of study drug on Day 1. If clinically indicated, the 12-lead ECGs will be repeated as 
close as possible following the end of the infusion of study drug administration on the day on which post-dose PK samples are drawn (Day 3, Day 4, or Day 5). The day on 
which the post-dose PK samples are drawn is at the discretion of the Investigator.  
28. Two sets of samples from 2 separate venipuncture sites are required for blood cultures in all patients. Each set of blood culture samples will be collected from a separate 
venipuncture site and will consist of 1 aerobic and 1 anaerobic blood culture bottle (an additional aerobic bottle is allowed if an anaerobic culture is not standard practice at 
the site). If Screening/baseline blood cultures are positive for ABC, repeat blood cultures should be obtained daily until negative or the patient is a treatment failure. To 
avoid unnecessary blood draws, the Investigator may wait until the result of the prior blood culture is known before performing the next blood culture. 
29. After screening, collect samples only as clinically indicated. To assess the primary indication and follow-up of the presenting indication, all specimens will be sent to the 
local laboratory for culture and susceptibility testing per institutional standards. Pure cultures of isolated pathogens will be shipped from the local laboratory to the central 
laboratory for confirmation of species identification, susceptibility testing, and possible molecular characterization.  
30. If the screening sample for culture that is growing ABC is taken per standard of care before the patient or patient’s legally authorized representative signs informed 
consent, that isolate may be used for baseline eligibility and sent to the central laboratory once consent is obtained, as long as the sample was collected within 72 hours 
prior to randomization. Additional samples for baseline culture should be collected again within 24 hours prior to randomization, at the specified time points and if 
clinically indicated.  
31. All patients will receive IV treatment for a minimum of 28 doses of ETX2514SUL plus 28 doses of imipenem/cilastatin or 14 doses of colistin plus 28 doses of 
imipenem/cilastatin (ie, 7 days for those without dose adjustments), as described in the protocol. For patients with normal renal function, study drug infusions will be 
administered q6h (15 minutes) for ETX2514SUL and imipenem/cilastatin and q12h (15 minutes) for colistin. 
32. Adverse events should be captured as described in the protocol. 
33. Intense PK samples will be collected for the first approximately 30 patients randomized in Part A, after the patient received at least 2 infusions on Day 1, at the end of the 
infusion after the infusion pump is turned off (+15 minutes), 1.5 hours (15 minutes) after the end of the infusion, and immediately prior to the start of the next infusion, 
and on Day 4 (1 day) at the end of the infusion after the infusion pump is turned off (+15 minutes), and immediately prior to the start of the next infusion. Sparse PK 
samples will be collected for all other patients enrolled in the study (Parts A and B) immediately prior to the start of the next infusion on Day 1 and Day 4 (1 day). The 
patient should have received at least 2 infusions before this schedule is implemented. In addition, the intense PK sampling will also be performed on the first 
approximately 20 patients randomized from China Mainland sites in Part A, following the same procedure as described above. 
ABC = Acinetobacter baumannii-calcoaceticus complex; APACHE = Acute Physiologic Assessment and Chronic Health Evaluation; BPP = Biofire FilmArray 2.0 
Pneumonia Panel; CT = computed tomography; ECG = electrocardiogram; EOT = End of Treatment; ET = Early Termination; ETX2514SUL = sulbactam-ETX2514; 
FiO2 = fraction of inspired oxygen; HABP = hospital-acquired bacterial pneumonia; ICF = informed consent form; IRT = interactive response technology; IV = intravenous; 
LFU = Late Follow-up; MRI = magnetic resonance imaging; PEEP = positive end-expiratory pressure; PK = pharmacokinetic; q6h = every 6 hours; q12h = every 12 hours; 
qSOFA = quick Sequential Organ Failure Assessment; QTcF = QT interval corrected using Fridericia’s formula; SOFA = Sequential Organ Failure Assessment; TOC = Test of 
Cure; VABP = ventilator-associated bacterial pneumonia; VP = ventilated pneumonia.  
 
 
 
 


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4. 
SAMPLE SIZE JUSTIFICATION 
Patients will be enrolled until there are 120 patients in the CRABC m-MITT Population in Part 
A. The study will have 80% power to demonstrate non-inferiority between Group 1 and 
Group 2 using a 20% non-inferiority margin and a 2-sided 95% CI. This assumes a mortality 
rate in the comparator group (Group 2) of 41% and in the ETX2514SUL group (Group 1) of 
36%. To have 120 patients in the CRABC m-MITT Population, Part A will need to enroll 
approximately 200 patients, assuming 60% of ABC clinical isolates are carbapenem-resistant. 
Patient enrollment in Part B (Group 3) will continue until Part A enrollment in the CRABC m-
MITT Population is complete. Rates of carbapenem resistance among isolates from Part A 
patients will be monitored by the unblinded data manager/designee at the Clinical Research 
Organization on an ongoing basis.  
5. 
EFFICACY ENDPOINTS AND ASSESSMENT 
5.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint for the study is 28-day all-cause mortality in the CRABC m-
MITT Population in Part A. 
5.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints for Part A and Part B include the following: 
 28-day all-cause mortality in the Intent-to-Treat (ITT) Population; 
 Clinical cure at TOC in the CRABC m-MITT Population; 
 Clinical cure at TOC in the m-MITT, Clinical Evaluable (CE), Microbiologic Evaluable 
(ME), and CRABC ME Populations; 
 Clinical cure at EOT, and LFU in the m-MITT, CRABC m-MITT, CE, ME, and CRABC 
ME Populations; 
 Microbiological favorable assessment at EOT, TOC, and LFU in the m-MITT, CRABC m-
MITT, ME, and CRABC ME Populations; 
 14-day all-cause mortality in the CRABC m-MITT and m-MITT Populations;  
 28-day all-cause mortality in the m-MITT and CRABC ME Populations; and 
 PK exposure of ETX2514 and sulbactam in the PK Population. 
5.3. 
Other Efficacy Endpoints 
The exploratory efficacy endpoints include the following: 
 Clinical cure based on MIC distribution of ETX2514SUL;  
 Clinical cure based on MIC distribution of colistin;  
 Clinical cure based on baseline resistance to ETX2514SUL, carbapenems, or colistin;  


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 Microbiologic favorable assessment based on MIC distribution of ETX2514SUL;  
 Microbiologic favorable assessment based on MIC distribution of colistin;  
 Microbiologic favorable assessment based on baseline resistance to ETX2514SUL, 
carbapenems, or colistin;  
 Number of days in the intensive care unit; 
 Number of patients transferred to the intensive care unit; 
 For patients with VABP, VP, or ventilated HABP, number of days on ventilators;  
 Number of days in the hospital; and 
 Number of days on study drug treatment. 
5.4. 
Assessment of 28-Day Survival 
Every attempt must be made to record survival status at Day 28 or anytime thereafter for all 
randomized patients (including HABP/VABP/VP patients who are randomized to Part A based 
on a positive BPP rapid test, but who subsequently do not have growth of ABC in their 
respiratory sample culture), regardless of their status of treatment, as long as the patient has 
not withdrawn consent from participation in the study. An in-person assessment is preferred; 
however, this assessment may also be performed via a telephone call if an in-person visit is not 
possible.  
For patients with an LFU Visit occurring before Day 28, a telephone call to assess survival 
will be made on Day 28 or anytime thereafter. 
5.5. 
Efficacy Assessments  
5.5.1. 
Clinical Outcome 
Clinical outcome will be used to determine a response of clinical success for all patients. Based 
on the assessment of signs and symptoms, the Investigator will choose 1 of the following 
clinical outcomes at the Day 5, Day 7, EOT, TOC, LFU and ET Visits, if applicable. In Part 
A, in addition to the unblinded Investigator, a blinded assessor will also determine clinical 
outcome. If there is a discrepancy between the assessment of the blinded assessor and 
unblinded Investigator, the assessment from the blinded assessor will be used. If there is a 
missing assessment from either the blinded assessor or unblinded Investigator, the other 
available assessment will be used. An adjudication committee may be organized for endpoint 
adjudication should it be deemed necessary by the DSMB. In such a case, a charter will be 
developed that describes their activities. 
Clinical cure: complete resolution or significant improvement of signs and symptoms that 
were present at baseline and no new symptoms, such that no additional Gram negative 
antimicrobial therapy is warranted. 
Clinical failure: symptoms present at study entry have not significantly improved or 
completely resolved, or new symptoms have developed and require the initiation of a non-
study Gram negative antibacterial drug therapy, death, or intolerance to study drug leading to 
discontinuation from the study treatment. 


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Clinical indeterminate: determination cannot be made because of missing data or the patient 
is lost to follow-up. 
5.5.2. 
Microbiologic Outcome 
5.5.2.1. 
Microbiologic Outcome for Bacteremia, Complicated Urinary Tract 
Infection, or Acute Pyelonephritis 
For patients with bacteremia, complicated urinary tract infection (cUTI), or acute 
pyelonephritis 
(AP), 
per-patient 
microbiological 
response 
will 
be 
determined 
programmatically as 1 of the following outcomes based on the results of blood and/or urine 
cultures at EOT, TOC and LFU Visits. A microbiological favorable assessment will include 
eradication and presumed eradications, as detailed below. 
Microbiologic eradication: 
 For patients with cUTI or AP: the baseline strain of ABC is reduced to <103 colony-forming 
units (CFU)/mL on urine culture and negative on repeat blood culture (if positive at 
baseline), or 
 For patients with bacteremia: absence of the baseline strain of ABC on culture. 
Microbiologic presumed eradication: no culture was done, and the patient meets clinical 
criteria for clinical cure. 
Microbiologic persistence: 
 For patients with cUTI or AP: the demonstration that the urine culture grew 103 CFU/mL 
of the baseline strain of ABC identified at study entry and/or a blood culture demonstrates 
the same baseline pathogen(s), or 
 For patients with bacteremia: presence of the baseline strain of ABC on repeat culture. 
Patients who are a persistence at EOT will be considered a persistence at TOC. 
Microbiologic presumed persistence: no culture was done, and the patient meets clinical 
criteria for clinical failure. 
Microbiologic indeterminate: if clinically indicated (for cUTI and bacteremia only), no follow-
up culture is available, the culture cannot be interpreted for any reason, or the culture is 
considered contaminated.  
Microbiologic recurrence:  
 For patients with cUTI or AP: the demonstration that the urine culture grew 103 CFU/mL 
of the baseline strain of ABC identified at study entry at any time after documented 
eradication at the TOC Visit up to and including the LFU Visit, or  
 For patients with bacteremia: a positive blood culture for ABC at any time after 
documented eradication at the TOC Visit up to and including the LFU Visit. 


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5.5.2.2. 
Microbiologic Outcome for Hospital-Acquired Bacterial Pneumonia, 
Ventilator-Associated Bacterial Pneumonia, Ventilated Pneumonia, or 
Surgical or Post-Traumatic Wound Infections 
Microbiologic presumed eradication: no culture was done, and the patient meets clinical 
criteria for clinical cure. For patients with HABP/VABP/VP or surgical or post-traumatic 
wound infections, where repeat culture samples may not be indicated, presumed eradication 
based on clinical improvement will be inferred. 
Microbiologic presumed persistence: no culture was done, and the patient meets clinical 
criteria for clinical failure. 
6. 
SAFETY ASSESSMENTS 
6.1. 
Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a clinical 
investigation patient administered a pharmaceutical product, which does not necessarily have 
a causal relationship with this treatment. An AE can therefore be any unfavorable and/or 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational medicinal product, whether or not related to the 
investigational medicinal product. All AEs, including observed or volunteered problems, 
complaints, or symptoms, are to be recorded on the appropriate eCRF. AEs will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA, Version 21.0). 
6.2. 
Laboratory Assessments 
Standard clinical laboratory profiles for chemistry will be evaluated at Screening, Day 1, Day 
3, Day 5, Day 7, the EOT Visit, the TOC Visit, the LFU Visit, and the ET Visit. Serum 
creatinine will be evaluated daily while the patient is receiving study drug and will be analyzed 
at the local laboratory to assess the need for dose adjustments. All Screening laboratories will 
be performed at the local laboratory and may have been collected as standard of care within 48 
hours prior to randomization, with the exception of serum creatinine determination, which 
must be obtained at the local laboratory within 24 hours before the first dose of study drug. All 
other samples are to be sent to the central laboratory. The Day 5 safety chemistry panel will be 
performed at the local laboratory and sent to the central laboratory. 
Standard clinical laboratory profiles for hematology including complete blood count (with red 
blood cell count, total white blood cell count with differential counts, platelet count, 
hemoglobin, and hematocrit) will be performed at Screening, Day 1, Day 3, Day 5, Day 7, the 
EOT Visit, the TOC Visit, the LFU Visit, and the ET Visit.  
A urinalysis including urine dipstick analysis for leukocytes, nitrites, or a catalase test of the 
urine specimen, microscopic evaluation, specific gravity, and pH will be performed at 
Screening, Day 1, Day 3, Day 5, Day 7, the EOT Visit, the TOC Visit, the LFU Visit, and the 
ET Visit. 
A highly sensitive urine or serum pregnancy test will be performed at Screening, the EOT 
Visit, and the ET Visit for women of childbearing potential. 


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Standard of care safety laboratory profiles should also be performed by the local laboratory. 
Abnormal values of laboratory parameters must be followed up to normalization or 
stabilization at the discretion of the Investigator. 
6.3. 
Vital Signs 
Vital signs (including systolic and diastolic blood pressure, heart rate, respiratory rate, and, for 
ventilated patients, oxygen therapy and respiratory settings including fraction of inspired 
oxygen [FiO2] and positive end-expiratory pressure [PEEP]) will be taken after at least 5 
minutes in a seated or supine position. Vital signs will be recorded at Screening, all days that 
the patient receives study drug treatment, the EOT Visit, the TOC Visit, the LFU Visit, and the 
ET Visit. Vital signs should be collected at the same time as assessments of signs and 
symptoms. 
6.4. 
Medical/Surgical History Assessments 
Medical and surgical history will be obtained and evaluated at Screening to confirm the 
patient’s eligibility to enroll in the study.   
6.5. 
Electrocardiograms 
Twelve-lead electrocardiograms (ECGs) will be performed for all patients at Screening, at the 
end of the first infusion of study drug on Day 1, at EOT, and at the ET Visit. If clinically 
indicated, the 12-lead ECGs will be repeated as close as possible following the end of the 
infusion of study drug on the day on which the post-dose PK samples are drawn (Day 4 [1 
day]; day selected at the discretion of the Investigator). All 12-lead ECGs will be performed 
after the end of the infusion and after the patient has been in a supine position for at least 
10 minutes. The value at Screening will be used for assessing the QT interval corrected using 
Fridericia’s formula (QTcF) exclusion criterion. All 12-lead ECGs will be performed and read 
locally. The following ECG parameters will be recorded: 
 Heart rate, 
 QRS interval, 
 PR interval, 
 RR interval, 
 QT interval, and  
 QTc interval. 
All ECGs will be evaluated for the presence of abnormalities by a qualified local physician. 
The ECGs will be classified as 1 of the following: 
 Normal, 
 Having a not clinically significant abnormality, or 
 Having a clinically significant abnormality. 
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6.6. 
Physical Examinations 
A complete physical examination will be performed at Screening, Day 3, Day 5, Day 7, the 
EOT Visit, and the ET Visit. A limited physical examination will be performed, if needed, at 
Day 2, Day 4, Day 6, Day 8 to Day 14 (if EOT has not already occurred), the TOC Visit, and 
the LFU Visit.  
A complete physical examination must include source documentation of weight, skin, head 
and neck, heart, lung, abdomen, extremities, back/flank/costo-vertebral angle tenderness, and 
neuromuscular assessments. Height will only be collected at Screening. Limited physical 
examinations are symptom-based. When clinically indicated, a prostate exam can be 
performed, at the discretion of the Investigator. 
Physical examinations may be performed at unscheduled time points if deemed necessary by 
the Investigator. 
6.7. 
Chest X-Ray/Radiology 
Chest X-rays, magnetic resonance imaging (MRI), or computed tomography (CT) scans will 
be performed in patients with HABP, VABP, or VP at Screening and the TOC Visit, and as 
clinically indicated to evaluate for the presence of infiltrates. Ultrasounds may also be 
performed for patients with HABP, VABP, or VP at Screening. If an ultrasound is performed, 
a confirmatory X-ray or CT scan should be performed within 24 hours. Imaging should be 
conducted per institutional guidelines and results recorded in the source documents and the 
eCRF. 
6.8. 
Mechanical Ventilator Assessments 
Patients whose primary indication for enrollment into the study is HABP, VABP, or VP and 
who require mechanical ventilation support will be managed by the study Investigators per 
institutional guidelines. Data regarding mechanical ventilation settings will be captured in the 
source documents and the eCRFs. 
6.9. 
Safety Monitoring and Assessment of Abnormal Liver Function Tests (LFT) 
Safety monitoring for LFTs will occur from randomization until 30 days following the last 
administration of study drug; however, any abnormal LFT will be monitored according to the 
Safety Monitoring Plan. Investigators should evaluate standard of care laboratory reports in 
addition to study laboratory reports when monitoring for LFTs. 
6.10. 
Data Safety Monitoring Board (DSMB) 
An independent DSMB will review the safety data periodically. The DSMB will also review 
serious adverse events (SAE) and deaths on an ongoing basis. They will make 
recommendations to the Sponsor based on the safety data. The PK assessment report of data 
from the initial cohort of patients in Part A from the independent PK assessor will be submitted 
to the DSMB for its approval of continued enrollment and initiation of Part B. Further details 
regarding the DSMB guidelines will be described in the DSMB Charter. 
7. 
PHARMACOKINETIC ASSESSMENTS 


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Intense and sparse PK samples will be collected as outlined in Table 1. The PK samples 
obtained from the ETX2514SUL group will be analyzed for ETX2514 and sulbactam 
concentrations using a validated assay by an approved bioanalytical laboratory.  
The actual PK sampling times will be captured on the eCRF. Actual dosing time will also be 
captured on the eCRF. Actual sampling time will be used for the PK calculations. 
7.1. 
Intense Pharmacokinetic Sampling 
As described in Section 9.2.3 of the protocol, approximately 30 patients randomized in Part A 
had samples collected for intense PK analysis to ensure that exposures observed in this 
severely ill cohort are comparable to those observed thus far in prior clinical studies.  
The intense PK sampling will also be performed on the first approximately 20 patients 
randomized in Part A from China Mainland sites. 
7.2. 
Sparse Pharmacokinetic Sampling 
All other patients enrolled in the study (Parts A and B) will have samples collected for sparse 
PK analysis.  
8. 
ANALYSIS POPULATIONS 
This study is designed to estimate treatment efficacy of ABC infections, with a pivotal 
component in Part A.  
8.1. 
Intent-to-Treat Population (ITT) 
The ITT Population will include all patients randomized to study drug treatment 
(ETX2514SUL plus imipenem/cilastatin or colistin plus imipenem/cilastatin) in Part A or 
enrolled in Part B, regardless of whether the patient actually receives study drug. 
8.2. 
Modified Intent-to-Treat Population (MITT) 
The MITT Population will include patients in Parts A and B who meet ITT criteria and receive 
any amount of study drug. The MITT Population will be considered the Safety Population. 
Patients with HABP/VABP/VP who were randomized to Part A on the basis of a BPP rapid 
test result, but were subsequently withdrawn due to a lack of a culture growing ABC, will be 
counted in the MITT and Safety Populations. 
8.3. 
Microbiologically Modified Intent-to-Treat Population (m-MITT) 
The m-MITT Population will include patients who meet MITT criteria and have an ABC 
organism isolated as the qualifying culture specimen, as confirmed by the central and/or local 
microbiology laboratory. If an isolate for testing at the central laboratory is not available, the 
local laboratory data can be used to confirm the presence of ABC organism, as long as the 
local laboratory uses modern methods of diagnosis such as molecular based tests, MALDITOF, 
Vitek, Phoenix, etc (ie, not conventional biochemical or manual phenotypic methods). Patients 
with HABP/VABP/VP who are enrolled based upon a positive BPP rapid test for ABC, but 
subsequently are found to have respiratory sample cultures that do not grow ABC (by the local 
laboratory), will be withdrawn from the study drug treatment. These patients will not be 


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included in the m-MITT Population but will remain in the MITT Population. 
8.4. 
Carbapenem-resistant ABC m-MITT Population (CRABC m-MITT) 
For Part A, the CRABC m-MITT Population will include patients who meet m-MITT criteria 
and have a baseline ABC organism that is confirmed to be carbapenem-resistant (MIC to 
imipenem/meropenem 8 mg/L) by the central laboratory or by the local laboratory if the 
central laboratory is not able to identify the isolate for any reason. Patients will be excluded 
from the CRABC m-MITT Population if they have isolates that are deemed by the central 
laboratory to be resistant to ETX2514SUL (MIC >4 mg/L) or colistin (MIC ≥4 mg/L), if their 
blood culture or respiratory samples are collected more than 72 hours prior to randomization, 
if they are transferred from Part A to Part B, or if they are enrolled with infections other than 
ABC pneumonia or bloodstream infection (ie, infections other than HABP, VABP, VP, and 
bacteremia). A sensitivity analysis for the primary efficacy endpoint will be performed for 
patients whose eligible culture is >48 hours from the first dose of treatment, as well as for all 
patients with and without evidence of non-susceptibility to colistin and ETX2514SUL at 
baseline. 
For Part B, the CRABC m-MITT Population will include patients who meet m-MITT criteria 
and have a baseline ABC organism that is confirmed to be carbapenem-resistant (MIC to 
imipenem/meropenem ≥8 mg/L) by the central laboratory or by the local laboratory if the 
central laboratory is not able to identify the isolate for any reason. Patients will be excluded 
from the CRABC m-MITT Population if their blood culture or respiratory samples are 
collected more than 72 hours prior to randomization. 
8.5. 
Clinical Evaluable Population (CE) 
The CE Population will include patients who meet m-MITT criteria and meet evaluability 
criteria (meet key inclusion criteria, do not have key exclusion criteria, received at least 72 
hours of study drug [ie, 12 doses of ETX2514SUL plus 12 doses of imipenem/cilastatin or 6 
doses of colistin plus 12 doses of imipenem/cilastatin in patients without dose adjustments] to 
be a clinical cure, received at least 48 hours of study drug [ie, 8 doses of ETX2514SUL plus 8 
doses of imipenem/cilastatin or 4 doses of colistin plus 8 doses of imipenem/cilastatin in 
patients without dose adjustments] to be a clinical failure, received 80% of anticipated doses, 
and did not have a clinical response of indeterminate at the TOC Visit). 
8.6. 
Microbiologic Evaluable Population (ME) 
The ME Population will include patients who meet m-MITT criteria and CE criteria and have 
an appropriately collected culture specimen and interpretable culture result when specimen 
collection is clinically indicated at the TOC Visit. 
8.7. 
Carbapenem-resistant ABC Microbiologic Evaluable Population (CRABC 
ME) 
The CRABC ME Population will include patients who meet both ME criteria and CRABC m-
MITT criteria. 


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8.8. 
Pharmacokinetic (PK) Population 
The PK Population will include patients who receive any amount of study drug and have 
evaluable PK data. 
9. 
STATISTICAL ANALYSIS 
9.1. 
General Statistical Considerations 
9.1.1. 
General Analysis Approach 
Continuous variables will be summarized using the number of non-missing observations, 
arithmetic mean, standard deviation, median, minimum, and maximum values as descriptive 
statistics. Categorical variables will be summarized by using the frequency count and the 
percentage of patients in each category as descriptive statistics.  
All comparisons in Part A will be for ETX2514SUL plus imipenem/cilastatin versus colistin 
plus imipenem/cilastatin. The efficacy endpoints for Part B will be summarized separately and 
will be used to supplement results in Part A. Listings of individual patient data will be 
produced.  
Data from central microbiology laboratory will be used for microbiological analysis. If the data 
from central microbiology laboratory is not available, the data from local microbiology 
laboratory will be used. 
9.1.2. 
Handling of Withdrawals and Missing Data 
For the clinical outcome, patients with missing data or who are lost to follow-up will be 
considered as an indeterminate outcome and are included in the denominator for the calculation 
of clinical cure rate. Thus, patients with an indeterminate outcome are considered as failures 
for the analysis. A clinical failure occurring at an earlier time point will be carried forward to 
the subsequent visits. 
In cases of missing or incomplete dates (e.g. AE and concomitant medications), the missing 
component(s) will be assumed as the most conservative value possible. For example, AEs with 
missing start dates, but with stop dates either overlapping into the treatment period or missing, 
will be counted as treatment-emergent, taking the worst-case approach. When partial dates are 
present in the data, both a partial start date and/or a partial stop date will be evaluated to 
determine whether it can be conclusively established that the AE started prior to the start of 
study drug or ended prior to the start of study drug. If the above cannot be conclusively 
established based on the partial and/or present dates, then the AE will be considered as 
treatment-emergent. Actual data values as they appear in the original eCRF will be presented 
in the data listings. 
Missing values for other variables will not be imputed and only observed values will be used 
in data analyses and summaries.          
9.1.3. 
Baseline Definition 
For microbiological data, baseline pathogen(s) are determined from the specimens collected 
prior to the first dose of study drug. 


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For all efficacy and safety endpoints, baseline is defined as the last measurement or assessment 
prior to the first dose of study drug. 
For safety endpoints, patients who were randomized into Part A then transferred into Part B 
will be included in both Part A and Part B, baseline is defined as the last measurement or 
assessment prior to the first dose of study drug of Part A for both Part A and Part B safety 
analysis. 
For efficacy endpoints, patients who were randomized into Part A then transferred into Part B 
will be included in Part B only, baseline is defined as the last measurement or assessment prior 
to the first dose of study drug of Part A for Part B efficacy analysis.  
9.2. 
Study Subjects 
9.2.1. 
Subject Disposition 
The number of patients randomized, treated, completed, and discontinued early from the study 
and the reasons for discontinuation will be summarized descriptively by treatment group for 
Part A and Part B in the ITT Population.  
The following subject disposition categories will be included in the summary: 
 Patients who were randomized, 
 Patients who were randomized and treated, 
 Patients who were randomized and not treated, 
 Patients who completed the study treatment,  
 Patients who did not complete the study treatment,  
 Patients who did not complete the study treatment related to Coronavirus Disease 2019 
(COVID-19); 
 Patients who completed the study,  
 Patients who did not complete the study, and 
 Patients who did not complete the study related to COVID-19 
For patients who did not complete the treatment, and patients who did not complete the study, 
a summary will be provided by reason of discontinuation. In addition, the number of patients 
in each analysis population and the reason(s) for exclusion from an analysis population (m-
MITT, CRABC m-MITT, CE, ME, and CRABC ME) will be summarized by treatment group 
and a corresponding listing will be provided showing each patient’s inclusion/exclusion from 
each population and reason(s) for exclusion.   
9.2.2. 
Protocol Deviations 
The number of patients with at least one reportable protocol deviation, and the number of 
patients with at least one reportable deviation in each category will be presented by treatment 
group for Part A and Part B in the ITT Population.  In addition, the protocol deviations related 
to COVID-19 will be categorized and summarized separately. 


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9.2.3. 
Demographic and Baseline Characteristics  
Demographics and baseline characteristics including age (as a continuous variable and 
categorized as <65, 65-75 and >75 years), sex, race, ethnicity, weight, body mass index (BMI) 
(as a continuous variable and categorized as <25, 25-<30, 30-<35 and ≥35), creatinine 
clearance (as a continuous variable and categorized as <15 mL/min, 15-<30 mL/min, 30-<60 
mL/min, 60-<90 mL/min and 90 mL/min), Charlson Comorbidity Index <3 or ≥3, septic 
shock status at baseline, mechanical ventilation status at baseline, infection type (bacteremia, 
HABP, VABP, VP, cUTI, AP, surgical wound infection, and post-traumatic wound infection), 
APACHE II score [<10, 10 to 19, 20 to 30 and >30], SOFA score [<7, 7 to 9 and 10], qSOFA 
score [<2, 2, 3 and >3], severity of illness (APACHE II [10-19]/SOFA [7-9]/qSOFA [2] and 
APACHE II [20-30]/SOFA [10]/qSOFA [3]) will be summarized by treatment group and 
baseline infection type (Overall, Bacteremia, HABP, VABP, VP, cUTI, AP, Surgical Wound 
Infection, and Post-traumatic Wound Infection) in the ITT, m-MITT,  and CRABC m-MITT 
Populations. The demographics and baseline characteristics will be summarized for all regions 
and repeated for Mainland Chinese patients.  
9.2.4. 
Baseline Pathogens  
The pathogenic organisms identified from the baseline culture will be summarized by genus 
and species and regions (Overall, North America, Europe, Latin America, Asia-Pacific, and 
China) and by treatment group for the m-MITT, CRABC m-MITT, ME, and CRABC ME 
Populations. The number and percentage of patients with a monomicrobial ABC, 
polymicrobial ABC + other Gram-negative, or polymicrobial ABC + Gram-positive (with or 
without Gram-negative) infections will also be provided.   
For the patients with cUTI or AP, the pathogen(s) cultured from urine at ≥105 CFU/mL or the 
same pathogen present in concurrent blood and urine cultures regardless of CFU values will 
be considered the baseline pathogen(s). If ≥3 bacterial isolates are identified from urine, the 
culture will be considered contaminated regardless of colony count unless 1 of the isolates that 
grows in the urine is also isolated from a blood culture. 
For each treatment group, the MIC summary data (MIC50, MIC90, and MIC range and number 
of unique pathogens tested) for baseline pathogens will be summarized by region (Overall, 
North America, Europe, Latin America, Asia-Pacific, and China) and by treatment group in 
the m-MITT, CRABC m-MITT, ME, and CRABC ME Populations. The MIC50 and MIC90 
will only be calculated for pathogens isolated from at least 10 patients within either treatment 
group.  
The summary of susceptibility (susceptible and resistant) to ETX2514SUL and colistin for 
ABC baseline pathogen by region (Overall, North America, Europe, Latin America, Asia-
Pacific, and China) will also be provided. For ABC baseline pathogens, ETX2514SUL 
susceptible is defined as MIC ≤4 mg/L and ETX2514SUL resistant is defined as MIC >4 mg/L. 
For ABC baseline pathogens, colistin susceptible is defined as MIC <4 mg/L and colistin 
resistant is defined as MIC ≥4 mg/L. 
9.2.5. 
Medical and Surgical History  
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surgical history will be summarized by treatment group and MedDRA system organ class 
(SOC) and preferred term in the Safety Population.  
All Medical and surgical history will be listed by patient.  
9.2.6. 
Prior and Concomitant Medications  
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary (Global B2 September 2018). Prior medications will include medications used 
before the first dose of study drug. Any medications used on or after the first dose of study 
drug will be included as concomitant medications.  
The number and percentage of patients taking prior antibiotics within 14 days prior to the first 
dose of study drug and other prior medications within 14 days prior to the first dose of study 
drug will be summarized in the m-MITT, and CRABC m-MITT Populations by Anatomical 
Therapeutic Chemical (ATC) class and preferred term for each treatment group. In addition, 
the number and percentage of patients taking prior antibiotics within 72 hours prior to the first 
dose of study drug will be summarized in the m-MITT, and CRABC m-MITT Populations for 
each treatment group. The number and percentage of patients taking prior antibiotics within 24 
hours prior to the first dose of study drug will also be summarized in the m-MITT, and CRABC 
m-MITT Populations for each treatment group. 
The number and percentage of patients taking concomitant medications will be summarized in 
the same manner. 
All prior and concomitant medications and procedures will be listed by patient.  
9.2.7. 
Dosing and Treatment Exposure  
Descriptive statistics for the duration of treatment will be summarized by treatment group for 
Part A and Part B for the Safety, m-MITT, and CRABC m-MITT Populations.  Duration of 
treatment will be calculated as the last dose date - the first dose date + 1 day. Contingency table 
will be provided to show the number and percentage of patients in each treatment group with 
duration of treatment in the following categories: 1-3 days, 4-7 days, 8-10 days, and > 10 days. 
The total number of doses of study drug received will also be summarized by treatment group 
using descriptive statistics. 
The compliance rate of study drug will be calculated as the total number of doses received 
divided by the total number of doses expected then multiplied by 100. The total number of 
expected doses is the number of medication days multiplied by the number of expected doses 
per day. Number of medication days is the total number of days from the date of the first dose 
of study drug to the date of the last dose of study drug.  
Percent compliance to study drug will be calculated using the following formula: 
%compliance = no. of doses received*100
total no. of doses expected 
Percent compliance will be summarized by treatment group for the Safety, m-MITT, and 
CRABC m-MITT Populations. In addition, contingency tables will be provided to show the 
number and percentage of patients in each treatment group with compliance in the following 
categories: <80% and ≥80%. 


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9.3. 
Efficacy Analyses 
The efficacy analyses will be analyzed for Part A and Part B separately. Patients who were 
randomized into Part A and stayed in Part A will be summarized/analyzed only for Part A. 
Patients who were randomized into Part A but then transferred into Part B will be 
summarized/analyzed only for Part B. 
9.3.1. 
Primary Efficacy Analyses 
The primary efficacy endpoint for the study is 28-day all-cause mortality in the CRABC            
m-MITT Population in Part A. Patients in the CRABC m-MITT Population who discontinue 
study drug prematurely in Part A for any reason will be included in the assessment of 28-day 
mortality, provided consent has not been withdrawn. Patients who withdraw consent from the 
survival status will be excluded from the analysis. Patients who have missing survival status 
will be treated as death. Patients who were randomized into Part A but then transferred into 
Part B will not be included in Part A analysis. 
The non-inferiority assessment will be based on the 2-sided 95% confidence intervals (CIs) 
computed using a continuity-corrected Z-statistic for the difference ([ETX2514SUL +  
imipenem/cilastatin] – [colistin + imipenem/cilastatin]) in 28-day all-cause mortality rates 
between the treatment groups. Non-inferiority will be concluded if the upper limit of the 2-
sided 95% CI is less than +20%. If non-inferiority is achieved, the superiority will be 
investigated. Superiority will be concluded if the upper limit of the 2-sided 95% CI is less than 
0. 
Sensitivity Analyses  
Sensitivity analyses of the primary efficacy endpoint will be conducted as follows: 
 Analysis of the primary efficacy endpoint will be performed for patients whose eligible 
culture is >48 hours prior to the first dose of treatment in the CRABC m-MITT Population.  
 Analysis of the primary efficacy endpoint will be performed for patients whose eligible 
culture is ≤48 hours prior to the first dose of treatment in the CRABC m-MITT Population.  
 Analysis of the primary efficacy endpoint will be performed for patients with ABC 
pathogens susceptible to ETX2514SUL and colistin at baseline in the CRABC m-MITT 
Population.  
 Analysis of the primary efficacy endpoint will be performed for patients without ABC 
susceptibility results for ETX2514SUL or colistin at baseline in the CRABC m-MITT 
Population.  
 Analysis of the primary efficacy endpoint will be performed including the patients who 
were randomized into Part A but then transferred into Part B in the ITT Population. 
 Analysis of the primary efficacy endpoint will be performed excluding the patients who 
have missing survival status in the CRABC m-MITT Population.  
Analysis of the primary efficacy endpoint and the sensitivity analysis will be repeated 
including the patients who withdraw consent from the survival status. 


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9.3.2. 
Secondary Efficacy Analyses 
The secondary efficacy endpoints for Part A and Part B include the following: 
 28-day all-cause mortality in the ITT Population; 
 Clinical cure at TOC in the CRABC m-MITT Population; 
 Clinical cure at TOC in the m-MITT, Clinical Evaluable (CE), Microbiologic Evaluable 
(ME), and CRABC ME Populations; 
 Clinical cure at EOT, and LFU in the m-MITT, CRABC m-MITT, CE, ME, and CRABC 
ME Populations; 
 Microbiological favorable assessment at EOT, TOC, and LFU by overall, monomicrobic 
infection and polymicrobic infection in the m-MITT, CRABC m-MITT, ME, and CRABC 
ME Populations. Monomicrobic infection is defined as subjects with only ABC pathogens 
isolated at Baseline, Polymicrobic infection is defined as subjects with both ABC 
pathogens and non-ABC pathogens isolated at Baseline; 
 14-day all-cause mortality in the CRABC m-MITT and m-MITT Populations; and 
 28-day all-cause mortality in the m-MITT and CRABC ME Populations. 
All secondary efficacy analyses will be analyzed including the patients who withdraw consent 
from the survival status. 
In addition, the primary analysis will be repeated for 28-day all-cause mortality in the ITT, m-
MITT and CRABC ME Populations excluding the patients who withdraw consent from the 
survival status for Part A. 14-day all-cause mortality in the CRABC m-MITT and m-MITT 
Populations will be performed in a same manner excluding the patients who withdraw consent 
prior to Day 14 for Part A.   
Similarly, the analysis of clinical response and the microbiologic response will be repeated 
excluding patients who withdraw consent from the survival status in the CRABC m-MITT 
Population for Part A.   
The number and percentage of patients in each response category for the secondary efficacy 
endpoints will be summarized by treatment group. Two-sided 95% CIs computed using a 
continuity-corrected Z-statistic for the difference in outcome rates between the treatment 
groups in Part A will be provided. Patients who initially randomized to Part A and transferred 
to Part B will not be included in Part A analysis and will be included in Part B analysis from 
the time point of transfer. Patients with a missing secondary efficacy value, the efficacy 
variable will be considered as non-responder. In addition, time to death will be analyzed using 
log rank test between the treatment groups for Part A.  
In Part A, if there is a discrepancy between the assessment of the blinded assessor and 
unblinded Investigator for clinical outcome, the assessment from the blinded assessor will be 
used. If there is a missing assessment from either the blinded assessor or unblinded 
Investigator, the other available assessment will be used. 
Part B data will be summarized separately from Part A using descriptive statistics. Patients 
who transfer from Part A to Part B, Part B data will be summarized from the time point of 
transfer. 


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9.3.3. 
Exploratory Efficacy Analyses 
The following exploratory efficacy endpoints will be summarized by treatment group for the 
CRABC m-MITT Population for Part A and Part B: 
 Clinical cure based on baseline ABC pathogen MIC distribution of ETX2514SUL by 
overall, monomicrobic infection and polymicrobic infection;  
 Clinical cure based on baseline ABC pathogen MIC distribution of colistin by overall, 
monomicrobic infection and polymicrobic infection;  
 Microbiological favorable assessment (including microbiologic eradication and 
microbiologic presumed eradication) based on baseline ABC pathogen MIC distribution of 
ETX2514SUL by overall, monomicrobic infection and polymicrobic infection; 
 Microbiological favorable assessment (including microbiologic eradication and 
microbiologic presumed eradication) based on baseline ABC pathogen MIC distribution of 
colistin by overall, monomicrobic infection and polymicrobic infection; 
 Number of days in the intensive care unit (ICU); 
 Number of patients transferred to the ICU; 
 Number of days on ventilators for patients with VABP, VP, or ventilated HABP, number 
of days on ventilators; 
 Number of days in the hospital; 
 Number of days on study drug treatment. 
The following exploratory efficacy endpoints will be summarized by treatment group for the 
m-MITT Population for Part A: 
 Clinical cure based on baseline ABC pathogen resistance to ETX2514SUL, carbapenems, 
or colistin by overall, monomicrobic infection and polymicrobic infection; 
 Microbiological favorable assessment (including microbiologic eradication and 
microbiologic presumed eradication) based on baseline ABC pathogen resistance to 
ETX2514SUL, carbapenems, or colistin by overall, monomicrobic infection and 
polymicrobic infection. 
Monomicrobic infection is defined as subjects with ABC pathogens only isolated at Baseline. 
Polymicrobic infection is defined as subjects with both ABC pathogens and non-ABC 
pathogens isolated at Baseline. 
Exploratory endpoints for health resource utilization difference between treatment groups will 
be reported separately.  
9.3.4. 
Subgroup Analyses 
The following subgroups based on baseline characteristics will be used for subgroup analyses 
for the primary efficacy endpoint excluding patients who withdraw consent from the survival 
status:  
 Age group (<65, 65-75 and >75 years) 


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 Gender (Male and Female) 
 BMI (<25, 25-<30, 30-<35, and ≥35 kg/m2) 
 Charlson comorbidity index (<3 and ≥3) 
 Diagnosis type (Bacteremia, HABP, VABP, and VP) 
 Severity of illness (APACHE II [10-19]/SOFA [7-9]/qSOFA [2] and APACHE II [20-
30]/SOFA [10]/qSOFA [3]) 
 Creatinine clearance group (<30 mL/min, 30-<60 mL/min, 60-<90 mL/min, and 90 
mL/min)  
 Duration of ICU stay (no ICU stay, <5, 5-14, >14 days) 
 HABP/VABP/VP who are identified as positive for ABC by BPP molecular methodology  
 Monomicrobial ABC infection vs polymicrobial infection 
 Bacteremia patients with negative blood cultures for ABC at randomization or first dose 
date with a positive blood culture for ABC previously at baseline vs. Rest of bacteremia 
patients 
 Received prior antibiotics within 24 hours prior to the first dose of study drug vs. Not 
Received 
 Received prior antibiotics vs. Not Received  
 Septic Shock status at baseline (Yes vs. No) 
 Mechanical Ventilation status at baseline (Yes vs. No) 
 By region (North America, Europe, Latin America, Asia-Pacific, China; North 
America/Europe vs. Latin America/Asia-Pacific/China; China vs. rest of the world) 
 By COVID-19 status (Positive vs. Negative) 
A forest plot will be presented for subgroup analyses. 
9.4. 
Safety Analyses 
All safety summaries and analyses will be performed on the Safety Population. All patients 
will be summarized based on the actual treatment received. Safety endpoints include the 
assessment of adverse events and the evaluation of changes from baseline in safety laboratory 
test results, ECGs, vital signs, and physical examinations. 
For each safety endpoint, unless otherwise stated, the last assessment made prior to the first 
administration of study drug will be used as the baseline value for all analyses. 
The safety analyses will be analyzed for Part A and Part B separately. For the patients who 
were randomized into Part A but then transferred into Part B, safety will be 
summarized/analyzed until the date of transfer for Part A; safety reported on or after the date 
of transfer will be summarized/analyzed for Part B. Baseline is the last measurement or 
assessment prior to the first dose of study drug of Part A for both Part A and Part B safety 
analysis. 


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9.4.1. 
Adverse Events 
A treatment-emergent adverse event (TEAE) is defined as an adverse event occurring on or 
after the administration of the first dose of study drug. An overview of adverse events will be 
provided which summarizes the incidence of the following categories:  
 All AEs,  
 All TEAEs, 
 Drug-related TEAEs, 
 TEAEs by severity, 
 SAEs, 
 Drug-related SAEs, 
 SAE leading to death, 
 TEAE leading to discontinuation of study drug, and 
 SAE leading to discontinuation of study drug. 
Patients with multiple events will be counted only once within each category.  Severity grade 
and relationship will be counted using the maximum severity and the strongest relationship 
respectively for a patient with multiple TEAEs. 
The number and percentage of patients reporting a TEAE in each treatment group will be 
tabulated by SOC and PT; by SOC, PT, and severity; and by SOC, PT, and relationship (related 
or unrelated to study drug and imipenem/cilastatin). Summary tables will be presented 
alphabetically by SOC and decreasing frequency of PT in the EXT2514SUL group within 
SOC. For all analyses of TEAEs, if the same AE (based on PT) is reported for the same patient 
more than once, the AE is counted only once for that PT and at the highest severity and 
strongest relationship to study drug.  
The number and percentage of patients reporting a drug-related TEAE, a SAE, a treatment 
emergent SAE, a drug-related treatment-emergent serious adverse event (TESAE), and a 
TEAE leading to discontinuation of study drug in each treatment group will be summarized by 
SOC and PT. 
A list of patients who have SAEs, a list of patients who discontinue from study drug, and a list 
of death will be provided. All adverse events will be listed. 
Adverse Events of Special Interest 
Adverse events of special interest and their definitions include the following: 
 Allergic and hypersensitivity reactions: Severe and serious adverse drug reactions from the 
Medical Dictionary for Regulatory Activities (MedDRA) Standardized MedDRA Queries 
of allergy and hypersensitivity, 
 Nephrotoxicity: Using the RIFLE criteria for the duration of the study (see Table 2)1, and  


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 Emergent infections and superinfections: All serious and severe events in the MedDRA 
system organ class of infections and infestations other than the indication infection (ie, 
ABC). 
 Clostridiodes difficile infection 
Table 2.     Definition of RIFLE Criteria 
Term 
Definition 
Risk (R) 
Increased creatinine level 1.5 or GFR decrease 
25% 
Injury (I) 
Increased creatinine level 2 or GFR decrease 50% 
Failure (F) 
Increased creatinine level 3, GFR decrease 75%, 
or creatinine level 4 mg/dL 
Loss (L) 
Persistent acute renal failure or complete loss of 
function for 4 weeks 
ESKD (E) 
ESKD for 3 months 
ESKD = end-stage kidney disease; GFR = glomerular filtration rate; RIFLE = Risk–Injury–Failure–Loss–End-stage renal 
disease. 
The number and percentage of patients reporting adverse events of special interest will be 
summarized by each category and treatment group in Part A in the Safety and CE Populations. 
In addition, proportion of patients with nephrotoxicity will be compared between the 
investigational and control groups using Chi-square test. The Chronic hemodialysis patients 
will not be included in the nephrotoxicity analysis. 
9.4.2. 
Clinical Laboratory Evaluations 
Laboratory test results (hematology, serum chemistry, and urinalysis) at each scheduled visit 
and change from baseline will be summarized by treatment group for Part A and Part B for 
Mainland Chinese patients or other patients separately. 
Shift tables from baseline to each scheduled post-baseline visit will be provided for selected 
chemistry parameters (alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
total bilirubin, creatinine, creatine kinase, alkaline phosphatase [ALP], potassium) and 
hematology parameters (hematocrit, hemoglobin, platelets, white blood cell count and 
differential). For chemistry parameters, the following categories will be used: < the lower limit 
of normal (LLN), normal, > the upper limit of normal (ULN) to ≤3×ULN, >3×ULN to 
≤5×ULN, >5×ULN, and missing. For hematology parameters, the following categories will be 
used: low, normal, high, and missing.  
The number and percentage (based on the number of patients with a normal level at baseline) 
of patients in each treatment group with an ALT (>3×ULN, >5×ULN, and >10×ULN), an AST 
(>3×ULN, >5×ULN, and >10×ULN), an ALT or AST >3×ULN, and a total bilirubin 
(>1.5×ULN and >2×ULN) will be presented by study visit. A listing of patients who meet the 
laboratory criteria for Hy’s law will also be provided. The laboratory criteria for Hy’s law is 
defined as concurrent ALT or AST>3×ULN, ALP ≤2.0×ULN, and total bilirubin >2×ULN. A 
listing will also be provided for the potentially clinically significant (PCS) values for the above 
parameters. 
All clinical laboratory data will be listed. Values outside the normal ranges will be flagged. 


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9.4.3. 
Vital Signs 
Descriptive statistics will be provided for vital sign data (systolic and diastolic blood pressure, 
heart rate, and respiratory rate) presented as both actual values and changes from baseline over 
time by treatment group for Part A and Part B. 
A listing of all vital signs will be provided by patient. 
9.4.4. 
Electrocardiograms (ECG) 
Descriptive statistics will be provided for 12-lead ECG findings (heart rate, QRS, PR, RR, QT, 
and QTcF) and changes from baseline for each scheduled visit for Part A and Part B. QTcF 
will be calculated as follows: 
 
 
The number and percentage of patients with notable ECG changes in maximum QTcF (>450 
msec, >480 msec, and >500 msec) over all post-baseline evaluations, as well as in QTcF 
maximum changes from baseline (>30 msec and >60 msec) over all post-baseline evaluations 
will be summarized by treatment group. 
All ECG measurements and the overall interpretation will be listed by patient. 
9.4.5. 
Physical Examination 
Physical examination findings will be listed by patient.  
9.5. 
Pharmacokinetic Analyses 
The pharmacokinetic analyses will be performed by another vendor and reported separately. 
 
 


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10. 
REFERENCES 
1. Hartzell JD, Neff R, Ake J, et al. Nephrotoxicity associated with intravenous colistin 
(colistimethate sodium) treatment at a tertiary care medical center. Clin Infect Dis. 
2009;48(12):1724-1728.