Conditions: Bacteremia
Keywords: Bacteremia Staphylococcus aureus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 121
Healthy volunteers: no

Brief summary:
This is a multicenter, randomized, open-label, noninferiority trial of telavancin versus standard IV therapy control (e.g., vancomycin, daptomycin, anti-staphylococcal penicillin (PCN), or cefazolin) in the treatment of subjects with complicated Staphylococcus aureus (S. aureus) bacteremia and SA right-sided infective endocarditis (SA-RIE).

Detailed description:

Arms:
arm 1: 7.5 mg/kg administered intravenously once every 24 hours daily over 60 minutes arm 2: Vancomycin, Daptomycin, synthetic penicillin or Cefazolin

Interventions: intervention 1: Telavancin intervention 2: Vancomycin intervention 3: Daptomycin intervention 4: Synthetic penicillin intervention 5: Cefazolin
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None

Protocol document:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 3 Multicenter, Randomized, Open-label, Clinical 
Trial of Telavancin Versus Standard Intravenous Therapy in 
the Treatment of Subjects with Staphylococcus aureus 
Bacteremia Including Infective Endocarditis  
Sponsor Study No.: 
0112 
Protocol Date/Version 
16 January 2018, Amendment 4 
Test Product: 
Telavancin 
US IND: 
60,237 
Eudra CT Number 
2014-004372-27 
ClinicalTrials.gov Identifier 
NCT02208063 
Sponsor: 
Theravance Biopharma Ireland Limited 
Connaught House 
1 Burlington Road 
Dublin 4   
D04 C5Y6 
Ireland 
 
Telephone: +1 (650) 808-6000 
 
Facsimile: 
+1 (650) 808-6464 
Clinical Study Director: 
Bibiana Castaneda, MD 
Senior Director, Clinical Development  
Theravance Biopharma US, Inc. 
Telephone: 
+1 (650) 808-4052 
 
Global Clinical Study 
Manager 
Roger Kohler 
Senior Manager, Clinical Operations  
Theravance Biopharma US, Inc. 
Telephone: 
+1 (650) 808-6401 
This study will be conducted according to the principles of Good Clinical Practice. 
CONFIDENTIAL 
This document is confidential and property of Theravance Biopharma US, Inc. It may not be 
copied or provided to any other party without the express written consent of 
Theravance Biopharma US, Inc. 
Theravance Biopharma US, Inc. (Unpublished Work). All rights reserved. 


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PROTOCOL SYNOPSIS 
 
Study Number and Title:  Study 0112: A Phase 3 Multicenter, Randomized, Open-label 
Clinical Trial of Telavancin Versus Standard Intravenous Therapy in the Treatment of 
Subjects with Staphylococcus aureus Bacteremia Including Infective Endocarditis.  
Estimated Number of Study Centers and Countries or Regions:  Approximately 
120 study centers in the United States, Europe, and Latin America  
Background and Rationale:  
Bacteremia due to Staphylococcus aureus (S. aureus) is a frequently encountered serious 
infection that is often associated with infective endocarditis [1-3]. Treatment of bacteremia 
is challenging; infection metastasis and relapse are common, as is the involvement of 
antibiotic-resistant bacterial strains, including methicillin-resistant S. aureus (MRSA) [4]. In 
the treatment guidelines for MRSA bacteremia from the Infectious Diseases Society of 
America, only two agents are recommended: vancomycin, the traditional first-line therapy 
for MRSA infections, and daptomycin [5]. Both of these agents have recognized 
shortcomings. Vancomycin has limited tissue penetration, is slowly bactericidal [6], is 
suboptimal against methicillin-susceptible S. aureus (MSSA) [7, 8] and evidence suggests 
decreasing susceptibility among Gram-positive pathogens [7, 9, 10]. Resistance to 
daptomycin has more recently emerged, together with evidence suggesting that reduced 
susceptibility to vancomycin may also impact susceptibility to daptomycin [11, 12]. As such, 
there is a critical need for additional agents appropriate for the treatment of S. aureus 
bacteremia. 
Telavancin is a rapidly bactericidal lipoglycopeptide antibiotic that is active against a range 
of clinically relevant Gram-positive pathogens, including MRSA. Telavancin exhibits 
concentration-dependent bactericidal effects via a dual mechanism of action (inhibition of 
bacterial cell wall synthesis and disruption of bacterial cell membrane barrier function), 
which may help to minimize the potential for the selection of resistance. In global 
surveillance studies, telavancin has demonstrated consistent in vitro microbiologic activity 
within the telavancin susceptible ranges against Gram-positive isolates, including MRSA, 
regardless of susceptibility to other agents or geographic region. Telavancin minimum 
inhibitory concentration (MIC) MIC50/MIC90 values consistently show activity against 
S. aureus comparable or superior to other agents.  
In vitro pharmacokinetic (PK)/pharmacodynamic models of simulated endocardial 
vegetations have demonstrated superior telavancin bactericidal activity against S. aureus 
strains compared with vancomycin and daptomycin. In vitro biofilm studies have 
demonstrated the potential efficacy of telavancin in the treatment of staphylococcal 
biofilm-associated infections [13]. Furthermore, studies using animal models of infection 
also have supported the potential for telavancin in the effective treatment of S. aureus 
bacteremia and infective endocarditis. In murine models of bacteremia and rabbit models 
of infective endocarditis, telavancin has demonstrated greater efficacy than 


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vancomycin [14]. 
The efficacy and safety of telavancin have been demonstrated in Phase 3 clinical trials for 
the treatment of subjects with complicated skin and skin structure infections (cSSSI) due to 
Gram-positive pathogens (ATLAS studies) and subjects with hospital-acquired or 
ventilator-associated bacterial pneumonia (HABP/VABP) due to Gram-positive pathogens 
(ATTAIN studies). Telavancin, 10 mg/kg administered intravenously (IV) over 60 minutes, 
once every 24 hours for 7 to 14 days is the currently approved dosage for the treatment of 
adult patients with cSSSI caused by susceptible Gram-positive bacteria. The same 
telavancin dose, for a duration of 7 to 21 days, is the currently approved dosage for the 
treatment of adult patients with HABP/VABP caused by susceptible isolates of S. aureus, 
when alternative treatments are not suitable.  
Limited data are available from post hoc analyses of subjects with concurrent bacteremia 
from these Phase 3 cSSSI and HABP/VABP studies. Of the 1784 subjects in the ATe 
population in the 2 cSSSI trials, 32 subjects had baseline S. aureus bacteremia: 21 (2.4%, 
including 13 with MRSA) subjects were treated with telavancin and 11 (1.2%, including 
4 with MRSA) subjects were treated with vancomycin. In these bacteremic subjects, the 
clinical cure rate at test of cure (TOC) was 57.1% (12/21) for the telavancin-treated 
subjects and 54.6% (6/11) for the vancomycin-treated subjects. In subjects with 
Gram-positive bacteremic HABP/VABP in the ATTAIN studies, the clinical cure rates for 
telavancin and vancomycin were 46% (11/24) versus 37% (10/27), respectively. Moreover, 
only one telavancin-treated subject (1/34) compared with six vancomycin-treated subjects 
(6/39) had bacteremia that persisted beyond baseline cultures. 
In a Phase 2 proof-of-concept study, comparing telavancin with standard therapy 
(vancomycin or anti-staphylococcal penicillin) for treatment of subjects with uncomplicated 
S. aureus bacteremia (ASSURE study), compared with standard therapy, similar 
proportions of the clinically evaluable (CE) population (n = 17) were cured at a long-term 
follow-up visit (Day 84; 88% vs. 89%, respectively). However, the number of clinically 
evaluable subjects limits the strength of a conclusion regarding the comparative safety and 
efficacy of telavancin and standard therapy in this population. 
In a retrospective case series, telavancin provided a favorable cure rate and rapid 
clearance of bacteremia in difficult-to-treat subjects with refractory MRSA bacteremia with 
or without infective endocarditis [15]. Additional case reports of subjects with 
vancomycin-intermediate S. aureus (VISA) or MRSA endocarditis have demonstrated 
successful treatment with telavancin [16, 17]. 
To explore means by which the telavancin risk: benefit profile could be improved, the 
Sponsor recently performed additional integrated retrospective analyses of PK and 
outcomes data from the VIBATIV® (telavancin) Phase 3 studies for cSSSI and 
HABP/VABP. Based on the results of the integrated retrospective data analyses, the 
Sponsor believes that a reduction in the telavancin dose could optimize the risk: benefit 
profile of telavancin for the treatment of bacteremia. In separate independent CART and 
logistic regression analyses of data from the Phase 3 studies, a telavancin 
exposure-response relationship with acute kidney injury was confirmed. The analyses 


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support the conclusions that a dose reduction from 10 mg/kg to 7.5 mg/kg once daily would 
decrease the risk of nephrotoxicity and improve overall safety while having little to no 
impact on efficacy. Mortality was also examined in these analyses and despite small 
numbers and confounding factors, there was an exposure-response relationship in a 
subset of HABP/VABP subjects with creatinine clearance (CrCl) ≤50 mL/min. This risk may 
also be decreased with the proposed dose reduction. Therefore, the Sponsor proposes to 
reduce the exposure of telavancin by incorporating the following three changes in the dose 
and dosing regimen: 1) decreasing the dose by 25% in all subjects; 2) decreasing the dose 
by 62% to 3.8 mg/kg from 10 mg/kg and altering the dosing schedule for severe renal 
impairment (creatinine clearance of 10 to <30 mL/min) to once daily rather than every 
48 hours; and 3) recommending the dose not exceed 750 mg (or 560 and 380 mg in 
moderate or severe renal impairment) for subjects weighing greater than 100 kg. In 
addition, for subjects undergoing chronic hemodialysis, telavancin should be administered 
IV at a dose of 3.8 mg/kg (maximum dose of 380 mg) once daily by infusion over 
60 minutes (following hemodialysis on hemodialysis days). 
Telavancin dosed at 7.5 mg/kg has been studied in Phase 2 and Phase 3 studies in 
192 patients with cSSSI. In the Phase 2 and Phase 3 cSSSI studies, the cure rates at TOC 
in the CE population are similar for the two dosing regimens (93.2% [150/161] for 
7.5 mg/kg and 89.1% [732/822] for 10 mg/kg), supporting the efficacy of the 7.5 mg/kg 
dose. No noticeable difference between telavancin 7.5 mg/kg and 10 mg/kg was observed 
regarding the adverse events (AEs) profile in the Phase 2 and Phase 3 cSSSI studies. 
However, the difference in sample size between the two telavancin doses limits the ability 
to derive a conclusion about AE rates, especially in cases where the incidence was low 
(eg, serious adverse event [SAE] or renal AE). 
This study will be conducted in a population of subjects who are seriously ill with S. aureus 
bacteremia. Extra precautions have been built into the protocol to protect subject safety; 
however, by utilizing the proposed alterations in telavancin dose, the Sponsor believes that 
safety risks could potentially be reduced without loss of efficacy. This study will allow 
evaluation of the revised telavancin dose in a prospective, controlled fashion, and in an 
appropriate population of subjects. 
Regarding the rationale for standard IV therapy as the comparator in this trial, in adult 
patients with MRSA bacteremia or infective native valve endocarditis, current 
recommendations include treatment with vancomycin or daptomycin. Vancomycin is 
recommended for empiric therapy for S. aureus bacteremia in healthcare settings with an 
elevated prevalence of MRSA. Guidelines recommend that vancomycin be administered at 
doses providing trough concentrations of 15 to 20 μg/mL. For institutions in which the 
preponderance of MRSA isolates have vancomycin minimum inhibitory concentration (MIC) 
values >2 μg/mL, alternative agents, such as daptomycin, should be used [18]. Daptomycin 
is currently approved at a dosage of 6 mg/kg for the treatment of S. aureus bacteremia, 
including those with right-sided infective endocarditis, however, some experts recommend 
higher doses of up to 8 to 10 mg/kg [19-23]. For patients with methicillin-susceptible 
S. aureus, a β-lactam antibiotic with anti-staphylococcal activity (eg, nafcillin, oxacillin, 


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cefazolin) is the recommended treatment.  
Guidelines recommend treatment durations of at least 2 weeks for uncomplicated 
bacteremia (UCB), 4 to 6 weeks for complicated bacteremia (CB), and 6 weeks for infective 
native valve endocarditis [18]. 
To summarize, the use of telavancin for this study is supported by data from the post hoc 
analyses of subjects with bacteremia included in the Phase 3 studies of cSSSI and 
HABP/VABP, a Phase 2 proof-of-concept study of telavancin in subjects with 
uncomplicated S. aureus bacteremia, retrospective case series of subjects with refractory 
MRSA bacteremia, and case reports of subjects with VISA or MRSA endocarditis [15-17]. 
The available data describing telavancin for the treatment of bacteremia are limited, but are 
supportive of additional evaluation in larger, prospective studies including subjects with 
bacteremia due to S. aureus (specifically MRSA). Further prospective clinical studies are 
needed to assess the efficacy and safety of telavancin therapy in larger numbers of 
subjects with bacteremia and infective endocarditis. 
Objectives:  The primary objective of the study is as follows: 
• 
To compare telavancin to standard intravenous therapy (ie, vancomycin, 
daptomycin, anti-staphylococcal penicillin, or cefazolin) clinical outcomes in the 
treatment of S. aureus bacteremia including S. aureus right-sided infective 
endocarditis (SA-RIE). 
The secondary objectives of the study are as follows: 
• 
To evaluate the safety and tolerability of telavancin compared with standard 
intravenous therapy in the treatment of S. aureus bacteremia, including SA-RIE. 
• 
To evaluate the PK profiles of telavancin and vancomycin in subjects with S. aureus 
bacteremia, including SA-RIE. 
Study Design:  This is a multicenter, randomized, open-label, noninferiority trial of 
telavancin versus standard IV therapy control (ie, vancomycin, daptomycin, or a β-lactam 
antibiotic with anti-staphylococcal activity [eg, nafcillin, oxacillin, cefazolin]) in the treatment 
of subjects with complicated S. aureus bacteremia and SA-RIE. The primary efficacy 
endpoint is clinical outcome at TOC, analyzed in subjects with a baseline diagnosis of 
UCB, CB, or right-sided infective endocarditis (RIE) in the microbiological all-treated (mAT) 
population. The baseline diagnosis and the clinical outcome will be assessed by a blinded 
Independent Efficacy Adjudication Committee (IEAC). Safety will be monitored by an 
Independent Data Monitoring Committee (IDMC). 
Eligible subjects with confirmed S. aureus bacteremia will be randomized in a ratio of 1:1 to 
receive open-label telavancin or standard IV therapy. Randomization will be stratified by 
geographic region. Standard IV therapy, depending on the antibacterial susceptibility of the 
causative pathogen, will include vancomycin or daptomycin for subjects with known or 
suspected MRSA (daptomycin should be used for subjects with S. aureus with vancomycin 
MIC values >1 μg/mL); or a protocol-specified β-lactam antibiotic with anti-staphylococcal 
activity (ie, nafcillin, oxacillin, cloxacillin, or cefazolin) for subjects with known MSSA. 


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Subjects with a confirmed or suspected mixed polymicrobial infection with a Gram-negative 
pathogen requiring coverage with an antibiotic with Gram-negative activity at enrollment 
will be excluded from participation in the study. Subjects that develop an infection during 
study participation requiring coverage with an antibiotic with gram-negative activity may be 
allowed to continue on study after discussing the concomitant antibiotic treatment with the 
medical monitor. 
Each subject must have at least one blood culture positive for S. aureus before 
randomization, referred to as the qualifying blood culture (QBC). The initial identification of 
S. aureus in the QBC can be done via standard culture identification methods or by use of 
a rapid diagnostic test.  Use of a rapid diagnostic system, if available, is preferred, but not 
obligatory, for determination of S. aureus bacteremia. Regardless of method or the time 
that the blood sample was obtained, the identification of S. aureus bacteremia must be 
within 48 hours prior to randomization. 
The study population will be enriched for subjects with CB by requiring subjects to have at 
least one risk factor for CB at enrollment.  All subjects with CB will receive study drug for a 
minimum of 4 weeks and a maximum of 6 weeks (28 to 42 days) of therapy.  Subjects with 
infective endocarditis, will receive 6 weeks (42 +/- 3 days) of therapy.  Subjects with UCB 
will receive a minimum of 2 weeks and a maximum of 4 weeks (14 to 28 days) of therapy 
as per standard of care. 
The calendar day of first study drug administration is designated as Day 1; subsequent 
calendar days are Days 2, 3, etc.  
Procedures to control or eliminate the infection source, eg, by removal of intravascular 
lines or drainage and debridement of the primary infection site, will be completed within the 
first 3 days of study drug treatment.  
Follow-up blood cultures will be performed daily until two successive post-randomization 
blood cultures are negative for S. aureus. 
On or before Day 8, each subject must undergo echocardiogram (either transthoracic 
echocardiogram [TTE] or transesophageal echocardiogram [TEE]; TEE is strongly 
preferred) and will be evaluated by a physician investigator to determine the origin and 
extent of the S. aureus infection to establish the classification of infection type as one of the 
following: 
• 
Uncomplicated bacteremia (UCB):  A QBC, defined as a blood culture positive for 
S. aureus before randomization, no evidence of infective endocarditis, and all of the 
following: 
 
Catheter-associated infection and removal of the catheter or cutaneous 
infection-associated infection and source control within 3 days after 
randomization. 
 
A negative post-QBC blood culture drawn within 72 hours after start of study 
medication. 


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 
Defervescence within 3 days after start of study medication. 
 
Absence of valvular findings on echocardiography predisposing to 
infective endocarditis. 
 
No signs or symptoms suggestive of metastatic infection. 
• 
Complicated bacteremia (CB):  A QBC, defined as a blood culture positive for 
S. aureus before randomization, no evidence of infective endocarditis, and at least 
one of the following: 
 
Follow-up post-QBC blood culture positive for S. aureus drawn after Day 3 and 
with known S. aureus identification on or before Day 8. 
 
For subjects febrile at screening, persistence of fever on or beyond Day 3 after 
the start of study medication. 
 
Evidence of metastatic infection (eg, septic arthritis, septic thrombophlebitis, 
deep tissue abscess). 
 
Evidence of venous catheter line thrombosis or septic thrombosis associated 
with a venous catheter. 
NOTE: On or before Day 8, subjects with a central venous catheter as the 
presumed source of the infection should also undergo central venous 
ultrasound to evaluate for venous thrombosis associated with the central line. 
Subjects who have documented central venous thrombosis, and therefore 
septic thrombophlebitis, should be classified as CB. 
• 
Right-sided infective endocarditis (RIE): Defined as having a QBC and Definite or 
Possible endocarditis according to Modified Duke Criteria [24] (Appendix 1) without 
predisposing abnormalities or active infection of mitral or aortic valve. 
• 
Left-sided infective endocarditis (LIE): Defined as having a QBC and Definite or 
Possible LIE according to Modified Duke Criteria [24] (Appendix 1). 
On or before Day 8, subjects will be assigned to receive therapy based on the classification 
of infection type: 
• 
For UCB, subjects will receive a minimum of 2 weeks and maximum of 4 weeks 
(14 to 28 days) of therapy.  
• 
For CB, subjects will receive a minimum of 4 weeks and a maximum of 6 weeks 
(28 to 42 days) of therapy.  
• 
For endocarditis, subjects will receive 6 weeks (42 days +/- 3 days) of therapy.   
Prior to or on Day 8, a signs and symptoms worksheet will be completed to determine the 
infection type including metastatic disease (UCB, CB, RIE, LIE) and sent to the medical 
monitor to review. Subsequently, weekly worksheets noting signs and symptoms of 
potential metastatic S. aureus infection will be reviewed and completed by the physician 
investigator and forwarded to the medical monitor to optimize diagnosis and treatment of 
both the primary infection source and new metastatic foci of S. aureus.   


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Development of new signs or symptoms consistent with S. aureus infection will be 
assessed daily, during the hospital stay or during the study drug treatment period as 
clinically indicated, by clinical evaluation and other diagnostic modalities, eg, chest X-ray, 
ultrasonography, bone scan, computed tomography (CT), magnetic resonance imaging 
(MRI), and/or positron emission tomography (PET). 
After Day 8, if signs and symptoms lead to a subsequent confirmed diagnosis of new 
metastatic foci, it will be criteria for clinical failure. Management of the subject 
(eg, discontinuation of study drug) will be at the discretion of the investigator based on 
his/her standard routine care. 
Study visits for endpoint assessment will be conducted as follows: 
• 
End of therapy (EOT) Visit:  Within 3 days after the last dose of study drug 
• 
Test of cure (TOC) Visit:   
 
For subjects with UCB and assigned to receive 2 to 4 weeks (14 to 28 days) of 
treatment, their TOC is 38 (+/-2) days after randomization  regardless of the 
total duration of  study drug therapy  
 
For subjects with CB and assigned to receive 4 to 6 weeks of treatment (28 to 
42 days), their TOC is 52 (+/- 2) days after randomization regardless of the total 
duration of study drug therapy 
 
For subjects with endocarditis assigned to receive 6 weeks (42 +/-3 days) of 
treatment, their TOC is 52 (+/- 2) days after randomization regardless of the 
total duration of study drug therapy 
A post-EOT blood culture will be obtained at least 4 days after the EOT visit, and results 
must be available prior to the TOC visit. The results of this blood culture will be part of the 
assessment of clinical outcome at TOC.  
Subjects who are discharged from the hospital during the treatment or follow-up period will 
return to the hospital once per week for a study visit. After all the weekly visits are 
complete, the subject will also return to the hospital for the End of Therapy Visit, the 
Post-End of Treatment Visit, and the TOC visit. 
The TOC visit will occur based on infection classification as described above and is also 
the end of study (EOS). 
Duration of Study Participation:  The duration of study involvement for each subject will 
be up to approximately 8 weeks (ie, up to 52 days [+/- 2] days after randomization [to TOC 
evaluation]). 
Number of Subjects per Group:  The planned enrollment is 248 subjects (124 subjects 
per treatment group). 
Study Population: 
This study will enroll adult subjects with confirmed MSSA or MRSA bacteremia. 


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Inclusion Criteria: 
1. Male or female at least 18 years old at the time of consent 
2. Subject has signed an informed consent form. If a subject is unable to give consent, 
when legally permitted, consent must be obtained from the subject’s legally acceptable 
representative  
NOTE: Subject, or appropriate legal representative, must be able to communicate 
effectively with investigator and site staff 
3. At least one blood culture positive for S. aureus within 48 hours before randomization, 
referred to as the QBC 
4. In addition to the QBC, subject must have at least one of the following signs or 
symptoms of bacteremia: 
• 
Temperature ≥ 38.0°C  
• 
White blood cell (WBC) count > 10,000 or < 4,000 cells/µL, or > 10% immature 
neutrophils (bands) regardless of total peripheral WBC count 
• 
Tachycardia (heart rate > 90 bpm) 
• 
Tachypnea (respiratory rate >20 breaths/min) 
• 
Hypotension (systolic blood pressure <90 mmHg) 
• 
Signs and symptoms of localized catheter-related infection (tenderness and/or pain, 
erythema, swelling, purulent exudate within 2 cm of entry site) 
5. Subject must, at enrollment, have either 1) known right-sided infective endocarditis by 
Modified Duke’s Criteria, 2) known CB, demonstrated as signs or symptoms of 
metastatic foci of S. aureus infection (eg, any infection remote from the primary focus 
caused by hematogenous seeding or extension of infection beyond the primary focus), 
or 3) known bacteremia with at least one of the following risk factors for CB [25-28]: 
• 
Any venous catheter considered to be the source of the infection, demonstrated by 
inflammation or purulent drainage from the catheter insertion site AND evidence of 
catheter-associated thrombosis upon removal  
NOTE: A peripheral venous catheter with just inflammation or purulent drainage from 
the catheter insertion site without evidence of thrombus is not consistent with CB. 
• 
A central venous catheter (CVC) considered to be the source of infection, 
demonstrated by inflammation or purulent drainage from the CVC insertion site or 
presence of thrombus on ultrasound 
• 
A long-term intravascular catheter (eg, tunneled cuffed intravascular catheter or 
subcutaneous port catheter) considered to be the source of infection, demonstrated 
by inflammation or purulent drainage from the catheter insertion site or presence of 
thrombus on ultrasound 
• 
New onset cardiac murmur consistent with tricuspid regurgitation  


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• 
Community onset bacteremia (eg, subject does not live in a healthcare facility)   
• 
Pathogen known to be MRSA at enrollment  
• 
Duration of symptoms ≥2 days at time of presentation (prior to start of antibiotic 
therapy) 
• 
Skin exam findings suggesting acute systemic infection (ie, petechiae, vasculitis, 
infarcts, ecchymoses or pustules due to the infection) 
6. Willing to receive intravenous antibiotics for the duration of treatment 
7. Expected survival of at least 3 months 
8. Female subjects must be non-pregnant and non-lactating. If a female subject is of 
childbearing potential, must have a documented negative pregnancy test at screening 
 
NOTE: All females are considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 2 years) or documented to be surgically 
sterile (bilateral tubal ligation or total hysterectomy). A subject may be admitted to the 
study on the basis of a negative urine pregnancy test (local laboratory), pending the 
result of the serum pregnancy test. 
9. If sexually active, must agree to use a highly effective method of birth control with 
partners of childbearing potential during the study and for 1 month after study drug 
dosing 
NOTE: A highly effective method of birth control is defined as one that results in a low 
failure rate (ie, < 1% per year) when used consistently and correctly, such as implants, 
injectables, combined oral contraceptives, some intra-uterine devices (IUDs), sexual 
abstinence, or a vasectomized partner. Male subjects must agree to use medically 
acceptable birth control for at least one month following last dose of study medication. 
A vasectomy or a condom used with a spermicide is a medically acceptable birth 
control method for males. 
10. Considered likely to comply with the study procedures and to return for scheduled 
evaluations. 
Exclusion Criteria:   
1. Treatment regimen greater than 60 hours with any potentially effective (anti-
staphylococcal) systemic antibiotic(s) within 7 days before randomization 
NOTE: It is preferable to have no more than 48 hours of total prior antibiotic therapy 
within 7 days before randomization. 
EXCEPTION: Documented resistance to the prior systemic antibacterial therapy, 
confirmed by a microbiological laboratory report. 
2. Requirement or anticipated requirement of non-study systemic antibiotics during the 
study 
3. Presence of an infection source (eg, intravascular line, abscess, septic arthritis, 
infected prosthetic material, infected wound) that will not be managed or controlled 


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(eg, removal or replacement of the infected line, drainage of abscess, aspiration or 
drainage of septic arthritis, removal or replacement of infected prosthesis, or 
debridement of infected wound) within the first 3 days of study drug treatment 
4. Presence of prosthetic cardiac valve or cardiac device (eg, implantable cardioverter 
defibrillator [ICD]), permanent pacemaker, or cardiac valve support ring) 
5. Known or suspected LIE at enrollment, according to Modified Duke Criteria 
(Appendix 1) 
NOTE: Right-sided infective endocarditis (RIE) is permitted. If the subject is diagnosed 
with LIE after enrollment, subject will be allowed to remain on study. 
6. At the time of enrollment, known or highly suspected osteomyelitis, meningitis, or 
metastatic septic foci involving the central nervous system (CNS) 
NOTE: Investigators should use clinical judgment to determine whether additional 
imaging studies (eg, X-ray, computed tomography scan, magnetic resonance imaging) 
are indicated at screening to rule out the presence of osteomyelitis, meningitis, or 
metastatic septic foci in the CNS. 
7. Known at the time of enrollment to have MRSA bacteremia that is non-susceptible to 
daptomycin AND has a vancomycin MIC ≥2 μg/mL 
8. Confirmed evidence (identification or Gram stain) of a mixed polymicrobial infection 
with a Gram-negative pathogen that requires non-study antibiotic treatment with 
agent(s) that have activity against Gram-negative pathogens 
9. Previous participation in an anti-infective study during the past 12 months 
10. A history of significant hypersensitivity, allergy or intolerance to telavancin 
NOTE: Caution should be taken in subjects with a history of severe hypersensitivity 
reaction to vancomycin. If the pathogen is known MRSA, allergy to both vancomycin 
and daptomycin may require exclusion. If the pathogen is known MSSA, allergy to both 
anti-staphylococcal penicillin (PCN)/cephalosporin and daptomycin may require 
exclusion. Investigator discretion is advised on a case-by-case basis. 
 
11. Solid organ transplantation or bone marrow transplantation within 6 months before 
randomization 
12. Severe neutropenia, defined as an absolute neutrophil count (ANC) 
<500 cells per microliter, or expected development of severe neutropenia during study 
13. Known or suspected human immunodeficiency (HIV) infection with a CD4+ T-cell count 
<200/μL within the previous 6 months 
14. Subjects requiring concomitant administration of anti-coagulation therapy 
(eg, intravenous heparin sodium) AND requiring specific coagulation testing known to 
have interference by telavancin (prothrombin time/international normalized ratio, 
activated partial thromboplastin time, or activated clotting time, or coagulation-based 
Factor X activity assay) 
NOTE: Although telavancin does not interfere with coagulation, it interferes with some 
assays used to monitor coagulation. The use of unfractionated heparin or a low 
molecular weight heparin AND testing using an Anti-Xa chromogenic testing assay 


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would be permissible. 
15. Severe liver disease, ie, Child-Pugh Class C (Appendix 2), or aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) more than 10 times the 
upper limit of normal (ULN) 
16. Requirement for acute renal replacement therapy; or acute kidney injury (AKI) defined 
as an acute decrease in CrCl to < 30 mL/min and at least one of the following: 
 
≥2x increase in serum Cr or 50% decrease in glomerular filtration rate (GFR) within 
the 2 weeks prior to enrollment (RIFLE stage 2 injury (Appendix 3) 
 
Oliguria defined as urine output <0.5 mL/kg per hour for ≥12 hours at any time 
during screening 
NOTE:  Chronic renal insufficiency with a stable CrCl <30 mL/min, including chronic 
hemodialysis, is permitted. 
17. Shock or hypotension (supine systolic blood pressure <80 mm Hg) unresponsive to 
fluids or pressors within 24 hours prior to randomization 
18. QTc >460 ms (using either the Bazett or Fridericia formula), congenital long QT 
syndrome, uncompensated or new onset heart failure, aortic stenosis, 
aorticinsufficiency, or mitral insufficiency 
19. Serum creatine kinase (CK) ≥2000 U/L 
20. Breast-feeding or pregnant or intending to become pregnant (self or partner) at any 
time during the study 
21. Any other condition that in the opinion of the investigator would jeopardize the safety or 
rights of a subject or would render the subject unable to comply with the protocol; or 
any other condition that in the opinion of the investigator may confound the data. 
Test Product, Dose, and Route of Administration; Regimen; Duration of Treatment:  
For subjects with normal renal function: Telavancin, 7.5 mg/kg, IV in either 5% dextrose 
injection (D5W); sterile water for injection; or 0.9% sodium chloride; in 100 to 250 mL over 
60 (+/- 10) minutes, once every 24 hours.  
Subjects with renal impairment, either at baseline or which develops during the course of 
study treatment, should have the dosage of telavancin modified, based on estimated 
creatinine clearance, as follows: 
Creatinine Clearancea 
(mL/min) 
Telavancin Dosage Regimen 
Maximum Daily Dose 
>50 
7.5 mg/kg every 24 hours 
750 mg 
30-50 
5.6 mg/kg every 24 hours 
560 mg 
10 to <30 
3.8 mg/kg every 24 hours 
380 mg 
Stable chronic hemodialysisb 
3.8 mg/kg every 24 hours 
380 mg 
a 
For subjects receiving telavancin, the creatinine clearance for dosing should be calculated using the 
Cockcroft-Gault formula and ideal body weight (IBW). Use actual body weight if it is less than IBW. 
b 
On days when subject receives hemodialysis, telavancin should be administered following completion 
of hemodialysis. 
 


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For subjects weighing more than 100 kg, the daily telavancin dose should not exceed 
750 mg for those with normal renal function, 560 mg for those with moderate renal 
impairment, and 380 mg for subjects with severe renal impairment (creatinine clearance of 
10 to <30 mL/min) or those undergoing chronic hemodialysis (see dosing table). 
Reference Therapy, Dose, and Route of Administration; Regimen; Duration of 
Treatment:  Open-label standard IV therapy, administered for 2 to 6 weeks, includes:  
• 
Vancomycin (recommended dose of 15 mg/kg IV q12 hours); dose may be adjusted 
per local or regional product information/guidelines or local standard of care 
• 
Daptomycin (recommended dose of 6 mg/kg IV q24 hours); dose may be adjusted 
per local or regional product information/guidelines or local standard of care  
• 
Anti-staphylococcal penicillin (ie, nafcillin, oxacillin, or cloxacillin) recommended 
dose of 2 gm IV q4 hours or 12 gm IV continuous  infusion over 24 hours; dose may 
be adjusted per local or regional product information/guidelines or local standard of 
care 
• 
Cefazolin (recommended dose of 2 gm IV q8 hours); dose may be adjusted per local 
or regional product information/guidelines or local standard of care. 
Study Evaluations 
Safety Assessments: 
Adverse events (AE) (including SAEs), clinical laboratory tests (including hematology, 
serum chemistry, urinalysis, and creatine kinase), vital signs, use of concomitant 
medications, and physical examination will be used to assess safety. Additional information 
regarding renal AEs (eg, laboratory and radiographic results at the time of potential renal 
injury) will be obtained and recorded in the renal AE eCRF. 
Efficacy Assessments: 
Efficacy assessments include evaluation of signs and symptoms consistent with S. aureus 
infection such as blood cultures, physical examination, and echocardiography (TEE, or 
TTE if TEE is not possible); and may also include, but are not limited to, chest X-ray, 
additional specimen cultures, ultrasonography, bone scan, CT, MRI, and PET scan.   
Pharmacokinetic Assessments: 
Pharmacokinetic samples will be collected while in the hospital setting and, as feasible, in 
the outpatient setting, from randomized subjects who receive telavancin or vancomycin as 
follows:  
For all subjects receiving telavancin: 
• 
On Day 1: At 1 hour (+15 min window) after the start of the infusion, between 4 to 
8 hours after the start of the infusion. On Day 2 prior to the start of the infusion 
(within 30 minutes before dosing). On Days 3 and 5, predose (within 30 minutes 
before dosing). On Day 7, predose (within 30 minutes before dosing), and between 


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4 to 8 hours after the start of the infusion.  On Day 14, predose (within 30 minutes 
before dosing). 
• 
As feasible, following each change in telavancin dosing during the first 2 weeks of 
therapy due to a change in renal function classification:  Predose (within 30 minutes 
before dosing), between 1 to 4 hours after the start of the infusion (sample must be 
collected following completion of the infusion), and on the next day prior to the start 
of the next infusion (within 30 minutes before dosing).  
NOTE: These blood samples are in addition to scheduled samples. In the case where the 
additional sample coincides with a planned time point, then only one sample is to be drawn 
at that time. 
For all subjects receiving vancomycin: 
• 
On Day 1: At 1 hour (+15 min window) after the beginning of the infusion.  On Day 3, 
predose (within 30 minutes before dosing).  On Day 5, predose (within 30 minutes 
before dosing), and at 1, 5, 8, and 12 hours after the beginning of the infusion 
(+15 minute window).  On Day 14, predose (within 30 minutes before dosing). 
For subjects receiving vancomycin, trough levels as determined by the hospital for use in 
determining the dosing amount will be recorded. 
Study Endpoints: 
The primary efficacy endpoint is clinical outcome at TOC analyzed in subjects with a 
baseline diagnosis of UCB, CB or RIE in the mAT population.  
The key secondary efficacy endpoints are as follows: 
• 
Clinical outcome at TOC by baseline diagnosis in the mAT and microbiological 
evaluable (ME) populations 
• 
Clinical response at EOT in the mAT and ME populations 
• 
Development of new metastatic foci of S. aureus infection after Day 8 in the mAT 
and ME populations 
• 
Duration of treatment with study medication by baseline clinical diagnosis in the mAT 
and ME populations 
• 
For subjects with a positive S. aureus blood culture on Day 1, time to all blood 
cultures negative for S. aureus for two days in succession (ie, clearance of 
bacteremia) (does not have to be consecutive calendar days) in the mAT and 
ME populations; date will be first of the two days in succession 
• 
28-day all-cause mortality for subjects with a baseline diagnosis of CB or RIE in the 
mAT and ME populations 
• 
Incidence of AEs, treatment-emergent AEs, SAEs, and deaths in the safety 
population 
• 
Incidence of key laboratory indices in the safety population, to be further described in 
the Statistical Analysis Plan (SAP). 


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The efficacy endpoint of clinical outcome at TOC will be determined by the investigator and 
adjudicated by the blinded IEAC. Specific evaluability criteria (outlined in the SAP) will be 
applied to determine subject eligibility for each population.  
Exploratory analyses will be conducted to assess a variety of health utilization variables. 
Methods of analysis for these variables will be outlined in a separate health economics 
outcomes statistical analysis plan (HEOR SAP). The results of these analyses will be 
presented separately and not included in the clinical study report (CSR). 
Statistical Methods 
Analysis Populations: 
The All-Treated (AT) population is defined as all randomized subjects who have received at 
least one dose of study drug and were enrolled after protocol Amendment 1.  Subjects 
enrolled prior to Protocol Amendment 1 will be excluded from all efficacy analyses, 
because the dose of telavancin was decreased following Protocol Amendment 1.  Analyses 
conducted based on the AT population will assign subjects according to their randomized 
treatments. 
The mAT population includes subjects in the AT population who have a mono-microbial 
QBC positive for S. aureus. 
The ME population is a subset of the mAT population and includes subjects who meet the 
following criteria: 
1. Completed at least 80% of prescribed study medication for their baseline diagnosis 
2. Did not miss more than 2 consecutive doses of study medication 
3. Completed the TOC visit 
4. Did not have any recorded major protocol deviations 
5. If assessed as failure at TOC, received at least 2 days of study medication 
6. If assessed as cure at TOC, received at least 5 days of study medication 
7. Did not receive any prohibited concomitant, potentially effective antibiotic (other than 
study medication). 
The safety population will be defined as all subjects from the AT population and subject 
assignment according to actual study treatments they receive.  
The PK population will be defined as all subjects from the safety population who provide 
evaluable PK data from at least one postdose sample in plasma. 
Analysis: 
The primary analysis will test both clinical noninferiority and superiority of telavancin 
relative to standard IV therapy in the treatment of S. aureus bacteremia including SA-RIE. 
Both tests will be conducted at a one-sided 2.5% significance level. No adjustment of the 


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Type I error rate is necessary for conducting these two tests sequentially as the process is 
supported by the closed-testing principle. 
Secondary efficacy endpoints will be tested in a hierarchical fashion at the two-sided 5% 
level of significance until a failure to reject occurs. For all supportive analyses, p-values 
and confidence intervals will be evaluated at the two-sided 5% level with no adjustment for 
multiplicity.  
The analysis of the primary endpoint will be conducted based on the mAT population with a 
diagnosis of UCB, CB, or RIE, and the point estimate and confidence interval (CI) for the 
treatment difference in clinical cure rates will be calculated using the normal approximation 
to the binomial distribution without continuity correction.  
Analysis of other endpoints focusing on incidence of occurrence (eg, development of new 
metastatic foci of infection) will be similar to the primary analysis of clinical outcome 
previously described. 
Time-to-event endpoints will be reported graphically using Kaplan-Meier survival curves 
and, as appropriate, treatment differences will be evaluated using log-rank tests, stratified 
by geographic region. 
Safety endpoints will be evaluated for the safety population. Unless specified otherwise, 
safety assessments will be summarized descriptively by treatment group. 
For subjects who receive telavancin or vancomycin and have at least one post-dose PK 
sample collected, plasma concentration profiles will be estimated. Estimated PK 
parameters may include: 
Time of maximum concentration (Tmax) 
Maximum observed plasma concentration (Cmax) 
Area under the plasma concentration versus time curve from time 0 to the last sample with 
measurable analyte concentration (AUC0−t) 
Area under the concentration versus time curve extrapolated to infinity (AUC0-inf) 
Terminal elimination half-life (t1/2)  
Plasma clearance (CLp) 
Volume of distribution at steady-state (Vdss) 
Noncompartmental and nonlinear mixed-effects modeling methods will be used for 
determination of PK parameters, as appropriate.  
All PK parameters will be presented as individual listings and as summary statistics (mean, 
geometric mean, median, range, standard deviation, coefficient of variation, minimum, 
maximum, and number of subjects).  
 
 


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Sample Size: 
Assuming a population clinical cure rate of 70% for standard IV therapy and 72.5% for 
telavancin, a total sample size of 210 (105 per treatment group) is deemed sufficient 
(80% power) to demonstrate noninferiority based on a noninferiority margin of 15% at a 
one-sided significance level of 2.5%.  This calculation does not take into account potential 
stopping for futility at an interim analysis.  A total of 248 subjects will be enrolled to allow 
for exclusion of up to 15% of subjects from the primary analysis set due to an LIE diagnosis 
or not meeting the mAT population criteria. 
Interim Analysis: A single interim assessment allowing early stopping for futility will be 
performed based on the subjects who completed or discontinued from the study on or 
before October 31, 2017.   
Conditional power to show non-inferiority under the current trend will be computed using 
the normal approximation to the non-inferiority test statistic.  The IDMC may recommend 
stopping for futility, if the conditional power is 50% or less. 
 


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SCHEDULE OF STUDY PROCEDURES 
 
Table 1: 
Schedule of Study Procedures 
Procedure 
Screening/ 
Enrollmenta 
Treatment Period 
Post-Treatment Period 
Daily  
(Day 1 
up to 
EOT) 
Additional 
Daily  
(Day 1 up 
to Day 8) 
Weekly 
(± 3 
days)  
Otherb 
EOT/ 
Termination/ 
Early 
Withdrawal 
Visitc 
Post-EOT 
Blood 
Culture 
Weekly 
(± 3 
days) 
TOC 
Visitd 
(EOS) 
Informed Consente 
X 
 
 
 
 
 
 
 
 
Review of Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
Medication and Medical History 
X 
 
 
 
 
 
 
 
 
Body Temperaturef 
X 
X 
 
 
 
X 
 
X 
X 
Physical Examination, including Vital 
Signs 
X 
 
 
 
 
X 
 
 
X 
Evaluate Signs/Symptoms of 
S. aureus Infection, including 
Metastatic Foci of Infection  
X 
 
 Xg 
Xg 
 
 Xg 
 
 Xg 
X 
Chest X-Ray or CT Scan (chest)h 
X 
 
 
 
 
 
 
 
 
Blood Culturei 
Xj 
 Xk 
 
 
 
 
Xl 
 
 
Urine Culturebb 
  Xaa 
 
 
 
 
 
 
 
 
Infection Site Specimen Culturem 
X 
 
 
 
 
 
 
 
 
Hematology, Serum Chemistry, 
Creatine Kinase  
X 
 
 
Xz 
 
X 
 
 
 
Urinalysis with Microscopybb 
X 
 
 
 
 
X 
 
 
 
Additional Serum Creatinine, 
Creatinine Clearancen 
 
 
Xo 
 
Xo 
 
 
 
 


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Table 1: 
Schedule of Study Procedures 
Procedure 
Screening/ 
Enrollmenta 
Treatment Period 
Post-Treatment Period 
Daily  
(Day 1 
up to 
EOT) 
Additional 
Daily  
(Day 1 up 
to Day 8) 
Weekly 
(± 3 
days)  
Otherb 
EOT/ 
Termination/ 
Early 
Withdrawal 
Visitc 
Post-EOT 
Blood 
Culture 
Weekly 
(± 3 
days) 
TOC 
Visitd 
(EOS) 
Pregnancy Testp 
X 
 
 
 
X 
 
 
 
X 
Electrocardiogram (12-lead)q 
X 
 
 
 
X 
X 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
Study Drug Dosingr 
 
X 
 
 
 
 
 
 
 
Infection Source Controls 
 
 
 
 
X 
 
 
 
 
Classification of Infection Typet 
 
 
 
 
X 
 
 
 
 
Echocardiographyu 
 
 
 
 
X 
 
 
 
 
Central Venous Ultrasonographyv 
 
 
 
 
X 
 
 
 
 
Recording of significant procedures 
(eg, surgical, radiographic) 
X 
 
X 
X 
 
X 
 
X 
X 
Pharmacokinetic Blood Collectionw 
telavancin and vancomycin subjects only 
 
 
 
 
X 
 
 
 
 
Serum CRP 
X 
 
 
X 
X 
X 
 
 
 
Serum IL-10 
X 
 
 
 
 
X 
 
 
 
Obtain Urine for Renal Biomarker 
Quantificationbb 
X 
 
 
 
 
X 
 
 
 
APACHE II Assessmentx 
X 
 
 
 
 
 
 
 
 
Concomitant Medications 
 
X 
 
 
 
X 
 
X 
X 


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SCHEDULE OF STUDY PROCEDURES (CONTINUED) 
 
Confidential – Property of Theravance Biopharma US, Inc. 
Table 1: 
Schedule of Study Procedures 
Procedure 
Screening/ 
Enrollmenta 
Treatment Period 
Post-Treatment Period 
Daily  
(Day 1 
up to 
EOT) 
Additional 
Daily  
(Day 1 up 
to Day 8) 
Weekly 
(± 3 
days)  
Otherb 
EOT/ 
Termination/ 
Early 
Withdrawal 
Visitc 
Post-EOT 
Blood 
Culture 
Weekly 
(± 3 
days) 
TOC 
Visitd 
(EOS) 
Assessment of Adverse Eventsy 
X 
X 
 
 
 
X 
 
X 
X 
Clinical Outcome Assessment 
 
 
 
 
 
X 
 
 
X 
a Pretreatment (screening) evaluations will be performed within 48 hours before randomization unless otherwise specified. If the screening assessments and 
results are obtained within this 48-hour period, they will be considered valid screening evaluations and do not need to be repeated following ICF signature. 
Local laboratory test results will be used to determine a subject’s eligibility for enrollment. 
b Procedures to be completed at time points other than daily or weekly. 
c End of therapy (EOT) visit occurs within 3 days after the last dose of study drug. 
d   Test of cure (TOC) visit: For subjects with uncomplicated bacteremia and assigned to receive 2 to 4 weeks (14-28 days) of treatment, their TOC is 
38 (+/- 2) days after randomization  regardless of the total duration of  study drug therapy. For subjects with complicated bacteremia and assigned to receive 
4 to 6 weeks of treatment (28 to 42 days), their TOC is 52 (+/- 2) days after randomization regardless of the total duration of study drug therapy. For subjects 
with endocarditis assigned to receive 6 weeks (42 +/-3 days) of treatment, their TOC is 52 (+/- 2) days after randomization regardless of the total duration of 
study drug therapy. The TOC visit is also the end of study (EOS). 
e In the event that a subject is unable to give consent, when legally permitted, the subject's legally acceptable representative must do so. 
f 
Obtain and record highest daily temperature and method of measurement on electronic case report form (eCRF).  Use same method for consistency. 
g  Evaluate for metastatic S. aureus infection daily, up to Day 8. Prior to or on Day 8 a signs and symptoms worksheet will be completed to determine the 
infection type including metastatic disease (UCB, CB, RIE, LIE) and sent to the medical monitor to review. Subsequently, weekly worksheets noting signs and 
symptoms of potential metastatic S. aureus infection will be reviewed and completed by the physician investigator and forwarded to the medical monitor to 
optimize diagnosis and treatment of both the primary infection source and new metastatic foci of S. aureus. Additional procedures may include a physical 
exam, chest X-ray, ultrasonography, bone scan, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) 
scan, and may be done at any time during the study, when clinically indicated, to evaluate extent of infection.  
h Obtain chest x-ray or CT of chest within 3 days after the report of the QBC. If a chest x-ray or CT of chest is obtained during the screening period (within 
48 hours prior to randomization), a repeat chest x-ray or CT does not need to be done. 
i 
The investigator may initiate study treatment based on a single blood culture positive for S. aureus on Day -2 or -1. Perform culture and organism identification 
at the local or regional laboratory, as applicable. All S. aureus isolates should be sent to the central laboratory for organism identification and susceptibility 
testing. Record identification of all non-S. aureus isolates in the electronic case report form (eCRF). 


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j 
At baseline, a blood culture is to be obtained from a fresh venipuncture site. To be eligible for randomization, this blood culture must be positive for S. aureus, 
within 48 hours of randomization and is referred to as the QBC. All S. aureus isolates should be sent to the central laboratory for organism identification and 
susceptibility testing. 
k Blood cultures will be obtained daily by fresh venipuncture during the treatment period until two successive blood cultures are negative for S. aureus (need not 
be consecutive calendar days) post-randomization. Blood cultures should be obtained at any time during the study when clinically indicated, eg, bacteremia is 
suspected. All S. aureus isolates should be sent to the central laboratory for organism identification and susceptibility testing. 
l 
Follow-up blood cultures must be obtained at least 4 days after the EOT visit and results must be available prior to the TOC visit. These blood cultures consist 
of 2 samples (8-10 mL) from separate sites inoculated into 2 standard aerobic blood culture bottles. For subjects who are no longer hospitalized, this visit may 
be coordinated to occur when the subject returns for his/her weekly visit. For subjects not completing study treatment, two blood cultures from separate fresh 
venipuncture sites will be obtained at the early termination visit. All S. aureus isolates should be sent to the central laboratory for organism identification and 
susceptibility testing. 
m Obtain specimen for culture when a primary source of bacteremia is identified. If there is no clinical evidence of the primary source of bacteremia, no culture is 
required. Any central or peripheral catheters present at the time of the bacteremia will be removed. Removed catheters can be replaced, but in the case of 
central catheters they cannot be replaced using wire-guided methods, or placed in the same site if there is clinical evidence of infection at the entry site.  
n Creatinine clearance will be calculated by the central and local laboratories using the Cockcroft Gault Formula and actual body weight. For subjects on 
telavancin only, if dose adjustment is necessary due to renal impairment, per Table 3 in Section 5.2.1, the pharmacist will calculate creatinine clearance using 
the Cockcroft-Gault formula and ideal body weight (IBW). Use actual body weight if it is less than IBW. 
o Obtain serum creatinine and creatinine clearance daily (sample will be sent to both the local and central lab), up to Day 8, while the subject is hospitalized. 
After Day 8, or if subject is discharged from the hospital to outpatient parenteral antibiotic therapy (OPAT) or home health care (HHC), serum creatinine and 
creatinine clearance will be obtained every 2 to 3 days (samples to be sent to central laboratory) while on study drug. On the days where the weekly safety lab 
coincides with the creatinine monitoring, serum creatinine and creatinine clearance will be tested using the weekly safety lab kit.  
p Subjects may be enrolled into the study on the basis of a negative urine pregnancy test (local laboratory), pending the result of the serum pregnancy test. If 
the result of the serum test is subsequently positive, study drug must be discontinued, EOT evaluations performed, and an EOS visit scheduled. A urine 
pregnancy test (local laboratory) will be performed once per month (ie, in subjects treated for 6 weeks) as per local regulatory requirements. 
q One 12-lead electrocardiogram (ECG) will be obtained at the prestudy treatment evaluation. If the QTc is >460 ms (using either the Bazett or Fridericia 
formula) at the screening ECG, the subject will not be entered into the study. Additional ECGs will be obtained at Week 3, 6, or at the Early Termination visit. 
Subject should be withdrawn from treatment if the QTc time is >500 ms or if the QTc time is ≥60 ms above baseline. Any other relevant ECG abnormalities 
noted at Week 3, 6, or unscheduled ECGs, should be classified as an AE and additional ECGs will be required weekly until the subject discontinues from the 
study. If feasible, every effort should be made to obtain duplicates of all ECGs. All original ECGs obtained for each time point (not photocopied) will be held 
with the study files for analysis in the event that a central reader is required. 
r 
Daily dosing of study drug will be administered according to the infection classification.  For uncomplicated bacteremia, subjects will receive a minimum of 
2 weeks and maximum of 4 weeks (14 to 28 days) of therapy.  For complicated bacteremia, subjects will receive a minimum of 4 weeks and a maximum of 
6 weeks (28 to 42 days) of therapy.  For endocarditis, subjects will receive 6 weeks (42 +/- 3 days) of therapy.   
s Procedures to control or eliminate the infection source, eg, by removal of intravascular lines or drainage and debridement of the primary infection site, will be 
completed within the first 3 days of study drug treatment. All microbiological specimens must be cultured. 
t 
Prior to or on Day 8 a signs and symptoms worksheet will be completed to determine the infection type including metastatic disease (UCB, CB, RIE, LIE) and 
sent to the medical monitor to review.  


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u Echocardiography (either TTE or TEE; TEE is strongly preferred) will be performed on or before Day 8. All echocardiograms will undergo blinded review by an 
independent echocardiography core laboratory. 
v On or before Day 8, subjects with a central venous catheter (CVC) as the presumed source of the infection, should also undergo central venous ultrasound to 
evaluate for venous thrombosis associated with the central line. 
w Pharmacokinetic (PK) samples will only be obtained from subjects on telavancin or vancomycin while in the hospital setting and as feasible in the outpatient 
setting.  
For subjects receiving telavancin: Blood samples will be obtained for PK on Day 1: At 1 hour (+15 minute window), between 4 to 8 hours after the beginning of 
the infusion. On Day 2 prior to beginning the next infusion (within 30 minutes before dosing). On Days 3 and 5, predose (within 30 minutes before dosing). On 
Day 7, predose (within 30 minutes before dosing), and between 4 to 8 hours after the beginning of the infusion.  On Day 14, predose (within 30 minutes before 
dosing). As feasible, following each change in telavancin dosing during the first 2 weeks of therapy due to a change in renal function classification:  Predose 
(within 30 minutes before dosing), between 1 to 4 hours after the beginning of the infusion (sample must be collected following completion of the infusion), and 
24 hours after the beginning of the infusion and prior to beginning the next infusion (within 30 minutes before dosing). These blood samples are in addition to 
scheduled samples. In the case where the additional sample coincides with a planned time point, then only one sample is to be drawn at that time. 
For subjects receiving vancomycin: Blood samples will be obtained for PK on Day 1: at 1 hour after the beginning of the infusion (+15 minute window).  
On Day 3, predose (within 30 minutes before dosing).  On Day 5, predose (within 30 minutes before dosing), and at 1, 5, 8, and 12 hours after the beginning 
of the infusion (+15 minute window).  On Day 14, predose (within 30 minutes before dosing). 
x The Acute Physiologic and Chronic Health Evaluation (APACHE) scoring system requires the input of many clinical variables, from which a severity score is 
derived. The resulting severity score is entered into a logistical regression equation, which predicts hospital mortality.  Obtain within 24 hours prior to 
randomization. 
y Additional information regarding renal AEs (eg, laboratory and radiographic results at the time of potential renal injury) will be obtained and recorded in the 
renal AE eCRF. 
z Safety labs (hematology, serum chemistry, and creatine kinase) obtained at the completion of the first week should be obtained on Day 7 (+/- 1 day). 
Subsequent weekly safety labs should be obtained weekly (+/- 3 days). 
aa Send only S. aureus isolates from the screening urine culture to the central laboratory. 
bb Subjects on hemodialysis may have the urine assessments waived due to anuria. 
 


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Figure 1: 
Study Diagram 
 
 
* Minimum treatment period for: uncomplicated bacteremia is 2 weeks (14 days), 4 weeks (28 days) for complicated bacteremia and 6 weeks (42 +/-3days) for 
endocarditis 
 
 
 
IV Telavancin 
Standard IV Therapy 
Screening Assessments 
TOC / 
EOS 
EOT 
EOT 
Treatment Period*   
2 to 6 weeks  
 (14 to 42 days) 
 
EOT Visit 
Within 3 days 
after last dose 
TOC / EOS Visit 
Either 38 (+/- 2) or 52 (+/- 2) 
days after randomization, 
depending infection classification 
(see Figure 2)  
Screening 
 Within 48 hours prior to 
randomization 


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Figure 2: 
Dosing Duration by Infection Classification 
 
Infection 
Treatment Period 
Test of Cure (TOC) 
 
 
 


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Figure 3: 
PK Collection Timepoints for Telavancin 
Day 
Telavancin PK collection 
Day 1 
1 hour (+15 min window) after start of infusion 
Between 4 to 8 hours after start of infusion 
Day 2 
Prior to start of the infusion (within 30 minutes before dosing) 
Day 3 
Predose (within 30 minutes before dosing) 
Day 5 
Predose (within 30 minutes before dosing) 
Day 7 
Predose (within 30 minutes before dosing) 
Between 4 to 8 hours after start of infusion 
Day 14 
Predose (within 30 minutes before dosing) 
PK Collection for Every Telavancin Dose Change Due to Renal Function Classification  
(within first 2 weeks only, as feasible) 
Predose (within 30 minutes before dosing) 
Between 1 to 4 hours after start of infusion (sample must be collected following completion of the 
infusion) 
Prior to start of the next infusion (within 30 minutes before dosing) 
 


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Figure 4: 
PK Collection Timepoints for Vancomycin 
Day 
Vancomycin* PK collection 
Day 1 
1 hour (+15 min window) after start of infusion 
Day 3 
Predose (within 30 minutes before dosing) 
Day 5 
Predose (within 30 minutes before dosing) 
1 hour (+15 min) after start of infusion 
5 hour (+15 min) after start of infusion 
8 hour (+15 min) after start of infusion 
12 hour (+15 min) after start of infusion 
Day 14 
Predose (within 30 minutes before dosing) 
 
*  Trough levels of vancomycin are determined by the hospital laboratory for use in adjusting vancomycin dosing 
will be recorded. 
 
 
 


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TABLE OF CONTENTS 
PAGE 
PROTOCOL SYNOPSIS ....................................................................................................... 2 
SCHEDULE OF STUDY PROCEDURES ............................................................................ 18 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................ 30 
1 
INTRODUCTION ..................................................................................................... 33 
1.1 
Background and Rationale ........................................................................... 33 
1.2 
Nonclinical Profile ......................................................................................... 37 
1.3 
Clinical Experience ....................................................................................... 37 
1.4 
Risks and Benefits ....................................................................................... 38 
2 
OBJECTIVES .......................................................................................................... 40 
3 
STUDY DESIGN ...................................................................................................... 41 
3.1 
Overview ...................................................................................................... 41 
3.2 
Rationale for Study Design ........................................................................... 44 
3.3 
Selection of Dose and Duration of Treatment ............................................... 45 
3.3.1 
Telavancin ........................................................................................ 45 
3.3.2 
Standard Intravenous Therapy ......................................................... 46 
3.3.3 
Switching to Another Intravenous Antibiotic Therapy ........................ 47 
3.4 
Study Endpoints ........................................................................................... 48 
3.4.1 
Safety Endpoints .............................................................................. 48 
3.4.2 
Primary Efficacy Endpoint ................................................................. 48 
3.4.3 
Secondary Efficacy Endpoints .......................................................... 50 
3.4.4 
Pharmacokinetic Endpoints .............................................................. 51 
3.5 
Minimization of Bias ..................................................................................... 52 
3.5.1 
Treatment Assignment ...................................................................... 52 
3.5.2 
Blinding............................................................................................. 52 
4 
STUDY POPULATION ............................................................................................ 53 
4.1 
Inclusion Criteria .......................................................................................... 53 
4.2 
Exclusion Criteria ......................................................................................... 55 
5 
STUDY DRUGS ...................................................................................................... 57 
5.1 
Description of Study Drugs ........................................................................... 57 
5.2 
Dosage and Administration .......................................................................... 57 
5.2.1 
Telavancin ........................................................................................ 57 
5.2.2 
Vancomycin ...................................................................................... 58 
5.2.3 
Daptomycin ...................................................................................... 58 
5.2.4 
Anti-Staphylococcal Penicillin ........................................................... 59 
5.2.5 
Cefazolin .......................................................................................... 59 
5.3 
Criteria for Hospital Discharge (Outpatient Study Drug Administration) ........ 59 
5.4 
Guidance to Investigators on Duration of Treatment .................................... 60 
5.5 
Treatment Compliance ................................................................................. 60 
5.6 
Drug Accountability and Reconciliation ........................................................ 60 
6 
STUDY PROCEDURES .......................................................................................... 62 
6.1 
Schedule of Study Procedures ..................................................................... 62 
6.2 
Procedures by Visit ...................................................................................... 62 
6.2.1 
Pretreatment Screening Evaluation .................................................. 62 
6.2.2 
Daily Procedures .............................................................................. 64 
6.2.3 
Additional Procedures On or Before Day 8 ....................................... 65 


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6.2.4 
Weekly Procedures After Day 8 ........................................................ 66 
6.2.5 
End of Therapy Visit / Termination / Early Withdrawal ...................... 67 
6.2.6 
Post-End of Therapy Blood Culture .................................................. 68 
6.2.7 
Test of Cure Visit / End of Study ....................................................... 68 
6.3 
Description of Study Assessments and Procedures ..................................... 69 
6.3.1 
Efficacy Assessments ....................................................................... 69 
6.3.2 
Safety Assessments ......................................................................... 69 
6.3.2.1 
Adverse Events ............................................................... 69 
6.3.2.2 
Medical History ................................................................ 69 
6.3.2.3 
Physical Examination ...................................................... 70 
6.3.2.4 
Vital Signs ....................................................................... 70 
6.3.2.5 
Electrocardiogram ........................................................... 70 
6.3.2.6 
Laboratory Tests ............................................................. 71 
6.3.3 
Pharmacokinetic Assessments ......................................................... 72 
6.4 
Laboratory Test Interference ........................................................................ 74 
6.4.1 
Coagulation Tests ............................................................................. 74 
6.4.2 
Urine Protein Tests ........................................................................... 75 
6.5 
Prohibited Concomitant Medications ............................................................ 75 
6.6 
Restrictions .................................................................................................. 76 
6.7 
Discontinuation ............................................................................................ 76 
6.7.1 
Subject Discontinuation .................................................................... 76 
6.7.2 
Subject Replacement ........................................................................ 77 
6.7.3 
Study Discontinuation ....................................................................... 77 
6.8 
Pregnancy .................................................................................................... 77 
7 
ADVERSE EVENTS ................................................................................................ 78 
7.1 
Regulatory Definition of an Adverse Event ................................................... 78 
7.2 
Adverse Event Definition for the Purposes of This Study .............................. 78 
7.3 
Assessment of Adverse Events .................................................................... 79 
7.4 
Serious Adverse Events ............................................................................... 80 
7.5 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as Adverse Events or Serious Adverse Events ............................................ 81 
7.6 
Serious Adverse Event Reporting ................................................................ 81 
7.7 
Adverse Event Follow-up ............................................................................. 82 
8 
STATISTICAL CONSIDERATIONS ......................................................................... 83 
8.1 
Sample Size and Power ............................................................................... 83 
8.2 
General Considerations ................................................................................ 83 
8.3 
Analysis Populations .................................................................................... 83 
8.3.1 
Efficacy Analysis Populations ........................................................... 83 
8.3.2 
Safety Analysis Population ............................................................... 84 
8.3.3 
Pharmacokinetic Analysis Population ............................................... 84 
8.3.4 
Examination of Subgroups ................................................................ 84 
8.4 
Analyses ...................................................................................................... 85 
8.4.1 
Disposition, Demographics, Baseline Characteristics, and 
Exposure .......................................................................................... 85 
8.4.2 
Analysis of Efficacy ........................................................................... 85 
8.4.3 
Analysis of Safety ............................................................................. 87 


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8.5 
Analysis of Pharmacokinetics ....................................................................... 88 
8.6 
Handling of Missing Data ............................................................................. 89 
8.7 
Multiple Testing: Order of Hypotheses ......................................................... 89 
8.8 
Interim Analysis ............................................................................................ 89 
8.9 
Independent Efficacy Adjudication Committee ............................................. 90 
8.10 
Independent Data Monitoring Committee ..................................................... 90 
9 
STUDY ADMINISTRATION ..................................................................................... 91 
9.1 
Principal Investigator Responsibilities .......................................................... 91 
9.2 
Institutional Review Board/Independent Ethics Committee ........................... 92 
9.3 
Informed Consent ......................................................................................... 92 
9.4 
Data Recording and Quality Assurance ........................................................ 93 
9.5 
Document Retention .................................................................................... 94 
9.6 
Confidentiality .............................................................................................. 94 
9.7 
Access to Data and Documents ................................................................... 95 
9.8 
Quality Control: Study Monitoring and Auditing ............................................ 95 
9.9 
End of Study ................................................................................................ 96 
9.10 
Publication ................................................................................................... 96 
10 
REFERENCES ........................................................................................................ 98 
11 
APPENDICES ....................................................................................................... 100 
 
LIST OF TABLES 
 
Table 1: 
Schedule of Study Procedures ......................................................... 18 
Table 2: 
Clinical Outcome at TOC .................................................................. 50 
Table 3: 
Telavancin Dosage Adjustment in Subjects with Renal 
Impairment ....................................................................................... 58 
Table 4: 
Coagulation Tests Affected and Unaffected by Telavancin ............... 75 
 
LIST OF FIGURES 
 
Figure 1: 
Study Diagram .................................................................................. 23 
Figure 2: 
Dosing Duration by Infection Classification ....................................... 24 
Figure 3: 
PK Collection Timepoints for Telavancin ........................................... 25 
Figure 4: 
PK Collection Timepoints for Vancomycin ........................................ 26 
 
LIST OF APPENDICES 
 
Appendix 1: 
Modified Duke Criteria for Endocarditis ........................................... 100 
Appendix 2: 
Child-Turcotte-Pugh Chronic Liver Disease Score .......................... 102 
Appendix 3: 
RIFLE Criteria for Acute Kidney Injury ............................................ 103 
Appendix 4: 
APACHE II Assessment Criteria ..................................................... 104 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Description 
AE 
adverse event 
AKI 
acute kidney injury 
ALT 
alanine aminotransferase 
ANC 
Absolute neutrophil count 
APACHE 
Acute Physiologic and Chronic Health Evaluation 
aPTT 
activated partial thromboplastin time 
AT 
All-Treated 
AST 
aspartate aminotransferase 
AUC0-inf 
area under the concentration versus time curve extrapolated to infinity 
AUC0-t 
area under the plasma concentration versus time curve from time 0 to the last 
sample with measurable analyte concentration 
BMI 
body mass Index 
BP 
blood pressure 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CB 
complicated bacteremia 
CE 
clinically evaluable (analysis population) 
CFR 
(United States) Code of Federal Regulations 
CI 
confidence interval 
CK 
creatine kinase 
CLp 
plasma clearance 
Cmax 
maximum observed plasma concentration 
CNS 
central nervous system 
CrCl 
creatinine clearance 
CRF 
case report form 
CRP 
C-reactive protein 
CSR 
clinical study report 
cSSSI 
complicated skin and skin structure infection 
CT 
computed tomography 
CVC 
central venous catheter 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
end of study 
EOT 
end of therapy 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Description 
HABP 
hospital-acquired bacterial pneumonia 
HEOR SAP 
Health economics statistical analysis plan 
HHC 
home health care 
HIV 
human immunodeficiency virus 
HR 
heart rate 
IB 
investigator's brochure 
IBW 
ideal body weight 
IL-10 
interleukin-10 
ICD 
implantable cardioverter defibrillator 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IDMC 
Independent data monitoring committee 
IE 
infective endocarditis 
IEAC 
independent efficacy adjudication committee 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IUD 
Intra-uterine device 
IV 
Intravenous 
IXRS 
interactive response system 
LAR 
legally authorized representative 
LDH 
lactate dehydrogenase 
LIE 
left-sided infective endocarditis 
mAT 
Microbiological all-treated (analysis population) 
ME 
Microbiological evaluable (analysis population) 
MedDRA® 
Medical Dictionary for Regulatory Activities  
MIC 
minimum inhibitory concentration 
MRI 
magnetic resonance imaging 
MRSA 
methicillin-resistant Staphylococcus aureus 
MSSA 
methicillin-sensitive Staphylococcus aureus 
NP 
nosocomial pneumonia 
OPAT 
outpatient parenteral antibiotic therapy (facility) 
PCN 
Penicillin 
PET 
positron emission tomography 
PI 
principal investigator 
PK 
Pharmacokinetics 
PT 
prothrombin time 
QBC 
qualifying blood culture 
QTc 
corrected QT interval 
REB 
Research Ethics Board 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Description 
RIE 
right-sided infective endocarditis 
RIFLE 
Risk, Injury, and Failure; and Loss; and End-stage kidney disease 
RR 
respiratory rate 
SAE 
serious adverse event(s) 
SA-RIE 
right-sided infective endocarditis caused by Staphylococcus aureus 
SAP 
statistical analysis plan 
SOP 
standard operating procedure 
S. aureus 
Staphylococcus aureus 
t1/2 
terminal elimination half-life 
TEAE 
treatment emergent adverse event(s) 
TEE 
transesophageal echocardiogram 
Tmax 
time of maximum concentration 
TOC 
test of cure 
TTE 
transthoracic echocardiogram 
UCB 
uncomplicated bacteremia 
ULN 
upper limit of normal range 
VABP 
ventilator associated bacterial pneumonia 
Vdss 
volume of distribution at steady-state 
VISA 
vancomycin-intermediate S. aureus 
WBC 
white blood cell 
 


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1 
INTRODUCTION 
1.1 
Background and Rationale 
Bacteremia due to S. aureus is a frequently encountered serious infection that is often 
associated with infective endocarditis [1-3]. Treatment of bacteremia is challenging; infection 
metastasis and relapse are common, as is the involvement of antibiotic-resistant bacterial 
strains, including methicillin-resistant S. aureus (MRSA) [4]. In the treatment guidelines for 
MRSA bacteremia from the Infectious Diseases Society of America, only two agents are 
recommended: vancomycin, the traditional first-line therapy for MRSA infections, and 
daptomycin [5]. Both of these agents have recognized shortcomings. Vancomycin has 
limited tissue penetration, is slowly bactericidal [6], is suboptimal against 
methicillin-susceptible S. aureus (MSSA) [7, 8], and evidence suggests decreasing 
susceptibility among Gram-positive pathogens [7, 9, 10]. Resistance to daptomycin has 
more recently emerged, together with evidence suggesting that reduced susceptibility to 
vancomycin may also impact susceptibility to daptomycin [11, 12]. As such, there is a critical 
need for additional agents appropriate for the treatment of S. aureus bacteremia. 
Telavancin is a rapidly bactericidal lipoglycopeptide antibiotic that is active against a range 
of clinically relevant Gram-positive pathogens, including MRSA. Telavancin exhibits 
concentration-dependent bactericidal effects via a dual mechanism of action (inhibition of 
bacterial cell wall synthesis and disruption of bacterial cell membrane barrier function), 
which may help to minimize the potential for the selection of resistance. In global 
surveillance studies, telavancin has demonstrated consistent in vitro microbiologic activity 
within the telavancin susceptible ranges against Gram-positive isolates, including MRSA, 
regardless of susceptibility to other agents or geographic region. Telavancin minimum 
inhibitory concentration (MIC) MIC50/MIC90 values consistently show activity against 
S. aureus comparable or superior to other agents.  
In vitro pharmacokinetic (PK)/pharmacodynamic models of simulated endocardial 
vegetations have demonstrated superior telavancin bactericidal activity against S. aureus 
strains compared with daptomycin and vancomycin. In vitro biofilm studies have 
demonstrated the potential efficacy of telavancin in the treatment of staphylococcal 
biofilm-associated infections [13]. Furthermore, studies using animal models of infection also 
have supported the potential for telavancin in the effective treatment of S. aureus 


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bacteremia and infective endocarditis. In murine models of bacteremia and rabbit models of 
infective endocarditis, telavancin has demonstrated greater efficacy than vancomycin [14]. 
The efficacy and safety of telavancin have been demonstrated in Phase 3 clinical trials for 
the treatment of subjects with complicated skin and skin structure infections (cSSSI) due to 
Gram-positive pathogens (ATLAS studies) and subjects with hospital-acquired or 
ventilator-associated bacterial pneumonia (HABP/VABP) due to Gram-positive pathogens 
(ATTAIN studies). Telavancin, 10 mg/kg administered intravenously (IV) over 60 minutes, 
once every 24 hours for 7 to 14 days is the currently approved dosage for the treatment of 
adult patients with cSSSI caused by susceptible Gram-positive bacteria. The same 
telavancin dose, for a duration of 7 to 21 days, is the currently approved dosage for the 
treatment of adult patients with HABP/VABP caused by susceptible isolates of S. aureus, 
when alternative treatments are not suitable.  
Limited data are available from post hoc analyses of subjects with concurrent bacteremia 
from these Phase 3 cSSSI and HABP/VABP studies. Of the 1784 subjects in the ATe 
population in the 2 cSSSI trials, 32 subjects had baseline S. aureus bacteremia: 21 
(2.4%, including 13 with MRSA) subjects were treated with telavancin and 11 (1.2%, 
including 4 with MRSA) subjects were treated with vancomycin. In these bacteremic 
subjects, the clinical cure rate at test of cure (TOC) was 57.1% (12/21) for the telavancin-
treated subjects and 54.6% (6/11) for the vancomycin-treated subjects. In subjects with 
Gram-positive bacteremic HABP/VABP in the ATTAIN studies, the clinical cure rates for 
telavancin and vancomycin were 46% (11/24) versus 37% (10/27), respectively. Moreover, 
only one telavancin-treated subject (1/34) compared with six vancomycin-treated subjects 
(6/39) had bacteremia that persisted beyond baseline cultures. 
In a Phase 2 proof-of-concept study, comparing telavancin with standard therapy 
(vancomycin or anti-staphylococcal penicillin) for treatment of subjects with uncomplicated 
S. aureus bacteremia (the ASSURE study), compared with standard therapy, similar 
proportions of the clinically evaluable (CE) population (n = 17) were cured at a long-term 
follow-up visit (Day 84; 88% vs. 89%, respectively). However, the number of clinically 
evaluable subjects limits the strength of a conclusion regarding the comparative safety and 
efficacy of telavancin and standard therapy in this population. 


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In a retrospective case series, telavancin provided a favorable cure rate and rapid clearance 
of bacteremia in difficult-to-treat subjects with refractory MRSA bacteremia with or without 
infective endocarditis [15]. Additional case reports of subjects with vancomycin-intermediate 
S. aureus (VISA) or MRSA endocarditis have demonstrated successful treatment with 
telavancin [16, 17]. 
To explore means by which the telavancin risk-benefit profile could be improved the 
Sponsor recently performed additional integrated retrospective analyses of PK and 
outcomes data from the telavancin Phase 3 studies for cSSSI and HABP/VABP. Based on 
the results of the integrated retrospective data analyses, the Sponsor believes that a 
reduction in the telavancin dose could optimize the risk-benefit profile of telavancin for the 
treatment of bacteremia. In separate independent CART and logistic regression analyses of 
data from the Phase 3 studies, a telavancin exposure-response relationship with acute 
kidney injury was confirmed. 
In the telavancin program a dose of 7.5 mg/kg was used in a limited number of patients with 
complicated skin and skin structure infections. (n=192). There were 4 studies that initially 
treated subjects with telavancin at a dose of 7.5 mg/kg IV once daily, including two phase 2 
studies (Studies 202a, 202b) and two phase 3 studies, (0017 and 0018). In these four 
studies, the dose was subsequently amended.  In the phase 2 studies the comparator 
consisted of either vancomycin or anti-staphylococcal penicillin.  In the phase 3 studies, the 
comparator was vancomycin.  Given the post-hoc nature of the comparisons between 
telavancin dose groups pre-and post-amendment and the paucity of data for patients dosed 
at 7.5 mg/kg, descriptive analyses were undertaken. In the pooled data from the 
4 mentioned studies, no noticeable differences in the frequency of adverse events (AEs) 
between telavancin 7.5 mg/kg and 10 mg/kg were observed. However, the difference in 
sample size between the two telavancin doses (7.5 mg/kg, n=192 and 10 mg/kg, n=1029) 
compromises the ability to derive a definitive conclusion about AE rates, especially for 
events where the incidence was low. 
The analyses support the conclusions that a dose reduction from 10 mg/kg to 7.5 mg/kg 
once daily would decrease the risk of nephrotoxicity and improve overall safety while having 
little to no impact on efficacy. Mortality was also examined in these analyses and despite 
small numbers and confounding factors, there was an exposure-response relationship in a 
subset of HABP/VABP subjects with creatinine clearance (CrCl) ≤50 mL/min. This risk may 


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also be decreased with the proposed dose reduction. Therefore, the Sponsor proposes to 
reduce the exposure of telavancin by incorporating the following three changes in the dose 
and dosing regimen: 1) decreasing the dose by 25% in all subjects; 2) decreasing the dose 
by 62% to 3.8 mg/kg from 10 mg/kg and altering the dosing schedule for severe renal 
impairment (creatinine clearance of 10 to <30 mL/min) to once daily rather than every 
48 hours; and 3) recommending the dose not exceed 750 mg (or 560 and 380 mg in 
moderate or severe renal impairment) for subjects weighing greater than 100 kg. In addition, 
for subjects undergoing chronic hemodialysis, telavancin should be administered IV at a 
dose of 3.8 mg/kg (maximum dose of 380 mg) once daily by infusion over 60 minutes 
(following hemodialysis on hemodialysis days). 
This study will be conducted in a population of subjects who are seriously ill with S. aureus 
bacteremia. Extra precautions have been built into the protocol to protect subject safety; 
however, by utilizing the proposed alterations in telavancin dose, the Sponsor believes that 
safety risks could potentially be reduced without loss of efficacy. This study will allow 
evaluation of the revised telavancin dose in a prospective, controlled fashion, and in an 
appropriate population of subjects. 
Regarding the rationale for standard IV therapy as the comparator in this trial, in adult 
patients with MRSA bacteremia or infective native valve endocarditis, current 
recommendations include treatment with vancomycin or daptomycin. Vancomycin is 
recommended for empiric therapy for S. aureus bacteremia in healthcare settings with an 
elevated prevalence of MRSA. Guidelines recommend that vancomycin be administered at 
doses providing trough concentrations of 15 to 20 μg/mL, increasing the probability of 
optimal target serum concentrations and improving clinical outcomes of complicated 
infections. For institutions in which the preponderance of MRSA isolates have vancomycin 
MIC values >2 μg/mL, alternative agents, such as daptomycin, should be used [18]. 
Daptomycin is currently approved in the US at a dosage of 6mg/kg for the treatment of 
S. aureus bacteremia, including those with right-sided infective endocarditis, however, some 
experts recommend higher doses of up to 8 to 10 mg/kg [19-23]. For patients with 
methicillin-susceptible S. aureus, a β-lactam antibiotic with anti-staphylococcal activity 
(eg, nafcillin, oxacillin, cefazolin) is the recommended treatment. 
Guidelines recommend treatment durations of at least 2 weeks for uncomplicated 
bacteremia (UCB), 4 to 6 weeks for complicated bacteremia (CB), and 6 weeks for infective 


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native valve endocarditis [18]. Although enriched for CB, it is anticipated that few patients 
enrolled may be deemed to suffer from UCB. As the final diagnosis for CB may take up to 
8 days all efforts should be implemented to minimize the enrollment of patients with UCB. 
This includes monitoring strict adherence to the inclusion and exclusion criteria and 
discussion with the principal investigators to reinforce the intent of the protocol population.  
To summarize, the use of telavancin for this study is supported by data from the post hoc 
analyses of subjects with bacteremia included in the Phase 3 studies of cSSSI and 
HABP/VABP, a Phase 2 proof-of-concept study of telavancin in subjects with uncomplicated 
S. aureus bacteremia, retrospective case series of subjects with refractory MRSA 
bacteremia, and case reports of subjects with VISA or MRSA endocarditis [15-17]. The 
available data describing telavancin for the treatment of bacteremia are limited, but are 
supportive of additional evaluation in larger, prospective studies including subjects with 
bacteremia due to S. aureus (specifically MRSA). Further prospective clinical studies are 
needed to assess the efficacy and safety of telavancin therapy in larger numbers of subjects 
with bacteremia and infective endocarditis. 
1.2 
Nonclinical Profile 
A review of the nonclinical profile of telavancin can be found in the current version of the 
Investigator’s Brochure (IB). 
1.3 
Clinical Experience 
A description of the clinical experience with telavancin is provided in the current version of 
the IB and the Prescribing Information for VIBATIV® (telavancin).  
The most common AEs occurring in ≥10% of telavancin-treated patients in Phase 3 studies 
of cSSSI were taste disturbance, nausea, vomiting, and foamy urine. Serious adverse 
events (SAE) were reported in 7% of patients treated with telavancin and most commonly 
included renal, respiratory, or cardiac events. Treatment discontinuations due to AE 
occurred in 8% of patients treated with telavancin, the most common events being nausea 
and rash. The incidence of AE indicative of renal impairment (increased serum creatinine, 
renal insufficiency, and renal failure) was 3% of telavancin-treated patients, and SAEs 
indicative of renal impairment occurred in 1% of telavancin-treated patients. 


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In Phase 3 studies of HABP/VABP, SAE were reported in 31% of patients treated with 
telavancin. Treatment discontinuations due to AE occurred in 8% of patients who received 
telavancin, with the most common events being acute renal failure and corrected QT interval 
(QTc) prolongation. Treatment-emergent AE that were reported in 5% or more of telavancin-
treated patients included nausea, vomiting, and acute renal failure. The incidence of AE 
indicative of renal impairment (acute renal failure and increased serum creatinine) was 10% 
of telavancin-treated patients, and SAE indicative of renal impairment occurred in 2% of 
telavancin-treated patients. 
1.4 
Risks and Benefits 
Telavancin is a lipoglycopeptide that has potent bactericidal activity against Gram-positive 
bacteria including clinically relevant Gram-positive pathogens: staphylococci (including 
methicillin-resistant and vancomycin-intermediate strains), streptococci (including 
multidrug-resistant pneumococci), enterococci (including many vancomycin-resistant 
strains), Gram-positive anaerobes such as clostridia (including Clostridium difficile), and 
other less commonly encountered pathogens. The bactericidal activity of telavancin results 
from a dual mode of action that includes inhibition of cell wall synthesis and disruption of 
bacterial plasma membrane function. Results from in vitro studies indicate that telavancin 
has a low potential to select for resistance. Importantly, development of resistance to 
telavancin in clinical studies has not been observed. Although some vancomycin-resistant 
enterococci (vanA genotype) have reduced susceptibility to telavancin, there is no known 
cross-resistance between telavancin and other classes of antibiotics. Organisms resistant to 
daptomycin or linezolid remain susceptible to telavancin at the proposed MIC breakpoints. In 
vivo pharmacology studies showed that telavancin is efficacious and demonstrates 
bactericidal activity in models of soft tissue (neutropenic murine thigh, murine subcutaneous 
infection), deep seated (rat and rabbit endocarditis), systemic (murine bacteremia) and lung 
(murine pneumonia) infections. 
Telavancin (VIBATIV®) is approved in the United States for the treatment of adults with 
cSSSI and HABP/VABP caused by susceptible isolates of Staphylococcus aureus; in 
Canada for the treatment of adults with cSSSI; and in various countries in Europe for the 
treatment of adults with nosocomial pneumonia (NP), including ventilator associated 
pneumonia, known or suspected to be caused by MRSA.  At the time of finalization of this 


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protocol amendment the medicinal product is currently approved in a total of 34 countries 
(US, Canada, Russia, and 31 countries in Europe via the centralized procedure).  
In a Phase 2, randomized, double-blind, active-controlled, parallel-group, multicenter, 
multinational trial of telavancin (10 mg/kg IV once daily) or standard therapy (vancomycin 
1 g every 12 hours IV or nafcillin, oxacillin, or cloxacillin 2 g every 6 hours IV) in adults with 
uncomplicated S. aureus bacteremia, similar proportions of the CE population (n = 17) were 
cured at a long-term follow-up visit (Day 84; 88% for telavancin vs. 89% for standard 
therapy). The conclusions that can be drawn from this study are limited owing to the low 
number of CE patients. Limited data are available from analyses of patients with bacteremia 
included in the Phase 3 studies. In the Phase 3 studies of cSSSI, the clinical cure rates for 
telavancin and vancomycin, respectively, were 55% versus 50% in the all-treated 
bacteremia group (n = 32) and 65% versus 83% respectively in the CE group (n = 23). 
In patients with Gram-positive bacteremic HABP/VABP in the Phase 3 studies of NP, the 
clinical cure rates for telavancin and vancomycin were 46% versus 37%, respectively 
(n = 51). Only one telavancin-treated patient compared with six vancomycin-treated patients 
had bacteremia that persisted beyond baseline cultures. A summary of known and potential 
risks to human subjects is provided in the IB in the Summary of Data and Guidance for the 
Investigator and the Prescribing Information [29]. 


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2 
OBJECTIVES 
The primary objective of the study is as follows: 
• 
To compare telavancin to standard intravenous therapy (ie, vancomycin, daptomycin, 
anti-staphylococcal penicillin, or cefazolin) clinical outcomes in the treatment of 
S. aureus bacteremia including S. aureus right-sided infective endocarditis (SA-RIE). 
The secondary objectives of the study are as follows: 
• 
To evaluate the safety and tolerability of telavancin compared with standard 
intravenous therapy in the treatment of S. aureus bacteremia, including SA-RIE. 
• 
To evaluate the PK profiles of telavancin and vancomycin in subjects with S. aureus 
bacteremia, including SA-RIE. 


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3 
STUDY DESIGN 
3.1 
Overview 
This is a multicenter, randomized, open-label, noninferiority trial of telavancin versus 
standard IV therapy control (ie, vancomycin, daptomycin, or a β-lactam antibiotic with 
anti-staphylococcal activity [eg, nafcillin, oxacillin, cefazolin]) in the treatment of subjects 
with complicated S. aureus bacteremia and SA-RIE. The primary efficacy endpoint is clinical 
outcome at TOC, analyzed in subjects with a baseline diagnosis of UCB, CB, or right-sided 
infective endocarditis (RIE) in the microbiological all-treated (mAT) population. The baseline 
diagnosis and the clinical outcome will be assessed by a blinded Independent Efficacy 
Adjudication Committee (IEAC). Safety will be monitored by an Independent Data 
Monitoring Committee (IDMC). 
Eligible subjects with confirmed S. aureus bacteremia will be randomized in a ratio of 1:1 to 
receive open-label telavancin or standard IV therapy. Randomization will be stratified by 
geographic region. Standard IV therapy, depending on the antibacterial susceptibility of the 
causative pathogen, will include vancomycin or daptomycin for subjects with known or 
suspected MRSA (daptomycin should be used for subjects with S. aureus with vancomycin 
MIC values >1 μg/mL); or a protocol-specified β-lactam antibiotic with anti-staphylococcal 
activity (ie, nafcillin, oxacillin, cloxacillin, or cefazolin) for subjects with known MSSA.  
Subjects with a confirmed or suspected mixed polymicrobial infection with a Gram-negative 
pathogen requiring coverage with an antibiotic with Gram-negative activity at enrollment will 
be excluded from participation in the study. Subjects that develop an infection during study 
participation with a gram-negative pathogen may be allowed to continue on study after 
discussing the concomitant antibiotic treatment with the medical monitor. 
Each subject must have at least one blood culture positive for S. aureus within 48 hours 
before randomization, referred to as the qualifying blood culture (QBC). The initial 
identification of S. aureus in the QBC can be done via standard culture identification 
methods or by use of a rapid diagnostic test.  Use of a rapid diagnostic system, if available, 
is preferred, but not obligatory, for determination of S. aureus bacteremia. Regardless of 
method or the time that the blood sample was obtained, the identification of S. aureus 
bacteremia must be within 48 hours prior to randomization. 


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The study population will be enriched for subjects with CB by requiring subjects to have at 
least one risk factor for CB at enrollment.  All subjects with CB will receive study drug for a 
minimum of 4 weeks and a maximum of 6 weeks (28 to 42 days) of therapy.  Subjects with 
infective endocarditis, will receive 6 weeks (42 +/- 3 days) of therapy.  Subjects with UCB 
will receive a minimum of 2 weeks and a maximum of 4 weeks (14 to 28 days) of therapy as 
per standard of care. As this protocol is designed to enhance the enrollment of patients with 
CB, all efforts should be implemented to minimize the enrollment of patients with UCB. This 
includes monitoring strict adherence to the inclusion and exclusion criteria and discussion 
with the principal investigators to reinforce the intent of the protocol population.  
The calendar day of first study drug administration is designated as Day 1; subsequent 
calendar days are Days 2, 3, etc.  
Procedures to control or eliminate the infection source, eg, by removal of intravascular lines 
or drainage and debridement of the primary infection site, will be completed within the first 
3 days of study drug treatment.  
Follow-up blood cultures will be performed daily until two successive post-randomization 
blood cultures are negative for S. aureus. 
On or before Day 8, each subject must undergo echocardiogram (either transthoracic 
echocardiogram [TTE] or transesophageal echocardiogram [TEE]; TEE is strongly preferred) 
and will be evaluated by a physician investigator to determine the origin and extent of the 
S. aureus infection to establish the classification of infection type as one of the following: 
• 
Uncomplicated bacteremia (UCB):  A QBC, defined as a blood culture positive for 
S. aureus before randomization, no evidence of infective endocarditis, and all of the 
following: 
 
Catheter-associated infection and removal of the catheter or cutaneous 
infection-associated infection and source control within 3 days after 
randomization. 
 
A negative post-QBC blood culture drawn within 72 hours after start of study 
medication. 
 
Defervescence within 3 days after start of study medication. 
 
Absence of valvular findings on echocardiography predisposing to infective 
endocarditis. 
 
No signs or symptoms suggestive of metastatic infection. 


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• 
Complicated bacteremia (CB):  A QBC, defined as a blood culture positive for 
S. aureus before randomization, no evidence of infective endocarditis, and at least 
one of the following: 
 
Follow-up post-QBC blood culture positive for S. aureus drawn after Day 3 and 
with known S. aureus identification on or before Day 8. 
 
For subjects febrile at screening, persistence of fever on or beyond Day 3 after 
the start of study medication. 
 
Evidence of metastatic infection (eg, septic arthritis, septic thrombophlebitis, 
deep tissue abscess). 
 
Evidence of venous catheter line thrombosis or septic thrombosis associated 
with a venous catheter. 
NOTE: On or before Day 8, subjects with a central venous catheter (CVC) as 
the presumed source of the infection should also undergo central venous 
ultrasound to evaluate for venous thrombosis associated with the central line. 
Subjects who have documented central venous thrombosis, and therefore septic 
thrombophlebitis, should be classified as CB 
• 
Right-sided infective endocarditis (RIE):  Defined as having a QBC and Definite or 
Possible endocarditis according to Modified Duke Criteria [24] (Appendix 1) without 
predisposing abnormalities or active infection of mitral or aortic valve. 
• 
Left-sided infective endocarditis (LIE):  Defined having a QBC and Definite or 
Possible LIE according to Modified Duke Criteria [24] (Appendix 1). 
On or before Day 8, subjects will be assigned to receive therapy based on the classification 
of infection type:   
• 
For UCB, subjects will receive a minimum of 2 weeks and maximum of 4 weeks 
(14 to 28 days) of therapy.  
• 
For CB, subjects will receive a minimum of 4 weeks and a maximum of 6 weeks 
(28 to 42 days) of therapy.  
• 
For endocarditis, subjects will receive 6 weeks (42 days +/- 3 days) of therapy.   
Prior to or on Day 8 a signs and symptoms worksheet will be completed to determine the 
infection type including metastatic disease (UCB, CB, RIE, LIE) and sent to the medical 
monitor to review.  Subsequently, weekly worksheets noting signs and symptoms of 
potential metastatic S. aureus infection will be reviewed and completed by the physician 
investigator and forwarded to the medical monitor to optimize diagnosis and treatment of 
both the primary infection source and new metastatic foci of S. aureus.  
Development of new signs or symptoms consistent with S. aureus infection will be assessed 
daily, during the hospital stay, or during the study drug treatment period as clinically 


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indicated, by clinical evaluation and other diagnostic modalities, eg, chest X-ray, 
ultrasonography, bone scan, computed tomography (CT), magnetic resonance imaging 
(MRI), and/or positron emission tomography (PET). 
After Day 8, if signs and symptoms lead to a subsequent confirmed diagnosis of new 
metastatic foci, it will be criteria for clinical failure. Management of the subject 
(eg, discontinuation of study drug) will be at the discretion of the investigator based on 
his/her standard routine care.  
Study visits for endpoint assessment will be conducted as follows: 
• 
End of therapy (EOT) Visit: Within 3 days after the last dose of study drug 
• 
Test of cure (TOC) Visit:  
 
For subjects with UCB and assigned to receive 2 to 4 weeks (14 to 28 days) of 
treatment, their TOC is 38 (+/-2) days after randomization regardless of the total 
duration of study drug therapy  
 
For subjects with CB and assigned to receive 4 to 6 weeks of treatment (28 to 
42 days), their TOC is 52 (+/- 2) days after randomization regardless of the total 
duration of study drug therapy 
 
For subjects with endocarditis assigned to receive 6 weeks (42 +/-3 days) of 
treatment, their TOC is 52 (+/- 2) days after randomization regardless of the total 
duration of study drug therapy 
A post-EOT blood culture will be obtained at least 4 days after the EOT visit, and results 
must be available prior to the TOC visit. The results of this blood culture will be part of the 
assessment of clinical outcome at TOC.  
Subjects who are discharged from the hospital during the treatment or follow-up period, will 
return to the hospital once per week for a study visit. After all the weekly visits are complete, 
the subject will also return to the hospital for the End of Therapy Visit, the Post-End of 
Treatment Visit, and the TOC visit. The TOC visit will occur based on infection classification 
as described above and is also the end of study (EOS). 
3.2 
Rationale for Study Design 
This study is designed to evaluate the safety and efficacy of telavancin in subjects with 
S. aureus bacteremia by randomizing them to treatment with either telavancin or standard IV 
therapy. The study aim is to demonstrate that telavancin is noninferior to standard IV 
therapy in the treatment of S. aureus bacteremia including S. aureus right-sided infective 
endocarditis (SA-RIE). Standard IV therapy will be selected by the investigator depending 


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on known or suspected antibiotic susceptibility of the causative pathogen. Efficacy will be 
evaluated as clinical outcome at TOC visit. See Figure 1 for the study diagram. Safety and 
tolerability will be assessed throughout the study treatment period via laboratory 
measurements (eg, hematology, chemistry, and urinalysis) and monitoring of AE.  
3.3 
Selection of Dose and Duration of Treatment 
3.3.1 Telavancin 
A telavancin dose of 10 mg/kg administered over 60 minutes by intravenous infusion once 
every 24 hours for 7 to 14 days is the currently approved dosage for the treatment of adult 
patients with cSSSI caused by susceptible Gram-positive bacteria. The use of telavancin for 
this study is supported by data from a Phase 2 proof-of-concept study of telavancin in 
subjects with UCB, post hoc analyses of subjects with bacteremia included in the Phase 3 
studies of cSSSI and HABP/VABP, a retrospective case series of bacteremia in 
difficult-to-treat subjects with refractory MRSA bacteremia, and case reports of subjects with 
VISA or MRSA endocarditis. Based on results of integrated retrospective analyses of the 
VIBATIV Phase 3 study data, the Sponsor believes that a reduction in the telavancin dose 
could optimize the risk-benefit profile of telavancin for the treatment of bacteremia. The 
Sponsor proposes to reduce the exposure of telavancin by incorporating the following three 
changes in the dose and dosing regimen: 1) decreasing the dose by 25% in all subjects; 
2) decreasing the dose by 62% to 3.8 mg/kg from 10 mg/kg and altering the dosing 
schedule for severe renal impairment (creatinine clearance of 10 to <30 mL/min) to once 
daily rather than every 48 hours; and 3) recommending the dose not exceed 750 mg (or 560 
and 380 mg in moderate or severe renal impairment) for subjects weighing greater than 
100 kg. 
For subjects with renal impairment, the telavancin dosage should be adjusted as described 
in Section 5.2.1.  
Serum creatinine and CrCl will be obtained daily, up to Day 8, while the subject is 
hospitalized. After Day 8, or if subject is discharged from the hospital to outpatient 
parenteral antibiotic therapy (OPAT) facility or home health care (HHC), serum creatinine 
and creatinine clearance will be obtained every 2 to 3 days while on study drug. Close 
monitoring of renal function is being done in order to make appropriate dosage adjustments 
as described in Section 5.2.1, as well as monitoring for the need to discontinue study drug 


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due to renal dysfunction. If, in the opinion of the investigator, it is judged that development of 
or worsening of renal dysfunction is most likely secondary to the use of study drug. 
Examples of laboratory values often associated with clinically significant changes in renal 
function might include an increase from baseline in serum creatinine > 2  value at 
enrollment; a serum creatinine of >1.5 mg/dL on two consecutive measurements if the 
baseline serum creatinine was within normal limits; or two or more post-baseline 
measurements of CrCl showing a ≥50% decline from baseline. In the absence of other more 
likely explanations for acute renal injury, and alternatives exist to treat the underlying 
infection, then study drug should be discontinued after consultation with the medical 
monitor.  
Clinical practice guidelines recommend treatment durations of at least 2 weeks for UCB, 4 to 
6 weeks for CB, and 6 weeks for infective native valve endocarditis [5]. The study population 
will be enriched for subjects with CB by requiring subjects to have at least 1 risk factor for 
CB at enrollment. All subjects with CB will receive study drug for 4 to 6 weeks (28 to 
42 days), depending on extent of the infection. Uncomplicated bacteremia with risk factors 
for complicated disease, will receive 2 to 4 weeks (14 to 28 days) of therapy, and infective 
endocarditis will receive 6 weeks (42 +/- 3 days) of therapy. Cases with metastatic foci will 
receive 4 to 6 weeks, per the discretion of the investigator, depending on the location and 
extent of the metastatic S. aureus infection.  
3.3.2 Standard Intravenous Therapy 
Regarding the rationale for standard IV therapy as the comparator, in adult patients with 
bacteremia or infective native valve endocarditis, current recommendations include 
treatment with vancomycin or daptomycin. Vancomycin is recommended for empiric therapy 
for S. aureus bacteremia in healthcare settings with an elevated prevalence of MRSA. 
Guidelines recommend vancomycin to be dosed to provide trough concentrations of 15 to 
20 μg/mL, increasing the probability of optimal target serum concentrations and improving 
clinical outcomes of complicated infections. For institutions in which the preponderance of 
MRSA isolates have vancomycin MIC values >2 μg/mL, alternative agents, such as 
daptomycin, should be used [18]. For patients with methicillin-susceptible S. aureus, an 
anti-staphylococcal PCN, such as nafcillin or oxacillin, is the preferred treatment with 
cefazolin as an alternative treatment [18]. 


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Standard IV therapy will be selected by the investigator based on antibiotic susceptibility of 
the causative pathogen, and will include vancomycin or daptomycin for subjects with known 
or suspected MRSA (daptomycin should be used for subjects with MRSA with vancomycin 
MIC values >1 μg/mL); or. S. aureus, a β-lactam antibiotic with anti-staphylococcal activity 
(eg, nafcillin, oxacillin, cefazolin) is the recommended treatment for subjects with known 
MSSA. 
• 
Vancomycin (recommended of dose of 15 mg/kg IV q12 hours); dose may be 
adjusted per local or regional product information/guidelines or local standard of 
care.  
• 
Daptomycin (recommended dose of 6 mg/kg IV q24 hours); dose may be adjusted 
per local or regional product information/guidelines or local standard of care. 
• 
Anti-staphylococcal PCN (eg, nafcillin, oxacillin or cloxacillin), recommended dose of 
2 gm IV q4 hours or 12 gm IV continuous infusion over 24 hours); dose may be 
adjusted per local or regional product information/guidelines or local standard of 
care. 
• 
Cefazolin (recommended dose of 2 gm IV q8 hours); dose may be adjusted per local 
or regional product information/guidelines or local standard of care. 
All subjects with CB will receive study drug for 4 to 6 weeks (28 to 42 days), depending on 
the extent of the infection. Subjects with endocarditis will receive 6 weeks (42 +/- 3 days) of 
therapy; subjects with UCB may receive a minimum of 2 week and a maximum of 4 weeks 
(14 to 28 days) of therapy based on standard of care. 
3.3.3 Switching to Another Intravenous Antibiotic Therapy 
Switching to another protocol-permitted comparator IV therapy based on susceptibility of the 
pathogen is permitted prior to Day 8. Examples include switching from cefazolin to 
vancomycin for MRSA, switching from vancomycin to daptomycin for a vancomycin 
MIC >1 μg/mL, or switching from daptomycin to vancomycin if daptomycin non-susceptible 
and the vancomycin MIC is ≤1 μg/mL.  
Subjects with a pathogen identified to be MRSA that is daptomycin non-susceptible and has 
a vancomycin MIC >1 μg/mL have no other protocol-permitted standard IV therapy options. 
The clinical outcome for these subjects will be classified as clinical failure.  
Subjects should receive at least 3 days of therapy before it is determined the subject is not 
responding to therapy (eg, worsening signs and symptoms of S. aureus bacteremia). 
Subjects who, in the opinion of the investigator, must switch therapy based on failure to 
respond clinically will be classified as treatment failures. Protocol-permitted standard IV 


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therapy may be selected based on the subject’s known medication allergies; however, 
switching IV antibiotic therapy as a result of an AE will result in the clinical outcome 
classified as clinical failure.  
3.4 
Study Endpoints 
This study will evaluate the safety, efficacy, and PK of telavancin compared to standard IV 
therapy in the treatment of adults with S. aureus bacteremia and SA-RIE. 
3.4.1 Safety Endpoints 
Safety endpoints include AE, clinical laboratory results (including hematology, serum 
chemistry, creatine kinase, and urinalysis), vital signs, use of concomitant medical and 
physical examination. Additional information regarding renal AEs (eg, laboratory and 
radiographic results at the time of potential renal injury) will be obtained and recorded in the 
renal AE eCRF. 
3.4.2 Primary Efficacy Endpoint 
The primary efficacy endpoint is clinical outcome at TOC. 
The efficacy endpoint of clinical outcome at TOC will be determined by the investigator and 
adjudicated by the blinded IEAC. Specific evaluability criteria (outlined in the statistical 
analysis plan [SAP]) will be applied to determine subject eligibility for each population. 
Subjects who meet all of the following criteria of the composite endpoint will be classified as 
a clinical success (Table 2):  
• 
Alive at TOC 
• 
Resolution of all clinical signs and symptoms of the S aureus infection at TOC; 
excluding signs and symptoms more likely explained by an alternative diagnosis   
• 
No evidence of microbiological persistence or relapse  
 
Persistence defined as no successive days of sterile blood cultures by the 
eighth day of study drug 
 
Relapse defined as all blood cultures negative for S. aureus for two successive 
days (need not be consecutive days) followed by a positive blood culture of the 
same organism before or at TOC 


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• 
No new foci of metastatic S. aureus infection after Day 8 
 
Defined as any infection remote from the primary focus not present at the time 
of the classification of infection type (on or before Day 8), caused by 
(1) hematogenous seeding (eg, endocarditis or vertebral osteomyelitis) or 
(2) extension of infection beyond the primary focus (eg, septic thrombophlebitis 
or abscess); all cases of metastatic infection will be defined by either radiologic 
imaging, culture of S. aureus from a normally sterile site, or the use of a 
validated diagnostic criteria; embolic stroke will be defined as radiologic 
evidence of an acute thromboembolic event; the infection must be a result 
seeding or extension from the primary focus of S. aureus infection.  
Subjects will be classified as a clinical failure if they meet one of the following: 1) who do not 
meet all of the criteria of clinical success; 2) Subject receives potentially effective non-study 
antibiotic up to TOC visit; 3) Subject switches study antibiotic due to lack of clinical response 
or an AE; 4) Subject discontinued study drug due to treatment-emergent, drug-related AE; 
5) Subject required further antibacterial therapy for the S. aureus infection beyond the 
assigned treatment duration (exemption: oral prophylaxis); 6) New foci of metastatic 
S. aureus infection after Day 8.  
Once assigned, on or before Day 8, to receive 2 to 4 weeks (14 to 28 days) for UCB, 4 to 
6 weeks (28 to 42 days) for CB, or 6 weeks (42 +/-3 days) for endocarditis, any antibiotic 
treatment for S. aureus infection beyond the assigned treatment durations will be classified 
as a clinical failure. If the subject discontinues study drug prior to their assigned treatment 
duration, their TOC visit remains either 38 (+/- 2) days, 52 (+/-2) days, or 52 (+/- 2) days 
after randomization, respectively. 
Subject outcomes will be classified as indeterminate if they discontinued the study 
prematurely for one or more the following reasons: 
• 
Withdrew consent 
• 
Discontinued study drug therapy against medical advice. 
• 
Lost to follow-up 
Note:  Every effort should be made to retain each subject in the study. If therapy is 
withdrawn, all outcome data should be collected according to the protocol. 
Once a subject is determined to be a clinical failure, all outcome data should be collected 
according to the Schedule of Study Procedures (Table 1); subjects must undergo the EOT, 
post-EOT blood culture, and TOC evaluations (Sections 6.2.5, 6.2.6, and 6.2.7, 


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respectively).  Once the subject is classified as failure, the weekly assessments are not 
mandated unless the subject is still hospitalized. A blood culture obtained after EOT and 
before TOC is encouraged, but optional for cases of clinical failure. 
Table 2: 
Clinical Outcome at TOC 
Outcome 
Definition 
Clinical Success 
Must meet all of the following criteria: 
• 
Subject alive at TOC 
• 
Resolution of all clinical signs and symptoms of the S. aureus 
infection at TOC (unless explained by a more likely alternative 
diagnosis) 
• 
No evidence of microbiological persistence or relapse 
• 
No new foci of metastatic S. aureus infection after Day 8 
Clinical Failure 
Meets any of the following: 
• 
Subject did not meet all the criteria for clinical success 
• 
Subject receives potentially effective non-study antibiotic up to TOC 
visit 
• 
Subject switches study antibiotic due to lack of clinical response or 
an AE 
• 
Subject discontinued study drug due to treatment-emergent, 
drug-related AE  
• 
Subject required further study antibacterial therapy for the S. aureus 
infection beyond assigned treatment duration (exemption: oral 
prophylaxis) 
• 
New foci of metastatic S. aureus infection after Day 8 
Indeterminate 
Meets one or more of the following: 
• 
Subject withdrew consent 
• 
Subject remains lost to follow-up 
• 
Subject discontinued study drug against medical advice  
3.4.3 Secondary Efficacy Endpoints 
The key secondary efficacy endpoints are as follows (see Section 8.4.2): 
• 
Clinical outcome (success or failure) at TOC by baseline diagnosis in the mAT and 
microbiological evaluable (ME) populations. 
• 
Clinical response (success or failure) at EOT in the mAT and ME populations. 
• 
Development of new metastatic foci of S. aureus infection after Day 8 in the mAT 
and ME populations. 
• 
Duration of treatment with study medication by baseline clinical diagnosis in the mAT 
and ME populations. 
• 
For subjects with a positive S. aureus blood culture on Day 1, time to all blood 
cultures negative for S. aureus for two days in succession (ie, clearance of 


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bacteremia) (does not have to be consecutive calendar days) in the mAT and 
ME populations; date will be first of the two days in succession. 
• 
28-day all-cause mortality for subjects with a baseline diagnosis of CB or RIE in the 
mAT and ME populations. 
• 
Incidence of AEs, treatment-emergent AEs (TEAEs), SAEs, and deaths in the safety 
population. 
• 
Incidence of key laboratory indices in the safety population to be further described in 
the SAP. 
Definitions for additional efficacy endpoints will be as follows: 
• 
Clearance of bacteremia is defined as occurring on the first date of all blood cultures 
negative for S. aureus for two successive days post-randomization; date of clearance 
will be the first of the two successive days.  
• 
For subjects with a positive S. aureus blood culture on Day 1, the duration of 
S. aureus bacteremia is defined as the time (days) from randomization to all blood 
cultures negative for S. aureus for two successive days (post-randomization; date 
will be first of the two days in succession. 
• 
28-day all-cause mortality is defined as all deaths that occur during the study, 
regardless of cause, on or before Day 28. 
In addition, analyses evaluating evidence of treatment-emergent resistance to telavancin, 
vancomycin, daptomycin, anti-staphylococcal PCNs, or cefazolin may be conducted. 
NOTE: Echocardiograms (TTEs and TEEs) will undergo blinded review by an independent 
echocardiography core laboratory. 
Exploratory analyses will be conducted to assess a variety of health utilization variables. 
Methods of analysis for these variables will be outlined in a separate health economics 
outcomes statistical analysis plan (HEOR SAP). The results of these analyses will be 
presented separately and not included in the clinical study report (CSR). 
The study will also evaluate the safety and tolerability of telavancin compared with standard 
IV therapy in the treatment of S. aureus bacteremia and SA-RIE. 
3.4.4 Pharmacokinetic Endpoints 
Pharmacokinetic endpoints include AUC and Cmax as measures of drug exposure. Additional 
information regarding the relationship between selected subject covariates and drug 
exposure may be generated. 


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3.5 
Minimization of Bias 
Study design measures used to minimize bias include treatment assignment by 
randomization. As described in Section 3.5.2, a blinded IEAC will review data from each 
subject to establish the diagnosis and clinical outcome at EOT and TOC. The Sponsor will 
remain blinded to the IEAC’s adjudication results until after database lock. 
3.5.1 Treatment Assignment 
Subjects will be randomized to receive either telavancin or standard IV therapy in a ratio of 
1:1, stratified by geographic region. Randomization will be generated using a centralized 
computer-generated block randomization schedule. The reference therapy (ie, standard IV 
therapy) will be selected by the investigator depending on known or suspected antibacterial 
susceptibility of the pathogen.  
As a subject qualifies for the study, the investigator will notify the site pharmacist (or other 
authorized staff member), who will access a centralized interactive response system (IXRS) 
to obtain a treatment assignment. 
3.5.2 Blinding 
This is an open-label study. A blinded IEAC of clinical experts in acute care, hospital-based 
medicine will review the data from each subject to establish the diagnosis and outcome. The 
outcome of the primary composite endpoint will be assessed and determined by IEAC and 
the adjudication will be conducted without information regarding treatment assignments. 
Neither Sponsor employees nor study personnel will participate in the closed sessions 
where the committee members discuss the subject outcomes. The Sponsor will remain 
blinded to the IEAC’s adjudication results until after database lock.  
In addition, the preparation of reports for the IDMC will be conducted by an independent 
statistical group outside of the Sponsor.  


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4 
STUDY POPULATION 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
eligible for enrollment into this study. 
4.1 
Inclusion Criteria 
1. Male or female at least 18 years old at the time of consent. 
2. Subject has signed an informed consent form. If a subject is unable to give consent, 
when legally permitted, consent must be obtained from the subject’s legally acceptable 
representative.  
NOTE: Subject, or appropriate legal representative, must be able to communicate 
effectively with investigator and site staff. 
3. At least one blood culture positive for S. aureus within 48 hours before randomization, 
referred to as the QBC. 
4. In addition to the QBC, subject must have at least one of the following signs or 
symptoms of bacteremia: 
• 
Temperature ≥38.0°C 
• 
White blood cell (WBC) count >10,000 or <4,000 cells/µL, or >10% immature 
neutrophils (bands) regardless of total peripheral WBC count 
• 
Tachycardia (heart rate >90 bpm) 
• 
Tachypnea (respiratory rate >20 breaths/min) 
• 
Hypotension (systolic blood pressure <90 mmHg) 
• 
Signs and symptoms of localized catheter-related infection (tenderness and/or 
pain, erythema, swelling, purulent exudate within 2 cm of entry site) 
5. Subject must, at enrollment, have either 1) known right-sided infective endocarditis by 
Modified Duke Criteria, 2) known CB, demonstrated as signs or symptoms of metastatic 
foci of S. aureus infection (eg, any infection remote from the primary focus caused by 
hematogenous seeding or extension of infection beyond the primary focus), or 3) known 
bacteremia with at least one of the following risk factors for CB [25-28]: 
• 
Any venous catheter considered to be the source of the infection, demonstrated by 
inflammation or purulent drainage from the catheter insertion site AND evidence of 
catheter-associated thrombosis upon removal  
NOTE: A peripheral venous catheter with just inflammation or purulent drainage from 
the catheter insertion site without evidence of thrombus is not consistent with CB. 
• 
A CVC considered to be the source of infection, demonstrated by inflammation or 
purulent drainage from the CVC insertion site or presence of thrombus on ultrasound 


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• 
A long-term intravascular catheter (eg, tunneled cuffed intravascular catheter or 
subcutaneous port catheter) considered to be the source of infection, demonstrated 
by inflammation or purulent drainage from the catheter insertion site or presence of 
thrombus on ultrasound 
• 
New onset cardiac murmur consistent with tricuspid regurgitation  
• 
Community onset bacteremia (eg, subject does not live in a healthcare facility)   
• 
Pathogen known to be MRSA at enrollment  
• 
Duration of symptoms ≥2 days at time of presentation (prior to start of antibiotic 
therapy) 
• 
Skin exam findings suggesting acute systemic infection (ie, petechiae, vasculitis, 
infarcts, ecchymoses or pustules due to the infection) 
6. Willing to receive intravenous antibiotics for the duration of treatment. 
7. Expected survival of at least 3 months. 
8. Female subjects must be non-pregnant and non-lactating. If a female subject is of 
childbearing potential, must have a documented negative pregnancy test at screening. 
NOTE: All females are considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 2 years) or documented to be surgically 
sterile (bilateral tubal ligation or total hysterectomy). A subject may be admitted to the 
study on the basis of a negative urine pregnancy test (local laboratory), pending the 
result of the serum pregnancy test. 
9. If sexually active, must agree to use a highly effective method of birth control with 
partners of childbearing potential during the study and for 1 month after study drug 
dosing 
NOTE: A highly effective method of birth control is defined as one that results in a low 
failure rate (ie, < 1% per year) when used consistently and correctly, such as implants, 
injectables, combined oral contraceptives, some IUDs, sexual abstinence, or a 
vasectomized partner. Male subjects must agree to use medically acceptable birth 
control for at least one month following last dose of study medication. A vasectomy or a 
condom used with a spermicide is a medically acceptable birth control method for 
males. 
10. Considered likely to comply with the study procedures and to return for scheduled 
evaluations. 


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4.2 
Exclusion Criteria 
Subjects who satisfy any of the following criteria are not eligible for study enrollment: 
1. Treatment regimen greater than 60 hours with any potentially effective 
(anti-staphylococcal) systemic antibiotic(s) within 7 days before randomization.  
NOTE: It is preferable to have no more than 48 hours of total prior antibiotic therapy 
within 7 days before randomization. 
EXCEPTION: Documented resistance to the prior systemic antibacterial therapy, 
confirmed by a microbiological laboratory report. 
2. Requirement or anticipated requirement of non-study systemic antibiotics during the 
study 
3. Presence of an infection source (eg, intravascular line, abscess, septic arthritis, infected 
prosthetic material, infected wound) that will not be managed or controlled (eg, removal 
or replacement of the infected line, drainage of abscess, aspiration or drainage of septic 
arthritis, removal or replacement of infected prosthesis, or debridement of infected 
wound) within the first 3 days of study drug treatment 
4. Presence of prosthetic cardiac valve or cardiac device (eg, implantable cardioverter 
defibrillator [ICD]), permanent pacemaker, or cardiac valve support ring)  
5. Known or suspected LIE at enrollment, according to Modified Duke Criteria (Appendix 1) 
NOTE: Right-sided infective endocarditis (RIE) is permitted. If the subject is diagnosed 
with LIE after enrollment, subject will be allowed to remain on study. 
6. At the time of enrollment, known or highly suspected osteomyelitis, meningitis, or 
metastatic septic foci involving the central nervous system (CNS) 
NOTE: Investigators should use clinical judgment to determine whether additional 
imaging studies (eg, X-ray, computed tomography scan, magnetic resonance imaging) 
are indicated at screening to rule out the presence of osteomyelitis, meningitis, or 
metastatic septic foci in the CNS. 
7. Known at the time of enrollment to have MRSA bacteremia that is non-susceptible to 
daptomycin AND has a vancomycin MIC ≥2 μg/mL  
8. Confirmed evidence (identification or Gram stain) of a mixed polymicrobial infection with 
a Gram-negative pathogen that requires non-study antibiotic treatment with agent(s) that 
have activity against Gram-negative pathogens 
9. Previous participation in an anti-infective study during the past 12 months 
10. A history of significant hypersensitivity, allergy or intolerance to telavancin 
NOTE: Caution should be taken in subjects with a history of severe hypersensitivity 
reaction to vancomycin. If the pathogen is known MRSA, allergy to both vancomycin and 
daptomycin may require exclusion. If the pathogen is known MSSA, allergy to both 
anti-staphylococcal PCN/cephalosporin and daptomycin may require exclusion. 
Investigator discretion is advised on a case-by-case basis. 
11. Solid organ transplantation or bone marrow transplantation within 6 months before 
randomization 


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12. Severe neutropenia, defined as an absolute neutrophil count (ANC) <500 
cells per microliter, or expected development of severe neutropenia during study 
13. Known or suspected human immunodeficiency (HIV) infection with a CD4+ T-cell count 
<200/μL within the previous 6 months  
14. Subjects requiring concomitant administration of anti-coagulation therapy 
(eg, intravenous heparin sodium) AND requiring specific coagulation testing known to 
have interference by telavancin (prothrombin time [PT]/international normalized ratio, 
activated partial thromboplastin time [aPTT], or activated clotting time, or 
coagulation-based Factor X activity assay) 
NOTE: Although telavancin does not interfere with coagulation, it interferes with some 
assays used to monitor coagulation. The use of unfractionated heparin or a low 
molecular weight heparin AND testing using an Anti-Xa chromogenic testing assay 
would be permissible. 
15. Severe liver disease, ie, Child-Pugh Class C (Appendix 2), or aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) more than 10 times the 
upper limit of normal (ULN) 
16. Requirement for acute renal replacement therapy; or acute kidney injury (AKI) defined as 
an acute decrease in CrCl to < 30 mL/min and at least one of the following: 
 
≥2x increase in serum Cr or 50% decrease in glomerular filtration rate (GFR) within 
the 2 weeks prior to enrollment (RIFLE stage 2 injury (Appendix 3) 
 
Oliguria defined as urine output <0.5 mL/kg per hour for ≥12 hours at any time during 
screening 
NOTE:  Chronic renal insufficiency with a stable CrCl <30 mL/min, including chronic 
hemodialysis, is permitted. 
17. Shock or hypotension (supine systolic blood pressure <80 mm Hg) unresponsive to 
fluids or pressors within 24 hours prior to randomization 
18. QTc >460 ms (using either the Bazett or Fridericia formula), congenital long QT 
syndrome, uncompensated or new onset heart failure, aortic stenosis, aortic 
insufficiency, or mitral insufficiency 
19. Serum creatine kinase (CK) ≥2000 U/L 
20. Breast-feeding or pregnant or intending to become pregnant (self or partner) at any time 
during the study 
21. Any other condition that in the opinion of the investigator would jeopardize the safety or 
rights of a subject or would render the subject unable to comply with the protocol; or any 
other condition that in the opinion of the investigator may confound the data. 


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5 
STUDY DRUGS 
All study drug supplied by the Sponsor must be stored in a secure location accessible only 
to designated study personnel.  
5.1 
Description of Study Drugs 
Descriptions of telavancin, including physical, chemical, and pharmaceutical properties, 
formulations and dosage forms, packaging and labeling, storage and handling, and 
preparation for administration, are provided in the study Pharmacy Manual.  For standard IV 
therapy (ie, vancomycin, daptomycin, anti-staphylococcal PCN, cefazolin) sites should refer 
to the applicable approved country specific drug package inserts for descriptions of 
pharmaceutical properties, formulations, dosage forms, packaging, labeling, storage and 
handling as well as preparation and administration for the standard of care therapy 
administered to the subjects. 
5.2 
Dosage and Administration 
Enrolled subjects will be randomized in a ratio of 1:1 to receive either open-label telavancin 
or standard IV therapy (ie, vancomycin, daptomycin, anti-staphylococcal PCN, or cefazolin). 
Standard IV therapy will be selected by the investigator based on known or suspected 
antibiotic susceptibility of the causative pathogen. Duration of therapy will be guided based 
on the initial diagnosis on or before Day 8.  All subjects with CB will receive study drug for a 
minimum of 4 weeks and a maximum of 6 weeks (28 to 42 days) of therapy.  Subjects with 
infective endocarditis, will receive 6 weeks (42 +/- 3 days) of therapy.  Subjects with UCB 
will receive a minimum of 2 weeks and a maximum of 4 weeks (14-28 days) of therapy as 
per standard of care. 
5.2.1 Telavancin 
Telavancin should be prepared and administered as described in the Pharmacy Manual. For 
subjects with normal renal function, telavancin should be administered IV at a dose of 
7.5 mg/kg, in either 5% dextrose injection (D5W), sterile water for injection, or 0.9% sodium 
chloride; in 100 to 250 mL over 60 (+/- 10) minutes, once every 24 hours.  
Subjects with renal impairment, either at baseline or which develops during the course of 
study treatment, should have the dosage of telavancin modified, based on estimated 
creatinine clearance, as listed in Table 3. 


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The pharmacist will calculate the estimated creatinine clearance using the creatinine value 
provided by the local and/or central laboratory, the Cockcroft-Gault formula and ideal body 
weight (IBW). If the actual body weight is less than IBW, the actual weight will be used.  
Calculation for IBW: 
• 
If subject is male, then  IBW(kg) = 50.0 + 0.9*[height(cm) – 152.0] 
• 
If subject is female, then IBW(kg) = 45.5 + 0.9*[height(cm) – 152.0] 
Table 3: 
Telavancin Dosage Adjustment in Subjects with Renal Impairment 
Creatinine Clearancea 
(mL/min) 
Telavancin Dosage Regimen 
Maximum Daily Dose 
>50 
7.5 mg/kg every 24 hours 
750 mg 
30-50 
5.6 mg/kg every 24 hours 
560 mg 
10 to <30 
3.8 mg/kg every 24 hours 
380 mg 
Stable chronic hemodialysisb 
3.8 mg/kg every 24 hours 
380 mg 
a 
For subjects receiving telavancin, the creatinine clearance for dosing should be calculated using the 
Cockcroft-Gault formula and ideal body weight (IBW). Use actual body weight if it is less than IBW. 
b 
On days when subject receives hemodialysis, telavancin should be administered following completion 
of hemodialysis. 
For subjects weighing more than 100 kg, the daily telavancin dose should not exceed 
750 mg for those with normal renal function, 560 mg for those with moderate renal 
impairment, and 380 mg for subjects with severe renal impairment (creatinine clearance of 
10 to <30 mL/min) or those undergoing chronic hemodialysis (Table 3). 
5.2.2 Vancomycin 
For subjects with known or suspected MRSA, vancomycin should be administered.  The 
recommended dose of vancomycin is 15 mg/kg administered IV q12h (doses may be 
adjusted per local or regional product information/guidelines or local standard of care). For 
subjects with renal impairment, including those receiving chronic hemodialysis, vancomycin 
should be dosed per local or regional product information/guidelines or local standard of 
care. 
5.2.3 Daptomycin 
For subjects with known or suspected MRSA (and for subjects with a vancomycin MIC value 
>1 μg/mL), daptomycin should be administered.  The recommended dose of daptomycin is 
6 mg/kg IV q 24h by infusion over 30 minutes (doses may be adjusted per local or regional 
product information/guidelines or local standard of care). For subjects with renal impairment, 


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including those receiving chronic hemodialysis, daptomycin should be dosed per local or 
regional product information/guidelines or local standard of care. For patients with 
pneumonia and concurrent bacteremia, daptomycin should not be used. 
5.2.4 Anti-Staphylococcal Penicillin 
For subjects with known or suspected MSSA, an anti-staphylococcal PCN, also known as a 
penicillinase-resistant PCN, (eg, nafcillin, oxacillin, or cloxacillin) is the preferred therapy.  
The recommended dose is 2 gm IV q 4h, or 12 gm IV continuous infusion over 24 hours 
(doses may be adjusted per local or regional product information/guidelines or local 
standard of care). For subjects with renal impairment, including those receiving chronic 
hemodialysis, anti-staphylococcal PCNs should be dosed per local or regional product 
information/guidelines. 
5.2.5 Cefazolin 
For subjects with known or suspected MSSA, cefazolin is an acceptable alternative therapy.  
The recommended dose is 2 gm IV q8h (doses may be adjusted per local or regional 
product information/guidelines or local standard of care). For subjects with renal impairment, 
including those receiving chronic hemodialysis, cefazolin should be dosed per local or 
regional product information/guidelines. 
5.3 
Criteria for Hospital Discharge (Outpatient Study Drug Administration) 
Subjects may be discharged from the hospital and study drug may be provided on an 
outpatient basis through an OPAT facility or HHC agency, prior to completing study drug, if 
the criteria listed below are met.  
• 
All procedures required on or before Day 8 have been performed 
• 
The Sponsor has approved use of the OPAT facility or HHC agency  
• 
Investigator will obtain IRB approval for the use of OPAT or HHC agency and ensure 
the proper documentation/approval of such use in the ICF  
• 
The subject is a good candidate for outpatient therapy per the investigator’s 
judgment and is able to receive treatment daily in home or at an approved OPAT 
facility 
• 
The subject has initially received study drug while hospitalized and has shown 
objective clinical improvement warranting study drug infusion continuation through an 
OPAT facility or HHC agency. Objective clinical improvement is defined as:  


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• 
All blood cultures negative for S. aureus for two successive days (need not be 
consecutive days) post-randomization 
• 
Improvement (resolution not necessary) in all clinical signs and symptoms of 
S. aureus infection  
• 
Afebrile (< 38oC; highest recorded daily temperature) for at least 24 hours  
• 
Normalizing WBC count (WBC should not be trending upwards) 
• 
The investigator or designee is capable of conducting all study assessments 
(Table 1), including face-to-face evaluations, at every time point required by the 
protocol while the subject is treated through a HHC agency or OPAT facility  
• 
The OPAT and HHC personnel are trained in protocol procedures and training is 
documented in study files 
• 
The investigator can ensure that appropriate safety monitoring will be implemented 
and all protocol-specified assessments and procedures will be conducted 
• 
The investigator can ensure appropriate oversight and proper documentation of IP 
transfer, patient care and AE/SAE reporting 
• 
The subject agrees to return to the primary investigative site for weekly visits, during 
treatment as well as post-treatment, and for EOT, post-EOT and TOC visits  
5.4 
Guidance to Investigators on Duration of Treatment 
On or before Day 8, subjects will be assigned to receive study medication for a specified 
duration based on the classification of infection. Uncomplicated bacteremia will receive a 
minimum of 2 weeks and a maximum of 4 weeks (14 to 28 days), CB will receive 4 to 
6 weeks (28 to 42 days) of therapy, and infective endocarditis will receive 6 weeks 
(42 +/- 3 days) of therapy. If possible, oral prophylaxis following primary therapy should be 
avoided during participation in the study.  
5.5 
Treatment Compliance 
All study drug is to be administered by study personnel and documented in the case report 
forms. 
5.6 
Drug Accountability and Reconciliation 
The investigator or designee is responsible for maintaining accountability records for all 
study drug(s) received from the Sponsor in accordance with applicable government 
regulations and study procedures. The accountability record will include entries for receipt, 
distribution or dispensing, and destruction of the material(s), as well as manufacturer and lot 


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number for all IV comparator medications. The IV comparator manufacturer and lot numbers 
will be entered into the electronic case report form.  Unused and expired study drugs will be 
disposed of in accordance with written instructions from the Sponsor. 


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6 
STUDY PROCEDURES 
6.1 
Schedule of Study Procedures 
The schedule of study procedures is summarized in Table 1. 
6.2 
Procedures by Visit 
The calendar day of first study drug administration is designated as Day 1; subsequent 
calendar days are Days 2, 3, etc. Written informed consent must be obtained prior to 
performing any protocol specific procedures.  
6.2.1 Pretreatment Screening Evaluation 
After providing full informed consent, subjects will undergo a medical screen to determine 
their eligibility for participation based on the criteria outlined in this protocol. 
The following procedures will be performed within 48 hours before randomization unless 
otherwise specified. If the screening assessments and results are obtained within this 
48-hour period, they will be considered valid screening evaluations and do not need to be 
repeated following ICF signature. Local laboratory test results will be used to determine a 
subject’s eligibility for enrollment. Of note, subjects on hemodialysis may have the urine 
assessments waived due to anuria.   
• 
Written informed consent (signed and dated) after the nature of the study has been 
explained and before any study procedure is performed (in the event that a subject is 
unable to give consent, when legally permitted, the subject's legally acceptable 
representative must do so). 
• 
Confirm blood culture within 48 hours before randomization is positive for S. aureus, 
referred to as the QBC. 
• 
All S. aureus isolates should be sent to the central laboratory for organism 
identification and susceptibility testing (refer to Central Laboratory Manual for 
instructions on shipping microbiology samples to the central laboratory). Record 
identification of all non-S. aureus isolates in the electronic case report form (eCRF). 
• 
Medical history and medication history. 
• 
Body temperature; obtain and record highest daily temperature and method of 
measurement on the eCRF. The same method for obtaining body temperature 
should be used for consistency. 
• 
Physical examination, including vital signs. 


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• 
Obtain chest x-ray or CT of chest within 3 days after the report of the QBC. If a chest 
x-ray or CT of chest is obtained during the screening period (within 48 hours prior to 
randomization), a repeat chest x-ray or CT does not need to be done. 
• 
Assessment of all signs and symptoms consistent with S. aureus infection. 
• 
Rigorous evaluation for evidence of metastatic foci of infection, as clinically 
indicated (eg, embolic phenomena to the skin, retina, lungs, bone or CNS; new 
heart murmur; new onset arthritis). Evaluations may include, but are not limited 
to, chest X-ray, ultrasonography, bone scan, CT, MRI and PET imaging. 
• 
Investigators should use clinical judgment to determine whether additional 
imaging studies (eg, x-ray, nuclear scan, CT or MRI) are indicated at screening 
to rule out the presence of osteomyelitis. If osteomyelitis is confirmed or highly 
likely by radiological tests, the subject must not be enrolled. 
• 
Obtain and send blood and urine samples to the central laboratory for the following 
tests (refer to the Central Laboratory Manual for instructions on shipping samples to 
the central laboratory). 
• 
Hematology 
• 
Serum chemistry 
• 
Creatine kinase 
• 
C-reactive protein (CRP) 
• 
Serum interleukin-10 (IL-10) 
• 
Urinalysis 
• 
Quantification of prospective urinary biomarkers of renal function 
• 
Obtain serum and urine for βhCG pregnancy test, if subject is female. Subjects may 
be enrolled into the study on the basis of a negative pregnancy urine test (local 
laboratory), pending the result of the serum pregnancy test (If the result of the serum 
test is subsequently positive, study drug must be discontinued, End of Therapy 
evaluations performed and an End-of-Study visit scheduled). 
• 
Obtain one 12-lead electrocardiogram (ECG). If the QTc is >460 ms (using either the 
Bazett or Fridericia formula) at the screening ECG, the subject will not be entered 
into the study.  
• 
Obtain a urine culture with an aseptic technique. If the subject has a urinary catheter, 
obtain the culture utilizing an aseptic needle stick through the catheter wall). All 
S. aureus isolates should be sent to the central laboratory for organism identification 
and susceptibility testing.  
• 
Obtain specimen for culture when a primary source of bacteremia is identified 
(eg, pus from the entry site of the catheter, central line tip, purulent secretion from a 
wound, sputum). All S. aureus isolates should be sent to the central laboratory for 


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organism identification and susceptibility testing (refer to Central Laboratory Manual 
for instructions on shipping microbiology samples to the central laboratory). If there is 
no clinical evidence of the primary source of infection causing the bacteremia, no 
additional culture is required.  
• 
Assessment of Acute Physiologic and Chronic Health Evaluation (APACHE) criteria 
(Appendix 4). Obtain within 24 hours prior to randomization. 
• 
Confirm subject meets all inclusion criteria and no exclusion criteria. 
• 
If the subject qualifies for the study, the IXRS will be contacted for assignment of 
study drug regimen, and the subject will be considered randomized in the study. 
• 
Assessment of AE(s). 
6.2.2 Daily Procedures  
Day 1 procedures are to be completed after administration of the first dose of study drug. 
The following procedures will be performed daily during the treatment period:   
• 
Administration of study drug per protocol. 
• 
Obtain and record highest daily temperature and method of measurement on the 
eCRF. The same method for obtaining body temperature should be used for 
consistency. 
• 
Recording of all concomitant medications, including those used during procedures. 
• 
Assessment of AE(s). 
• 
Follow-up blood cultures will be performed daily, starting on Day 1, until two 
successive post-randomization blood cultures are negative for S. aureus. 
 
Daily draws for blood culture consist of 2 samples from separate sites inoculated 
into 2 standard aerobic blood culture bottles. 
 
Additional blood cultures should be obtained at any time during the study when 
clinically indicated (eg, bacteremia is suspected or subject has a fever spike). 
 
Perform culture and organism identification at the local or regional laboratory, as 
applicable. All S. aureus isolates should be sent to the central laboratory for 
organism identification and susceptibility testing (refer to Central Laboratory 
Manual for instructions on shipping microbiology samples to the central 
laboratory). 
 
For all non-S. aureus isolates record identification (genus and species) and 
susceptibility (if known) in the eCRF. 
• 
For all subjects randomized to receive telavancin or vancomycin, obtain PK samples 
as noted in the Schedule of Assessments (Figure 3 and Figure 4) and detailed in 
Section 6.3.3.  


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• 
For subjects receiving vancomycin, trough levels of vancomycin as determined by 
the hospital laboratory for use in determining and adjusting the dosing amount will be 
recorded.  
6.2.3 Additional Procedures On or Before Day 8 
The following procedures will be performed on or before Day 8 while the subject is 
hospitalized: 
• 
Echocardiography (either TTE or TEE; TEE is strongly preferred). All 
echocardiograms will undergo blinded review by an independent echocardiography 
core lab. 
• 
For subjects presumed to have S. aureus bacteremia due to a CVC, obtain a central 
venous ultrasound to evaluate for venous thrombosis associated with the CVC.  
• 
Within the first 3 days of starting study drug treatment, procedures to control or 
eliminate the infection source (eg, by removal of intravascular lines’ drainage of 
abscesses, removal of infected prosthesis, or debridement of wounds), will be 
completed. Record any significant procedures, such as incision and drainage, 
debridement, suture removal, radiological procedures, surgery, etc. 
 
Removed catheters can be replaced, but in the case of central catheters they 
cannot be replaced using wire-guided methods, or placed in the same site if 
there is clinical evidence of infection at the entry site. 
 
All microbiological specimens must be cultured. All S. aureus isolates (obtained 
in the workup of S. aureus bacteremia) should be sent to the central laboratory 
for confirmation of organism identification and susceptibility testing (refer to 
Central Laboratory Manual for instructions on shipping microbiology samples to 
the central laboratory). 
• 
Prior to or on Day 8 a signs and symptoms worksheet will be completed to determine 
the infection type including metastatic disease (UCB, CB, RIE, LIE) and sent to the 
medical monitor to review. 
• 
For all subjects randomized to receive telavancin or vancomycin, obtain PK samples 
as noted in the Schedule of Assessments (Figure 3 and Figure 4) and detailed in 
Section 6.3.3.  
• 
On Day 7 (+/- 1 day), obtain and send to the central laboratory blood samples for the 
following tests (refer to the Central Laboratory Manual for instructions on shipping 
samples to the central laboratory). 
 
Hematology 
 
Serum chemistry 
 
Creatine kinase 
 
CRP 
• 
Assessment of all signs and symptoms consistent with S. aureus infection. 


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 
Rigorous evaluation for evidence of metastatic foci of infection, as clinically 
indicated (eg, embolic phenomena to the skin, retina, lungs, bone or CNS; new 
heart murmur; new onset arthritis). Evaluations may include, but are not limited 
to, chest X-ray, ultrasonography, bone scan, CT, MRI and PET imaging. 
• 
Obtain serum creatinine and creatinine clearance daily, up to Day 8, while the 
subject is hospitalized.  
6.2.4 Weekly Procedures After Day 8 
After Day 8, the following procedures will be performed each week (+/- 3 days) until TOC 
Visit: 
• 
Obtain and record highest daily temperature and method of measurement on the 
eCRF. The same method for obtaining body temperature should be used for 
consistency. 
• 
Recording of all concomitant medications, including those used during procedures. 
• 
Assessment of AE(s). 
• 
Assessment of all signs and symptoms consistent with S. aureus infection. 
 
Rigorous evaluation for evidence of metastatic foci of infection, as clinically 
indicated (eg, embolic phenomena to the skin, retina, lungs, bone or CNS; new 
heart murmur; new onset arthritis). Evaluations may include, but are not limited 
to, chest X-ray, ultrasonography, bone scan, CT, MRI, and PET imaging. 
• 
Weekly worksheets noting signs and symptoms of potential metastatic S. aureus 
infection will be reviewed and completed by the physician investigator and forwarded 
to the medical monitor to optimize diagnosis and treatment of both the primary 
infection source and new metastatic foci of S. aureus. 
• 
Recording of any significant procedures such as incision and drainage, debridement, 
suture removal, radiological procedures, surgery, etc. 
• 
For all subjects randomized to receive telavancin or vancomycin, obtain PK samples 
as noted in the Schedule of Assessments (Figure 3 and Figure 4) and detailed in 
Section 6.3.3.  
• 
Obtain and send to the central laboratory blood samples for the following tests (refer 
to the Central Laboratory Manual for instructions on shipping samples to the central 
laboratory). Obtain weekly until EOT Visit. 
• 
Hematology 
• 
Serum chemistry 
• 
Creatine kinase 
• 
CRP  


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• 
After Day 8, while subject is hospitalized, obtain serum creatinine and creatinine 
clearance every 2 days while on study drug (local and central laboratory). After 
Day 8, or if subject is discharged from the hospital to outpatient parenteral antibiotic 
therapy (OPAT) or home health care (HHC), obtain serum creatinine and creatinine 
clearance every 2 to 3 days (central laboratory) while on study drug (on the days 
where the weekly safety lab coincides with the creatinine monitoring, a sample will 
be sent to both the local and central laboratory). 
• 
For female subjects, a urine pregnancy test (local laboratory) will be performed once 
per month (ie, in subjects treated for 6 weeks) as per local regulatory requirements. 
• 
A single 12-lead ECG will be obtained at Week 3 and Week 6. If the QTc time is 
>500 ms or if the QTc time is ≥60 ms above baseline, the subject should be 
withdrawn from treatment. Any other relevant ECG abnormalities noted at Week 3, 6, 
or unscheduled ECGs, should be classified as an AE and additional ECGs will be 
required weekly until the subject discontinues from the study. If feasible, every effort 
should be made to obtain duplicates of all ECGs. All original ECGs obtained for each 
time point (not photocopied) will be held with the study files for analysis in the event 
that a central reader is required. 
6.2.5 End of Therapy Visit / Termination / Early Withdrawal  
The following procedures will be performed within 3 calendar days after the last dose of 
study drug at the End of Therapy (EOT) Visit: 
• 
Investigator evaluation of clinical response at EOT visit. 
• 
Obtain and record highest daily temperature and method of measurement on the 
eCRF. The same method for obtaining body temperature should be used for 
consistency.  
• 
Obtain and send to the central laboratory, blood and urine samples for the following 
tests (refer to Central Laboratory Manual for instructions on shipping samples to the 
central laboratory). 
• 
Hematology 
• 
Serum chemistry 
• 
Creatine kinase 
• 
CRP 
• 
IL-10  
• 
Urinalysis 
• 
Quantification of prospective urinary biomarkers of renal function 
• 
Physical examination including vital signs. 
• 
Assessment of all signs and symptoms consistent with S. aureus infection. 


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 
Rigorous evaluation for evidence of metastatic foci of infection, as clinically 
indicated (eg, embolic phenomena to the skin, retina, lungs, bone or CNS; new 
heart murmur; new onset arthritis). Evaluations may include, but are not limited 
to, chest X-ray, ultrasonography, bone scan, CT, MRI, and PET imaging. 
• 
A single 12-lead ECG will be obtained at EOT or Early Termination prior to Week 6. 
Any clinically significant ECG abnormalities should be classified as an AE and 
reported accordingly. 
• 
Recording of any significant procedures (performed from last intravenous treatment 
day to the time of the EOT Visit), such as incision and drainage, debridement, 
amputation, suture removal, etc. 
• 
Record all concomitant medications. 
• 
Assessment of AE(s). 
6.2.6 Post-End of Therapy Blood Culture 
The following must occur at least 4 days after the EOT visit and results must be available 
prior to the TOC visit. The results will be part of the assessment of clinical outcome at TOC. 
For subjects who are no longer hospitalized, this visit may be coordinated to occur when the 
subject returns for his/her weekly visit: 
• 
Obtain follow-up blood culture specimen. These blood cultures consist of 2 samples 
(8-10 mL) from separate sites inoculated into 2 standard aerobic blood culture 
bottles. All S. aureus isolates should be sent to the central laboratory for organism 
identification and susceptibility testing. (NOTE: For subjects not completing study 
treatment, two blood cultures from separate fresh venipuncture sites will be obtained 
at the early termination visit.) 
6.2.7 Test of Cure Visit / End of Study 
The TOC visit is also the EOS visit. The following procedures will be performed at the TOC 
visit: 
• 
Investigator evaluation of clinical outcome at TOC Visit. 
• 
Obtain and record highest daily temperature and method of measurement on the 
eCRF. The same method for obtaining body temperature should be used for 
consistency. 
• 
Physical examination including vital signs. 
• 
Assessment of all signs and symptoms consistent with S. aureus infection. 
 
Rigorous evaluation for evidence of metastatic foci of infection, as clinically 
indicated (eg, embolic phenomena to the skin, retina, lungs, bone or CNS; new 


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heart murmur; new onset arthritis). Evaluations may include, but are not limited 
to, chest X-ray, ultrasonography, bone scan, CT, MRI, and PET imaging 
• 
Recording of any significant procedures performed since the EOT Visit to the time of 
the TOC Visit (eg, incision and drainage, debridement, amputation) 
• 
Obtain serum and urine for βhCG pregnancy test, if subject is female. 
• 
Record all concomitant medications  
• 
Assessment of AE 
6.3 
Description of Study Assessments and Procedures 
6.3.1 Efficacy Assessments 
Efficacy assessments include evaluation of signs and symptoms consistent with S. aureus 
infection such as blood cultures, physical examination, and echocardiography (TEE, or TTE 
if TEE is not possible); and may also include, but are not limited to, chest X-ray, additional 
specimen cultures, ultrasonography, bone scan, CT, MRI, and PET scan. 
6.3.2 Safety Assessments 
6.3.2.1 Adverse Events 
AEs will be reviewed and recorded from signing of the informed consent through the last day 
of the TOC visit. AE may be observed by the site study personnel or spontaneously reported 
by the subject. 
All AEs must be recorded in the subject’s case report form and, if applicable, reported as 
described in Section 7. 
The investigator must take all therapeutic measures necessary for resolution of AE. Any 
medications necessary for the treatment of an AE must be recorded in the subject’s CRF. 
Refer to Section 7. 
6.3.2.2 Medical History 
Complete medical history at the pretreatment screening evaluation will include evaluation for 
past and present cardiovascular, respiratory, gastrointestinal, renal, hepatic, neurological, 
endocrine, lymphatic, hematologic, immunologic, dermatologic, psychiatric, genitourinary, 
substance abuse, surgical history, previous S. aureus infections, or any other diseases or 


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disorders. If any worsening in severity or frequency occurs for an existing condition or a new 
event occurs after signing of the informed consent, this must be recorded as an AE. 
6.3.2.3 Physical Examination 
The physical examinations at the pretreatment screening evaluation will be performed by an 
appropriately qualified individual (eg, physician, nurse practitioner, physician’s assistant or 
equivalent under the supervision of a physician), and will include examination of the 
following:  general appearance; head, ears, eyes, nose, and throat; neck, skin; 
cardiovascular system; respiratory system; abdominal system; lymphatic system, 
dermatologic system, musculoskeletal system, and nervous system. Subsequent physical 
examinations will be abbreviated and symptomatic, largely focused on evaluation of AEs, if 
any, and any abnormalities identified on the screening examination. 
6.3.2.4 Vital Signs 
Vital signs assessments will include heart rate (HR), blood pressure (BP), respiratory rate 
(RR), and body temperature and will be obtained according to the schedule of assessments 
(Table 1).  
6.3.2.5 Electrocardiogram 
One ECG will be obtained at the prestudy treatment evaluation. If the QTc is >460 ms (using 
either the Bazett or Fridericia formula) at the screening ECG, the subject will not be entered 
into the study. Additional ECGs will be obtained at Week 3, 6, or at the Early Termination 
visit.  
Subject should be withdrawn from treatment if, at any point in the study, the QTc time is 
>500 ms or if the QTc time is ≥60 ms above baseline (screening ECG).  
Any other relevant ECG abnormalities noted at Week 3, 6, or unscheduled ECGs, should be 
classified as an AE and additional ECGs will be required weekly until the subject 
discontinues from the study.  
If feasible, every effort should be made to obtain duplicates of all ECGs. All original ECGs 
obtained for each time point (not photocopied) will be held with the study files for analysis in 
the event that a central reader is required. 


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6.3.2.6 Laboratory Tests 
Blood (for hematology, serum chemistry, CRP, and creatine kinase) and urine (for urinalysis 
and urine renal biomarkers) should be sent to a central laboratory according to the schedule 
of assessments (Table 1). Pretreatment screening blood samples for hematology and serum 
chemistry will also be sent to local laboratory and will be used to determine a subject’s 
eligibility for enrollment. 
6.3.2.6.1 Hematology 
Hematology tests include the following:  hematocrit; hemoglobin; WBC count, including 
differential count by microscopy with percentage of immature neutrophils (bands), mature 
neutrophils, and eosinophils; and platelet count. 
6.3.2.6.2 Serum Chemistry 
Serum chemistry tests include the following:  potassium, magnesium, blood urea nitrogen 
(BUN), creatinine, albumin, total bilirubin, alkaline phosphatase, lactate dehydrogenase 
(LDH), ALT, and AST. 
6.3.2.6.3 Additional Serum Creatinine and Creatinine Clearance 
Serum creatinine and CrCl will be obtained daily while the subject is hospitalized up to 
Day 8. Sample will be sent to both the local and central laboratory. After Day 8, or if subject 
is discharged from the hospital to OPAT or HHC, obtain serum creatinine and creatinine 
clearance every 2 to 3 days (central laboratory) while on study drug (on the days where the 
weekly safety lab coincides with the creatinine monitoring, serum creatinine and creatinine 
clearance will be tested using the weekly safety lab kit).  
6.3.2.6.4 Creatine Kinase (CK) 
Serum creatine kinase (CK) will be obtained at screening, weekly while on study drug, and 
at the EOT visit. 
6.3.2.6.5 C-Reactive Protein (CRP) 
Serum C-reactive protein (CRP) will be obtained at screening, weekly while on study drug, 
and at the EOT visit. 


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6.3.2.6.6 Serum Interleukin-10 (IL-10) 
Serum IL-10, an anti-inflammatory cytokine, will be obtained at screening, and at the EOT 
visit. 
6.3.2.6.7 Pregnancy Test  
For all female subjects, serum and urine β-human chorionic gonadotropin pregnancy tests 
will be conducted at screening visit, and serum pregnancy test at EOS visit as specified in 
(Table 1). Subjects may be enrolled into the study on the basis of a negative urine 
pregnancy test (local laboratory), pending the result of the serum pregnancy test. If the 
result of the serum test is subsequently positive, study drug must be discontinued, EOT 
evaluations performed, and an EOS visit scheduled. A urine pregnancy test (local 
laboratory) will be performed once per month (ie, in subjects treated for 6 weeks) as per 
local regulatory requirements. 
6.3.2.6.8 Urinalysis and Urine Culture 
Urinalysis tests include the following:  presence of blood, bilirubin, urobilinogen, nitrite, and 
leukocytes, (if dipstick positive) microscopic examination of sediment; urine creatinine and 
urine microalbumin; and urine culture. Urine will also be collected for prospective 
assessment of urine renal biomarkers. 
6.3.3 Pharmacokinetic Assessments 
Pharmacokinetic (PK) samples will be collected while in the hospital setting and, as feasible, 
in the outpatient setting, from randomized subjects who receive telavancin or vancomycin.  
A total of 8 samples will be obtained per subject if no dose adjustment is made and sent to 
the central laboratory for analysis. For subjects receiving telavancin, an additional 3 samples 
will be obtained per subject each time a dose adjustment is made within the first two weeks 
of treatment, due to a change in renal functional classification and sent to the central 
laboratory for analysis. Samples should be collected from the opposite arm of the infusion 
site.  
The following sample collection time points are relative to the active dose infusion on that 
day:  
From all subjects randomized to receive telavancin, eight blood samples for PK assessment 
will be obtained as follows: 


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• 
On Day 1: At 1 hour (+15 minute window) and between 4 to 8 hours after the start of 
the infusion. 
• 
On Day 2 prior to start of the infusion (within 30 minutes before dosing).  
• 
On Days 3 and 5: Predose (within 30 minutes before dosing). 
• 
On Day 7: Predose (within 30 minutes before dosing), and between 4 to 8 hours after 
the start of the infusion. 
• 
On Day 14: Predose (within 30 minutes before dosing). 
• 
As feasible, following each change in telavancin dosing during the first 2 weeks of 
therapy due to a change in renal function classification. 
o Predose (within 30 minutes before dosing), between 1 to 4 hours after the start of 
the infusion (sample must be collected following completion of the infusion), and 
24 hours post the initial infusion and prior to the start of the next infusion (within 
30 minutes before dosing). 
NOTE: These blood samples are in addition to scheduled samples. In the case 
where the additional sample coincides with a planned time point, then only one 
sample is to be drawn at that time.  Blood samples should be collected at 
pretreatment and prior to the infusion (trough blood levels) on the day that PK 
samples are obtained.  
From all subjects randomized to receive vancomycin, eight blood samples for PK 
assessment will be obtained as follows: 
• 
On Day 1: At 1 hour (+15 min window) after the start of the infusion. 
• 
On Day 3: Predose (within 30 minutes before dosing). 
• 
On Day 5: Predose (within 30 minutes before dosing), and at 1, 5, 8, and 12 hours 
after the start of the infusion (+15 minute window). 
• 
On Day 14: Predose (within 30 minutes before dosing). 
For subjects receiving vancomycin, trough levels as determined by the hospital for use in 
determining the dosing amount will be recorded. 
Additional details regarding PK sample collection will be provided in the central laboratory 
manual. 
The following plasma PK parameters may be estimated: 
• 
Time of maximum concentration (Tmax) 
• 
Maximum observed plasma concentration (Cmax) 


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• 
Area under the plasma concentration versus time curve from time 0 to the last 
sample with measurable analyte concentration (AUC0-t) 
• 
Area under the concentration versus time curve extrapolated to infinity (AUC0-inf) 
• 
Terminal elimination half-life (t1/2) 
• 
Plasma clearance (CLp) 
• 
Volume of distribution at steady-state (Vdss) 
Pharmacokinetic parameters will be derived using noncompartmental and nonlinear mixed 
effect modeling methods, as appropriate. 
6.4 
Laboratory Test Interference 
6.4.1 Coagulation Tests 
Although telavancin does not interfere with coagulation, it interferes with certain tests used 
to monitor coagulation (Table 4), when conducted using samples drawn 0 to 18 hours after 
telavancin administration for subjects being treated once every 24 hours. Telavancin has the 
potential to prolong both PT and aPTT in vitro. The effect of telavancin on these coagulation 
tests is dose-dependent and varies according to the reagents used. The effects of 
telavancin on PT and aPTT are most likely because of in vitro interference with these 
assays, and do not reflect alterations in coagulation mechanisms in vivo. An increased 
bleeding risk has not been observed in toxicology studies or in large-scale clinical trials of 
telavancin. However, clinicians should be aware of the potential for interference by 
telavancin with routine coagulation assays resulting in apparent prolongations, specifically 
the PT and aPTT. 
As noted in the FDA-approved prescribing information, use of intravenous unfractionated 
heparin sodium is contraindicated with telavancin administration because the aPTT test 
results are expected to be artificially prolonged for 0 to 18 hours after telavancin 
administration, and patients receiving this form of IV heparin may be in the titration phase 
where aPTT is obtained frequently until therapeutic levels are reached. However, in a study 
by Barriere et al. [30], telavancin at trough concentrations was not associated with a 
potentially significant or consistent increase in aPTT with any of the seven reagents tested. 
For subjects who require aPTT monitoring while being treated with telavancin, a 
nonphospholipid dependent coagulation test such as a Factor Xa (chromogenic) assay or an 
alternative anticoagulant not requiring aPTT monitoring may be considered. Blood samples 


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for coagulation tests affected by telavancin should be collected as close as possible prior to 
a patient’s next dose of telavancin. 
Regarding PT prolongation, in the study by Barriere et al. [30], telavancin at trough 
concentrations was associated with a potentially significant increase in PT with only one 
(HemosIL PT-Fibrinogen Recombinant) of the 16 reagents tested. Warfarin therapy may be 
monitored with a functional Factor X assay. As noted in the FDA-approved prescribing 
information, blood samples for coagulation tests affected by telavancin should be collected 
as close as possible prior to a patient’s next dose of telavancin.  
Blood samples for coagulation tests unaffected by telavancin may be collected at any time. 
Table 4: 
Coagulation Tests Affected and Unaffected by Telavancin 
Affected by Telavancin 
Unaffected by Telavancin 
Prothrombin time/international 
normalized ratio 
Activated partial thromboplastin time 
Activated clotting time 
Coagulation based factor X activity 
assay 
Thrombin time 
Whole blood (Lee-White) clotting time 
Platelet aggregation study 
Chromogenic anti-factor Xa assay 
Functional (chromogenic) factor X activity assay 
Bleeding time 
D-dimer 
Fibrin degradation products 
 
6.4.2 Urine Protein Tests 
Proteinuria may be monitored by available quantitative urine protein assays that are not 
affected by telavancin (eg, microalbumin).  
6.5 
Prohibited Concomitant Medications 
All concomitant medications administered should be recorded on the case report form. 
The following concomitant medications are prohibited (see exclusionary criteria specified in 
Section 4.2): 
• 
Potentially effective (anti-staphylococcal) non-study systemic antibacterials  
• 
Agents containing cyclodextrin (intravenous itraconazole or voriconazole) 
• 
Other investigational agents 
• 
Intravenous unfractionated heparin sodium (refer to Section 6.4.1) 


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6.6 
Restrictions 
Not applicable. 
6.7 
Discontinuation 
6.7.1 Subject Discontinuation 
Study drug therapy may be discontinued at any time at the discretion of the investigator and 
in accordance with his or her clinical judgment. If study therapy is withdrawn, all outcome 
data should be collected according to the Schedule of Study Procedures (Table 1); subjects 
must undergo the EOT, post-EOT blood culture, and TOC evaluations (Sections 6.2.5, 
6.2.6, and 6.2.7, respectively), including all safety and efficacy assessments, as outlined in 
the protocol. The Sponsor will be notified of all subject withdrawals. 
Reasons for which the investigator or the Sponsor may withdraw a subject from study drug 
therapy include, but are not limited to, the following: 
• 
AE 
• 
Insufficient therapeutic effect (lack of efficacy) after 72 hours of IV study drug therapy 
• 
Causative pathogen has developed a resistance to the administered study drug and 
no clinical improvement is observed 
• 
Major violation of the protocol 
• 
Pregnancy 
• 
Need for prohibited concomitant medication 
• 
Need for adjunctive antibiotic therapy or need for rescue antibiotic therapy due to 
failure to respond to study drug 
• 
Termination of the study by the Sponsor 
• 
Withdrawal of consent (subject’s choice) 
• 
Other  
• 
After Day 8, if signs and symptoms lead to a subsequent confirmed diagnosis of new 
metastatic foci, it will be criteria for clinical failure. Management of the subject 
(eg, discontinuation of study drug) will be the discretion of the investigator based on 
his/her standard routine care.  
Once a subject is determined to be a clinical failure, all outcome data should be collected 
according to the Schedule of Study Procedures (Table 1); subjects must undergo the EOT, 
post-EOT blood culture, and TOC evaluations (Sections 6.2.5, 6.2.6, and 6.2.7, 


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respectively).  Once the subject is classified as failure, the weekly assessments are not 
mandated unless the subject is still hospitalized. A blood culture obtained after EOT and 
before TOC is encouraged, but optional for cases of clinical failure. 
Any subject (or his or her legally authorized representative) may withdraw their consent to 
participate in the study at any time without prejudice. The investigator must withdraw from 
the study any subject who requests to be withdrawn. If a subject withdraws consent, all 
appropriate outcome and safety assessments at the time of study withdrawal should be 
obtained if possible. Assessments listed in the Schedule of Study Procedures (Table 1) for 
the EOT visit and EOS visit should be carried out, as applicable.  
Every effort should be made to retain each subject as a participant in the study. If a subject 
fails to return for scheduled visits, a documented effort must be made to determine the 
reason. If a subject withdraws before completing the study, the reason for withdrawal is to 
be documented on the CRF. 
6.7.2 Subject Replacement 
Discontinued subjects will not be replaced. 
6.7.3 Study Discontinuation 
The Sponsor reserves the right to discontinue this study at any time for any reason. 
6.8 
Pregnancy 
If a female subject becomes pregnant during the study, the Sponsor’s clinical study director 
(or designee) must be notified immediately and the subject will be withdrawn from the study. 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae 
in the infant will be required. 


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7 
ADVERSE EVENTS 
7.1 
Regulatory Definition of an Adverse Event 
In the International Conference on Harmonization (ICH) E6 Guideline for Good Clinical 
Practice (GCP), Section 1.2 defines an AE as any untoward medical occurrence in a subject 
or clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether 
or not considered related to the medicinal (investigational) product. 
7.2 
Adverse Event Definition for the Purposes of This Study 
For the purposes of this clinical study, AE will be defined as follows: 
An AE is any untoward medical occurrence in a subject who has signed an informed 
consent form and is participating in a clinical investigation. An AE can be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease, 
whether or not considered related to the study drug (investigational product). 
Preexisting events that increase in frequency or severity or change in nature during or as a 
consequence of participation in clinical studies will also be considered as AE. An AE may 
also include pre- or post-treatment complications that occur as a result of a 
protocol-mandated procedure (such as a biopsy). 
Any medical condition or clinically significant laboratory abnormality with an onset date prior 
to the time the subject signed the informed consent form is considered to be preexisting and 
should be documented in the medical history CRF, if applicable for the study. 
Whenever possible, the diagnosis (rather than a series of terms related to a diagnosis) 
should be recorded as the AE term. 
An AE does not include the following: 
• 
Worsening of the primary infection under study in this protocol (S. aureus 
bacteremia), such as the diagnosis of metastatic foci of S. aureus infection (eg, septic 
pulmonary emboli). These events will be captured in the assessment of clinical signs 
and symptoms of S. aureus bacteremia. EXCEPTION: Death due to progression of 
S. aureus bacteremia will be reported as an SAE. 


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• 
Medical or surgical procedures (such as surgery, endoscopy, tooth extraction, or 
transfusion); the condition that leads to the procedure is an AE 
• 
Preexisting diseases or conditions present or detected before signing an informed 
consent form that do not worsen 
• 
Situations where an untoward medical occurrence has not occurred (such as 
hospitalization for elective surgery or social and/or convenience admissions) 
• 
Overdose of either study drug or concomitant medication without any signs or 
symptoms, unless the subject is hospitalized for observation 
7.3 
Assessment of Adverse Events 
All AEs will be assessed by the investigator and recorded in the case report form, including 
the dates of onset and resolution, severity, relationship to study drug, outcome, and action 
taken with study drug. 
Clinical severity should be recorded and graded using mild, moderate or severe as 
described below. 
Mild 
= Awareness of signs or symptoms, but easily tolerated 
Moderate 
= Discomfort sufficient to cause interference with usual activities 
Severe 
= Incapacitation with inability to work or perform usual activities 
 
The relationship to study drug therapy should be assessed using the following definitions: 
• 
Not Related:  Evidence exists that the AE has an etiology other than the study drug 
(such as a preexisting condition, underlying disease, intercurrent illness, or 
concomitant medication). 
• 
Possibly/Probably Related: A temporal relationship exists between the event onset 
and administration of the study drug. It cannot be readily explained by the subject’s 
clinical state or concomitant therapies and appears with some degree of certainty to 
be related based on the known therapeutic and pharmacologic actions of the drug. In 
case of cessation or reduction of the dose, the event abates or resolves and 
reappears upon rechallenge. It should be emphasized that ineffective treatment 
should not be considered as causally related in the context of AE reporting. 
These criteria in addition to good clinical judgment should be used as a guide for 
determining the causal assessment. If it is felt that the event is not related to study drug 
therapy, then an alternative explanation should be provided. 


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7.4 
Serious Adverse Events 
An SAE is defined as any adverse drug experience occurring at any dose that results in any 
of the following outcomes: 
• 
Death (including death due to progression of S. aureus bacteremia) 
• 
Life-threatening situation (subject is at immediate risk of death) 
• 
Inpatient hospitalization or prolongation of existing hospitalization (excluding those for 
study therapy or placement of an indwelling catheter, unless associated with other 
serious events) 
• 
Congenital anomaly/birth defect in the offspring of a subject who received study drug 
• 
Other: Important medical events that may not result in death, be immediately 
life-threatening, or require hospitalization, may be considered an SAE when, based 
upon appropriate medical judgment, they may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such events are as follows: 
• 
Intensive treatment in an emergency room or at home for allergic 
bronchospasm 
• 
Blood dyscrasias or convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse 
Additional Considerations for Serious Adverse Events 
• 
Death is an outcome of an AE and not an AE in itself. In reports of death due to 
disease progression, where no other information is provided, the death will be 
assumed to have resulted from progression of the disease being treated with the 
study drug(s). 
• 
All deaths, regardless of cause, must be reported for subjects if the death occurs 
while the subject is participating in the study. 
• 
“Occurring at any dose” does not imply that the subject is receiving study drug at the 
time of the event; dosing may have been given as treatment cycles or interrupted 
temporarily before the onset of the SAE, but may have contributed to the event. 
• 
“Life-threatening” means that the subject was at immediate risk of death from the 
event as it occurred. This does not include an event that might have led to death, if it 
had occurred with greater severity. 
• 
Complications that occur during hospitalizations are AEs. If a complication prolongs 
hospitalization, it is an SAE. 
• 
“Inpatient hospitalization” means the subject has been formally admitted to a hospital 
for medical reasons, for any length of time. This may or may not be overnight. It does 
not include presentation and care within an emergency department. 


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• 
The investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and/or SAE and not the individual signs/symptoms. 
7.5 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events 
Abnormal laboratory findings (such as clinical chemistry, hematology, or urinalysis) or other 
abnormal assessments (such as X-rays or vital signs) that are associated with signs and/or 
symptoms or are considered clinically significant in the judgment of the investigator must be 
recorded as AEs or SAEs if they meet the definition of an AE (or SAE), as described in 
Sections 7.2 (Adverse Event Definition for the Purposes of This Study) and 7.4 (Serious 
Adverse Events). 
If there are any AE questions, the investigator is encouraged to contact the Sponsor to 
discuss. 
7.6 
Serious Adverse Event Reporting 
Any SAE that occurs after a subject signs an informed consent form through the 
End-of-Study (TOC visit) (or at the time a subject is determined to be ineligible to continue 
participation in the study, or who does not enroll in the study), regardless of causal 
relationship, must be reported to the Sponsor within 24 hours of the investigator’s 
knowledge of the event. To report an SAE, complete and fax the SAE Report Form to the 
following: 
Theravance Biopharma US, Inc. Clinical Drug Safety 
Email: 0112_safety@theravance.com  
 
For medical questions regarding an SAE, contact the Sponsor’s medical monitor (or 
designee) by telephone as follows: 
Medical Monitor Contact Information: 
Gino Girardi, MD 
Lead Medical Monitor, North America and Latin America 
INC Research 
Cell:  
+1 (919) 418-5164 
 
Krzysztof Kacik, MD 
Medical Monitor, Europe 
INC Research 
Office: + 48126462570 
Cell: 
+ 48602648836 


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For fatal or life-threatening events, also fax copies of hospital case reports, autopsy reports, 
and other documents when requested. Additional information may be requested from the 
investigator to ensure the timely completion of accurate safety reports. 
An SAE may qualify for reporting to regulatory authorities if the SAE is possibly attributable 
to the study drug and is unexpected/unlisted based on the current IB. In this case, all 
investigators will receive notification of the event. The investigator is responsible for notifying 
the Institutional Review Board or Ethics Committee and documenting the notification, as 
required by local regulatory authorities and in accordance with the local institutional policy. 
7.7 
Adverse Event Follow-up 
A subject experiencing an AE or SAE will be followed by the investigator or his/her trained 
delegate(s) through the TOC visit or until the investigator and/or the Sponsor has 
determined that the AE or SAE has resolved or a stable clinical endpoint is reached, 
whichever is longer. The Sponsor may request follow-up of certain AE until resolution and 
documentation of assessments made during this period. 
The investigator must take all therapeutic measures necessary for resolution of an SAE. Any 
medications necessary for the treatment of the SAE must be recorded in the concomitant 
medication section of the case report form. 


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8 
STATISTICAL CONSIDERATIONS 
8.1 
Sample Size and Power 
Assuming a population clinical cure rate of 70% for standard IV therapy and 72.5% for 
telavancin, a total sample size of 210 (105 per treatment group) is deemed sufficient 
(80% power) to demonstrate noninferiority based on a noninferiority margin of 15% at a 
one-sided significance level of 2.5%.  This calculation does not take into account potential 
stopping for futility at the interim analysis.  A total of 248 subjects will be enrolled to allow for 
exclusion of up to 15% of subjects from the primary analysis set due to an LIE diagnosis or 
not meeting the mAT population criteria. 
8.2 
General Considerations 
All individual data will be listed as measured. All statistical summaries and analyses will be 
performed using SAS software (SAS Institute, Cary, North Carolina, USA).  
Continuous data will be summarized using an 8-point descriptive summary (n, mean, 
standard deviation, median, interquartile range (IQR) [25% quartile, 75% quartile]), minimum 
and maximum unless otherwise stated. Categorical data will be summarized using the 
frequency of events and percentage of total events. 
Any changes to the protocol-specified analyses will be pre-specified in the SAP prior to 
database lock. 
8.3 
Analysis Populations 
Specific criteria for subject evaluability will be outlined in the SAP and, when applicable, 
programmatically applied.  
8.3.1 Efficacy Analysis Populations 
The AT population is defined as all randomized subjects who have received at least one 
dose of study drug and were enrolled after protocol Amendment 1.  Subjects enrolled prior 
to Protocol Amendment 1 will be excluded from all efficacy analyses, because the dose of 
telavancin was decreased following Protocol Amendment 1.  Analyses conducted based on 
the AT population will assign subjects according to their randomized treatments. 


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The mAT population includes subjects in the AT population who have a mono-microbial 
QBC positive for S. aureus. 
The mAT subjects with a diagnosis of UCB, CB, or RIE will constitute the primary analysis 
population for efficacy. 
The ME population is a subset of the mAT population and includes subjects who meet the 
following criteria: 
1. Completed at least 80% of prescribed study medication for their baseline diagnosis 
2. Did not miss more than 2 consecutive doses of study medication 
3. Completed the TOC visit 
4. Did not have any recorded major protocol deviations 
5. If assessed as failure at TOC, received at least 2 days of study medication 
6. If assessed as cure at TOC, received at least 5 days of study medication 
7. Did not receive any prohibited concomitant, potentially effective antibiotic (other than 
study medication) 
8.3.2 Safety Analysis Population 
The safety population will be defined as all subjects from the AT population and subject 
assignment according to actual study treatments they receive.  
8.3.3 Pharmacokinetic Analysis Population 
The PK population will be defined as all subjects from the safety population who provide 
evaluable PK data from at least one postdose sample in plasma. 
8.3.4 Examination of Subgroups 
Additional efficacy evaluations, conducted for the primary and secondary efficacy endpoints, 
will include subset analyses by vancomycin MIC values (eg, MIC ≤1, or MIC >1), and by 
infection type (eg, UCB, CB, RIE and LIE).  
In addition, evaluation of the primary and key secondary endpoints may be performed for 
the following subgroups/factors: 
 


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• 
Infection with MRSA 
• 
Infection with MSSA 
• 
Presence or absence of diabetes 
• 
Subgroups defined by baseline renal function, as determined by baseline 
creatinine clearance 
• 
Baseline modified APACHE II score (chronic health assessment not included in 
modified score) 
• 
Subject age 
• 
Geographic region 
Details of subset analyses will be defined in the SAP. Subset analyses will proceed if it is 
deemed that a sufficient number of subjects are available to render a meaningful summary. 
8.4 
Analyses 
8.4.1 Disposition, Demographics, Baseline Characteristics, and Exposure 
Summaries will present, by treatment group, the number of subjects randomized; the 
number in each population; the number completing and discontinuing early from study; the 
reason for termination from study; race, age, sex, and baseline clinical characteristics; the 
number of days of study drug dosing, and reason for final discontinuation of study drug. 
For analyses of demographics and other baseline characteristics, the mAT, ME, and safety 
populations will be prepared in separate tables. 
8.4.2 Analysis of Efficacy 
The primary efficacy endpoint is clinical outcome at the TOC visit (See Section 3.4.2). 
Specifically, clinical cure rate, defined as proportion of subjects with the clinical outcome of 
success, at TOC will be evaluated.  The primary efficacy endpoint will be determined by the 
investigator and adjudicated by the IEAC blinded to treatment assignments.  
In order to evaluate secondary efficacy endpoints described in Section 3.4.3, clinical cure 
rate at EOT, proportion of subjects with new metastatic loci of infection, and duration of 
treatment with study medication will be derived. 
In addition, analyses evaluating evidence of treatment-emergent resistance to telavancin, 
vancomycin, daptomycin, anti-staphylococcal PCNs, or cefazolin may be conducted. 


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Exploratory analyses will be conducted to assess a variety of health utilization variables. 
Methods of analysis for these variables will be outlined in a separate HEOR SAP. The 
results of these analyses will be presented separately and not included in the clinical study 
report (CSR). 
The primary analysis will be to first test the hypothesis of telavancin’s clinical noninferiority to 
standard therapy, employing a noninferiority margin (the “∆”) of 15 percentage points on the 
difference of proportions scale, in the mAT subjects with a diagnosis of UCB, CB, or RIE.  
The null hypothesis is that telavancin is clinically inferior to standard therapy, where 
“clinically inferior” is defined as having a population clinical cure rate that is 15 percentage 
points (or more) lower than that for standard IV therapy. The alternative hypothesis is that 
telavancin is at least clinically noninferior to standard IV therapy, where “clinical 
noninferiority” is defined as having population clinical cure rates that differ by less than 
15 percentage points. Expressed symbolically, the null hypothesis (H0) and the alternative 
hypothesis (H1) are as follows: 
H0:  πTLV − πSTD ≤ −15% 
H1:  πTLV − πSTD > −15% 
where πTLV and πSTD denote the population clinical cure rates of telavancin and standard IV 
therapy, respectively. 
Final testing will be conducted at a one-sided 2.5% significance level. Testing will be 
implemented by the construction of a two-sided 95% confidence interval (CI) on the 
treatment difference, πTLV – πSTD.  
If the lower confidence limit (CLLOWER) is less than or equal to -15%, then the null hypothesis 
of inferiority will not be rejected. If CLLOWER > -15%, then the null hypothesis of clinical 
inferiority will be rejected in favor of the alternative hypothesis of clinical noninferiority. 
If the above analysis concludes that telavancin is clinically noninferior to standard IV 
therapy, then a test for superiority will be conducted. The superiority analysis is to test the 
null hypothesis that telavancin is the same as (or worse than) standard IV therapy, against 
the alternative hypothesis that telavancin is superior to standard therapy, in the mAT 
subjects with a diagnosis of UCB, CB, or RIE. Expressed symbolically, the null and 
alternative hypotheses were as follows: 


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H0:  πTLV − πSTD ≤ 0 
H1:  πTLV − πSTD > 0 
If the CLLOWER of the previously described CI is zero or less, then the null hypothesis will not 
be rejected. If CLLOWER is greater than zero, then the null hypothesis will be rejected in favor 
of the alternative hypothesis of superiority. 
By the close-testing principle, no adjustment on the Type I error rate will be necessary for 
performing the noninferiority and superiority tests sequentially, because the two null 
hypotheses constitute a closed family, and the hypothesis of clinical inferiority 
(H0: πTLV - πSTD ≤ −15%) implies the hypothesis of nonsuperiority (H0:  πTLV − πSTD ≤0). 
For the primary efficacy analysis, the point estimate and CI for the treatment difference will 
be calculated using the normal approximation to the binomial distribution without continuity 
correction. If any cell size is less than 10, as might have occurred during a subgroup 
analysis, the CI will be calculated using the method of Agresti and Caffo [31] to adjust for the 
sparse cell size.  
Analysis of other endpoints focusing on incidence of occurrence (eg, development of new 
metastatic foci of infection) will be similar to the primary analysis of clinical outcome 
previously described. 
Time-to-event endpoints, including 28-day all-cause mortality and time to two successive 
negative blood cultures, will be reported graphically using Kaplan-Meier survival curves and, 
as appropriate, treatment differences will be evaluated using log-rank tests, stratified by 
geographic region. 
Additional supportive or exploratory analyses of the AT, mAT, ME, and safety populations 
will be described in the SAP. 
8.4.3 Analysis of Safety 
All safety endpoints will be evaluated for the safety population as defined in Section 8.3.2.  
Unless specified otherwise, safety assessments will be summarized descriptively by 
treatment group. Safety endpoints to be summarized include vital signs, AE, clinical 
laboratory results (hematology, chemistry, and urinalysis).  


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Treatment-emergent AEs are defined as AE with onset on or after initiation of study drug. 
The number and percentage of subjects reporting TEAEs will be tabulated by Medical 
Dictionary for Regulatory Activities system organ class and preferred term, severity, and 
relationship to study drug. Serious TEAEs and TEAEs resulting in discontinuation of study 
drug will be summarized separately. 
Additional summaries of AEs of special interest (eg, renal injury) may be prepared. 
Concomitant medications will be mapped using the WHODRUG dictionary. The number and 
percentage of subjects taking each concomitant medication will be tabulated. Separate 
summaries of prior and concomitant antibiotics will be prepared. 
Subject eligibility for enrollment will be made based on laboratory results performed at the 
study centers. Analysis of laboratory results will be based on those reported by the Central 
Laboratory. Continuous laboratory measurements will be descriptively summarized for 
observed values and changes from baseline. Categorical laboratory measurements will be 
summarized by the number and percentage of subjects with low, normal and high values. 
A shift table of laboratory measurements comparing pre- and post-treatment values relative 
to normal ranges (for example, normal to low, normal to normal, or normal to high) will also 
be summarized. Listing of laboratory results will flag values that are outside of normal range. 
Vital signs parameters will be summarized for observed values and changes from baseline.  
8.5 
Analysis of Pharmacokinetics 
For subjects who receive telavancin or vancomycin and have at least one post-dose PK 
sample collected, plasma concentration profiles will be estimated.  
Summary statistics for plasma telavancin and vancomycin concentrations (mean, standard 
deviation, median, minimum, maximum, number of subjects, and coefficient of variation) will 
be calculated for each predose time point. 
For subjects with at least one post-dose PK sample collected, telavancin plasma 
concentration-time profiles will be estimated. Estimated PK parameters may include the 
following: Tmax, Cmax, AUCo-t, AUCo-inf, t1/2, CLp, and Vdss.  
Noncompartmental and nonlinear mixed-effects modeling methods will be used for 
determination of PK parameters, as appropriate. All PK parameters will be presented as 


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individual listings and as summary statistics (mean, geometric mean, median, range, 
standard deviation, coefficient of variation, minimum, maximum, and number of subjects). 
Plasma concentration data may also be analyzed using non-linear mixed effects 
PK modeling techniques. The following covariates will be obtained for each subject: height, 
weight, body surface area (BSA), body mass index (BMI), age, sex, and relevant laboratory 
tests that reflect the function of organs responsible for drug elimination. The relationship 
between these parameters and PK of the drug of interest will be examined using suitable 
statistical techniques and study designs. Reporting of any population PK analysis from this 
study will be reported separately. 
8.6 
Handling of Missing Data 
Estimates of event rates (eg, the clinical cure rate) will be calculated relative to the number 
of subjects in the given analysis population. For example, any patient in the analysis 
population with an “indeterminate” or missing value for clinical outcome will be counted in 
the denominator when calculating clinical cure rate. 
8.7 
Multiple Testing: Order of Hypotheses 
The primary analysis will test both clinical noninferiority and superiority of telavancin relative 
to standard IV therapy in the treatment of S. aureus bacteremia and SA-RIE. Both tests will 
be conducted at a one-sided 2.5% significance level. No adjustment of the Type I error rate 
is necessary for conducting these two tests sequentially as the process is supported by the 
closed-testing principle. 
Secondary analysis hypotheses will be tested in hierarchical order at the two-sided 5% level 
of significance until a failure to reject occurs. 
For all supportive analyses of the primary efficacy endpoint and secondary efficacy 
endpoints, p-values and confidence intervals will be reported at the two-sided 5% level, with 
no adjustment for multiplicity.  
8.8 
Interim Analysis 
A single interim assessment allowing early stopping for futility will be conducted by the IDMC 
(see Section 8.10) based on the subjects who completed or discontinued from the study on 
or before October 31, 2017. 


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Conditional power to show non-inferiority under the current trend will be computed using the 
normal approximation to the non-inferiority test statistic. 
The IDMC may recommend stopping for futility, if the conditional power is 50% or less.  With 
this futility analysis, the overall power of the study is approximately 64%.  Conditional power 
of 50% or less would be associated with the negative point estimate of the treatment 
difference πTLV − πSTD. 
Furthermore, the IDMC may recommend stopping the study if the point estimate of the 
treatment difference, πTLV − πSTD in the subset of subjects with CB or RIE is not positive.   
8.9 
Independent Efficacy Adjudication Committee 
A blinded IEAC of clinical experts will review the data from each subject to establish the 
1) classification of infection type, and 2) clinical outcome at TOC, on an on-going basis. The 
committee will perform adjudication of efficacy events without having access to the subjects’ 
treatment assignments. A separate charter describes the blinding plan and the adjudication 
committee’s activities. 
8.10 
Independent Data Monitoring Committee 
An unblinded IDMC will act in an advisory capacity to the Sponsor to monitor subject safety 
and the efficacy of the study drug. The IDMC responsibilities will be defined in a charter and 
are as follows: 
• 
Review the following documents before commencing activities as a IDMC: draft IDMC 
charter, investigator brochure, study protocols, blank informed consent form, blank 
case report forms and mockups of proposed data presentations 
• 
Evaluate the progress of the study; timeliness and quality of the data; subject 
recruitment, accrual, and retention; risk versus benefit to subjects; and other factors 
that might affect the outcome of the study 
• 
Consider relevant information that may have an impact on subject safety or the ethics 
of the study 
• 
Make recommendations to the Sponsor concerning continuation, termination, or other 
modifications to the study based on their observations of the study and its data 
• 
Conduct a review of interim analysis of safety and efficacy 
A full IDMC charter will be prepared to govern the activities of the committee. 


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9 
STUDY ADMINISTRATION 
This study will be conducted in compliance with all applicable regulations. 
9.1 
Principal Investigator Responsibilities 
Before beginning the study, the principal investigator (PI) at each site must provide to the 
Sponsor or its designee a fully executed and signed Form FDA 1572 and, if applicable, a 
financial disclosure form. For applicable studies, financial disclosure forms must also be 
completed for all subinvestigators who will be directly involved in the treatment or evaluation 
of research subjects in this study. (A subinvestigator is defined in ICH E6 as any individual 
member of the clinical study team designated and supervised by the investigator at a study 
site to perform critical study-related procedures and/or to make important study-related 
decisions [eg, associates, residents, research fellows].) 
The PI will ensure the following: 
• 
He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of subjects. 
• 
He or she will personally conduct or supervise the study. 
• 
He or she will inform any potential subjects, or any persons used as controls, that the 
drugs are being used for investigational purposes and he or she will ensure that the 
requirements relating to obtaining informed consent in 21 CFR Part 50 and 
institutional review board (IRB) review and approval in 21 CFR Part 56 are met. 
• 
He or she will report to the sponsor adverse experiences that occur in the course of 
the investigation in accordance with 21 CFR 312.64. 
• 
He or she has read and understands the information in the VIBATIV® (telavancin) 
Investigator’s Brochure, including potential risks and side effects of the drug. 
• 
His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments. 
• 
If subjects are discharged to an OPAT facility or HHC agency, he or she will provide 
appropriate oversight and proper documentation of IP transfer, patient care, AE/SAE 
reporting, IRB approval for the use of OPAT or HHC agency and the proper 
documentation/approval of such use in the ICF  
• 
He or she will ensure that adequate and accurate records in accordance with 
21 CFR 312.62 and to make those records available for inspection in accordance with 
21 CFR 312.68. 
• 
He or she will ensure that the IRB/IEC complies with the requirements of 
21 CFR Part 56, and other applicable regulations, and conducts initial and ongoing 
reviews and approvals of the study. He or she will also ensure that any change in 
research activity and all problems involving risks to human subjects or others are 


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reported to the IRB/IEC. Additionally, he or she will not make any changes in the 
research without IRB/IEC approval, except where necessary to eliminate apparent 
immediate hazards to human subjects. 
• 
He or she agrees to comply with all other requirements regarding the obligations of 
clinical investigators and all other pertinent requirements in 21 CFR Part 312. 
9.2 
Institutional Review Board/Independent Ethics Committee 
Before beginning study-specific research, the investigator will obtain written confirmation 
that the IRB, IEC, or Research Ethics Board (REB) is properly constituted and compliant 
with ICH and GCP requirements, applicable laws, and local regulations. A copy of the 
confirmation from the IRB/IEC/REB will be provided to the Sponsor or its designee. The 
protocol, informed consent form (ICF), IB, use of OPAT or HHC agency, and any other 
appropriate written information provided to the subjects that the IRB/IEC/REB may require to 
fulfill its responsibilities will be submitted to the IRB/IEC/REB in advance of the study. The 
Sponsor or its designee must approve the ICF and all subject recruitment materials before 
they are submitted to the IRB/IEC/REB. The study will not proceed until appropriate 
documents from the IRB/IEC/REB confirming unconditional approval of the protocol and the 
ICF are obtained by the investigator and copies are received by the Sponsor or its designee. 
If possible, the approval document should refer to the study by study protocol title and the 
Sponsor’s study number, identify the documents reviewed, and include the date of the 
review and approval. The written approval of the IRB/IEC/REB will be retained as part of the 
study file. The study may proceed before approval of consent forms and other study 
documents translated to a language other than the native language of the clinical site, 
provided that written IRB/IEC/REB approval of the translated documents is obtained before 
they are used. Any amendments to the protocol should be reviewed promptly. 
The investigator must provide the appropriate periodic reports on the progress of the study 
to the IRB/IEC/REB and the Sponsor in accordance with local IRB/IEC/REB requirements 
and applicable governmental regulations, whichever is strictest. 
9.3 
Informed Consent 
A properly written and executed ICF, in compliance with ICH E6 (GCP Guideline, 
Section 4.8), 21 CFR §50, and other applicable local regulations, will be obtained for each 
subject before enrollment of the subject into the study. The investigator will prepare the ICF 
or revise the template ICF and provide the documents to the Sponsor (or designee) for 


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approval before submission to the IRB/IEC/REB. The Sponsor and the IRB/IEC/REB must 
approve the documents before they are implemented. 
If a legally authorized representative (LAR) provides informed consent on behalf of the 
subject, documentation will also be required to indicate the relationship of the LAR to the 
subject. 
The investigator will provide copies of the signed ICF to each subject (or the subject’s legally 
authorized representative) and will maintain the original in the subject’s record file. 
9.4 
Data Recording and Quality Assurance 
As used in this protocol, the term case report form (CRF) should be understood to refer to 
either a paper form or an electronic data record or both, depending on the data collection 
method used. 
Electronic data capture (EDC) technology will be used for this study. All clinical information 
requested in this protocol will be recorded on the electronic case report forms approved by 
the Sponsor, or via other data collection methods, eg, electronic laboratory data transfer. 
Study site personnel will enter (in English) study data into the CRFs for each randomized 
subject. Training on the EDC application will be completed and documented before access 
to the EDC system is given. 
In the event of a CRF data change (eg, correction of an error or addition of new information), 
corrections will be made to the CRF. Corrections to the CRFs, including the reason for 
change, will be automatically documented through the EDC system’s audit trail. 
The investigator is responsible for reviewing all CRFs, verifying them for accuracy, and 
approving them via an electronic signature. The investigator is designated as the signatory 
coordinating investigator. 
An electronic copy of the CRF casebooks will be sent to the site for retention with other 
study documents after full completion of the study, ie, after database lock. 
The investigator is responsible for maintaining accurate, authentic, complete, and up-to-date 
records for each subject. The investigator is also responsible for ensuring the availability of 
any original source documentation related to the study (including any films, tracings, 


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computer discs, tapes, and worksheets). In most cases the source is the subject’s medical 
record. Data collected on the CRFs must match the source documents. 
In some cases, the CRF may also serve as the source document. In these cases, a 
document should be available at the investigator’s site and clearly identify those data that 
will be recorded in the CRF and for which the CRF will stand as the source document. 
9.5 
Document Retention 
Until otherwise notified by the Sponsor, an investigative site must retain in a controlled 
manner all study documents required by the Sponsor and by the applicable regulations. The 
investigative site must take measures to prevent accidental or premature destruction of 
essential documents, that is, documents that individually and collectively permit evaluation 
of the conduct of a study and the quality of the data produced, including paper copies of 
study records (eg, subject charts) and any original source documents that are electronic, as 
required by applicable regulations. 
The investigator must consult a Sponsor representative before disposal of any study records 
and must notify the Sponsor of any change in the location or disposition of the study files. If 
an investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping the study documents, custody must be transferred to a person who will accept the 
responsibility. The Sponsor must be notified in writing of the name and address of the new 
custodian and must approve this transfer of responsibility. 
9.6 
Confidentiality 
The investigator or designee must explain to each subject, before enrollment into the study, 
that, for evaluation of study results, the subject’s confidential medical information obtained 
during the study may be shared with the study sponsor, regulatory agencies, and the 
institutional review board (IRB) or independent ethics committee (IEC). The investigator 
(or designee) is responsible for obtaining written permission to use confidential medical 
information in accordance with country-specific regulations (such as the Health Insurance 
Portability and Accountability Act in the United States) from each subject or, if appropriate, 
the subject’s legally authorized representative. If permission to use confidential medical 
information is withdrawn, the investigator is responsible for documenting that no further data 
from the subject will be collected. 


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Subject medical information obtained during this study is confidential, and disclosure to 
unauthorized third parties is prohibited. The pertinent sections of data protection laws will be 
complied with in full. Study records containing subject information will only be identified by 
the subject identification number, subject initials, date of birth, and study number, and not by 
the subject’s full name, except the subject consent form, which is archived at the study 
center only. The subject’s name will not be used in any public report of the study. 
During the course of the study, a confidential subject identification list will be maintained by 
the investigator and archived at the investigative site. 
Before and during the conduct of the study, no study-related details may be disclosed, 
ie, placed on the internet, published, or otherwise publicized, or provided to a third party 
without prior written permission from the Sponsor. The policy for publication of data after 
completion of the study is described in Section 9.10 (Publication). 
9.7 
Access to Data and Documents 
Upon receipt of the subject’s permission, medical information may be given to his or her 
personal physician or other appropriate medical personnel responsible for his or her welfare. 
Study data recorded on the CRFs must be verifiable to the source data. All original 
recordings, laboratory reports, and subject records generated by this study must be 
available to the Sponsor, representatives of the Sponsor, the IRB/IEC/REB, and applicable 
regulatory authorities, and they may be used for submission to regulatory authorities. In 
addition, all source data should be attributable (signed and dated), consistent with local 
medical practice. The investigator must therefore agree to allow direct access to all source 
data. Subjects (or their legally authorized representatives) must also allow access to their 
medical records, and subjects will be informed of this and will confirm their agreement when 
giving informed consent. 
9.8 
Quality Control: Study Monitoring and Auditing 
Qualified individuals designated by the Sponsor will monitor all aspects of the study 
according to GCP and standard operating procedures (SOPs) for compliance with 
applicable government regulations. The investigator agrees to allow these monitors direct 
access to the clinical data and supplies, dispensing, and storage areas and, if requested, 
agrees to assist the monitors. The investigator and staff are responsible for being present or 


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available for consultation during routinely scheduled site visits conducted by the Sponsor or 
its designees. 
Members of the Sponsor’s GCP Quality Assurance Department or designees may conduct 
an audit of a clinical site at any time during or after completion of the study. The investigator 
will be informed if an audit is to take place and advised as to the scope of the audit. 
Inspections and audits are typically carried out during the clinical and reporting phases of 
this study to ensure that the study is conducted and data are generated, documented, and 
reported in compliance with the protocol, GCP, written SOPs and applicable laws, rules, and 
regulations. 
Representatives of the FDA or other Regulatory Agencies, including IRB/IEC 
representatives may also conduct an audit of the study. If informed of such an inspection, 
the investigator should notify the Sponsor immediately. The investigator will ensure that the 
auditors have access to the clinical supplies, study site facilities, laboratory and all data 
(including original source documentation) and all study files are available, if requested. 
Noncompliance with the protocol, ICH, GCP, or local regulatory requirements by an 
investigator, institution, institution staff, or representatives of the Sponsor will lead to prompt 
action by the Sponsor to secure compliance. Continued noncompliance may result in 
termination of the investigator’s involvement in the study. The IRB/IEC/REB and relevant 
regulatory authority will be informed. 
9.9 
End of Study 
For each participating European Union (EU) country, the end of the study according to the 
EU Clinical Trial Directive will be reached when the last visit of the last patient for all centers 
in the respective country has occurred. 
9.10 
Publication 
The Sponsor recognizes the importance of communicating medical study data and therefore 
encourages their publication in reputable scientific journals and presentation at seminars or 
conferences. The Sponsor will retain the ownership of the data collected in this study. The 
investigator will provide any proposed manuscript or abstract to the Sponsor before 
submission for publication or presentation of any results or data obtained in this study. 


Protocol 0112, Amendment 4 
16JAN2018 
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Page 97 
 
Confidential – Property of Theravance Biopharma US, Inc. 
Additional details of the processes of producing and reviewing reports, manuscripts, and 
presentations based on the data from this study will be described in the Clinical Trial 
Agreement between the Sponsor and the investigator. 


Protocol 0112, Amendment 4 
16JAN2018 
Telavancin 
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Confidential – Property of Theravance Biopharma US, Inc. 
10 
REFERENCES 
1. 
Klevens, R.M., et al., Invasive methicillin-resistant Staphylococcus aureus infections 
in the United States. JAMA: The Journal of the American Medical Association, 2007. 
298(15): p. 1763-1771. 
2. 
Chu, V.H., et al., Staphylococcus aureus bacteremia in patients with prosthetic 
devices: costs and outcomes. Am J Med, 2005. 118(12): p. 1416. 
3. 
Rieg, S., et al., Mortality of S. aureus bacteremia and infectious diseases specialist 
consultation--a study of 521 patients in Germany. J Infect, 2009. 59(4): p. 232-9. 
4. 
Boucher, H.W. and G.R. Corey, Epidemiology of methicillin-resistant Staphylococcus 
aureus. Clin Infect Dis, 2008. 46 Suppl 5: p. S344-9. 
5. 
Liu, C., 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): p. 285-92. 
6. 
Levine, D.P., B.S. Fromm, and B.R. Reddy, Slow response to vancomycin or 
vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis. 
Ann Intern Med, 1991. 115(9): p. 674-80. 
7. 
Chang, F.Y., et al., Staphylococcus aureus bacteremia: recurrence and the impact of 
antibiotic treatment in a prospective multicenter study. Medicine (Baltimore), 2003. 
82(5): p. 333-9. 
8. 
Stryjewski, M.E., et al., Use of vancomycin or first-generation cephalosporins for the 
treatment of hemodialysis-dependent patients with methicillin-susceptible 
Staphylococcus aureus bacteremia. Clin Infect Dis, 2007. 44(2): p. 190-6. 
9. 
Hawser, S.P., et al., Rising incidence of Staphylococcus aureus with reduced 
susceptibility to vancomycin and susceptibility to antibiotics: a global analysis 2004-
2009. Int J Antimicrob Agents, 2011. 37(3): p. 219-224. 
10. 
Fowler, V.G., Jr., et al., Recurrent Staphylococcus aureus bacteremia: pulsed-field 
gel electrophoresis findings in 29 patients. J Infect Dis, 1999. 179(5): p. 1157-61. 
11. 
van Hal, S.J., D.L. Paterson, and I.B. Gosbell, Emergence of daptomycin resistance 
following vancomycin-unresponsive Staphylococcus aureus bacteraemia in a 
daptomycin-naive patient--a review of the literature. Eur J Clin Microbiol Infect Dis, 
2011. 30(5): p. 603-10. 
12. 
Cui, L., et al., Correlation between Reduced Daptomycin Susceptibility and 
Vancomycin Resistance in Vancomycin-Intermediate Staphylococcus aureus. 
Antimicrob Agents Chemother, 2006. 50(3): p. 1079-82. 
13. 
Kirker, K.R., S.T. Fisher, and G.A. James, Potency and penetration of telavancin in 
staphylococcal biofilms. Int J Antimicrob Agents, 2015. 
14. 
Chan, C., T.C. Hardin, and J.I. Smart, A review of telavancin activity in in vitro 
biofilms and animal models of biofilm-associated infections. Future Microbiol, 2015: 
p. 1-14. 
15. 
Ruggero, M.A., D.R. Peaper, and J.E. Topal, Telavancin for refractory methicillin-
resistant Staphylococcus aureus bacteremia with and without endocarditis. Paper 
presented at: Infectious Diseases Society of America Annual Meeting, Oct 17-21, 
2012; San Diego, CA USA. 
16. 
Marcos, L.A. and B.C. Camins, Successful treatment of vancomycin-intermediate 
Staphylococcus aureus pacemaker lead infective endocarditis with telavancin. 
Antimicrob Agents Chemother, 2010. 54(12): p. 5376-8. 
17. 
Nace, H. and B. Lorber, Successful treatment of methicillin-resistant Staphylococcus 
aureus endocarditis with telavancin. J Antimicrob Chemother, 2010. 65(6): p. 1315-6. 


Protocol 0112, Amendment 4 
16JAN2018 
Telavancin 
Page 99 
 
Confidential – Property of Theravance Biopharma US, Inc. 
18. 
Mermel, L.A., et al., Clinical practice guidelines for the diagnosis and management of 
intravascular catheter-related infection: 2009 Update by the Infectious Diseases 
Society of America. Clin Infect Dis, 2009. 49(1): p. 1-45. 
19. 
Figueroa, D.A., et al., Safety of high-dose intravenous daptomycin treatment: three-
year cumulative experience in a clinical program. Clin Infect Dis, 2009. 49(2): p. 177-
80. 
20. 
Benvenuto, M., et al., Pharmacokinetics and tolerability of daptomycin at doses up to 
12 milligrams per kilogram of body weight once daily in healthy volunteers. 
Antimicrob Agents Chemother, 2006. 50(10): p. 3245-9. 
21. 
Weston, A. and H.W. Boucher, Early high-dose daptomycin for methicillin-resistant 
Staphylococcus aureus bloodstream infections with elevated vancomycin minimum 
inhibitory concentrations: ready for prime time? Clin Infect Dis, 2013. 56(11): p. 
1570-2. 
22. 
Moise, P.A., et al., Safety and clinical outcomes when utilizing high-dose (> or =8 
mg/kg) daptomycin therapy. Ann Pharmacother, 2009. 43(7): p. 1211-9. 
23. 
Wu, G., et al., Daptomycin: evaluation of a high-dose treatment strategy. Int J 
Antimicrob Agents, 2011. 38(3): p. 192-6. 
24. 
Li, J.S., et al., Proposed modifications to the Duke criteria for the diagnosis of 
infective endocarditis. Clin Infect Dis, 2000. 30(4): p. 633-8. 
25. 
Fowler, V.G., Jr., et al., Clinical identifiers of complicated Staphylococcus aureus 
bacteremia. Arch Intern Med, 2003. 163(17): p. 2066-72. 
26. 
Fowler, V.G., Jr., et al., Risk factors for hematogenous complications of intravascular 
catheter-associated Staphylococcus aureus bacteremia. Clin Infect Dis, 2005. 40(5): 
p. 695-703. 
27. 
Crowley, A.L., et al., Venous thrombosis in patients with short- and long-term central 
venous catheter-associated Staphylococcus aureus bacteremia. Crit Care Med, 
2008. 36(2): p. 385-90. 
28. 
Hawkins, C., et al., Persistent Staphylococcus aureus bacteremia: an analysis of risk 
factors and outcomes. Arch Intern Med, 2007. 167(17): p. 1861-7. 
29. 
Theravance, I., Prescribing Information for VIBATIV® (telavancin).  March 2014.  
Accessed at: http://www.vibativ.com/docs/VIBATIV_PI_Final.pdf. 
30. 
Barriere, S.L., et al., Effects of telavancin on coagulation test results. Int J Clin Pract, 
2011. 65(7): p. 784-9. 
31. 
Agresti, A. and B. Caffo, Simple and effective confidence intervals for proportions 
and differences of proportions result from adding two successes and two failures. 
The American Statistician, 2000. 54(4): p. 280-288. 
32. 
Pugh, R.N., et al., Transection of the oesophagus for bleeding oesophageal varices. 
Br J Surg, 1973. 60(8): p. 646-9. 
33. 
Bellomo, R., et al., Acute renal failure - definition, outcome measures, animal 
models, fluid therapy and information technology needs: the Second International 
Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit 
Care, 2004. 8(4): p. R204-12. 
34. 
Knaus, W.A., et al., APACHE II: a severity of disease classification system. Crit Care 
Med, 1985. 13(10): p. 818-829. 
 


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11 
APPENDICES 
Appendix 1: 
Modified Duke Criteria for Endocarditis 
Definition of infective endocarditis (IE) according to the proposed modified Duke criteria [24]: 
Definite infective endocarditis 
 
A. Pathologic criteria: 
(1) Microorganisms demonstrated by culture or histologic examination of a vegetation, a 
vegetation that has embolized, or an intracardiac abscess specimen; or 
(2) Pathologic lesions; vegetation or intracardiac abscess confirmed by histologic 
examination showing active endocarditis 
B. Clinical criteria:a  
(1) 2 major criteria; or 
(2) 1 major criterion and 3 minor criteria; or 
(3) 5 minor criteria 
Possible infective endocarditis 
(1) 1 major criterion and 1 minor criterion; or 
(2) 3 minor criteria 
Rejected 
(1) Firm alternate diagnosis explaining evidence of infective endocarditis; or 
(2) Resolution of infective endocarditis syndrome with antibiotic therapy for ≤4 days; or 
(3) No pathologic evidence of infective endocarditis at surgery or autopsy, with antibiotic 
therapy for ≤4 days; or 
(4) Does not meet criteria for possible infective endocarditis, as above 
a See following table for definitions of major and minor criteria. 


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A. Major criteria 
(1) Blood culture positive for IE 
(2) Typical microorganisms consistent with IE from 2 separate blood cultures: 
• 
Viridans streptococci, Streptococcus bovis, HACEK group, Staphylococcus 
aureus; or 
• 
Community-acquired enterococci, in the absence of a primary focus; or 
• 
Microorganisms consistent with IE from persistently positive blood cultures, 
defined as follows: 
• 
At least 2 positive cultures of blood samples drawn >12 h apart; or 
• 
All of 3 or a majority of ≥ 4 separate cultures of blood (with first and last 
sample drawn at least 1 h apart) 
(3) Single positive blood culture for Coxiella burnetii or antiphase I IgG antibody titer 
>1:800  
(4) Evidence of endocardial involvement 
(5) Echocardiogram positive for IE defined as follows: 
• 
Oscillating intracardiac mass on valve or supporting structures, in the path of 
regurgitant jets, or on implanted material in the absence of an alternative 
anatomic explanation; or 
• 
Abscess; or 
• 
New partial dehiscence of prosthetic valve 
(6) New valvular regurgitation confirmed by echocardiogram 
B. Minor criteria 
(1) Predisposition, predisposing heart condition or injection drug use 
(2) Fever, temperature >38°C 
(3) Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic 
aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway's 
lesions 
(4) Immunologic phenomena: glomerulonephritis, Osler's nodes, Roth's spots, and 
rheumatoid factor 
(5) Microbiological evidence: positive blood culture but does not meet a major criterion 
as noted aboveb or serological evidence of active infection with organism consistent 
with IE 
b 
Excludes single positive cultures for coagulase-negative staphylococci and organisms that do not cause 
endocarditis. 


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Appendix 2: 
Child-Turcotte-Pugh Chronic Liver Disease Score 
Scoring for Child-Turcotte-Pugh classification of severity of cirrhosis [32]: 
 
Parameter 
Points assigned 
1 
2 
3 
Ascites 
Absent 
Slight 
Moderate 
Bilirubin 
<2 mg/dL (<34.2 
micromol/liter) 
2 to 3 mg/dL (34.2 to 51.3 
micromol/liter) 
>3 mg/dL (>51.3 
micromol/liter) 
Albumin 
>3.5 g/dL (35 g/liter) 
2.8 to 3.5 g/dL (28 to 35 
g/liter) 
<2.8 g/dL (<28 g/liter) 
Prothrombin time 
Seconds over 
control 
<4 
4 to 6 
>6 
INR 
<1.7 
1.7 to 2.3 
>2.3 
Encephalopathy 
None 
Grade 1 to 2 
Grade 3 to 4 
 
Liver Disease Classification by Total Child-Pugh Score: 
• 
Mild liver disease: Childs-Pugh Score A (5-6) 
• 
Moderate liver disease: Childs-Pugh Score B (7-9) 
• 
Severe liver disease: Childs-Pugh Score C (10-15) 


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Appendix 3: 
RIFLE Criteria for Acute Kidney Injury 
RIFLE is an acronym of Risk, Injury, and Failure; and Loss; and End-stage kidney disease. 
The RIFLE criteria consists of three graded levels of kidney dysfunction (Risk, Injury, and 
Failure), based upon either the magnitude of increase in serum creatinine or urine output, 
and two outcome measures (Loss and End-stage renal disease [ESRD]) [33]. 
 
Stage 
GFRa Criteria 
UOb Criteria 
Stage 1: Risk 
SCrc increased 1.5-2 times baseline 
or 
GFR decreased >25% 
UO < 0.5 mL/kg/h < 6 h 
Stage 2: Injury 
SCr increased 2-3 times baseline 
or 
GFR decreased >50% 
UO < 0.5 mL/kg/h >12 h 
Stage 3: Failure 
SCr increased >3 times baseline 
or 
GFR decreased 75% 
or 
SCr ≥4 mg/dL; acute rise ≥0.5 mg/dL 
UO < 0.3 mL/kg/h 24 h 
(oliguria) 
or 
anuria 12 h 
Loss of function 
Persistent acute renal failure: complete loss of kidney function >4 weeks 
(requiring dialysis) 
ESRDd 
Complete loss of kidney function >3 months (requiring dialysis) 
a GFR = glomerular filtration rate. 
b UO = urine output. 
c SCr = serum creatinine. 
d ESRD = end-stage renal disease. 
 


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Appendix 4: 
APACHE II Assessment Criteria 
The Acute Physiologic and Chronic Health Evaluation (APACHE) scoring system requires 
the input of many clinical variables, from which a severity score is derived [34]. The resulting 
severity score is entered into a logistical regression equation, which predicts hospital 
mortality. 
The APACHE II Severity of Disease Classification System: 
 
Physiologic Variable 
+4 
+3 
+2 
+1 
0 
+1 
+2 
+3 
+4 
Temperature – rectal 
(°C) 
≥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 
(mm Hg) 
≥160 
130-159 
110-129 
 
70-109 
 
50-69 
 
≤49 
Heart Rate  
≥180 
140-179 
110-139 
 
70-109 
 
55-69 
40-54 
≤39 
Respiratory Rate 
(non-ventilated or ventilated) 
≥50 
35-49 
 
25-34 
12-24 
10-11 
6-9 
 
≤5 
Oxygenation (mm Hg) 
a. Fio2 >0.5 use A-aDO2 
b. Fio2 <0.5 us Pao2 
a 
≥500 
350-499 
200-349 
 
<200 
 
b 
 
>70 
61-70 
 
55-60 
<55 
Arterial pH 
≥7.7 
7.6-7.69 
 
7.5-7.59 
7.33-7.49 
 
7.25-7.32 
7.15-7.24 
<7.15 
Serum Sodium (mmol/l) 
≥180 
160-179 
155-159 
150-154 
130-149 
 
120-129 
111-119 
≤110 
Serum Potassium (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, Double point score 
for acute renal failure) 
≥3.5 
2-3.4 
1.5-1.9 
 
0.6-1.4 
 
<0.6 
 
 
Hermatocrit (%) 
≥60 
 
50-59.9 
45-49.9 
30-45.9 
 
20-29.9 
 
<20 
White Blood Count 
(in 1000/mm3) 
≥40 
 
20-39.9 
15-19.9 
3-14.9 
 
1-2.9 
 
<1 
Glasgow-Coma-Scale 
(GCS) 
Score = 15 minus actual GCS 
Serum HCO3 (venous, 
mmol/l, use if no ABGs) 
≥52 
41-51.9 
 
32-40.9 
22-31.9 
 
18-21.9 
15-17.9 
<15 
A = Total Acute Physiology 
Score APS 
Sum of the 12 individual variable points 
B = Age Points 
C = Chronic Health Points 
If the patient has a history of severe organ system insufficiency or is immunocompromised, assign points as follows: 
 
a. For non-operative or emergency postoperative patients – 5 points 
 
b. For elective postoperative patients – 2 points 
≤44 years 
0 points 
45-54 years 
2 points 
55-64 years 
3 points 
65-74 years 
5 points 
≥75 years 
6 points 
APACHE II Score = Sum of A (APS points) + B (Age points) + C (Chronic Health points) 
 

SAP_001.pdf: 
Statistical Analysis Plan
Study 0112
Version 1.0, 26APR2018
telavancin
Page 1
STATISTICAL ANALYSIS PLAN
Compound:
telavancin
Study Number:
Study 0112
Study Title:
A Phase 3 Multicenter, Randomized, Open-label, Clinical Trial 
of Telavancin Versus Standard Intravenous Therapy in the 
Treatment of Subjects with Staphylococcus aureus Bacteremia 
Including Infective Endocarditis
Protocol Version:
Version 1.0:     12 September 2014
Amendment 4: 16 January 2018
Sponsor:
Theravance Biopharma Antibiotics, Inc.
c/o Theravance Biopharma US, Inc.
901 Gateway Boulevard
South San Francisco, CA  94080
Plan Version:
Version 1.0, 26APR2018
Plan History:
No prior versions
Plan Prepared by:
David A. Lombardi, PhD
Senior Statistician, Biostatistics
Theravance Biopharma US, Inc.
CONFIDENTIAL
This document is confidential and property of Theravance Biopharma, Inc.
It may not be copied or provided to any other party without the express written consent of 
Theravance Biopharma, Inc.
¤2018 Theravance Biopharma US, Inc.




Statistical Analysis Plan
Study 0112
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telavancin
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Confidential – Property of Theravance Biopharma, Inc.
TABLE OF CONTENTS
PAGE
TABLE OF CONTENTS ........................................................................................................ 3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................. 6 
1 
INTRODUCTION....................................................................................................... 8 
2 
STUDY OBJECTIVES ............................................................................................... 9 
2.1 
Primary Objective........................................................................................... 9 
2.2 
Secondary Objectives .................................................................................... 9 
3 
OVERVIEW OF STUDY DESIGN............................................................................10 
3.1 
Study Design................................................................................................10 
3.2 
Study Procedures.........................................................................................10 
3.3 
Protocol Amendments..................................................................................11 
3.4 
Blinding of the Sponsor Clinical Team..........................................................13 
3.5 
Interim Analysis............................................................................................13 
4 
SAMPLE SIZE AND POWER ..................................................................................14 
5 
STUDY ENDPOINTS...............................................................................................15 
5.1 
General Endpoints .......................................................................................15 
5.2 
Pathogen Endpoints.....................................................................................17 
5.3 
Efficacy Endpoints........................................................................................18 
5.4 
Changes from Protocol-defined Efficacy Endpoints......................................18 
5.4.1 
Changes in the Categorization of Endpoints.....................................18 
5.4.2 
Duration of Bacteremia Definition .....................................................19 
5.4.3 
Definition of All-cause 28-day Mortality.............................................19 
5.5 
Safety Endpoints..........................................................................................20 
6 
GENERAL ANALYSIS CONSIDERATIONS ............................................................21 
6.1 
Global Definitions and Conventions..............................................................21 
6.2 
Baseline Definition .......................................................................................21 
6.3 
Analysis Windows ........................................................................................21 
6.4 
Evaluable Efficacy Assessment....................................................................24 
6.5 
Missing Data ................................................................................................24 
6.6 
Adverse Events............................................................................................26 
6.7 
Medications..................................................................................................26 
6.8 
Medical History ............................................................................................26 
6.9 
General Considerations for Summaries........................................................26 
6.10 
Tables, Figures and Listings (TFLs) .............................................................27 
7 
ANALYSIS SETS.....................................................................................................28 
7.1 
All-Treated Population..................................................................................28 
7.2 
Microbiological All-Treated (mAT) Population...............................................28 
7.2.1 
Subpopulations of MAT Population According to Primary 
Infection Type...................................................................................28 


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7.3 
Microbiological Evaluable (ME) Population...................................................29 
7.3.1 
Subpopulations of ME Population According to Primary 
Infection Type...................................................................................29 
7.4 
Safety...........................................................................................................30 
7.5 
Strata and Covariates ..................................................................................30 
7.6 
Examination of Subgroups ...........................................................................30 
7.7 
Inclusion and Exclusion Deviations ..............................................................31 
7.8 
Major Analysis Protocol Deviations ..............................................................31 
8 
DEFINITION OF ANALYSIS VARIABLES ...............................................................31 
8.1 
Demographic and Baseline Characteristics..................................................31 
8.1.1 
Demographics ..................................................................................31 
8.1.2 
Clinical Characteristics .....................................................................32 
8.1.3 
Disease-specific Clinical Characteristics...........................................33 
8.2 
Efficacy Variables.........................................................................................37 
8.3 
Safety Variables...........................................................................................39 
8.3.1 
Adverse Events ................................................................................39 
8.3.2 
Prior and Concomitant Medications ..................................................39 
8.3.3 
Systemic Antimicrobial Therapy........................................................39 
8.3.3.1 
Potentially Effective Non-study Antibiotic (PENSAB) 
Definition...........................................................................39 
8.3.3.2 
Systemic Antimicrobial Therapy Timing.............................40 
9 
ANALYSES..............................................................................................................42 
9.1 
General Analyses.........................................................................................42 
9.1.1 
Analysis Sets....................................................................................42 
9.1.2 
Subject Disposition ...........................................................................43 
9.1.3 
Demographics and Baseline Characteristics.....................................44 
9.1.4 
Classification of Infection Type .........................................................44 
9.1.5 
Clinical Characteristics at Baseline...................................................45 
9.1.6 
Select Medical History ......................................................................46 
9.1.7 
Pathogens Isolated from Qualifying Blood Cultures ..........................46 
9.1.8 
Signs and Symptoms of Bacteremia at Enrollment ...........................47 
9.1.9 
Characteristics of Bacteremia at Enrollment .....................................47 
9.1.10 Baseline modified APACHE II Scores...............................................48 
9.2 
Efficacy Analyses.........................................................................................49 
9.2.1 
General Considerations for Efficacy Analyses ..................................49 
9.2.2 
Primary Efficacy Evaluation: Adjudicated Clinical Outcome at 
TOC..................................................................................................49 
9.2.3 
Sensitivity Analyses of the Primary Endpoint ....................................51 
9.2.4 
Secondary Efficacy Evaluation: Adjudicated Clinical Response 
at EOT..............................................................................................53 
9.2.5 
Secondary Efficacy Evaluation: Investigator Clinical Outcome 
at TOC..............................................................................................54 


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9.2.6 
Secondary Efficacy Evaluation: Investigator Clinical Response 
at EOT..............................................................................................54 
9.2.7 
Secondary Efficacy Evaluation: Time to initial clearance of S. 
aureus bacteremia............................................................................55 
9.2.8 
Secondary Efficacy Evaluation: 28-day all-cause mortality ...............56 
9.2.9 
Multiplicity Adjustment ......................................................................56 
9.3 
Safety Analyses ...........................................................................................56 
9.3.1 
Extent of Exposure ...........................................................................57 
9.3.2 
Adverse Events ................................................................................58 
9.3.2.1 
Renal Adverse Events.......................................................59 
9.3.3 
Vital Signs ........................................................................................59 
9.3.4 
ECG ................................................................................................. 60 
9.3.5 
Clinical Laboratory Results ...............................................................61 
9.3.6 
Medical History.................................................................................61 
9.3.7 
Prior and Concomitant Medications ..................................................62 
10 
REFERENCES........................................................................................................62 
LIST OF TABLES
Table 1: 
Overview of Protocol Requirements for Treatment Duration 
and TOC Visit Windows....................................................................12 
Table 2: 
Table of General Endpoints ..............................................................15 
Table 3: 
Table of Pathogen Endpoints............................................................17 
Table 4: 
Table of Efficacy Endpoints ..............................................................18 
Table 5: 
Table of Safety Endpoints................................................................. 20 
Table 6: 
Visit Analysis Windows.....................................................................22 
Table 7: 
Analysis Windows for Efficacy Endpoints..........................................23 
Table 8: 
Analysis Windows for Safety Endpoints............................................23 
Table 9: 
Vital Signs Outlier Thresholds...........................................................59 
Table 10: 
ECG Test Outlier Thresholds............................................................61 
LIST OF APPENDICES
Appendix 1: 
Reporting Structures for Data Summary ...........................................63 
Appendix 2: 
List of Nephrotoxic Medications ........................................................64 
Appendix 3: 
List of Antibiotic Medications.............................................................69 
Appendix 4: 
List of Coded Pathogens ..................................................................72 
Appendix 5: 
Coding Categories for Reason of Failure..........................................74 
Appendix 6: 
Summary of TFLs.............................................................................75 


Statistical Analysis Plan
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Confidential – Property of Theravance Biopharma, Inc.
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Description
ADAM
Analysis data model
AE
adverse event
AT
All-treated (analysis population)
BLQ
Below level of quantification
BMI
body mass index
BP
blood pressure
CB
complicated bacteremia
CI
confidence interval
CFB
change from baseline
CP
conditional power
CRO
contract research organization
CSR
clinical study report
ECG
electrocardiogram
eCRF
electronic case report form
EOT
end-of-treatment
HR
heart rate
IDMC
Independent Data Monitoring Committee
IEAC
Independent Efficacy Adjudication Committee
IV
intravenous
LIE
left-sided infective endocarditis
LOD
limit of detection
mAT (CB, RIE)
mAT subjects with a diagnosis of CB, or RIE
mAT (UCB, CB, RIE)
mAT subjects with a diagnosis of UCB, CB, or RIE (the primary analysis 
population)
MedDRA
Medical Dictionary for Regulatory Activities
NC
non-calculable
NQ
non-quantifiable
PENSAB
Potentially effective non-study antibiotic
PK
pharmacokinetic
PP
Per-protocol
PT
preferred term
QBC
qualifying blood culture
RIE
right-sided infective endocarditis
SAE
serious adverse event
SAP
statistical analysis plan
SOC
system organ class
TEAE
treatment-emergent adverse event
TEE
transesophageal echocardiogram


Statistical Analysis Plan
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Description
TOC
test-of-cure
TTE
transthoracic echocardiogram
UCB
Uncomplicated bacteremia
WHODD
World Health Organization Drug dictionary


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1 
INTRODUCTION
This document outlines the initial plan for the summarization and analysis of clinical data 
collected in Study 0112 for telavancin. 
The analysis of pharmacokinetics (data derivation and summary of individual PK 
parameters) is outside the scope of this document and is not addressed here.
This document describes the a priori plan for analysis.  Once the analysis is in progress, it 
may become apparent from the data that the planned analysis should be modified.  Any 
substantive modification to the original analysis plan will be identified in the clinical study 
report (CSR).


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2
STUDY OBJECTIVES
2.1
Primary Objective
The primary objective of the study is:
x
To compare telavancin to standard IV therapy (ie, vancomycin, daptomycin, 
anti-staphylococcal penicillin, or cefazolin) in clinical outcomes in the treatment of 
S. aureus bacteremia including S. aureus right-sided infective endocarditis (RIE).
2.2
Secondary Objectives
The secondary objectives of the study are:
x
To evaluate the safety and tolerability of telavancin compared with standard 
intravenous therapy in the treatment of S. aureus bacteremia, including SA-RIE,
x
To evaluate the PK profiles of telavancin and vancomycin in subjects with S. aureus 
bacteremia, including SA-RIE.


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3
OVERVIEW OF STUDY DESIGN
3.1
Study Design
This is a multicenter, randomized, open-label, noninferiority trial of telavancin versus 
standard intravenous (IV) therapy control (ie, vancomycin, daptomycin, or a ȕ-lactam 
antibiotic with anti-staphylococcal activity [eg, nafcillin, oxacillin, and cefazolin]) in the 
treatment of subjects with S. aureus bacteremia and S. aureus RIE.  
The primary efficacy endpoint is clinical outcome at the test-of-cure (TOC) visit analyzed in
subjects with a baseline diagnosis of complicated bacteremia (CB), uncomplicated 
bacteremia (UCB), or RIE in the microbiological all-treated (mAT) population. 
The baseline diagnosis and the clinical outcome will be adjudicated by a blinded 
Independent Efficacy Adjudication Committee (IEAC). Safety will be monitored by an
Independent Data Monitoring Committee (IDMC).
3.2
Study Procedures
Eligible subjects with confirmed S. aureus bacteremia will be randomized in a ratio of 1:1 to 
receive open-label telavancin or open-label standard IV therapy.  Randomization will be 
stratified by geographic region.  Standard IV therapy, depending on the antibacterial 
susceptibility of the causative pathogen, will include vancomycin or daptomycin for subjects 
with known or suspected MRSA (daptomycin should be used for subjects with S. aureus
ZLWKYDQFRP\FLQ0,&YDOXHV!ȝJP/RUDSURWRFRO-VSHFLILHGȕ-lactam antibiotic with anti-
staphylococcal activity (ie, nafcillin, oxacillin, cloxacillin, or cefazolin) for subjects with known 
MSSA.
Each subject must have at least one blood culture positive for S. aureus within 48 hours 
before randomization, referred to as the qualifying blood culture (QBC).
Procedures to control or eliminate the infection source will be completed within the first 
3 days of study drug treatment. Follow-up blood cultures will be performed daily until two 
successive post-randomization blood cultures are negative for S. aureus.


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On or before Day 8, each subject will be evaluated by a physician investigator to determine 
the origin and extent of the S. aureus infection to establish the classification of infection type 
as:  
x
Uncomplicated bacteremia (UCB),
x
Complicated bacteremia (CB),
x
Right-sided infective endocarditis (RIE), or,
x
Left-sided infective endocarditis (LIE).
Subjects will be assigned to receive therapy based on the classification of infection type
(see Table 1).
Subjects who are discharged from the hospital during the treatment or follow-up period, will 
return to the hospital once per week for a study visit.  
After all the weekly visits are complete, the subject will also return to the hospital for the End 
of Therapy Visit, the Post-End of Treatment Visit, and the TOC visit.  The TOC visit is also 
the end of study (EOS).
Development of new signs or symptoms consistent with S. aureus infection will be assessed 
daily, during the hospital stay, or during the study drug treatment period as clinically
indicated. After Day 8, if signs and symptoms lead to a subsequent confirmed diagnosis of 
new metastatic foci, it will be criteria for clinical failure. 
Study visits for endpoint assessment will be conducted as follows:
x
End of therapy (EOT) visit: within 3 days after the last dose of study drug
x
A post-EOT blood culture will be obtained at least 4 days after the EOT visit, and
results must be available prior to the TOC visit.  The results of this blood culture will
be part of the assessment of clinical outcome at TOC.
x
Test of cure (TOC) visit timing was defined by the classification of infection type,
assigned treatment duration, and Study Protocol version (see Table 1).
3.3
Protocol Amendments
Study Protocol was originally finalized on 12 September 2014.  The protocol underwent four 
major amendments finalized on 17 February 2015, 14 September 2015, 21 September 
2016, and 16 January 2018.


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Subjects could have consented to a more recent version of the Study Protocol during the 
study participation.  The most recent version of the protocol consented to by Study Day 8 
was used to determine the applicable protocol version for any assessments after the first 
dose of study drug.  The original version was applicable for screening assessments 
(eg, eligibility criteria).
Requirements for study treatment duration and the timing of follow up assessments changed 
with Study protocol Amendment 2, and again with Amendment 3.
Table 1: 
Overview of Protocol Requirements for Treatment Duration and TOC Visit 
Windows
Protocol Version 
Subject Classification
Treatment Duration
TOC Visit 
Windowa
Minimum
Maximum
Original/ 
Amendment 1
Assigned 4 weeks of treatment
Not specified
Not specified
56±2 days
Assigned 6 weeks of treatment
Not specified
Not specified
70±2 days
Amendment 2
UCB
2 weeks
4 weeksb
42±2 days
CB
4 weeks
6 weeksb
56±2 days
LIE/RIE
6 weeks
6 weeksb
70±2 days
Amendment 3
UCB
2 weeks
4 weeksb
38±2 days
CB
4 weeks
6 weeksb
52±2 days
LIE/RIE
6 weeks
6 weeksb
a TOC visit windows were specified in the protocol as days from or after randomization
b treatment durations longer than 28 days for UCB, 42 days for CB, or 45 days for LIE or RIE would render 
subject’s outcome failure (at TOC)
The EOT visit was to occur within 3 days after study drug discontinuation in all versions of 
the protocol.
An interim analysis allowing stopping for futility was introduced in Study Protocol 
Amendment 4.


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3.4
Blinding of the Sponsor Clinical Team
While the study is open label, the following steps have been taken to establish blinding of 
the clinical team at Theravance, as of June of 2017.  
x
Notifications of randomization sent to Theravance by an Independent Randomization 
Technology system were stopped.
x
Pharmacokinetic sample collection, treatment assignment, and treatment 
administration information has been excluded from the clinical data base extracts 
sent to Theravance.  
x
Tables and listings produced for internal safety and data monitoring exclude 
treatment assignments.  
x
Only open session IDMC reports, meeting minutes, and recommendations were 
routinely shared with Theravance; open reports present data in a blinded fashion, 
with data pooled.
3.5
Interim Analysis
A single interim assessment allowing early stopping for futility will be performed based on 
the subjects who discontinued from the study on or before October 31, 2017.  Conditional 
power to show non-inferiority under the current trend will be computed using the normal 
approximation to the non-inferiority test statistic.  The IDMC may recommend stopping for 
futility, if the conditional power is 50% or less.
At the interim analysis, a decision was made by the company to discontinue further 
enrollment in the study when viewing the overall study costs within the overall portfolio of the 
company.


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4
SAMPLE SIZE AND POWER
Assuming a population clinical cure rate of 70% for standard IV therapy and 72.5% for 
telavancin, a total sample size of 210 (105 per treatment group) is deemed sufficient (80% 
power) to demonstrate noninferiority based on a noninferiority margin of 15% at a one sided 
significance level of 2.5%.  This calculation does not take into account a potential stopping 
for futility at an interim analysis. With the futility analysis, the overall power of the study is 
approximately 64%.
A total of 248 subjects will be enrolled to allow for exclusion of up to 15% of subjects from 
the primary analysis set due to an LIE diagnosis or not meeting the mAT population criteria.


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5
STUDY ENDPOINTS
All study endpoints and/or assessments include an evaluation type, ie, absolute value, 
change from baseline, an ADAM Type, either raw data or derived from raw data, ie, CRF or 
Lab-type data, an evaluation window, ie, screening ,Day 1, Days 1-85, and a summary type, 
ie, continuous, frequency, normal least squares.
5.1
General Endpoints
The following general endpoints will be summarized.
Table 2:
Table of General Endpoints
Endpoint
Evaluation 
Type
ADaM 
Type
Reporting 
Window
Summary 
Type(s)
age
ABS
derived
D1-PD
C
age category by 65
CAT
derived
D1-PD
F
age category by 75
CAT
derived
D1-PD
F
sex
CAT
raw
D1-PD
F
ethnicity
CAT
raw
D1-PD
MF
race
CAT
raw
D1-PD
MF
height
ABS
raw
D1-PD
C
Actual weight
ABS
raw
D1-PD
C
Ideal body weight
ABS
raw
D1-PD
C
BMI
ABS
derived
D1-PD
C
Geographic region 1 (strata)
CAT
raw
D1-PD
MF
Geographic region 2 (US, Ex-US)
CAT
raw
D1-PD
F
Diabetes mellitus from CRF
CAT
raw
D1-PD
F
Diabetes mellitus from medical history
CAT
raw
D1-PD
F
Diabetes mellitus from CRF or medical history
CAT
raw
D1-PD
F
History of injection drug use w/in last 2 years
CAT
raw
D1-PD
F
Previous history of infective endocarditis w/in last 2
years
CAT
raw
D1-PD
F
HIV infection
CAT
raw
D1-PD
F
Hemodialysis
CAT
raw
D1-PD
F
Hepatitis C
CAT
raw
D1-PD
F
Liver Cirrhosis
CAT
raw
D1-PD
F
Malignancy requiring Chemo w/in last 2 years
CAT
raw
D1-PD
F


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Endpoint
Evaluation 
Type
ADaM 
Type
Reporting 
Window
Summary 
Type(s)
Admission to hospital in previous 3 months
CAT 
raw 
D1-PD 
F 
Active immunosuppression
CAT 
raw 
D1-PD 
F 
Valvular heart disease
CAT 
raw 
D1-PD 
F 
Prosthetic cardiac devices
CAT 
raw 
D1-PD 
F 
Other non-cardiac prosthetic devices
CAT 
raw 
D1-PD 
F 
Creatinine Clearance using Ideal Body Weight, 
Central Lab
ABS
derived
D1-PD 
C 
Creatinine Clearance using Actual Body Weight, 
Central Lab
ABS
derived
D1-PD 
C 
Central echocardiogram parameters
ABS
Raw
D1-PD 
C 
Study disposition
ABS 
raw 
EOS
F 
Reasons for study discontinuation
ABS 
raw 
EOS
text
Study drug disposition
ABS 
raw 
EOS
MF 
Reasons for study drug discontinuation
ABS 
raw 
EOS
text
Days of therapy
ABS
derived
treatment 
C 
Primary infection type – IEAC adjudicated
CAT 
raw 
Day 1-8 
MF 
Safety Flag
CAT
Derived
NA
F 
AT flag
CAT
Derived
NA
F 
mAT flag
CAT
Derived
NA
F 
mAT (UCB, CB, RIE)
CAT
Derived
NA
F 
mAT (CB, RIE)
CAT
Derived
NA
F 
mAT (UCB)
CAT
Derived
NA
F 
mAT (CB)
CAT
Derived
NA
F 
mAT (LIE)
CAT
Derived
NA
F 
mAT (RIE)
CAT
Derived
NA
F 
ME Flag
CAT
Derived
NA
F 
ME (UCB, CB, RIE)
CAT
Derived
NA
F 
ME (CB, RIE)
CAT
Derived
NA
F 
ME (UCB)
CAT
Derived
NA
F 
ME (CB)
CAT
Derived
NA
F 
ME (LIE)
CAT
Derived
NA
F 
ME (RIE)
CAT
Derived
NA
F 
Note: D: day, CFB: change from baseline, ABS: absolute value or observed value; CAT: categorical/binary
Note: summary type, see Appendix 1:Reporting Structures for summary type abbreviations


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5.2
Pathogen Endpoints
The following screening endpoints will be summarized.
Table 3: 
Table of Pathogen Endpoints
Endpoint
Evaluation 
Type
ADaM 
Type
Summary 
Type(s)
QBC collected (Y/N)
CAT
raw 
F 
Rapid diagnostic test type
CAT
raw 
MF 
QBC S. aureus type (MSSA, MRSA)
CAT
derived
MF
QBC status (no, mono, poly)
CAT
derived
MF
Post baseline S. aureus Status (mono, poly)
CAT
derived
MF
Type of S. aureus derived from central laboratory blood 
culture results  (MSSA, MRSA)
CAT
derived
MF
Type of S. aureus identified by site in blood culture (MSSA, 
MRSA) 
CAT
Derived
MF
Pathogens identified in baseline blood culture, site-reported
CAT
raw 
MF
Vancomycin MIC (maximum)
ABS
derived 
C 
S. Aureus vancomycin MIC 1 (1 mg/L)
CAT
Derived 
F 
S. Aureus vancomycin MIC 2: (2 mg/L) 
CAT
Derived 
F 
Clindamycin resistance
CAT
derived 
F 
Penicillin resistance
CAT
derived 
F 
S. aureus susceptibility to the study drug
CAT
derived 
F 
Note: D: day, CFB: change from baseline, ABS: absolute value or observed value; CAT: categorical/binary
Note: summary type, see Appendix 1: Reporting Structures for summary type abbreviations


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5.3
Efficacy Endpoints
The following efficacy endpoints will be summarized (see Section 8.2 for definitions)
Table 4: 
Table of Efficacy Endpoints
Endpoint
Evaluation 
Type
ADaM
Type
Reporting
Window
Summary 
Type(s)
Clinical outcome at TOC – IEAC adjudicated
CAT
Raw
TOC
MF 
Clinical response at EOT – IEAC adjudicated
CAT
Raw
EOT
MF 
Development of new metastatic foci of S. 
aureus infection
CAT
Derived
Day 9 through 
end of study
MF 
Time to initial clearance of S. aureus
bacteremia 
TTE
Derived
Day 1 through 
end of study
KM
28-day all-cause mortality
TTE
Derived
Treatment+28 
days
KM
Clinical outcome at TOC – investigator-
reported
CAT
Derived
TOC
MF 
Clinical response at EOT – investigator-
reported
CAT
Raw
EOT
MF 
Note: D: day, CFB: change from baseline, ABS: absolute value or observed value; CAT: categorical/binary; TTE: 
time-to-event
Note: summary type, see Appendix 1: Reporting Structures for summary type abbreviations
5.4
Changes from Protocol-defined Efficacy Endpoints
5.4.1
Changes in the Categorization of Endpoints
The following endpoints were listed in the study protocol as key efficacy endpoints and are 
deemed safety endpoints in the Statistical analysis plan: 
x
Duration of treatment with study medication by baseline clinical diagnosis in the mAT 
and ME populations;
x
Incidence of AEs, treatment-emergent AEs (TEAEs), SAEs, and deaths in the safety 
population;
x
Incidence of key laboratory indices in the safety population.


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5.4.2
Duration of Bacteremia Definition
Study Protocol describes the duration of bacteremia endpoint for subjects with a positive 
S. aureus blood culture on Day 1, as “the time (days) from randomization to all blood 
cultures negative for S. aureus for two successive days”.  This SAP changes the endpoint 
name and definition for the following reasons:
x
to specify the pathogen of interest,
x
to clarify that this is based on locally analyzed samples, because negative samples
were not sent to the central lab,
x
the reference date changed from randomization to the first dose of study drug, for
consistency with other endpoints,
x
the endpoint was defined for all subjects, for completeness,
x
to indicate that time-to-event endpoint definition and analysis methods will be
applicable,
x
to limit the time when this endpoint is applicable to the initial treatment period,
because after that the sampling may become sparse,
x
to limit the time when this endpoint is applicable to the time prior to any treatment
with a potentially effective non-study antibiotic (PENSAB),
x
to specify censoring methodology for the subjects who did not achieve two
consecutive blood negative blood cultures within the initial treatment period or those
who received PENSABs.
5.4.3
Definition of All-cause 28-day Mortality
All-cause 28-day mortality was defined as all deaths that occur during the study, regardless 
of cause, on or before Day 28. The definition was modified to include deaths off study 
occurring on or before Day 28 and to specify time to event derivation and censoring 
methodology.


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Furthermore, Study Protocol Section 3.4.3 states that 28-day all-cause mortality will be 
evaluated for subjects with a baseline diagnosis of CB or RIE in the mAT and ME 
populations. Exclusion of UCB subjects from the analysis population specified for this 
endpoint in the protocol is due to an oversight.  The primary efficacy analysis population for 
this endpoint is the mAT (UCB, CB, and RIE).
5.5
Safety Endpoints
The following safety endpoints will be summarized (see Section 8.3 for definitions).
Table 5: 
Table of Safety Endpoints
Endpoint
Evaluation 
Type
ADaM Type
Reporting
Window
Summary 
Type(s)
Study drug duration
ABS
Derived
Treatment 
C 
Number of days on Study Drug
ABS
Derived
Treatment 
C 
Per protocol study drug compliance
ABS
Derived
Treatment 
C 
On-treatment study drug compliance
ABS
Derived
Treatment 
C 
Prior Medication flag
ABS
Derived
Prior day 1 
F 
Concomitant medication flag
ABS
Derived
Treatment 
F 
Post study drug medication flag
ABS
Derived
Post EOT 
F 
Antibiotic medication flag
ABS
Derived
NA
F 
Nephrotoxic  Medication flag
ABS
Raw
NA
F 
Renal adverse event flag
ABS
Raw
Treatment 
F 
Renal replacement therapy flag
ABS
Raw
Treatment 
F 
Clinical laboratory results (ie, hematology, 
serum chemistry, and urinalysis)
ABS
Raw
Treatment 
C 
Creatinine clearance: Day 2, 4, 8, 15, 22, 29, 
36, and 43 on treatment 
ABS
Derived
Treatment 
C 
Creatinine clearance: worst value on 
treatment through Day 8
ABS
Derived
Treatment 
C 
Creatinine clearance: worst value on-
treatment at any time
ABS
Derived
Treatment 
C 
Creatinine clearance: last on treatment value 
ABS 
Derived 
Treatment 
C 
Creatinine clearance: last value on study 
ABS 
Derived
Treatment 
C 


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6 
GENERAL ANALYSIS CONSIDERATIONS
6.1
Global Definitions and Conventions
All data from scheduled and unscheduled visits will be presented in the subject listings; 
however, unless noted otherwise, only data from scheduled visits will be included in the 
summaries, statistical analysis, and calculation of derived parameters.
6.2
Baseline Definition
For the derivation of baseline blood culture microbiology variables (Section 8.1.3), pre-dose
blood cultures will be those collected before the first dose of study drug, but not more than 
8 days before the 1st dose. The same will apply to variables based on central laboratory 
non-blood culture results.  For derivation of baseline non-blood culture variables based on 
local laboratory results, sample collection time is not always available, and therefore 
samples collected on or prior Study Day 1 will be considered pre-dose.
For central laboratory safety measurements, vital signs, and ECG, baseline will be defined 
as the last (most recent) value before the first dose of study drug.
For temperature measurements, collection time was not always available, therefore baseline 
will be the latest (most recent) measurement of those either collected prior to Study Day 1 or 
collected on Day 1 within the nominal Screening visit.
6.3
Analysis Windows
All assessments will be summarized using analysis windows. The terminology of 
unscheduled will be applied to assessments that are outside an analysis window regardless
of the nominal label associated with the assessments in the EDC system.
All data (scheduled and unscheduled visits) will be presented in the subject listings; 
however, unless noted otherwise, only data from assessments within analysis windows will 
be included in the summaries, statistical analysis, and calculation of derived parameters.


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Selection of Data in the Event of Multiple Records in an Analysis Window
In general, if multiple, valid, non-missing observations exist at a visit or collection time point 
then records will be chosen based on the following:
x
The record closest to the nominal time point in question, or,
x
The later record if the two visits are equidistant from the time point, or,
x
The average (arithmetic mean) if there is more than one record at the time point
(generally applies to assessments done in triplicate).
The following visit windows will be used in the summary of clinical data.
Table 6: 
Visit Analysis Windows
Nominal Visit
Nominal Day
Start
Stop 
Screening/ Baseline

See Section 6.2
Time of 1st dose of study 
drug
Days 1-4 
1-4.  
Time of 1st dose of study 
drug
Day 4
Week 1
8 
Day 5
Day 11
Week 2
15
Day 12
Day 18
Week 3
22
Day 19
Day 25
Week 4
29
Day 26
Day 32
Week 5
36
Day 33
Day 39
Week 6
43
Day 40
Day 46
Week 7
50
Day 47
Day 53
Week 8
57
Day 54
Day 60
Efficacy Endpoints with Unique Windows
The following windows will be used for the clinical outcome at TOC and clinical response at 
EOT endpoints, both IEAC adjudicated and investigator-reported.


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Table 7: 
Analysis Windows for Efficacy Endpoints
Visit
Protocol Version 
Subject 
Classification
Nominal Day 
Start 
Stop 
EOT/ Post 
Treatment
Any 
Any 
Day of last 
dose of study 
drug
Day of last 
dose of study 
drug
TOC
TOC/ EOS
Original/ 
Amendment 1
Assigned 4 weeks 
of treatment
Day 57
Day 54
Day 64
Assigned 6 weeks 
of treatment
Day 71
Day 68
Day 78
Amendment 2
UCB
Day 43
Day 40
Day 50
CB
Day 57
Day 54
Day 64
LIE/RIE
Day 71
Day 68
Day 78
Amendment 3
UCB
Day 39
Day 36
Day 46
CB/LIE/RIE
Day 53
Day 50
Day 60
EOS = end of study; EOT = end of treatment; TOC = test of cure
Safety Endpoints
The following windows summarize the definition of analysis windows applicable specifically 
to safety endpoints (defined in Section 8.3). 
Table 8: 
Analysis Windows for Safety Endpoints
Window
Start 
Stop 
Adverse events
Sign of ICF
Maximum of follow-up visit or last 
contact
Treatment-emergent Adverse 
events, ECGs and abnormal 
safety laboratory values 
First dose of study drug
Last dose + 28 days
On treatment creatinine clearance 
assessments
First dose of study drug
Last dose + 3 days
Medications post study drug 
medications
Medication start time after last 
dose of study drug + 24 hours
N/A
Medications prior to study drug
N/A
Medication end time prior to first 
dose of study drug
Medications concomitant with 
study drug
Post first dose, ie medication end 
time not prior to first dose of study 
drug
Last dose + 24 hours, ie 
medication start time is not after 
last dose + 24 hours
Systemic antimicrobial therapy
starting prior to the first dose of 
study drug
Medication start time before 1st
dose of study drug
N/A


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Window
Start 
Stop 
Systemic antimicrobial therapy
administered after Day 1 
N/A
Medication end time is Day 2 or 
later or ongoing
Systemic antimicrobial therapy
administered upon study drug 
discontinuation
Medication start day the same as
the last dose of study drug or later
N/A
Day 2a
Time of 1st dose of study drug
Day 2
Day 4a
Day 3
Day 4
EOTb
Time of last dose of study drug
Time of last dose of study drug + 7 
days
TOC/EOSc
Time of last dose of study drug + 8
days
Day of study completion or 
discontinuation
EOT = end of treatment; EOS = end of study; TOC = test of cure
a The visit window applies to Creatinine and Creatinine clearance samples only.  In case of multiple non-missing 
observations in the time window, the record closest to the nominal time point (Day 2 or Day 4) will be selected
b In case of multiple non-missing observations in the time window, the earliest record will be selected.
c In case of multiple non-missing observations in the time window, the latest record will be selected
6.4
Evaluable Efficacy Assessment
Clinical response at EOT and clinical outcome at TOC endpoints, both investigator-reported 
and adjudicated, could only be considered evaluable, if they fall within the corresponding 
analysis windows (EOT or TOC).
All on-study assessments of development of new metastatic foci of S. aureus infection after 
Day 8 will be considered evaluable.
Blood cultures for determination of time to initial clearance of bacteremia collected after 
administration of potentially effective non-study antibiotics (as defined in Section 8.3.3) on or 
after Day 2 would be considered non-evaluable.
Death after study discontinuation but prior to Study Day 28 will be included in the derivation 
of the 28-day all-cause mortality endpoint.
6.5
Missing Data
In general, it is not anticipated that there will be considerable missing data.  In general, 
missing data will not be imputed.  Missing data for the following specific endpoints will be 
handled as follows:


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Primary Efficacy Endpoint
Estimates of the clinical cure rate at TOC will be calculated relative to the number of 
subjects in the applicable analysis population. For example, any patient in the analysis 
population with an “indeterminate” or missing value for clinical outcome will be counted in 
both the numerator (as “failure”) and denominator when calculating clinical cure rate. 
Time to Initial Clearance of S. aureus bacteremia
Missing data for time to initial clearance of S. aureus bacteremia will be censored.
Twenty-eight Day All-Cause Mortality
Missing data for 28-day all-cause mortality will be censored.
Adverse Events
For graded adverse event summaries, subjects with an AE and no grade on the CRF will be 
graded as severe. 
Missing dates/time for Adverse Events and Concomitant Medications
Missing dates will be handled as follows:
x
Complete missing start date will be imputed as the same as first dose date;
x
Partial missing start date imputation:
o
Missing start day with same month as first dose: minimum day (1, first dose day);
o
Missing start day with different month as first dose: 1
o
Missing start month with same year as first dose: minimum (January, first dose
month);
o
Missing start month with different year as first dose: January
x
Complete missing stop date will be considered as ongoing and not imputed;
x
Partial missing stop date imputation:
o
Missing stop day: last day of month;
o
Missing stop month with same year as last dose: minimum (December, last dose
month);
o
Missing stop month with different year as last dose: December
Missing times will be handled as follows:
x
If a start or stop time is missing, the start time is imputed as 1 minute after a.m.
midnight (00:01) and stop time is imputed to be 1 min before p.m. midnight (23:59).


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Laboratory Data
For non-efficacy laboratory data, a missing baseline value will be replaced with the last 
available assessment, generally the screening assessment.  A retest value will be used if 
the first test is invalidated, eg, specimen hemolyzed.
Laboratory data that are continuous in nature but are less than the lower limit of 
quantitation/limit of detection (LOD) will be, in general, imputed as follows:
x
A value that is 1 unit less than the LOD will be used for calculation of descriptive
statistics if the data are reported in the form of “< x” (x is considered as the LOD).
0RUHVSHFLILFDOO\[íLVXVHGIRUGDWDVXPPDUL]DWLRQLIWKHGDWDare reported in the
IRUPRI³[´DQG[HZKHUHH GíZLOOEHXVHGIRUDQDO\VLVLIWKHGDWDDUHUHSRUted
in the form of “< x.d”;
x
The LOD will be used for calculation of descriptive statistics if the data is reported in
WKHIRUPRI³[´RU³[
6.6
Adverse Events
Recorded adverse events will be mapped according to the MedDRA thesaurus by the data 
management CRO for this study, with Theravance review and approval of the mappings. 
MedDRA, version 18.1 will be used.
6.7
Medications
Recorded prior and concomitant medication names will be mapped according to the World 
Health Organization Drug Dictionary (WHODD) by the data management CRO for this study 
with Theravance review and approval of the mappings.  The CRO will use the September 
2015 version of the WHODD.
6.8
Medical History
Medical history will be mapped according to MedDRA version 18.1. 
6.9
General Considerations for Summaries
Analyses and tabulations will generally be prepared using SAS£, version 9.4 or later. 


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Presenting Multiple Summaries on Same Table Summary
In summary tables where multiple single line frequency summaries are being presented, the 
“n line” can be suppressed in the individual summaries and presented at the top of the 
summary a single time.
Ordering of Treatment Headers in Summary Tables
In summary tables, treatment headers will be presented in the following order:
x
Standard Intravenous Therapy, 
x
telavancin, 
x
Total (Applicable to General Analysis and Exposure summaries).
Rounding
In general, the convention for rounding percentages is as follows:
x
Values greater than or equal to x.x5 are rounded up, 
x
Values between 0 and less than x.x5 are rounded down, 
x
Values between –x.x5 and 0 are rounded up, 
x
Values less than or equal to x.x5 are rounded down.
Significant Digits
Raw measurements will be reported the same as the data captured electronically or on the 
CRFs. Exceptions will be made for values reported with greater than 4 significant digits 
(round to 4 significant digits using a similar criterion as for percentages with the 5 in the last 
digit). 
The following significant digit convention will be used for the purposes of summarizing data:
x
Mean, median: 2 significant digits, 
x
Standard deviation: 3 significant digits, 
x
Minimum, maximum: 2 significant digits, 
x
Percentages: 1 decimal place.
6.10
Tables, Figures and Listings (TFLs)
A line listing of Tables, listings, and figures to be generated are in Appendix 6, respectively.  
Selected table, listing or figure mock-ups will be in a separate document.


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7 
ANALYSIS SETS
7.1
All-Treated Population
The All-Treated (AT) analysis population will include all subjects who
(1) Were randomized into the study after protocol Amendment 1 (that is, excluding any 
subjects enrolled under the original protocol).
(2) Received at least one dose of study drug (telavancin or standard intravenous 
therapy), 
(3) Were classified according to the infection type (UCB, CB, RIE, or LIE),  
Treatment assignment will be based on the treatment randomized. Subjects excluded from 
the AT population will be excluded from all efficacy data summaries and analyses.
Note: One subject enrolled under the original protocol will be excluded, because the subject 
was randomized to a higher dose of telavancin than the rest of the subjects.  Another 
subject was discontinued from the study drug and the study prior to sufficient assessments 
to determine the infection type.
7.2
Microbiological All-Treated (mAT) Population
The Microbiological All-Treated (mAT) analysis population will include all subjects in the AT
population who have a mono-microbial QBC positive for S. aureus. The mono-microbial 
status will be defined by the local and central microbiology laboratory analysis of baseline 
blood samples as presence of S. aureus in at least one such sample and no other 
pathogens in any of those samples (see Section 8.1 for details).
Reasons for exclusion from the mAT population will be summarized using the following 
categories: “Randomized but Not Treated”; “Enrolled prior to Amendment 1”, “Infection Type 
not Classified”, “No QBC Positive for S. aureus”; “Poly-microbial QBC”.
Treatment assignment will be based on randomized treatment. 
7.2.1
Subpopulations of MAT Population According to Primary Infection Type
Efficacy summary and analyses will be performed within the subpopulations of the mAT 
population based on the IEAC-adjudicated primary infection type: 


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x
mAT (UCB, CB, RIE),
x
mAT (CB, RIE),
x
mAT (UCB),
x
mAT (CB), 
x
mAT (LIE),
x
mAT (RIE). 
7.3
Microbiological Evaluable (ME) Population
The Microbiological Evaluable (ME) population will include all subjects in the mAT 
population who meet the following criteria:
x
Treatment compliance of 80% of prescribed study medication for their baseline 
diagnosis, 
x
Did not miss more than 2 consecutive doses of study medication, 
x
Completed the TOC visit within the window defined in Table 7, 
x
Did not have any recorded major protocol deviations, 
x
If assessed as failure at TOC, received at least 2 days of study medication, 
x
If assessed as cure at TOC, received at least 5 days of study medication, 
x
Did not receive any prohibited concomitant, potentially effective antibiotic. 
Treatment assignment will be based on randomized treatment.
7.3.1
Subpopulations of ME Population According to Primary Infection Type
Exploratory efficacy summary and analyses may be performed within the subpopulations 
based on the IEAC-adjudicated primary infection type:
x
ME (UCB, CB, RIE),
x
ME (CB, RIE),
x
ME (UCB),
x
ME (CB),
x
ME (LIE),
x
ME (RIE).


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7.4
Safety
The Safety analysis set will include all subjects who
(1) Were randomized into the study, and,
(2) Received at least one dose of study drug (telavancin or standard intravenous 
therapy). 
Treatment assignment will be based on actual treatment. The Safety analysis set is the 
primary analysis set for safety analyses.
7.5
Strata and Covariates
At randomization, subjects will be stratified by geographic region:
x
[a] United States, [b] Europe-1 (Germany, Italy, Latvia, Spain), [c] Europe-2 (Czech 
Republic, Georgia, Hungary, Poland, Romania), [d] South America (Argentina, Brazil, 
Colombia, Mexico, Peru).  
Due the low enrollment outside of the US (strata b-d), the analysis will not be stratified by 
geographic region.
7.6
Examination of Subgroups
The following baseline subgroups are pre-defined:
x
Age: [a] < \HDUV>E@ 65 years;
x
Age: [a] < \HDUV>E@ 75 years;
x
Gender: [a] male; [b] female;
x
Geographic region: [a] US, [b] non-US;
x
Type of S. aureus derived from central lab results: [a] MSSA; [b] MRSA;
x
S. Aureus vancomycin MIC>D@ 1 mg/L; [b] > 1 mg/L;
x
S. Aureus YDQFRP\FLQ0,&>D@ 2 mg/L; [b] > 2 mg/L;
x
Baseline modified APACHE II score: [a] 15 points ; [b] > 15 points;
x
Medical history of diabetes mellitus: [a] No; [b] Yes;
x
Creatinine clearance categories: [a] > 50 mL/min>E@ 50 mL/min.
Selected analysis will be conducted using the subgroup analysis sets.


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7.7
Inclusion and Exclusion Deviations
Deviations to inclusion and exclusion criteria will be identified prior to database lock and we 
be summarized in a listing with the deviation and the protocol version associated with the 
deviation.
7.8
Major Analysis Protocol Deviations
Major analysis protocol deviations that could potentially affect the conclusions of the study 
will be identified prior to database lock.  Major analysis protocol deviations are defined as 
follows:
x
Randomized subjects who did not satisfy efficacy inclusion ( Amendment 4: 3,4,5) 
and exclusion criteria (Amendment 4: 1,2,3,4,8)
x
Randomized subjects for whom pre-dose S. aureus sample was collected more than 
7 days prior to 1st dose of study drug 
x
Subjects who received the wrong treatment,
x
Subjects who received an excluded concomitant treatment or medication,
x
Subjects who are less than 80% compliant with study medication,
x
Subjects who are out of window for the primary efficacy assessment.
Subjects with major analysis protocol deviations will be identified before the database lock
and provided in a listing.
In addition, a listing of all major deviations will be provided whether they impact analysis.
8
DEFINITION OF ANALYSIS VARIABLES
8.1
Demographic and Baseline Characteristics
8.1.1
Demographics
Age
Age will be calculated as of the date of informed consent form (ICF) and truncated to its 
integer value. The following formula is used:
ܽ݃݁= ݂݈݋݋ݎቀ
ூ஼ி ௌ௜௚௡௜௡௚ି஽௔௧௘ ௢௙ ஻௜௥௧௛
ଷ଺ହ.ଶହ
ቁ
In demographic data summaries, age will be characterized as < 65 years, 65 to < 75 years, 
DQG 75 years.


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Geographic region
United States, Europe 1 (Germany, Italy, Latvia, Spain), Europe 2 (Czech Republic, 
Georgia, Hungary, Poland, Romania), South America (Argentina, Brazil, Colombia, Mexico, 
Peru).
8.1.2
Clinical Characteristics
BMI
BMI will be calculated and converted to metric units by the following:




 
2
2
/
.
weight kg
BMI kg m
height m
 
Ideal body weight (IBW)
Males:
ࡵ࡮ࢃ(࢑ࢍ) = ૞૙. ૙+ ૙. ૢ(ࢎࢋ࢏ࢍࢎ࢚െ૚૞૛. ૙)
Females:
ࡵ࡮ࢃ(࢑ࢍ) = ૝૞. ૞+ ૙. ૢ(ࢎࢋ࢏ࢍࢎ࢚െ૚૞૛. ૙)
For both males and females, if actual weight < ideal, then actual is ideal.
Creatinine clearance using ideal body weight 
࡯࢘ࢉࡸ(࢓ࡸ/࢓࢏࢔) = (૚૝૙െࢇࢍࢋ)(ࡵ࡮ࢃ)
(࡯࢘ࢋࢇ࢚࡮ࡸ)ૠ૛
For females, multiply by 0.85.
Serum creatinine must be in mg/dL: mg/dL= umol/L * 0.0113.
Subjects on hemodialysis or subjects with renal replacement will not have a baseline CrCL 
calculated and will be excluded from mean summaries.


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8.1.3
Disease-specific Clinical Characteristics
Qualifying blood culture (QBC) S. aureus status
The QBC status will be defined by the local and/or central microbiology laboratory analysis 
of pre-dose blood culture samples.
QBC positive for S. aureus: if S. aureus (reported as “MRSA”, “MSSA”, or “Staphylococcus 
aureus”) is detected in at least one pre-dose local or central microbiology blood culture. 
QBC positive for mono-microbial S. aureus: if there are no other pathogens in any pre-dose 
local or central microbiology blood culture samples. 
QBC positive for poly-microbial S. aureus: if additional pathogens other than S. aureus are 
detected in pre-dose blood cultures 
QBC status will be defined as follows: 
x
“No QBC positive for S. aureus”, 
x
“Mono-microbial QBC positive for S. aureus”, 
x
“Poly-microbial QBC positive for S. aureus”.
Post baseline S. aureus status
The post baseline S. aureus status will be defined by the local and/or central microbiology 
laboratory analysis of post-dose blood culture samples. 
Positive for mono-microbial S. aureus: if there are no other pathogens in any post-dose local 
or central microbiology blood culture samples. 
Positive for poly-microbial S. aureus: if additional pathogens other than S. aureus are 
detected in post-dose blood cultures 
QBC status will be defined as follows: 
x
“Mono-microbial post dose positive for S. aureus”, 
x
“Poly-microbial post dose positive for S. aureus”.  


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Type of S. aureus derived from central laboratory blood culture results
Subjects with at least one pre-dose centrally analyzed blood culture with S. aureus resistant 
to oxacillin are classified as having MRSA.  
All other subjects with at least one pre-dose centrally analyzed blood culture positive for 
S. aureus are classified as having MSSA.
Blood culture S. aureus vancomycin minimal inhibitory concentration (MIC) (mg/L)
Vancomycin MIC will be defined as the highest S. aureus vancomycin MIC value of all 
pre-dose centrally analyzed blood cultures for the subject.
Blood culture S. aureus clindamycin resistance
Subjects with at least one pre-dose centrally analyzed blood culture with S. aureus resistant 
to clindamycin are classified as being resistant to clindamycin.
All other subjects with at least one pre-dose centrally analyzed blood culture positive for 
S. aureus are classified as susceptible to clindamycin.
Blood culture S. aureus penicillin resistance
Subjects with at least one pre-dose centrally analyzed blood culture with S. aureus resistant 
to penicillin are classified as being resistant to penicillin.  All other subjects with at least one 
pre-dose centrally analyzed blood culture positive for S. aureus are classified as susceptible 
to penicillin.
Blood culture S. aureus other antibiotic MIC and susceptibility
Blood culture MIC (mg/dL) and, when possible, susceptibility to the following antibiotics was 
routinely assessed by the central microbiology lab:
x
Ampicillin 
x
Cefazolin
x
Cefoxitin
x
Ceftaroline
x
Clindamycin
x
Daptomycin
x
Erythromycin


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x
Linezolid
x
Oxacillin
x
Penicillin
x
Telavancin
x
Trimethoprim/sulfamethoxazole
x
Vancomycin
If needed, baseline resistance or baseline MIC may be derived for these antibiotics as 
outlined above for clindamycin or vancomycin.
Blood culture S. aureus susceptibility to the study drug
Baseline S. aureus blood culture will be considered “Nonsusceptible” (for daptomycin) or 
“Resistant” (for other treatments) to the study drug, if at least one pre-dose centrally 
analyzed blood culture for the subject is nonsusceptible or resistant to the initial study drug.  
If there is at least one pre-dose S. aureus sample, and all pre-dose samples are susceptible 
to the study drug, then baseline S. aureus blood culture will be considered “Susceptible”.
Pathogens derived from local laboratory blood culture results
Subjects with at least one pre-dose locally analyzed MRSA blood culture are classified as 
having MRSA.  
All other subjects with at least one pre-dose locally analyzed blood culture positive for
MSSA are classified as having MSSA.
Non-S. aureus pathogens identified by the local laboratory in pre-dose blood cultures will be 
summarized within the following categories:
x
Gram-positive pathogens are the pathogens with genus or species names containing 
any of the following (not case sensitive): “Enterococcus”, “Propionibacterium”,
“Staph”, “Staphylococcus”, “Strep”, “Streptococcus”.
x
Gram negative pathogens are the pathogens with genus or species names 
containing any of the following (not case sensitive): “Acinetobacter”, “Enterobacter”,
“Escherichia”, “Proteus”, “Pseudomonas”, “Serratia”, “Sphingomonas”.
x
Other pathogens are those that are not classified as gram-negative or gram-positive.


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Type of S. aureus derived from central laboratory urine culture results
Subjects with at least one pre-dose centrally analyzed urine culture with S. aureus resistant 
to oxacillin are classified as having MRSA.  
All other subjects with at least one pre-dose centrally analyzed urine culture positive for 
S. aureus are classified as having MSSA.
Pathogens derived from local laboratory urine culture results
Subjects with at least one pre-dose locally analyzed MRSA urine culture are classified as 
having “MRSA positive urine culture”.  
All other subjects with at least one pre-dose locally analyzed urine culture positive for MSSA 
are classified as having “MSSA positive urine culture”. 
Subjects who have at least one pre-dose locally analyzed urine culture sample, but no such 
samples positive for S. aureus will be classified as “No S. aureus in urine culture”.  Subjects 
who don’t have any pre-dose locally analyzed urine culture samples will be classified as 
“Missing urine culture”. 
Non-S. aureus pathogens identified by the local laboratory in pre-dose urine culture will be 
summarized.


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8.2
Efficacy Variables
Clinical outcome at TOC
Clinical cure rate, defined as proportion of subjects with the clinical outcome of success, at 
TOC will be evaluated.  The primary efficacy endpoint will be adjudicated by the IEAC 
blinded to treatment assignments.
Subjects with IEAC-adjudicated failure at EOT will be classified as having failure at TOC, 
regardless of the classification at TOC reported on the adjudication eCRF.
Clinical Response at EOT
Clinical response rate at EOT will be defined as the proportion of subjects with the clinical 
response of success at EOT.
Clinical outcome at TOC and clinical response at EOT (success, failure, indeterminate, or 
missing) will be summarized categorically.
Time to Initial Clearance of S. aureus Bacteremia
Clearance of S. aureus bacteremia is defined as occurring on the first date of all blood 
cultures negative for S. aureus for two successive days (need not be consecutive calendar 
days) after the first dose of study drug, in absence of PENSABs administered after Study 
Day 1 (defined in Section 8.3.3). This determination is based on locally analyzed blood 
cultures.
Time to initial clearance of S. aureus bacteremia will be defined, based on locally analyzed 
blood cultures, as (date of S. aureus bacteremia clearance) minus (date of the first dose of 
study drug) + 1, where the date of clearance is on Study Day 7 or earlier.
Subjects without any blood cultures between the first dose of study drug and Day 8, 
inclusively, will be censored at Day 1.
Subjects with at least one blood culture between the first dose of study drug and Day 8, 
inclusively, but without clearance of S. aureus bacteremia during that time will be censored 
at the last day a blood culture was collected on or before Day 8 or the day of the first 
PENSAB after Day 1, whichever is the earlier. 


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Development of New Metastatic Foci of S. aureus Infection
Development of new metastatic foci of S. aureus infection, defined as the development of 
new signs or symptoms consistent with S. aureus infection, will be assessed after Day 8 
through the end of study (Yes, No, or missing) and summarized categorically.
28-day All-cause Mortality
Twenty-eight-day all-cause mortality is based on all deaths that occur on or before Day 28,
irrespective of the cause. Deaths are defined as adverse events with fatal outcome reported
on the AE eCRF; the date of death is the AE end date.  Deaths on study (fatal AE end date 
is the same as the date of the end of study participation) and deaths off study (fatal AE end 
date after the end of study participation) will be included, as long as they occur on or before 
Day 28.
Twenty-eight-day all-cause mortality is a time-to-event endpoint defined, for the subjects 
who died on or before Day 28, as (date of death) minus (date of the first dose of study drug) 
+ 1. Subjects without fatal adverse events and subjects who died after Day 28 will be 
censored at the earlier of Day 28 and the Study Day of study discontinuation.
For sensitivity analyses, 28-day on-study all-cause mortality may be defined similarly, based 
only on deaths on study.
Investigator Assessment of Clinical Outcome at TOC and Clinical Response at EOT
Investigator assessment of clinical outcome at TOC and investigator assessment of clinical 
response at EOT will be derived for each subject using the data reported by the investigator 
on eCRF.  
Clinical response at EOT will be success, failure, indeterminate, or missing, as reported. 
Clinical outcome at TOC will be clinical success, failure, indeterminate, or missing as 
reported, except subjects with clinical response = failure at EOT will be considered as 
having failure at TOC regardless of the assessment reported on eCRF.


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8.3
Safety Variables
The list of safety variables is provided in Section 5.5.
8.3.1
Adverse Events
Adverse events (AEs) are recorded from signing of the informed consent form through the 
final follow-up assessment.  Unless otherwise specified, only treatment-emergent AEs will 
be summarized in the tables.  Treatment-emergent AEs are defined as AEs with an onset 
date on or after the initiation of the first study drug up to the last day of study drug plus
28 days or the date of study completion or discontinuation, whichever is the earlier.
Renal adverse events are those coded to the renal and urinary disorders system organ 
class. 
8.3.2
Prior and Concomitant Medications
Prior and concomitant antimicrobial therapy will be collected on a dedicated eCRF 
throughout the subject’s study participation.  Other prior and concomitant medications will be 
collected on another eCRF.  
Nephrotoxic medications will be identified by the Medical Monitor review of the list of 
WHODD coded preferred drug names and routes of administration of the concomitant 
antimicrobial therapy and other medications.  The final medical review identifying 
nephrotoxic medications will occur after all subject data have been reviewed, verified, and 
soft locked and prior to the data base lock (Appendix 2).
For the purposes of safety data reporting, the medications will be classified as prior to, 
concomitant with, or post study drug (mutually exclusive categories) as described in Table 8. 
8.3.3
Systemic Antimicrobial Therapy
8.3.3.1 Potentially Effective Non-study Antibiotic (PENSAB) Definition
Potentially effective non-study antibiotics (PENSABs) will be defined using a two-tier review 
of antimicrobial therapy by a Study Medical Monitor.  The final medical review identifying 
PENSABs will occur after all subject data have been reviewed, verified, and soft locked and 
prior to the data base lock.


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First, the list of WHODD coded preferred drug names and routes of administration of the 
concomitant antimicrobial therapy will be reviewed, and the medications will be classified as:
x
MRSA coverage: yes/no/possible
x
MSSA coverage: yes/no/possible
x
Systemic therapy: yes/no
This information will be merged with the subject type of S. aureus derived from central 
laboratory blood culture results. 
The following medications will be considered not PENSABs:
x
Those classified as Systemic therapy = “no”
x
In subjects with MRSA,  medications with potential MRSA coverage = “no”
x
In subjects with MSSA,  medications with potential MSSA coverage = “no”
The following systemic therapy will be considered PENSABs:
x
In subjects with MRSA,  medications with potential MRSA coverage = “yes”
x
In subjects with MSSA,  medications with potential MSSA coverage = “yes”
Second, for the subjects with systemic coverage and the medications with “possible” 
coverage of the subject’s S. aureus type (MRSA or MSSA), the medication will be flagged as 
“possible” PENSAB, and additional subject level information will be reviewed to determine 
whether the medication is a PENSAB, for instance: how long the  medication was 
administered for; medication indication; baseline clindamycin or penicillin resistance (if the 
medication is clindamycin or penicillin); antibiotic susceptibility of the centrally analyzed S. 
aureus blood and other cultures.
8.3.3.2 Systemic Antimicrobial Therapy Timing
For the purposes of assessing impact on efficacy evaluation, systemic antimicrobial therapy
will be classified by: 
x
Whether or not the medication started prior to the first dose of study drug (yes/no);  
x
Whether or not the medication was administered at any time after Study Day 1 as 
described in Table 8 (yes/no); 
x
Whether or not the medication started upon study drug discontinuation (yes/no); 
Note that a medication administered after the first dose of study drug could have also 
started prior to the first dose or upon study drug discontinuation. 


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For the systemic antimicrobial therapy starting prior to the first dose of study drug, the 
number of hours from the start of medication to the first dose of study drug will be computed.  
For the purposes of this calculation, if the start time of the medication is unknown, it will be 
imputed as 00:01 on the day of the medication start.  If the start date is unknown, it will be 
imputed with the 1st of the month; if the start month is unknown, it will be imputed with 
January.  The number of hours derived based on imputed values will be flagged.


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9
ANALYSES
Table, figures and listing titles are denoted in underlined text.
9.1
General Analyses
9.1.1
Analysis Sets
Analysis populations will be summarized by counts and percentages as follows:
x
All Randomized, n
x
Safety, n
x
All (AT), n [100%]
x
Microbiological All Treated (mAT), n [% of AT]
x
mAT (UCB, CB, RIE), n [% of AT] (% of mAT)
x
mAT (CB, RIE), n [% of AT] (% of mAT)
x
mAT (UCB), n [% of AT] (% of mAT)
x
mAT (CB), n [% of AT] (% of mAT)
x
mAT (LIE), n [% of AT] (% of mAT)
x
mAT (RIE), n [% of AT] (% of mAT)
x
Microbiological Evaluable (ME), n [% of AT] (% of mAT)
x
ME (UCB, CB, RIE), n [% of AT] (% of mAT) [[% of ME]]
x
ME (CB, RIE), n [% of AT] (% of mAT) [[% of ME]]
x
ME (UCB), n [% of AT] (% of mAT) [[% of ME]]
x
ME (CB), n [% of AT] (% of mAT) [[% of ME]]
x
ME (LIE), n [% of AT] (% of mAT) [[% of ME]]
x
ME (RIE), n [% of AT] (% of mAT) [[% of ME]].


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9.1.2
Subject Disposition
Subject disposition information will be summarized for all subjects by dose.  The summary
will include: 
x
Number of randomized subjects,
x
Number and percentage of subjects randomized and treated with study drug (AT),
x
Number and percentage of subjects completing the study,
x
Number and percentage of subjects by reason discontinuing the study
o
Completed
o
Lost to follow-up
o
Withdrawal by subject
o
Death
o
Other
x
Number and percentage of subjects completing the study drug,
x
Number and percentage of subjects by reason discontinuing the study drug
o
Subjects completed dosing regimen
o
Adverse Event
o
Withdrawal by subject
o
Lost to follow-up
o
Physician decision
o
Pregnancy
o
Protocol violation
o
Study terminated by Sponsor
o
Death
o
Other
A listing of subject disposition will include the AT analysis set status, the initial date of 
informed consent signed, the date of first dose and last dose of study drug, primary category
for subject discontinuation of study medication, the date of last visit, study completion status, 
primary category for study termination, and the date of last contact.
In addition, all subjects with a discontinuation or disposition category of (1) Other,
(2) physician decision, or (3) Withdrawal by subject will include verbatim explanations in the 
listing


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9.1.3
Demographics and Baseline Characteristics
Demographics and baseline characteristics, age, sex, race, ethnicity, height, weight, and 
BMI) will be summarized for the AT analysis set.
A listing will also be provided.
9.1.4
Classification of Infection Type
Classification of infection type will be summarized as follows:
Investigator Assessments:
x
Subjects in AT Population, n
o
Uncomplicated Bacteremia (UCB), n (%)
o
Complicated Bacteremia (CB), n (%)
o
Right-Sided Infective Endocarditis (RIE), n (%)
o
Left-Sided Infective Endocarditis (LIE), n (%)
o
Unknown (missing), n (%)
x
Subjects in mAT Population, n
o
Uncomplicated Bacteremia (UCB), n (%)
o
Complicated Bacteremia (CB), n (%)
o
Right-Sided Infective Endocarditis (RIE), n (%)
o
Left-Sided Infective Endocarditis (LIE), n (%)
o
Unknown (missing), n (%)
Adjudicated Investigator Assessments:
x
Subjects in AT Population, n
o
Uncomplicated Bacteremia (UCB), n (%)
o
Complicated Bacteremia (CB), n (%)
o
Right-Sided Infective Endocarditis (RIE), n (%)
o
Left-Sided Infective Endocarditis (LIE), n (%)
o
Unknown (missing), n (%)
o
Not adjudicated, n (%)
x
Subjects in mAT Population, n
o
Uncomplicated Bacteremia (UCB), n (%)
o
Complicated Bacteremia (CB), n (%)
o
Right-Sided Infective Endocarditis (RIE), n (%)
o
Left-Sided Infective Endocarditis (LIE), n (%)


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o
Unknown (missing), n (%)
o
Not adjudicated, n (%)
9.1.5
Clinical Characteristics at Baseline
Three summary of baseline clinical characteristics will be provided, one each for the AT, 
mAT and ME populations:
x
Age Category
o
<65 years, n (%)
o
65, <75 years, n (%)
o
 75 years, n (%)
x
Creatinine clearance, based on ideal body weight (mL/min),
x
Creatinine clearance, based on actual body weight (mL/min),
x
Type of S. aureus identified by the site
o
MRSA, n (%)
o
MSSA, n (%)
o
Unknown (missing), n (%)
x
Type of S. aureus derived from central lab results
o
MRSA, n (%)
o
MSSA, n (%)
o
Unknown (missing), n (%)
x
Blood culture S. aureus Vancomycin MIC (mg/L)
o
 1 mg/L, n (%)
o
> 1 mg/L, n (%)
o
 2 mg/L, n (%)
o
> 2 mg/L, n (%)
x
Blood culture S. aureus antibiotic resistance
o
clindamycin, n (%)
o
penicillin, n (%)
A listing will also be provided. 


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9.1.6
Select Medical History
A summary of select medical history will be provided using the AT and the mAT populations: 
x
Diabetes mellitus (from CRF or MH), n (%)
x
History of injection drug use w/in last 2 years, n (%)
x
Previous history of infective endocarditis w/in last 2 years, n (%)
x
HIV infection, n (%)
x
Hemodialysis, n (%)
x
Hepatitis C, n (%)
x
Liver Cirrhosis, n (%)
x
Malignancy requiring Chemo w/in last 2 years, n (%)
x
Admission to hospital in previous 3 months, n (%)
x
Active immunosuppression, n (%)
x
Valvular heart disease, n (%)
x
Prosthetic cardiac devices, n (%)
x
Other non-cardiac prosthetic devices, n (%)
9.1.7
Pathogens Isolated from Qualifying Blood Cultures
Three summaries of isolated pathogens will be provided. A summary of pathogens isolated 
from blood cultures by the site, a summary of pathogens isolated from blood cultures by 
Central lab and a summary of pathogens isolated from blood cultures by the Site OR Central 
lab will be provided as follows (by baseline and by post baseline):
Rapid diagnostic test for qualifying blood culture
x
PNA-FSH, n (%)
x
MALDI-TOF, n (%)
x
Qualitative PCR, n (%)
x
Multiplex microarray, n (%)
x
Multiplex PCR, n (%)
x
Other, n (%)
x
Not applicable, n (%)
Baseline (qualifying blood culture) 
x
Number of subjects in the AT population, n (%)
x
Number of subjects with confirmed pathogens isolated from blood cultures, n (%)
x
Gram-positive pathogens, n (%) [by pathogen]


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x
Gram-negative pathogens, n (%) [by pathogen]
x
Other, n (%) [by pathogen]
Post Baseline 
x
Number of subjects in the AT population, n (%)
x
Number of subjects with confirmed pathogens isolated from blood cultures, n (%)
x
Gram-positive pathogens, n (%) [by pathogen]
x
Gram-negative pathogens, n (%) [by pathogen]
x
Other, n (%) [by pathogen]
9.1.8
Signs and Symptoms of Bacteremia at Enrollment
A summary of signs and symptoms of bacteremia at enrollment will summarize the following:
x
Subjects with at least one signs and symptom of bacteremia, n (%)
x
Temperature  38.0o C, n (%)
x
White blood cell (WBC) count > 10,000 or < 4,000 cells/μL, or > 10% immature
neutrophils (bands) regardless of total peripheral WBC count, n (%)
x
Tachycardia (heart rate > 90 bpm), n (%)
x
Tachypnea (respiratory rate >20 breaths/min), n (%)
x
Hypotension (systolic blood pressure <90 mmHg), n (%)
x
Signs and symptoms of localized catheter-related infection, n (%)
9.1.9
Characteristics of Bacteremia at Enrollment
A summary of the characteristics of bacteremia at enrollment will summarize the following:
x
Subjects with complicated bacteremia with known metastatic foci of S. aureus
infection, n (%)
x
Endocarditis, n (%)
x
Lung (Septic Pulmonary Emboli), n (%)
x
Vein (Septic Thrombophlebitis), n (%)
x
Epidural Abscess, n (%)
x
Septic Arthritis (Joint), n (%)
x
Renal Abscess, n (%)
x
Splenic Abscess, n (%)
x
Hepatic Abscess, n (%)
x
Soft Tissue Abscess, n (%)


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x
Other Location, n (%)
In addition, a summary of risk factors for bacteremia will summarize the following:
x
Subject with at least one risk factor for bacteremia, n (%)
x
A Central Venous Catheter (CVC) in the Internal Jugular or Subclavian Vein, n (%)
x
Any CVC Considered to be the Source of the Infection, n (%)
x
Presence of a Long-term Intravascular Catheter, n (%)
x
New or Diastolic Cardiac Murmur, n (%)
x
Community Onset Bacteremia, n (%)
x
Pathogen known to be MRSA at Enrollment, n (%)
x
Duration of Symptoms >= 2 Days at Time of Presentation, n (%)
x
Skin Exam Findings Suggesting Acute Systemic Infection, n (%)
9.1.10 Baseline modified APACHE II Scores
A summary of the Baseline modified APACHE II Scores and Components will summarize 
the following (see Appendix 4 for APACHE II Assessment Criteria details)
x
Total Baseline modified APACHE II Score, calculated as the sum of A (Total Acute 
Physiology Score (APS points)) + B (Age points) + C (Chronic Health points),
x
APS points (A)
x
Age points (B)
x
Chronic Health points (C)
Acute Physiology Score (APS) Variables
x
Temperature – rectal (°C)
x
Mean Arterial Pressure (mm Hg)
x
Heart Rate 
x
Respiratory Rate (non-ventilated or ventilated)
x
Oxygenation (mm Hg)
x
Arterial pH
x
Serum Sodium (mmol/l)
x
Serum Potassium (mmol/l)
x
Serum Creatinine (mg/dl, Double point score for acute renal failure)
x
Hematocrit (%)
x
White Blood Count (in 1000/mm3)
x
Glasgow-Coma-Scale (GCS)


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x
Serum HCO3 (venous, mmol/l, use if no ABGs)
A listing will also be provided.
9.2
Efficacy Analyses
For all efficacy data analyses, the mAT (UCB, CB, and RIE) group will be used unless 
otherwise specified. 
9.2.1
General Considerations for Efficacy Analyses
Analysis Set for Efficacy Analyses
For all efficacy data analyses, the mAT (UCB, CB, and RIE) analysis population will be used 
unless otherwise specified. 
9.2.2
Primary Efficacy Evaluation: Adjudicated Clinical Outcome at TOC
Hypothesis
The primary estimate of interest, proportion of subjects with adjudicated clinical cure at end 
of treatment, is used to evaluate the effectiveness of telavancin therapy relative to standard 
intravenous therapy, as assessed through a non-inferiority margin of 15%, in all patients in 
the microbiological all treated population with a bacteremia type of uncomplicated 
bacteremia, complicated bacteremia and right-side infective endocarditis.
The following hypothesis testing schema will be employed to assess the primary endpoint:
The null hypothesis is that telavancin is clinically inferior to standard therapy, where 
“clinically inferior” is defined as having a population clinical cure rate that is 15 percentage 
points (or more) lower than that for standard IV therapy.  The alternative hypothesis is that 
telavancin is at least clinically noninferior to standard IV therapy, where “clinical 
noninferiority” is defined as having population clinical cure rates that differ by less than 
15 percentage points. Expressed symbolically, the null hypothesis (H0) and the alternative 
hypothesis (H1) are as follows:
ܪ଴:ߨ்െߨௌ൑െ15%
ܪଵ: ߨ்െߨௌ> െ15%,


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where ߨ்and ߨௌdenote the population clinical cure rates of telavancin and standard IV 
therapy, respectively. 
A two-sided 95% confidence interval (CI) on the treatment difference, ߨ்െߨௌ, will be 
constructed.
If the lower confidence limit (ܥܮ௅) is less than or equal to -15%, then the null hypothesis of 
inferiority will not be rejected. If ܥܮ௅is greater than -15%, then the null hypothesis of clinical
inferiority will be rejected in in favor of the alternative hypothesis of clinical noninferiority.
Analysis and Summary Tables
Adjudicated clinical outcome at TOC (cure, failure, indeterminate, or missing) will be 
summarized categorically. The proportion of subjects with clinical cure is the number of 
subjects with an adjudicated outcome of “cure” at TOC divided by the total number of 
subjects for each treatment group.
The point estimate and CI for the treatment difference will be calculated using the normal 
approximation to the binomial distribution without continuity correction. If any cell size is 
less than 10, the CI will be calculated using the method of Agresti and Caffo [1] to adjust for 
the sparse cell size.  
A summary of adjudicated clinical outcome at TOC will include observed counts and 
proportions for each outcome and the corresponding point estimate for the difference of 
proportions and 95% CI.


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9.2.3
Sensitivity Analyses of the Primary Endpoint
Sensitivity Analysis: Analysis Populations
A summary of adjudicated clinical outcome at TOC by analysis population will repeat the 
primary analysis on the following analysis populations summarizing only the “cure” counts, 
proportions, treatment difference and 95% CI for the following analysis populations:
x
All (AT),
x
Microbiological All Treated (mAT),
x
mAT (UCB, CB, RIE)[primary]
x
mAT (CB, RIE),
x
mAT (UCB),
x
mAT (CB),
x
mAT (LIE),
x
mAT (RIE),
x
Microbiological Evaluable (ME),
x
ME (UCB, CB, RIE), 
x
ME (CB, RIE),
x
ME (UCB),
x
ME (CB),
x
ME (LIE),
x
ME (RIE).
Sensitivity Analysis: Subgroups
A summary of adjudicated clinical outcome at TOC by subgroups (mAT UCB, CB, and RIE)
will repeat the primary analysis on the following analysis populations by subgroups
summarizing only the “cure” counts and proportions, treatment difference and 95% CI for the 
following analysis populations:
x
mAT (UCB, CB, RIE): < 65 years
x
mAT (UCB, CB, RIE):  65 years
x
mAT (UCB, CB, RIE): < 75 years
x
mAT (UCB, CB, RIE):  75 years
x
mAT (UCB, CB, RIE): male
x
mAT (UCB, CB, RIE): female
x
mAT (UCB, CB, RIE): US


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x
mAT (UCB, CB, RIE): ex-US
x
mAT (UCB, CB, RIE): MSSA
x
mAT (UCB, CB, RIE): MRSA
x
mAT (UCB, CB, RIE): S. Aureus vaQFRP\FLQ0,& 1 mg/L
x
mAT (UCB, CB, RIE): S. Aureus vancomycin MIC > 1 mg/L
x
mAT (UCB, CB, RIE): S. Aureus YDQFRP\FLQ0,& 2 mg/L
x
mAT (UCB, CB, RIE): S. Aureus vancomycin MIC > 2 mg/L
x
mAT (UCB, CB, RIE): CrCL > 50 mL/min
x
mAT (UCB, CB, RIE): CrCL  50 mL/min
A summary of adjudicated clinical outcome at TOC by subgroups (ME UCB, CB, and RIE)
will repeat the primary analysis on the following analysis populations by subgroups 
summarizing only the “cure” counts, proportions, treatment difference and 95% CI for the 
following analysis populations:
x
ME (UCB, CB, RIE): < 65 years
x
ME (UCB, CB, RIE):  65 years
x
ME (UCB, CB, RIE): < 75 years
x
ME (UCB, CB, RIE):  75 years
x
ME (UCB, CB, RIE): male
x
ME (UCB, CB, RIE): female
x
ME (UCB, CB, RIE): US
x
ME (UCB, CB, RIE): ex-US
x
ME (UCB, CB, RIE): MSSA
x
ME (UCB, CB, RIE): MRSA
x
ME (UCB, CB, RIE): S. Aureus vancomycin 0,& 1 mg/L
x
ME (UCB, CB, RIE): S. Aureus vancomycin MIC > 1 mg/L
x
ME (UCB, CB, RIE): S. Aureus YDQFRP\FLQ0,& 2 mg/L
x
ME (UCB, CB, RIE): S. Aureus vancomycin MIC > 2 mg/L
x
ME (UCB, CB, RIE): CrCL > 50 mL/min
x
ME (UCB, CB, RIE): CrCL  50 mL/min


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9.2.4
Secondary Efficacy Evaluation: Adjudicated Clinical Response at EOT  
Clinical response at EOT is handled in the similar manner as the clinical outcome at TOC.
Analysis and Summary Tables
Adjudicated Clinical response at EOT (cure, failure, indeterminate, or missing) will be 
summarized categorically. The proportion of subjects with clinical response is the number of 
subjects with an adjudicated outcome of “success” at EOT divided by the total number of 
subjects for each treatment group.
The point estimate and CI for the treatment difference will be calculated using the normal 
approximation to the binomial distribution without continuity correction. If any cell size is 
less than 10, the CI will be calculated using the method of Agresti and Caffo [1] to adjust for 
the sparse cell size.
A summary of adjudicated clinical response at EOT will include observed counts and 
proportions for each outcome and the corresponding point estimate for the difference of 
proportions and 95% CI.
A summary of adjudicated clinical response at EOT by analysis population will repeat the 
primary analysis on the same analysis populations as the corresponding summary for the 
primary endpoint summarizing only the “success” counts and proportions, treatment 
difference and 95% CI for the following analysis populations.
A summary of adjudicated clinical response at EOT by subgroups (mAT UCB, CB, and RIE)
will repeat the primary analysis on the same analysis populations as the corresponding 
summary for the primary endpoint summarizing only the “success” counts and proportions, 
treatment difference and 95% CI for the following analysis populations.
A summary of adjudicated clinical response at EOT by subgroups (ME UCB, CB, and RIE)
will repeat the primary analysis on the same analysis populations as the corresponding 
summary for the primary endpoint summarizing only the “success” counts and proportions, 
treatment difference and 95% CI for the following analysis populations.


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9.2.5
Secondary Efficacy Evaluation: Investigator Clinical Outcome at TOC
A summary of investigator clinical outcome at TOC will include observed counts and 
proportions for each outcome and the corresponding point estimate for the difference of 
proportions and 95% CI.
A summary of investigator clinical outcome at TOC by analysis population will repeat the 
primary analysis on the same analysis populations as the corresponding summary for the 
primary endpoint summarizing only the “cure” counts and proportions, treatment difference 
and 95% CI for the following analysis populations.
A summary of investigator clinical outcome at TOC by subgroups (mAT UCB, CB, and RIE)
will repeat the primary analysis on the same analysis populations as the corresponding 
summary for the primary endpoint summarizing only the “cure” counts and proportions, 
treatment difference and 95% CI for the following analysis populations.
A summary of investigator clinical outcome at TOC by subgroups (ME UCB, CB, and RIE) 
will repeat the primary analysis on the same analysis populations as the corresponding 
summary for the primary endpoint summarizing only the “cure” counts and proportions, 
treatment difference and 95% CI for the following analysis populations.
In addition, the Reasons for Failure or Indeterminate in Clinical Response at Test-of-Cure 
(Investigator-Assessed) will summarize the reasons for lack of response (Appendix 5).
9.2.6
Secondary Efficacy Evaluation: Investigator Clinical Response at EOT
A summary of investigator clinical response at EOT will include observed counts and 
proportions for each outcome and the corresponding point estimate for the difference of 
proportions and 95% CI.
A summary of investigator clinical response at EOT by analysis population will repeat the 
primary analysis on the same analysis populations as the corresponding summary for the 
primary endpoint summarizing only the “success” counts and proportions, treatment 
difference and 95% CI for the following analysis populations.
A summary of investigator clinical response at EOT by subgroups (mAT UCB, CB, and RIE)
will repeat the primary analysis on the same analysis populations as the corresponding 


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summary for the primary endpoint summarizing only the “success” counts and proportions, 
treatment difference and 95% CI for the following analysis populations.
A summary of investigator clinical response at EOT by subgroups (ME UCB, CB, and RIE)
will repeat the primary analysis on the same analysis populations as the corresponding 
summary for the primary endpoint summarizing only the “success” counts and proportions, 
treatment difference and 95% CI for the following analysis populations.
In addition, the Reasons for Failure or Indeterminate in Clinical Response at EOT
(Investigator-Assessed) will summarize the reasons for lack of response (Appendix 5).
9.2.7
Secondary Efficacy Evaluation: Time to initial clearance of S. aureus
bacteremia
Analysis and Summary Tables
Time to event endpoints will be handled using Kaplan-Meier methodology. Subjects not 
experiencing the event in question up to and including the specified time period will be 
considered to be censored at the specified end of evaluation.
Sample code for the procedure in SAS is specified below:
proc lifetest data=data1; 
time timeto*event(0); 
strata trt01pn; 
ods output 
quartiles=medci(where=(percent=50))  
ProductLimitEstimates=estimate(keep=trt01pn timeto survival 
stderr where=(survival>=0 and timeto>0.0)) 
 
 
ProductLimitEstimates=atrisk(keep=trt01pn timeto failed left); 
A summary of the time to initial clearance of S. aureus bacteremia will include the survival 
estimate and number at risk for each time point with an event, regardless if the event 
occurred within all treatment groups.  Summaries will include up to the end of the maximum 
nominal evaluation period. Treatment groups not having an overlapping time will have the 
survival probability for the preceding time repeated until and event occurs within said 
treatment group.  The cumulative number of events will be summarized.
The time to event reporting structure will be used to summarize the time to first event.


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Nominal p-values will be reported.
Figures
Inverse Survival Plot
The Inverse Survival plot of the Kaplan-Meier estimates will be provided.
9.2.8
Secondary Efficacy Evaluation: 28-day all-cause mortality
Analysis and Summary Tables
Time to event endpoints will be handled using Kaplan-Meier methodology.  Subjects not 
experiencing the event in question up to and including the specified time period will be 
considered to be censored at the specified end of evaluation.
A summary of the 28-day mortality will include the survival estimate and number at risk for 
each time point with an event, regardless if the event occurred within all treatment groups.  
Summaries will include up to the end of the maximum nominal evaluation period. Treatment 
groups not having an overlapping time will have the survival probability for the preceding 
time repeated until and event occurs within said treatment group.  The cumulative number of 
events will be summarized.
The time to event reporting structure will be used to summarize the time to first event.
Nominal p-values will be reported.
Figures
Inverse Survival Plot
The Inverse Survival plot of the Kaplan-Meier estimates will be provided.
9.2.9
Multiplicity Adjustment
No adjustment for multiplicity is planned as all inferences are confidence interval based.
9.3
Safety Analyses
For all safety analyses, the safety analysis population will be used.


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Safety variables to be summarized include vital signs, adverse events, clinical laboratory 
results (hematology, chemistry, and urinalysis), and quantitative parameters from 12-lead 
ECGs. Vital signs will be summarized in terms of observed values and changes from 
baseline.
9.3.1
Extent of Exposure
Study drug exposure and compliance will summarize the number of days of study 
medication and to total duration of study treatment. Study drug duration will be defined 
based on the number of days within a given treatment period (date of last dose – date of first 
dose + 1). 
x
Actual number of days of study medication
x
Duration of study treatment
x
Compliance rate (%)
In addition, Study drug exposure and compliance by infection type will summarize the 
following exposure and compliance metrics will be summarized by infection type ([1] CB 
[2] LIE [3] RIE [4] UCB)
x
Actual number of days of study medication
x
Duration of study treatment
x
Compliance rate (%)
x
Compliance rate to protocol stated treatment duration (%)
Compliance rate is defined as:
x
number of doses / treatment duration for a once daily IV therapy
x
number of doses / (2*treatment duration) for a 2x daily IV therapy
x
number of doses / (3*treatment duration) for a 3x daily IV therapy
x
number of doses / (4*treatment duration) for a 4x daily IV therapy
Compliance rate to protocol stated treatment duration is defined as the minimum of 
compliance rate and:
x
number of doses / minimum treatment duration for the infection type for a once daily
IV therapy
x
number of doses / (2* minimum treatment duration for the infection type) for a
2x daily IV therapy
x
number of doses / (3* minimum treatment duration for the infection type) for a
3x daily IV therapy


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x
number of doses / (4* minimum treatment duration for the infection type) for a 
4x daily IV therapy
9.3.2
Adverse Events
Adverse events will be coded to the preferred terms of the Medical Dictionary for Regulatory 
Activities (MedDRA®). Summaries will present by system organ class (SOC), preferred term 
(PT) and severity and/or relatedness, the frequency and percentage of subjects reporting 
each observed event.
A treatment-emergent adverse event (TEAE) will be defined as any AE that begins on or 
after the date of first dose of study drug up to the date of last dose of study drug plus the 
number of days in the follow-up period.  AEs observed during the period from obtaining 
informed consent to the start of administration of study drug will be regarded separately from 
TEAEs.
All AEs and all TEAEs will be listed by subject. 
Subjects who experienced treatment-limiting AEs will be listed. Treatment-limiting AEs are 
defined as any event that leads to permanent or temporary discontinuation from treatment, 
or a reduction in the treatment dose.
Summary of adverse events will be dependent on adverse events observed.  If no adverse 
events meeting a specific table are observed, the summary table will not be completed. 
Blank summary tables will not be utilized.  
The following is the list of adverse event tables:
Overall:
x
Overall Summary of Adverse Events
By preferred term:
x
Treatment-emergent Adverse Events by SOC and PT
x
Treatment-emergent Adverse Events by PT
x
Treatment-emergent Adverse Events by SOC and PT occurring in more than 5% of 
Study population


Statistical Analysis Plan
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By severity:
x
Treatment-emergent Adverse Events by SOC, PT and Severity
x
Moderate or Severe Treatment-emergent Adverse Events by SOC and PT
x
Serious Adverse Events
x
Deaths during or Post Study
By relatedness:
x
Drug-Related Treatment-emergent Adverse Events by SOC and PT
x
Drug-Related Treatment-emergent Adverse Events by SOC, PT and Severity
x
Moderate or Severe Drug-Related Treatment-emergent Adverse Events by SOC and 
PT
x
Drug-related Serious Adverse Events
Other:
x
Adverse events leading to premature study drug discontinuation
x
Adverse events leading to temporary interruption of study drug
The overall summary of adverse events will include the following summary lines, any AE, 
Moderate or severe AEs, Moderate or severe AEs related to Study Drug, Serious AEs, 
Serious AEs related to Study Drug, AEs leading to discontinuation, AEs leading to 
interruption, Deaths during Study.
9.3.2.1 Renal Adverse Events
A summary of Renal AE, by visit, will summarize the number and percentage of subjects 
with a renal AE in the renal and urinary SOC.
A listing of additional information collected for renal AEs will be provided.
9.3.3
Vital Signs
For each nominal time point, vital signs will be summarized in terms of observed values and 
changes from Baseline. Outlier values of vital signs will be flagged in the listing.
Table 9:
Vital Signs Outlier Thresholds
Heart Rate
(bpm)
Systolic Blood Pressure
(mmHg)
Diastolic Blood Pressure
(mmHg)
<40
>110
<85
>160
<45
>100


Statistical Analysis Plan
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9.3.4
ECG
A summary of ECG parameters, parameters reported separately QTcF, PR interval, QT 
interval, QRS duration, RR, and HR, will be summarized in terms of observed values and 
change from baseline. 
Subjects without post-baseline measurement for a given treatment period will be excluded
from the summary statistic (eg, denominator of the summary statistic) for that time point.  
All recorded values by central reader at ECG core lab for the standard 12-lead 
electrocardiogram parameters will be presented in a by-subject listing.
Outlier Analysis
The number of subjects with absolute ECG values and change from baseline in the ranges 
shown in Table 10 will be presented in Electrocardiogram Outlier Summary by Visit and 
Time Point. 
In addition in the same summary, QTcF will also be summarized by the following categories,
Normal (males 430, females 450), Borderline (males (>430, 450); females (>450, 470))
and Prolonged (males >450, females >470).
Individual ECG data collected during the study will be presented in a listing. A separate 
listing of subjects with values of QTcF > 500 msec or an increase > 60 msec will be 
provided, as necessary. 
Investigator Assessment of ECG Readings
The investigators’ assessment of ECGs as normal, abnormal and clinically significant, or 
abnormal but not clinically significant will be summarized for baseline and for each visit.


Statistical Analysis Plan
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Table 10:
ECG Test Outlier Thresholds
Heart 
Rate 
(bpm)
Heart Rate 
Change from 
Baseline (bpm)
PR
Interval 
(msec)
PR Percentage 
Change From 
Baseline (%)
QRS
Interval
(msec)
QTcF 
(msec)
QTcF change 
from Baseline 
(msec)
>120
>20
> 200
> 15
> 120
Males:

>130
>30
> 220
> 25
 430
!
> 430
> 60
> 450
> 470
> 480
> 500
Females:
 450
> 450
> 470
> 480
> 500
9.3.5
Clinical Laboratory Results
Laboratory data, hematology, serum chemistry and urinalysis, will be summarized in terms 
of observed values, changes from baseline for each period.  In addition, changes from 
baseline for each period relative to normal ranges (eg, shifts from normal to abnormal
high/low) will be summarized in hematology: shift from baseline, serum chemistry: shift from 
baseline and urinalysis: shift from baseline.
Listings will flag laboratory values that are outside of normal range.
A listing of all abnormal lab values will be provided.
9.3.6
Medical History
Medical history collected at screening will be provided in a table and data listing.


Statistical Analysis Plan
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9.3.7
Prior and Concomitant Medications
Prior, concomitant and post study drug medications will be listed and summarized 
separately. The following summaries will be provided:
x
Prior Systemic Antimicrobials
x
Concomitant Systemic Antimicrobials
x
Post Study Drug Systemic Antimicrobials
x
Nephrotoxic Medications Prior to Study Drug
x
Concomitant Nephrotoxic Medications 
x
Post Study Drug Nephrotoxic Medications
x
Prior Medications
x
Concomitant Medications
x
Post Study Drug Medications
10
REFERENCES
1.
Agresti, A. and B. Caffo, Simple and effective confidence intervals for
proportions and differences of proportions result from adding two successes and 
two failures. The American Statistician, 2000. 54(4): p. 280-288.


Statistical Analysis Plan
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Appendix 1:
Reporting Structures for Data Summary
Reporting Structures
C: Continuous endpoints will be presented with an 8-point summary using the following 
reporting structure, unless otherwise noted,
N
x
Mean (SD)
x.xx (x.xx)
Median
x
Q1, Q3
xx.x, xx.x
Minimum, Maximum
xx.x, xx.x
F: Frequency endpoints will be presented by a 3-point summary using the following 
reporting structure, unless otherwise noted,
n
x
Count (%)
x (xx.x)
MF Categorical variables (multiple frequency) will be presented by a 3-point summary using 
the following reporting structure, unless otherwise noted, where the sum of the category n’s 
is the total n
n
x
Category 1 count (%)
x (x.x)
Category 2 count (%)
x (x.x)
KM: Time to event summaries will be summarized with the following reporting structure:
Time to First Event
Median (95% CI)
xx.x (xx.x, xx.x)
Q1, Q3
xx.x, xx.x
Minimum, Maximum
xx.x, xx.x
Total Number Censored
x
P-Value vs. Placebo
0.xxxx
IEAC-assessed clinical cure rate at TOC in the primary analysis population will be
summarized as follows:
Standard IV 
Therapy
(N = xx)
Telavancin
(N = xx)
Difference in Cure
Rates Telavancin –
Standard Therapy
Difference (95% CI)
Cure
XX (XX.X%)
XX (XX.X%)
XX.X% (XX.X% , XX.X%)
Failure
XX (XX.X%)
XX (XX.X%)
Indeterminate
XX (XX.X%)
XX (XX.X%)
Missing
XX (XX.X%)
XX (XX.X%)


Statistical Analysis Plan
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Confidential – Property of Theravance Biopharma, Inc.
Appendix 2:
List of Nephrotoxic Medications
Source: \\theravance\thrx\DEPARTMENTS\BIOMETRICS_2700\SAS_PE\Dev\TD-
6424\0112\csr\documents\ nephmeds_20180411_gg    Note: Filter if Nephrotoxic=Y from Excel
Medication
Route of Administration
Nephrotoxic
ACECLOFENAC
ORAL
Y
ACEMETACIN
ORAL
Y
ACETAZOLAMIDE
ORAL
Y
ACETYLSALICYLIC ACID
ORAL
Y
ACICLOVIR
INTRAVENOUS
Y
ACICLOVIR
ORAL
Y
ADENOSINE
INTRAVENOUS
Y
AMIKACIN
INTRAVENOUS
Y
AMILORIDE W/HYDROCHLOROTHIAZIDE
ORAL
Y
AMOXI-CLAVULANICO
ORAL
Y
AMOXICILLIN
ORAL
Y
AMOXICILLIN W/CLAVULANATE POTASSIUM
INTRAVENOUS
Y
AMPHOTERICIN B
INTRAVENOUS
Y
AMPICILLIN
INTRAVENOUS
Y
ARTHROTEC
ORAL
Y
AZTREONAM
INTRAVENOUS
Y
BACTRIM
ORAL
Y
BENAZEPRIL
ORAL
Y
BENAZEPRIL HYDROCHLORIDE
ORAL
Y
BUMETANIDE
INTRAVENOUS
Y
BUMETANIDE
ORAL
Y
CANDESARTAN CILEXETIL
ORAL
Y
CAPTOPRIL
ORAL
Y
CARBOPLATIN
INTRAVENOUS
Y
CEFALEXIN
ORAL
Y
CEFAZOLIN
INTRAVENOUS
Y
CEFAZOLIN
WOUND IRRIGATION
Y
CEFOTETAN
INTRAVENOUS
Y
CEFRADINE
ORAL
Y
CEFTAZIDIME
INTRAVENOUS
Y
CEFTAZIDIME
INTRVITREAL
Y


Statistical Analysis Plan
Study 0112
Version 1.0, 26APR2018
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Confidential – Property of Theravance Biopharma, Inc.
Medication
Route of Administration
Nephrotoxic
CEFTIZOXIME
INTRAVENOUS
Y
CEFTRIAXONE
INTRAVENOUS
Y
CEFTRIAXONE
UNKNOWN
Y
CEFTRIAXONE SODIUM
INTRAVENOUS
Y
CEFUROXIME
INTRAVENOUS
y
CEFUROXIME
ORAL
Y
CELECOXIB
ORAL
Y
CHLOROTHIAZIDE
INTRAVENOUS
Y
CHLORTALIDONE
ORAL
Y
CILAZAPRIL
ORAL
Y
CLONIXIN
INTRAVENOUS
Y
CLOXACILLIN
INTRAVENOUS
Y
CO-DIOVAN
ORAL
Y
COLISTIN
NEBULIZED
Y
CONTRAST MEDIA
INTRAVENOUS
Y
CREATINE
ORAL
Y
DEXKETOPROFEN
INTRAVENOUS
Y
DEXKETOPROFEN TROMETAMOL
INTRAVENOUS
Y
DEXKETOPROFEN TROMETAMOL
ORAL
Y
DICLOFENAC
ORAL
Y
DICLOFENAC POTASSIUM
ORAL
Y
DICLOFENAC SODIUM
INTRAVENOUS
Y
DICLOFENAC SODIUM
ORAL
Y
DOXEPIN
ORAL
Y
DUOCID
INTRAVENOUS
Y
DYAZIDE
ORAL
Y
ENALAPRIL
ORAL
Y
ENALAPRIL MALEATE
INTRAVENOUS
Y
ENALAPRIL MALEATE
ORAL
Y
ENALAPRILAT
INTRAVENOUS
Y
ENOXAPARIN SODIUM
INTRAVENOUS
Y
ETODOLAC
ORAL
Y
ETORICOXIB
ORAL
Y
FLEET
RECTAL
Y
FLURBIPROFEN
INTRAVENOUS
Y


Statistical Analysis Plan
Study 0112
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Confidential – Property of Theravance Biopharma, Inc.
Medication
Route of Administration
Nephrotoxic
FOSINOPRIL
ORAL
Y
FOSINOPRIL SODIUM
ORAL
Y
FRUMIL
ORAL
Y
FUROSEMIDE
INTRAVENOUS
Y
FUROSEMIDE
ORAL
Y
GENTAMICIN
INTRAVENOUS
Y
HETASTARCH
INTRAVENOUS
Y
HYDROCHLOROTHIAZIDE
ORAL
Y
HYDROCHLOROTHIAZIDE W/LOSARTAN
ORAL
Y
HYZAAR
ORAL
Y
IBUPROFEN
ORAL
Y
INDAPAMIDE
ORAL
Y
INDOMETACIN
ORAL
Y
IODIXANOL
INTRAVENOUS
Y
IOHEXOL
INTRAVENOUS
Y
IOPROMIDE
INTRAVENOUS
Y
IRBESARTAN
ORAL
Y
KARVEA HCT
ORAL
Y
KETOPROFEN
INTRAVENOUS
Y
KETOROLAC
INTRAMUSCULAR
Y
KETOROLAC
INTRAVENOUS
Y
KETOROLAC TROMETHAMINE
INTRAMUSCULAR
Y
KETOROLAC TROMETHAMINE
INTRAVENOUS
Y
KETOROLAC TROMETHAMINE
ORAL
Y
LISINOPRIL
ORAL
Y
LISINOPRIL DIHYDRATE
ORAL
Y
LORNOXICAM
INTRAMUSCULAR
Y
LORNOXICAM
INTRAVENOUS
Y
LOSARTAN
ORAL
Y
LOSARTAN POTASSIUM
ORAL
Y
MANNITOL
INTRAVENOUS
Y
MELOXICAM
ORAL
Y
METAMIZOLE
INTRAVENOUS
Y
METAMIZOLE SODIUM
INTRAVENOUS
Y
METAMIZOLE SODIUM
ORAL
Y


Statistical Analysis Plan
Study 0112
Version 1.0, 26APR2018
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Confidential – Property of Theravance Biopharma, Inc.
Medication
Route of Administration
Nephrotoxic
METOCLOPRAMIDE
INTRAMUSCULAR
Y
METOLAZONE
ORAL
Y
MINOCYCLINE
ORAL
Y
NAFCILLIN
INTRAVENOUS
Y
NAPROXEN
ORAL
Y
NAPROXEN SODIUM
ORAL
Y
NESIRITIDE
INTRAVENOUS
Y
OLMESARTAN
ORAL
Y
OLMESARTAN MEDOXOMIL
ORAL
Y
OXACILLIN
INTRAVENOUS
Y
PARECOXIB
INTRAVENOUS
Y
PENICILLIN NOS
INTRAVENOUS
Y
PERINDOPRIL
ORAL
Y
PERINDOPRIL ERBUMINE
ORAL
Y
PIPERACILLIN
INTRAVENOUS
Y
PIPERACILLIN W/TAZOBACTAM
INTRAVENOUS
Y
PIROXICAM
ORAL
Y
PRITORPLUS
ORAL
Y
QUINAPRIL
ORAL
Y
QUINAPRIL HYDROCHLORIDE
ORAL
Y
RAMIPRIL
ORAL
Y
ROFECOXIB
ORAL
Y
SODIUM PHOSPHATE
INTRAVENOUS
Y
SODIUM PHOSPHATE
RECTAL
Y
SPEKTRAMOX
INTRAVENOUS
Y
SPIRONOLACTONE
ORAL
Y
SULINDAC
ORAL
Y
SULTAMICILLIN
INTRAVENOUS
Y
TACROLIMUS
ORAL
Y
TACROLIMUS
TOPICAL
Y
TELMISARTAN
ORAL
Y
TORASEMIDE
INTRAVENOUS
Y
TORASEMIDE
ORAL
Y
TRANDOLAPRIL
ORAL
Y
TRIAMTERENE
ORAL
Y


Statistical Analysis Plan
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Medication
Route of Administration
Nephrotoxic
TRICHLORMETHIAZIDE
ORAL
Y
VALSARTAN 
ORAL
Y
VANCOMYCIN
INTRAVENOUS
Y
VANCOMYCIN
INTRAVITREAL 
Y
VANCOMYCIN
TOPICAL 
Y
VANCOMYCIN
URETERAL
Y
VASERETIC 
ORAL
Y
VERAPAMIL 
ORAL
Y
VERAPAMIL HYDROCHLORIDE
ORAL
Y


Statistical Analysis Plan
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Confidential – Property of Theravance Biopharma, Inc.
Appendix 3:
List of Antibiotic Medications
Source:\\theravance\thrx\DEPARTMENTS\BIOMETRICS_2700\SAS_PE\Dev\TD-
6424\0112\documents\Antibiotics_20180411_gg
Medication
Route of Administration
MRSA 
Coverage
MSSA 
Coverage
Systemic
AMIKACIN
INTRAVENOUS
yes
yes
yes
AMOXI-CLAVULANICO
ORAL
No
Yes
yes
AMOXICILLIN
ORAL
No
Yes
yes
AMOXICILLIN W/CLAVULANATE 
POTASSIUM
INTRAVENOUS
no
yes
yes
AMPICILLIN
INTRAVENOUS
no
yes
yes
AUGMENTIN
INTRAVENOUS
no
yes
yes
AUGMENTIN
ORAL
no
yes
yes
AZITHROMYCIN
INTRAVENOUS
no
yes
yes
AZITHROMYCIN
ORAL
no
yes
yes
AZTREONAM
INTRAVENOUS
no
no
yes
BACTRIM
ORAL
yes
yes
yes
CEFALEXIN
ORAL
no
yes
yes
CEFAZOLIN
INTRAVENOUS
no
yes
yes
CEFAZOLIN
WOUND IRRIGATION
no
no
no
CEFDINIR
ORAL
no
yes
yes
CEFEPIME
INTRAVENOUS
no
yes
yes
CEFEPIME HYDROCHLORIDE
INTRAVENOUS
no
yes
yes
CEFTAROLINE
INTRAVENOUS
yes
yes
yes
CEFTAZIDIME
INTRAVENOUS
no
yes
yes
CEFTAZIDIME
INTRVITREAL
no
no
no
CEFTRIAXONE
INTRAVENOUS
no
yes
yes
CEFTRIAXONE
UNKNOWN
no
yes
yes
CEFTRIAXONE SODIUM
INTRAVENOUS
no
yes
yes
CEFUROXIME
INTRAVENOUS
no
yes
yes
CEFUROXIME
ORAL
no
yes
yes
CIPROFLOXACIN
INTAOCCULAR
no
no
no
CIPROFLOXACIN
INTRACCCULAR
no
no
no
CIPROFLOXACIN
INTRAVENOUS
no
possible
yes
CIPROFLOXACIN
ORAL
no
possible
yes


Statistical Analysis Plan
Study 0112
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Confidential – Property of Theravance Biopharma, Inc.
Medication
Route of Administration
MRSA 
Coverage
MSSA 
Coverage
Systemic
CIPROFLOXACIN 
HYDROCHLORIDE
INTRAVENOUS
no
possible
yes
CLINDAMYCIN
INTRAVENOUS
possible
yes
yes
CLINDAMYCIN
ORAL
no
yes
yes
CLINDAMYCIN HYDROCHLORIDE
ORAL
yes
yes
yes
CLINDAMYCIN PHOSPHATE
INTRAVENOUS
no
yes
yes
CLOXACILLIN
INTRAVENOUS
no
yes
yes
DAPTOMYCIN
INTRAVENOUS
yes
yes
yes
DOXYCYCLINE
ORAL
possible
possible
yes
DOXYCYCLINE HYCLATE
ORAL
possible
possible
yes
DOXYCYCLINE MONOHYDRATE
ORAL
possible
possible
yes
DUOCID
INTRAVENOUS
no
yes
yes
ERTAPENEM
INTRAVENOUS
no
yes
yes
FLUCLOXACILLIN
OPHTHALMIC
no
no
no
FLUCONAZOLE
INTRAVENOUS
no
no
yes
FLUCONAZOLE
ORAL
no
no
yes
FOSFOMYCIN
INTRAVENOUS
yes
yes
yes
FOSFOMYCIN TROMETAMOL
ORAL
yes
yes
yes
GENTAMICIN
INTRAVENOUS
yes
yes
yes
GENTAMICIN
OPHTHALMIC
yes
yes
no
KETOCONAZOLE
ORAL
no
no
yes
LEVOFLOXACIN
INTRAVENOUS
no
yes
yes
LEVOFLOXACIN
ORAL
no
yes
yes
LINEZOLID
INTRAVENOUS
yes
yes
yes
LINEZOLID
ORAL
yes
yes
yes
MEROPENEM
INTRAVENOUS
no
yes
yes
MEROPENEM TRIHYDRATE
INTRAVENOUS
no
yes
yes
METHENAMINE HIPPURATE
ORAL
no
no
no
METRONIDAZOLE
INTRAVENOUS
no
no
yes
METRONIDAZOLE
ORAL
no
no
yes
MICONAZOLE NITRATE
TOPICAL
no
no
no
MINOCYCLINE
ORAL
possible
yes
yes
MOXIFLOXACIN
INTRAVENOUS
yes
yes
yes
NAFCILLIN
INTRAVENOUS
no
yes
yes


Statistical Analysis Plan
Study 0112
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telavancin
Page 71
Confidential – Property of Theravance Biopharma, Inc.
Medication
Route of Administration
MRSA 
Coverage
MSSA 
Coverage
Systemic
NITROFURANTOIN
ORAL
no
no
yes
OFLOXACIN
OPHTHALMIC
no
no
no
OXACILLIN
INTRAVENOUS
no
yes
yes
PENICILLIN NOS
INTRAVENOUS
no
possible
yes
PIPERACILLIN
INTRAVENOUS
no
yes
yes
PIPERACILLIN W/TAZOBACTAM
INTRAVENOUS
no
yes
yes
PRIMAXIN
INTRAVENOUS
no
yes
yes
RIFAMPICIN
INTRAVENOUS
yes
yes
yes
RIFAMPICIN
ORAL
yes
yes
yes
SPEKTRAMOX
INTRAVENOUS
no
yes
yes
SULTAMICILLIN
INTRAVENOUS
no
yes
yes
TAZOBACTAM
INTRAVENOUS
no
no
yes
TEICOPLANIN
INTRAVENOUS
yes
yes
yes
TELAVANCIN
INTRAVENOUS
yes
yes
yes
TOBRAMYCIN
INTRAVENOUS
yes
yes
yes
UNACID
INTRAVENOUS
no
yes
yes
VANCOMYCIN
INTRAVENOUS
yes
yes
yes
VANCOMYCIN
INTRAVITREAL
yes
yes
no
VANCOMYCIN
ORAL
no
no
no
VANCOMYCIN
TOPICAL
no
no
no


Statistical Analysis Plan
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Confidential – Property of Theravance Biopharma, Inc.
Appendix 4:
List of Coded Pathogens
Source: \\theravance\thrx\DEPARTMENTS\BIOMETRICS_2700\SAS_PE\Dev\TD-
6424\0112\csr\documents\pathogens_20180326
Pathogen
Pathogen Updated
ACINETOBACTER BAUMANII
ACINETOBACTER BAUMANNII
ACITENOBACTER BAUMANNII
ACTINOBACTER BAUMANNII
AEROCOCCUS VIRIDANS
ASPERGILLUS NIGER
CANDIDA ALBICANS
CANDIDA GLABRATA (TORULOPSIS GLABRATE)
CITROBACTER FREUNDI
CITROBACTER KOSERI
CLOSTRIDIUM DIFFICILE
COAG NEGATIVE STAPH (S. EPIDERMIDIS)
ENTEROBACTER CLOACAE SPECIES COMPLEX
ENTEROBACTER CLOACIAE
ENTEROBACTER CLOCAE
ENTEROBACTER SPECIES
ENTEROCOCCUS FAECALIS
ENTEROCOCCUS FAECIUM
ESCHERICHIA COLI
GROUP A STREP (S. AGALACTIAE)
GROUP B STREP (S. PYOGENES)
GROWTH
KLEBSIELLA PNEUMONIA
MRSA
MSSA
PROBABLE PROPIONIBACTERIUM SPECIES
PROTEUS MIRABILIS
PSEUDOMONAS AERUGINOSA
ROTHIA SP. (ROTHIA TERRAE)
S. AUREUS SUSCEPTIBILITY UNKNOWN
SERRATIA MARCESCENS
SPHINGOMONAS PAUCIMOBILIS
STAPH LUGDUNESIS
STAPH SAPROPHYTICUS
STAPHYLOCOCCUS AUREUS


Statistical Analysis Plan
Study 0112
Version 1.0, 26APR2018
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Confidential – Property of Theravance Biopharma, Inc.
Pathogen
Pathogen Updated
STAPHYLOCOCCUS EPIDERMIDIS
STAPHYLOCOCCUS HAEMOLYTICUS
STAPHYLOCOCCUS HOMINIS
STAPHYLOCOCCUS HOMINIS SS. HOMINIS
STAPHYLOCOCCUS HOMINIS SSP HOMINIS
STAPHYLOCOCCUS WARNERI
STREPTOCOCCUS AGALACTIAE
STREPTOCOCCUS ANGINOSUS
STREPTOCOCCUS GALLOLYTICUS
VIRIDANS GROUP STREPTOCOCCUS
YEAST


Statistical Analysis Plan
Study 0112
Version 1.0, 26APR2018
telavancin
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Confidential – Property of Theravance Biopharma, Inc.
Appendix 5:
Coding Categories for Reason of Failure
REASON
ORIGINAL 
PROTOCOL
Map to
New Foci of Metastatic S Aureus Infect
Amendment 3
New Foci of Metastatic S Aureus Infection after Day 8
Subj Did Not Meet All Criteria
Amendment 1
Did Not Meet All Criteria for Clinical Success
Subj Did Not Meet All Criteria
Amendment 2
Did Not Meet All Criteria for Clinical Success
Subj Did Not Meet All Criteria
Amendment 3
Did Not Meet All Criteria for Clinical Success
Subj Discon SD Against Medical Advice
Amendment 3
Discontinued Study Drug against Medical Advice
Subj Discontinued SD due to AE
Amendment 1
Discontinued Study Drug due to Adverse Event and Required Further Antibacterial Therapy for S 
Aureus Infection before or at This Visit
Subj Discontinued SD due to AE
Amendment 2
Discontinued Study Drug due to Adverse Event and did Not Complete the Minimum Assigned 
Duration of Treatment
Subj Discontinued SD due to AE
Amendment 3
Discontinued Study Drug due to Treatment-emergent, Drug-related Adverse Event
Subj Rcvd Pot Effective Non-study Anti
Amendment 2
Received Potentially Effective Non-study Antibiotic before or at This Visit
Subj Rcvd Pot Effective Non-study Anti
Amendment 3
Received Potentially Effective Non-study Antibiotic before or at This Visit
Subj Req Further Study Anti Therapy
Amendment 2
Required Further Study Antibacterial Therapy for the S. aureus Infection Beyond Assigned 
Treatment Duration
Subj Req Further Study Anti Therapy
Amendment 3
Required Further Study Antibacterial Therapy for the S. aureus Infection beyond Assigned 
Treatment Duration, except Oral Prophylaxis
Subj Switch Antibiotic Lack of CR or AE
Amendment 2
Switched Study Antibiotic due to Lack of Clinical Response or Adverse Event
Subj Switch Antibiotic Lack of CR or AE
Amendment 3
Switched Study Antibiotic due to Lack of Clinical Response or an Adverse Event
Subject Remains Lost to Follow-up
Amendment 3
Remains Lost to Follow-up
Subject Withdrew Consent
Amendment 2
Withdrew Consent


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Appendix 6:
Summary of TFLs
Number
Title
Safety
mAT+
14.1.1.1
Enrollment By Investigator- All Randomized
NA
NA
14.1.1.3
Analysis Populations
NA
NA
14.1.1.4
Subject Disposition
X
14.1.2.1
Demographics And Baseline Characteristics
X
14.1.2.2
Classification Of Infection Type
X
14.1.2.3
Summary Of Baseline Clinical Characteristics
X
14.1.2.4
Summary Of Pathogens Isolated From Blood Cultures By The Site
X
14.1.2.5
Summary Of Pathogens Isolated From Blood Cultures By Central Lab
X
14.1.2.6
Summary Of Pathogens Isolated From Blood Cultures By The Site Or Central Lab
X
14.1.2.7
Summary Of Signs And Symptoms Of Bacteremia At Enrollment
X
14.1.2.8
Summary Of The Characteristics Of Bacteremia At Enrollment
X
14.1.2.9
Summary Of Risk Factors For Bacteremia
X
14.1.2.10
Summary of the Baseline modified APACHE II Scores And Components
X
14.1.3.1
Summary Of Select Medical History
X
14.1.3.2
Medical History
X
14.2.1.1
Summary Of Adjudicated Clinical Outcome At Test-Of-Cure
X
14.2.1.2
Summary Of Adjudicated Clinical Outcome At Test-Of-Cure By Analysis Population
X
14.2.1.3
Summary Of Adjudicated Clinical Outcome At Test-Of-Cure By Subgroups (Mat UCB, CB, and RIE)
X
14.2.1.4
Summary Of Adjudicated Clinical Outcome At Test-Of-Cure By Subgroups (ME UCB, CB, and RIE)
X
14.2.1.5
Reasons For Failure Or Indeterminate In Clinical Response At Test-Of-Cure (Investigator-Assessed)
X


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Number
Title
Safety
mAT+
14.2.2.1
Summary Of Adjudicated Clinical Response At End Of Treatment 
X
14.2.2.2
Summary Of Adjudicated Clinical Response At End Of Treatment By Analysis Population
X
14.2.2.3
Summary Of Adjudicated Clinical Response At End Of Treatment By Subgroups (Mat UCB, CB, and RIE)
X
14.2.2.4
Summary Of Adjudicated Clinical Response At End Of Treatment By Subgroups (Me UCB, CB, and RIE)
X
14.2.2.5
Reasons For Failure Or Indeterminate In Clinical Response At End Of Treatment (Investigator-Assessed)
X
14.2.3.1
Summary Of Investigator Clinical Outcome At Test-Of-Cure
X
14.2.3.2
Summary Of Investigator Clinical Outcome At Test-Of-Cure By Analysis Population
X
14.2.3.3
Summary Of Investigator Clinical Outcome At Test-Of-Cure By Subgroups (Mat UCB, CB, and RIE)
X
14.2.3.4
Summary Of Investigator Clinical Outcome At Test-Of-Cure By Subgroups (ME UCB, CB, and RIE)
X
14.2.4.1
Summary Of Investigator Clinical Response At End Of Treatment
X
14.2.4.2
Summary Of Investigator Clinical Response At End Of Treatment By Analysis Population
X
14.2.4.3
Summary Of Investigator Clinical Response At End Of Treatment By Subgroups (Mat UCB, CB, and RIE)
X
14.2.4.4
Summary Of Investigator Clinical Response At End Of Treatment By Subgroups (Me UCB, CB, and RIE)
X
14.2.5.1
Summary Of The Time To Initial Clearance Of S. Aureus Bacteremia
X
14.2.6.1
Summary Of The 28-Day Mortality
X
14.2.6.2.1
Summary Of The 28-Day Mortality by Baseline CrCL <50
X
14.2.6.2.2
Summary Of The 28-Day Mortality by Baseline CrCL >=50
X
14.3.1.1
Study Drug Exposure And Compliance
X
14.3.1.2
Study Drug Exposure And Compliance by Infection Type
X
14.3.3.1
Overall Summary Of Adverse Events
X
14.3.3.2
Treatment-Emergent Adverse Events By System Organ Class And Preferred Term
X


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Number
Title
Safety
mAT+
14.3.3.3
Treatment-Emergent Adverse Events By Preferred Term
X
14.3.3.4
Treatment-Emergent Adverse Events By System Organ Class And Preferred Term Occurring In More Than 5% 
Of Study Population
X
14.3.3.5
Treatment-Emergent Adverse Events By System Organ Class, Preferred Term And Severity
X
14.3.3.6
Moderate Or Severe Treatment-Emergent Adverse Events By System Organ Class And Preferred Term
X
14.3.3.7
Serious Adverse Events
X
14.3.3.8
Deaths During Or Post Study
X
14.3.3.9
Drug-Related Treatment-Emergent Adverse Events By System Organ Class And Preferred Term
X
14.3.3.10
Drug-Related Treatment-Emergent Adverse Events By System Organ Class And Preferred Term And Severity
X
14.3.3.11
Moderate Or Severe Drug-Related Treatment-Emergent Adverse Events By System Organ Class And 
Preferred Term
X
14.3.3.12
Drug-Related Serious Adverse Events
X
14.3.3.13
Adverse Events Leading To Premature Study Drug Discontinuation
X
14.3.3.14
Adverse Events Leading To Temporary Interruption Of Study Drug
X
14.3.3.15
Renal Adverse Events
X
14.3.4.1.1
Hematology
X
14.3.4.2.1
Serum Chemistry
X
14.3.4.3.1
Urinalysis
X
14.3.4.1.2
Hematology: Shift From Baseline
X
14.3.4.2.2
Serum Chemistry: Shift From Baseline
X
14.3.4.3.2
Urinalysis: Shift From Baseline
X
14.3.4.4.1
Summary Of Change From Baseline Of Central Lab Creatinine And  Creatinine Clearance By Time Points
X


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Number
Title
Safety
mAT+
14.3.4.4.2
Summary Of Last And Worst Creatinine Clearance Change From Baseline
X
14.3.5.1
Vital Signs – Heart Rate
X
14.3.5.2
Vital Signs – Respiration Rate
X
14.3.5.3
Vital Signs – Systolic Blood Pressure
X
14.3.5.4
Vital Signs – Diastolic Blood Pressure
X
14.3.6.1
Prior Systemic Antimicrobials
X
14.3.6.2
Concomitant Systemic Antimicrobials
X
14.3.6.3
Post Study Drug Systemic Antimicrobials
X
14.3.6.4
Nephrotoxic Medications Prior to Study Drug
X
14.3.6.5
Concomitant Nephrotoxic Medications 
X
14.3.6.6
Post Study Drug Nephrotoxic Medications
X
14.3.6.7
Prior Medications
X
14.3.6.8
Concomitant Medications
X
14.3.6.9
Post Study Drug Medications
X
14.3.7.1.1
Electrocardiogram Summary: HR
X
14.3.7.1.2
Electrocardiogram Summary: PR
X
14.3.7.1.3
Electrocardiogram Summary: QRS
X
14.3.7.1.4
Electrocardiogram Summary: QT
X
14.3.7.1.5
Electrocardiogram Summary: QTcB
X
14.3.7.1.6
Electrocardiogram Summary: QTcF
X
14.3.7.1.7
Electrocardiogram Summary: RR
X


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Number
Title
Safety
mAT+
14.3.7.2
Electrocardiogram Threshold Summary
X 
14.3.7.3
Electrocardiogram Outlier Summary by Visit and Time Point
X 
14.3.8.1.1
Echocardiogram: Left Atrial and Ventricular Volumes and LVEF 
X 
14.3.8.1.2
Echocardiogram: LVOT and HR
X 
14.3.8.1.3
Echocardiogram: Regurgitation and Vegetation
X 
14.3.8.1.4
Echocardiogram: Quality  Evaluation
X 
14.3.8.1.5 
Echocardiogram Endocarditis Assessment Through Day 8
X 


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Listings
Number
Title
Population
16.2.1.1
Disposition and Analysis Sets 
All Randomized Subjects
16.2.2.1
Protocol Versions 
All Randomized Subjects
16.2.2.2 
Major Protocol Deviations
All Randomized Subjects
16.2.4.1.1
Clinical Outcomes
AT
16.2.7.1
Adverse Events 
All Randomized Subjects
16.2.7.2.1
Renal Adverse Events
Safety
16.2.7.2.2
Renal Replacement During Study
Safety
16.2.4.2.4.1
Demographics 
AT
16.2.4.2.4.2 
Relevant Medical History
AT
16.2.4.2.4.3 
General and Relevant Medical History
AT
16.2.4.2.4.4 
Baseline modified APACHE II Scores and Components
AT
16.2.5.3.2
Prior and Concomitant Medications
Safety
16.2.5.3.3
Prior and Concomitant Nephrotoxic Medications
Safety
16.2.5.3.4 
Antimicrobial Therapy
All Randomized Subjects
16.2.6.2.1
Microbiology: Blood Cultures
AT
16.2.6.2.2
Microbiology: Specimens Other Than Blood Cultures
Safety
16.2.8.1.1.1
Central Laboratory Tests: Hematology: Part 1
Safety
16.2.8.1.1.2
Central Laboratory Tests: Hematology: Part 2
Safety
16.2.8.1.1.3
Central Laboratory Tests: Hematology: Part 3
Safety
16.2.8.1.1.4
Central Laboratory Tests: Hematology: Part 4
Safety
16.2.8.1.1.5
Central Laboratory Tests: Hematology: Part 5
Safety
16.2.8.1.1.6
Local Laboratory Tests: Hematology: White Blood Cells
Safety
16.2.8.1.1.7
Central Lab Hematology: Abnormal Differentials
Safety


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Number
Title
Population
16.2.8.1.2.1
Central Laboratory Tests: Serum Chemistry: Part 1
Safety
16.2.8.1.2.2
Central Laboratory Tests: Serum Chemistry: Part 2
Safety
16.2.8.1.2.3
Central Laboratory Tests: Serum Chemistry: Part 3
Safety
16.2.8.1.2.4
Central Laboratory Tests: Creatine Kinase, C-reactive Protein, and Interleukin 10 
Safety
16.2.8.1.2.5
Central Laboratory Tests: Creatinine and Creatinine Clearance
Safety
16.2.8.1.2.6
Local Laboratory Tests: Creatinine and Creatinine Clearance
Safety
16.2.8.1.3.1
Central Laboratory Urinalysis: Qualitative
Safety
16.2.8.1.3.2
Central Laboratory Urinalysis: Quantitative
Safety
16.2.8.1.3.3
Central Laboratory Urinalysis: Other Findings
Safety
16.2.9.1.1
Vital Signs
Safety
16.2.9.1.2
Temperature Log
Safety
16.2.11.1
12-lead Safety Electrocardiogram 
Safety
16.2.11.2
12-lead Safety Electrocardiogram QTcF >500 msec or QTcF Increase >60 msec 
Safety
16.2.12.1
Echocardiogram: Left Atrial and Ventricular Volumes and LVEF 
Safety
16.2.12.2
Echocardiogram: LVOT and HR
Safety
16.2.12.3
Echocardiogram: Regurgitation and Vegetation Part 1 of 2
Safety
16.2.12.4
Echocardiogram: Regurgitation and Vegetation Part 2 of 2
Safety
16.2.12.5
Echocardiogram: Quality Evaluation and Comment
Safety
16.2.12.6
Echocardiogram Endocarditis Assessment Through Day 8
Safety


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Figures
Number
Title
Figure Type
ITT
PP
Safety
15.2.1.1.1
Kaplan-Meier Survival Function: Time to initial clearance of S. aureus bacteremia with censoring at 
Day 8
X 
X 
15.2.1.1.2
Kaplan-Meier Survival Function: Time to initial clearance of S. aureus bacteremia with no censoring
X 
X 
15.2.1.2 
Kaplan-Meier Survival Function: Days from Last Treatment Day to Test of Cure Visit
X 
X 
15.2.1.3 
Kaplan-Meier Survival Function: 28-day all-cause mortality
X 
X 
X 
15.2.1.3.1
Kaplan-Meier Survival Function: 28-day all-cause mortality by baseline CrCL <50
X 
X 
X 
15.2.1.3.2
Kaplan-Meier Survival Function: 28-day all-cause mortality by baseline CrCL >=50
X 
X 
X