Conditions: Pneumonia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 726
Healthy volunteers: no

Brief summary:
This is a 1:1 ratio, randomized, double-blind, double-dummy, multicenter, global Phase 3 study of tedizolid phosphate (TR-701 FA) 200 mg intravenous (IV) once daily for 7 days versus linezolid (Zyvox®, Zyvoxid®, etc) 600 mg IV every 12 hours for 10 days for the treatment of ventilated participants with presumed gram-positive hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP), collectively referred to as ventilated nosocomial pneumonia (VNP). Participants with concurrent gram-positive bacteremia are to receive 14 days of active therapy in either treatment arm.

The primary objective is to determine the noninferiority (NI) in all-cause mortality (ACM) within 28 days after randomization of IV tedizolid phosphate compared with IV linezolid in the Intent to Treat (ITT) Analysis Set (NI is declared when the lower bound of the 95% CI \> -10).

Detailed description:

Arms:
arm 1: Ventilated HABP/VABP participants receive tedizolid phosphate 200 mg IV once daily for 7 days, or for 14 days for concurrent bacteremia. arm 2: Ventilated HABP/VABP participants receive linezolid 600 mg IV every 12 hours for 10 days, or for 14 days for concurrent bacteremia.

Interventions: intervention 1: Tedizolid phosphate intervention 2: Linezolid
Intervention descriptions: intervention 1: Tedizolid phosphate IV 200 mg once daily intervention 2: Linezolid IV 600 mg twice daily

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT02019420 
Document Date: 
10-Aug-2018
A Phase 3 Randomized Double-blind Study Comparing 
TR-701 FA and Linezolid in Ventilated Gram-Positive 
Nosocomial Pneumonia


 
 
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INVESTIGATOR’S AGREEMENT
Protocol Title: 
A Phase 3 Randomized Double-blind Study Comparing TR-701 FA and 
Linezolid in Ventilated Gram-positive Nosocomial Pneumonia 
Study No: 
TR-701-132 (MK-1986-002)
EudraCT No: 
2013-004154-22
Original Protocol Date: 
30 May 2013
Amendment 1 Date: 
26 August 2013
Amendment 2 Date: 
15 January2014
Amendment 3 Date:
11 November 2014
Amendment 4 Date:
24-January-2017
Amendment 5 Date:
10-August-2018
I have read the protocol, including all appendices, and I agree that it contains all of the 
necessary information for me and my staff to conduct this study as described. I will conduct 
this study as outlined herein, in accordance with the regulations stated in the Federal Code of 
Regulations for Good Clinical Practices and International Council on Harmonisation 
guidelines, and will make a reasonable effort to complete the study within the time 
designated.
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Cubist Pharmaceuticals, LLC or 
specified designees. I will discuss the material with them to ensure that they are fully 
informed about Cubist Pharmaceuticals, LLC and the study.
Investigator’s Signature: ___________________________________________
Printed Name:  ____________________________________________________
Name of Institution/Company: ______________________________________
Date: ________________________
Please submit an original copy of this page to Cubist Pharmaceuticals, LLC and file a copy in 
the Investigator site file.
 
 
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SYNOPSIS
Title
A Phase 3 Randomized Double-blind Study Comparing TR-701 FA and Linezolid in 
Ventilated Gram-positive Nosocomial Pneumonia 
Objectives
The primary objective is to determine the noninferiority (NI) in all-cause mortality 
(ACM) within 28 days after randomization of intravenous (IV) TR-701 FA (tedizolid 
phosphate, MK-1986) compared with IV linezolid in the Intent to Treat (ITT) Analysis 
Set in ventilated patients with presumed gram-positive hospital-acquired bacterial 
pneumonia (HABP) or gram-positive ventilator-associated bacterial pneumonia 
(VABP), collectively defined as ventilated nosocomial pneumonia (VNP).
Secondary objectives:

To compare the ACM observed with TR-701 FA and linezolid within 28 days 
after randomization in the microbiological ITT (Micro-ITT) Analysis Set

To compare clinical response for TR-701 FA and linezolid treatment at Test of 
Cure (TOC) in the ITT (European Medicines Agency [EMA] and Japan 
Ministry of Health, Labour, and Welfare primary endpoint) and Clinically 
Evaluable (CE) Analysis Sets.  Clinical response at TOC is derived from the 
Investigator’s assessment at the End of Therapy (EOT) and TOC Visits as 
detailed in the Statistical Analysis Plan (SAP)

To compare the per-patient favorable microbiological response rate at EOT in 
the Micro-ITT and Microbiologically Evaluable (ME)-1 Analysis Sets and at 
TOC in the Micro-ITT and ME-2 Analysis Sets

To evaluate the safety profile of TR-701 FA and compare with that of 
linezolid

To assess the population pharmacokinetic (PK) and PK/pharmacodynamic 
(PD) profile of TR-700
The protocol has been designed to meet Food and Drug Administration (FDA) and 
EMA regulatory requirements. In addition, the efficacy and safety of TR-701 FA in the 
Sepsis Population are evaluated under this Japan-specific amendment. 
Methodology/ 
Study Design
This is a 1:1 ratio, randomized, double-blind, double-dummy, multicenter, global 
Phase 3 study of TR-701 FA 200 mg IV once daily for 7 days versus linezolid (Zyvox®, 
Zyvoxid®, etc.) 600 mg IV every 12 hours for 10 days for the treatment of ventilated 
patients with presumed gram-positive HABP or VABP.  Patients with concurrent 
gram-positive bacteremia are to receive 14 days of active therapy in either treatment 
arm.
Cubist Pharmaceuticals, LLC (hereafter referred to as Cubist) (with the exception of the
Clinical Drug Supply manager and the Unblinded Global Study team), and the 
Investigators, study statistician, clinical study personnel, study staff participating in 
patient care or clinical evaluations, and patients will be blinded to therapy assignment 
until the database is locked.  Pharmacy staff or designee, the independent Statistics 
Reporting Group (SRG), the Data and Safety Monitoring Board (DSMB), will be 
unblinded.  All study drug infusion bags and IV tubing will be covered and sealed with 
tamper-evident material in order to maintain the blind.
Approximately 300 sites will participate in this global study.  Ventilated patients with 
HABP/VABP caused by presumed gram-positive pathogen(s) at baseline as determined 
by positive Gram stain will be randomized 1:1 to study drug treatment using an 
interactive voice response system.  Randomization will be stratified by geographic 
region, age (≥65 years or <65 years), and underlying diagnosis (trauma or nontrauma
admitting diagnosis).
 
 
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Number of  
Patients 
Approximately 726 patients will be randomized (ITT Analysis Set) and are expected to 
include approximately 363 (50%) patients with a gram-positive pathogen isolated based 
on respiratory culture (Micro-ITT Analysis Set).  Data from approximately 580 patients 
are expected to be included in the CE Analysis Set.
Inclusion 
Criteria
Patients who meet all the following diagnostic and inclusion criteria are eligible for the 
study.
1.
Males or females 18 years old
2.
Adequate venous access for IV study drug administration
3.
Intubated (via endotracheal tube, including tracheostomy patients) and 
mechanically ventilated, AND

For HABP, at least 1 of the following signs or symptoms presenting 
within 24 hours prior to intubation of a patient hospitalized, including 
patients institutionalized in long-term care facilities, for ≥48 hours.  If the 
patient has been discharged, discharge must have been within 7 days:
o
A new onset of cough (or worsening of baseline cough) 
o
Dyspnea, tachypnea, or respiratory rate >30/minute, particularly if 
any or all of these signs or symptoms are progressive in nature
o
Hypoxemia (eg, a partial pressure of oxygen <60 mm Hg while the 
patient is breathing on room air as determined by arterial blood gas 
[ABG] or oxygen saturation <90% while the patient is breathing on 
room air as determined by pulse oximetry), or worsening (decline 
from any earlier finding) of the ratio of the partial pressure of oxygen 
to the fraction of inspired oxygen (PaO2/FiO2), or respiratory failure 
requiring mechanical ventilation

For VABP, receiving mechanical ventilation ≥48 hours and at least one of 
the following:
o
Acute changes made in the ventilator support system to enhance 
oxygenation, as determined by ABG, or worsening PaO2/FiO2
o
Hypoxemia (eg, a partial pressure of oxygen less than 60 millimeters 
of mercury while receiving FiO2 of 25%-30%, as determined by 
ABG or worsening of the ratio of the partial pressure of oxygen to the 
fraction of inspired oxygen (PaO2/FiO2)
o
New onset or worsening pulmonary symptoms or signs, such as 
cough, asymmetric breath sounds, tachypnea (eg, respiratory rate 
greater than 25 breaths per minute), need for increased oxygenation 
or ventilation support,
4.
Chest radiograph shows the presence of new or progressive infiltrate(s) 
suggestive of bacterial pneumonia (based on Investigator evaluation; report 
from qualified medical professional who is not the Investigator to be provided) 
5.
Clinical findings to support diagnosis of HABP/VABP

New onset of suctioned respiratory secretions characterized by purulent 
appearance indicative of bacterial pneumonia

And at least 1 of the following:
o
Documented fever (oral ≥38°C [100.4°F] or a tympanic, temporal, 
rectal, or core temperature ≥38.3°C [101°F]) OR
o
Hypothermia (core body temperature ≤35°C [95.2°F]) OR
 
 
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o
Total peripheral white blood cell (WBC) count ≥10,000 cells/mm3
OR
o
Leukopenia with total WBC ≤4500 cells/mm3 OR
o
≥15% immature neutrophils (bands; if local laboratory has 
capabilities to measure) 
6.
High probability of pneumonia caused by gram-positive bacteria only or in a 
mixed infection defined as follows:
Respiratory Sample 

Sample acquired and Gram stain performed within 36 hours prior to first 
infusion of study drug using an acceptable purulent respiratory specimen such as 
sputum or endotracheal aspirate sample (with <10 squamous epithelial cells 
[SEC] and >25 polymorphonuclear [PMN] cells per low-power field) showing 
gram-positive bacteria (with or without gram-negative bacteria) OR

Sample acquired and Gram stain performed within 36 hours prior to first 
infusion of study drug using an acceptable respiratory specimen such as 
protected specimen brush, bronchoalveolar lavage (BAL), mini-BAL, or sample 
from an exudative pleural effusion showing gram-positive bacteria (with or 
without gram-negative bacteria) OR

Culture from lower respiratory sample obtained within 72 hours prior to first 
infusion of study drug positive for methicillin-resistant Staphylococcus aureus
(MRSA) OR

Rapid molecular diagnostic test (for example Xpert®) positive for MRSA
Exclusion 
Criteria
Patients who meet any of the following criteria are not eligible to participate in this 
study:
1.
Known or suspected community-acquired bacterial pneumonia or viral, fungal 
(presence of Candida in lower respiratory tract is not exclusionary), or 
parasitic pneumonia
2.
Any of the following health conditions:

Legionella infection (Legionella pneumophila pneumonia)

Cystic fibrosis

Human immunodeficiency virus (HIV) infection with last known CD4 
count <200 cell/mm³ (HIV testing is not required)

Known or suspected Pneumocystis jirovecii pneumonia

Known or suspected active tuberculosis

Lung abscess

Evidence of endocarditis 

Tracheobronchitis (if no evidence of pneumonia)
3.
Received systemic or inhaled antibiotic therapy effective for gram-positive 
pathogens that cause VNP for >24 hours (for example, >1 dose of a once-daily 
antibiotic, >2 doses of a twice daily antibiotic) in the last 72 hours 
EXCEPTIONS

Progression of disease on the prior antibacterial regimen for this episode 
of VNP after >48 hours of treatment, OR
 
 
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
Patient developed symptoms of pneumonia and a new infiltrate while 
receiving the prior antibacterial regimen for reasons other than the current 
VNP, OR

Patient received systemic antibacterial therapy that does not cover the 
gram-positive pathogen isolated on respiratory culture, OR

Antibiotic therapy for gut decontamination or gut motility (example, 
low-dose erythromycin) or C. difficile infection 
4.
Receipt of monoamine oxidase A and B inhibitors (see Appendix 1) from 
2 weeks prior to randomization or planned use through the EOT Visit
5.
Planned use of agents with serotonergic activity (see Appendix 1 and 
Section 1.4) through the EOT Visit
6.
Administration of linezolid or tedizolid phosphate ≤30 days before the first 
infusion of study drug, except for receipt of a single administration of 
linezolid, within 24 hours prior to the first administration of study drug to treat 
the current VNP 
7.
Bronchial obstruction or a history of postobstructive pneumonia (this does not 
exclude patients with pneumonia who have underlying chronic obstructive 
pulmonary disease)
7.
Primary lung cancer or another malignancy metastatic to the lungs
8.
Recent opportunistic infection where the underlying cause of the infection is 
still active (eg, leukemia, transplant, acquired immunodeficiency syndrome)
9.
Expected survival <72 hours or any 1 of the following:

Comfort care measures only

Acute respiratory distress syndrome/acute lung injury secondary to septic 
shock, or due to third degree burns or inhalation injury

Nonresolving pulmonary edema secondary to congestive heart failure
10. Burns >40% of total body surface area
11. Current or anticipated neutropenia with absolute neutrophil count 
<500 cells/mm3
12. Severe renal disease requiring peritoneal dialysis.  Patients with severe renal 
disease on hemodialysis, venovenous dialysis, or other forms of renal filtration 
may be enrolled
13. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 10× 
upper limit of normal OR severe hepatic disease with Child-Pugh score >9  
14. Investigator’s opinion of clinically significant electrocardiogram (ECG) 
finding such as ischemia, infarct, or ventricular arrhythmia with immediate 
potential for a fatal outcome, or, prior to the current infection, a history of 
New York Heart Association Class IV cardiac failure defined as severe 
limitations - experiences symptoms even while at rest, mostly bedbound 
patients, within 1 year
15. Patients with uncontrolled hypertension (defined as high blood pressure that is 
clinically an issue and uncontrolled on multiple medications), 
pheochromocytoma, carcinoid syndrome, or thyrotoxicosis
16. Treatment with investigational medicinal product ≤30 days before the first 
infusion of study drug or prior randomization in this protocol
 
 
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17. Investigational device present, or removed <30 days before the first infusion of 
study drug or presence of device-related infection  
18. Hypersensitivity to oxazolidinones (eg, linezolid) or any component in the 
formulation 
19. Women who are pregnant or nursing, or who are of childbearing potential and 
unwilling to use an acceptable method of birth control (eg, intrauterine device, 
double-barrier method [eg, condoms, diaphragm, or cervical cap with 
spermicidal foam, cream or gel], or male partner sterilization); excluding 
women ≥2 years postmenopausal or surgically sterile
Test Product(s), 
Dose, Mode of 
Administration, 
and Duration of 
Treatment
TR-701 FA 200 mg once daily in 250 mL sterile saline for injection as a single 
60-minute IV infusion for 7 days (14 days for patients with gram-positive bacteremia).
Linezolid 600 mg IV Injection twice daily in 300 mL sterile saline for injection as a 
60-minute infusion for 10 days (14 days for patients with gram-positive bacteremia).
In this double-dummy study, patients will receive placebo unique to each active 
treatment, placebo infusion unique for TR-701 FA (250 mL) and placebo infusion 
unique for linezolid (300 mL).  No dosage adjustments are allowed.
Duration of 
Study
The overall duration of the study will be approximately 58 months.  Patient 
participation will be up to 33 days from the Screening Visit to the Follow-up Visit, 
unless a patient is being monitored for an adverse event (AE).  Patients will be 
monitored for AEs through the last study visit and serious AEs (SAEs) will be followed 
using the SAE report form until stabilization, resolution/death, or consent is withdrawn.
Efficacy 
Outcomes
The primary outcome is ACM within 28 days after randomization in the ITT Analysis 
Set.
Secondary outcomes include the following:

ACM within 28 days after randomization (Micro-ITT Analysis Set) 

Clinical response at TOC in the ITT (EMA and Japan Ministry of Health, 
Labour, and Welfare primary endpoint) and CE Analysis Sets.  Clinical 
response at TOC is derived from the Investigator’s assessment at the EOT and 
TOC Visits

Microbiological response at EOT and TOC (Micro-ITT, ME-1 and ME-2 
Analysis Sets)

ACM in patients with methicillin-susceptible Staphylococcus aureus (MSSA) 
or MRSA (Micro-ITT Analysis Set)

Clinical response by Investigator in patients with MSSA or MRSA (Micro-ITT 
and ME-2 Analysis Sets)
Safety 
Variables
Safety will be evaluated through assessment of AEs, laboratory evaluations 
(hematology and chemistry), vital signs, and physical examinations including a 
neurologic examination and visual acuity examination 
PK Variables
Include maximum plasma concentrations and estimated PK parameters (eg, area under 
the concentration-time curve)
Analysis Sets
1.
ITT Analysis Set:  data from all randomized patients 
2.
Safety Analysis Set:  data from all patients in the ITT Analysis Set who receive 
any amount of study drug 
3.
Micro-ITT Analysis Set:  data from all patients in the Safety Analysis Set who 
have gram-positive pathogen(s) confirmed by culture results from a respiratory 
 
 
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tract or pleural fluid specimen obtained within 36 hours (or if culture positive for 
MRSA within 72 hours) before first administration of study drug, and documented 
bacterial pathogen known to cause VNP against which the investigational drug has 
antibacterial activity
4.
ME-1 Analysis Set:  data from all patients in the Micro-ITT Analysis Set who did 
not receive an antibiotic (other than study drug) with activity against the baseline 
pathogen received up through 28 days after randomization  
5.
ME-2 Analysis Set:  data from all patients in the Micro-ITT Analysis Set who did 
not receive an antibiotic (other than study drug) with activity against the baseline 
pathogen received up through the TOC Visit and also in the CE Analysis Set 
6.
CE Analysis Set:  data from all patients in the Safety Analysis Set who had a TOC 
response assessment recorded (if the patient was assessed by the Investigator as a 
clinical failure at the EOT Visit, a response assessment at the TOC Visit is not 
required), had no confounding events or factors as detailed in the SAP
Statistical 
Methods
To demonstrate the NI of TR-701 FA to linezolid with respect to the difference in 
28-day ACM rates, using an NI margin of 10%, a sample size of 726 randomized 
patients (363 per arm) in the ITT Analysis Set will have 92% power at a 1-sided 
significance level of 0.025, assuming a 28-day ACM rate of 20% in both TR-701 FA 
and linezolid arms.  
The study is also sufficiently powered for the secondary outcome measure of clinical 
cure as derived from the Investigator’s assessment at TOC in the ITT and CE Analysis 
Sets. A total of 726 patients will be randomized in the ITT Analysis Set, which 
provides 87% power to show NI assuming a 50% clinical success rate and an NI margin 
of 12.5%.  If the clinical evaluability rate will be 80%, with a 12.5% NI margin, 80% 
power, a 1-sided alpha=0.0125, and a clinical cure rate of 60% in the CE Analysis Set, 
a total of 580 patients are required in the CE Analysis Set.
Primary Outcome 
(28-Day ACM)
Secondary Outcome 
(Clinical Response*)
Analysis Set
ITT
ITT
CE
Outcome Rate
20%
50%
60%
Evaluability Rate
NA
NA
80%
Margin
10%
12.5%
12.5%
N
726
726
580
Power
92%
87%
80%
Abbreviations:  CE=clinically evaluable; ITT=intent to treat; NA=not applicable
*As derived from the Investigator’s assessment at the EOT and TOC Visits
The DSMB will be convened when approximately 30% (218 patients), 50% (363 
patients), and 75% (545 patients) of patients have been randomized in the ITT Analysis 
Set and completed 28 days of follow-up.  A DSMB will review safety and efficacy data 
including ACM, treatment-emergent adverse events (TEAEs), incidence of serious 
TEAEs, study drug-related TEAEs, and study drug discontinuation due to study drug-
related TEAEs and other safety and efficacy related data at 30%, 50%, and 75% of 
patient enrollment.  Only data for the first and the second interim looks will be 
unblinded (Treatment A vs Treatment B). At the first and second interim analysis, 
futility analysis based on the primary efficacy outcome of 28-day ACM in the ITT 
Analysis Set will be performed.  The futility boundaries will be derived from the 
Gamma (-4.27) error spending function and constructed to be nonbinding.  The futility 
boundaries will be calculated using the actual information fractions at the time of the 
DSMB interim analysis.   The DSMB charter will detail the review of safety, efficacy 
data and the futility analyses.  The study is designed to show the NI of TR-701 FA 
 
 
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versus linezolid in ACM within 28 days after randomization in the ITT Analysis Set.  A 
2-sided 95% confidence interval (CI) for the difference in proportions for ACM rate 
will be calculated.  TR-701 FA will be considered NI to linezolid if the lower limit of 
the 2-sided 95% CI around the difference is greater than minus 10%.  Secondary 
efficacy analyses will be conducted to support the efficacy findings of the primary 
outcome.  For the secondary outcome of 28-day ACM in the Micro-ITT Analysis Set, a 
2-sided 95% CI for the difference in proportions for ACM will be calculated.  For the 
secondary outcome measure of clinical response at TOC in the ITT and CE Analysis 
Sets, the risk difference in cure rates will be determined, and a 2-sided 95% CI and a 
2-sided 97.5% CI will be calculated (method of Miettinen and Nurminen).  The 
difference in proportions for 28-day ACM (TR-701 FA versus linezolid) in patients 
with MSSA and MRSA will also be determined and a 95% CI will be calculated.  The 
risk difference in favorable microbiological response rates at EOT in the ITT and ME-1 
Analysis Sets and at TOC in the ITT and ME-2 Analysis Sets will be determined and a 
95% CI will be calculated.  The risk difference in cure rates based on the Investigators 
assessment of clinical response at TOC in patients with MSSA and MRSA will also be 
determined and a 95% CI will be calculated.
Additional efficacy analyses will be conducted to support the efficacy findings of the 
primary and secondary outcomes but no formal conclusions of NI will be made.  For 
other outcomes, descriptive statistics including the number and percentage will be 
provided and 2-sided 95% CIs for the risk difference will be determined (Miettinen and 
Nurminen).  Descriptive statistics (mean, standard deviation, median, minimum and 
maximum) will be used for continuous variables.
The incidence of treatment-emergent AEs will be presented by system organ class and 
preferred term for each treatment group according to the Medical Dictionary of 
Regulatory Activities, relationship to study drug, and severity in the Safety Analysis 
Set.  Descriptive statistics of clinical laboratory results (hematology and chemistry), 
vital sign measurements, and the change from Baseline will be presented, as will a 
summary of laboratory values classified based on Division of Microbiology and 
Infectious Disease (National Institute of Allergy and Infectious Disease, Department of 
Health and Human Services, United States) toxicity scale.
 
 
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TABLE OF CONTENTS
INVESTIGATOR’S AGREEMENT..................................................................................... 2
SYNOPSIS .............................................................................................................................. 3
TABLE OF CONTENTS ..................................................................................................... 10
LIST OF TABLES ................................................................................................................ 14
LIST OF FIGURES .............................................................................................................. 15
SUMMARY OF CHANGES................................................................................................ 16
ABBREVIATIONS............................................................................................................... 17
1.0
INTRODUCTION AND RATIONALE.................................................................. 20
Relevant Nonclinical Findings ............................................................................. 21
1.1
Relevant Clinical Findings ................................................................................... 23
1.2
Safety Precautions for TR-701 FA ...................................................................... 25
1.3
Potential Side Effects.......................................................................................... 25
1.3.1
Unknown Risks................................................................................................... 25
1.3.2
Safety Precautions for Patients Treated with Serotonergic Agents Prior to 
1.4
Randomization ...................................................................................................... 26
Study Design Rationale ........................................................................................ 26
1.5
2.0
STUDY OBJECTIVES............................................................................................. 28
Primary Objectives............................................................................................... 28
2.1
Secondary Objectives ........................................................................................... 28
2.2
Exploratory Objectives......................................................................................... 28
2.3
Outcomes ............................................................................................................... 29
2.4
3.0
INVESTIGATIONAL PLAN .................................................................................. 30
4.0
POPULATION.......................................................................................................... 32
Selection and Withdrawal of Patients................................................................. 32
4.1
Inclusion Criteria.................................................................................................. 32
4.2
Exclusion Criteria................................................................................................. 34
4.3
 
 
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Patient Withdrawal from the Study.................................................................... 36
4.4
Discontinuation of Treatment.............................................................................. 36
4.5
Study Discontinuation .......................................................................................... 37
4.6
Prohibited Medications ........................................................................................ 37
4.7
5.0
STUDY TREATMENT ............................................................................................ 38
Description of Study Drug ................................................................................... 38
5.1
TR-701 FA.......................................................................................................... 38
5.1.1
Linezolid ............................................................................................................. 38
5.1.2
Adjunctive Therapy ............................................................................................ 38
5.1.3
Packaging, Labeling, and Storage....................................................................... 38
5.2
Dose, Blinding, and Administration.................................................................... 39
5.3
Dose .................................................................................................................... 39
5.3.1
Blinding............................................................................................................... 39
5.3.2
Administration .................................................................................................... 39
5.3.3
Method of Assigning Patient to Study Treatment ............................................. 44
5.4
Maintaining the Randomization Codes and Breaking the Study Blind .......... 44
5.5
Measures of Treatment Compliance ................................................................... 45
5.6
Study Drug Accountability and Retention ......................................................... 45
5.7
6.0
DESCRIPTION OF STUDY PROCEDURES ....................................................... 46
Screening................................................................................................................ 46
6.1
Study Day 1............................................................................................................ 50
6.2
Study Day 2............................................................................................................ 51
6.3
Study Day 3............................................................................................................ 52
6.4
Study Days 4 to 10 for Nonbacteremic Patients; Study Days 4 to 14 for 
6.5
Gram-positive Bacteremic Patients..................................................................... 54
End of Therapy Visit (EOT; up to 3 days after last study drug infusion)....... 56
6.6
Test of Cure Visit (7 to 14 days after last study drug infusion or at time of 
6.7
failure).................................................................................................................... 59
Late Follow-Up Visit (28 to 32 days after randomization)................................ 61
6.8
7.0
PHARMACOKINETIC ANALYSIS ...................................................................... 64
 
 
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8.0
EFFICACY................................................................................................................ 65
Assessment of Efficacy – Response Definitions.................................................. 65
8.1
All-Cause Mortality ............................................................................................ 65
8.1.1
Investigator’s Assessment of Clinical Response ................................................ 65
8.1.2
Microbiologic Response Definitions.................................................................... 67
8.2
9.0
SAFETY..................................................................................................................... 69
Definition of Adverse Events ............................................................................... 69
9.1
Reporting Period for Adverse Events ................................................................. 71
9.1.1
Severity of Adverse Events................................................................................. 72
9.1.2
Relationship of Adverse Events to Study Drug .................................................. 72
9.1.3
Reporting Serious Adverse Events...................................................................... 73
9.2
Adverse Events Requiring Additional Information .......................................... 73
9.3
Follow-Up of Adverse Events............................................................................... 74
9.4
Pregnancy .............................................................................................................. 74
9.5
Overdose of TR-701 or TR-701 FA..................................................................... 74
9.6
10.0
STATISTICAL METHODS .................................................................................... 75
Sample Size............................................................................................................ 75
10.1
Analysis Sets .......................................................................................................... 76
10.2
Process for Determining Inclusion in Analysis Sets........................................... 77
10.2.1
General Statistical Considerations ...................................................................... 78
10.3
Patient Population and Characteristics .............................................................. 78
10.4
Efficacy Analysis................................................................................................... 79
10.5
Primary Efficacy Analysis .................................................................................. 79
10.5.1
Additional Analyses of the Primary Efficacy Outcome .............................. 79
10.5.1.1
Secondary Efficacy Analyses.............................................................................. 80
10.5.2
Additional Efficacy Analyses ............................................................................. 81
10.5.3
Safety Analysis ...................................................................................................... 82
10.6
Adverse Events ................................................................................................... 82
10.6.1
Laboratory Evaluations....................................................................................... 82
10.6.2
Additional Safety ................................................................................................ 83
10.6.3
 
 
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Interim Analysis.................................................................................................. 83
10.6.4
Monitoring Committees ...................................................................................... 83
10.6.5
Handling of Missing Data..................................................................................... 84
10.7
11.0
ADMINISTRATIVE CONSIDERATIONS ........................................................... 85
Ethical Conduct of the Study............................................................................... 85
11.1
Institutional Review Board/Ethics Committee................................................... 85
11.2
Informed Consent ................................................................................................. 85
11.3
Confidentiality....................................................................................................... 86
11.4
Patient Confidentiality ........................................................................................ 86
11.4.1
Confidentiality of Investigator Information........................................................ 87
11.4.2
Confidentiality of IRB/IEC Information............................................................. 87
11.4.3
Compliance with Financial Disclosure Requirements....................................... 87
11.5
Case Report Forms and Study Records.............................................................. 87
11.6
Protocol Deviations............................................................................................... 88
11.7
Data Quality Assurance........................................................................................ 88
11.8
Investigator Requirements................................................................................... 89
11.9
Sponsor Requirements ......................................................................................... 89
11.10
Study Monitoring......................................................................................... 89
11.10.1
Study Auditing............................................................................................. 89
11.10.2
Designation of Coordinating Investigator.................................................... 89
11.10.3
Retention of Data .................................................................................................. 90
11.11
Compliance with Trial Registration and Results Posting Requirements ........ 90
11.12
Publication Policy and Disclosure Policy............................................................ 90
11.13
12.0
REFERENCES.......................................................................................................... 92
13.0
APPENDICES........................................................................................................... 95
 
 
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LIST OF TABLES
Table 1.
Daily Dose Schedule by Treatment Group.......................................................... 42
Table 2.
Daily Dose Schedule by Treatment Group:  Patients with Gram-positive 
Bacteremia........................................................................................................... 43
Table 3.
Screening Samples for Safety Laboratory Assessments ..................................... 47
Table 4.
Screening Samples for Microbiology Assessments ............................................ 49
Table 5.
Day 2 Samples for Microbiology Assessments................................................... 51
Table 6.
Day 3 Samples for Microbiology Assessments................................................... 53
Table 7.
Day 7 and Day 10 (and Day 14 for bacteremic patients only) Samples for 
Safety Laboratory Assessments........................................................................... 54
Table 8.
Days 4 to 10 (Days 4 to 14 for gram-positive bacteremic patients) Samples 
for Microbiology Assessments............................................................................ 55
Table 9.
End of Therapy Samples for Safety Laboratory Assessments ............................ 57
Table 10.
End of Therapy Samples for Microbiology Assessments ................................... 58
Table 11.
Test of Cure Samples for Safety Laboratory Assessments ................................. 60
Table 12.
Test of Cure Samples for Microbiology Assessments ........................................ 61
Table 13.
Late Follow-Up Samples for Safety Laboratory Assessments............................ 62
Table 14.
Late Follow-Up Samples for Microbiology Assessments................................... 63
Table 15.
Investigator’s Assessment of Clinical Response - Definitions at the EOT and 
TOC Visits........................................................................................................... 66
Table 16.
Investigator’s Assessment of Clinical Response - Definitions at the LFU 
Visit ..................................................................................................................... 67
Table 17.
Microbiologic Response Definitions................................................................... 68
Table 18.
Sample Size and Power for the Primary and Secondary Efficacy Outcomes ..... 75
 
 
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LIST OF FIGURES
Figure 1.
Study Schema for Study TR701-132 .................................................................. 31
Figure 2.
Infusion Schema.................................................................................................. 41
Figure 3.
Overview of the Analysis Sets............................................................................ 77
 
 
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SUMMARY OF CHANGES
PRIMARY REASONS FOR THIS AMENDMENT:
Section 
Number(s)
Section Title(s)
Description of Changes
Rationale
Synopsis,
2.0
Objectives,
Study Objectives
Added text explaining that the efficacy and 
safety of TR-701 FA in patients with sepsis 
will be evaluated under this Japan-specific 
amendment.
To evaluate the efficacy and safety of TR-
701 FA in patients with sepsis.
Appendix 12
Assessment Plan of 
Sepsis
Added the Assessment Plan of Sepsis.
To describe the plan for assessment of sepsis.
 
 
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ABBREVIATIONS
Abbreviation
Definition
ABG
arterial blood gas
ABSSSI
acute bacterial skin and skin structure infection
ACM
all-cause mortality
AE
adverse event
ALT
alanine aminotransferase
AM
alveolar macrophages
APACHE
Acute Physiology and Chronic Health Evaluation
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
BAL
bronchoalveolar lavage
BCRP
breast cancer resistant protein
BSA
body surface area
CBA
colistin base activity
CBC
complete blood count
CLcr
creatinine clearance
CE
clinically evaluable
cfr
chloramphenicol-florfenicol resistance 
CFR
Code of Federal Regulations
CI
confidence interval
CPIS
Clinical Pulmonary Infection Score
CSR
clinical study report
CT
computed tomography
CVVH
continuous venovenous hemofiltration 
CVVHD
continuous venovenous hemodialysis
DSMB
Data and Safety Monitoring Board
EC
Ethics Committee
ECG
electrocardiogram
e-CRF
electronic case report form
ELF
epithelial lining fluid
EMA
European Medicines Agency
EOT
end of therapy
ERT
Evaluability Review Team
EU
European Union
FiO2
fraction of inspired oxygen
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
GCP
Good Clinical Practice
HABP
hospital-acquired bacterial pneumonia
 
 
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Abbreviation
Definition
HAP
hospital-acquired pneumonia
hCG
beta-human chorionic gonadotropin hormone  
HIV
human immunodeficiency virus
IB
Investigator’s brochure
ICF
Informed Consent Form
ICH
International Council on Harmonisation
IND
Investigational New Drug
INR
international normalized ratio
IRB
Institutional Review Board
ICU
intensive care unit
IRB
Institutional Review Board
ISI
international sensitivity index of a tissue factor (for calculating INR)
ITT
intent to treat
IVRS
interactive voice response system
IV
intravenous(ly) 
LAR
legally-authorized representative
LRT
Lower respiratory tract
MAOI
monoamine oxidase inhibitor
ME
microbiologically evaluable
MHRA
Medicines and Healthcare Products Regulatory Agency (United Kingdom)
MIC
minimum inhibitory concentration
Micro-ITT
microbiological intent to treat
MRSA
methicillin-resistant Staphylococcus aureus
MSSA
methicillin-susceptible Staphylococcus aureus
NI
noninferiority
NOAEL
no observed adverse effect level
PaO2
partial pressure of oxygen
PCR
polymerase chain reaction
PD
pharmacodynamic
PK
pharmacokinetic(s)
PMN 
polymorphonuclear
PT
prothrombin time
PTT
Partial thromboplastin time
REB
Research Ethics Board
SAE
serious adverse event 
SAP
statistical analysis plan
SAR
suspected adverse reaction
SEC
squamous epithelial cells
SOFA
Sepsis-related Organ Failure Assessment
SRG
Statistics Reporting Group
 
 
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Abbreviation
Definition
TEAE
treatment-emergent adverse event
TFA
Treatment failure approach
TOC
test of cure
ULN
upper limit of normal
WBC
white blood cell
VAP
ventilator-associated pneumonia
VABP
ventilator-associated bacterial pneumonia
VNP
ventilated nosocomial pneumonia
 
 
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1.0 INTRODUCTION AND RATIONALE
Ventilator-associated bacterial pneumonia (VABP) and ventilated hospital-acquired bacterial 
pneumonia (HABP) are collectively termed ventilated nosocomial pneumonia (VNP).  
HABP is defined as an acute infection of the pulmonary parenchyma associated with clinical 
signs and symptoms such as fever or hypothermia, chills, rigors, cough, purulent sputum 
production, chest pain, or dyspnea; accompanied by a new or progressive infiltrate on a chest 
radiograph in a patient hospitalized for more than 48 hours or that develops within 7 days 
after hospital discharge.  VABP is associated with the same clinical syndrome as HABP with 
increased oxygen requirements in patients receiving mechanical ventilation via an 
endotracheal tube for at least 48 hours.  VABP is the leading cause of morbidity and 
mortality in intensive care units (ICUs) with an incidence ranging from 7% to 70% in 
different studies and mortality rates of 20 to 75% according to the study population (Alp 
2006).  Patients with VABP also have longer durations of mechanical ventilation, longer ICU 
stays, and prolonged hospitalization (Alp 2006).
Infections due to gram-positive cocci such as Staphylococcus aureus and particularly 
methicillin-resistant S aureus (MRSA) are common in HABP/VABP; other common 
pathogens include P aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Acinetobacter 
species (ATS Guidelines 2005; Torres 2009).  Currently, there are only 2 agents approved for 
the treatment of MRSA nosocomial pneumonia, vancomycin and linezolid.  In a Phase 4 
post-approval prospective, double-blind, controlled, multicenter study of intravenous (IV) 
linezolid versus vancomycin involving hospitalized adult patients with hospital-acquired or 
healthcare-associated MRSA pneumonia, clinical response at the end of 7 to 14 days of 
treatment in the per protocol analysis set was significantly higher with linezolid than with 
vancomycin but there was no difference in all-cause mortality (ACM) between the 2 agents 
(Wunderink 2012).  Based on the ongoing decline in vancomycin activity in nosocomial 
pneumonia (Pletz 2010), interest in linezolid use has increased as first-line treatment for VNP 
due to MRSA.
The draft Food and Drug Administration (FDA) guidance for clinical study design for the 
HABP/VABP indication was discussed with key stakeholders at public workshops in 
November 2011, reaching consensus on the key elements to support development of new 
treatments for HABP and VABP in the US.  In the European Union, a separate series of 
workshops hosted by the European Medicines Agency (EMA) in 2011 and 2012 led to the 
recent draft Addendum to the Note for Guidance on Evaluation of Medicinal Products 
Indicated for Treatment of Bacterial Infections to Address Indication-specific Clinical Data 
issued in July 2012.  This protocol has been designed to integrate both US and European 
guidance and reflect recent interactions and scientific advice obtained from regulatory 
authorities. While the FDA established 28-day ACM in the Microbiological Intent to Treat 
(ITT) Analysis Set as the primary endpoint with a 1.71 noninferiority (NI) margin for the 
odds ratio (equivalent to a 10% NI margin for the risk difference), the Medicines and 
Healthcare Products Regulatory Agency (MHRA) in the United Kingdom stipulated the clinical 
response at Test of Cure (TOC; 7 to 14 days after the end of therapy [EOT] Visit) as derived 
from the Investigator’s assessment at the EOT and TOC Visits as a primary endpoint with a 
 
 
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12.5% NI margin for the risk difference.  More recently in 2013, FDA agreed with the 
Sponsor to use the Intent to Treat Analysis Set as the primary analysis set for evaluation of 
the primary outcome measure, instead of the microbiological ITT (Micro-ITT) Analysis Set.  
Additionally, the Sponsor met with the EMA in March 2013 and there was agreement on 
overall trial design, including the clinical response at TOC (as derived from the Investigator’s 
assessment at the EOT and TOC Visits) in the ITT and Clinically Evaluable (CE) Analysis 
Sets as the primary outcome for support of registration for the EMA (EMA 2012).  In 
Amendment 4, the Sponsor updated the primary endpoint to support registration for the EU 
to clinical response at TOC (as derived from the Investigator’s assessment at the TOC Visit) 
in the ITT Analysis Set.  According to the current draft of FDA Guidance for Industry 
(HABP and VABP: Developing Drugs for Treatment, May 2014): “The primary efficacy 
analysis should be based on the difference between treatment groups in the proportions of 
success on the primary outcome measure, assessing either non-inferiority or superiority.”  
This protocol reflects this requirement.
TR-701 FA, also known as tedizolid phosphate and MK-1986, is a phosphate prodrug of the 
microbiologically active molecule TR-700 (tedizolid), a protein synthesis inhibitor that has 
potent bactericidal gram-positive activity.  TR-701 FA administered as an IV infusion of 200 
mg once daily for 7 days (or 14 days for gram-positive bacteremia) is predicted to achieve 
systemic and pulmonary levels with a high probability of antimicrobial efficacy against 
clinically relevant gram-positive pathogens in critically ill patients.
Relevant Nonclinical Findings
1.1
Results from relevant nonclinical studies of TR-701, TR-701 FA, and TR-700 are 
summarized in this section.  Further information is provided in the Investigator’s Brochure 
(IB).
Susceptibility testing results from multiple studies of TR-701 demonstrate that overall, TR-
700 is 4- to 16-fold more potent than linezolid against all S aureus, and streptococcal species 
(including penicillin-susceptible and -resistant strains).  The TR-700 MIC90 values for gram-
positive pathogens were 0.25 to 0.5 µg/mL compared with 2 to 4 µg/mL for linezolid.  TR-
700 retained activity against vancomycin-resistant and linezolid-resistant staphylococcal and 
enterococcal clinical isolates.  TR-700 has activity against strains harboring chromosomal 
23S rRNA mutations and strains that contain the chloramphenicol-florfenicol resistance (cfr) 
transposon-borne gene that confers resistance to linezolid.  Additional in vivo efficacy 
studies confirmed the greater potency of TR-700 versus linezolid against linezolid-resistant 
MRSA cfr strain CM/05.  Resistance development to TR-700 was 16-fold lower than to 
linezolid.  TR-700 demonstrated no antagonism or synergy against bacterial isolates with 
other antibacterial and antifungal agents of different classes. In vivo nonclinical studies have 
been conducted to evaluate the antibacterial activity of TR-700 and to determine the 
pharmacokinetic (PK) and pharmacodynamic (PD) parameters correlating with efficacy.  
TR-701 FA demonstrated advantages over linezolid and vancomycin in pulmonary 
penetration and exhibited potent staphylococcal killing.  The key PD target for TR-700 is 
 
 
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free area under the concentration-time curve (AUCfree)/minimum inhibitory concentration 
(MIC).
Once-daily dosing provided the same efficacy as the equivalent dose apportioned into 
multiple equally divided doses (Louie ECCMID 2009).  Drusano and colleagues 
(Drusano 2011) found an enhancement of TR-700 staphylococcal killing in the presence of 
granulocytes in a mouse thigh model on the order of 25-fold compared to a neutropenic 
model.  Lemaire and colleagues (Lemaire 2009) demonstrated that TR-700 penetrates into 
macrophages better than linezolid and kills intracellular staphylococci to a significantly 
greater extent (approximately 15-fold).
Pichereau and colleagues (Pichereau 2009) compared the efficacy of TR-701 to linezolid in a 
neutropenic murine model of staphylococcal pneumonia. Test mice required 4.6- to 5.5-fold 
less TR-701 compared with linezolid (on a mg/kg basis) to produce stasis and a 1-log 
reduction in colony forming units in lung tissue.  The AUCfree/MIC values achieving stasis 
and 1-log kill at 24 hours after TR-701 administration were approximately 10 and 25, 
respectively.  These ratios are considerably lower than observed in the neutropenic thigh 
infection model and may be due to greater partitioning of TR-700 into lung fluids.  Tessier 
and colleagues (Tessier 2012) compared the antibacterial activity and pulmonary epithelial 
lining fluid (ELF) exposures of TR-700, linezolid, and vancomycin in an immunocompetent 
mouse pneumonia model.  Overall, at these human-simulated ELF exposure levels, 
vancomycin resulted in minimal reductions in bacterial counts.  TR-701 and linezolid 
regimens were not statistically different against the 3 MRSA isolates tested, although both 
treatments were significantly different from controls and considered effective.  Vancomycin 
was less protective than either TR-701 or linezolid, with overall survival of 61.1% versus 
94.7% and 89.5%, respectively.  Based on these results, an exposure response relationship 
can be predicted for TR-701.  The human ELF exposure level predicted from the proposed 
dose of TR-701 FA 200 mg IV once daily should be appropriate for treatment of MRSA 
pneumonia.
Population PK analysis and PD simulations have demonstrated that a 200 mg 
human-equivalent TR-701 FA dose corresponding to 165 mg of TR-700 is expected to 
provide maximal killing effect (Louie ICAAC 2009).
In subchronic studies, the primary target organs of TR-701/TR-701 FA toxicity were the 
hematopoietic system in rats and the gastrointestinal system in rats and dogs.  Safety margins 
generated from repeat-dose toxicity studies in rats and dogs for proposed IV and oral human 
doses based on systemic exposure (AUC) were determined.  After IV administration, the 
safety margin to the anticipated therapeutic dose in humans (200 mg) for systemic toxicity is 
5.6- and 3.8-fold in male and female rats, respectively.  In dogs, the safety margin is 3.4- and 
4.4-fold in males and females, respectively.  The no observed adverse effect level (NOAEL) 
for systemic toxicity of TR-701 is 7- to 14-fold greater than linezolid based on the ratio of 
NOAELs established in 1-month toxicology studies in rats and dogs, respectively, relative to 
the recommended oral dose in humans.  Results from comprehensive in vivo and in vitro 
genotoxicity studies indicate little genotoxic risk to humans.  In a fertility study of TR-701 FA 
 
 
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in rats, no effects on either male or female reproductive performance were observed at any dose 
tested.  In addition, no effect on intrauterine survival of embryos or testicular sperm counts was 
observed.
Relevant Clinical Findings
1.2
Pharmacokinetic parameters for TR-700 generally increased linearly and proportionally with 
dose, with low to moderate intersubject variability and low accumulation of approximately 
28% following multiple once-daily oral or IV administrations (TR701-101 and TR701-107).  
Steady-state concentrations are achieved within 3 days in most individuals and plasma 
concentrations achieved with the first dose are similar to steady-state concentrations.
Pharmacokinetic studies have demonstrated that TR-700 rapidly distributes into tissues 
(TR701-119, TR701-102).  Both TR-701 and TR-700 are moderately highly protein bound in 
human plasma (70% to 90%), and binding appeared to be independent of concentration.  
Study TR701-119 examined the steady-state plasma PK and disposition of TR-700 into the 
ELF and alveolar macrophages (AM) of 20 healthy volunteers given TR-701 FA 200 mg 
once daily for 3 days.  The TR-700 penetration ratio into the ELF and AM (ELF or AM 
AUC0-24 compared with the AUC0-24 in plasma, adjusted for protein binding) was 41.2 and 
20.0, respectively.  These results indicate that TR-700 concentrates in the ELF and AM and 
that TR-701 FA 200 mg once daily appears adequate for the treatment of lung infections 
caused by susceptible pathogens.
Results from the Phase 1 Study TR701-107 in healthy volunteers indicate that TR-701 FA 
was well tolerated when administered via peripheral vein as a single administration up to 400 
mg and multiple administrations of 200 mg IV once daily.  A placebo-controlled arm of 
study TR701-107 showed that peripheral administration of IV TR-701 over 3 days showed a 
venous tolerability similar to a placebo regimen.  Results from studies in elderly (TR701-
109) or in subjects with renal impairment (with or without hemodialysis) (TR701-123) or 
hepatic impairment (TR701-124) showed that TR-701 FA was well tolerated with no 
meaningful changes noted in laboratory, vital sign, physical examination, or 
electrocardiogram (ECG) data.  Moreover, these studies have shown that the dosing regimen
does not require adjustment in these patients.  Hence, the 200 mg QD dose can be used in all 
patient populations investigated to date.
In vitro studies evaluated the potential of tedizolid (TR700) and tedizolid phosphate (TR701) 
to inhibit the efflux transporter breast cancer resistant protein (BCRP) in human colorectal 
adenocarcinoma (Caco2) cells (IB).  The BCRP transporters were inhibited at TR701 
concentrations achievable in the intestinal lumen, suggesting that orally administered TR701 
could interact with and raise the AUC of BCRP substrates (eg, rosuvastatin, methotrexate 
and topotecan).  Co-administration of oral TR701 and oral rosuvastatin resulted in a 70% 
increase in AUC values for rosuvastatin.  However, IV TR701 does not reach systemic 
concentrations that could inhibit BCRP (IB).  Because this protocol requires the use of IV 
TR701 and this is an exclusively oral interaction, there is no risk of interaction in this trial.
 
 
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Two pivotal Phase 3 studies, TR701-112 and TR701-113, were NI, global, multicenter, 
randomized, double-blind, double-dummy studies evaluating the efficacy and safety of oral 
(TR701-112) or IV to oral (TR701-113) TR-701 FA 200 mg once daily for 6 days versus oral 
linezolid 600 mg every 12 hours for 10 days for the treatment of acute bacterial skin and skin 
structure infection (ABSSSI) in adult patients.  In TR701-112, 79.5% of patients in the TR-
701 FA group (N=332) and 79.4% in the linezolid group (N=335) were responders at the 
48-72 Hour Visit (ITT Analysis Set).  A total of 85.5% and 86.0% of patients in the TR-701 
FA and linezolid groups, respectively, were considered to be a clinical success based on the 
Investigator’s assessment of clinical response at post-treatment evaluation in the ITT 
Analysis Set.  In TR701-113, 85.2% of patients in the TR-701 FA group (N=332) and 82.6% 
in the linezolid group (N=334) were responders at the 48-72 Hour Visit (ITT Analysis Set).  
A total of 88.0% and 87.7% of patients in the TR-701 FA and linezolid groups, respectively, 
were considered to be a clinical success based on the Investigator’s assessment of clinical 
response at post-treatment evaluation in the ITT Analysis Set (see the IB for additional 
details).  These 2 studies provide evidence that tedizolid phosphate is effective in ABSSSI, a 
moderately severe infection, and is safe and well tolerated by oral or IV route.  Results from 
a multiple-dose 21-day study (TR701-101) of oral 200, 300, or 400 mg TR-701 once daily 
showed that TR-701 was generally well tolerated over the 21-day treatment period; however, 
over time, a higher incidence of adverse events (AEs) at the 400 mg TR-701 dose was noted.  
The most common treatment-emergent adverse events (TEAEs) were generally in the 
Nervous System and Gastrointestinal Disorders system organ class category, including 
headache, nausea, and stomach discomfort.  No remarkable hematologic effects were 
observed at 200 mg TR-701 once daily over 21 days; however, at higher doses of TR-701, 
hematologic effects gradually increased over time and were generally similar between 
subjects receiving 400 mg TR-701 once daily or 600 mg linezolid twice daily.
Taken together, results from these studies support the selection of 200 mg IV TR-701 FA 
once daily for 7 or 14 days in HABP/VABP.
Recent study results indicate that use of continuous venovenous hemofiltration (CVVH) and 
continuous venovenous hemodialysis (CVVHD) results in minimal loss of tedizolid.  The 
amount of drug lost is unlikely to require an adjustment in dose for patients using CVVH or 
CVVHD.  The study, performed at the University of Michigan, included the two most 
common membranes used in CVVH and CVVHD and measured the percent loss of drug at 
different hemofiltration rates.  The findings showed that the rate of removal of tedizolid from 
the blood was low and similar to the amounts observed with normal renal excretion and 
previous testing performed with intermittent hemodialysis which showed decreases of 
approximately 10% (Flanagan 2014).  There was significant loss of tedizolid (approximately 
50%) due to adsorption to the membrane and/or apparatus.  Despite the losses observed in the 
model, the tedizolid losses in humans should not be significant since very little tedizolid is in 
the circulation given its low unbound drug concentrations and high volume of distribution.  
These results have been submitted for presentation at the International Symposium of 
Intensive Care and Emergency Medicine 2015 with journal submission anticipated.
 
 
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In countries where tedizolid (SIVEXTRO) is approved, please consult the local prescribing 
information for additional information.
Safety Precautions for TR-701 FA
1.3
Potential Side Effects 
1.3.1
Integrated AE data from Phase 1 studies indicated that the most common TEAEs were 
infusion site erythema, hematoma, pain, and swelling; vessel puncture site hematoma and 
pain; and headache, nausea, and diarrhea.  Within the peripheral IV administration groups, 
the most common TEAEs included infusion site pain, erythema, and swelling; and vessel 
puncture site hematoma.  Integrated AE data from oral Phase 2 and 3 studies in patients 
indicated that the most common TEAEs were nausea, diarrhea, and vomiting, abscess limb, 
and headache.  In this integrated analysis, the type of AEs reported was similar between the 
TR-701 FA and linezolid groups.  Additional information is provided in the IB.
Information on AEs considered associated with TR-701 FA is presented in an appendix of 
the IB.  Information on the necessary warnings and precautions for use and the known safety 
profiles of linezolid are provided in the package insert (use local brand name prescribing 
information).
Unknown Risks
1.3.2
It is possible that study drug-related AEs that are unknown at this time could occur.  It is also 
unknown whether TR-701 FA will be as efficacious as the comparator treatment.  As
linezolid will be used as a comparator, the safety considerations recommended in the package 
insert will be extended to all patients as a precaution (use local linezolid prescribing 
information).  The linezolid label contains warnings for myelosuppression and C difficile-
associated diarrhea, and also has precautions for lactic acidosis, serotonin syndrome, 
peripheral and optic neuropathy, and convulsions.  Please consult the summary of data and 
guidance for the Investigator in the IB for additional important safety information for TR-701 
FA and the local brand name prescribing information for linezolid.
Because TR-701 and linezolid are in the same class of antibiotic, oxazolidinones, and both 
drugs will be used in a blinded manner in the present study, the safety warnings and 
restrictions of linezolid should extend to TR-701 FA treated patients, as a precaution.  Visual 
effects, peripheral neuropathy, and lactic acidosis have been observed following prolonged 
linezolid therapy, generally after more than 28 days of treatment.  Any such occurrences 
should be carefully monitored in this study.
The risks to the fetus are unknown at this time.  It is also unknown whether TR-700 is 
excreted in breast milk.  Therefore, women who are pregnant or nursing are excluded from 
this clinical study and women of childbearing potential must use appropriate birth control.
 
 
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Safety Precautions for Patients Treated with Serotonergic Agents Prior to 
1.4
Randomization
Serotonin syndrome is a serious, life-threatening condition that has been reported when 
linezolid was coadministered with monoamine oxidase inhibitors (MAOIs) or other 
serotonergic drugs (Appendix 1).  Although the risk is extremely low, with a postmarketing 
review of worldwide data identifying 29 possible cases between 1997-2005 (Lawrence 
2006), the latest linezolid drug safety update 
(http://www.fda.gov/Drugs/DrugSafety/ucm265305.htm#hcp) states that linezolid should 
generally not be given to patients taking serotonergic drugs.  However, life-threatening 
conditions, including nosocomial pneumonia caused by MRSA, may warrant the risk and 
justify the use of linezolid.
With the reduction in vancomycin effectiveness, linezolid is now viewed as the therapy of 
choice for MRSA pneumonia (Wunderink 2012).  Given the rarity of serotonin syndrome, 
linezolid provides a health benefit with little risk of this serious adverse reaction and provides 
an advantage over vancomycin in critically ill patients with unstable hemodynamics or renal 
impairment where drug levels must be monitored.  The current prescribing information for 
linezolid indicates a contraindication for use with MAOIs and a warning and precaution for 
use with serotonergic agents.  For this reason, patients receiving MAOIs within 2 weeks prior 
to randomization are excluded from enrollment and patients taking serotonergic drugs prior 
to randomization must discontinue the drugs during the study.  As indicated in the FDA 
safety update, all patients receiving potentially interacting drugs within 30 days prior to 
randomization will need to be closely monitored for symptoms of central nervous system 
toxicity through the treatment period and for 24 hours following the end of study drug 
therapy.  There is no evidence that TR-701 FA interacts with serotonergic agents; however, 
clinical experience is limited.  Therefore, the same precautions should apply to patients 
receiving either TR-701 FA or linezolid.  Please refer to local linezolid prescribing 
information for additional information.
Study Design Rationale
1.5
This protocol, ventilated pneumonia treatment with tedizolid phosphate and linezolid 
(VITAL), is designed as an NI study to address both FDA and EMA regulatory requirements 
for developing antimicrobial drugs for treatment of HABP/VABP.  The primary efficacy 
outcome for this protocol is defined as 28-day ACM in the ITT Analysis Set, as defined by 
Sorbello et al. (Sorbello 2010).  Clinical response at TOC (derived from the Investigator’s 
assessment at the EOT and TOC Visits) in the ITT Analysis Set will be used as the primary 
outcome for support of registration for the EMA (EMA 2012).  The criteria for efficacy and 
selection of the NI margins in this protocol are also consistent with the draft FDA and EMA 
guidances.  This study provides 7 days of TR-701 FA treatment and 10 days of linezolid 
treatment for VNP, increasing to 14 days of either drug in patients with gram-positive 
bacteremia due to the same pathogen causing VNP.  Treatment duration of TR-701 FA is 
based on results from a study by Chastre et al. (Chastre 2003), who demonstrated that a short 
course of therapy was similar in terms of ACM and relapse/recurrence rates compared to a 
 
 
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15-day course of treatment, except for infections due to nonfermenting gram-negative bacilli.  
Current consensus recommends 7 to 8 days for treatment of uncomplicated hospital-acquired 
pneumonia (HAP) or ventilator-associated pneumonia (VAP) in patients who initially 
received appropriate therapy (ATS Guideline 2005, Torres 2009) and 14 days of therapy for 
patients with uncomplicated bacteremia (Liu 2011). Linezolid is currently approved for first-
line therapy of nosocomial pneumonia due to gram-positive pathogens in adult and 
adolescent patients, with a recommended treatment duration of 10-14 days.
The dosage selected for this study, TR-701 FA 200 mg IV once daily, is predicted to achieve 
adequate systemic and lung exposures resulting in antimicrobial efficacy against gram-
positive bacterial respiratory infections in adult and adolescent patients.  Anticipated 
physiologic changes in critically ill patients (eg, changes in regional blood flow to target and 
clearance organs, plasma protein levels, total body volume changes, and other treatment 
modalities that may impact drug disposition) are not expected to significantly alter TR-700 
kinetics.  This prediction is based on a review of studies investigating nonclinical and clinical 
microbiology, pharmacology, PK, PK/PD and safety/efficacy of TR-701 FA as detailed in 
the IB.  In addition, recent results from a Phase 3 clinical study in adults with ABSSSI have 
provided evidence of efficacy and safety of TR-701 FA 200 mg once daily and support the 
continuation of the development plan in the HABP/VABP indication.
 
 
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2.0 STUDY OBJECTIVES
The study objectives accommodate the unique requirements of different regulatory 
jurisdictions. In addition, the efficacy and safety of TR701-FA in the population of patients 
with sepsis will be evaluated under a Japan-Specific amendment. Further details are provided 
in Appendix 12.
Primary Objectives
2.1
The primary objective is to determine the noninferiority in all-cause mortality within 28 days 
after randomization of intravenous TR-701 FA compared with IV linezolid in the ITT 
Analysis Set in ventilated patients with presumed gram-positive hospital-acquired bacterial 
pneumonia or gram-positive ventilator-associated bacterial pneumonia, collectively defined 
as ventilated nosocomial pneumonia.
Secondary Objectives
2.2
The secondary objectives are as follows:

To compare the ACM observed with TR-701 FA and linezolid within 28 days after 
randomization in the Micro-ITT Analysis Set

To compare the clinical response for TR-701 FA and linezolid treatment at TOC in the 
ITT (EMA and Japan Ministry of Health, Labour, and Welfare primary endpoint) and CE 
Analysis Sets.  Clinical response at TOC is derived from the Investigator’s assessment at 
the EOT and TOC Visits, as detailed in the statistical analysis plan (SAP)

To compare the per-patient favorable microbiological response rate at EOT in the Micro-
ITT and Microbiologically Evaluable (ME)-1 Analysis sets and at TOC in the Micro-ITT 
and ME-2 Analysis Sets

To evaluate the safety profile of TR-701 FA and compare with that of linezolid

To assess the population PK and PK/ PD profile of TR-700
Exploratory Objectives
2.3
Additional efficacy objectives of this study to further characterize any difference between 
treatment groups include the following:

To compare the ACM rates following TR-701 FA and linezolid therapy within 28 days 
after randomization (CE, Microbiologically Evaluable-1 [ME-1], and ME-2 Analysis 
Sets) and 14 days after randomization (ITT, Micro-ITT, and ME-1 Analysis Sets)

To evaluate the activity of study drug as measured by change from baseline in 
procalcitonin level at Day 7 in the ITT and Micro-ITT Analysis Sets
 
 
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
To characterize the plasma concentrations of TR-700 in patients with HABP/VABP, 
including estimation of typical PK parameters (eg, AUC) and inter-individual and 
residual variability 

To estimate the effects in patient-specific covariate factors of TR-700 PK

To provide individual metrics of TR-700 exposure for modeling probabilities of clinical 
cure, microbiologic response, or safety outcomes
Outcomes
2.4
The primary outcome is ACM within 28 days after randomization in the ITT Analysis Set.
Secondary outcomes include the following:

ACM within 28 days after randomization (Micro-ITT Analysis Set) 

Clinical response at TOC (ITT and CE Analysis Sets).  Clinical response at TOC is 
derived from the Investigator’s assessment at the EOT and TOC Visits

Microbiological response at EOT and TOC (Micro-ITT, ME-1, and ME-2 Analysis Sets)

ACM in patients with methicillin-susceptible S aureus (MSSA) or MRSA (Micro-ITT 
Analysis Set)

Clinical response by Investigator in patients with MSSA or MRSA (Micro-ITT and ME-2 
Analysis Sets)
Key exploratory outcome variables to be analyzed include the following:

ACM within 28 days after randomization (CE, ME-1, and ME-2 Analysis Sets)

ACM within 14 days after randomization (ITT, Micro-ITT, CE, and ME-1 Analysis Sets) 

Proportion of patients discharged from the acute care hospital within 28 days after 
randomization (ITT and Micro-ITT Analysis Sets)

Change from baseline in procalcitonin level at Day 7 (ITT Analysis Set)

Per-pathogen clinical response rate at TOC (Micro-ITT, ME-1, and ME-2 Analysis Sets)

Per-pathogen ACM rate at 28 days after randomization (Micro-ITT, and ME-1, ME-2 
Analysis Sets)

Number of days in the ICU through 28 days after randomization (ITT and CE Analysis 
Sets)
Number of days on a ventilator through 28 days after randomization (ITT and CE Analysis 
Set)
 
 
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3.0 INVESTIGATIONAL PLAN
This is a 1:1 ratio, randomized, double-blind, double-dummy, multicenter, global Phase 3 
study of TR-701 FA 200 mg IV once daily for 7 days versus linezolid (Zyvox®, Zyvoxid®, 
etc) 600 mg IV every 12 hours for 10 days for the treatment of ventilated patients with 
presumed gram-positive HABP and VABP.  Patients with concurrent gram-positive 
bacteremia are to receive 14 days of active therapy in either treatment arm.
Cubist (with the exception of the Clinical Drug Supply manager, and the Unblinded Global 
Study team), and the Investigators, study statistician, clinical study personnel, study staff 
participating in patient care or clinical evaluations, and patients will be blinded to therapy 
assignment until the database is locked.  Pharmacy staff or designee, the independent 
Statistics Reporting Group (SRG), and the Data and Safety Monitoring Board (DSMB), will 
be unblinded.  All study drug infusion bags and IV tubing will be covered and sealed with 
tamper-evident material in order to maintain the blind.
Approximately 300 sites will participate in this global study of approximately 
726 randomized patients of which approximately 363 (50%) are expected to have a gram-
positive pathogen isolated based on respiratory culture (Micro-ITT Analysis Set).  Ventilated 
patients with HABP/VABP caused by presumed gram-positive pathogen(s) at baseline as 
determined by positive Gram stain will be randomized 1:1 to study drug treatment using an 
interactive voice response system (IVRS).  Randomization will be stratified by geographic 
region, age (≥65 years or <65 years), and underlying diagnosis (trauma or nontrauma).  A 
minimum of 50% of patients will have a diagnosis of VABP.  Adjunctive therapy for 
appropriate gram-negative coverage will be selected based on Gram stain and site 
epidemiology (see Appendix 4).
The DSMB will be convened when approximately 30% (218 patients), 50% (363 patients), 
and 75% (545 patients) of patients have been randomized and complete 28 days of follow-up.  
A DSMB will review safety and efficacy data including ACM, TEAEs, incidence of serious 
TEAEs, study drug-related TEAEs, and study drug discontinuation due to study drug-related 
TEAEs, and other safety and efficacy related data.  Only data for the first and the second 
interim looks will be unblinded (Treatment A vs Treatment B).  At the first and second 
interim analysis, futility analysis based on the primary efficacy outcome of 28-day ACM in 
the ITT Analysis Set will be performed.  The futility boundaries will be derived from the 
Gamma (-4.27) error spending function (Hwang 1990) and constructed to be nonbinding.  
The futility boundaries will be calculated using the actual information fractions at the time of 
the DSMB interim analysis.  The DSMB charter will detail the review of safety, efficacy data 
and the futility analyses.  The independent SRG will receive the blinded study data from 
Cubist and treatment assignment data directly from the IVRS vendor.  The responsibility of 
SRG will be reviewing, analyzing, and preparing the DSMB interim data reports, including 
tables, listings, and figures, to be reviewed by DSMB members during DSMB meetings.  The 
study is expected to complete enrollment in approximately 58 months and the duration of 
patient participation is up to 33 days (the Screening Visit through the Follow-Up Visit), 
unless a patient is being monitored for an AE.  Patients are to be monitored for all AEs until 
 
 
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the last study visit (ie, 28 to 32 days after randomization).  Serious adverse events (SAEs) are 
to be followed until stabilization, resolution/death, or consent is withdrawn.
A schema showing the study visits is presented in Figure 1.  A more detailed Schedule of 
Study Procedures is provided in Appendix 11.
Figure 1.
Study Schema for Study TR701-132
Screening 
Day 1 Visit
Randomized 1:1 to TR-701 FA or linezolid
Administer study drug
Daily Procedural Visits
Administer study drug
End of Therapy Visit
1 to 3 days after last study drug infusion
Test of Cure Visit
7 to 14 days after last study drug infusion
Late Follow-Up Visit
28 to 32 days after randomization
 
 
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4.0 POPULATION
Selection and Withdrawal of Patients
4.1
Patients who meet the diagnostic criteria and all of the other inclusion criteria and none of the 
exclusion criteria are eligible to participate in this study.
Inclusion Criteria
4.2
Patients who meet all of the following criteria are eligible to participate in this study:
1. Males or females 18 years old
2. Adequate venous access for IV study drug administration
3. Intubated (via endotracheal tube, including tracheostomy patients) and mechanically 
ventilated, AND

For HABP, at least 1 of the following signs or symptoms presenting within 24 
hours prior to intubation of a patient hospitalized, including patients 
institutionalized in long-term care facilities, for ≥48 hours.  If the patient has 
been discharged, discharge must have been within 7 days:
o
A new onset of cough (or worsening of baseline cough)
o
Dyspnea, tachypnea, or respiratory rate >30/minute, particularly if any or all 
of these signs or symptoms are progressive in nature
o
Hypoxemia (eg, a partial pressure of oxygen <60 mm Hg while the patient is 
breathing on room air as determined by arterial blood gas [ABG] or oxygen 
saturation <90% while the patient is breathing on room air as determined by 
pulse oximetry), or worsening (decline from any earlier finding) of the ratio 
of the partial pressure of oxygen to the fraction of inspired oxygen 
(PaO2/FiO2), or respiratory failure requiring mechanical ventilation

For VABP, receiving mechanical ventilation ≥48 hours and at least one of the 
following:
o
Acute changes made in the ventilator support system to enhance 
oxygenation, as determined by ABG, or worsening PaO2/FiO2
o
Hypoxemia (eg, a partial pressure of oxygen less than 60 millimeters of 
mercury while receiving FiO2 of 25-30%, as determined by ABG or 
worsening of the ratio of the partial pressure of oxygen to the fraction of 
inspired oxygen (PaO2/FiO2)
o
New onset or worsening pulmonary symptoms or signs, such as cough, 
asymmetric breath sounds, tachypnea (eg, respiratory rate greater than 25 
breaths per minute), need for increased oxygenation or ventilation support
 
 
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4. Chest radiograph shows the presence of new or progressive infiltrate(s) suggestive 
of bacterial pneumonia (based on Investigator evaluation; report from qualified 
medical professional who is not the Investigator to be provided)
5. Clinical findings to support diagnosis of HABP/VABP

New onset of suctioned respiratory secretions characterized by purulent 
appearance indicative of bacterial pneumonia

And at least 1 of the following:
o
Documented fever (oral ≥38°C [100.4°F] or a tympanic, temporal, rectal, or 
core temperature ≥38.3°C [101°F]) OR
o
Hypothermia (core body temperature ≤35°C [95.2°F]) OR
o
Total peripheral white blood cell (WBC) count ≥10,000 cells/mm3 OR
o
Leukopenia with total WBC ≤4500 cells/mm3 OR
o
≥15% immature neutrophils (bands; if local laboratory has capabilities to 
measure) 
6. High probability of pneumonia caused by gram-positive bacteria only or in a mixed 
infection defined as follows:
Respiratory Sample

Sample acquired and Gram stain performed within 36 hours prior to first infusion 
of study drug using an acceptable purulent respiratory specimen such as sputum 
or endotracheal aspirate sample with <10 squamous epithelial cells (SEC) and 
>25 polymorphonuclear (PMN) cells per low-power field showing gram-positive 
bacteria (with or without gram-negative bacteria) OR

Sample acquired and Gram stain performed within 36 hours prior to first infusion 
of study drug using an acceptable respiratory specimen such as protected 
specimen brush, bronchoalveolar lavage (BAL), mini-BAL, or sample from an 
exudative pleural effusion showing gram-positive bacteria (with or without gram-
negative bacteria) OR

Culture from lower respiratory sample obtained within 72 hours prior to first 
infusion of study drug positive for methicillin-resistant S aureus (MRSA) OR

Rapid molecular diagnostic test (for example Xpert®) positive for MRSA
 
 
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Exclusion Criteria
4.3
Patients who meet any of the following criteria are not eligible to participate in this study:
1. Known or suspected community-acquired bacterial pneumonia or viral, fungal 
(presence of Candida in lower respiratory tract is not exclusionary), or parasitic 
pneumonia
2. Any of the following health conditions:

Legionella infection (Legionella pneumophila pneumonia)

Cystic fibrosis

Human immunodeficiency virus (HIV) infection with last known CD4 count 
<200 cell/mm³ (HIV testing is not required)

Known or suspected Pneumocystis jirovecii pneumonia

Known or suspected active tuberculosis

Lung abscess

Evidence of endocarditis 

Tracheobronchitis (if no evidence of pneumonia)
3. Received systemic or inhaled antibiotic therapy effective for gram-positive 
pathogens that cause VNP for >24 hours (for example, >1 dose of a once-daily 
antibiotic, >2 doses of a twice daily antibiotic) in the last 72 hours
EXCEPTIONS

Progression of disease on the prior antibacterial regimen for this episode of VNP 
after >48 hours of treatment, OR

Patient developed symptoms of pneumonia and a new infiltrate while receiving 
the prior antibacterial regimen for reasons other than the current VNP, OR

Patient received systemic antibacterial therapy that does not cover the 
gram-positive pathogen isolated on respiratory culture, OR 

Antibiotic therapy for gut decontamination or gut motility (example, low-dose 
erythromycin) or C difficile infection 
4. Receipt of monoamine oxidase A and B inhibitors (see Appendix 1) from 2 weeks 
prior to randomized or planned use through the EOT Visit
5. Planned use of agents with serotonergic activity (see Appendix 1 and Section 1.4) 
through the EOT Visit
6. Administration of linezolid or tedizolid phosphate ≤30 days before the first infusion 
of study drug, except for receipt of a single administration of linezolid, within 24 
hours prior to the first administration of study drug to treat the current VNP 
 
 
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7. Bronchial obstruction or a history of post-obstructive pneumonia (this does not 
exclude patients with pneumonia who have underlying chronic obstructive 
pulmonary disease)
8. Primary lung cancer or another malignancy metastatic to the lungs
9. Recent opportunistic infection where the underlying cause of the infection is still 
active (eg, leukemia, transplant, acquired immunodeficiency syndrome)
10. Expected survival <72 hours or any 1 of the following:

Comfort care measures only

Acute respiratory distress syndrome/acute lung injury secondary to septic shock, 
or due to third degree burns or inhalation injury

Nonresolving pulmonary edema secondary to congestive heart failure
11. Burns >40% of total body surface area
12. Current or anticipated neutropenia with absolute neutrophil count <500 cells/mm3
13. Severe renal disease requiring peritoneal dialysis.  Patients with severe renal disease 
on hemodialysis, venovenous dialysis, or other forms of renal filtration may be 
enrolled
14. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 10× upper 
limit of normal OR severe hepatic disease with Child-Pugh score >9
15. Investigator’s opinion of clinically significant ECG finding such as ischemia, 
infarct, or ventricular arrhythmia with immediate potential for a fatal outcome, or, 
prior to the current infection, a history of New York Heart Association Class IV 
cardiac failure defined as severe limitations - experiences symptoms even while at 
rest, mostly bedbound patients, within 1 year
16. Patients with uncontrolled hypertension (defined as high blood pressure that is 
clinically an issue and uncontrolled on multiple medications), pheochromocytoma, 
carcinoid syndrome, or thyrotoxicosis
17. Treatment with investigational medicinal product ≤30 days before the first infusion 
of study drug or prior randomization in this protocol
18. Investigational device present, or removed <30 days before the first infusion of 
study drug or presence of device-related infection
19. Hypersensitivity to oxazolidinones (eg, linezolid) or any component in the 
formulation
20. Women who are pregnant or nursing, or who are of childbearing potential and 
unwilling to use an acceptable method of birth control (eg, intrauterine device, 
double-barrier method [eg, condoms, diaphragm, or cervical cap with spermicidal 
foam, cream or gel], or male partner sterilization); excluding women ≥2 years 
postmenopausal or surgically sterile
 
 
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Patient Withdrawal from the Study
4.4
Patients may withdraw or be withdrawn from the study at any time.  Patients may be 
discontinued from the study at the request of the Investigator or Cubist.  Reasonable efforts 
are to be made to complete all protocol-specified assessments listed for the EOT Visit at the 
time of withdrawal (Section 6.6) and to perform follow-up safety assessments as specified in 
Section 6.8 at the protocol-defined time points.  The safety assessments at the EOT Visit are 
to be completed before beginning new antibiotic therapy.  Patients who withdraw or are 
withdrawn will not be replaced.
Discontinuation of Treatment
4.5
Reasons for discontinuation of study drug include, but are not limited to, the following:

Patient or legally authorized representative requests discontinuation of the study drug or 
withdrawal from the study

Unacceptable toxicity
In the case of unacceptable toxicity leading to consideration of study drug discontinuation, 
the Medical Monitor is to be consulted immediately for additional advice regarding patient 
management and data collection requirements.

AEs or laboratory changes considered clinically relevant, documented to be worsening 
from the Screening Visit on repeat testing, and considered to be at least possibly related 
to study drug; eg, anemia or hemoglobin <8 g/dL, thrombocytopenia or platelet count 
<50,000 plts/mm3, leukopenia/neutropenia or total WBC count ≤1000 cells/mm3 or 
absolute neutrophil count ≤500 cells/mm3, or pancytopenia

Evidence of new or worsening hepatic function during study treatment, ie, ALT or AST 
≥3× upper limit of normal (ULN) with either elevated total bilirubin ≥2× ULN or 
international normalized ratio (INR) >1.5 or AST/ALT >3× ULN with the appearance of 
right upper quadrant pain or tenderness, or peripheral eosinophilia (>5%), rash, and/or 
fever.  Study drug is to be discontinued and serum ALT, AST, alkaline phosphatase, and 
total bilirubin and/or INR testing are to be repeated at 48 to 72 hours after discontinuation 
of study drug and until medically stable (FDA Guidance, Drug-Induced Liver Injury 
2009)

Evidence of optic neuropathy (AEs including new or worsening visual impairment not 
explained by an alternative cause, such as persistent and/or worsening blurred vision, 
visual field cut, color blindness, or reduction in light perception).  Development of optic 
neuropathy should prompt a consultation with an ophthalmologist.  Investigators are 
strongly recommended to have patients consult with a neurologist as appropriate

Evidence of serious peripheral neuropathy or serious cranial neuropathy (eg, facial nerve 
palsy) not explained by an alternative cause.  Development of serious peripheral 
neuropathy or serious cranial neuropathy should prompt a consultation with a neurologist 
(if appropriate) who will decide whether an electromyogram and/or nerve conduction 
studies are appropriate
 
 
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
Patient becomes pregnant 

Investigator-assessed treatment failure (patient should receive rescue therapy following 
Investigator’s judgment)

Investigator considers a change of therapy would be in the best interest of the patient
Patients MAY be discontinued from the study if culture results from the respiratory sample 
taken at the Screening Visit shows either only gram-negative bacteria OR gram-positive 
bacteria that is below the prospective site-specific and respiratory specimen-specific 
quantitative threshold (sites may use either qualitative results or thresholds).  Prior to 
discontinuation, Investigators should consider the initial Gram stain result and the timing of 
antibiotic therapy in relation to respiratory sample acquisition.  In some instances, prior 
antibiotic use may affect culture results if administered prior to sample acquisition.
Study Discontinuation
4.6
Cubist reserves the option to terminate the study at any time.  Reasons for terminating the 
study or terminating the participation of a specific site include, but are not limited to, the 
following:

The incidence or severity of AEs in this or other studies with the study drug indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory

Data recording is inaccurate or incomplete

The Investigator does not adhere to the protocol or applicable regulatory guidelines in 
conducting the study

The Institutional Review Board (IRB)/Ethics Committee (EC)/Research Ethics Board 
(REB) decides to terminate or suspend approval for the study or the Investigator

The Investigator asks to withdraw from study participation
Prohibited Medications
4.7
Receipt of MAOIs is prohibited in the 2 weeks prior to randomization through the EOT Visit 
(see Appendix 1).  Receipt of the following medications is prohibited between the first study 
drug infusion through the EOT Visit: serotonergic agents including antidepressants such as 
SSRIs, tricyclic antidepressants, and serotonin 5-HT1 receptor agonists (triptans), meperidine 
(or other phenylpiperidines), or buspirone.  Considerations should be made to use alternatives 
to meperidine.
 
 
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5.0 STUDY TREATMENT
Description of Study Drug
5.1
TR-701 FA
5.1.1
TR-701 FA is formulated as a sterile lyophilized powder for injection for IV administration.  
TR-701 FA for Injection, 200 mg, is formulated with TR-701 FA, mannitol, and sodium 
hydroxide that are lyophilized in a 10 mL clear glass vial with a 20 mm gray butyl stopper, 
and a 20 mm seal with flip-off top.  The resulting drug product is a white to off-white cake 
that results in a clear, colorless to light-yellow solution after reconstitution.  
The vial should be reconstituted with 4 mL of Sterile Water for Injection and added to a 
250 mL IV bag containing 0.9% Sodium Chloride Injection, USP for IV administration.  
Study drug should be prepared by qualified clinical staff following directions provided in the 
Pharmacy Manual. 
TR-701 FA for Injection is manufactured according to Good Manufacturing Practice.  
Additional information is provided in the Pharmacy Manual.
Placebo for TR-701 FA for Injection, 200 mg, is a sterile saline solution in a 250 mL infusion 
bag.
Linezolid
5.1.2
Linezolid IV Injection (300 mL bag), 600 mg, a marketed ready-to-use product, is supplied 
by Cubist, a designee, or the site if approved by the Sponsor, and blinded by the site.
Placebo for Linezolid IV Injection is a sterile saline solution in a 300 mL infusion bag.
Adjunctive Therapy
5.1.3
Refer to Appendix 4 for information on adjunctive therapy.  Adjunctive therapy will be 
supplied by the site unless otherwise approved by Cubist.  Local prescribing guidance is to be 
followed regarding use of specific adjunctive therapy.
Packaging, Labeling, and Storage
5.2
A lyophilized vial of TR-701 FA for Injection, 200 mg (50 mg/mL) is to be prepared by 
qualified clinical staff following directions provided in the Pharmacy Manual.
TR-701 FA for Injection, 200 mg, should be stored at 20 to 25°C (68°F to 77°F); excursions 
are permitted to 15°C and 30°C (59°F to 86°F).  The study drug should be administered 
within 12 hours after reconstitution.
All medication (linezolid and adjunctive therapy) is to be stored according to the instructions 
in the package insert.
 
 
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The unblinding procedures are described in Section 5.5.
Dose, Blinding, and Administration
5.3
Dose
5.3.1
Patients will receive IV TR-701 FA 200 mg once daily for 7 days or IV linezolid 600 mg 
twice daily for 10 days.  If the patient has gram-positive bacteremia (see Appendix 5 for the 
list of pathogens), treatment duration for either study drug is 14 days.  Bacteremia is defined 
as 1 positive blood culture for S aureus, Streptococcus pneumoniae, or Streptococcus 
pyogenes, or 2 positive blood cultures for any other gram-positive lung pathogen.
Blinding
5.3.2
All infusion bags will be sealed with tamper-evident material.  Cubist (with the exception of 
the Clinical Drug Supply manager and Unblinded Global Study team), and the Investigator, 
study staff participating in direct patient care or clinical evaluations (study drug 
administration, efficacy and safety measurements, etc) and patients will be blinded to 
treatment assignment.  The staff responsible for IV study drug preparation will be unblinded 
to treatment and will prepare all infusion bags and attached tubing.  The unblinded pharmacy 
staff or designee are responsible for ensuring that a current record of inventory and drug 
accountability is maintained.  A designated unblinded study monitor will be responsible for 
verifying drug accountability at the sites.  Infusion bags will be returned to a secure location 
accessible only to staff unblinded to treatment, unless otherwise approved by Cubist.  
Detailed information on means of blinding of the infusion bags and tubing is included in the 
Pharmacy Manual.  Additionally, a DSMB will review unblinded safety and efficacy data.
Administration
5.3.3
Flush IV line before and after study drug administration.  No other IV therapy should be 
administered through the same lumen concurrent with the study drug.
Patients will receive 10 days of study drug administration, some of which may be placebo 
administration, or if the patient has gram-positive bacteremia, 14 days of active study drug.  
Bacteremia is defined as 1 positive blood culture for S aureus, Streptococcus pneumoniae, or 
Streptococcus pyogenes, or 2 positive blood cultures for any other gram-positive lung 
pathogen.  Personnel who are blinded to treatment are to notify the pharmacy staff or 
designee if blood cultures from the Screening Visit are positive, and the patient requires 
extended therapy (14 days).  Patients will receive 3 infusions daily.  The daily study drug 
administration schedule for patients without bacteremia is presented in Table 1 and with 
bacteremia in Table 2.
The entire contents of the infusion bag will be administered.  All infusions will be 
60±10 minutes and start and stop time will be recorded in the source documents and e-CRFs.  
Each odd-numbered IV dose (through dose 13 or 27, see Table 1 and Table 2) will consist of 
2 separate and serial infusions:  Infusion A will be administered over 60 minutes 
 
 
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(±10 minutes) and followed by a saline line flush, and then Infusion B will be administered
over 60 minutes (±10 minutes).  As shown in Table 1 and Table 2, Infusion A will always be 
active TR-701 FA or placebo TR-701 FA and Infusion B will always be active linezolid or 
placebo linezolid.  An infusion schema is provided in Figure 2. 
Doses should be given every 12 hours ± 2 hours from start of Infusion A of odd numbered 
dose (eg, Dose 1) to next even numbered dose (eg, Dose 2).  Initiate gram-negative therapy at 
Study Day 1 and continue according to Investigator’s judgment.  Gram-negative adjunctive 
therapy will be administered to all patients based on initial Gram stain results or a rapid 
diagnostic test, patients and site epidemiology, and then adjusted by the Investigator based on 
the results of the microbiology assessments (see Appendix 5).
 
 
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Figure 2.
Infusion Schema
 
 
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Table 1.
Daily Dose Schedule by Treatment Group
Dose
TR-701 FA (TR) Group 
Linezolid (LZ) Group 
Dose 1 
Infusion A:  Active TR
Infusion B:  Placebo LZ
Infusion A:  Placebo TR
Infusion B:  Active LZ
Dose 2
Placebo LZ
Active LZ
Dose 3
Infusion A:  Active TR
Infusion B:  Placebo LZ
Infusion A:  Placebo TR
Infusion B:  Active LZ
Dose 4
Placebo LZ
Active LZ
Dose 5
Infusion A:  Active TR
Infusion B:  Placebo LZ
Infusion A:  Placebo TR
Infusion B:  Active LZ
Dose 6
Placebo LZ
Active LZ
Dose 7
Infusion A:  Active TR
Infusion B:  Placebo LZ
Infusion A:  Placebo TR
Infusion B:  Active LZ
Dose 8
Placebo LZ
Active LZ
Dose 9
Infusion A:  Active TR
Infusion B:  Placebo LZ
Infusion A:  Placebo TR
Infusion B:  Active LZ
Dose 10
Placebo LZ
Active LZ
Dose 11
Infusion A:  Active TR
Infusion B:  Placebo LZ
Infusion A:  Placebo TR
Infusion B:  Active LZ
Dose 12
Placebo LZ
Active LZ
Dose 13
Infusion A:  Active TR
Infusion B:  Placebo LZ
Infusion A:  Placebo TR
Infusion B:  Active LZ
Dose 14
Placebo LZ
Active LZ
Dose 15
Placebo LZ
Active LZ
Dose 16
Placebo LZ
Active LZ
Dose 17
Placebo LZ
Active LZ
Dose 18
Placebo LZ
Active LZ
Dose 19
Placebo LZ
Active LZ
Dose 20
Placebo LZ
Active LZ
Abbreviations:  LZ=linezolid infusion bag (300 mL); TR=TR-701 FA infusion bag (250 mL).
Note:  Shading represents treatment days with active study drug.
 
 
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Table 2.
Daily Dose Schedule by Treatment Group: 
Patients with Gram-positive
Bacteremia
Dose
TR-701 FA (TR) Group 
Linezolid (LZ) Group 
Dose 1 
Infusion A:  Active TR
Infusion B:  Placebo LZ
Infusion A:  Placebo TR
Infusion B:  Active LZ
Dose 2
Placebo LZ
Active LZ
Dose 3
Infusion A:  Active TR
Infusion B:  Placebo LZ
Infusion A:  Placebo TR
Infusion B:  Active LZ
Dose 4
Placebo LZ
Active LZ
Dose 5
Infusion A:  Active TR
Infusion B:  Placebo LZ
Infusion A:  Placebo TR
Infusion B:  Active LZ
Dose 6
Placebo LZ
Active LZ
Dose 7
Infusion A:  Active TR
Infusion B:  Placebo LZ
Infusion A:  Placebo TR
Infusion B:  Active LZ
Dose 8
Placebo LZ
Active LZ
Dose 9
Infusion A:  Active TR
Infusion B:  Placebo LZ
Infusion A:  Placebo TR
Infusion B:  Active LZ
Dose 10
Placebo LZ
Active LZ
Dose 11
Infusion A:  Active TR
Infusion B:  Placebo LZ
Infusion A:  Placebo TR
Infusion B:  Active LZ
Dose 12
Placebo LZ
Active LZ
Dose 13
Infusion A:  Active TR
Infusion B:  Placebo LZ
Infusion A:  Placebo TR
Infusion B:  Active LZ
Dose 14
Placebo LZ
Active LZ
Dose 15
Infusion A:  Active TR
Infusion B:  Placebo LZ
Infusion A:  Placebo TR
Infusion B:  Active LZ
Dose 16
Placebo LZ
Active LZ
Dose 17
Infusion A:  Active TR
Infusion B:  Placebo LZ
Infusion A:  Placebo TR
Infusion B:  Active LZ
Dose 18
Placebo LZ
Active LZ
 
 
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Dose
TR-701 FA (TR) Group 
Linezolid (LZ) Group 
Dose 19
Infusion A:  Active TR
Infusion B:  Placebo LZ
Infusion A:  Placebo TR
Infusion B:  Active LZ
Dose 20
Placebo LZ
Active LZ
Dose 21
Infusion A:  Active TR
Infusion B:  Placebo LZ
Infusion A:  Placebo TR
Infusion B:  Active LZ
Dose 22
Placebo LZ
Active LZ
Dose 23
Infusion A:  Active TR
Infusion B:  Placebo LZ
Infusion A:  Placebo TR
Infusion B:  Active LZ
Dose 24
Placebo LZ
Active LZ
Dose 25
Infusion A:  Active TR
Infusion B:  Placebo LZ
Infusion A:  Placebo TR
Infusion B:  Active LZ
Dose 26
Placebo LZ
Active LZ
Dose 27
Infusion A:  Active TR
Infusion B:  Placebo LZ
Infusion A:  Placebo TR
Infusion B:  Active LZ
Dose 28
Placebo LZ
Active LZ
Abbreviations:  LZ=linezolid infusion bag (300 mL); TR=TR-701 FA infusion bag (250 mL).
Note:  Shading represents treatment days with active study drug.
Method of Assigning Patient to Study Treatment
5.4
Patients are to be assigned to receive TR-701 FA or linezolid in a 1:1 ratio with stratification 
by geographic region, age (18 to <65 and ≥65 years), and underlying diagnosis (trauma or 
nontrauma based on the most current diagnosis prior to intubation and mechanical 
ventilation) using block randomization via the IVRS.  Patients randomized into the study will 
be assigned the treatment corresponding to the next available number in the respective 
stratum of the computer-generated randomization schedule.
Maintaining the Randomization Codes and Breaking the Study Blind
5.5
Cubist designee (eg, study statistical team, IVRS vendor) will have a designated 
randomization administrator who will maintain the randomization codes in accordance with 
standard operating procedures to ensure the blind is properly maintained, and that only 
Cubist personnel who require knowledge of treatment assignments will be unblinded 
(eg, staff involved in maintaining the randomization codes, unblinded team monitoring study 
drug accountability, or SAE reporting).
 
 
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Investigators are not to break the study treatment blind except when information concerning 
the study drug is necessary for the medical treatment of the patient.  If a medical emergency 
requiring unblinding occurs, the Investigator (or designated physician) is strongly 
encouraged to contact the Regional Medical or Safety Monitor to assess the necessity of 
breaking the study treatment blind.  If unblinding is warranted, the site is to call the IVRS for 
information.  Every effort is to be made to limit study site personnel unblinding to only those 
individuals providing direct care to that patient.  Any intentional or unintentional breaking of 
the blind is to be reported immediately to Cubist.
The other circumstances in which unblinding may be necessary are at the request of a patient 
or the patient’s legally authorized representative in the case of pregnancy during the study or 
for regulatory reporting purposes.  The unblinding procedure outlined above is to be followed 
in the event of a pregnancy (see also Section 9.5).  The procedure for unblinding by Cubist 
for regulatory reporting of an expedited SAE is outlined in Section 9.2 and more details are 
available in the internal safety plan.
After the database is locked and the SAP is final, the study blind codes will be broken.
Measures of Treatment Compliance
5.6
The infusion date and start and stop times will be recorded in the source documents and 
electronic case report form (e-CRF).  In the event of a missed dose, please contact Cubist or 
designee to discuss how to continue therapy.
Study Drug Accountability and Retention
5.7
All TR-701 FA required for completion of this study will be provided by Cubist or Cubist’s 
designee, except saline for injection.  The recipient will acknowledge receipt of the drug 
indicating shipment content and condition.  Damaged supplies will be replaced.  Linezolid IV
is supplied by Cubist, a designee, or the site if approved by the Sponsor.  Accurate records of 
all study drug (TR-701 FA and linezolid) received and dispensed are to be maintained.  
A Study Monitor will be responsible for checking study drug accountability at the study site.  
Inventory records must be available for inspection by Cubist, a designee of Cubist, or the 
FDA at any time.  The Investigator will be responsible for ensuring the study drug is used in 
accordance with this protocol.
Additional information regarding study drug accountability and retention is provided in the 
Pharmacy Manual.
All unused IV materials and packaging are to be retained at the study site until receipt of 
written instruction from Cubist regarding disposition.  All records related to study drug 
supply and disposition are to be maintained by the study site.
 
 
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6.0 DESCRIPTION OF STUDY PROCEDURES
The Schedule of Study Procedures is provided in Appendix 11.
Screening
6.1

Review and obtain informed consent before any study procedures are performed.
The following assessments are to be performed within 24 hours before the first infusion, 
unless otherwise noted:

Record medical and surgical history for the previous 5 years

Perform a directed physical examination

Record prior medications taken ≤30 days before the first infusion

Record height and weight (estimate if necessary)

Record lowest and highest vital signs in the last 24 hours (blood pressure, heart rate, 
respiration rate) 

Record lowest and highest core (or core approximate, such as esophageal, pulmonary 
artery catheter (Swan-Ganz), urinary bladder, or rectal), temporal, or tympanic 
temperature in the last 24 hours 

Perform 12-lead ECG and record Investigator’s interpretation 

In patients who are receiving supplemental O2, determine oxygenation status in the last 
24 hours by documenting the lowest percentage oxygenation saturation by pulse oximetry 
or the lowest PaO2 by ABG if available

Record highest minute ventilation (L/min) and highest FiO2 in the last 24 hours

Determine Acute Physiology and Chronic Health Evaluation (APACHE) II score (if all 
components available, see Appendix 7)

Determine Glasgow Coma Scale score (see Appendix 8)

Collect and document CPIS (Appendix 2) and SOFA (Appendix 3) scores, if data from 
all components are available

Obtain chest x-ray (lateral and posteroanterior or portable when the patient’s condition 
does not permit transport to radiology), performed in supine position if possible.  
Computed tomography (CT) scan is also acceptable.  Perform within 36 hours prior to 
infusion

If the patient is medically able (ie, alert and extubated), perform a neurologic 
examination (including a cranial nerve examination [see Appendix 6] and screening for 
peripheral sensory and motor neuropathy) and a visual acuity examination.
 
 
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
Obtain and send clinical laboratory samples to the local laboratory and, for patients who 
are randomized, also send samples to the central laboratory, as shown in Table 3.
Table 3.
Screening Samples for Safety Laboratory Assessments
Sample
Test
Laboratory
Commentsb
Local
Centrala
Blood
Hematology panel, 
Complete blood count 
(CBC) with differential
×
×
Serum chemistry panel
×
×
Coagulation parameters 
×
Prothrombin time, partial thromboplastin 
time, and international normalized ratio  
Procalcitonin
×
Pregnancy 
×
All females of childbearing potential 
(excludes females who are 2 years 
postmenopausal or surgically sterile)
aSend samples to the central laboratory only for patients who will be randomized.  (Central laboratory 
evaluations will not be performed on patients who fail screening).
bUse local laboratory results for patient eligibility and timely treatment decisions.  A list of laboratory
evaluations is provided in Appendix 9.

Calculate whether the patient’s prothrombin time (PT) is prolonged compared with the 
control PT using the values provided by the local laboratory as follows:

PT prolongation (seconds prolonged) = [insert patient’s PT in sec] – [insert control time in sec]

OR

Calculate the patient’s INR using the patient and control PT values provided by the local 
laboratory and the international sensitivity index (ISI) of a tissue factor as follows:

INR =   (insert patient’s PT in seconds) ISI
             
(insert control PT in seconds)
 
 
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
Calculate the patient’s Child-Pugh score according to the following chart:
Parameter
Points
1
2
3
Ascites
None
Medically controlled
Poorly controlled
Encephalopathy*
None
Medically controlled
Poorly controlled
Total bilirubin (mg/dL)
<2
2 – 3
>3
Albumin (g/dL)
>3.5
2.8 – 3.5
<2.8
INR 
(or PT prolongation in sec)
<1.7
(<4)
1.7 – 2.3
(4 – 6)
>2.3
(>6)
*If sedated, use last known encephalopathy status before sedation

Estimate the patient’s creatinine clearance (CLcr) using the serum creatinine value 
provided by the local laboratory, actual body weight, and the appropriate Cockcroft-Gault 
formula.  If necessary, convert serum creatinine values from µmol/L to mg/dL by 
dividing by 88.4.  For example, 100 µmol/L divided by 88.4 equals 1.131 mg/dL
Males:
CLcr = (140 – [insert age in years]) × [insert weight in kg]
                  72 × [insert serum creatinine in mg/dL]
Females: 
CLcr = 0.85 × (140 – [insert age in years]) × [insert weight in kg]
                              72 × [insert serum creatinine in mg/dL]

Document any rapid diagnostic test or polymerase chain reaction (PCR) respiratory 
sample results if done at admission and/or within 72 hours prior to screening.  Document 
the most recent nasal swab since admission to hospital or ICU

Obtain microbiological specimen(s) from blood, urine for Legionella antigen assay, and 
the lower respiratory tract and/or pleural fluid within 36 hours (or if culture positive for 
MRSA within 72 hours) before administration of any antibiotic, if possible, and send to 
the local laboratory; for patients who are randomized, also send isolates to the central 
laboratory as shown in Table 4.  If blood culture is positive for gram-positive pathogen, 
extend treatment to 14 days
 
 
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Table 4.
Screening Samples for Microbiology Assessments
Screening Samples for Microbiology 
Assessments
Laboratory
Comments
Local
Centrala
Lower respiratory tract (LRT) 
specimen or pleural fluid 
specimen, unless there is isolation 
of MRSA from the LRT in the 72 
hours prior to 
screening/enrollment
All samples must be collected via valid sampling 
technique: sputum or endotracheal aspirate (with 
<10 squamous epithelial cells [SEC] and >25 
polymorphonuclear [PMN] cells per low-power 
field), protected specimen brush, BAL, and mini-
BAL, or exudative pleural effusion.
Quantitative cultures are recommended but not 
required.  Any quantitative or semiquantitative 
results are to be entered into the e-CRF.
Gram 
stain, 
culture, 
and 
susceptibility testing
×
Local susceptibility testing of oxacillin on S
aureus isolates is required.
Isolates from local laboratory 
culture 
for 
confirmation 
of 
identification and susceptibility 
testing
×
All isolates from the local laboratory culture are to 
be sent to the central laboratory except for those 
listed as never a pathogen in Appendix 5.
Blood Cultures
From each of 2 different veins or vascular access 
catheters, collect 1 vial for aerobic testing and 
1 for anaerobic testing (if available) from each 
vein for a total of 4 vials.  If anaerobic testing is 
not available at the site, collect only 1 vial for 
aerobic testing from each vein for a total of 2 vials
Gram stain (optional), culture, 
and susceptibility testing
×
Send all vials to same local laboratory
Isolates from blood culture for 
confirmation of identification and 
susceptibility testing
×
All isolates from a local laboratory culture are to 
be sent to the central laboratory
If positive, repeat within 24 hours
Urine 
Legionella pneumophila antigen
×
If positive, patient should not be randomized
aSend samples to the central laboratory only for patients who will be randomized.  (Central laboratory 
evaluations will not be performed on patients who fail screening).

Record any pretreatment AEs

Verify patient meets inclusion and exclusion criteria
 
 
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Study Day 1
6.2
Study Day 1 is defined as the calendar day on which the first infusion is administered.

If original consent was provided by someone other than the patient, the patient must be 
re-consented at any time during the study should he/she become medically able to do so.

Once Investigator has determined that the patient is eligible for entry into the study, 
randomize the patient using the IVRS as close to administration of the first infusion of 
study drug as possible

If the patient is medically able (ie, alert and extubated), perform a neurologic 
examination (including a cranial nerve examination [see Appendix 6] and screening for 
peripheral sensory and motor neuropathy) and a visual acuity examination.

Administer study drug Dose 1 as 2 separate and serial 60-minute infusions (±10 minutes).  
Initiate Infusion A, flush the line, and then initiate Infusion B  

Record any medications received after study drug administration and reason for use

Record lowest and highest vital signs (blood pressure, heart rate, respiration rate) 
obtained on the calendar day (Note:  Perform only if Day 1 is different calendar day from 
Screening)

Record lowest and highest core (or core approximate, such as esophageal, pulmonary 
artery catheter (Swan-Ganz), urinary bladder, or rectal), temporal, or tympanic 
temperature obtained on the calendar day (Note:  Perform only if Day 1 is different 
calendar day from Screening)

In patients who are receiving supplemental O2, determine oxygenation status in the last 
24 hours by documenting the lowest percentage oxygenation saturation by pulse oximetry 
or the lowest PaO2 by ABG if available.  (Note:  Perform only if Day 1 is different 
calendar day from Screening)

Select gram-negative adjunctive therapy as needed (see Appendix 4)

If approved by ethics and/or local regulatory authorities, collect 1 blood sample for 
PK analysis between 5 and 80 minutes after the completion of Dose 1, Infusion A, and 1 
sample between 4 and 12 hours after the completion of Dose 1, Infusion A; 
see Appendix 10 

Record any pretreatment AEs 

Record treatment-emergent adverse events (TEAEs) including any local reactions that 
develop during or after the infusion; document procedures performed due to an AE 

Document hospitalization status and ventilator status
 
 
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Study Day 2
6.3

If original consent was provided by someone other than the patient, the patient must be 
re-consented at any time during the study should he/she become medically able to do so.

If the patient is medically able (ie, alert and extubated), perform a neurologic 
examination (including a cranial nerve examination [see Appendix 6] and screening for 
peripheral sensory and motor neuropathy) and a visual acuity examination.

Record any new concomitant medication and the reason for its use

Record the daily lowest and highest temperature while the patient is hospitalized and 
receiving IV study drug therapy

Record lowest and highest vital signs obtained on the calendar day (blood pressure, heart 
rate, respiration rate) 

Perform directed physical examination

In patients who are receiving supplemental O2, determine oxygenation status in the last 
24 hours by documenting the lowest percentage oxygenation saturation by pulse oximetry 
or the lowest PaO2 by ABG if available

Record highest minute ventilation (L/min) and highest FiO2 obtained on the calendar day

If clinically indicated (see Section 8.2), obtain microbiological specimen(s) from the 
lower respiratory tract and/or pleural fluid, send to the local laboratory and send isolates 
to the central laboratory as shown in Table 5
Table 5.
Day 2 Samples for Microbiology Assessments
Sample
Test
Laboratory
Comments
Local
Central
Lower respiratory tract specimen or 
pleural 
fluid 
specimen 
(if clinically indicated, such as 
increased 
purulence, 
fever, 
expansion of the infiltrate on the 
x-ray, increased minute ventilation, 
etc.)
All samples must be collected via valid 
sampling 
technique:
sputum
or 
endotracheal aspirate (with <10 SEC and 
>25 PMN cells per low-power field), 
protected specimen brush, BAL, and mini-
BAL, or exudative pleural effusion.
Quantitative cultures are recommended but 
not required.  
Any quantitative or 
semiquantitative results are to be entered 
into the e-CRF.
Gram stain (optional), culture, and 
susceptibility testing
×
Local susceptibility testing of oxacillin on 
S aureus isolates is required.
Isolates 
from 
local 
laboratory 
culture 
for 
confirmation 
of 
identification 
and 
susceptibility 
testing
×
All isolates from the local laboratory 
culture are to be sent to the central 
laboratory, for samples collected on study 
drug dosing days, except for those listed as 
never a pathogen in Appendix 5.
 
 
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
Re-evaluate selection of adjunctive therapy based on microbiology and susceptibility 
results

Administer study drug

Assess any ongoing or new AEs including any local reactions that develop during or after 
the infusion; document procedures performed due to an AE

Document hospitalization status and ventilator status
Study Day 3
6.4

If original consent was provided by someone other than the patient, the patient must be 
re-consented at any time during the study should he/she become medically able to do so.

If the patient is medically able (ie, alert and extubated), perform a neurologic 
examination (including a cranial nerve examination [see Appendix 6] and screening for 
peripheral sensory and motor neuropathy) and a visual acuity examination.

Record any new concomitant medication and the reason for its use

Record the lowest and highest temperature obtained on the calendar day while the patient 
is hospitalized and receiving IV study drug therapy

Record lowest and highest vital signs (blood pressure, heart rate, respiration rate) 
obtained on the calendar day

Determine Glasgow Coma Scale score (see Appendix 8)

Perform directed physical examination

In patients who are receiving supplemental O2, determine oxygenation status in the last 
24 hours by documenting the lowest percentage oxygenation saturation by pulse oximetry 
or the lowest PaO2 by ABG if available.

Record highest minute ventilation (L/min) and highest FiO2 if patient remains ventilated

If clinically indicated (see Section 8.2), obtain microbiological specimen(s) from blood 
and/or the lower respiratory tract/or pleural fluid.  Send specimens to the local laboratory 
and isolates to the central laboratory as shown in Table 6.
 
 
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Table 6.
Day 3 Samples for Microbiology Assessments
Sample
Test
Laboratory
Comments
Local
Central
Lower respiratory tract specimen 
or pleural fluid specimen (if 
clinically 
indicated, 
such 
as 
increased 
purulence, 
fever, 
expansion of the infiltrate on the 
x-ray, increased minute ventilation, 
etc.)
All samples must be collected via valid sampling 
technique: sputum or endotracheal aspirate (with 
<10 SEC and >25 PMN cells per low-power 
field), protected specimen brush, BAL, and mini-
BAL, or exudative pleural effusion.
Quantitative cultures are recommended but not 
required.  Any quantitative or semiquantitative 
results are to be entered into the e-CRF.
Gram stain (optional), culture, and 
susceptibility testing
×
Local susceptibility testing of oxacillin on 
S aureus isolates is required.
Isolates from local laboratory 
culture 
for 
confirmation 
of 
identification and susceptibility 
testing
×
All isolates from the local laboratory culture are to 
be sent to the central laboratory except for those 
listed as never a pathogen in Appendix 5.
Blood 
Cultures 
(if 
clinically 
indicated)
From each of 2 different veins or vascular access 
catheters, collect 1 vial for aerobic testing and 
1 for anaerobic testing (if available) from each 
vein for a total of 4 vials.  If anaerobic testing is 
not available at the site, collect only 1 vial for 
aerobic testing from each vein for a total of 2 vials
Gram stain (optional), culture, 
and susceptibility testing
×
Send all vials to same local laboratory
Isolates from blood culture for 
confirmation of identification and 
susceptibility testing
×
All isolates from a local laboratory culture are to 
be sent to the central laboratory, for samples 
collected on study drug dosing days, except for 
those listed as never a pathogen in Appendix 5.
If blood culture is positive, repeat within 24 hours

Re-evaluate selection of adjunctive therapy and adjust according to microbiology and 
susceptibility results (Appendix 4)

Administer study drug

Assess any ongoing or new AEs including any local reactions that develop during or after 
the infusion; document procedures performed due to an AE

Document hospitalization status and ventilator status
 
 
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Study Days 4 to 10 for Nonbacteremic Patients; Study Days 4 to 14 for Gram-
6.5
positive Bacteremic Patients

If original consent was provided by someone other than the patient, the patient must be 
re-consented at any time during the study should he/she become medically able to do so.

If the patient is medically able (ie, alert and extubated) on any Study Day, perform a 
neurologic examination (including a cranial nerve examination [see Appendix 6] and 
screening for peripheral sensory and motor neuropathy) and a visual acuity examination.

Record any new concomitant medication and the reason for its use

Record the lowest and highest temperature obtained on the calendar day while the patient 
is hospitalized and receiving IV study drug therapy

Record lowest and highest vital signs (blood pressure, heart rate, respiration rate) 
obtained on the calendar day

Determine Glasgow Coma Scale score (see Appendix 8; Day 7 only)

Perform directed physical examination

In patients who are receiving supplemental O2, determine oxygenation status in the last 
24 hours by documenting the lowest percentage oxygenation saturation by pulse oximetry 
or the lowest PaO2 by ABG if available.

Record highest minute ventilation (L/min) and highest FiO2 if patient remains ventilated

Obtain and send clinical laboratory samples to the local and central laboratories on Day 
7, Day 10, and, for bacteremic patients only, on Day 14, as shown in Table 7
Table 7.
Day 7 and Day 10 (and Day 14 for bacteremic patients only) Samples for 
Safety Laboratory Assessments
Sample
Test
Laboratory
Comments
Local
Central
Blood
Hematology, CBC with 
differential
×
Serum chemistry panel
Procalcitonin a
×
×
Repeat test for any previous 
laboratory result of potential 
safety concern 
×
At the Investigator’s discretion; use 
local laboratory results for timely 
patient treatment decisions
aObtain sample on Day 7.
 
 
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
Day 4 or Day 5, and Day 7 only.  Day 4 or Day 5:  obtain blood sample for PK analysis 
before Infusion A (Dose 7 or Dose 9).  Day 7: obtain 3 samples for PK analysis, 2 
samples between 5 and 80 minutes after the completion of Infusion A (Dose 13) and 1 
sample between 4 and 12 hours after the completion of Infusion A (Dose 13); see 
Appendix 10

Obtain microbiological specimen(s) from blood and the lower respiratory tract/or pleural 
fluid, if clinically indicated.  Send specimens to the local laboratory and isolates to the 
central laboratory as shown in Table 8
Table 8.
Days 4 to 10 (Days 4 to 14 for gram-positive bacteremic patients) Samples for 
Microbiology Assessments
Sample
Test
Laboratory
Comments
Local
Central
Lower 
respiratory 
tract 
specimen 
or 
pleural 
fluid 
specimen (if clinically indicated, 
such as increased purulence, fever, 
expansion of the infiltrate on the 
x-ray, increased minute ventilation, 
etc.)
All samples must be collected via valid 
sampling technique: 
sputum or endotracheal 
aspirate (with <10 SEC and >25 PMN cells per 
low-power field), protected specimen brush, 
BAL, and mini-BAL, or exudative pleural 
effusion.
Quantitative cultures are recommended but not 
required.  Any quantitative or semiquantitative 
results are to be entered into the e-CRF.
Gram stain (optional), culture, 
and susceptibility testing
×
Local susceptibility testing of oxacillin on 
S aureus isolates is required.
Isolates from local laboratory 
culture 
for 
confirmation 
of 
identification and susceptibility 
testing
×
All isolates from the local laboratory culture are 
to be sent to the central laboratory except for 
those listed as never a pathogen in Appendix 5.
Blood 
Cultures 
(if 
clinically 
indicated)
From each of 2 different veins or vascular access 
catheters, collect 1 vial for aerobic testing and 
1 for anaerobic testing (if available) from each 
vein for a total of 4 vials.  If anaerobic testing is 
not available at the site, collect only 1 vial for 
aerobic testing from each vein for a total of 2 
vials
Gram stain (optional), culture, 
and susceptibility testing
×
Send all vials to same local laboratory
Isolates from blood culture for 
confirmation of identification 
and susceptibility testing
×
All isolates from a local laboratory culture are to 
be sent to the central laboratory, for samples 
collected on study drug dosing days, except for 
those listed as never a pathogen in Appendix 5.
If blood culture is positive, repeat within 
24 hours
 
 
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
Re-evaluate adjunctive therapy and adjust therapy based on microbiology and 
susceptibility results

Administer study drug

Assess any ongoing or new AEs including any local reactions that develop during or after 
the infusion; document procedures performed due to an AE

Document hospitalization status and ventilator status
End of Therapy Visit (EOT; up to 3 days after last study drug infusion)
6.6
Complete the EOT Visit procedures after infusion is completed for all patients who receive 
any study drug.  The EOT Visit is to occur up to 3 days after last study drug infusion except 
for patients considered a clinical failure, for whom EOT assessments should be completed as 
close to the date of failure as possible, and prior to initiating rescue therapy, if feasible.
Note:  Do not initiate SSRI/MAOI medications until at least 24 hours after the end of the last 
study drug infusion.

If original consent was provided by someone other than the patient, the patient must be 
re-consented at any time during the study should he/she become medically able to do so.

If the patient is medically able (ie, alert and extubated), perform a neurologic 
examination (including a cranial nerve examination [see Appendix 6] and screening for 
peripheral sensory and motor neuropathy) and a visual acuity examination.

Record any new concomitant medication and the reason for its use

Record lowest and highest temperature obtained on the calendar day

Record lowest and highest vital signs (blood pressure, heart rate, respiration rate) 
obtained on the calendar day

Perform directed physical examination

In patients who are receiving supplemental O2, determine oxygenation status in the last 
24 hours by documenting the lowest percentage oxygenation saturation by pulse oximetry 
or the lowest PaO2 by ABG, if available.

Record highest minute ventilation (L/min) and highest FiO2 if patient remains ventilated

Determine Investigator’s Assessment of Clinical Response (See Section 8.1.2 for 
definition)

Obtain and send clinical laboratory samples to the local and central laboratories, as 
shown in Table 9
 
 
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Table 9.
End of Therapy Samples for Safety Laboratory Assessments
Sample
Test
Laboratory
Comments
Local
Central
Blood
Hematology, CBC with 
differential
×
Serum chemistry panel
×
Repeat test for any previous 
laboratory result of potential 
safety concern 
×
At the Investigator’s discretion; use 
local laboratory results for timely 
patient treatment decisions

Obtain microbiological specimen(s) from blood and the lower respiratory tract/or pleural 
fluid if clinically indicated and send to the local laboratory and send isolates to the central 
laboratory as shown in Table 10
Note:  If the Investigator assesses the patient as a treatment failure at any time during study 
therapy, rescue antimicrobial therapy may be initiated at the Investigator’s discretion.  
Microbiologic assessments should be completed prior to initiation of alternative 
antimicrobial therapy when possible.
 
 
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Table 10.
End of Therapy Samples for Microbiology Assessments
Sample
Test
Laboratory
Comments
Local
Central
Lower 
respiratory 
tract 
specimen 
or 
pleural 
fluid 
specimen (if clinically indicated, 
such as increased purulence, fever, 
expansion of the infiltrate on the 
x-ray, increased minute ventilation, 
etc.)
All samples must be collected via valid 
sampling technique: 
sputum or endotracheal 
aspirate (with <10 SEC and >25 PMN cells per 
low-power field), protected specimen brush, 
BAL, and mini-BAL, or exudative pleural 
effusion.
Quantitative cultures are recommended but not 
required.  Any quantitative or semiquantitative 
results are to be entered into the e-CRF.
Gram stain (optional), culture, 
and susceptibility testing
×
Local susceptibility testing of oxacillin on 
S aureus isolates is required.
Isolates from local laboratory 
culture 
for 
confirmation 
of 
identification and susceptibility 
testing
×
All isolates from the local laboratory culture are 
to be sent to the central laboratory except for 
those listed as never a pathogen in Appendix 5. 
Blood 
Cultures 
(if 
clinically 
indicated)
From each of 2 different veins or vascular access 
catheters, collect 1 vial for aerobic testing and 
1 for anaerobic testing (if available) from each 
vein for a total of 4 vials.  If anaerobic testing is 
not available at the site, collect only 1 vial for 
aerobic testing from each vein for a total of 2 
vials
Gram stain (optional), culture, 
and susceptibility testing
×
Send all vials to same local laboratory
Isolates from blood culture for 
confirmation of identification 
and susceptibility testing
×
All isolates from a local laboratory culture are to 
be sent to the central laboratory, for samples 
collected on study drug dosing days, except for 
those listed as never a pathogen in Appendix 5.
If blood culture is positive, repeat within 
24 hours

Assess any ongoing or new AEs including any local reactions that develop during or after 
the infusion; document procedures performed due to an AE

Document hospitalization status and ventilator status
 
 
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Test of Cure Visit (7 to 14 days after last study drug infusion or at time of failure)
6.7
Complete the TOC Visit procedures for all patients who receive any study drug.  For patients 
considered a failure at the EOT Visit, complete procedures for safety follow-up only.  If the 
patient was categorized as a cure at the EOT Visit and has since been recategorized as a 
failure, perform the TOC Visit procedures as soon as possible after the assessment of failure.

If original consent was provided by the someone other than the patient, the patient must 
be re-consented at any time during the study should he/she become medically able to do 
so.

If the patient is medically able (ie, alert and extubated), perform a neurologic 
examination (including a cranial nerve examination [see Appendix 6] and screening for 
peripheral sensory and motor neuropathy) and a visual acuity examination.

Record any new concomitant medication and the reason for its use

If patient remains hospitalized, record lowest and highest temperature obtained on the 
calendar day.  If patient is NOT hospitalized, record temperature 

If patient remains hospitalized, record lowest and highest vital signs obtained on the 
calendar day.  If patient is NOT hospitalized, record vital signs (blood pressure, heart 
rate, respiration rate) 

Perform directed physical examination

In patients who are receiving supplemental O2, determine oxygenation status in the last 
24 hours by documenting the lowest percentage oxygenation saturation by pulse oximetry 
or the lowest PaO2 by ABG if available.

Record highest minute ventilation (L/min) and highest FiO2 if patient remains ventilated

Determine Investigator’s Assessment of Clinical Response (See Section 8.1.2) for 
definition

Obtain and send clinical laboratory samples to the local and central laboratories, as 
shown in Table 11
 
 
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Table 11.
Test of Cure Samples for Safety Laboratory Assessments
Sample
Test
Laboratory
Comments
Local
Central
Blood
Hematology, CBC with 
differential
×
Serum chemistry panel
×
Repeat test for any previous 
laboratory result of potential 
safety concern 
×
At the Investigator’s discretion; use local 
laboratory results for timely patient 
treatment decisions

Obtain microbiological specimen(s) from blood and the lower respiratory tract/or pleural 
fluid if clinically indicated and send to the local laboratory and send isolates to the central 
laboratory as shown in Table 12.
 
 
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Table 12.
Test of Cure Samples for Microbiology Assessments
Sample
Test
Laboratory
Comments
Local
Central
Lower 
respiratory 
tract 
specimen 
or 
pleural 
fluid 
specimen (if clinically indicated, 
such as increased purulence, fever, 
expansion of the infiltrate on the 
x-ray, increased minute ventilation, 
etc.)
All samples must be collected via valid 
sampling technique: 
sputum or endotracheal 
aspirate (with <10 SEC and >25 PMN cells per 
low-power field), protected specimen brush, 
BAL, and mini-BAL, or exudative pleural 
effusion.
Quantitative cultures are recommended but not 
required.  Any quantitative or semiquantitative 
results are to be entered into the e-CRF.
Gram stain (optional), culture, 
and susceptibility testing
×
Local susceptibility testing of oxacillin on 
S aureus isolates is required.
Isolates from local laboratory 
culture 
for 
confirmation 
of 
identification and susceptibility 
testing
×
All isolates from the local laboratory culture are 
to be sent to the central laboratory, for samples 
collected on study drug dosing days, except for 
those listed as never a pathogen in Appendix 5.
Blood 
Cultures 
(if 
clinically 
indicated)
From each of 2 different veins or vascular access 
catheters, collect 1 vial for aerobic testing and 
1 for anaerobic testing (if available) from each 
vein for a total of 4 vials.  If anaerobic testing is 
not available at the site, collect only 1 vial for 
aerobic testing from each vein for a total of 2 
vials
Gram stain (optional), culture, 
and susceptibility testing
×
Send all vials to same local laboratory
Isolates from blood culture for 
confirmation of identification 
and susceptibility testing
×
All isolates from a local laboratory culture are to 
be sent to the central laboratory, for samples 
collected on study drug dosing days, except for 
those listed as never a pathogen in Appendix 5.
If blood culture is positive, repeat within 
24 hours

Assess any ongoing or new AEs; document procedures performed due to an AE
Late Follow-Up Visit (28 to 32 days after randomization)
6.8

If original consent was provided by someone other than the patient, the patient must be 
re-consented at any time during the study should he/she become medically able to do so.

If the patient is medically able (ie, alert and extubated), perform a neurologic 
examination (including a cranial nerve examination [see Appendix 6] and screening for 
peripheral sensory and motor neuropathy) and a visual acuity examination.
 
 
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
Record any new concomitant medication and the reason for its use (only for patients with 
clinical relapse or who require treatment for an AE).

Determine survival status (contact patient and/or legally authorized representative if 
patient has been discharged from the hospital to ascertain if patient is alive or deceased; 
record date and cause[s] of death.  Obtain autopsy report if available.)

Assess for clinical relapse

Assess any ongoing or new AEs

Review laboratory results, and document any new abnormalities or clinically significant 
changes from Day 1

If an on-site follow-up visit is clinically indicated (eg, new or ongoing AEs or laboratory 
findings that require follow-up), or the patient has persistent or recurrent signs or 
symptoms of pneumonia or evidence of any complications, collect lower respiratory tract 
sample (if feasible), blood sample for culture, and/or blood samples for chemistry and 
hematology panels.  Send samples to the local laboratory and central laboratory as shown 
in Table 13 and Table 14.
Table 13.
Late Follow-Up Samples for Safety Laboratory Assessments
Sample
Test
Laboratory
Comments
Local
Central
Blood
Hematology, CBC with 
differential
×
Serum chemistry panel
×
Repeat test for any previous 
laboratory result of potential 
safety concern 
×
At the Investigator’s discretion; use local 
laboratory results for timely patient 
treatment decisions
 
 
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Table 14.
Late Follow-Up Samples for Microbiology Assessments
Sample
Test
Laboratory
Comments
Local
Central
Lower 
respiratory 
tract 
specimen 
or 
pleural 
fluid 
specimen (if clinically indicated, 
such as increased purulence, fever, 
expansion of the infiltrate on the 
x-ray, increased minute ventilation, 
etc.)
All samples must be collected via valid 
sampling technique: 
sputum or endotracheal 
aspirate (with <10 SEC and >25 PMN cells per 
low-power field), protected specimen brush, 
BAL, and mini-BAL, or exudative pleural 
effusion.
Quantitative cultures are recommended but not 
required.  Any quantitative or semiquantitative 
results are to be entered into the e-CRF.
Gram stain (optional), culture, 
and susceptibility testing
×
Local susceptibility testing of oxacillin on 
S aureus isolates is required.
Isolates from local laboratory 
culture 
for 
confirmation 
of 
identification and susceptibility 
testing
×
All isolates from the local laboratory culture are 
to be sent to the central laboratory except for 
those listed as never a pathogen in Appendix 5.
Blood 
Cultures 
(if 
clinically 
indicated)
From each of 2 different veins or vascular access 
catheters, collect 1 vial for aerobic testing and 
1 for anaerobic testing (if available) from each 
vein for a total of 4 vials.  If anaerobic testing is 
not available at the site, collect only 1 vial for 
aerobic testing from each vein for a total of 2 
vials
Gram stain (optional), culture, 
and susceptibility testing
×
Send all vials to same local laboratory
Isolates from blood culture for 
confirmation of identification 
and susceptibility testing
×
All isolates from a local laboratory culture are to 
be sent to the central laboratory, for samples 
collected on study drug dosing days, except for 
those listed as never a pathogen in Appendix 5.
If blood culture
is positive, repeat within 
24 hours
 
 
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7.0 PHARMACOKINETIC ANALYSIS
Unless otherwise approved by Cubist, sites will collect blood samples from all patients for 
pharmacokinetic analysis.  Blood samples are to be collected at the following timepoints for 
TR-700 plasma concentration measurement, and time of blood draw and time of study drug 
administration are to be recorded:

Day 1:  Collect 2 blood samples after completion of Dose 1, Infusion A:
o
1 sample between 5 minutes and 80 minutes after the completion of Dose 1, 
Infusion A
o
1 sample between 4 and 12 hours after the completion of Dose 1, Infusion A

Day 4 or 5: Collect 1 blood sample before Infusion A (Dose 7 or Dose 9)

Day 7: Collect 3 blood samples after the completion of Dose 13 Infusion A:
o
2 samples between 5 and 80 minutes after the completion of Dose 13, Infusion A 
o
1 sample between 4 and 12 hours after the completion of Dose 13, Infusion A 
Two samples are to be collected on Day 1, a single sample on Day 4 or Day 5, and 3 samples 
on Day 7.  One of the 2 samples collected on Day 7 between 5 and 80 minutes will be used in 
an optional exploratory analysis for metabolite identification (to be reported separately).  
Plasma samples will be analyzed for TR-700 concentrations (and optionally TR-701) using a 
validated tandem mass spectrometric assay in patients randomized to receive TR-701 FA 
only.  Analysis for linezolid plasma concentrations in patients randomized to receive 
linezolid will be optional.  Variables to be assessed include maximum plasma concentration, 
AUC, average plasma concentration, and half-life.
Population PK analysis will be conducted and results will be reported separately.
Detailed instructions on collecting and processing blood PK samples are provided in
Appendix 10 and the PK manual.
 
 
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8.0 EFFICACY
Assessment of Efficacy – Response Definitions
8.1
All-Cause Mortality
8.1.1
The primary efficacy outcome is ACM, defined by alive or deceased within 28 days after 
randomization into the clinical study.
Investigator’s Assessment of Clinical Response
8.1.2
Clinical response (cure, failure, or indeterminate) will be determined.  Clinical response at 
TOC (7 to 14 days after the last administration of study drug) is the primary efficacy 
endpoint for the EMA and Japan Ministry of Health, Labour, and Welfare, and a secondary 
endpoint for the FDA and is derived from the Investigator’s assessment at the EOT and TOC 
Visits as detailed in the SAP.
The Investigator will make an assessment of clinical response at the EOT Visit (up to 3 days 
after the last administration of study drug) and the TOC Visit as detailed in Table 15.  
Patients whose disease is progressing or who receive rescue or additional prohibited 
antimicrobial therapy prior to the EOT Visit will be considered a clinical failure at the EOT 
and TOC Visits.  Patients who are a failure at the EOT Visit or who relapse between the EOT 
and TOC Visits and receive antimicrobial therapy will be considered a failure at the TOC 
Visit.
 
 
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Table 15.
Investigator’s Assessment of Clinical Response - Definitions at the EOT and 
TOC Visits
Clinical 
Outcome
Definition
Cure

Complete resolution of most or all of the clinical signs and symptoms of VNP which 
were present at baseline, AND

No new signs/symptoms or complications attributable to VNP, AND

No additional antibiotic therapy administered for VNP or gram-positive bacteremia
except for adjunctive therapy that was given for 14 days, AND

Patient is alive 
Failure

Progression, relapse, or recurrence of new symptoms or complications attributable to 
VNP or gram-positive bacteremia due to the same pathogen isolated at baseline, OR

Lack of resolution (persistence) or insufficient improvement in signs and symptoms 
of VNP which were present at baseline that required new or prolonged antibiotic 
therapy, OR

Patient died of any cause 
Indeterminate
Study data are not available for the evaluation of efficacy for any reason 
including:

Diagnosis of gram-negative VNP with no gram-positive pathogen isolated 
within 5 days after randomization

Lost to follow-up 

Withdrawal of consent 

Insufficient clinical documentation precluding the classification of the 
clinical outcome of VNP

Randomized but did not receive study drug

Extenuating circumstances that preclude the classification of clinical 
outcome of VNP 
The Investigator will make an assessment of clinical response at the LFU Visit using 
definitions provided in Table 16.
 
 
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Table 16.
Investigator’s Assessment of Clinical Response - Definitions at the LFU Visit
Clinical 
Outcome
Definition
Sustained 
Clinical Cure

Complete resolution or marked improvement or return to baseline of all signs, 
AND

Symptoms of pneumonia and improvement or lack of progression of all chest x-
ray abnormalities, such that no additional antibacterial therapy is required for the 
treatment of the current infection
Relapse

Recurrence of signs or symptoms of pneumonia or new radiographic evidence of 
pneumonia or death due to pneumonia or pneumonia-related complications in a 
patient assessed as cured at the TOC visit
Indeterminate
Study data are not available for the evaluation of efficacy for any reason 
including:

Lost to follow-up 

Withdrawal of consent

Death unrelated to pneumonia

Extenuating circumstances that preclude the classification as cure or 
relapse
Microbiologic Response Definitions
8.2
Microbiological response definitions are presented in Table 17.  Note that microbiological 
samples are required only at the Screening Visit.  At subsequent visits, samples are required 
in patients with no improvement or as clinically indicated for worsening respiratory status 
suggesting a treatment failure or new infection, and if respiratory specimens are easily 
accessible.  Patients with an unfavorable microbiologic response (persistence or presumed 
persistence) at the EOT Visit will be assigned an unfavorable microbiological response at 
TOC.  Microbiological response will be determined programmatically based on the data from 
the central laboratory and the Investigator’s assessment of clinical response.
 
 
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Table 17.
Microbiologic Response Definitions
Term
Definition
Eradication
Absence of the baseline pathogen(s)
Presumed 
eradication
No source specimen to culture in a patient assessed as a clinical cure by the 
Investigator
Persistence
Continued presence of the original baseline pathogen(s)
Presumed 
persistence
No source specimen to culture in a patient assessed as a clinical failure by the 
Investigator
Indeterminate
The patient’s clinical response is Indeterminate or there is another circumstance 
that precludes a microbiologic evaluation
Superinfection
Isolation of a new pathogen (not present at baseline) in clinically significant 
quantities from the respiratory tract or bloodstream while the patient is on study 
drug and the patient has worsening or new signs or symptoms of VNP
New infection
Isolation of a new pathogen (not present at baseline) in clinically significant 
quantities from the respiratory tract or bloodstream after the patient 
discontinues/completes study drug and the patient has worsening or new signs 
or symptoms of VNP
Note:  Response is per pathogen and the per-patient outcome is based on all pathogens present at baseline.
 
 
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9.0 SAFETY
Safety will be evaluated through assessment of AEs, vital signs, physical examinations 
including a neurologic examination (Appendix 6), visual acuity examinations, and laboratory 
evaluations (hematology and chemistry; Appendix 9).
Definition of Adverse Events
9.1
Adverse Events
According to 21 Code of Federal Regulations (CFR) 312.32 (a) effective September 2011 
and FDA draft guidance “Safety Reporting Requirements for INDs and BA/BE Studies” 
dated December 2012, an AE is defined as follows:
“Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.”  An AE can be any unfavorable and 
unintended sign (eg, an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a drug, without any judgment about causality.  An AE can 
arise from any use of the drug (eg, off-label use, use in combination with another 
drug) and from any route of administration, formulation, or dose, including an 
overdose.”
Medical conditions present at the Screening Visit are considered medical history, and not 
AEs.  However, any worsening of a pre-existing medical condition during the AE reporting 
period (see Section 9.1.1) is to be reported as an AE.  
Suspected Adverse Reaction
A suspected adverse reaction (SAR) is defined as follows:
“Any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event.  For the purposes of Investigational New Drug (IND) safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which 
means any adverse event caused by a drug.”
Adverse Reaction
An adverse reaction is defined as follows:
“An adverse reaction means any adverse event caused by a drug.  Adverse reactions 
are a subset of all suspected adverse reactions where there is reason to conclude that 
the drug caused the event.”
 
 
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Unexpected
“An adverse event or suspected adverse reaction is considered unexpected if “it is not listed 
in the IB or is not listed at the specificity or severity that has been observed; or, if an IB is not 
required or available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application as amended.  For example, under 
this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the IB 
referred only to elevated hepatic enzymes or hepatitis.  Similarly, cerebral thromboembolism 
and cerebral vasculitis would be unexpected (by virtue of greater severity) if the IB listed 
only cerebral vascular accidents.  ‘Unexpected,’ as used in this definition, also refers to 
adverse events or suspected adverse reactions that are mentioned in the IB as occurring with 
a class of drugs or as anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under investigation.”
Known complications of VNP and mechanical ventilation including pleural effusion, 
empyema, pneumothorax, acute lung injury, acute respiratory distress syndrome, progression 
of VNP, and death unrelated to study drug are considered expected events for this protocol.
Serious
A serious AE is defined as follows:
“An adverse event or suspected 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 AE (Life-threatening refers to a situation in which the patient 
was at risk of death at the time of the event; it does not refer to an event which 
might have caused death if it were more severe)

Inpatient hospitalization or prolongation of existing hospitalization 

A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions

A congenital anomaly/birth defect

Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.”
 
 
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Life-Threatening
“An adverse event or suspected adverse reaction is considered life-threatening if, in the view 
of either the investigator or sponsor, its occurrence places the patient at immediate risk of 
death.  It does not include an adverse event or suspected adverse reaction that, had it occurred 
in a more severe form, might have caused death.”
Pretreatment Adverse Event
A pretreatment event is an untoward medical occurrence in a clinical investigational patient 
on Study Day 1 prior to Dose 1 of study drug; it does not necessarily have any causal
relationship with study participation.  If a patient experiences a worsening or complication of 
a pretreatment condition or AE after receiving Dose 1 of study drug, the worsening or 
complication is to be recorded as a treatment-emergent adverse event (TEAE).  Investigators 
are to ensure that the AE term recorded captures the change in condition (eg, “worsening 
of…”).
Treatment-Emergent Adverse Event
A TEAE is an event that emerges, or a pre-existing event that worsens, any time after the 
patient receives Dose 1 of study drug through the end of the AE reporting period 
(see Section 9.1.1).
Report laboratory test, vital sign, and ECG abnormalities as TEAEs only if the event leads to 
medical intervention (eg, additional concomitant medication, discontinuation of study drug).  
The Investigator is responsible for ensuring that all events occurring during the AE reporting 
period (Section 9.1.1) are reported.  Record the following information for each event:  onset 
and stop dates, duration, severity, seriousness, causality, action taken, and outcome. 
Study center personnel are to ask patients neutral questions when they are assessing the 
patient for AEs (eg, “How are you feeling?” or “Have you noticed any changes in your 
health?”).
Reporting Period for Adverse Events
9.1.1
Collect AEs from Study Day 1 through the Late Follow-Up Visit.  Ongoing AEs will be 
evaluated and documented at the last visit.  Follow ongoing AEs as described in Section 9.4.
 
 
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Severity of Adverse Events
9.1.2
Categorize the severity of each AE as follows:
Severity
Definition
Mild
Minor and does not cause significant discomfort to patient; patient aware of 
symptoms but symptoms easily tolerated without treatment
Moderate
An inconvenience or concern to patient, but patient able to tolerate.  
Treatment of symptom(s) may be needed
Severe
Symptom(s) of a sufficient severity to cause the patient severe discomfort.  
Severity may cause cessation of treatment with the study drug.  Treatment for 
symptom(s) needed
Relationship of Adverse Events to Study Drug
9.1.3
The Investigator will make a determination of the relationship of the AE to the study drug 
using a 4-category scale (not related, possible, probable, or definite) according to the 
definitions below.  Clinical failure, in and of itself, is considered unrelated to the toxicity of 
the study drug and is only related to the lack of efficacy of the study drug.
Category
Definition
Not Related
AE does not follow a reasonable temporal sequence from study drug 
administration and can be reasonably explained by other factors, including 
underlying disease, complications, concomitant drugs, or concurrent treatment
Possible
AE follows a reasonable temporal sequence from the study drug administration 
(including the course after study drug withdrawal) and cannot be excluded as 
possibly being caused by study drug (eg, existence of similar reports attributed 
to the suspected drug and/or its analogues; reactions attributable to the 
pharmacologic effect of the drug), although other factors such as underlying 
disease, complications, concomitant drugs, or concurrent treatment are 
presumable
Probable
AE follows a reasonable temporal sequence from study drug administration 
(including the course after study drug withdrawal) and can be excluded as 
possibly being caused by other factors, such as underlying disease, 
complications, concomitant drugs, or concurrent treatment
Definite
AE follows a reasonable temporal sequence from study drug administration 
(including the course after study drug withdrawal), follows a known or 
hypothesized cause-effect relationship, and (if appropriate) satisfies the 
following:

positive results obtained in drug sensitivity tests

toxic level of the drug present in blood or other body fluids
 
 
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Reporting Serious Adverse Events
9.2
Investigators are to report SAEs to Cubist or designee that occur during the reporting period 
(Section 9.1.1) within 24 hours after becoming aware of the SAE.
The SAE form (both the paper SAE form and the AE eCRF), which is to be completed in 
English and signed by the Investigator (or designee), is to include as much information as 
possible, but at a minimum must contain the following: 

A short description of the event and the reason why the event was categorized as serious

Patient identification number

Investigator’s name

Name of the study drug(s)

Causality assessment
Follow SAEs as described in Section 9.1.1.  The timelines and procedures for follow-up 
reports are the same as those for the initial report.
Cubist or designee will send copies of expedited reports for SAEs that are unexpected and at 
least possibly related to the study treatment to all concerned regulatory authorities and active 
Investigator(s).  The Investigator is responsible for sending reports to the IRBs/ECs/REBs in 
accordance with local and site-specific requirements.
Adverse Events Requiring Additional Information
9.3
Investigators are to report AEs requiring additional information to Cubist or designee that 
occur during the reporting period (Section 9.1.1) only at the request of the Sponsor 
(including, but not limited to, optic neuropathy and peripheral neuropathy or cranial 
neuropathy or other events deemed appropriate by the Medical Monitor).
The additional information form, which is to be completed in English and signed by the 
Investigator (or designee), is to include as much information as possible, but at a minimum 
must contain the following: 

A short description of the event and the reason why the event is being reported

Patient identification number

Investigator’s name

Causality assessment

Results of consultation and diagnostic tests 
 
 
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Follow-Up of Adverse Events
9.4
The Investigator is to follow AEs occurring during the AE reporting period (Section 9.1.1) 
with a clinically appropriate effort.  Patients are to be monitored for all AEs until the last 
study visit (ie, 28 to 32 days after randomization).  SAEs are to be followed using the SAE 
report form until stabilization, resolution/death, or consent is withdrawn.  AEs ongoing at the 
end of the study are to be recorded as ‘ongoing’ on the e-CRF.  Information received after the
subject’s last study contact is to be recorded on the paper SAE form.
Pregnancy
9.5
Instruct patients to notify the Investigator if they become pregnant.  If any patient is found to 
be pregnant during the study, she is to immediately discontinue any Cubist -supplied study 
drug and to have only safety assessments performed.  Report the pregnancy within 24 hours 
as outlined for SAEs in Section 9.2.  Follow reported pregnancies to final outcome, using the 
pregnancy form.  Report the outcome, including any premature termination, to Cubist.  
Follow live births for a minimum of 30 days or until the first well-baby visit.  Additional 
details are available in the internal safety plan.
If the patient gives permission for her primary physician to be informed, the Investigator is to 
notify the patient’s primary physician that she was participating in a clinical study at the time 
she became pregnant, and provide details of the treatment that the patient received.
Overdose of TR-701 or TR-701 FA
9.6
As of November 2016, no known incidents of overdose have occurred.  In Phase 1 clinical 
studies, the highest single oral dose of TR-701 administered was 1200 mg and the highest 
oral multiple dose was 400 mg once daily for 21 days.
The signs and symptoms of overdose in humans are unknown at this time.  In animals, signs 
of acute oral toxicity were alopecia, salivation, and decreased locomotor activity at 
1000 mg/kg in rats and emesis in dogs at 400 mg/kg.
An overdose is defined as deliberate or accidental administration of study drug, to or by a 
study patient, at a dose greater than the total 24-hour dose assigned to that patient according 
to the protocol.  Report signs and symptoms of an overdose, if any, as AEs as outlined in 
Section 9.1.
 
 
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10.0 STATISTICAL METHODS
Sample Size
10.1
The study is designed to show NI in the primary outcome measure of 28-day ACM in the 
ITT Analysis Set and the secondary outcome measure of clinical response (as derived from 
the Investigator’s assessment at the EOT and TOC Visits) in the ITT and CE Analysis Sets.  
Thus, a total of 726 patients will be randomized (ITT Analysis set). 
Analyses of previous studies presented by the FDA (Antibacterial Drugs 2011) indicate that 
the true rate of 28-day ACM is approximately 20% for mechanically-ventilated patients with 
HABP/VABP receiving antibiotics.  To demonstrate the NI of TR-701 FA to linezolid with 
respect to the difference in 28-day ACM rates, using an NI margin of 10%, a sample size of 
726 randomized patients (363 per arm) in the ITT Analysis Set will have 92% power at a 1-
sided significance level of 0.025, assuming a 28-day ACM rate of 20% in both TR-701 FA 
and linezolid arms.  The study is also sufficiently powered for the secondary outcome 
measure of clinical cure at TOC in the ITT and CE Analysis Sets as derived from the 
Investigator’s assessment at the EOT and TOC Visits.  A total of 726 patients will be 
randomized in the ITT Analysis Set, which provides 87% power to show NI assuming a 50% 
clinical success rate and an NI margin of 12.5%.  Data from the linezolid label and the 
Zephyr study (Wunderink 2012) indicate that the clinical cure rate for linezolid is 
approximately 60% in the CE Analysis Set.  If the clinical evaluability rate will be 80%, with 
a 12.5% NI margin, 80% power, a 1-sided alpha=0.0125, and a clinical cure rate of 60% in 
the CE Analysis Set, a total of 580 patients are required in the CE Analysis Set.   The sample 
size, outcome rates, and power for the primary and secondary outcomes are provided in
Table 18.
Table 18.
Sample Size and Power for the Primary and Secondary Efficacy Outcomes
Primary Outcome 
(28-Day ACM)
Secondary Outcome 
(Clinical Response*)
Analysis Set
ITT
ITT
CE
Outcome Rate
20%
50%
60%
Evaluability Rate
NA
NA
80%
Margin
10%
12.5%
12.5%
N
726
726
580
Power
92%
87%
80%
Abbreviations: ACM=all-cause mortality; CE=clinically evaluable; ITT=intent to treat; NA=not 
applicable.
*As derived from the Investigator’s assessment at the EOT and TOC Visits.
 
 
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Analysis Sets
10.2
The Analysis Sets are defined below; additional information is provided in the SAP.
1. ITT Analysis Set:  data from all randomized patients 
2. Safety Analysis Set:  data from all patients in the ITT Analysis Set who received any 
amount of study drug
3. Micro-ITT Analysis Set:  data from all patients in the Safety Analysis Set who have 
gram-positive pathogen(s) confirmed by culture results from a respiratory tract or 
pleural fluid specimen obtained within 36 hours (or if culture positive for MRSA 
within 72 hours) before first administration of study drug, and documented bacterial 
pathogen known to cause VNP (see Appendix 5) against which the investigational 
drug has antibacterial activity
4. ME-1 Analysis Set: data from all patients in the Micro-ITT Analysis Set who did not 
receive an antibiotic (other than study drug) with activity against the baseline 
pathogen received up through 28 days after randomization  
5. ME-2 Analysis Set:  data from all patients in the Micro-ITT Analysis Set who did not 
receive an antibiotic (other than study drug) with activity against the baseline 
pathogen received up through the TOC Visit and also in the CE Analysis Sets
6. CE Analysis Set:  data from all patients in the Safety Analysis Set who had a TOC 
response assessment recorded (if the patient was assessed by the Investigator as a 
clinical failure at the EOT Visit, a response assessment at the TOC Visit is not 
required), had no major confounding events or factors as detailed in the SAP
The relationship between the 6 analysis sets is shown in Figure 3.
 
 
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Figure 3.
Overview of the Analysis Sets
Abbreviations:  TOC=test of cure
Process for Determining Inclusion in Analysis Sets
10.2.1
Inclusion into the ITT and Safety Analysis Sets will be determined programmatically from 
the e-CRF data.  Inclusion into the ME-1, CE, and ME-2 Analysis Sets will be determined 
programmatically from the e-CRF data and the manual review conducted by the Evaluability 
Review Team (ERT) who may review patient data to confirm that analysis set criteria are 
satisfied.  Inclusion into the Micro-ITT Analysis Set will be determined programmatically 
and based on a manual review conducted by the ERT of the respiratory culture data.  The 
ERT will determine whether each isolate is considered a pathogen based on a review of the 
local and central laboratory genus and species identification, central laboratory (or local if 
central data not available) susceptibility data, and other microbiological and clinical data, if 
needed.
Safety Analysis Set
data from patients receiving study drug
Intent-to-Treat (ITT) Analysis Set
data from randomized patients
Microbiological ITT
(micro-ITT) Analysis Set
documented gram-positive pathogen
Microbiologically Evaluable-2 
(ME-2) Analysis Set
data from patients in the CE Analysis 
Set and Micro-ITT Analysis Set with 
no confounding antibiotic use
Clinically Evaluable (CE) Analysis Set
TOC response assessment, no confounding events 
Microbiologically Evaluable-1 
(ME-1) Analysis Set
data from patients in the Micro-ITT 
Analysis Set with no confounding 
antibiotic use
 
 
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General Statistical Considerations
10.3
For analyses of dichotomous endpoints, 2-sided 95% CIs for the difference in proportions 
between TR-701 FA versus linezolid will be calculated.  For negative endpoints, eg, 28-day 
ACM, the difference will be calculated as linezolid minus TR-701 FA; for positive 
endpoints, eg, clinical response at TOC, the difference will be calculated as TR-701 FA 
minus linezolid.  A 2 sided 95% CI will be constructed for the observed difference using the 
method of Miettinen and Nurminen (Miettinen 1985).
For time-to-event endpoints, Kaplan-Meier curves that are stratified by age (≥65 years or <65 
years), underlying diagnosis (trauma or nontrauma admitting diagnosis), and geographic 
region will be produced, along with an overall Kaplan Meier curve.  Comparisons of the 
survival curves between treatment groups will be based on a stratum-adjusted log-rank test.  
Patients who do not have the event outcome recorded will not be excluded from these 
analyses, but will be right-censored as of the patient’s last available evaluation, unless 
otherwise specified.  All tests will be 2-sided and will be conducted at the 0.05 significance 
level.
For time to event endpoints, summaries will include the number of patients, the number of 
patients who achieved the event of interest, the number of patients censored and the quartiles, 
ie, the 25th, 50th (median), and 75th percentiles of the distribution of the event times (in 
days).  A 95% CI will also be provided for the median event times.
Differences between treatment groups for baseline characteristics will be analyzed using 
Fisher’s exact test for dichotomous variables and the Wilcoxon Rank Sum test for ordinal 
variables and continuous variables.
For categorical data, descriptive statistics will consist of frequency and percentage for each 
category and 95% CIs will be constructed around the percentage, when appropriate.  
Descriptive statistics for continuous data will consist of sample size (n), mean, standard 
deviation, median, minimum, and maximum.  Summary tables will be presented by treatment 
groups.  Exploratory analyses may also be performed.  Listings of individual patient’s data 
will be produced.  A comprehensive SAP will be submitted to regulatory authorities prior to 
initiation of the study.
Patient Population and Characteristics
10.4
Enrollment, protocol deviations, and discontinuations from the study drug and the study will 
be summarized by treatment group.  Demographics (age, race, sex), medical and surgical 
history, APACHE II score, SOFA score, CPIS, baseline assessment of the clinical signs and 
symptoms, microbiological assessment, and study drug administration data will also be 
summarized.  Differences between treatment groups will be analyzed using Fisher’s exact 
test for dichotomous variables and the Wilcoxon Rank Sum test for ordinal variables and 
continuous variables.
 
 
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Efficacy Analysis
10.5
For all efficacy analyses, patient data will be analyzed in the group to which the patient was 
randomized.  For the analysis of the primary efficacy outcome, patients who are randomized 
to the wrong stratum will be analyzed in the stratum to which they were randomized.  A 
sensitivity analysis will be conducted in which these patients are analyzed in the stratum with 
which they correctly belong.
Primary Efficacy Analysis
10.5.1
The primary statistical goal of this study is to establish NI of TR-701 FA to linezolid with 
respect to the difference in the Day 28 all-cause mortality rates using a 10% NI margin in the 
ITT population.
The hypotheses for NI are as follows where p1 is the proportion of deceased patients on Day 
28 treated with linezolid and p2 is the proportion of deceased patients on Day 28 treated with 
TR-701 FA:
Null Hypothesis, H0: 
p1 – p2 ≤-10%
Alternative Hypothesis, H1: p1 – p2 >-10%.
A 2-sided 95% CI around the difference (linezolid minus TR-701 FA) in the Day 28 
all-cause mortality rates will be constructed, not adjusting for the stratification factors.  The 
estimated difference in proportions between the 2 groups and the 2-sided 95% CI for the 
difference will be calculated using the method of Miettinen and Nurminen without 
stratification.  TR-701 FA will be considered NI to linezolid if the lower limit of the 2 sided 
95% CI around the difference is greater than minus 10% (D’Agostino 2003).
Additional Analyses of the Primary Efficacy Outcome
10.5.1.1
The primary efficacy outcome will also be assessed across the stratification factors of age 
(≥65 years or <65 years), underlying diagnosis (trauma or nontrauma admitting diagnosis), 
and geographic region.  For each stratum, a 2-sided 95% CI for the treatment difference of 
28-day ACM will be calculated for the ITT Analysis Set.  
A Kaplan-Meier analysis in the ITT Analysis Set of the time to death in days from the date of 
the first administration of study drug will be conducted.  All patients will be monitored until 
the last trial evaluation.  Data from patients whose survival status is not known at the last trial 
evaluation will be censored on the date of last contact.  Mortality will be summarized by 
treatment group using the methodology described in Section 10.3.
Three sensitivity analyses of the primary outcome will be conducted using the ITT Analysis 
Set.  The first analysis will be an adjusted analysis (adjusted for the randomization 
stratification factors) based on the stratification factors to which the patient was randomized 
 
 
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and the second will be an adjusted analysis based on the stratification factors to which the 
patient correctly belongs.  Adjusted 95% CIs will be computed for the difference in 28-day 
ACM rates using the stratified method of Miettinen and Nurminen.  Cochran-Mantel-
Haenszel weights will be used for the stratum weights in the calculation of the CIs.  The third 
sensitivity analysis will consider all patients who are lost to follow-up prior to 28 days as 
alive.  The difference in 28-day ACM will be determined and a 95% CI for the difference 
will be computed.
Secondary Efficacy Analyses
10.5.2
The number and percentage of patients in each treatment group categorized with a clinical 
cure, clinical failure, or indeterminate based on the clinical response as derived from the 
Investigator’s assessment at the EOT and TOC Visits as detailed in the SAP, will be 
determined at TOC for the ITT Analysis Set (EMA and Japan Ministry of Health, Labour, 
and Welfare primary endpoint) and CE Analysis Set (by definition, patients in the CE 
Analysis Set cannot have a response of indeterminate).  In the ITT Analysis Set, patients with 
an indeterminate response are included in the denominator and thus, are essentially 
considered a clinical failure.  Patients categorized as clinical failure at the EOT Visit will be 
considered to have clinical failure at TOC.  A 2-sided 95% CI and a 2-sided 97.5% CI will be 
constructed for the observed difference (TR-701 FA group minus linezolid group) in the 
clinical cure rate using the method of Miettinen and Nurminen without stratification.  
Clinical response as derived from the Investigator’s assessment will also be assessed in those 
patients with a confirmed pathogen of MSSA and MRSA (micro-ITT and ME-2 Analysis 
Sets).  The difference between the treatment groups in the clinical cure rate will be presented 
along with the 2-sided 95% CI for the difference.
A sensitivity analysis of the secondary efficacy outcome of clinical response will be 
conducted whereby adjusted (adjusted for the randomization stratification factors to which 
the patient was randomized) 95% and 97.5% CIs for the difference in clinical cure rate will 
be determined using the stratified method of Miettinen and Nurminen.  Cochran-Mantel-
Haenszel weights will be used for the stratum weights in the calculation of the CIs.
The number and percentage of patients who are alive and deceased at 28 days after 
randomization in the Micro-ITT Analysis Sets will be provided.  Patients who are lost to 
follow-up (ie, are not known to be alive or deceased on Day 28) will be defined as 
indeterminate for the secondary analysis and are included in the denominator for the 
calculation of the 28-day ACM.  Thus, patients with an indeterminate outcome are 
considered deceased for the secondary analysis.  The 28-day ACM rate in each treatment 
group will be reported along with the treatment difference and unadjusted 2-sided 95% CI.  
The 28-day ACM rate will be determined in those patients with a confirmed pathogen of 
MSSA and MRSA.  The number of patients who are alive in each treatment group, the 
treatment difference and the unadjusted 2-sided 95% CI will be provided.
 
 
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The per-patient microbiological response at EOT in the Micro-ITT and ME-1 Analysis Sets 
and at TOC in the Micro-ITT and ME-2 Analysis Sets will be determined to support the 
clinical findings.  Per-patient microbiological response is based on per-pathogen outcomes.  
To have an overall favorable microbiological response, the outcome for each baseline 
pathogen must be favorable.  The number and percentage of patients classified with a 
favorable (eradication and presumed eradication) and unfavorable (persistence and presumed 
persistence) microbiological response will be tabulated for both treatment groups.  A 2-sided 
95% unstratified CI will be constructed for the observed difference in the per-patient 
favorable microbiological response rate between the TR-701 FA and linezolid groups using 
the method of Miettinen and Nurminen.
Two sensitivity analyses of 28-day ACM will be conducted for the Micro-ITT Analysis Set.  
The first analysis will be an adjusted analysis (adjusted for the randomization stratification 
factors) based on the strata to which the patient was randomized.  Adjusted 95% CIs will be 
computed for the treatment difference in 28-day ACM rates using the stratified method of 
Miettinen and Nurminen.  Cochran-Mantel-Haenszel weights will be used for the stratum 
weights in the calculation of the CIs.  The second sensitivity analysis will consider all 
patients who are lost to follow-up prior to 28 days as alive, and a 95% CI for the treatment 
difference will be computed.
The secondary efficacy outcomes of clinical response in the ITT and CE Analysis Sets and 
28-day ACM in the Micro-ITT Analysis Set will also be assessed across the stratification 
factors of age (≥65 years or <65 years), underlying diagnosis (trauma or nontrauma admitting 
diagnosis), and geographic region.  For each stratum, a 2-sided 95% CI for the difference 
(clinical response and 28-day ACM) will be calculated.
Additional Efficacy Analyses
10.5.3
Additional efficacy analyses will be conducted to support the efficacy findings of the primary 
and secondary outcomes.  Confidence intervals will be provided for descriptive purposes as 
indicated below, but no conclusions of NI will be made.
The number and percentage of patients who are alive or deceased at 14 days after 
randomization in the ITT, Micro-ITT, and ME-1 Analysis Sets; and at 28 days after 
randomization in the ME-1 and CE, Analysis Sets will be provided.  Patients who are lost to 
follow-up (ie, are not known to be alive or deceased on Day 14 or Day 28) will be defined as 
indeterminate and are included in the denominator for the calculation of the 14-day ACM and 
28-day ACM rate.  Thus, patients with an indeterminate outcome are considered deceased in 
this analysis.  The unadjusted 2-sided 95% CIs will be computed for the difference in 14-day 
ACM and 28-day ACM rates using the method of Miettinen and Nurminen.
 
 
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Descriptive summaries, including change from baseline, in the clinical findings that support 
the diagnosis of VNP (eg, temperature, WBC count) as well as the respiratory system 
findings will be provided for the ITT and CE Analysis Sets.  The respiratory system findings 
include presence of purulent respiratory secretions, cough, rales, rhonchi and/or bronchial 
breath sounds, respiratory rate and presence of dyspnea, ABG, minute ventilation, and 
PaO2/FiO2 ratio.  Procalcitonin levels and change from baseline to Day 7 will also be 
summarized in the ITT Analysis Set.
The number and percentage of patients in each treatment group with a favorable (eradication 
or presumed eradication) or unfavorable (persistence or presumed persistence) 
microbiological response at EOT and TOC, 28-day ACM, Investigator’ assessment of 
clinical success at TOC, for each baseline pathogen will be tabulated.  Analyses of per-
pathogen microbiological response, per-pathogen 28-day ACM and the per-pathogen clinical 
response will be conducted in those patients with a culture positive pathogen from the Micro-
ITT, ME-1 (for the EOT timepoint), and ME-2 (for the TOC timepoint) Analysis Sets.
Safety Analysis 
10.6
Safety will be assessed through summaries of TEAEs, laboratory evaluations (hematology 
and chemistry), vital signs, and physical examinations.  All safety analyses will be based on 
the Safety Analysis Set, as defined in Section 10.2 and will be summarized for each 
treatment group.  Patients who receive the wrong study drug for their entire course of 
treatment will be analyzed in the group based on the drug received.
Adverse Events
10.6.1
Adverse events will be coded using the Medical Dictionary of Regulatory Activities 
(MedDRA).  Adverse events reported on Day 1 before Dose 1 of study drug is administered 
(pretreatment AEs) will be collected and presented in a listing; no analyses will be 
performed.  Summary tables of TEAEs will be provided.  A TEAE is any AE that newly 
appeared, increased in frequency, or worsened in severity following initiation of study drug.  
The incidence of TEAEs will be tabulated by system organ class and preferred term for each 
treatment group, and by severity and relationship to treatment.  Tables of TEAEs leading to 
study drug discontinuation, death, and all SAEs will be provided.  The AE reporting period is 
defined in Section 9.1.1.
Laboratory Evaluations
10.6.2
Descriptive statistics summarizing central laboratory data (hematology and chemistry) will 
be presented for all study visits.  The change from baseline to each postbaseline visit and to 
the overall worst postbaseline value will also be summarized by treatment group.  Laboratory 
values will be classified according to a modified Division of Microbiology and Infectious 
Diseases Adult Toxicity Scale, November 2007 criteria, and shifts in toxicity grade from 
baseline to postbaseline will be summarized.  Selected laboratory values will also be 
classified as substantially abnormal from normal limits and summary data presented for the 
worst postbaseline value.
 
 
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Additional Safety
10.6.3
Additional safety assessments include vital signs, physical examinations, including a 
neurologic examination (cranial nerve examination and screening for peripheral sensory and 
motor neuropathy) and a visual acuity examination using the Snellen or other similar eye 
chart.  Descriptive statistics of the vital sign parameters will be presented by treatment group 
and study visit, as well as the change from baseline at each study visit.  The percentage of 
abnormalities based on the physical examination including neurological examination, as 
available, will be presented.  Visual acuity scores will be categorized as normal vision, near-
normal vision, moderate low vision, severe low vision, and profound low vision or worse 
than profound low vision (see SAP for definitions) and will be presented by treatment group.
Interim Analysis
10.6.4
Two unblinded interim analyses of safety and efficacy will be conducted.  The interim 
analyses of safety and efficacy will occur when 30% and 50% of the patients in the ITT 
Analysis Set (218 and 363 patients) have been randomized and monitored through Day 28.  
A futility analysis based on the primary efficacy outcome of 28-day ACM will be conducted.  
The futility boundaries will be derived from the Gamma (-4.27) error spending function 
(Hwang 1990) and constructed to be nonbinding.  The futility boundaries will be calculated 
using the actual information fractions at the time of each DSMB interim analysis (as 
indicated in the DSMB charter and SAP).   The DSMB may recommend that the study be 
stopped due to futility.
Monitoring Committees
10.6.5
The DSMB will be convened when approximately 30% (218 patients), 50% (363 patients), 
and 75% (545 patients) of patients have been randomized in the ITT Analysis Set and 
completed 28 days of follow-up.  A DSMB will review safety and efficacy data including 
ACM, treatment-emergent adverse events (TEAEs), incidence of serious TEAEs, study drug-
related TEAEs, and study drug discontinuation due to study drug-related TEAEs and other 
safety and efficacy related data at 30%, 50%, and 75% of patient enrollment.  Only data for 
the first and the second interim looks will be unblinded (Treatment A vs Treatment B).
The DSMB will include at least 4 members:  1 biostatistician and 3 clinicians with relevant 
expertise in critical care medicine, internal medicine, and/or infectious diseases.  The DSMB 
will operate in a fashion consistent with the FDA Guidance for Clinical Trial Sponsors:  
Establishment and Operation of Clinical Trial Data Monitoring Committees (2006).  The 
DSMB may recommend changes to study conduct on the basis of emerging safety 
information to protect the safety and welfare of clinical study patients.  Additional details 
will be provided in the DSMB charter.
 
 
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Handling of Missing Data
10.7
Missing values will not be imputed (except as detailed in the SAP) and only observed values 
will be used in the data analyses and presentations.  For the primary outcome measure, 28-
day ACM, if the patient’s status is unknown or missing at Day 28, the patient will be 
assumed deceased and time to death will be censored at the last study contact.  A sensitivity 
analysis of the primary outcome will be conducted in which patients with a missing status at 
Day 28 are considered to be alive and a time to death analysis will be conducted in which 
data from patients with missing survival status are censored at the last study contact.
For the secondary outcome measure of clinical response as derived from the Investigator’s 
assessment at the EOT and TOC Visits, if the response is unknown or missing, the patient 
will be assigned a response of indeterminate.  For the analysis in the ITT Analysis Set, 
indeterminate responses are included in the denominator and are thus considered failures.  
By definition, patients with an indeterminate response are excluded from the CE Analysis 
Set.  More details will be provided in the SAP.
 
 
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11.0
ADMINISTRATIVE CONSIDERATIONS
Ethical Conduct of the Study
11.1
This study will be conducted in accordance with applicable FDA clinical study regulations 
and guidelines, the International Council on Harmonisation (ICH) Good Clinical Practice 
(GCP) guideline (E6), the Basic Principles of the Declaration of Helsinki 
(http://www.wma.net/en/30publications/10policies/b3/), and the IRB/EC/REB and local legal 
requirements.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
Institutional Review Board/Ethics Committee
11.2
In accordance with 21 CFR 56, the protocol, the Informed Consent Form (ICF), patient 
information sheets, and advertisements (as appropriate) are to be reviewed and approved by 
the IRB/EC/REB.  Cubist will supply relevant material to the Investigator, and the 
Investigator is responsible for submitting the protocol to the IRB/EC/REB for review and 
approval.
The Investigator is to inform the IRB/EC/REB of any subsequent protocol amendment(s).  In 
addition the Investigator is to send any reports of any serious, unexpected AEs that have 
implications for the conduct of the study, as described in Section 9.2.  If requested, the 
Investigator is to permit audits and inspections by Cubist, the IRB/EC/REB, and any 
regulatory authority by providing direct access to source data/documents and ensuring study 
center personnel are available to answer questions.
Informed Consent
11.3
Cubist will review and endorse the draft ICFs before submission to the IRB/EC/REB, and the 
final IRB/EC/REB-approved documents are to be provided to Cubist for regulatory purposes.  
Cubist reserves the right to reject proposed modifications to the ICFs.
The Investigator or a designee is to explain the study and ICF to the patient or the patient’s 
legally-authorized representative (LAR) and answer any questions.  The ICF is to be signed 
by the patient or the patient’s LAR, before any study-related procedures are performed.  A 
copy of the ICF is to be provided to the patient or the patient’s LAR.  In some countries the 
consent may be signed by an authorized designee per local regulations or requirements, 
including but not limited to independent physicians qualified to provide consent for patients 
who are unable to provide consent for themselves.
 
 
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The signed ICF is to remain in each patient’s study file and be available for verification by 
study monitors or authorized regulatory representatives at any time.
Confidentiality
11.4
Patient Confidentiality
11.4.1
The information obtained during the conduct of this clinical study is confidential, and 
disclosure to third parties other than those noted is prohibited.
Information obtained during the conduct of this study is to be collected, processed, and 
transmitted to or for the benefit of Cubist in accordance with applicable law, as discussed 
below.  Information contained therein is to be maintained in accordance with applicable law 
protecting patient privacy and may be inspected by the clinical researcher, the researcher’s 
staff, and Cubist and its representatives to check, process, evaluate, and use the information 
collected during the study.  Processing, evaluation, or use of the information is to be 
performed by a health professional for medical and study purposes and/or by those operating 
under a duty of confidentiality that is equivalent to that of a health professional.  Information 
is to be transmitted and processed as Cubist may direct, including to Cubist and its 
representatives in the United States or elsewhere.  Information obtained from the study is 
likely to be used by Cubist in connection with study drug development, including possible 
filing of regulatory dossiers with governmental authorities for marketing approval, and for 
other pharmaceutical and medical research purposes.  The Investigator is obliged to provide 
Cubist with complete test results and data developed in this study.  This information will be 
disclosed to the FDA/applicable regulatory agencies as deemed necessary by Cubist, or to 
local health authorities as required by law.  Patient-specific information may be provided to 
other appropriate medical personnel only with the patient’s or the patient’s LAR’s 
permission.
Investigators and other research study personnel who process information from the study 
must take appropriate measures to prevent unauthorized or unlawful processing or disclosure 
of data.
To ensure compliance with current Federal Regulations and the ICH GCP E6 guideline, data 
generated by this study including source documentation must be available for inspection 
upon request by representatives of regulatory authorities (FDA, EMA, and national and local 
health authorities), Cubist, and the IRB/EC/REB for each study center.
 
 
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Confidentiality of Investigator Information
11.4.2
The investigator recognizes that certain personal identifying information with respect to the 
investigator, and all subinvestigators and trial site personnel, may be used and disclosed for 
trial management purposes, as part of a regulatory submissions, and as required by law. This 
information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators. By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
11.4.3
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
11.5
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
Case Report Forms and Study Records
11.6
Data will be collected using e-CRFs.  All e-CRF data are to be completed by the study 
coordinator or other designated site personnel.  Data entry, modification, or deletion is to be 
 
 
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recorded automatically in the electronic audit trail.  Data changes are to be clearly indicated 
with a means to locate prior values.
Electronic data entered by the site (including the electronic audit trail) is to be maintained or 
made available at the site in compliance with 21 CFR Part 11 and other applicable retention 
regulations.  Those entering data at the site are responsible for logging into the system using 
their unique identifier and for all actions performed on the system under their identifier, for 
logging off the system when leaving the work station, and for ensuring that their identifier is 
not used by others.  The computerized system is able to generate accurate and complete 
copies of records in paper or electronic form for inspection and review by applicable 
regulatory authorities, the IRB/EC/REB, and auditors or other designees authorized by 
Cubist.
In addition to capturing the user identification as part of the audit trail for data entry, the 
e-CRF allows for application of electronic signatures.  After review of the data in the e-CRF, 
the Investigator is to confirm the validity of each patient’s data by electronic signature.  This 
electronic signature is to be certified as outlined in 21 CFR Part 11.
Cubist will retain the original e-CRF data and audit trail.  An electronic or certified paper 
copy of completed e-CRF data, including query resolution correspondence, will be provided 
to the Investigator at the end of the study.
Protocol Deviations
11.7
Protocol deviations are to be recorded and categorized by type of deviation.  Deviations 
include, but are not limited to, the following:

Enrollment of a patient who did not satisfy the entry criteria

Failure to withdraw a patient who developed withdrawal criteria during the study

Administration of the incorrect dose

Receipt of an excluded concomitant treatment
Data Quality Assurance
11.8
Cubist or designee will perform logic and consistency checks on data entered into the e-CRFs 
to ensure accuracy and completeness.
Training sessions, regular monitoring of Investigators by Cubist or designated personnel, 
distribution of instruction manuals, data verification, cross-checking, and data audits are to 
be performed to ensure the quality of the study data. Investigator meetings and/or on-site 
study initiations are to be performed to prepare Investigators and other study personnel for 
appropriate collection of study data.
 
 
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Investigator Requirements
11.9
Each Investigator is to adhere to GCP guidelines, regulatory guidelines, local laws and 
regulations, and the protocol as detailed in this document.  The Investigator must obtain 
written approval of any changes to the protocol from Cubist prior to seeking approval from 
the IRB/EC/REB.  Each Investigator is responsible for enrolling only patients who meet 
protocol inclusion and exclusion criteria.
The investigator agrees not to seek reimbursement from subjects, their insurance providers, 
or from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Sponsor Requirements
11.10
Study Monitoring
11.10.1
An authorized Cubist representative will conduct study center visits to inspect study data, 
patient’s medical records, ICFs, e-CRFs, and clinical study material storage and 
accountability procedures in accordance with current ICH GCP guidelines and the respective 
national or regulatory government regulations and guidelines.  Monitors will be blinded to 
treatment group but unblinded monitors will support study drug accountability.  The Cubist 
representative will ensure that regulatory documents are complete and monitor protocol 
compliance.  Study-related documentation is to be made available to the Cubist 
representative.
Study Auditing
11.10.2
Cubist personnel or their designee may perform an audit at any time during or after 
completion of the clinical study.  If requested, the Investigator will provide study-related 
documentation to the designated auditor.  In addition, study center personnel will be 
available to answer any questions.  The Investigator will permit authorized representatives of 
Cubist and the respective national or local health authorities to inspect facilities and records 
relevant to this study.
Designation of Coordinating Investigator
11.10.3
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in a n EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
 
 
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trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report ) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (eg, availability of the Protocol/CSR CI 
during the anticipated review process, thorough understanding of clinical trial methods, 
appropriate enrollment of subject cohort, timely achievement of trial milestones).  The 
Protocol CI must be a participating trial investigator.
Retention of Data
11.11
The Investigator will retain records and documents pertaining to the conduct of this study 
including e-CRFs, source documents, ICFs, laboratory test results, and study drug inventory 
records for a period of at least 2 years after the last approval of a marketing application in an 
ICH region and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product.  No study records shall be destroyed without 
prior authorization from Cubist.
Compliance with Trial Registration and Results Posting Requirements
11.12
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. The Sponsor of this trial will review 
this protocol and submit the information necessary to fulfill these requirements.
The Sponsor’s entries are not limited to FDAAA or the EMA clinical trial directive mandated 
trials.  Information posted will allow subjects to identify potentially appropriate trials for 
their disease conditions and pursue participation by calling a central contact number for 
further information on appropriate trial locations and trial site contact information.
The investigator acknowledges that the statutory obligations under FDAAA, the EMA 
clinical trials directive or other locally mandated registries are that of the Sponsor and agrees 
not to submit any information about this trial or its results to those registries.
Publication Policy and Disclosure Policy
11.13
Cubist intends to pursue publication of the results of the study in cooperation with a lead 
Investigator, subject to the terms and conditions of the clinical study agreement between 
Cubist and Investigators.  Cubist approval in writing is required for publication of any data 
subsets.  Final authorship will be determined in accordance with the International Conference 
of Medical Journal Editors definition of authorship (eg, by contributions to study design, 
enrollment, data analysis, and/or interpretation of the results) (http://www.icmje.org/).  
Patient names and other personal data relating to an identified or identifiable patient (such as 
 
 
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photographs, audio, videotapes, or other factors specific to physical, physiological, mental, 
economic, cultural or social identity), may not be disclosed in any publication without prior 
written authorization from Cubist and the patient or the patient’s LAR.
 
 
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12.0 REFERENCES
Alp E, Voss, A. Ventilator associated pneumonia and infection control. Ann Clin Microbiol 
Antimicrob. 2006;5:7.
American Thoracic Society. Infectious Disease Society of America. Guidelines for the 
management of adults with hospital-acquired, ventilator-associated, and healthcare-
associated pneumonia. Am J Respir Crit Care Med. 2005;171(4):388–416.
Chastre J, Wolff M, Fagon JY, et al; for PneumA Trial Group. Comparison of 8 vs 15 days of 
antibiotic therapy for ventilator-associated pneumonia in adults.  JAMA. 2003; 
290(19):2588–2598.
D’Agostino RB, Massaro JM, Sullivan LM. Noninferiority trials: design concepts and issues: 
the encounters of academic consultants in statistics. Statistics in Medicine. 2003;(22):169-83.
Drusano GL, Liu W, Kulawy R, Louie A. Impact of granulocytes on the antimicrobial effect 
of tedizolid in a mouse thigh infection model. Antimicrob Agents Chemother. 
2011;55(11):5300–5305. 
EMA [Internet]. European Medicines Agency. Addendum issued June 2012 [accessed 2013 
October 31]. Addendum to the note for guidance on evaluation of medicinal products 
indicated for treatment of bacterial infections to address indication-specific clinical 
data. Available 
from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/0
7/WC500129443.pdf.
FDA [Internet]. US Food and Drug Administration. Draft guidance; issued November 2010 
[accessed 2013 October 31]. Hospital-acquired bacterial pneumonia and 
ventilator-associated bacterial pneumonia: developing drugs for treatment. Available 
from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G
uidances/UCM234907.pdf.
FDA [Internet]. US Food and Drug Administration. Developing antibacterial drugs for 
hospital-acquired bacterial pneumonia and ventilator-associated bacterial 
pneumonia. Presentation 04 November 2011 [accessed 2013 October 31]. Available 
from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/D
rugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM281975.pdf. 
FDA [Internet.] US Food and Drug Administration. Guidance issued March 2006 [accessed 
2013 October 31]. Establishment and operation of clinical trial data monitoring 
committees. Available 
from: http://www.fda.gov/RegulatoryInformation/Guidances/ucm127069.htm
FDA [Internet]. US Food and Drug Administration. Guidance issued July 2009 [accessed 
2013 October 31]. Drug-induced liver injury: premarketing clinical evaluation. Available 
from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ 
Guidances/UCM174090.pdf.
 
 
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Flanagan S, Minassian SL, Morris D, et al.  Pharmacokinetics of tedizolid in subjects with 
renal or hepatic impairment.  Antimicrob Agents Chemother. 2014;58(11):6471-6476.
Garonzik SM, Li J, Thamlikitkul V, et al. Population Pharmacokinetics of Colistin 
Methanesulfonate and Formed Colistin in Critically Ill Patients from a Multicenter Study 
Provide Dosing Suggestions for Various Categories of Patients. Antimicrob Agents 
Chemother. 2011;55(7): 3284–3294.
Hwang IK, Shih WJ, DeCani JS.  Group sequential designs using a family of type I error 
probability spending functions.  Statistics in Medicine 9:1439-1445, 1990.
Lawrence KR, Adra M, Gillman PK. Serotonin toxicity associated with the use of linezolid: a 
review of postmarketing data. Clin Infect Dis. 2006;42(11):1578-1583.
Lemaire S, Van Bambeke F, Appelbaum PC, Tulkens PM. Cellular pharmacokinetics and 
intracellular activity of torezolid (TR-700): studies with human macrophage (THP-1) and 
endothelial (HUVEC) cell lines. J Antimicrob Chemother. 2009;64(5):1035–1043. 
Lewis SJ, Switaj L, Mueller BA. Tedizolid clearance by in vitro continuous renal 
replacement therapy model. Tedizolid clearance by in vitro continuous renal replacement 
therapy model. Critical Care. 2015;19(Suppl 1):P113.
Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases 
Society of America for the treatment of methicillin-resistant Staphylococcus aureus
infections in adults and children: executive summary. Clin Infect Dis. 2011;52(3):285–292.
Louie A, Fregeau C, Liu W, Conde H, Kulaway R, Drusano GL. Defining the impact of 
granulocytes (G) on the kill of methicillin-resistant Staphylococcus aureus (MRSA) by the 
new oxazolidinone prodrug TR-701. Poster presented at: 49th Annual Interscience 
Conference on Antimicrobial Agents and Chemotherapy (ICAAC); Sep 12-15, 2009; San 
Francisco, CA. 
Louie A, Fregeau C, Liu W, Conde H, Kulawy R, Drusano GL. In vivo pharmacodynamics 
of TR-701, a new oxazolidinone antibiotic, against methicillin-susceptible and methicillin-
resistant Staphylococcus aureus strains [abstract]. Oral presentation at: 19th European 
Congress of Clinical Microbiology and Infectious Diseases (ECCMID); May 16–19, 2009; 
Helsinki, Finland. Abstract O28. 
Miettinen O, Nurminen M. Comparative analysis of two rates. Statistics in Medicine. 
1985;4(2):213-226.
Pichereau S, Bohrmuller J, Marchillo K, Stamstad T, Craig W, Andes D. Comparative 
pharmacodynamics of a novel oxazolidinone, torezolid phosphate (TR-701), against S. 
aureus in a neutropenic murine pneumonia infection model. Poster presented at: 49th 
Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); 
September 12–15, 2009; San Francisco, CA. Abstract A1-1939. 
Pletz MW, Burkhardt O, Welte T. Nosocomial methicillin-resistant Staphylococcus aureus
(MRSA) pneumonia: linezolid or vancomycin? Comparison of pharmacology and 
efficacy. Eur J Med Res. 2010;15(12): 507–513.
 
 
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Sorbello A, Komo S, Valappil T. Noninferiority margin for clinical trials of antibacterial 
drugs for nosocomial pneumonia. Drug Inf J. 2010;44(2):165–176.
Tessier PR, Keel RA, Hagihara M, Crandon JL, Nicolau DP. Comparative in vivo efficacy of 
epithelial lining fluid exposures of tedizolid, linezolid, and vancomycin for methicillin-
resistant Staphylococcus aureus in a mouse pneumonia model. Antimicrob Agents 
Chemother. 2012;56(5):2342–2346.
Torres A, Ewig S, Lode H, Carlet J; for European HAP Working Group. Defining, treating, 
and preventing hospital acquired pneumonia: European perspective. Intensive Care Med. 
2009;35(1):9–29. 
Wunderink RG, Niederman MS, Kollef MH, et al. Linezolid in methicillin-resistant 
Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Clin Infect 
Dis. 2012;54(5):621–629.
Zyvox® U.S. Prescribing Information. New York: Pfizer [revised 2013 May]. Accessed 2013 
October 31. Available from: http://www.pfizer.com/products/product-detail/zyvox
 
 
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13.0
APPENDICES
Appendix 1.
Examples of Prohibited Concomitant Medications
Receipt of MAOIs is prohibited in the 2 weeks prior to randomization through the EOT Visit.
Monoamine Oxidase Inhibitors
Iprindole
Moclobemide
Rasagiline
Iproniazid
Nialamide
Selegiline 
Iproclozide
Opipramol
Toloxatone 
Isocarboxazid
Phenelzine
Tranylcypromin
The following examples of prohibited concomitant medications are not all inclusive and 
should be used as a guide for exclusion from the protocol.
Receipt of the following medications is prohibited between the first study drug infusion 
through the EOT Visit: serotonergic agents including antidepressants such as SSRIs, tricyclic 
antidepressants, and serotonin 5-HT1 receptor agonists (triptans), meperidine (or other 
phenylpiperidines), or buspirone.
Examples
Selective Serotonin Reuptake Inhibitors
Citalopram
Fluoxetine 
Sertraline
Dapoxetine 
Fluvoxamine maleate
Vilazodone
Escitalopram oxalate
Paroxetine
Serotonin Norepinephrine Reuptake Inhibitors
Duloxetine
Desvenlaxifine
Venlafaxine
Tricyclic Antidepressants
Amitriptyline
Doxepin
Protriptyline
Clomipramine
Imipramine
Trimipramine
Desipramine
Lofepramine 
Dosulepin
Nortriptyline
Triptans and other medications with potential serotonergic activity
Amoxapine
Mirtazapine
Trazodone
Bupropion
Naratriptan
Trimeperidine
Buspirone 
Nefazodone
Zolmitriptan
Maprotiline
Rizatriptan
Meperidine
Sumatriptan
 
 
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Appendix 2.
Modified Clinical Pulmonary Infection Score (CPIS) 
The following data will be collected in the case report form in order to calculate the CPIS 
score.
(Adapted from Pugin 2002 and Wunderink 2012a)
Parameter
Criteria
Score
Temperature (ºC) 
>36.0 to 38.4
0
≥38.5 to 38.9
1
≤36.0 or ≥39.0
2
Leukocytosis (Peripheral white blood 
cell count, cells/mm3)
4000 to 11,000
0
<4000 or >11,000
1
<4000 or >11,000 AND Bands 
(immature forms) >500
2
Tracheal secretions
Absent
0
Nonpurulent
1
Purulent
2
Oxygenation (PaO2/FiO2, mmHg)
>240 or ARDSb
0
≤240 and no ARDS
2
Chest Radiography
No infiltrate/minimal
0
Diffuse or patchy infiltrate
1
Focal (localized) infiltrate
2
Radiographic response
Total clearing (<3 days)
-3
No change/minimal improvement
0
Sputum/tracheal culture
No growth or ≤1+ (rare/light) growth
0
Pathogenic bacteria >1+ 
(moderate or heavy) growth
1
Same pathogen identified on Gram stain and 
on culture
2
Minute ventilation
<10 L/min or off ventilator
0
10–13 L/min
1
>13 L/min
2
aPugin J. Clinical signs and scores for the diagnosis of ventilator-associated pneumonia. Minerva Anestesiol 
2002:68:261-265.
Wunderink RG, Niederman MS, Kollef MH, Shorr AF, Kunkel MJ, Baruch A, et al. Linezolid in methicillin-
resistant Staphylococcus aureus nosocomial pneumonia: A randomized, controlled study. Clin Infect Dis. 
2012:54(5):621-9.
bARDS=acute respiratory distress syndrome, defined clinically as having all of the following criteria: acute 
bilateral pulmonary infiltrates; PaO2/FiO2 <200; pulmonary arterial wedge pressure ≤18 mmHg (no heart failure 
or volume overload as the principal cause of pulmonary infiltrates).
 
 
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Appendix 3.
Sepsis-related Organ Failure Assessment (SOFA) Score
The following data will be collected in the case report form in order to calculate the SOFA 
score.
Score
0
1
2
3
4
Respiration
PaO2/FiO2
≥400
<400 to 300
<300 to 200
<200 to 100
<100
Coagulation
Platelets 
(103 plts/mm3)
≥150
<150 to 100
<100 to 50
<50 to 20
<20
Liver
Total Bilirubin (mg/dL)
[µmol/L]
<1.2
[<20]
1.2 to 1.9
[20-32]
2.0 to 5.9
[33-101]
6.0 to 11.9
[102-204]
≥12.0
[≥204]
Cardiovascular
Hypotension
None
MAP <70
Dopamine 
≤5 μg/kg/min or 
any Dobutamine
Dopamine 
>5 μg/kg/min or 
Epinephrine or 
Norepinephrine 
≤0.1 μg/kg/min
Dopamine 
>15 μg/kg/min or 
Epinephrine or 
Norepinephrine 
>0.1 μg/kg/min
Central Nervous System
Glasgow Coma Score
15
13-14
10-12
6-9
<6
Renal
Serum Creatinine (mg/dL) 
[µmol/L] or urine output 
(mL/day)
<1.2
[<110]
1.2-1.9
[110-170]
2.0-3.4 
[171-299]
3.5-4.9 
[300-440] or 
<500 mL
≥5.0 
[>440] or
<200 mL
Source:  adapted from Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, et al.  
The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction /failure. Intensive 
Care Med. 1996;22:707–710.
 
 
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Appendix 4.
Adjunctive Therapy Decision Tree (before respiratory tract specimens 
from the Screening Visit culture results are available)
Abbreviations: MDR=multidrug resistant; MRSA=methicillin-resistant S aureus.
aRisk of multidrug resistant gram-negative bacteria is determined by each individual site and its history of resistant bacteria 
requiring broad-spectrum antibiotics.
bIf first-line therapy is contraindicated or not available, use second-line therapy.  Avoid additional coverage for gram-
positive organisms when choosing antibiotic regimens.
Note:  On Day 3, once culture results have returned, an assessment of the gram-negative coverage should be performed and 
therapy may be changed for a different antibiotic; however, antibiotics with gram-positive coverage should be avoided, if 
possible.
The following are not acceptable adjunctive therapy due to overlapping MRSA coverage:

Vancomycin

Linezolid

Teicoplanin

Tigecycline
 
 
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
Ceftaroline

Any rifamycin (ex rifampin, rifampicin etc)
*Recommended aztreonam and colistin administration
Recommended aztreonam IV administration:

Normal renal function: 2 g every 6-8 hours

CLcr = 10 to 50 mL/min; if receiving continuous renal replacement therapy such as 
continuous veno-venous hemofiltration: 2 g load, then 1 g every 6-8 hours

CLcr <10 mL/min: 2 g load, then 500 mg every 8 hours; if receiving hemodialysis, an
additional 500 mg after hemodialysis
Recommended colistin base activity (CBA) administration based on target steady state of 2.5 
mg/L (Garonzik 2011).  Higher doses of colistin may be used for serious infections with a 
target of 3.0 mg/L or 3.5 mg/L.  These targets may be inserted in the equations below if the 
investigator believes it is warranted.  However, maintenance dosing should not exceed 475 
mg CBA/day under any circumstance.
Dosing is given in CBA because there are 2 options for colistimethate sodium and the 
recommended dosing varies by drug (Li 2006):

Colomycin is used as the CBA below with an IU conversion of 12,500 IU/mg.

Coly-mycin M: total dose of colistimethate sodium in this form is 2.4 times the CBA 
dose and IU conversion from CBA dosing is 30,000 IU/mg.  Convert doses as shown 
below:
Ask your pharmacist for help for CBA dosing with the option that is available at your site.
Loading Dose = body weight x 2.0 x target steady state (2.5 mg/L), but not to exceed 300
mg
Weight (kg)
Loading dose (mg)
40
200
50
250
60
300
>60
300
 
 
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Maintenance doses (starting 24 hours after loading dose):
Daily Maintenance Dose (mg to be divided to twice or three times daily) = target steady state 
(2.5 mg/L) x (1.5 x CLcr +30)
Creatinine Clearance 
(mL/min//1.73m2)
Daily Dose (mg/day)
Frequency
Dose (mg)
5
93.75
Twice daily
46.9
10
112.5
Twice daily
56.25
20
150
Twice daily
75
30
187.5
Twice daily
93.75
40
225
Twice daily
112.5
50
262.5
Twice daily
131.25
60
300
Three times daily
100
≥70
337.5
Three times daily
112.5
Dosing on Continuous Renal Replacement (regardless of weight or calculated CLcr):

480 mg/day divided twice daily = 240 mg/dose twice daily
Dosing on Intermittent Hemodialysis (regardless of weight or calculated CLcr):

Nonhemodialysis day: 75 mg/day twice daily = 37.5 mg/dose twice daily

Hemodialysis day (given after hemodialysis): 97.5 mg/day BID = 48.75 mg/dose twice 
daily
Weight is the lower value of the either the ideal body weight or the actual body weight
Creatinine Clearance is the Cockcroft-Gault calculation normalized for a body surface area 
(BSA) of 1.73 m2:
Glomerular filtration rate = [(140-age) x (weight in kg) x (0.85 if female)] / (72 x serum 
creatinine) x patient’s BSA/1.73 m2
Source: Li J, Nation RL, Turnidge JD, et al. Colistin: the re-emerging antibiotic for 
multidrug-resistant gram-negative bacterial infections. Lancet Infect Dis 2006;6:589-601
 
 
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Appendix 5.
Microbiological Sampling and Pathogen Determination
Appropriate specimens (sputum or endotracheal aspirate [with <10 SEC and >25 PMN cells 
per low-power field], protected specimen brush, BAL, and mini-BAL, or exudative pleural 
effusion) will be collected at various time points (see Appendix 11).  Note that 
microbiological samples are required only at the Screening Visit.  At subsequent visits, 
samples are required in patients with no improvement or as clinically indicated for worsening 
respiratory status suggesting a treatment failure or new infection.
It is recommended that the first aspirated specimen from an intubated patient be discarded 
and the second specimen and any subsequent aliquots aspirated after instillation of sterile 
saline should be collected for Gram stain and culture.  All cultures should be processed 
within 2 hours from the collection time; alternatively these tests can be performed within 
24 hours of collection if the specimen is stored at 2 to 8ºC before processing.  See 
Microbiology Laboratory Manual for additional detailed instructions.
Lower respiratory specimens should be sent to the site’s local laboratory (or other designated 
regional laboratory) for Gram stain and culture. Blood samples should be sent to the site’s 
local laboratory for culture (or other designated regional laboratory; Gram stain 
optional). Isolates should be identified using the local laboratory’s usual procedures. All 
unique organisms from the respiratory or pleural fluid specimens and/or blood samples will 
be stored and sent to the Cubist -designated central laboratory for confirmation of 
identification and susceptibility testing.
Backup samples of all organisms isolated from the respiratory or pleural fluid specimens and 
of blood should be stored frozen at each site’s local laboratory. The local laboratory should 
store these backup samples until the site/Investigator is notified by Cubist to discard them or 
ship them to Cubist designated Central Laboratory.
Additional information is provided in the Microbiology Laboratory Manual.
Recommendation for Gram stain Protocol from American Society of Microbiology:
1) Using a loop spread the respiratory sample onto a clear slide.  Fix the cells to the slide 
using heat so the excess liquid evaporates.
2) Flood the slide with crystal violet staining reagent for 1 minute.
3) Wash slide in a gentle and indirect stream of tap water for 2 seconds.
4) Flood slide with the mordant: Gram’s iodine for 1 minute.
5) Wash slide in a gentle and indirect stream of tap water for 2 seconds.
 
 
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6) Flood slide with decolorizing agent.  Wait 15 seconds or add drop by drop until 
decolorizing agent running from the slide runs clear.  This step is critical and time-
dependent as over-decolorizing the sample will make gram-positive bacteria appear to 
be gram-negative.
7) Flood slide with counterstain: safranin.  Wait 30-60 seconds.
8) Wash slide in a gentle and indirect stream of tap water until the fluid running off the 
slide runs clear then blot dry with absorbent paper.
9) Use low power (10x) to count squamous cells and white blood cells
10) Use high power (100x) with oil immersion to view bacteria
11) To remove oil immersion from the slide without damaging the smear, lay a piece of 
lens tissue on the slide and add a drop or two of xylene.  Draw the lens tissue across 
the slide and repeat as necessary.
All reagents can be made or purchased commercially from biological supply houses:
1) Primary Stain: Crystal Violet Staining Reagent
a.
Solution A
Crystal violet (certified 90% dye content), 2 g
Ethanol, 95% (vol/vol), 20 mL
b. Solution B
Ammonium oxalate, 0.8 g
Distilled water, 80 mL
Mix Solutions A and B to obtain the crystal violet staining reagent.  Store for 
24 hours and filter through filter paper before using.
2) Mordant: Gram’s Iodine
Iodine, 1.0 g
Potassium iodide, 2.0 g
Distilled water, 300 mL
 
 
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Grind the iodine and potassium iodide in a mortar and add water slowly with 
continuous grinding until the iodine is dissolved.  Store in amber (dark) 
bottles.
3) Decolorizing Agent
Ethanol, 95% (vol/vol)
Alternatively, a 1:1 mixture of acetone and 95% ethanol may be used.
4) Counterstain: Safranin
a.
Stock Solution
Safranin O, 2.5 g
Ethanol, 95% (vol/vol), 100 mL
b. Working Solution
Stock Solution, 10 mL
Distilled water, 90 mL
Gram Stain Requirements
Gram stains should be read and reported per your institution’s procedures so that required 
Gram stain data can be recorded on the e-CRF.
Determine the presence of WBCs in 20-40 fields of the smear under low power.  Skip fields 
where there are no cells or bacteria and do not record these. 
Report the presence of WBCs as follows:
o
No WBCs
o
1 to 25 WBCs per low-power field
o
>25 WBCs per low-power field
 
 
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
Report the presence of squamous cells as follows:
o
No squamous cells
o
1 to 9 squamous cells per low-power field
o
≥10 squamous cells per low-power field

Report the bacterial cell morphologies seen under high power (oil immersion) 
magnification in 20-40 fields of the smear as follows:
o
1+ (scant)
o
2+ (light)
o
3+ (moderate)
o
4+ (heavy)
Pathogen Determination 
Pathogen determination is based on the genus and species identification from the central 
laboratory. Three categories of pathogen classification are defined as follows:
1. Always a pathogen. If the organism was isolated from the culture, the following are 
always considered a pathogen:
Staphylococcus aureus
Streptococcus pneumoniae
Streptococcus pyogenes
Pseudomonas aeruginosa
Acinetobacter species
Stenotrophomonas maltophilia
Escherichia coli
Enterobacter species
Klebsiella species
Proteus species
Serratia species
 
 
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Citrobacter species
Morganella species
Haemophilus species
Hafnia species
2. Never a pathogen. If the organism was isolated from the culture, the following are never 
a pathogen: 
S. saprophyticus 
Corynebacterium spp.
S. epidermidis
Bacillus species
Diphtheroids
Micrococci
3. Case-by-case review. All organisms isolated from a blood culture and all isolates not 
defined by criteria 1 and 2 above will be assessed case-by-case with a manual review by 
Cubist.  If needed, patient clinical (eg, type of infection, type of specimen, patient 
underlying conditions) and microbiological information (eg, Gram stain) will be used to 
assist in determining if the isolate is a pathogen.
 
 
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Appendix 6.
Cranial Nerve Examination
Cranial Nerve Assessment
Nerve
Name
Function
Test (examples)
I
Olfactory
Smell
Have patient smell a familiar odor
II
Optic
Visual field
Check peripheral vision
III
Oculomotor
Pupillary Reaction
Shine light in the eye
IV
Trochlear
Eye Movement
Have patient follow a finger without moving the head
V
Trigeminal
Facial Sensation; Motor 
Function
Touch the face; Have patient hold mouth open
VI
Abducens
Motor Function
Check lateral eye movements
VII
Facial
Motor Function; Taste
Have patient smile, wrinkle face, puff cheeks; Evaluate 
taste
VIII
Acoustic
Hearing; Balance
Snap fingers by the ears; Romberg’s test
IX
Glossopharyngeal
Swallowing and Voice
Have patient swallow and say "Ah"
X
Vagus
Gag Reflex
Use tongue depressor to evaluate
XI
Spinal Accessory
Neck Motion
Evaluate shoulder shrugging
XII
Hypoglossal
Tongue Movement and 
Strength
Have patient stick out tongue; apply resistance with a 
tongue depressor
 
 
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Appendix 7. Acute Physiology and Chronic Health Evaluation (APACHE) II Score 
Point Value 
4 
3 
2 
1 
0 
1 
2 
3 
4 
Total 
Glasgow Coma Score 
Score = 15 minus actual Glasgow Coma Score 
 
Temperature (rectal, ºC) 
≥41 
39-40.9 
 
38.5-38.9 
36-38.4 
34-35.9 
32-33.9 
30-31.9 
≤29.9 
 
Mean Arterial Pressure (mmHg)a 
≥160 
130-159 
110-129 
 
70-109 
 
50-69 
 
≤49 
 
Heart Rate (bpm) 
≥180 
140-179 
110-139 
 
70-109 
 
55-69 
40-54 
≤39 
 
Respiration Rate 
≥50 
35-49 
 
25-34 
12-24 
10-11 
6-9 
 
≤5 
 
PaO2 (mmHg) or 
Alveolar-Arterial Oxygen 
Gradient (if FiO2≥50%) 
≥500 
350 to 499 
200 to 349 
 
<200 
 
>70 
61-70 
 
55-60 
<55 
 
Arterial pH 
OR 
Serum HCO3 (mEq/L) -(venous- 
if ABG not performed) 
≥7.7 
 
 
≥52 
7.6-7.69 
 
 
41-51.9 
 
7.5-7.59 
 
 
32-40.9 
7.33-7.49 
 
 
22-31.9 
 
7.25-7.32 
 
 
18-21.9 
7.15-7.24 
 
 
15-17.9 
<7.15 
 
 
<15 
 
Serum Na+ (mMol/L) 
≥180 
160-179 
155-159 
150-154 
130-149 
 
120-129 
111-119 
≤110 
 
Serum K+ (mMol/L) 
≥7 
6-6.9 
 
5.5-5.9 
3.5-5.4 
3-3.4 
2.5-2.9 
 
<2.5 
 
Serum creatinine (mg/dL) 
≥3.5 
2-3.4 
1.5-1.9 
 
0.6-1.4 
 
<0.6 
 
 
 
Acute renal failureb 
×2 creatinine point score if patient has acute renal failure 
 
Hematocrit, % 
≥60 
 
50-59.9 
46-49.9 
30-45.9 
 
20-29.9 
 
<20 
 
WBC, (109 cells/L or mm3) 
≥40 
 
20-39.9 
15-19.9 
3-14.9 
 
1-2.9 
 
<1 
 
Severe organ failure  
(liver, heart, or lung) or 
immunocompromisedc 
Add 5 points if patient is medical (no surgery) or postoperative for emergency surgery 
Add 2 points if patient is postelective surgery  
 
Age (years) points 
≤44=0 
45-54=2 
55-64=3 
65-74=5 
≥75=6 
 
 
Sum of all rows 
 
 
 
 
 
 
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Footnotes for Appendix 7: Acute Physiology and Chronic Health Evaluation (APACHE) II Score
Source:  Adapted from Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985). APACHE II: a severity of disease classification system. Critical Care 
Medicine 13 (10): 818–29.
aMean arterial pressure =Systolic blood pressure + 2 (diastolic blood pressure)
3
bAcute Renal Failure = a 0.5 mg/dL increase in serum creatinine if the baseline serum creatinine was ≤1.9 mg/dL, a 1.0 mg/dL increase in serum creatinine if 
the baseline serum creatinine was 2.0 to 4.9 mg/dL, and a 1.5 mg/dL increase in serum creatinine if the baseline serum creatinine was ≥5.0 mg/dL.
cOrgan insufficiency or immunocompromised state must have been evident prior to this hospital admission and conform to the following criteria: 
Liver – biopsy proven cirrhosis and documented portal hypertension; episodes of past upper GI bleeding attributed to portal hypertension; or prior 
episodes of hepatic failure/encephalopathy/coma. 
Cardiovascular – New York Heart Association Class IV. 
Respiratory – Chronic restrictive, obstructive, or vascular disease resulting in severe exercise restriction (ie, unable to climb stairs or perform household 
duties; or documented chronic hypoxia, hypercapnia, secondary polycythemia, severe pulmonary hypertension (>40 mmHg), or respirator 
dependency. 
Renal – receiving chronic dialysis. 
Immunocompromised – the patient has received therapy that suppresses resistance to infection (eg, immunosuppression, chemotherapy, radiation, long 
term or recent high dose steroids, or has a disease that is sufficiently advanced to suppress resistance to infection, eg, leukemia, lymphoma, AIDS).
 
 
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Appendix 8.
Glasgow Coma Scale
Sedating and paralytic agent use may confound the assessment of the Glasgow Coma Score.  
If sedation is reduced and patients awakened daily to perform neurologic assessments, assess 
the score during the period when the patient is not sedated.  If daily awakenings are not 
performed, please record the score as if the patient did not have sedating or paralytic agents 
preventing response.
Neurologic Response
Score
Best Eye Response (E)
Spontaneous-open with blinking at baseline
4
Opens to verbal command, speech or shout
3
Opens to pain (not applied to face)
2
None
1
Best Verbal Response 
(V)
Oriented
5
Confused conversation, but can answer 
questions
4
Inappropriate responses, words discernible
3
Incomprehensible speech
2
None
1
Best Motor Response (M)
Obeys commands for movement
6
Purposeful movement to painful stimulus
5
Withdraws from pain
4
Abnormal (spastic) flexion, decorticate posture
3
Extensor (rigid) response, decerebrate posture
2
None
1
Total Score
Source: Teasdale G, Jennet B.  “Assessment of coma and impaired consciousness”.  Lancet 1974; ii: 81–83.
 
 
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Appendix 9.
Clinical Laboratory Evaluations
Clinical Laboratory Evaluations
Chemistry Panel 
Total Bilirubina
Direct Bilirubin
Indirect Bilirubin
Albumina
Alkaline Phosphatase
Alanine aminotransferase (ALT)a
Aspartate aminotransferase (AST)a
Gamma-glutamyl transpeptidase (GGT)
Lactate dehydrogenase (LDH)
Urea Nitrogen
Creatininea
Glucose
Uric Acid
Calcium
Phosphorus
Total Protein
Cholesterol
Creatine kinase/creatine phosphokinase
Sodiumb
Potassiumb
Bicarbonateb
Chloride
Magnesium
Hematology/Differential Panel 
Hemoglobin
Hematocritb
Red blood cell count
White blood cell counta
Neutrophils (%, absolute)a
Lymphocytes (%, absolute)
Monocytes (%, absolute)
Eosinophils (%, absolute)
Basophils (%, absolute)
Bands (%, absolute)b
Platelet count
Pregnancy Test (all females of childbearing potential, excludes females 
2 years postmenopausal or surgically sterile)
Serum beta-human chorionic gonadotropin (beta-hCG) at 
Screening (local only)a
Urine Panel 
pH
Bilirubin
Glucose
Ketones
Urobilinogen
Coagulation Panel (local only)a
Prothrombin time (PT)
Partial thromboplastin time (PTT)
International Normalized Ratio (INR)
aLocal laboratory evaluations required at Screening; PT or INR are acceptable; PTT or activated PTT are 
acceptable.
bLocal laboratory evaluations required at Screening if local laboratory has capability to measure.
 
 
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Appendix 10. Pharmacokinetic Sampling
Blood will be collected from all patients to evaluate the systemic plasma concentrations of 
TR-700 and optionally TR-701 after administration of TR-701 FA using a validated assay.  
Detailed information on sample collection and processing is provided in the PK Manual.
Perform the following:
1. Collect blood in the tube provided by the Cubist-designated central laboratory
2. Slowly invert the tube at least 8 to 10 times
3. Place the tube in an ice water bath until centrifugation
4. Centrifuge the sample at 2000 g at 5ºC for 15 minutes.  If a refrigerated centrifuge is 
not available, place the tube in an ice bath immediately before and after the centrifugation 
for at least 5 minutes each time
5. Split the sample into 2 aliquots and store at -20ºC or colder 

One aliquot will be shipped to the Cubist-designated central laboratory

The other aliquot is to be stored at the study site as a back-up sample until notified 
by Cubist or designee that the sample either is to be sent to the Cubist-designated 
central laboratory or is to be destroyed
 
 
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Appendix 11. Schedule of Study Procedures
Study Visits
Study Day
End of 
Therapy
(EOT; 1-3 
days after 
last 
study 
drug)
Test of 
Cure
(TOC; 7-
14 days 
after last 
study 
drug)
Late 
Follow-
Upb (28-
32 days 
after 
randomiz
ation)
Study Procedure
Screenin
g (within 
24 hours 
before 
the first 
infusion)
1
2
3
4-10/14a
Informed consent (before any study 
procedures)c
X
At any time the patient is medically able (ie, alert and extubated)
Verify patient meets inclusion and 
exclusion criteria
X
Record relevant medical/surgical history 
(5 years)
X
Record height and weight (estimate if 
X
Perform 12-lead electrocardiogram
X
Determine APACHE II score (if all 
components available; see Appendix 7)
X
Determine Glasgow Coma Scale score (see 
Appendix 8)
X
X
X 
(Day 7 
only)
Obtain chest x-ray or CT scan (within 36 
hours prior to infusion)
X
Randomize via IVRS
X
Neurologic examination and screening for 
peripheral sensory and motor neuropathy 
(see Appendix 6) and visual acuity 
examination 
At any time the patient is medically able (ie, alert and extubated)
In patients who are receiving supplemental O2, 
determine oxygenation status obtained on the 
last 24 hours by documenting the lowest 
percentage oxygenation saturation by pulse 
oximetry or the lowest PaO2 by ABG if 
available.  Perform at Day 1 only if different 
from calendar day of Screening.
X
X
X
X
X
X
X
Record highest minute ventilation and FiO2
obtained on the calendar day
X
X
X
X
X
X
Collect and document components of CPIS 
and SOFA scores (see Appendix 2 and 
Appendix 3)
X
Perform a physical examination
X
X
X
X
X
X
Record prior and/or concomitant 
medications
Xd
X
X
X
X
X
X
Xe
Record lowest and highest vital signsf
X
X
X
X
X
X
X
Record lowest and highest temperatureg
X
X
X
X
X
X
X
 
 
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Appendix 11 (continued)
Schedule of Study Procedures
Study Visits
Study Day
End of 
Therapy
(EOT; 1-3 
days after 
last 
study 
drug)
Test of 
Cure
(TOC; 7-
14 days 
after last 
study 
drug)
Late 
Follow-
Upb (28-
32 days 
after 
randomiz
ation)
Study Procedure
Screenin
g (within 
24 hours 
before 
the first 
infusion)
1
2
3
4-10/14a
Obtain lower respiratory tract or pleural 
fluid microbiological specimensh
X
X
X
X
X
X
X (on-site 
visit only)
Document rapid diagnostic, PCR or nasal 
swab results if applicable
X
Collect blood sample for microbiologyi
X
X
X
X
X
X (on-site 
visit only)
Collect urine sample for Legionella
antigen
X
Collect sample for serum pregnancy testj
X
Collect blood sample for procalcitonin
X
X 
(Day 7 
only)
Collect blood samples for chemistry and 
hematology panels
X
X
(only 
Days 7 
and 10 
[all]; Day 
14 
[bacterem
ic])
X
X
X (on-site 
visit only)
Collect blood samples for PK analysisk
X
X
(Day 4 or 
5 and 
Day 7 
only)
Collect blood sample for coagulation panel
X
Calculate PT or INR; Child-Pugh; estimate 
CLcr
X
Administer study drug
X
l
X
X
X
Select or re-evaluate gram-negative 
adjunctive therapy based on microbiology 
and susceptibility results (see Appendix 4)
X
X
X
X
Determine Investigator’s assessment of 
Clinical Response
X
X
Assess for clinical relapse
X
Determine survival status
X
Assess AEs (pretreatment, 
treatment-emergent, or ongoing)
X
X
X
X
X
X
X
X
 
 
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Footnotes from Appendix 11: Schedule of Study Procedures
Abbreviations:  AE=adverse event; APACHE=Acute Physiology and Chronic Health Evaluation; 
CLcr=creatinine clearance; CPIS=Clinical Pulmonary Infection Score; EOT=end of therapy; hCG=human 
chorionic gonadotropin; INR=international normalized ratio; hCG=beta-human chorionic gonadotropin 
hormone; PK=pharmacokinetic; PT=prothrombin time; SOFA=Sepsis-related Organ Failure Assessment; 
TOC=test of cure.
a Days 4 to 10 for patients without bacteremia; Days 4 to 14 for patients with gram-positive bacteremia.
b For patients with bacteremia, this visit may be combined with and performed on the same day as the TOC.
c Obtain initial informed consent >24 hours before the first infusion. Patient must be re-consented at any time 
during the study should he/she become medically able to do so (only if original consent was provided by the 
patient’s legally authorized representative).
d Record medications taken ≤30 days before the first infusion.
e Only for patients with clinical relapse or who require treatment for an AE.
f Record blood pressure, heart rate, and respiration rate on calendar day.  Perform at Day 1 only if different from 
calendar day of Screening.  At the TOC Visit, record highest and lowest vital signs values if patient remains 
hospitalized; if patient is not hospitalized, record vital signs.
g Record temperature on calendar day.  Perform at Day 1 only if different from calendar day of Screening.  At 
the TOC Visit, record highest and lowest temperature if patient remains hospitalized; if patient is not 
hospitalized, record temperature.
h Samples must be collected via valid sampling technique.  All isolates from the local laboratory culture are to 
be sent to the central laboratory except for those listed as never a pathogen in Appendix 5.  Microbiological 
samples are required only at the Screening Visit.  At subsequent visits, samples are required in patients with no 
improvement or as clinically indicated for worsening respiratory status suggesting a treatment failure or new 
infection, and if respiratory specimens are easily accessible.
i Obtain blood samples on Days 3 to 10/14, and the EOT and TOC Visits, if clinically indicated.  Repeat blood 
samples if clinically significant pathogen is isolated.
j Perform a serum hCG pregnancy test at the local laboratory for the Screening Visit for female patients of 
childbearing potential (may be omitted for females 2 years postmenopausal or surgically sterile).
k If approved by ethics and/or local regulatory authorities, collect blood samples for PK analysis on Day 1 
between 5 and 80 minutes, and between 4 and 12 hours after the completion of Dose 1, Infusion A; on Day 4 
or 5 before Dose 7 or 9; on Day 7 between 5 and 80 minutes after Dose 13 (2 samples) and between 4 and 12 
hours after Dose 13.
l Administer study drug Dose 1 as 2 separate and serial 60-minute infusions (±10 minutes).  Initiate Infusion A, 
flush the line, and then initiate Infusion B.  Doses should be given every 12 hours ± 2 hours from start of 
infusion A of odd numbered dose to next even numbered dose.
 
 
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Appendix 12. Assessment Plan of Sepsis
1.0
DEFINITION OF SEPSIS
Sepsis is defined as bacteremia (positive blood culture at baseline) with systemic 
inflammatory symptoms/findings (Office of Pharmaceutical Safety and Environmental 
Health Bureau, Ministry of Health, Labour and Welfare [MHLW], 2017).
2.0
RATIONALE OF SEPSIS ASSESSMENT
Sepsis is associated with high mortality rates. Delays in treatment lead to complications, 
including multiple organ failure (circulatory failure, acute respiratory syndrome, 
disseminated intravascular coagulation, etc.), and associated poor outcomes. Therefore, 
prompt therapy with appropriate antibiotics is essential in patients with sepsis.
Sepsis assessment in this study is based on the Japanese Guideline for Clinical Assessment of 
Antibiotics on Sepsis and the definition of sepsis of Society of Critical Care Medicine and 
American College of Chest Physicians (MHLW 2017, Bone et al. 1992, JRS Guidelines
2017, JAID/JSC 2017).
3.0
TRIAL OBJECTIVES OF SEPSIS ASSESSMENT
The efficacy and safety of TR-701 FA in patients with sepsis will be evaluated under this 
Japan-specific amendment.
3.1
Study Objectives 
Primary objectives:
•
To evaluate the clinical response to TR-701 FA in the treatment of sepsis at the 
TOC Visit in the Sepsis Population. 
•
To evaluate the safety and tolerability of TR-701 FA in the Sepsis Population.
Secondary objective:
•
To evaluate the microbiological response to TR-701 FA in the treatment of sepsis 
at the TOC Visit in the Sepsis Population.
4.0
THE CRITERIA OF SEPSIS
A subject must satisfy all [that is, both 1) and 2)] of the following criteria. 
1)
Have at least 1 of the following clinical criteria within the 24 hours prior to the first 
dose of study drug:
•
Temperature >38°C (100.4°F) or <36°C (96.8°F)
•
WBC count >12,000 cells/mm3, <4,000 cells/mm3 or >10% immature neutrophils
•
Pulse (heart rate) >90 beats per minute
 
 
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•
PaO2
*/FiO2
**≤240 mmHg
•
Systolic blood pressure <90 mmHg
*In case percentage of oxygenation saturation was measured instead of PaO2, 
PaO2 value is calculated based on the method by Severinghaus (Severinghaus 
1979).
**Fraction of air oxygen (21%) is substituted for calculation in patients who 
were removed from ventilation.
2)
Meet the definition of bacteremia*(refer to Protocol Section 5.3.1) at baseline
*Definition of bacteremia (refer to Protocol Section 5.3.1): Bacteremia is defined as 
1 positive blood culture for S aureus, Streptococcus pneumoniae, or Streptococcus 
pyogenes, or 2 positive blood cultures for any other gram-positive lung pathogen. 
(Refer to Appendix 5 for details of pathogens.)
5.0
STATISTICS OF SEPSIS ASSESSMENT
This section outlines the statistical analysis strategy and procedures for the assessment.
5.1
Handling of Missing Data
For efficacy endpoints, missing data will be handled with a Treatment Failure Approach 
(TFA) for the Sepsis Population defined as follows:
•
TFA: All patients with an outcome of efficacy endpoint as indeterminate at the 
TOC Visit will be considered as treatment failures. In other words, all patients
with efficacy endpoint of indeterminate at the TOC visit who meet the Sepsis 
Population criteria will be included in the denominator.
•
For microbiological outcome, missing of blood culture will be considered 
presumed eradication or indeterminate as defined in Appendix 12 Table 2.
5.2
Population for Analysis
Sepsis Population:
The Sepsis Population will consist of all randomized patients who received at least 1 dose of 
study treatment and satisfy the sepsis criteria. Patients who receive the wrong study drug for 
the entire course of treatment will be analyzed in the group based on the drug received.
5.3
Study Endpoints
5.3.1
Efficacy Endpoints
Primary Endpoints:
•
Clinical response at the TOC Visit
 
 
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Secondary Endpoints:
•
Microbiological response at the TOC Visit
5.3.2
Safety Endpoint:
•
The incidence (n and %) of TEAEs, SAEs, and TEAEs leading to study drug 
discontinuation
5.4
Efficacy Endpoint Analyses
5.4.1
Primary Endpoint Analysis
The point estimates and 95% CI using the Clopper-Pearson method will be presented for the 
clinical response rate at TOC in the Sepsis Population in each treatment group (Clopper & 
Pearson 1934). Also, the difference in proportions and the 95% CI for the difference using 
the Meittinen & Nurminen method will be presented (Miettinen & Nurminen1985). The 
clinical response rate is defined as a proportion of patients who are judged to have a clinical 
outcome for sepsis as “Cure”. In addition, the analysis approach will be the same for this 
endpoint in patients with sepsis who also have blood cultures positive for MRSA at baseline.
5.4.2
Secondary Endpoint Analysis
The point estimates and 95% CI using the Clopper-Pearson method will be presented for the 
microbiological response rate at TOC in the Sepsis Population in each treatment group. Also, 
the difference in proportions and the 95% CI for the difference using the Meittinen & 
Nurminen method will be presented. The microbiological response rate is defined as a 
proportion of patients who are judged to have a microbiological outcome for sepsis as 
“Eradication” or “Presumed eradication”. In addition, the analysis approach will be the same 
for this endpoint in patients with sepsis who also have blood cultures positive for MRSA at 
baseline.
5.5
Safety Analysis
The incidence (n and %) of TEAEs, SAEs, and TEAEs leading to study drug discontinuation 
will be presented for patients in the Sepsis Population in each treatment arm. Additionally, 
AEs will be tabulated according to severity and relatedness categories as reported by the 
Investigator.  Adverse events will be presented in tables organized alphabetically by System 
Organ Class and Preferred Term.  Each subject will be counted only once for each AE 
reporting level.
5.6
Evaluation Criteria of Sepsis
5.6.1
Definition of Clinical Response for Sepsis
Clinical outcome assessment for sepsis will be based on the data collected from the TOC 
Visit.
 
 
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5.6.1.1 Clinical Outcome for Sepsis
Clinical response at the TOC Visit will be classified as cure, failure, or indeterminate 
(Appendix 12 Table 1).
Appendix 12 Table 1: Clinical Response Categories for Sepsis at the TOC Visit
Outcome
Definition
Cure
All clinical signs and symptoms of sepsis were resolved at the TOC Visit, 
which means subject did not meet any of the criteria of sepsis 1) in 
Appendix 12, Section 4.
Failure
All clinical signs and symptoms of sepsis were not resolved at the TOC Visit, 
which means subject met at least 1 of the criteria of sepsis 1) in Appendix 12, 
Section 4. 
Indeterminate
Study data was not available at TOC visit for the evaluation of clinical 
outcome for any reason, which means at least 1 item of the criteria of sepsis 
1) in Section 4 were not available even though subject had not met any of the 
other criteria of sepsis 1) in Appendix 12, Section 4.
5.6.2
Definition of Microbiological Response for Sepsis
Microbiological outcome assessment for sepsis will be determined based on the results of last 
blood culture up to and including the TOC Visit.
5.6.2.1 Microbiologic Outcome for Sepsis
Microbiological response for sepsis at the TOC Visit will be classified per-subject as 
eradication, presumed eradication, persistence or indeterminate (Appendix 12 Table 2).
Appendix 12 Table 2 : Microbiologic Outcome Categories for Sepsis at the TOC Visit
Outcome
Definition
Eradication
Last blood culture after the administration of the first dose of study drug 
through the TOC Visit showed no growth of gram-positive pathogens.
Presumed 
Eradication
A blood culture was not performed after the administration of the first dose 
of study drug, AND a subject deemed “a clinical cure” for clinical outcome 
of sepsis at the TOC Visit.
Persistence / New 
Pathogen
Last blood culture after the administration of the first dose of study drug 
through the TOC Visit showed the presence of gram-positive pathogens.
Indeterminate
A blood culture after the administration of the first dose of drug is not 
performed and a subject deemed other than clinical cure (failure or 
indeterminate) for clinical outcome of sepsis at the TOC Visit.
 
 
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6.0
LIST OF REFERENCES 
Notification No1023-3, 2017 October 23, issued by the Director of Office of Pharmaceutical 
Safety and Environmental Health Bureau, Ministry of Health. Labour and Welfare. Japanese 
Guideline for Clinical Assessment of Antibiotics on Sepsis.
Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA et al. Definitions for 
Sepsis and Organ Failure and Guidelines for the Use of Innovative Therapies in Sepsis. The 
ACCP/SCCM Consensus Conference Committee. American College of Chest 
Physicians/Society of Critical Care Medicine. Chest 1992;101 (6):1644-55.
The JRS Guidelines for the Management of Pneumonia in Adults 2017 Creating Committee. 
The JRS Guidelines for the Management of Pneumonia in Adults 2017.
The JAID/JSC Guide and Guidelines for Management of Infection Creating Committee. 
Working Group for Sepsis. The JAID/JSC Guide and Guidelines for Management of 
Infection 2017-Sepsis and Catheter-related Bloodstream Infections.
Severinghaus JW. Simple, accurate equations for human blood O2 dissociation
computations. J. Appl. Physiol 1979; 46(3): 599-602. (revisions, 1999, 2002, 2007)
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika 1934; 26(4): 404-13. 
Miettinen O, Nurminen M. Comparative Analysis of Two Rates. Statistics in Medicine 
1985;4: 213-26.
 
 
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