Dalbavancin as an Option for Treatment of S. Aureus Bacteremia (DOTS): A Phase 2b, Multicenter, Randomized, Open-Label, Assessor-Blinded Superiority Study to Compare the Efficacy and Safety of Dalbavancin to Standard of Care Antibiotic Therapy for the Completion of Treatment of Patients With Complicated S. Aureus Bacteremia
Phase: PHASE2
Conditions: Staphylococcal Bacteraemia
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

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Dalbavancin as an Option for Treatment of S. aureus Bacteremia 
(DOTS): A Phase 2b, Multicenter, Randomized, Open-Label, Assessor-
Blinded Superiority Study to Compare the Efficacy and Safety of 
Dalbavancin to Standard of Care Antibiotic Therapy for the 
Completion of Treatment of Patients with Complicated S. aureus 
Bacteremia 
DMID Protocol Number: 20-0002 
DMID Funding Mechanism: UM1AI104681 
Pharmaceutical Support: Allergan, a subsidiary of AbbVie 
IND Sponsor: National Institutes of Health (NIH)/National Institute of Allergy and Infectious 
Diseases (NIAID)/Division of Microbiology and Infectious Diseases (DMID) 
Lead Principal Investigator: Thomas L. Holland, M.D.  
DMID Clinical Project Manager: Maureen Mehigan, RN 
 
Draft or Version Number:  v6.0 
 
 
29 Sep 2023 
 
 
 
 

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STATEMENT OF ASSURANCE 
Each Institution will hold a current Federal Wide Assurance (FWA) issued by the Office of Human 
Research Protections (OHRP) for federally-funded human subjects research.  Each FWA will 
designate at least one Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
registered with OHRP, for which the research will be reviewed and approved by the IRB/IEC and 
will be subject to continuing review [45 CFR 46.103(b)]. The IRB/IEC designated under an FWA 
may include an institution’s IRB/IEC, an independent IRB/IEC, or an IRB/IEC of another institution 
after establishing a written agreement with that other institution. 
 

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STATEMENT OF COMPLIANCE 
The study trial will be carried out in accordance with Good Clinical Practice (GCP) and as required 
by the following: 
• United States Code of Federal Regulations (CFR) 45 CFR Part 46: Protection of Human Subjects 
• Food and Drug Administration (FDA) Regulations, as applicable: 21 CFR Part 50 (Protection of 
Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical Investigators), 21 CFR Part 
56 (Institutional Review Boards), 21 CFR Part 11, and 21 CFR Part 312 (Investigational New 
Drug Application), 21 CFR 812 (Investigational Device Exemptions) 
• International Conference on Harmonisation: Good Clinical Practice (ICH E6); 62 Federal 
Register 25691 (1997); and future revisions 
• Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research, Report of the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research 
• National Institutes of Health (NIH) Office of Extramural Research, Research Involving Human 
Subjects, as applicable 
• National Institute of Allergy and Infectious Diseases (NIAID) Clinical Terms of Award, as 
applicable 
• Applicable Federal, State, and Local Regulations and Guidance 

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SIGNATURE PAGE 
The signature below provides the necessary assurance that this trial will be conducted according to 
all stipulations of the protocol, including all statements regarding confidentiality, and according to 
local legal and regulatory requirements and applicable US federal regulations and ICH E6 Good 
Clinical Practice (GCP) guidelines. 
I agree to conduct the study in compliance with GCP and applicable regulatory requirements. 
I agree to conduct the study in accordance with the current protocol and will not make changes to the 
protocol without obtaining the sponsor’s approval and IRB/IEC approval, except when necessary to 
protect the safety, rights, or welfare of subjects. 
Site Investigator Signature: 
 
Signed: 
 
Date: 
 
 
Name 
Title 
 
 
 
 

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TABLE OF CONTENTS 
STATEMENT OF ASSURANCE ...................................................................................................2 
STATEMENT OF COMPLIANCE .................................................................................................3 
SIGNATURE PAGE .......................................................................................................................4 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF TABLES .........................................................................................................................10 
LIST OF FIGURES .......................................................................................................................11 
LIST OF ABBREVIATIONS ........................................................................................................12 
PROTOCOL SUMMARY .............................................................................................................15 
 
KEY ROLES.........................................................................................................................21 
 
BACKGROUND AND SCIENTIFIC RATIONALE ..........................................................22 
 
Background .................................................................................................................22 
 
Scientific Rationale .....................................................................................................24 
 Purpose of Study ............................................................................................24 
 Study Population ............................................................................................25 
 Selection of Dose ...........................................................................................25 
 
Potential Risks and Benefits .......................................................................................28 
 Potential Risks ...............................................................................................29 
2.3.1.1 
Dalbavancin ......................................................................................29 
2.3.1.2 
Cefazolin ...........................................................................................29 
2.3.1.3 
Nafcillin ............................................................................................29 
2.3.1.4 
Oxacillin............................................................................................30 
2.3.1.5 
Vancomycin ......................................................................................30 
2.3.1.6 
Daptomycin .......................................................................................31 
2.3.1.7 
Risks Associated with Intravenous Access .......................................31 
 Potential Benefits ...........................................................................................31 
 
STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR OUTCOME MEASURES .....32 
 
Study Design Description ...........................................................................................32 

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Study Objectives .........................................................................................................32 
 Primary ...........................................................................................................32 
 Secondary .......................................................................................................32 
 Exploratory ....................................................................................................33 
 
Study Endpoints or Outcome Measures .....................................................................34 
 Primary ...........................................................................................................34 
 Secondary .......................................................................................................35 
 Exploratory ....................................................................................................36 
 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT .........................................37 
 
Study Product Description ..........................................................................................37 
 Formulation, Packaging, and Labeling ..........................................................37 
 Product Storage and Stability .........................................................................38 
 
Acquisition/Distribution .............................................................................................38 
 
Dosage/Regimen, Preparation, Dispensing and Administration of Study 
Intervention/Investigational Product.........................................................................38 
 
Pre-determined Modification of Study Intervention/Investigational Product for an 
Individual Subject .....................................................................................................41 
 
Accountability Procedures for the Study Intervention/Investigational Product(s) .....41 
 
SELECTION OF SUBJECTS AND STUDY ENROLLMENT AND WITHDRAWAL ....42 
 
Eligibility Criteria .......................................................................................................42 
 Subject Inclusion Criteria...............................................................................42 
 Subject Exclusion Criteria .............................................................................43 
 
Withdrawal from the Study, Discontinuation of Study Product, or Study Termination44 
 Withdrawal from the Study or Discontinuation of the Study Product ...........44 
 Subject Replacement ......................................................................................46 
 Study Termination .........................................................................................46 
 
STUDY PROCEDURES ......................................................................................................47 
 
Induction Period: Visit 0 (Pre-screening, Day -10 to Day 1) .....................................47 
 
Screening: Visit 1 (Day -1 to Day 1) ..........................................................................47 
 
Open-label Treatment Period, Planned Study Visits ..................................................48 

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 Baseline (Randomization): Visit 2 (Day 1) ...................................................48 
 Visit 3 (Day 8 ± 1 day)...................................................................................49 
 Visit 4 (Day 22 ± 2 days) ...............................................................................50 
 Visit 5 (Day 42 ± 3 days) ...............................................................................50 
 Test of Cure: Visit 6 (Day 70 ± 7 days) .........................................................51 
 Visit 7 (Day 180 ± 14 days – only for subjects with osteomyelitis) ..............51 
 Final Study Visit ............................................................................................52 
 Early Termination Visit .................................................................................52 
 
Unscheduled Study Visits ...........................................................................................53 
 
Protocol Deviations ....................................................................................................53 
 
DESCRIPTION OF CLINICAL AND LABORATORY EVALUATIONS .......................54 
 
Clinical Evaluations ....................................................................................................54 
 Research Procedures ......................................................................................54 
 Assessment of Concomitant Medications/Treatments Other Than Study Product
 ........................................................................................................................55 
 Assessment of Subject Compliance with Study Intervention/Investigational 
Product/Investigational Device ......................................................................56 
 Non-Research Standard of Care .....................................................................56 
 
Laboratory Evaluations ...............................................................................................57 
 Clinical Laboratory Evaluations ....................................................................57 
 Research Assays .............................................................................................57 
7.2.2.1 
Laboratory Specimen Preparation, Handling, and Storage ...............58 
7.2.2.2 
Laboratory Specimen Shipping ........................................................58 
 
ASSESSMENT OF SAFETY ...............................................................................................59 
 
Assessing and Recording Safety Parameters ..............................................................59 
 Adverse Events (AEs) ....................................................................................59 
8.1.1.1 
Adverse Events Grading ...................................................................60 
 Serious Adverse Events (SAEs) .....................................................................61 
 
Specification of Safety Parameters .............................................................................62 
 Adverse Events of Special Interest (AESIs) ..................................................63 

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Reporting Procedures ..................................................................................................63 
 Reporting Serious Adverse Events ................................................................63 
 Regulatory Reporting for Studies Conducted Under DMID Sponsored IND64 
 Reporting of Pregnancy .................................................................................65 
 
Type and Duration of Follow-up of Subjects after Adverse Events ...........................65 
 
Halting Rules ..............................................................................................................65 
 Study Halting Criteria ....................................................................................65 
 Individual Halting Rules ................................................................................66 
 
Safety Oversight .........................................................................................................66 
 Data and Safety Monitoring Board (DSMB) .................................................66 
 
HUMAN SUBJECTS PROTECTION .................................................................................68 
 
Institutional Review Board/Independent Ethics Committee ......................................68 
 
Informed Consent Process ..........................................................................................68 
 Other Informed Consent Procedures ..............................................................70 
 
Exclusion of Women, Minorities, and Children (Special Populations) ......................71 
 
Subject Confidentiality ...............................................................................................71 
 
Certificate of Confidentiality ......................................................................................71 
 
Costs, Subject Compensation, and Research Related Injuries ...................................72 
 
STATISTICAL CONSIDERATIONS .................................................................................73 
 Study Hypotheses .......................................................................................................73 
 Sample Size Considerations .......................................................................................74 
 Treatment Assignment Procedures .............................................................................74 
 Randomization Procedures ............................................................................74 
 Masking Procedures .......................................................................................75 
 Planned Interim Analyses ...........................................................................................75 
 Interim Safety Review ...................................................................................75 
 Interim Futility Review ..................................................................................75 
 Final Analysis Plan .....................................................................................................76 
 Study Populations ..........................................................................................76 

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 Patient Disposition .........................................................................................76 
 Demographics and Other Baseline Characteristics ........................................77 
 Extent of Exposure and Treatment Compliance ............................................77 
 Efficacy Analysis ...........................................................................................77 
10.5.5.1 Primary Efficacy Analysis ................................................................77 
10.5.5.2 Secondary Efficacy Outcomes ..........................................................78 
10.5.5.3 Additional Efficacy Parameters ........................................................78 
 Safety Analyses ..............................................................................................79 
10.5.6.1 Adverse Events .................................................................................79 
10.5.6.2 Clinical Laboratory Parameters, and Vital Signs..............................79 
10.5.6.3 Exploratory Dalbavancin Plasma Pharmacokinetic Analyses ..........80 
 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ..............83 
 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................84 
 
DATA HANDLING AND RECORD KEEPING ................................................................85 
 Data Management Responsibilities ............................................................................85 
 Data Coordinating Center/Biostatistician Responsibilities ........................................85 
 Data Capture Methods ................................................................................................85 
 Types of Data ..............................................................................................................85 
 Study Records Retention ............................................................................................86 
 
CLINICAL MONITORING .................................................................................................87 
 
PUBLICATION POLICY ....................................................................................................88 
 
LITERATURE REFERENCES ............................................................................................89 
 
APPENDICES ......................................................................................................................92 
 
Schedule of Events............................................................................93 
 
Definitions ........................................................................................96 
 
ARLG Bloodstream Infection Quality of Life Measure .................100 
 
 

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LIST OF TABLES 
Table 1: Treatment Arms ...............................................................................................................19 
Table 2: Activity of Dalbavancin Against Gram-Positive Pathogens Collected in 2014 US 
Surveillance ................................................................................................................23 
Table 3: Activity of Dalbavancin Against Gram –Positive Pathogens Collected in 2014 EU 
Surveillance ................................................................................................................23 
Table 4: Substitution Patterns for Dalbavancin API Homologs ....................................................37 
Table 5: Acceptable SOC Antibiotics ............................................................................................40 
 
 

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LIST OF FIGURES 
Figure 1: Schematic of Study Design ............................................................................................20 
Figure 2: Simulated Mean Plasma PK Profile for Dalbavancin (Source: Allergen data on 
file) ..............................................................................................................................27 
Figure 3: Dalbavancin Concentration Time Course for a Typical Subject Under the Proposed 
Regimen (Source: Allergen data on file) ....................................................................28 
 
 

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LIST OF ABBREVIATIONS 
ADL 
Activity of Daily Living 
AE 
Adverse Event/Adverse Experience 
AESI 
Adverse Events of Special Interest 
AUC 
Area Under Curve 
CNS 
Central Nervous System 
CE 
Clinically Evaluable 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CMS 
Clinical Material Services 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DILI 
Drug-Induced Liver Injury 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, 
NIH, DHHS 
DOOR 
Desirability of Outcome Ranking 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
FWA 
Federal Wide Assurance 
GCP 
Good Clinical Practice 
HEOR 
Health Economics and Outcomes Research 
HLGT 
High Level Group Term 

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HIPAA 
Health Insurance Portability and Accountability Act 
ICD 
Implantable Cardioverter Defibrillator 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IE 
Infective Endocarditis  
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
Minimum Inhibitory Concentration 
mITT 
Modified Intent to Treat 
MM 
Medical Monitor 
MOP 
Manual of Procedures 
MRSA 
Methicillin-resistant Staphylococcus aureus 
MSSA 
Methicillin-sensitive Staphylococcus aureus 
N 
Number (typically refers to subjects) 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, 
DHHS 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PCS 
Potentially Clinically Significant 
PID 
Patient Identification 
PD 
Pharmacodynamic 
PHI 
Protected Health Information 
PI 
Principal Investigator 

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PK 
Pharmacokinetics 
PWID 
Persons Who Inject Drugs 
QA 
Quality Assurance 
QC 
Quality Control 
QoL 
Quality of Life 
SAE 
SUSAR                                  
Serious Adverse Event/Serious Adverse Experience 
Suspected Unexpected Serious Adverse Reaction   
SD 
Standard Deviation 
SOC 
Standard of Care 
TOC 
Test of Cure 
ULN 
Upper Limit of Normal 
US 
United States 
 
 
 
 

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PROTOCOL SUMMARY 
 
Title: 
Dalbavancin as an Option for Treatment of S. aureus Bacteremia 
(DOTS): A Phase 2b, Multicenter, Randomized, Open-Label, 
Assessor-Blinded Superiority Study to Compare the Efficacy and 
Safety of Dalbavancin to Standard of Care Antibiotic Therapy 
for the Completion of Treatment of Patients with Complicated S. 
aureus Bacteremia  
Design of the Study: 
Multicenter, randomized, open-label, assessor-blinded, 
superiority, active-controlled, parallel-group study 
Study Phase: 
2b 
Study Population: 
200 adult subjects (≥ 18 years old) diagnosed with complicated 
S. aureus bacteremia including definite or possible right-sided 
infective endocarditis (IE) treated with effective antibiotic 
therapy for at least 72 hours (maximum 10 days) and with 
subsequent clearance of bacteremia prior to randomization to 
study treatment 
Number of Sites: 
Approximately 20 
 
Description of Study 
Product or Intervention: 
• Dalbavancin 1500 mg intravenously (IV) over 30 (± 10) 
minutes on Day 1 and 1500 mg intravenously (IV) over 30 (± 
10) minutes on Day 8 (if creatinine clearance ≥ 30 mL/min or 
if on regular hemodialysis or peritoneal dialysis) 
• Dalbavancin 1125 mg IV over 30 (±10) minutes on Day 1 
and Dalbavancin 1125 mg IV over 30 (±10) minutes on Day 
8 (if creatinine clearance < 30 mL/min and not receiving 
regular hemodialysis or peritoneal dialysis)  
Study Objectives: 
Primary: 

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• To compare the Desirability of Outcome Ranking (DOOR) at 
Day 70 of dalbavancin to that of standard of care antibiotic 
therapy used to consolidate therapy for the treatment of 
subjects with complicated S. aureus bacteremia in the intent-
to-treat (ITT) population. 
Secondary: 
• To compare the clinical outcomes of dalbavancin with the 
standard of care antibiotic therapy at day 70 in the modified 
intent-to-treat (mITT) population.  
• To compare the safety of dalbavancin with that of the 
standard of care treatment in the mITT.  
• To compare each individual component of the DOOR 
outcome by treatment arm, in the ITT population. 
Exploratory: 
• To compare the clinical outcomes of dalbavancin with the 
standard of care antibiotic therapy at day 70 in the clinically 
evaluable (CE) population.   
• To compare the DOOR endpoint of subjects on dalbavancin 
with that of subjects receiving standard of care antimicrobial 
therapy at day 42 in the ITT, mITT, and CE populations.   
• To compare the clinical and microbiologic outcomes of 
dalbavancin with the standard of care antibiotic therapy at 
day 42 in ITT, mITT and CE populations. 
• To compare clinical and microbiologic outcomes of 
dalbavancin with standard of care antibiotic therapy between 
clinically important subgroups, including a) those with 
MSSA versus MRSA; b) persons who inject drugs (PWID) vs 
non-PWID; c) those who received infectious disease 
consultation vs those who did not; d) underlying site of 
infection (endovascular, bone and joint, skin, pulmonary); e) 

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subjects with immune-suppression1; f) divided by duration of 
initial bacteremia in the ITT, mITT, and CE populations  
• To compare Quality of Life (QoL) of subjects on dalbavancin 
with that of subjects receiving standard of care antibiotic 
therapy at Baseline, Day 42, and Day 70, in the ITT, mITT, 
and CE populations 
• To characterize the population pharmacokinetic profile for 
dalbavancin administered via a 2-dose regimen (1500 mg on 
day 1 and day 8, renally adjusted when appropriate) in 
patients with Staphylococcus aureus bacteremia  
• To assess patient-level and clinical covariates associated with 
dalbavancin pharmacokinetics in patients with 
Staphylococcus aureus bacteremia 
• Examine the association between individualized plasma 
concentration profiles and clinical and microbiologic 
outcomes at day 42 and TOC  
• Examine the association between individualized plasma 
concentration profiles and occurrence of adverse drug events, 
including AST/ALT elevations >3X upper limit of normal 
• Examine the association between individualized plasma 
concentration profiles and late recurrence risk among the 
subset of patients with osteomyelitis and a 6 month follow-up 
visit 
Duration of Individual 
Subject Participation: 
 
Approximately 70 ± 7 days, with a late post-treatment follow-up 
visit for the subset of patients with osteomyelitis at 6 months 
 
 
1 Defined as: On chemotherapy or immunotherapy for active hematologic malignancy expected to cause ANC < 500 
cells/mm3 lasting > 7 days during the study period, chronic high dose oral steroids (equivalent of ≥ 20 mg prednisolone 
per day for or equivalent, for >2 weeks within the last month), HIV infection with a CD4 cell count < 100 cells/mm3 
based on last known measurement or patient-reported value 

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Estimated Time to Last 
Subject/Last Study Day: 
Approximately 30 months, from site activation to the last 
subject’s last study day. 
 
 

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Table 1: Treatment Arms 
Dalbavancin  
100 
subjects 
Dalbavancin 1500 mg IV over 30 (± 10) minutes on Day 1 and 
1500 mg IV over 30 (± 10) minutes on Day 8, renally dose-
adjusted to 1125 mg for subjects with CrCl <30 and not on 
dialysis 
Standard of 
Carea 
100 
subjects 
• Methicillin-sensitive Staphylococcus aureus (MSSA): 
nafcillin (2 g IV q4h × 4-6 weeks)b OR oxacillin (2 g IV Q4h 
x 4-6 weeks)b OR cefazolin (2 g IV q8h × 4-6 weeks) b,c  
• Methicillin-resistant Staphylococcus aureus (MRSA): 
vancomycin (dose per local standard of care × 4-6 weeks) 
OR daptomycin (6-10 mg/kg IV daily × 4-6 weeks)c 
aRenally dose-adjusted as appropriate, per local standard of care 
bAs applicable per site standard of care, beta-lactams may be administered at an equivalent dose via 
continuous IV infusion (e.g., nafcillin 12g/24h IV continuous) 
cIf there are extenuating circumstances in which preferred standard of care antibiotics cannot be 
used, for example complex allergy history, then an alternative antibiotic may be used after 
discussion with the protocol PIs and DMID Medical Officer 
 
 
 

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Figure 1: Schematic of Study Design 
 
 
 
  
 

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KEY ROLES 
Lead Principal 
Investigator: 
 
Thomas L. Holland, MD 
Associate Professor of Medicine, Duke University 
155 Hanes House, Box 102359 
Duke University Medical Center 
Durham, NC, 27710 
Email: thomas.holland@duke.edu 
 
DMID Clinical Project 
Manager: 
Maureen Mehigan, RN 
5601 Fishers Lane,  
Rockville MD 20852 
Phone: 1 (240) 627-3317 
Email: mmehigan@niaid.nih.gov 
 
Statistical and Data 
Coordinating Center: 
 
The Emmes Company, LLC 
401 N. Washington St. Suite 700 
Rockville, MD  20850 
Email: arlg_studies@emmes.com 
Phone: 1 (301) 251-1161 
 
 

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BACKGROUND AND SCIENTIFIC RATIONALE 
 
Background  
Staphylococcus aureus bacteremia is a life-threatening infection with case fatality rates ranging from 
15-50% (van Hal 2012).  S. aureus bacteremia is also a leading cause of IE in industrialized nations 
(Tong 2015) and is associated with in-hospital mortality rates ranging from 16% to 25% (Thuny 
2005, Murdoch 2009, Sy 2010, Selton-Suty 2012). Standard treatment of complicated S. aureus 
bacteremia and IE requires prolonged IV antibiotic therapy (4-6 weeks), typically necessitating 
placement of a central IV catheter, prolonged hospitalization, and home nursing or admission to a 
long-term care facility.  Treatment is associated with high cost and healthcare burden, as well as 
complications such as catheter related bloodstream infections and catheter associated thrombosis 
(Keller 2018).  Safe and effective alternative treatment strategies are needed.   
Dalbavancin is a lipoglycopeptide that has potent activity against Gram-positive pathogens including 
MRSA (Table 2, Table 3).  It is currently approved for treatment of acute bacterial skin and skin 
structure infection in the US and EU as a single dose or 2-dose regimen.  A 2-dose, once weekly 
regimen can provide systemic therapy for 6 weeks, eliminating the need for a centrally placed 
catheter or prolonged IV access for antibiotic administration.    

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Table 2: Activity of Dalbavancin Against Gram-Positive Pathogens Collected in 2014 US 
Surveillance 
Organism 
N 
Dalbavancin MIC (µg/mL) 
% Susceptiblea 
Range 
50% 
90% 
S aureus: all 
1625 
0.008 - 0.12 
0.06 
0.06 
100 
Methicillin-susceptible 
875 
0.008 - 0.12 
0.06 
0.06 
100 
Methicillin-resistant 
750 
0.008 - 0.12 
0.06 
0.06 
100 
Viridans group streptococci 
220 
≤ 0.002 - 0.12 
0.015 
0.03 
100 
Penicillin-nonsusceptible 
46 
0.004 - 0.06 
0.015 
0.03 
100 
S pyogenes 
108 
≤ 0.002 - 0.06 
0.008 
0.03 
100 
S dysgalactiae 
75 
≤ 0.004 - 0.12 
0.015 
0.03 
100 
E faecalis  
151 
0.02 - > 0.25 
0.06 
0.06 
97.6 
Bacterial pathogens frequently implicated as causative agents of IE include S aureus (including MRSA), 
Streptococcus pyogenes, viridans group streptococci, Group C and G streptococci, and Enterococcus spp. 
IE = infective endocarditis; MRSA = methicillin-resistant S aureus; MIC = minimum inhibitory concentration 
a Susceptible at ≤ 0.25 µg/mL 
Source: Dalbavancin International (Two Continents) Surveillance Report for 2014, JMI Laboratories; 
Protocol 14-DUR-01, May 2015. 
 
Table 3: Activity of Dalbavancin Against Gram –Positive Pathogens Collected in 2014 EU 
Surveillance 
Organism 
N 
Dalbavancin MIC (µg/mL) 
% Susceptiblea 
Range 
50% 
90% 
S aureus: all 
1625 
0.004 - 0.12 
0.06 
0.06 
100 
Methicillin-susceptible 
1209 
0.015 - 0.12 
0.06 
0.06 
100 
Methicillin-resistant 
416 
0.004 - 0.12 
0.03 
0.06 
100 
Viridans group streptococci 
213 
≤ 0.002 - 0.12 
0.015 
0.03 
100 
Penicillin-nonsusceptible 
57 
≤ 0.002 - 0.06 
0.015 
0.03 
100 
S pyogenes 
106 
0.004 - 0.12 
0.008 
0.03 
100 
S dysgalactiae 
94 
≤ 0.002 - 0.12 
0.015 
0.03 
100 
E faecalis  
305 
0.03 - > 0.25 
0.06 
0.06 
98.4 
Bacterial pathogens frequently implicated as causative agents of IE include S aureus (including MRSA), 
Streptococcus pyogenes, viridans group streptococci, Group C and G streptococci, and Enterococcus spp. 
IE = infective endocarditis; MRSA = methicillin-resistant S aureus; MIC = minimum inhibitory concentration 
a Susceptible at ≤ 0.25 µg/mL 
Source: Dalbavancin International (Two Continents) Surveillance Report for 2014, JMI Laboratories; 
Protocol 14-DUR-01, May 2015.  
 
Dalbavancin appeared effective in rat and rabbit models of S. aureus IE (Candiani 1999, Lefort 
2004).  In the rat model of staphylococcal IE, dalbavancin was as effective as vancomycin and 
teicoplanin at reducing the bacterial load in the heart, but with a lower dose and less frequent dosing 

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intervals compared to standard of care (Candiani 1999).   In a rabbit model of IE, dalbavancin given 
once daily (10 mg/kg for 4 days) or as a single dose of 40 mg/kg was effective against a strain of S. 
aureus with reduced susceptibility to vancomycin and teicoplanin (Lefort, 2004).  Additionally, 5 
Phase 2/3 clinical studies that evaluated the efficacy and safety of dalbavancin administered as a 
single dose or 2-dose regimen found that 100% of patients (55 of 55 evaluable subjects) with S. 
aureus bacteremia achieved clearance of bacteremia (Raad 2005, Dunne 2016, Boucher 2014, 
Selzter 2003, Jauregui 2005).  Thus, dalbavancin may be a safe and effective alternative therapy for 
S. aureus bacteremia/IE, including highly antibiotic-resistant strains.  
The safety profile of dalbavancin has been characterized for a total cumulative dose of 1500 mg, 
whether administered as a single dose or in split weekly doses (1000 mg on Day 1 followed by 500 
mg on Day 8).  Adverse reactions have been evaluated for 2473 patients treated with dalbavancin.  
Overall, the most common adverse reactions were nausea (4.7%), headache (3.8%), and diarrhea 
(3.4%).  The median duration of adverse reactions was 3 days for patients receiving dalbavancin and 
4 days for patients receiving a comparator.  The safety database for the 3000 mg total dose includes 
12 subjects from a Phase 1 study: 6 received a total of 3500 mg dalbavancin over 6 weeks (with a 
total of 2 mild adverse events), and 6 received a total of 4500 mg dalbavancin over 8 weeks (with 
total of 4 mild adverse events and 1 moderate adverse event). Elevations in ALT >3x the upper limit 
of normal have been reported, though at a frequency not significantly different than comparator arms 
in trials conducted to date. Per product insert, 4.9% (121/2473) subjects receiving dalbavancin 
experienced SAEs, with 2.6% (64/2473) discontinuing the medication as a result.   
 
Scientific Rationale 
 
Purpose of Study 
The current standard of care for the antibiotic treatment of complicated bacteremia or IE uses a 
stepwise approach. The initial phase of treatment involves the initiation of empirical antibiotic 
therapy, definitive diagnosis (as per the modified Duke criteria), and the assessment of the need for 
early valve replacement, if applicable. Subsequent identification of the causative pathogen, including 
antibiotic susceptibility and MICs supports the choice of definitive antibiotic therapy and 
determination of the required duration of antibiotic treatment. Guidelines for the use of outpatient 
parenteral antibiotic therapy in the treatment of complicated bacteremia or IE similarly advocate that 
antibiotic therapy can be divided into an initial phase during which life threatening complications of 
complicated bacteremia or IE are likely to occur (approximately 14 days) and a completion phase of 
therapy (2 weeks to 6 weeks) (Holland 2018). 
The proposed clinical study design of dalbavancin in the treatment of complicated bacteremia or IE 
is consistent with this standard of care. Specifically, prior to study eligibility, patients will receive 
pre-randomization antibiotic therapy pending a definitive diagnosis of complicated S. aureus 

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bacteremia or IE, as well as the resolution of bacteremia. Eligible patients will then be randomized 
into the study to complete their antibiotic therapy with either a 2-dose regimen of dalbavancin or the 
current standard of care with daily IV administration of antibiotic therapy for a total duration of 4 to 
6 weeks (Baddour 2015) for most patients, and up to 8 weeks for patients with vertebral 
osteomyelitis/discitis. 
The proposed clinical study design offers a number of advantages. First, it will support enrollment of 
patients with a confirmed diagnosis of complicated bacteremia or IE. Prior studies have been limited 
by the inability to confidently determine complicated vs uncomplicated status prior to randomization 
(Corey 2009). Second, the proposed study design addresses a true area of need in S. aureus 
bacteremia management and reflects the likely pattern of “real world” dalbavancin use by clinicians 
for the completion of systemic antibiotic therapy for complicated bacteremia or IE without the need 
for indwelling IV access to support daily therapy. This takes full advantage of the unusual PK profile 
of dalbavancin and the introduction of this therapy into clinical practice would potentially have a 
major impact on patient well-being and quality of life (QoL). In this study, presence or absence of 
these potential QoL effects will be assessed using an ARLG Bloodstream Infection QoL Measure 
developed specifically for this purpose (King 2020). Additionally, two previously validated 
measures (EQ-5D-5L, https://euroqol.org/eq-5d-instruments/sample-demo/ and the PROMIS Global 
Health short form, 
http://www.healthmeasures.net/administrator/components/com_instruments/uploads/Global%20Heal
th%20Scale%20v1.2%2008.22.2016.pdf) will also be collected. Third, adequate treatment of 
complicated bacteremia or IE requires prolonged systemic antibiotic therapy to prevent relapse. 
Introduction of the 2-dose dalbavancin regimen may decrease the risk of relapse. Finally, the 
proposed design of this clinical study is consistent with antibiotic stewardship principles, reserving 
dalbavancin therapy for patients with fully characterized infections and pathogens. 
 
Study Population 
Approximately 200 eligible subjects will be enrolled to the study in the United States and Canada.  
Eligible subjects are adults who have been diagnosed with complicated bacteremia or right-sided IE 
due to S. aureus, have been treated with appropriate empiric/targeted antibiotic therapy, and in 
whom the blood cultures have become negative after at least 72 hours of initial antibiotic therapy 
(maximum 10 days).  Subjects with uncomplicated bacteremia due to S. aureus will be excluded.  
More details regarding subject inclusion and exclusion criteria can be found in Section 5.1. 
 
Selection of Dose 
The dalbavancin dosing regimen consists of 1500 mg on Day 1 and 1500 mg on Day 8 for subjects 
with normal renal function or who are receiving dialysis, administered over 30 minutes by IV 
infusion. Patients with CrCl <30 who are not receiving dialysis will receive a reduced dose (1125mg 
on Day 1 and 1125 mg on Day 8). Based on a comparison to the updated nonclinical 

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pharmacokinetic (PK)/pharmacodynamics (PD) target of the area under the unbound drug 
concentration-time curve [fAUC]/MIC (Lepak 2015), this regimen is expected to provide sufficient 
therapeutic concentrations of free drug against S. aureus through Day 42. 
Consistent with prior nonclinical investigation (Andes 2007), Lepak et al (Lepak 2015) found 
fAUC/MIC to be the most relevant PK/PD index in a neutropenic murine thigh infection model, with 
mean free drug daily area under the curve (AUC)/minimum inhibitory concentration (MIC)s for net 
stasis, 1log kill, and 2log kill of 27.1, 53.3, and 111.1, respectively. To justify the proposed dosing 
regimen, a target attainment analysis was conducted using the updated population PK model 
(Carrothers 2020). In the PK simulation, the proposed regimen was simulated using the Bayesian 
post hoc estimates of each of the 703 patients in the merged Phase 2/3 population PK dataset. As 
with previous target attainment analyses, free drug levels were assumed to be 7% of total drug 
concentrations. As a conservative assumption, the mean daily AUC for target attainment was 
calculated based on dalbavancin levels on Day 42. For the MIC, the dalbavancin S. aureus MIC90 of 
0.06 mg/L was used. Results of this simulation analysis showed target attainments of > 99%, > 99%, 
and 90% for the net stasis, 1log kill, and 2log kill targets, respectively. For an even more 
conservative estimate, the US breakpoint for susceptibility of S. aureus to dalbavancin of 0.25 mg/L 
was also used: the 90% target attainment was achieved through Day 42 (stasis), Day 36 (1-log kill), 
and Day 28 (2-log kill) after clearance of bacteremia. 
Simulations designed to evaluate plasma concentration-time profiles suggest that a 2-dose regimen 
of dalbavancin of 1500 mg given on Days 1 and 8 will provide plasma concentrations above the 
MIC99 of S. aureus for an average of 49 days after the start of therapy Figure 2. 

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Figure 2: Simulated Mean Plasma PK Profile for Dalbavancin (Source: Allergen data on file) 
 
Figure 3 shows the time course of total dalbavancin concentration over the 6-week course of therapy 
for a typical patient. For this typical patient, Day 42 total drug concentration was 6.7 μg/mL 
[free drug = 7% × 6.7 = 0.47 μg/mL], which is greater than 7-fold the MIC90 value of 0.06 μg/mL for 
S. aureus, and > 15-fold the MIC90 value of 0.03 μg/mL for beta-hemolytic streptococci 
(Dalbavancin International [Two Continents] Surveillance Report for 2014) even at the end of a 
6-week course of therapy. 

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Figure 3: Dalbavancin Concentration Time Course for a Typical Subject Under the Proposed 
Regimen (Source: Allergen data on file) 
 
 
Potential Risks and Benefits 
Dalbavancin is FDA-approved for the treatment of acute bacterial skin and skin structure infections 
caused by Gram positive organisms, though at lower doses than proposed for treatment of 
bacteremia here and has been the subject of one prior randomized controlled clinical trial for 
osteomyelitis using the same dosing regimen proposed in this study. Risk information is derived 
from both the product insert and previously conducted trials. 
For those randomized to standard of care arms, the antistaphylococcal beta-lactams, cefazolin, 
vancomycin and daptomycin are all commonly used for treatment of S. aureus bacteremia and are 
associated with potential risks as well – outlined below from product inserts. These include risks 
associated with an indwelling vascular catheter, primarily secondary infections or thromboses. These 
also include the need for frequent blood draws to monitor for antibiotic toxicities.   

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Potential Risks 
2.3.1.1 
Dalbavancin 
Hypersensitivity Reactions: Hypersensitivity reactions (both anaphylactic and limited cutaneous 
reactions) have been reported with glycopeptide antibiotics, including dalbavancin. Subjects will be 
excluded from this study if they report any history of anaphylactic reaction to glycopeptide 
antibiotics or dalbavancin. 
Infusion-related Reactions: Rapid infusion of dalbavancin has been reported to cause flushing, 
urticarial, pruritic, or rash reactions resembling the “Red-Man Syndrome” described in association 
with vancomycin. Stopping or slowing the infusion typically resolves these reactions. 
Central Nervous System Reactions: Headache has been infrequently reported with dalbavancin 
receipt (<4%). 
Gastrointestinal: Nausea (4.7%) and diarrhea (<4%) have been infrequently reported with 
dalbavancin receipt (<4%).  
C. difficile Infection: C. difficile-associated diarrhea has been reported with nearly all antibacterial 
agents, including dalbavancin.  
Hepatic: Elevations of AST/ALT have been reported in clinical trials. 
2.3.1.2 
Cefazolin 
Hypersensitivity Reactions: Anaphylaxis and a range of cutaneous drug eruptions have been reported 
with cefazolin. 
Localized Reactions: Phlebitis has been rarely reported with cefazolin.  
Nephrotoxicity: Elevations in BUN and creatinine, infrequently even acute renal failure, have been 
reported.   
Gastrointestinal: Nausea, diarrhea and anorexia have been reported.  
C. difficile Diarrhea: C. difficile diarrhea has been reported with nearly all antibiotics.  
Hematologic: Neutropenia and thrombocytopenia have both been infrequently reported and are 
generally reversible upon discontinuation.  
Hepatic:  Transient elevations in AST/ALT have been reported. 
2.3.1.3 
Nafcillin 
Hypersensitivity Reactions: Anaphylaxis and a range of cutaneous drug eruptions have been reported 
with nafcillin. 

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Localized Reactions: Phlebitis, sometimes even with skin sloughing, has been rarely reported with 
nafcillin.  
Nephrotoxicity: Elevations in BUN and creatinine, infrequently even acute renal failure or acute 
interstitial nephritis, have been reported.   
Gastrointestinal: Nausea, diarrhea and anorexia have been reported.  
C. difficile Diarrhea: C. difficile diarrhea has been reported with nearly all antibiotics.  
Hematologic: Neutropenia or even agranulocytosis has been reported with nafcillin and is generally 
reversible upon discontinuation.  
Hepatic: Transient elevations in AST/ALT have been reported. 
2.3.1.4 
Oxacillin 
Hypersensitivity Reactions: Anaphylaxis and a range of cutaneous drug eruptions have been reported 
with oxacillin. 
Nephrotoxicity: Elevations in BUN and creatinine, infrequently even acute renal failure or acute 
interstitial nephritis, have been reported.   
Gastrointestinal: Nausea, diarrhea and anorexia have been reported.  
C. difficile Diarrhea: C. difficile diarrhea has been reported with nearly all antibiotics.  
Hematologic: Neutropenia or even agranulocytosis has been reported with oxacillin and is generally 
reversible upon discontinuation.  
Hepatic: Transient elevations in AST/ALT have been reported. 
2.3.1.5 
Vancomycin 
Infusion Reactions: Rapid infusion of vancomycin has been reported to cause flushing, urticarial, 
pruritic, or rash reactions known as the “Red-Man Syndrome”. Stopping or slowing the infusion 
typically resolves these reactions. 
Phlebitis and Localized Cutaneous Reactions: Vancomycin can be irritating to soft tissues, including 
causing thrombophlebitis at infusion sites. Inadvertent extravasation may result in localized pain, 
tenderness, or even necrosis.  
Hypersensitivity Reactions: Hypersensitivity reactions including anaphylaxis have been reported 
with vancomycin.  
Nephrotoxicity: When administered systemically, vancomycin can cause acute kidney injury. Risk 
of injury increases with supratherapeutic levels.  

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Ototoxicity: Hearing loss and tinnitus have been reported with vancomycin, reported mostly in 
patients with supratherapeutic levels, underlying hearing loss, or concomitant receipt of other 
ototoxic agents.  
C. difficile Diarrhea: C. difficile associated diarrhea has been reported with the use of nearly all 
antibiotics. 
Hematologic: Vancomycin has occasionally been associated with neutropenia or rarely 
thrombocytopenia. Cytopenias are usually reversible upon discontinuation.   
2.3.1.6 
Daptomycin 
Hypersensitivity Reactions: Anaphylaxis and a range of cutaneous drug eruptions have been reported 
with daptomycin. 
Myopathy/Rhabdomyolysis: Daptomycin has been reported to cause a myositis characterized by 
elevated creatine kinase levels, muscle pain, and muscle weakness. Risk may be increased upon co-
administration with statins. Myopathy is generally reversible upon discontinuation.  
Eosinophilic Pneumonia: Daptomycin has been rarely reported to cause eosinophilic pneumonia 
which may present with fever, dyspnea and pulmonary opacities.  
Neuropathy: There are rare reports of peripheral neuropathy with daptomycin.  
C. difficile Diarrhea: C. difficile diarrhea has been reported with nearly all antibiotics. 
2.3.1.7 
Risks Associated with Intravenous Access 
The risks associated with peripheral IV placement are minimal and include minor bruising/bleeding, 
localized discomfort at the site, and rarely infection or a superficial clot.   
The risks associated with peripherally inserted central venous catheters (PICC lines) or central lines 
include bleeding, discomfort at the site, deep venous thrombosis (blood clot), infection, rarely nerve 
injury or an irregular heartbeat. 
 
Potential Benefits 
Dalbavancin may or may not improve the clinical outcome of an individual subject who participates 
in this trial. There is potential benefit to society from their participation in this study resulting from 
insights gained about outcomes with dalbavancin among patients with S. aureus bacteremia. Since 
standard of care for complicated S. aureus bacteremia currently requires dosing via indwelling 
central venous access, with frequent dosing and prolonged duration of therapy, the potential benefit 
is the possible demonstration that a dalbavancin treatment strategy may avoid prolonged hospital 
stays and the need for central venous access.  

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STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR 
OUTCOME MEASURES 
 
Study Design Description 
This clinical study will be a Phase 2b, multicenter, randomized, open-label, assessor-blinded, 
superiority study. The study will compare dalbavancin to standard of care antibiotic therapy for the 
completion of therapy in patients with complicated bacteremia or right-sided native valve IE caused 
by S. aureus who have cleared their baseline bacteremia. 
Approximately 200 subjects will be randomized 1:1 to receive either dalbavancin or a standard of 
care antibiotic regimen that is based upon the identification and antibiotic susceptibility pattern of 
the baseline organism. Those randomized to the dalbavancin treatment group will receive 2 doses of 
dalbavancin IV 1 week apart (1500 mg on Day 1 and Day 8 after randomization, with renal dose 
adjustment if appropriate). Those subjects randomized to the standard of care antibiotic therapy 
treatment group will receive an antibiotic regimen considered to be standard of care based on the 
methicillin susceptibility pattern of the pathogen isolated at Baseline for a duration of 4 to 6 weeks.  
Figure 1 provides a schematic of the study design. Study procedures are presented in Section 6. 
Detailed descriptions of each study visit can be found in Section 6.3. 
 
Study Objectives 
 
Primary  
• To compare the Desirability of Outcome Ranking (DOOR) at Day 70 of dalbavancin to that of 
standard of care antibiotic therapy used to consolidate therapy for the treatment of subjects with 
complicated S. aureus bacteremia in the intent-to-treat (ITT) population. 
 
Secondary 
• To compare the clinical outcomes of dalbavancin with the standard of care antibiotic therapy at 
day 70 in the mITT population (see Section 10.5.1 for definitions of study populations).  
• To compare the safety of dalbavancin with that of the standard of care treatment in the mITT 
population.  
• To compare each individual component of the DOOR outcome by treatment arm, in the ITT 
population. 

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Exploratory  
 To compare the clinical outcomes of dalbavancin with the standard of care antibiotic therapy at 
day 70 in the CE population (see Section 10.5.1 for definition).   
 To compare the DOOR endpoint of subjects on dalbavancin with that of subjects receiving 
standard of care antimicrobial therapy at day 42, in the ITT, mITT and CE populations.   
 To compare the clinical and microbiologic outcomes of dalbavancin with the standard of care 
antibiotic therapy at day 42 in ITT, mITT and CE populations. 
 To compare clinical and microbiologic outcomes of dalbavancin with standard of care antibiotic 
therapy between clinically important subgroups, including a) those with MSSA versus MRSA; b) 
persons who inject drugs (PWID) vs non-PWID; c) those who received infectious disease 
consultation vs those who did not; d) underlying site of infection (endovascular, bone and joint, 
skin, pulmonary);  e) subjects with immune-suppression2; f) divided by duration of initial 
bacteremia, in the ITT, mITT, and CE populations. 
 To compare Quality of Life (QoL) of subjects on dalbavancin with that of subjects receiving 
standard of care antibiotic therapy at Baseline, Day 42, and Day 70, in the ITT, mITT, and CE 
populations. 
 To characterize the population pharmacokinetic profile for dalbavancin administered via a 2-
dose regimen (1500 mg on day 1 and 1500 mg on day 8; renally adjusted when appropriate) in 
patients with S. aureus bacteremia. 
 To assess patient-level and clinical covariates associated with dalbavancin pharmacokinetics in 
patients with S. aureus bacteremia. 
 Examine the association between individualized plasma concentration profiles and clinical and 
microbiologic outcomes at day 42 and TOC.  
 Examine the association between individualized plasma concentration profiles and occurrence of 
adverse drug events, including AST/ALT elevations >3X upper limit of normal. 
 Examine the association between individualized plasma concentration profiles and late 
recurrence risk among the subset of patients with osteomyelitis and a 6-month follow-up visit. 
 
 
2 Defined as: On chemotherapy or immunotherapy for active hematologic malignancy expected to cause ANC < 500 
cells/mm3 lasting > 7 days during the study period, chronic high dose oral steroids (equivalent of ≥ 20 mg prednisolone 
per day for or equivalent, for >2 weeks within the last month), HIV infection with a CD4 cell count < 100 cells/mm3 
based on last known measurement or patient-reported value 

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Study Endpoints or Outcome Measures 
 
Primary  
The primary outcome measure is the DOOR endpoint at day 70.  The clinical components of the 
DOOR endpoint (success/failure and infectious complications) will be completed by an independent 
adjudication committee, blinded to treatment assignment.  Day 70 was selected in this study as it 
occurs approximately 4 weeks after treatment completion for most patients, allowing time for 
detection of relapse. 
There are 5 possible rankings in the DOOR endpoint: 
 
Rank 1:  Alive without any of the following: (1) evidence of clinical failure; (2) an infectious 
complication; or (3) any SAE, or an AE leading to study drug discontinuation  
Rank 2: Alive but with one of the following: (1) evidence of clinical failure; (2) an infectious 
complication; or (3) any SAE, or an AE leading to study drug discontinuation   
Rank 3: Alive but with two of the following: (1) evidence of clinical failure; (2) an infectious 
complication; or (3) any SAE, or an AE leading to study drug discontinuation  
Rank 4: Alive but with all of the following: (1) evidence of clinical failure; (2) an infectious 
complication; or (3) any SAE, or an AE leading to study drug discontinuation  
Rank 5: Death 
Clinical failure, infectious complications, and adverse events are each binary (yes/no) components of 
the DOOR endpoint. 
For the primary endpoint, quality of life will be measured as a change from baseline QoL to day 70 
QoL score, as assessed by the ARLG Bloodstream Infection QoL Measure (Appendix C).  

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Definitions for the DOOR endpoint: 
Clinical Success: Resolution of clinical signs and symptoms of S. aureus bacteremia such that no 
additional antibiotic therapy is required or anticipated for its treatment.  
 
Note that it is possible to achieve this overall Clinical Success status at Day 70 even if Infectious 
Complications have occurred prior to that time. For example, a patient who has a new metastatic 
focus of infection diagnosed after randomization, but who subsequently completes treatment and is 
felt to be cured at Day 70 would be considered a Clinical Success (and the Infectious Complication 
would result in a lower DOOR). That is, Clinical Success reflects the patient’s overall status at the 
time of that assessment. 
 
Clinical Failure: Absence of clinical success 
Infectious Complications: occurrence of any of the following, between randomization and day 70:  
• Endocarditis 
• New evidence of metastatic foci of infection – e.g. osteomyelitis, visceral abscess, septic joint 
• Relapse – isolation of baseline S. aureus pathogen from a blood culture drawn after 
randomization 
• Readmission for subsequent care of indication under study 
• Need for additional unplanned source control procedures – e.g. abscess debridement or drainage, 
cardiac valve replacement 
• Change in antibiotic therapy due to inadequate clinical response. For any changes to study drug 
in the standard of care group, or when new antibiotics are started in either treatment group, the 
site PI will record the reason for the antibiotic change. 
 
Secondary  
The secondary efficacy outcome is as follows.  
• Clinical efficacy, defined as none of: 1) Clinical failure; 2) Infectious complications; 3) All-
cause mortality  
The secondary safety outcome is as follows. 

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• Proportion of patients who have either 1) an SAE; or 2) an AE leading to study drug 
discontinuation 
Each component of the DOOR will also be examined separately: 
• clinical success 
• infectious complications 
• SAEs 
• AEs leading to study drug discontinuation 
• all-cause mortality 
 
Exploratory  
 Clinical efficacy by treatment group in the CE population at day 70 
 DOOR endpoint by treatment group at day 42 in the ITT, mITT, and CE populations 
 Clinical and microbiologic outcomes by treatment group at day 42 in the ITT, mITT, and CE 
populations 
 Clinical and microbiologic outcomes by treatment group, within each subgroup of clinical 
interest, at day 42 and day 70 in the ITT, mITT, and CE populations.  A microbiologic success 
will be defined as no post-randomization growth (e.g., no positive cultures) of the baseline 
pathogen from blood cultures or another sterile body site  
 QoL at Baseline, Day 42, and Day 70, which will be assessed using the ARLG Bloodstream 
Infection QoL Measure (Appendix C) as well as two additional comparator measures (EQ-5D-
5L, https://euroqol.org/eq-5d-instruments/sample-demo/ and PROMIS Global Health short form, 
http://www.healthmeasures.net/administrator/components/com_instruments/uploads/Global%20
Health%20Scale%20v1.2%2008.22.2016.pdf) in the ITT, mITT, and CE populations 
 Population mean PK parameter estimates and the magnitude of the associated inter individual 
variability for the 2-dose dalbavancin regimen in patients with S. aureus bacteremia. 
 Individual post hoc PK parameter estimates and calculated exposure measures for the 2-dose 
dalbavancin regimen in patients with S. aureus bacteremia. 
 Clinical and microbiologic response at day 42 and Day 70 according to individual plasma 
dalbavancin concentration curves. 
 Occurrence of grade 3 or higher adverse drug events, adverse events of special interest (AESIs), 
and occurrence of AST/ALT elevations >3x upper limit of normal (ULN) from first dose of 
dalbavancin through follow-up period.  
 Late recurrence within the osteomyelitis population will be defined by the presence of the 
following up to 6 months after randomization: progressive imaging changes along with isolation 
of S. aureus from blood, bone biopsy, associated fluid aspiration, or operative tissue culture.  

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STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
 
Study Product Description 
Dalbavancin is a lyophilized, white to off-white to pale yellow solid.  It is a lipoglycopeptide 
synthesized from a fermentation product of Nonomuraea species.  Dalbavancin is a mixture of five 
closely related active homologs (A0, A1, B0, B1, and B2), shown in Table 4, below.  The homolog B0 
is the major component of dalbavancin.  The homologs share the same core structure and differ in 
the fatty acid side chain of the N-acylaminogluronic acid moiety (R1) structure and/or the presence 
of an additional methyl group (R2) on the terminal amino group, shown in Table 4 below.  The B0 
INN chemical name is 5,31-dichloro-38-de(methoxycarbonyl)-7-demethyl-19-deoxy-56-O [2-deoxy-
2-[(10-methylundecanoyl)amino]-β-D-glucopyranuronosyl]-38-[[3-(dimethylamino)propyl] 
carbamoyl]-42-O-α-D-mannopyranosyl-15-N-methyl(ristomycin A aglycone) hydrochloride.  Please 
refer to the package insert and/or Investigator’s Brochure for further details. 
Table 4: Substitution Patterns for Dalbavancin API Homologs 
 
 
 
Formulation, Packaging, and Labeling 
Dalbavancin 
Dalbavancin is supplied in clear glass vials as a sterile, lyophilized, preservative-free, white to off-
white to pale yellow solid.  Each vial contains dalbavancin HCl equivalent to 500 mg of 
dalbavancin.   
Investigational dalbavancin vials will be labeled according to manufacturer or regulatory 
specifications and include the statement “Caution: New Drug – Limited by Federal Law to 
Investigational Use.”  The dispensed study product (IV bags) will be labeled with the cautionary 
statement “For Investigational Use Only.” 

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The standard of care (SOC) antibiotics (Cefazolin, nafcillin, oxacillin, vancomycin, and daptomycin) 
will be prepared and labeled in accordance with the clinical site pharmacy’s standard operating 
procedures (SOPs).  
 
Product Storage and Stability 
Dalbavancin 
Unreconstituted dalbavancin for injection should be stored at 25°C (77°F); excursions permitted to 
15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].   
Reconstituted vials may be stored either refrigerated at 2°C to 8°C (36°F to 46°F), or at controlled 
room temperature 20°C to 25°C (68°F to 77°F).  Do not freeze.   
Once diluted into an intravenous bag , dalbavancin may be stored either refrigerated at 2°C to 8°C 
(36°F to 46°F), or at controlled room temperature 20°C to 25°C (68°F to 77°F).  Do not freeze.   
The total time from reconstitution to dilution to administration should not exceed 48 hours. 
SOC Antibiotics:  Cefazolin, nafcillin, oxacillin, vancomycin, and daptomycin 
Store per manufacturer’s instructions. 
 
Acquisition/Distribution 
Dalbavancin for injection will be supplied by Allergan, a subsidiary of AbbVie and will be obtained 
from the DMID Clinical Materials Services (CMS), Fisher BioServices, upon request by the study 
sites and approval by DMID. 
SOC antibiotics (cefazolin, nafcillin, oxacillin, vancomycin, and daptomycin) specified for use in the 
study will be obtained locally by each participating site.   
Any diluents or other vehicles for preparation of dalbavancin and SOC antibiotics for use in the 
study will also be obtained locally by each participating site. 
 
Dosage/Regimen, Preparation, Dispensing and Administration of Study 
Intervention/Investigational Product 
 Dalbavancin Group 
For subjects randomized to the dalbavancin treatment group, the dosage of dalbavancin administered 
will be determined based on individual estimated serum creatinine clearance (CrCl) levels and 
presence of regular hemodialysis or peritoneal dialysis as follows: 

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Subjects with CrCl ≥ 30 mL/min and subjects receiving regular hemodialysis or peritoneal dialysis 
will receive 1500 mg IV dalbavancin over 30 (± 10) minutes on Day 1 and on Day 8. 
Subjects with CrCl < 30 mL/min who are not receiving regular hemodialysis or peritoneal dialysis 
will receive 1125 mg IV dalbavancin over 30 (± 10) minutes on Day 1 and on Day 8. 
A repeat serum creatinine will be required within the 72 hours prior to the second (Day 8) 
dalbavancin dose. Whether creatinine clearance needs to be reassessed on Day 8 will be left to the 
clinical judgment of the study investigator. For example, a subject with stable renal function up to 72 
hours before the second dalbavancin dose and no anticipated change to renal function may not 
require a repeat creatinine clearance measurement on Day 8. In contrast, if the subject had either 
fluctuating renal function or renal function near the threshold for dose adjustment, it would be 
entirely appropriate to repeat a creatinine measurement prior to the Day 8 dose.  
If CrCl crosses the 30ml/min threshold in either direction after Day 1 but before the Day 8 dose, then 
the dose should be adjusted accordingly. That is, if a subject has CrCl ≥ 30 mL/min on Day 1 and 
received 1500mg IV dalbavancin, but the CrCl is < 30 mL/min on day 8then that subject will receive 
1125mg IV for the Day 8 dose. If the CrCl improves to ≥ 30 mL/min between Day 1 and Day 8, then 
the dose will receive 1500mg IV dalbavancin for the Day 8 dose. 
Standard of Care Group 
Subjects randomized to the standard of care antibiotic therapy treatment group will receive an 
antibiotic considered standard of care, generally for a duration of 4 to 6 weeks (but up to a maximum 
of 8 weeks, which may be standard practice for vertebral osteomyelitis at some sites) and based on 
the results of antibiotic susceptibility testing for baseline pathogen. The site PI (or licensed sub-
investigator listed on the Form FDA 1572), in agreement with the patient’s treating clinician, will 
designate which antibiotic is considered the study drug for patients randomized to the standard of 
care group; this will generally be the antibiotic already being used to treat their infection. For 
example, a patient randomized to the standard of care group who is receiving vancomycin for 
treatment of bacteremia, would most likely continue to be treated with vancomycin and this would 
be designated as their study drug. If the treating clinician is changing the antibiotic regimen at the 
time of randomization, for example to an antibiotic that would be easier to administer in the 
outpatient setting, then that new antibiotic would be designated as the study drug.  
Any changes to study drug (discontinuation or dose adjustment) will be captured and the reason for 
this change will be recorded, with the exception that vancomycin dose adjustments do not need to be 
captured.   
For subjects randomized to standard of care antibiotic therapy, the counting of days for the duration 
of therapy may begin on the first day on which blood cultures are negative during the Induction 
Period.  

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Subjects randomized to the standard of care antibiotic therapy treatment group will receive the 
following antibiotic(s) shown in Table 5 for the specified duration based on baseline pathogen: 
Table 5: Acceptable SOC Antibiotics 
Baseline Pathogen 
Standard of Care Therapy (doses may be adjusted for renal 
function)b 
MSSAa  
nafcillin (2 g IV q4h × 4-6 weeksc)e 
OR  
oxacillin (2 g IV Q4h x 4-6 weeksc)e 
OR 
cefazolin (2 g IV q8h × 4-6 weeksc)e  
MRSA  
vancomycin (dose per local standard of care × 4-6 weeksc) 
d OR 
daptomycin (6-10 mg/kg IV daily × 4-6 weeksc)  
IV = intravenous; qxh = every x hours; MRSA = methicillin--resistant Staphylococcus aureus; MSSA = 
methicillin--susceptible Staphylococcus aureus 
a Vancomycin or daptomycin are also appropriate for patients with MSSA and anaphylactoid-type hypersensitivity to 
beta-lactams. 
b If there are extenuating circumstances in which preferred standard of care antibiotics cannot be used, for example 
complex allergy history, then an alternative antibiotic may be used after discussion with the protocol PIs and DMID 
Medical Officer. 
c Duration of antibiotics reflects usual standard of care for complicated SAB. It may be extended to a maximum of 8 
weeks at the discretion of the treating clinician. 
d Patients on vancomycin will have dose adjustment and monitoring based on local standard of care 
e As applicable per site standard of care, beta-lactams may be administered at an equivalent dose via continuous IV 
infusion (e.g., nafcillin 12g/24h IV continuous).  
 
Complete instructions for dosage, preparation, labeling, storage, stability, and administration for 
dalbavancin and SOC antibiotics are provided in the protocol-specific Manual of Procedures (MOP). 
Regarding vancomycin dosing, dose adjustments and monitoring will be performed in accordance 
with local standard of care. Vancomycin monitoring may be performed by trough levels, area under 
the curve (AUC) based protocols, or other methods guided by sites’ local standards. Because 
vancomycin dosing and monitoring is determined by these local standards of care, we will not 
require specific doses or levels to be recorded.  

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Pre-determined Modification of Study Intervention/Investigational 
Product for an Individual Subject 
Dalbavancin dose will be modified per package insert for renal function only. Any contraindication 
to receipt of the second dose, including an allergic reaction, pregnancy or other adverse event (see 
individual halting rules in Section 8.5.2), should be discussed with the DMID Medical Officer. 
Subjects with impaired renal function will have their dosage of standard of care antibiotic treatment 
adjusted as needed, based on local standard of care.  
Any alteration in study drug therapy because of unusual clinical circumstances must be discussed 
with the DMID Medical Officer. 
 
Accountability Procedures for the Study Intervention/Investigational 
Product(s) 
Dalbavancin will be stored and shipped from the DMID contract Clinical Material Services (CMS) 
to the Clinical Sites. Once received, dalbavancin will be stored in and dispensed by the 
Investigational Pharmacy.  
The Food and Drug Administration (FDA) requires accounting for the disposition of all 
investigational products. The Investigator is responsible for ensuring that a current record of product 
disposition is maintained and product is dispensed only at an official study site by authorized 
personnel as required by applicable regulations and guidelines. Records of product disposition, as 
required by federal law, consist of the date received, date administered, quantity administered, and 
the subject number to whom the drug was administered.  
The Investigational Pharmacist will be responsible for maintaining accurate records of the shipment 
and dispensing of the investigational product. The pharmacy records must be available for inspection 
by the DMID monitoring contractors, and is subject to inspection by a regulatory agency (e.g., FDA) 
at any time. An assigned Study Monitor will review the pharmacy records. 
Unused unreconstituted investigational product (dalbavancin) vials will be stored at 25oC (77oF); 
excursions permitted to 15oC to 30oC (59oF to 86oF) [see USP controlled room temperature] in the 
Investigational Pharmacy until clinical trial accountability is completed. At study termination, all 
unused investigational product will be disposed in accordance with the MOP following complete 
drug accountability and monitoring. 

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SELECTION OF SUBJECTS AND STUDY ENROLLMENT 
AND WITHDRAWAL 
Subject Inclusion and Exclusion Criteria must be confirmed by a study investigator listed on the 
Form FDA 1572. 
No exemptions are granted on Subject Inclusion/Exclusion Criteria in DMID-sponsored studies. 
Clarifications regarding applicability of specific inclusion and exclusion criteria may be discussed 
with a protocol clinician. Questions about eligibility will also be directed toward the DMID Medical 
Officer. 
 
Eligibility Criteria 
 
Subject Inclusion Criteria 
A subject must meet all of the following criteria to be considered eligible for inclusion in the study: 
 Written informed consent obtained from the patient or legally authorized representative before 
the initiation of any study‑specific procedures.  
 Patients ≥ 18 years old. 
 A diagnosis of complicated S. aureus (either MSSA or MRSA) bloodstream infection (see 
definition of uncomplicated bacteremia in Exclusion criterion #1). 
 Treated with effective antibiotic therapy for at least 72 hours (maximum 10 days)3. 
 Subsequent defervescence for at least 24 hours and clearance of bacteremia from the qualifying 
pathogen (at Screening), with negative blood culture incubated for at least 48 hours.4 
 Provider willing to treat with either dalbavancin for two doses, or standard of care intravenous 
monotherapy for at least 4 and no more than 8 weeks from randomization. 
 Patients must be willing and able, if discharged, to return to the hospital or designated clinic for 
scheduled treatment, laboratory tests, or other procedures as required by the protocol. 
 
 
3 Ten consecutive days prior to randomization is the maximum allowed treatment duration.  If a subject has received 
intermittent or incomplete therapy earlier in the treatment course for this episode of S. aureus bacteremia, then discuss 
with the protocol PI and DMID Medical Officer prior to enrollment. 
4 Two negative blood cultures incubated for 48 hours are preferred. However, if only a single blood culture set is drawn, 
no growth at 48 hours will be considered adequate to demonstrate clearance. If more than one culture set is drawn, all 
must show no growth at 48 hours to be considered evidence of clearance (e.g., 1 of 2 positive cultures would still be 
considered as ongoing bacteremia). 

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 According to the site PI or sub-investigator assessment, patients must be expected to survive 
with appropriate antibiotic therapy and appropriate supportive care throughout the study. 
 
Subject Exclusion Criteria 
 Uncomplicated bacteremia5 (Appendix B). 
 Infectious CNS events, including septic emboli, ischemic or hemorrhagic stroke, epidural 
abscess, or meningitis (prior/unrelated CNS events are not exclusion criteria). 
 Known or suspected left-sided endocarditis or presence of a perivalvular abscess. 
 Planned right-sided valve replacement surgery in the first 3 days following randomization. 
 Presence of prosthetic heart valve, cardiac device6 UNLESS removal is planned within 4 days 
post-randomization. 
 Presence of intravascular graft or intravascular material7 UNLESS removal is planned within 4 
days post-randomization. 
 Infected prosthetic joint or extravascular hardware UNLESS removal is planned within 4 days 
post-randomization OR hardware was placed >60 days before bacteremia and clinically appears 
uninfected. 
 Polymicrobial bacteremia unless the non-S. aureus organism is a contaminant [see Definitions 
(Appendix B)].8  
 Significant hepatic insufficiency (Child-Pugh class C or AST/ALT values >5x ULN at the time 
of randomization). 
 Immunosuppression.9  
 
 
5 Uncomplicated Staphylococcus aureus bacteremia is defined as all of the following: exclusion of endocarditis by 
echocardiography; catheter‑associated bacteremia and removal of catheter; no implanted prostheses; follow-up blood 
cultures drawn within 48 hours after initial set that do not grow screening pathogen and all follow‑up blood cultures 
thereafter do not grow the screening pathogen; defervescence within 72 hours of initiating effective therapy; and no 
evidence of metastatic sites of infection. Any patient not meeting these strict criteria is considered to have complicated 
bacteremia and is eligible. 
6 Implantable cardioverter defibrillator (ICD), permanent pacemaker, valve support ring, ventricular assist device (VAD) 
7 Excluding cardiac stents, inferior vena cava filters in place for >6 weeks, vascular stents in place for >6 weeks, non-
hemodialysis grafts in place >90 days, and hemodialysis grafts not used within the past 12 months and not previously 
infected. A fistula constructed from native veins or a biologic vascular graft (without synthetic graft material) does not 
count as intravascular graft/material.  
8 Note: If a gram-negative bacteremia or fungemia develops after the qualifying S. aureus blood culture, AND the patient 
does not have right-sided endocarditis, AND the infection can be treated with an antibiotic without efficacy against the 
patient’s S. aureus isolate (e.g. aztreonam), then the patient may remain eligible. Discussion with the DMID Medical 
Officer is strongly encouraged. 
9 On chemotherapy or immunotherapy for active hematologic malignancy expected to cause > 7 days of ANC < 100 
cells/mm3, recent bone marrow transplant (in the past 90 days), solid organ transplantation within prior 3 months or 
receipt of augmented immunosuppression for rejection within 3 months, chronic granulomatous disease, HIV infection 
with a CD4 cell count < 50 cells/mm3 based on last known measurement or patient-reported value. 

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 History of hypersensitivity reaction to dalbavancin or other drugs of the glycopeptide class of 
antibiotics. 
 Treatment with either dalbavancin or oritavancin in the 60 days prior to enrollment. 
 Infection with S. aureus not susceptible to dalbavancin (dalbavancin mean inhibitory 
concentration [MIC] > 0.25 μg/mL) or vancomycin (vancomycin MIC > 2 μg/mL). 
 Planned treatment with concomitant systemic antibacterial therapy with potential efficacy against 
the patient’s qualifying S. aureus isolate, other than that allowed in the protocol. 
 Pregnant/ nursing females.  
 Females of childbearing potential must have a negative pregnancy test10 within 48h of 
randomization and use effective contraception for trial duration (Appendix B). 
 Other medical or psychiatric condition that may, in the judgment of the investigator, increase the 
risk of study participation or interfere with interpretation of study results. 
 Unwilling or unable to follow study procedures. 
 Treatment with an investigational drug within 30 days preceding the first dose of study 
medication. 
 
Withdrawal from the Study, Discontinuation of Study Product, or 
Study Termination  
 
Withdrawal from the Study or Discontinuation of the Study Product  
Subjects may voluntarily withdraw their consent for study participation at any time without penalty 
or loss of benefits to which they are otherwise entitled.   
An investigator may also discontinue a subject from receiving the study product (i.e., dalbavancin or 
SOC antibiotic) for any reason. Follow-up safety evaluations for discontinued subjects will be 
conducted, if the subject agrees.  If a subject withdraws or is withdrawn prior to completion of the 
study, the reason for this decision must be recorded in the case report forms (CRFs).  
The reasons to withdraw from the study might include, but are not limited to, the following: 
• Subject no longer meets eligibility criteria 
• Subject withdraws consent 
 
 
10 If the serum pregnancy test results cannot be obtained before randomization, a urine pregnancy test may be used for 
enrollment. 

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• Subject lost to follow-up 
• Subject becomes non-compliant 
• Medical disease or condition, or new clinical finding(s) for which continued participation, in the 
opinion of the investigator might compromise the safety of the subject, interfere with the 
subject's successful completion of this study, or interfere with the evaluation of responses 
• Study or site prematurely terminated by the sponsor for any reason 
The reasons to discontinue study product (i.e., dalbavancin or SOC antibiotic) might include, but are 
not limited to, the following: 
• Subject meets individual halting criteria (see Section 8.5.2) 
• Subject becomes pregnant, if applicable 
• Occurrence of an AE that, in the opinion of the investigator, warrants the subject’s permanent 
discontinuation from IV study drug (i.e., dalbavancin or SOC antibiotic)  
• Subject has an insufficient therapeutic response to study drug (i.e., lack of efficacy for SAB). A 
patient who does not show signs of improvement despite treatment with study drug for an 
appropriate length of time or a patient who shows signs of clinical worsening at any time may be 
prematurely discontinued from study drug therapy and treated with salvage therapy as directed 
by their treating clinician. These patients would still continue to be followed in the study unless 
withdrawn for another reason. 
A subject who is prematurely discontinued from study drug or withdrawn from the study should 
have the assessments for Early Termination (ET) as detailed in the Schedule of Events (Appendix 
A). A clear description of reason for early withdrawal or discontinuation from study product (i.e., 
dalbavancin or SOC antibiotic) must be documented. The reasons for early withdrawal or premature 
discontinuation from study drug will be reflected on the relevant disposition page of the electronic 
case report form (eCRF).  
The investigator should be explicit regarding study follow-up (e.g. safety and efficacy follow-up) 
that might be carried out despite the fact the subject will not receive further study product.  If the 
subject consents, every attempt will be made to follow all AEs through resolution or through the end 
of the study, whichever occurs first.  The procedures that collect safety data for the purposes of 
research must be inclusive in the original informed consent. 
The investigator will inform the subject that already collected data will be retained and analyzed 
even if the subject withdraws from this study.  

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Subject Replacement 
Subjects who withdraw, or are withdrawn from this study, or are lost to follow-up after signing the 
informed consent form (ICF) and administration of the study product will not be replaced.  Subjects 
who withdraw, or are withdrawn from this study, or are lost to follow-up after randomization but 
before administration of the study product will not be replaced.       
 
Study Termination  
The sponsor reserves the right to terminate the study in its entirety or at a specific study center 
before study completion. 
If the study is prematurely terminated by the sponsor, any regulatory authority, or the investigator 
for any reason, the investigator will promptly inform the currently enrolled study subjects and assure 
appropriate therapy or follow-up for the subjects, as necessary. The investigator will provide a 
detailed written explanation of the termination to the IRB/IEC. 

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STUDY PROCEDURES 
The study schedule is outlined below and in the Schedule of Events (Appendix A). The descriptions 
of the procedures to be performed at each visit are provided below. 
 
Induction Period: Visit 0 (Pre-screening, Day -10 to Day 1) 
During the pre-screening period (Visit 0), chart review may be performed to determine if a patient is 
potentially eligible for the study. No study-related procedures will be requested or performed prior to 
obtaining informed consent: 
• Confirm the subject is potentially eligible for the study based on chart review of 
inclusion/exclusion criteria 
 
Screening: Visit 1 (Day -1 to Day 1) 
• Obtain informed consent  
• Obtain medical and surgical history, to include targeted/pertinent medical and surgical history 
only 
• Collect medication history (from 30 days prior to ICF signing; extended review specifically for 
dalbavancin or oritavancin receipt in the prior 60 days given long half-lives of these two drugs) 
• Review and record relevant medical events that occurred during the induction period. Examples 
include source control procedures [see Definitions (Appendix B)], vascular access procedures 
[see Definitions (Appendix B)], and complications of pre-randomization antibiotic therapy. 
• Collect blood samples for hematology, serum chemistry laboratory assessments, and coagulation 
lab tests (PT/PTT and /or INR), if not already complete per standard of care within 48 hours 
prior to randomization (see Section 7.2.1) 
• Record most recent vital signs (blood pressure, respiration rate, pulse rate, and temperature); 
these must be performed within 48 hours prior to randomization   
• Perform physical examination (see Section 7.1.1) 
• Perform pregnancy test for women of childbearing potential (see definition in Appendix B) 
within 48 hours of randomization; ensure test is negative before randomization. If the serum test 
results cannot be obtained before randomization, a urine pregnancy test may be used for 
enrollment. 

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• Collect results of echocardiography to evaluate for endocarditis; perform an echocardiogram if it 
has not already been done as part of standard of care for this episode of bacteremia/endocarditis. 
Either a transthoracic or transesophageal echocardiogram is acceptable. 
• Review concomitant medications   
• Review and record any concomitant nondrug interventions (e.g., procedures performed with a 
goal of source control). 
 
Open-label Treatment Period, Planned Study Visits 
 
Baseline (Randomization): Visit 2 (Day 1) 
After a subject signs the ICF at the Screening Visit, any additional evaluations required to confirm 
eligibility will be performed (see Section 6.2). Subjects that do not meet all eligibility criteria after 
signing informed consent, for example due to an abnormal laboratory result, will be considered 
screen failures. Subject eligibility should be confirmed (or reconfirmed) within a maximum of 24 
hours prior to randomization.  
Once eligibility is confirmed, the subject may be randomized. Enrollment of subjects will be done 
online using the enrollment module of Advantage eClinical.  Subjects will be randomized to receive 
either a 2-dose regimen of dalbavancin, or to completion of 4 to 6 weeks (maximum of 8) of 
standard of care antibiotic therapy in a 1:1 allocation ratio based on the randomization schedule 
further described in Section 10.3.1. 
The Baseline Visit (Visit 2) will be conducted within a maximum of 10 days of effective antibiotic 
therapy for the qualifying bloodstream infection, after having confirmed defervescence for at least 24 
hours and clearance of bacteremia from the qualifying pathogen, with negative blood culture 
incubated for at least 48 hours. Study procedures will be reviewed with the patient and the caregiver, 
if applicable.  
At Baseline (Visit 2), the following procedures will be performed: 
• Review medical and surgical history. 
• Review concomitant medications (medications post first dose of study product). 
• Collect QoL data. 
• Randomization. 
• Measure vital signs (blood pressure, respiration rate, pulse rate, and temperature).  
• Perform targeted physical examination, focused on changes from screening. 

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• Administer IV dalbavancin or standard of care antibiotic therapy according to randomization as 
outlined in Section 4.3. The provider should designate which antibiotic is assigned as the study 
drug for patients randomized to standard of care group. 
• Document study drug administration. 
• For subjects receiving dalbavancin, collect blood samples for pharmacokinetic parameters prior 
to first dose, at end of infusion (+10 minutes), 6 (+/- 2) hours post end of dose, 12 hours (+/- 4) 
hours post end of dose, 24 (+/- 6) hours post end of dose, with documented draw time and date 
for each sample.  
• Review and record AEs/SAEs/AESIs after study product (i.e., dalbavancin or SOC antibiotic) 
administration.  
• Review and record any concomitant nondrug interventions (e.g., procedures performed with a 
goal of source control).  
 
Visit 3 (Day 8 ± 1 day) 
At Visit 3 the following procedures will be performed: 
• Review and record AEs/SAEs/AESIs. 
• Measure vital signs and perform targeted physical exam focused on changes from baseline, for 
patients who remain in the hospital or are receiving care at a location where research personnel 
can provide an in-person assessment (e.g. at an infusion center). Patients in the standard of care 
group who have been discharged from the hospital may have their symptoms assessed by 
telephone. If assessed by telephone, then all assessments for this visit will be done by phone and 
absence of vital signs/physical exam will not be a protocol deviation. 
• For subjects receiving dalbavancin, collect blood samples for pharmacokinetic parameters prior 
to 2nd dose of dalbavancin on day 8 (+/- 1 day) with documented draw time and date.  
• For subjects receiving dalbavancin, a serum creatinine assessment is required within 72 hours 
prior to the administration of the second dalbavancin dose.  Whether a serum creatinine must be 
repeated on Day 8 will be at the discretion of the site investigator based upon stability of the 
serum creatinine in the preceding 72 hours and whether the serum creatinine is near the threshold 
where dose adjustment would be necessary (e.g., near 30 mL/min). 
• Review concomitant medications. 
• Review and record any concomitant nondrug interventions (e.g. procedures performed with a 
goal of source control).  

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• Document study drug administration. 
• Collect QoL data. 
 
Visit 4 (Day 22 ± 2 days) 
At Visit 4 the following procedures will be performed: 
• Review and record AEs/SAEs/AESIs. 
• Measure vital signs (blood pressure, respiration rate, pulse rate, and temperature) and perform 
targeted physical examination, focused on changes from prior examinations.  
• Collect blood samples for hematology and serum chemistry. 
• For subjects who received dalbavancin, collect blood samples for pharmacokinetic parameters if 
feasible on day 22 (+/- 2 days) with documented time of draw and date.  
• Review concomitant medications. 
• Review and record any concomitant nondrug interventions (e.g. procedures performed with a 
goal of source control). 
• Administer IV standard of care antibiotic therapy according to randomization as outlined in 
Section 4.3 and document compliance.  
• Collect QoL data. 
 
Visit 5 (Day 42 ± 3 days) 
At Visit 5, the following procedures will be performed: 
• Review and record AEs/SAEs/AESIs. 
• Update medical history.  
• Measure vital signs (blood pressure, respiration rate, pulse rate, and temperature) and perform 
targeted physical examination, focused on changes from prior examinations. 
• Collect blood samples for hematology and serum chemistry. 
• For subjects who received dalbavancin, collect blood samples for pharmacokinetic parameters if 
feasible on day 42 (+/- 3 days) with documented time of draw and date.  
• Review concomitant medications.  

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• Review and record any concomitant nondrug interventions (e.g., procedures performed with a 
goal of source control). 
• Administer IV standard of care antibiotic therapy according to randomization as outlined in 
Section 4.3 and document, if ongoing. 
• Complete investigator assessment of efficacy. 
• Collect QoL data. 
 
Test of Cure: Visit 6 (Day 70 ± 7 days) 
It is preferred that this visit be performed in-person, however a telephone visit is an acceptable 
alternative. If performed by telephone, then the subject should be asked about new symptoms (e.g. 
fever, pain) in lieu of a physical exam. 
At Visit 6 (Day 70), the following procedures will be performed: 
• Review and record AEs/SAEs/AESIs. 
• Update medical history. 
• Measure vital signs (blood pressure, respiration rate, pulse rate, and temperature) for patients 
with in-person visit.  
• Perform targeted physical examination, focused on changes from prior examinations. 
• For subjects who received dalbavancin, collect blood samples for pharmacokinetic parameters if 
feasible on day 70 (± 7 days) with documented time of draw and date. 
• Review concomitant medications.   
• Review and record any concomitant nondrug interventions (e.g., procedures performed with a 
goal of source control). 
• Complete investigator assessment of efficacy. 
• Collect QoL data. 
 
Visit 7 (Day 180 ± 14 days – only for subjects with osteomyelitis) 
Visit 7 will only be performed for subjects with osteomyelitis present at baseline assessment in order 
to determine long-term recurrence risk. As with visit 6, an in-person visit will be preferred however 
a telephone alternative will also be considered acceptable. If performed by telephone, the subject 
should be asked about specific symptoms (fever, back pain), resumption/continuation/repeat 
treatment with antibiotics for S. aureus osteomyelitis, or surgical intervention for osteomyelitis.  

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At Visit 7 (Day 180), the following procedures will be performed:  
• Measure vital signs (blood pressure, respiration rate, pulse rate, and temperature) for patients 
with in-person visit.  
• Perform targeted physical examination, focused on changes from prior examinations (especially 
point tenderness to spine or presence of neurologic deficits).  
• Complete investigator assessment of efficacy. 
• Collect QoL data. 
• Review concomitant medications and concomitant nondrug interventions that are related to the 
treatment of osteomyelitis. 
 
Final Study Visit 
• For subjects without osteomyelitis, the final study visit will be Visit 6 (Day 70 ± 7 days) as 
above. For subjects with osteomyelitis, the final study visit will be Visit 7 (Day 180 ± 14 days) 
as above.  
 
Early Termination Visit  
In circumstances where a subject withdraws from the study or discontinues the study product (i.e., 
dalbavancin or SOC antibiotic) early, an Early Termination Visit will be performed, which include 
the following procedures: 
• Review and record AEs/SAEs/AESIs. 
• Update medical history. 
• Measure vital signs (blood pressure, respiration rate, pulse rate, and temperature) and perform 
targeted physical examination, focused on changes from prior examinations. 
• If clinically indicated, blood cultures should be collected at time of treatment discontinuation or 
for determination of treatment failure.  
• Review concomitant medications.  
• Review and record any concomitant nondrug interventions (e.g., procedures performed with a 
goal of source control).  
• Complete investigator assessment of efficacy. 
• For subjects who received dalbavancin, collect blood samples for pharmacokinetic parameters if 
feasible with documented time of draw and date. 

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• Collect QoL data. 
 
Unscheduled Study Visits  
An unscheduled study visit may be initiated by the subject/subject’s LAR or investigator, if a subject 
is not improving on therapy, has a grade 3 and above AE or an SAE, or for any other reason. In 
addition, the reason for the visit will be documented, including who initiated the visit, what 
complaints the subject/subject’s LAR has, and/or what concerns the primary medical team or site 
investigator have. Clinical outcome and any safety assessments will be documented. 
Assessments to be completed at unscheduled study visits should include: 
• Review and record AEs/SAEs/AESIs. 
• Update medical history. 
• Measure vital signs (blood pressure, respiration rate, pulse rate, and temperature) and perform 
targeted physical examination, focused on changes from prior examinations. 
• Review concomitant medications.  
• Review and record any concomitant nondrug interventions (e.g., procedures performed with a 
goal of source control). 
 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or protocol-specific 
Manual of Procedures (MOP) requirements.  The noncompliance may be either on the part of the 
subject, the investigator, or the study site staff.  As a result of deviations, corrective actions should 
be developed by the site and implemented promptly.  It is the responsibility of the site Principal 
Investigator and other study personnel to use continuous vigilance to identify and report protocol 
deviations.  All individual protocol deviations will be addressed in subject study records.  All 
protocol deviations, either individual, product, or site-specific will be collected and the record stored 
in a sponsor-determined location.  Protocol deviations must be sent to the IRB/IEC on which it relies 
per its guidelines as well as to the sites’ local IRB/IEC if required.  The site Principal Investigator 
and other study personnel are responsible for knowing and adhering to the requirements of their 
local IRB/IEC as well as the requirements of the IRB/IEC on which it relies. 
Inability to draw pharmacokinetic samples will not be considered a violation of protocol, as 
pharmacokinetic sampling is being conducted for exploratory purposes only and does not alter in any 
way the planned treatment course for subjects.  

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DESCRIPTION OF CLINICAL AND LABORATORY 
EVALUATIONS 
 
Clinical Evaluations 
 
Research Procedures  
• Medical and Surgical History: includes targeted/pertinent medical and surgical history only. 
• Medication History: from 30 days prior to signing the ICF, and 60 days for any prior 
lipoglycopeptides (oritavancin or dalbavancin) as reported by patient.11 
• Vital Signs: Vital sign measurements will be documented at every in-person visit. The 
parameters are blood pressure (BP), respiration rate, pulse rate, and temperature. It is 
recommended that heart rate and BP readings be taken after the patient has been sitting for at 
least 5 minutes. 
• Physical Examination: A physical examination (including general appearance, examination of 
head, eyes, ears, nose, throat, neck, skin, heart, lungs, abdomen, neurologic system, 
musculoskeletal system, extremities, height, and body weight) will be done at Screening 
(Visit 1).  Physical examinations should be performed by a professionally trained physician or 
health professional licensed to perform physical examinations. Body weight and height will be 
measured at Screening (Visit 1). If height or weight is not obtainable (e.g., patient is 
immobilized), the last known or stated height and weight may be used. At subsequent visits, a 
targeted physical exam should focus on changes from prior exams and on the evaluation of 
newly reported symptoms. 
• Echocardiograms: A transthoracic echocardiogram will be performed, or if clinically indicated, a 
transesophageal echocardiogram will be performed, unless one has been performed as standard 
of care for this episode of bacteremia/endocarditis. The overall interpretation and determination 
of the clinical significance of echocardiography findings will be the responsibility of the 
investigator, and the findings of all echocardiograms will be recorded in the patient’s eCRF. 
• Quality of Life Instruments: The following three QoL measures will be administered:  
 
 
11 As patients may receive medication prescriptions from multiple sources, patient-reported medications are intended to 
serve as the primary source for concomitant medications. For sites that have the ability to cross-query reported 
medications against prescription or medication administration records, this can be used as a secondary source but is not 
required. 

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• The ARLG Bloodstream Infection QoL Measure (Appendix C) is a 41-item questionnaire 
covering multiple domains of QoL.  
• The EQ-5D-5L (https://euroqol.org/eq-5d-instruments/sample-demo/) is an instrument that 
comprises five dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression, as well as an overall self-rated health on a vertical visual analogue scale.  
• The PROMIS Global Health short form 
(http://www.healthmeasures.net/administrator/components/com_instruments/uploads/Global
%20Health%20Scale%20v1.2%2008.22.2016.pdf) is a 10-item instrument that assesses 
general health and five primary domains (physical function, fatigue, pain, emotional distress, 
and social health). 
 
Assessment of Concomitant Medications/Treatments Other Than Study Product 
Patient-reported medication history during the 30 days prior to ICF signing will be recorded at 
Screening (Visit 1) in the eCRF.12 Thereafter, any changes in concomitant medications or new 
medications added will be recorded in the eCRF. 
While most systemic medications taken by the subject, other than study drug, are considered 
concomitant medications and should be recorded, the following specific exceptions do not need to be 
recorded:  
1. Topical medications (eye drops, ear drops, intranasal drops or sprays, dermatologic 
treatments, topical lidocaine) 
2. Vitamins and supplements (e.g., vitamins, minerals, herbal supplements, dietary 
supplements, iron/ferrous sulfate, magnesium, calcium, electrolyte replacements)  
3. Symptomatic care medications (e.g., antipyretics such as ibuprofen or acetaminophen, 
antihistamines, decongestants, non-steroidal anti-inflammatory drugs [NSAIDs]) 
4. Gastrointestinal agents (prokinetic agents, laxatives, stool softeners, gastrointestinal 
stimulants, antacids) 
5. Nicotine replacement products (e.g., patches, lozenges, gums, nasal sprays) 
6. Heparin flushes (e.g., as used for vascular access flushes) 
All relevant concomitant systemic medications from Screening (Visit 1) through Day 70 ± 7 days 
(Visit 6) must be recorded in the subject’s medical record and on the eCRFs. Specific dosages or 
 
 
12 As patients may receive medication prescriptions from multiple sources, patient-reported medications are intended to 
serve as the primary source for concomitant medications. For sites that have the ability to cross-query reported 
medications against prescription or medication administration records, this can be used as a secondary source but is not 
required.  

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dose changes for concomitant medications do not need to be recorded in the eCRFs. After Visit 6, 
for subjects with osteomyelitis, who are followed until Day 180 ± 14 days (Visit 7), the only 
concomitant medications that must be recorded are new antibiotics that are prescribed for the 
treatment of osteomyelitis. At each visit the investigator will obtain information on any therapeutic 
interventions (e.g., drug and nondrug therapy or surgery) provided. Subjects may not participate in 
any other antibiotic treatment trials or interventional studies involving non-FDA approved 
investigational products concomitantly while in this study.  
Concomitant systemic antibacterials (other than dalbavancin or comparator study drug) for 
adjunctive therapy of the subject’s S. aureus bacteremia are prohibited during the study, up to Day 
70. This includes concomitant treatment with an aminoglycoside. 
Patients who require additional therapy due to inadequate clinical response will be assessed as 
having lack of efficacy of study drug.  
• Where possible, antibiotic treatment of intercurrent infections should be done with antibiotics 
that are not active against the patient’s S. aureus isolate. Discussion with the DMID Medical 
Officer is encouraged before or within 24 hours of initiation of concomitant antibiotics for 
another indication. Exceptions include: Vancomycin oral 125 mg up to 500mg every 6 hours 
may be used in both treatment groups for the treatment of Clostridium difficile infections and 
may be continued as required throughout the duration of the study. The sponsor will not provide 
oral vancomycin. 
• Metronidazole IV or oral 500 mg every 8 hours may be used in both treatment groups for the 
treatment of C. difficile infections and may be continued as required throughout the duration of 
the study. The sponsor will not provide metronidazole. 
• Other antibacterials that do not achieve therapeutic levels in the serum (e.g., nitrofurantoin) may 
be considered. Consultation with the DMID Medical Officer is advised before use of these 
antibiotics. 
 
Assessment of Subject Compliance with Study Intervention/Investigational 
Product/Investigational Device  
Dalbavancin will be administered under the supervision of investigative site personnel, and infusion 
date, start, and stop time will be documented in the eCRF, as well as any infusion interruptions. 
 
Non-Research Standard of Care  
If clinically indicated, any surgical or non-surgical procedures required to achieve infection source 
control should be performed for patients enrolled in either treatment group. The necessity and timing 
of any such procedures will be decided upon by the patient’s treating physicians. Procedures 
frequently required for source control in Staphylococcus aureus bacteremia may include 

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debridement of osteomyelitis, removal of indwelling vascular access device, prosthetic devices or 
materials, incision and drainage of any abscesses, or heart valve replacement. 
 
Laboratory Evaluations 
 
Clinical Laboratory Evaluations 
The following laboratory evaluations will be evaluated during the study, per the schedule of events 
(Appendix A) 
• Hematology:  absolute and differential white blood cell (WBC) count, erythrocyte count, 
hemoglobin, hematocrit, and platelet count.. 
• Coagulation lab tests (PT/PTT and/or INR). 
• Chemistry:  sodium, potassium, calcium, chloride, bicarbonate, glucose, blood urea nitrogen, 
creatinine, total protein, alkaline phosphatase, albumin, total bilirubin, AST, and ALT. 
• If clinically indicated, blood cultures should be collected at the time of treatment discontinuation 
or for determination of treatment failure. Blood cultures should be repeated every 24-48 hours 
upon knowledge of a positive result from any visit until clearance of bacteremia is confirmed. 
When blood cultures are required, 2 sets of blood samples (1 aerobic and 1 anaerobic bottle) 
should be obtained from 2 separate venipuncture sites. 
• Culture, organism identification, and susceptibility testing will be conducted at the local 
laboratory. All pathogens will be tested for susceptibility; microbiological specimens and isolates 
will be collected, processed, and stored in accordance with local procedures. 
• Pregnancy test (urine or serum). 
 
Research Assays  
Dalbavancin Concentration Measurements: Venous blood samples for PK analyses will be collected 
at Visit 2 (Day 1), Visit 3 (Day 8 ± 1 day),Visit 4 (Day 22 ± 2 days), Visit 5 (Day 42 ± 3 days), Visit 
6 (Day 70 ± 7 days), or any early termination (ET) visit as outlined in Section 6 and Appendix A. 
The actual date and time of each blood sample collection will be recorded in the subjects’ source 
document and the eCRF.  Blood collected will be processed for plasma separation at the study site’s 
laboratory; subsequent PK analyses will be performed on the plasma samples at a central laboratory. 
PK sample collection, labeling, processing, storage, and shipment instructions will be provided in 
the MOP. 

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7.2.2.1 
Laboratory Specimen Preparation, Handling, and Storage 
Plasma PK specimens will be processed and stored in a -70oC or below freezer until time of 
shipment to the central PK laboratory for analysis.  Detailed instructions for the preparation, 
handling, and storage of plasma PK specimens are detailed in the study MOP including aliquots of 
specimens, temperature requirements, where they will be stored, and how they will be labeled. 
7.2.2.2 
Laboratory Specimen Shipping 
Plasma PK samples will be shipped on dry ice to the central PK laboratory. Samples will be shipped 
in compliance with the International Air Transport Association (IATA) regulations.   Instructions for 
the shipment of specimens are outlined in the study MOP. 

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ASSESSMENT OF SAFETY 
 
Assessing and Recording Safety Parameters 
This study will assist in determining the safety of dalbavancin compared to that of standard of care 
for the treatment of complicated S. aureus bacteremia.  Safety will be assessed by the frequency of 
SAEs, AESIs, and the frequency of AEs leading to study drug discontinuation in each treatment arm. 
 
Adverse Events (AEs) 
ICH E6 defines an AE as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product regardless of its causal relationship to the study 
treatment.  FDA defines an AE as any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of medicinal product.  The 
occurrence of an AE may come to the attention of study personnel during study visits and interviews 
of a study recipient presenting for medical care, or upon review by a study monitor.  
All AEs of grade 3 or higher including lab abnormalities (per CTCAE table, version 5.0, 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Refer
ence_8.5x11.pdf) will be captured on the appropriate data collection form and eCRF.  All AEs, 
regardless of grade, leading to study drug discontinuation will be captured on the appropriate data 
collection form and eCRF.  AESIs of all grades will also be captured (see Section 8.2.1). Information 
to be collected for AEs includes event description, date of onset, assessment of severity, relationship 
to study product (i.e., dalbavancin or SOC antibiotic) and alternate etiology (assessed only by those 
with the training and authority to make a diagnosis and listed on the Form FDA 1572 as an 
investigator), date of resolution, seriousness and outcome.  AEs and AESIs that meet reporting 
criteria and occur during the trial collection and reporting period will be documented appropriately 
regardless of relationship and will be followed through resolution or through the end of the study, 
whichever occurs first. Resolution of an AE is defined as the return to pre-treatment status or 
stabilization of the condition with the expectation that it will remain chronic. 
For the purpose of the site’s data collection responsibilities, any untoward event that was reported 
from the time of first study drug dose (i.e., dalbavancin or SOC antibiotic) after randomization at the 
Baseline Visit (Visit 2) until study Visit 6 is to be considered an AE. 
Examples of AEs are as follows: 
• Changes in the general condition of the patient from baseline 

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• Subjective symptoms offered by or elicited from the patient 
• Objective signs observed by the investigator or other study center personnel 
• All diseases that occur after administration of study drug at the Baseline Visit, including any 
change in severity or frequency of pre-existing disease 
• All clinically significant abnormalities in laboratory values or clinically significant physical 
findings that occur during the study collection and reporting period. However, a single abnormal 
laboratory result does not automatically indicate progression of a chronic condition.  For 
example, a transient spike in blood glucose level for a subject with diabetes is not reported as an 
AE. 
Please note that hospital admissions and/or medical/surgical procedures scheduled prior to study 
drug administration but occurring during the study should not be captured as AEs, but should be 
listed in the medical history if related to a pre-existing condition. 
Any medical condition that is present at the time of signing of ICF when the subject is screened will 
be considered as baseline and not reported as an AE.    However, if the severity of any pre-existing 
medical condition increases, it should be recorded in source documents as an AE. In this trial, only 
Grade 3 and higher AEs, AEs of any grade leading study drug discontinuation, and AESIs will be 
captured in the eCRF. 
Any abnormal test result that is determined to be an error does not require reporting as an AE. 
Additional diagnostic testing or medical/surgical interventions that occur as a result of an AE due to 
an abnormal laboratory test finding should be noted in the eCRF, if it meets protocol-specified 
reporting criteria.  
8.1.1.1 
Adverse Events Grading 
All AEs (laboratory and clinical symptoms) will be graded for severity (per CTCAE table, version 
5.0, 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Refer
ence_8.5x11.pdf) and assessed for relationship to study product (i.e., dalbavancin or SOC antibiotic) 
as outlined below. AEs characterized as intermittent require documentation of onset and duration of 
each episode.  The start and stop date of each reported AE will be recorded on the appropriate data 
collection form and eCRF. Changes in the severity of an AE will be documented in the source 
documents at the site to allow an assessment of the duration of the event at each level of intensity. 
Severity of Event:   
AEs will be assessed by the investigator (those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572) using the CTCAE, version 5.0 

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(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Refe
rence_8.5x11.pdf). The investigator will provide an assessment of the severity of each AE by 
recording a severity rating on the appropriate source documentation. Severity, which is a description 
of the intensity of manifestation of the AE, is distinct from seriousness, which implies a patient 
outcome or AE-required treatment measure associated with a threat to life or functionality (Section 
8.1.2). Severity will be assessed according to CTCAE, version 5.0 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Refe
rence_8.5x11.pdf), which follows the following general guideline: 
• Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
• Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activity of daily living (ADL).  
• Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL.  
• Grade 4 Life-threatening consequences; urgent intervention indicated.  
• Grade 5 Death related to AE. 
Relationship to Study Product: The assessment of the AE’s relationship to study product (i.e., 
dalbavancin or SOC antibiotic) will be done by a licensed study investigator indicated on the Form 
FDA 1572 and the assessment will be part of the documentation process.  Whether the AE is related 
or not, is not a factor in determining what is or is not reported in this trial.  If there is any doubt as to 
whether a clinical observation is an AE, the event should be reported.   
In a clinical trial, the study product must always be suspect.  The relationship to study product (i.e., 
dalbavancin or SOC antibiotic) will be assessed for AEs using the terms related or not related: 
• Related – There is a reasonable possibility that the study product caused the AE. Reasonable 
possibility means that there is evidence to suggest a causal relationship between the study 
product and the AE. 
• Not Related – There is not a reasonable possibility that the administration of the study product 
caused the event.  
 
Serious Adverse Events (SAEs) 
An AE or suspected adverse reaction is considered a serious adverse event (SAE) if, in the view of 
either the site principal investigator or sponsor, it results in any of the following outcomes:  
• Death, 

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• A life-threatening adverse event1,  
• Inpatient hospitalization or prolongation of existing hospitalization,  
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or  
• A congenital anomaly/birth defect.   
• Important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical judgment they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
1 Life-threatening adverse event. An AE is considered “life-threatening” if, in the view of either the 
site principal investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death.  It does not include an AE that, had it occurred in a more severe form, might have caused 
death. 
SAEs will be: 
• Assessed for severity and relationship to study product (i.e., dalbavancin or SOC antibiotic) and 
alternate etiology (if not related to study product) by a licensed study physician listed on the 
Form FDA 1572 or by the Institution as the site Principal Investigator or Sub-Investigator. 
• Recorded on the appropriate SAE data collection form and eCRF. 
• Followed through resolution by a licensed study physician (for IND studies, a physician listed on 
the Form FDA 1572 as the site Principal Investigator or Sub-Investigator). 
• Reviewed and evaluated by DMID, the DSMB (periodic review unless related), and the 
IRB/IEC. 
 
Specification of Safety Parameters 
Safety will be assessed by the frequency and severity of AEs, AESIs, and SAEs. 
Safety will be assessed using descriptive statistics of AEs, vital signs, and laboratory tests by 
treatment group. For each safety parameter, the last assessment made before the first dose of study 
product will be used as the baseline for all analyses of that safety parameter. 

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Adverse Events of Special Interest (AESIs) 
Adverse events of special interest (AESIs) are AEs that are common and known to occur following 
administration of study product (i.e., dalbavancin or SOC antibiotic). AESIs that are related to study 
product (i.e. dalbavancin or SOC antibiotic) will be collected after first dose of study product (i.e., 
dalbavancin or SOC antibiotic) is given and until final study visit. AESIs will be recorded on the 
eCRF and entered into the EDC. AESIs will include any CTCAE grades of allergic reaction, 
catheter-related infection, vascular access complication, infusion site extravasation, infusion-related 
reaction, alanine aminotransferase increases, aspartate aminotransferase increases, and acute kidney 
injury.  
If an intravascular catheter related complication is related to the catheter or vascular access device 
itself and not to study medication being administered (e.g., catheter-associated thrombosis or 
catheter-associated infection), this should still be recorded as an adverse event of special interest but 
can be marked as not related to study drug.  
 
Reporting Procedures 
 
Reporting Serious Adverse Events 
SAEs will be followed until resolution even if this extends beyond the study-reporting period.  
Resolution of an AE is defined as the return to pretreatment status or stabilization of the condition 
with the expectation that it will remain chronic.  
Any AE that meets a protocol-defined serious criterion that is judged to be related to either 
study product (i.e., dalbavancin or SOC antibiotic) must be submitted immediately (within 24 
hours of site awareness) on an SAE form to the DMID Pharmacovigilance Group, at the 
following address: 
 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 

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In addition to the SAE form, select SAE data fields must also be entered into the data coordinating 
center (DCC) database system, regardless of relationship to study product (i.e., dalbavancin or SOC 
antibiotic). Please see the protocol-specific MOP for details regarding this procedure.  
Other supporting documentation of the event may be requested by the DMID Pharmacovigilance 
Group and should be provided as soon as possible.  
The DMID Medical Monitor and DMID Clinical Project Manager will be notified of the related SAE 
by the DMID Pharmacovigilance Group.  The DMID Medical Monitor will review and assess the 
SAE for regulatory reporting and potential impact on study subject safety and protocol conduct. 
SAEs that that are judged to be not related to study product (i.e., dalbavancin or SOC antibiotic) 
will be captured on the appropriate data collection form and eCRF, but do not require separate 
reporting to the DMID Pharmacovigilance Group.   
At any time after completion of the study, if the site principal investigator or appropriate sub-
investigator becomes aware of an SAE that is suspected to be related to dalbavancin that occurred 
during the subject's participation in the study, the site principal investigator or appropriate sub-
investigator will report the event to the DMID Pharmacovigilance Group. 
 
Regulatory Reporting for Studies Conducted Under DMID Sponsored IND 
Following notification from the site Principal Investigator or appropriate sub-investigator, DMID, as 
the IND sponsor, will report any suspected unexpected serious adverse event.  DMID will report an 
SAE as a Suspected Unexpected Serious Adverse Reaction (SUSAR) only if there is evidence to 
suggest a causal relationship between the study intervention and the SAE and based on whether that 
event is listed in the investigator brochure.  DMID will submit an IND safety report to the FDA and 
will notify all participating site Principal Investigators (i.e., all Principal Investigators to whom the 
sponsor is providing drug under its IND(s) or under any Principal Investigator’s IND(s) of potential 
serious risks from clinical studies or any other source, as soon as possible.  DMID will report to the 
FDA any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in 
no case later than 7 calendar days after the sponsor’s initial receipt of the information.  If the event is 
not fatal or life-threatening the IND safety report will be submitted within 15 calendar days after the 
sponsor determines that the information qualifies for reporting as specified in 21 CFR Part 312.32.  
Relevant follow up information to an IND safety report will be submitted as soon as the information 
is available.  Upon request from FDA, DMID will submit to the FDA any additional data or 
information that the agency deems necessary, as soon as possible, but in no case later than 15 
calendar days after receiving the request.   
All SAEs designated as “not related” to study product(s), will be reported to the FDA at least 
annually in a summary format. 

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Reporting of Pregnancy 
Female subjects of childbearing age who become pregnant during the study prior to day 8 will not 
receive the second dose of dalbavancin (if randomized to the dalbavancin group) and will be 
followed for pregnancy outcome.  Pregnancy occurring during a subject’s participation in the study 
must be recorded in the database within 5 days of site awareness, on the Pregnancy Report form.  
The report will include pregnancy outcome (e.g., any premature terminations, elective or therapeutic, 
any spontaneous abortions or stillbirths), as well as the health status of the mother and child, 
including date of delivery and infant’s sex and weight.  Any subject with a positive pregnancy test, 
who has received study product(s), will be followed through eight (8) weeks post-live delivery or 
elective or natural termination of the pregnancy, whichever occurs first.  If the database is locked at 
time of pregnancy, a supplemental report will be generated and completed after birth, which will be 
appended to the database.  Any occurring AEs or SAEs that occur to the mother or fetus will be 
recorded in the eCRF in the database and on the SAE Report form.  
The site is responsible for notifying the IRB/IEC on which it relies of any pregnancies in accordance 
with their policies as well as notifying their local IRB/IEC of any pregnancies in accordance with 
local policies. 
 
Type and Duration of Follow-up of Subjects after Adverse Events 
AEs will be assessed, and AEs that are CTCAE grade 3 and higher, as well as all AESIs, will be 
followed from initial recognition of the AE until resolution or through the end of the study, 
whichever occurs first. 
SAEs will be followed up through resolution even if duration of follow-up goes beyond the protocol-
defined follow-up period (test of cure). 
Resolution of an AE is defined as the return to pre-treatment status or stabilization of the condition 
with the expectation that it will remain chronic. 
 
Halting Rules 
 
Study Halting Criteria 
The halting rules outlined below will be used to evaluate whether it is safe to proceed with dosing or 
whether the study should be suspended for further safety evaluation.   
If any of the halting rules below are met, further enrollment will be halted pending DSMB review of 
safety data and recommendations. The continuation of the administration of dalbavancin (the second 
dose) or switch to SOC will be at the site PI discretion. 

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• More than one subject death (e.g., 2 or more deaths) during participation in the study that is 
suspected to be related to the treatment with dalbavancin.  Note that mortality among patients 
with S. aureus bacteremia is not uncommon, and deaths that are not directly and solely related to 
dalbavancin will not by themselves trigger this halting rule. 
• Five or more subjects in the study are suspected with development of drug induced liver injury 
(DILI) that are assessed as related to dalbavancin. 
• Five or more subjects in the study experience a Grade 4 related to dalbavancin AEs (laboratory 
or systemic) that are coded in the same HLGT per MedDRA classification. 
 
 
Individual Halting Rules 
A subject will be discontinued from further dosing in either treatment group if any of the following 
criteria are met: 
• An individual infusion must be stopped if a drug-related hypersensitivity (grade 2 or higher) to 
dalbavancin or standard of care study drug is suspected, including anaphylaxis. Note that 
dalbavancin infusion can cause reactions that resemble “Red-Man Syndrome,” including 
flushing of the upper body, urticaria, pruritus, and/or rash. Stopping or slowing the infusion may 
result in cessation of these reactions and this reaction is not by itself a reason to discontinue 
dalbavancin for an individual subject. 
• New onset of illness or condition that meets exclusion criteria, at the investigator’s discretion  
• The treatment of any subject may be stopped for SAEs, clinically significant adverse events, 
including severe laboratory abnormalities that indicate to the Investigator that continued dosing 
is not in the best interest of the patient. 
 
Safety Oversight  
 
Data and Safety Monitoring Board (DSMB) 
Safety oversight will be conducted by a DSMB that is an independent group with expertise to 
interpret data from this study and will monitor subject safety and advise DMID. The DSMB 
members will be separate and independent of study personnel participating in the study and should 
not have scientific, financial, or other conflict of interest related to this study.  DSMBs must consist 
of at least three voting members, including a biostatistician experienced in statistical methods for 
clinical trials and a clinician with relevant expertise. 

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The DSMB will operate under the rules of a DMID-approved charter that defines the data elements 
to be assessed and the procedures for data reviews and will be written at the organizational meeting 
of the DSMB. Procedures for DSMB reviews/meetings will be defined in the charter. Reports may 
include enrollment and demographic information, medical history, concomitant medications, 
physical assessments, clinical laboratory values, dosing compliance, and solicited and unsolicited 
AE/SAEs.  The DSMB will review SAEs on a regular basis and ad hoc during this trial. The DMID 
Medical Monitor will be responsible for reviewing SAEs in real time.  
As defined in the charter, the DSMB will review data at specified times during the course of the 
study for subject and overall study progress and will conduct ad hoc reviews as appropriate when a 
halting rule is met or for immediate concerns regarding observations during this study. 
The DSMB will conduct the following meetings:  
• Organizational meeting 
• Data review meeting for safety  
• Every year 
• An Interim analysis for futility after at least approximately 50% of subjects have completed the 
study 
• Ad hoc meetings will occur when a halting rule is met, or when DMID or the DSMB chair has 
immediate concerns regarding observations during the trial 
• Final review meeting will occur 6-8 months after the clinical database is locked to review 
cumulative safety and efficacy data. The final CSR, if available, will be provided for this review. 
The DSMB may be asked to provide recommendations in response to DMID’s questions. 
Additional data may be requested by the DSMB, and interim statistical reports may be generated as 
deemed necessary and appropriate by DMID. The DSMB may receive data in aggregate and 
presented by treatment arm. The DSMB may also be provided with expected and observed rates of 
the expected AEs. The DSMB will review grouped data in the closed session only. As an outcome of 
each review/meeting, the DSMB will make a recommendation as to the advisability of proceeding 
with study treatments), and to continue, modify, or terminate this trial. 

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HUMAN SUBJECTS PROTECTION 
 
Institutional Review Board/Independent Ethics Committee 
Each site principal investigator will obtain IRB approval for this protocol to be conducted at his/her 
research site(s) and send supporting documentation to the DMID before initiating recruitment of 
subjects.  The investigator will submit applicable information to the IRB/IEC on which it relies for 
the review, to conduct the review in accordance with 45 CFR 46, ICH E6 GCP, and as applicable, 21 
CFR 56 (Institutional Review Boards) and 21 CFR 50 (Protection of Human Subjects), other federal, 
state, and local regulations. The IRB/IEC must be registered with OHRP as applicable to the 
research.  DMID must receive the documentation that verifies IRB/IEC-approval for this protocol, 
associated informed consent documents, and upon request any recruitment material and handouts or 
surveys intended for the subjects, prior to the recruitment and enrollment of subjects. 
Any amendments to the protocol or consent materials will be approved by the IRB/IEC before they 
are implemented.  IRB/IEC review and approval will occur at least annually throughout the 
enrollment and follow-up of subjects and may cease if annual review is no longer required by 
applicable regulations and the IRB/IEC.  The investigator will notify the IRB/IEC of deviations from 
the protocol and reportable SAEs, as applicable to the IRB/IEC policy. 
Each institution engaged in this research will hold a current FWA issued by the Office of Human 
Research Protection (OHRP) for federally funded research. 
A single IRB of record, (WIRB Copernicus Group), will be accountable for compliance with 
regulatory requirements for this multi-centered study, at participating sites.  A formal Reliance 
Agreement will be required between the single IRB and participating sites.  The formal Reliance 
Agreement will set forth the specific responsibilities of the IRB and each participating site.  
Participating sites will then rely on the IRB of record to satisfy the regulatory requirements relevant 
to the IRB review. The participating sites will maintain essential required documentation of IRB 
reviews, approvals, and correspondence, and must provide copies of any agreements and essential 
documentation to the DMID or regulatory authorities upon request. 
 
Informed Consent Process 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a trial 
and continuing throughout the individual’s trial participation.  Before any study procedures are 
performed, informed consent will be obtained and documented.  Subjects will receive a concise and 
focused presentation of key information about the clinical trial, verbally and with a written consent 

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form. The explanation will be organized, and presented in lay terminology and language that 
facilitates understanding why one might or might not want to participate. 
An investigator or designee will describe the protocol to potential subjects face-to-face. The key 
information about the purpose of the study, the procedures and experimental aspects of the study, 
risks and discomforts (including the PK sampling plan for subjects receiving dalbavancin), any 
expected benefits to the subject, and alternative treatment will be presented first to the subject.   
Subjects will also receive an explanation that the trial involves research, and a detailed summary of 
the proposed study procedures and study interventions/products.  This will include aspects of the 
trial that are experimental, the probability for random assignment to treatment groups, any expected 
benefits, all possible risks (including a statement that the particular treatment or procedure may 
involve risks to the subject or to the embryo or fetus, if the subject is or may become pregnant, that 
are currently unforeseeable), the expected duration of the subject’s participation in the trial, 
alternative procedures that may be available and the important potential benefits and risks of these 
available alternative procedures.  
Subjects will be informed that they will be notified in a timely manner if information becomes 
available that may be relevant to their willingness to continue participation in the trial. Subjects will 
receive an explanation as to whether any compensation and any medical treatments are available if 
injury occurs, and, if so, what they consist of, or where further information may be obtained. 
Subjects will be informed of the anticipated financial expenses, if any, to the subject for participating 
in the trial, as well as any anticipated prorated payments, if any, to the subject for participating in the 
trial. They will be informed of whom to contact (e.g., the investigator) for answers to any questions 
relating to the research project.  
Information will also include the foreseeable circumstances and/or reasons under which the subject’s 
participation in the trial may be terminated. The subjects will be informed that participation is 
voluntary and that they are free to withdraw from the study for any reason at any time without 
penalty or loss of benefits to which the subject is otherwise entitled.   
The extent of the confidentiality of the subjects’ records will be defined, and subjects will be 
informed that applicable data protection legislation will be followed. Subjects will be informed that 
the monitor(s), auditors(s), IRB, NIAID, and regulatory authority(ies) will be granted direct access 
to the subject’s original medical records for verification of clinical trial procedures and/or data 
without violating the confidentiality of the subject, to the extent permitted by the applicable laws and 
regulations, and that, by signing a written informed consent form, the subject is authorizing such 
access.  
Subjects will be informed that records identifying the subject will be kept confidential, and, to the 
extent permitted by the applicable laws and/or regulations, will not be made publicly available and, 
if the results of the trial are published, the subject’s identity will remain confidential. Subjects will 

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be informed whether private information collected from this research and/or specimens will be used 
for additional research, even if identifiers are removed.   
Subjects will be allowed sufficient time to consider participation in this research trial, and have the 
opportunity to discuss this trial with their family, friends or legally authorized representative, or 
think about it prior to agreeing to participate. 
Informed consent forms will be IRB-approved and subjects will be asked to read and review the 
consent form. Subjects must sign the informed consent form prior to starting any study procedures 
being done specifically for this trial. 
Once signed, a copy of the informed consent form will be given to the subject(s) for their records.  
The subject(s) may withdraw consent at any time throughout the course of the trial.  The rights and 
welfare of the subject(s) will be protected by emphasizing to them that the quality of their medical 
care will not be adversely affected if they decline to participate in this study. 
Study personnel may employ recruitment efforts prior to obtaining study consent if a patient-specific 
screening consent is on record or if the IRB has agreed that chart review is allowed without a fully 
executed screening consent.  In cases where there is not a patient-specific screening consent on 
record, site Clinical staff may pre-screen via chart review and refer potential subjects to the Research 
staff.  Research staff would obtain written consent per the standard informed consent process before 
conducting protocol-specific screening activities. 
New information will be communicated by the site principal investigator to subjects who consent to 
participate in this trial in accordance with IRB requirements.  The informed consent document will 
be updated and subjects will be re-consented per IRB requirements, if necessary.  Subjects will be 
given a copy of all informed consent forms that they sign. 
 
Other Informed Consent Procedures  
Use of a Legally Authorized Representative (LAR) 
Potential subjects for this study are adults but may be unable to provide legally effective informed 
consent due to their health status (i.e., dementia, intubated, sedated).  The subjects may be enrolled 
in the study if consent is obtained from the LAR.  The investigator will be familiar with the IRB/IEC 
policy on which he/she relies regarding the priority list of LAR and whether enrollment in a study is 
permitted by an advanced directive (e.g., living will, durable power of attorney for proxy consent).  
Additionally, subjects will be informed about the study to the extent compatible with the person’s 
understanding, and enrollment declined if the subject refuses participation. 
If a LAR originally provides legally effective informed consent and the subject’s condition 
improves, the subject will also be informed about the study as soon as is feasible and will be re-
consented. The subject may continue in the study only if the subject’s consent is provided.  

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Exclusion of Women, Minorities, and Children (Special Populations) 
Children will be excluded from this trial. Management algorithms for S. aureus bacteremia are 
different in children and their participation would thus not be appropriate. 
 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality includes documentation, investigation data, 
subject’s clinical information, and all other information generated during participation in the study. 
No information concerning the study or the data generated from the study will be released to any 
unauthorized third party without prior written approval of the DMID and the subject. Subject 
confidentiality will be maintained when study results are published or discussed in conferences.  The 
study monitor or other authorized representatives of the sponsor or governmental regulatory agencies 
may inspect all documents and records required to be maintained by the investigator, including but 
not limited to, medical records (office, clinic, or hospital) and pharmacy records for the subjects in 
this study. The clinical study site will permit access to such records. 
All records will be kept locked and all computer entry and networking programs will be carried out 
with coded numbers only and with password protected systems. All non-clinical specimens, 
evaluation forms, reports, and other records that leave the site will be identified only by a coded 
number. 
 
Certificate of Confidentiality 
To protect privacy, we have received a Certificate of Confidentiality.  With this Certificate, the 
researchers cannot be forced to release information that may identify the research subject, even by a 
court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings.  The researchers will use the Certificate to resist any demands for information that 
would identify the subject, except as explained below. 
The Certificate cannot be used to resist a demand for information from personnel of the United 
States Government that is used for auditing or evaluation of federally funded projects, like this 
study, or for information that must be released in order to meet the requirements of the Federal Food 
and Drug Administration (FDA). 
A Certificate of Confidentiality does not prevent the subject from voluntarily releasing information 
about themselves or their involvement in this research.  If any person or agency obtains a written 
consent to receive research information, then the researchers may not use the Certificate to withhold 
that information.   
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subject’s consent, information that would identify the subject as a participant in the research project 
regarding matters that must be legally reported including: child and elder abuse, sexual abuse, or 
wanting to harm themselves or others.   
The release of individual private information or specimens for other research will only occur if 
consent was obtained from the individual to whom the information, document, or biospecimen 
pertains.  
 
Costs, Subject Compensation, and Research Related Injuries 
There is no cost to subjects for the research tests, procedures, and study product while taking part in 
this trial.  Procedures and treatment for clinical care may be billed to the subject, subject’s insurance 
or third party.  Subjects may be compensated for their participation in this trial.  Compensation will 
be in accordance with the local IRB’s policies and procedures, and subject to IRB approval. 
If it is determined by the site principal investigator that an injury occurred to a subject as a direct 
result of the tests or treatments that are done for this trial, then referrals to appropriate health care 
facilities will be provided to the subject.  Study personnel will try to reduce, control, and treat any 
complications from this trial.  Immediate medical treatment may be provided by the participating 
site.  No financial compensation will be provided to the subject by the NIAID, NIH to the subject for 
any injury suffered due to participation in this trial. 

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STATISTICAL CONSIDERATIONS 
This is a phase 2b, multicenter, open-label, randomized, assessor-blinded, superiority study 
comparing a 2-dose dalbavancin regimen to standard of care therapy for the treatment of 
complicated bacteremia caused by S. aureus. Participants will be followed for 70 days, except for the 
subset with osteomyelitis who will be followed for 180 days.   
On the basis of the intention-to-treat (ITT) principle, the primary outcome will be analyzed on the 
ITT set (defined as all participants as randomized regardless of whether they received the 
randomized treatment). A sensitivity analysis will be conducted using the modified ITT (mITT) 
population - defined as all participants who received at least one dose of study drug. Additionally, as 
one of the secondary assessments, we will compare the individual components of the DOOR 
outcome by treatment arm within the ITT population. 
The secondary efficacy assessment, a non-inferiority analysis of overall clinical success rates by 
treatment group, will be conducted on the mITT population.   
The secondary safety assessment will analyze rates of SAEs or of AEs leading to study drug 
discontinuation on the mITT population.  
For all tests, P values will be two-sided with alpha < 0.05 level of significance. All reported 
confidence intervals will be two-sided 95%. 
The outcomes could be missing for subjects who withdraw from the trial. The reasons for 
withdrawal will be reported and compared qualitatively by groups. The effect that any missing data 
might have on results will be assessed via sensitivity analysis. If the pattern of missing data is 
different to that envisaged at the design stage, further sensitivity analyses will be provided that are 
tailored to the missing data pattern observed. 
The statistical analysis plan, which includes more technical and detailed elaboration of the principal 
features stated in the protocol, will be prepared separately. 
 
Study Hypotheses 
The primary objective is to compare the Desirability of Outcome Ranking (DOOR) at day 70 for 
dalbavancin versus standard of care antibiotic therapy for the treatment of complicated S. aureus 
bacteremia, conducted as a superiority assessment within the intention to treat population. We 
hypothesize that dalbavancin will have a higher DOOR relative to standard of care (e.g., the 
probability of a randomly selected patient having a better DOOR if assigned to receive dalbavancin 
versus standard of care (plus half the probability of a tied DOOR) is >50%). The null hypothesis 
would be no significant difference in DOOR between dalbavancin versus standard of care.   

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The key secondary objective will assess traditional clinical efficacy examining composite occurrence 
of clinical failure, infectious complications, or mortality as a non-inferiority comparison within the 
intention to treat population. We hypothesize that dalbavancin will have a non-inferior clinical 
efficacy rate relative to standard of care within a 20% absolute margin. The null hypothesis would be 
that dalbavancin has an inferior clinical efficacy relative to standard of care. The selection of a 20% 
non-inferiority margin is in line with previously published SAB trials, including the registrational 
trial of daptomycin versus standard of care (Fowler et al 2006). The protocol for an upcoming trial of 
ceftobiprole versus daptomycin includes a similar margin constructed around the particular context 
of SAB, noting that a non-inferiority margin of 20% includes more than half of the anticipated 
benefit of active-control treatment relative to untreated subjects (Hamed et al 2020). Additional 
secondary objectives will include a safety assessment and evaluation of the individual components 
of the primary DOOR outcome. Safety will be assessed by comparing the occurrence of serious 
(grade 3 or worse) adverse drug events between the dalbavancin and standard of care arms within the 
safety population. Each of the components of the DOOR outcome will be compared between the 
dalbavancin arm and standard of care arm within the ITT population.   
 
Sample Size Considerations 
The study is powered for a superiority comparison based on the primary objective, a comparison of 
DOOR outcomes. The probability of a subject from the dalbavancin arm having a superior DOOR 
ranking relative to a subject from the standard of care arm will be calculated along with a 95% 
confidence interval. Superiority will be considered to have been achieved if the 95% confidence 
interval for probability of having a superior DOOR ranking with dalbavancin does not cross 50%. If 
the confidence interval crosses 50% however, the null hypothesis cannot be rejected.   
Sample size was calculated on the basis of the primary hypothesis. Assuming a 65% probability of a 
better DOOR in the dalbavancin treatment group versus the standard of care treatment group, with a 
90% power and alpha=0.025 (by one-sided Wilcoxon rank sum test), 78 participants would be 
required in each treatment group. To allow for some inflation assuming around 12% of missing data 
or other study imperfections, using the method in Lachin (1981), we plan to recruit 100 per arm (200 
subjects in total).  Sample size was calculated using nQuery (MTT1-1 Module) (Version 8, 
Statistical Solution Ltd).  
 
Treatment Assignment Procedures 
 
Randomization Procedures 
Once consented and upon entry of demographic data and confirmation of eligibility for the trial, the 
subject will be enrolled. Enrollment of subjects will be done online using the enrollment module of 

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Advantage eClinical. Subjects will be randomized 1:1 to dalbavancin or standard of care.  
Randomization will be stratified based on screening pathogen, MSSA vs. MRSA. 
The list of randomized treatment assignments will be prepared by statisticians at the DCC (The 
Emmes Company). Emmes will assign each subject a treatment code and treatment assignment from 
the list after demographic and eligibility data have been entered.  
Instructions for use of the enrollment module are included in the Advantage eClinical User’s Guide. 
Manual back-up procedures and instructions are provided for use in case the site temporarily loses 
access to the internet or the online enrollment system is unavailable. 
 
Masking Procedures 
Study subjects and treating physicians will not be masked to treatment, as this is an open label study.  
Treatment group will be masked for study adjudicators. 
 
Planned Interim Analyses 
The DSMB will review interim reports of efficacy by treatment strategy. There will be one formal 
interim analysis of futility after approximately 50% of subjects have completed the trial. The 
statistical methods for the interim analysis will be fully specified in advance in a statistical analysis 
plan (SAP), to be prepared by a statistician, and summarized briefly in Section 10.4.2 below.  
 
Interim Safety Review  
The DSMB will evaluate safety at pre-specified intervals and at least yearly; however, ongoing 
review and summary of subject safety will occur to allow for early detection of a safety signal that 
may result from an AE or lack of efficacy of study drug. The DSMB will advise DMID on whether 
to continue, modify, or terminate the trial based on a risk-benefit assessment. 
 
Interim Futility Review 
A single interim analysis will be performed after approximately 50% of subjects have completed the 
trial. The interim futility analysis will consist of a quantitative evaluation of potential effect sizes and 
associated precision using a predicted intervals and predicted interval plots (PIPS) approach. Briefly, 
predicted intervals for both primary DOOR and secondary clinical failure outcomes will be modeled 
under a range of assumptions including: 1) the trends in outcomes observed at interim analysis 
continue to end of study, 2) the alternative hypothesis is true, 3) the null hypothesis is true, and 4) 
best and worst case scenarios for remaining outcomes. By relying on prediction intervals, no 
statistical hypothesis testing is required and no power is lost at interim analysis.   

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Final Analysis Plan 
Results from primary and secondary endpoint analyses may be distributed by the SDCC to key study 
team members (protocol PIs, protocol statisticians, and other necessary study team members) after 
database lock and prior to the generation of all the CSR Tables, Listings, and Figures. These 
analyses may be used by the company collaborator for planning subsequent trials or by the lead 
principal investigator for manuscript and abstract development while the CSR is being finalized. 
 
Study Populations 
Five populations will be considered in the statistical analysis of the study: 
 Screened Population: The screened population will consist of all patients who undergo the 
Screening Visit (Visit 1) and receive a Patient Identification (PID) number. 
 Intent-to-Treat/Randomized Population: The intent-to-treat (ITT) population will consist of all 
randomized patients regardless whether or not they received study treatment. 
 Safety Population: The safety population will consist of all randomized patients who received at 
least 1 dose of study drug. Patients will be analyzed based on the treatment received. 
 Modified Intent-to-Treat Population: The modified intent-to-treat (mITT) population will consist 
of all patients in the ITT population who received at least one dose of study drug. 
 Clinically Evaluable Population: The CE population will consist of all patients in the mITT 
population who met criteria for clinical evaluability. Patients will be considered clinically 
evaluable if they have a primary outcome assessment and do not have missing data or major 
protocol violations that prevent the adjudication committee from evaluating their outcomes. 
An independent, blinded adjudication committee will be used to review the data from each patient to 
establish the baseline diagnosis, final diagnosis, and final outcome (including DOOR outcome and 
its individual components), including reasons for treatment failure. This committee will consist of 3-
4 infectious disease experts with no relevant conflicts of interest. 
 
Patient Disposition 
The number of subjects in four of the study populations (ITT, Safety, mITT, and CE) will be 
summarized by treatment group and study center; the screened population will only be summarized 
by study center.  
Screen failures (i.e., patients screened but not randomized) and the associated reasons for failure will 
be tabulated overall. The number and percentage of subjects who complete the treatment period (up 
to Day 42) and of subjects who prematurely discontinue during the same period will be presented for 
each treatment group and pooled across treatment groups for the ITT population. The reasons for 
premature discontinuation as recorded on the termination pages of the eCRF will be summarized 
(number and percentage) by treatment group for all randomized subjects, along with the number of 
subjects completing each visit. 

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Demographics and Other Baseline Characteristics  
Demographic parameters (i.e., age, race, ethnicity, sex, weight, height, body mass index) and other 
baseline characteristics will be summarized by treatment group for the Safety and ITT populations. 
Continuous variables will be summarized by number of subjects and mean, standard deviation (SD), 
median, minimum, and maximum values. Categorical variables will be summarized by number and 
percentage of subjects. The number and percentage of subjects with abnormalities in medical and 
surgical histories in each system organ class and preferred term will be summarized by treatment 
group for the ITT population. 
Prior medication is defined as any medication taken before the date of the first dose of study product. 
Concomitant medication is defined as any medication started on or after the date of the first dose of 
study product.  
Both prior and concomitant medication use will be summarized by the number and proportion of 
subjects in each treatment group receiving each medication within each therapeutic class for the 
safety population. If a subject took a specific medication multiple times or took multiple medications 
within a specific therapeutic class, that subject would be counted only once for the coded drug name 
or therapeutic class. 
 
Extent of Exposure and Treatment Compliance 
Exposure to study product for the safety population will be summarized for treatment duration, 
calculated as the number of doses of dalbavancin received for patients in the dalbavancin group, and 
by start and stop dates for standard of care antibiotics. Descriptive statistics (n, mean, standard 
deviation, minimum, median, and maximum) will be presented by treatment group. 
 
Efficacy Analysis 
10.5.5.1 
Primary Efficacy Analysis 
The primary efficacy endpoint is the DOOR outcome at Day 70 post study entry (test of cure) in the 
ITT population. The clinical components of the DOOR outcome (survival, clinical success/failure, 
and infectious complications) will be determined by the blinded clinical adjudication committee (on 
a rolling basis). The DOOR probability is calculated, using the equation: 
DOOR probability = Pr[DOORD > DOORSOC] + ½ Pr[DOORD = DOORSOC],  
where DOORD and DOORSOC are the DOOR outcomes for dalbavancin and standard care groups, 
respectively, and Pr[DOORD > DOORSOC] is the probability of a DOOR from dalbavancin exceeding 
a DOOR from standard care and Pr[DOORD = DOORSOC] is the proportion of two DOOR outcomes 
being same. Pathogen (MSSA versus MRSA), which is considered in the permuted block 
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corresponding 95% confidence interval (the stratified analysis). In addition, the DOOR probability 
and 95% confidence interval without strata will be calculated.  
As a secondary analysis of the primary outcome will be: 
i. DOOR distribution by groups 
ii. Cumulative difference in DOOR categories for dalbavancin vs. Standard Care 
iii. Point estimate and confidence interval of difference in mean partial credit vs. Standard Care 
iv. Expected DOOR distribution for Standard Care and the expected numbers gained loss in 
each category with treatment 
The same analysis above will be repeatedly conducted on the DOOR outcome at Day 42. 
As an explanatory analysis of the primary outcome, in addition to pathogen (MSSA vs. MRSA), 
baseline covariate-adjustment analysis and subgroup analysis will be conducted. 
10.5.5.2 
Secondary Efficacy Outcomes 
As the secondary efficacy outcomes, each component of the DOOR will also be examined 
separately: clinical success, infectious complications, SAEs, AEs leading to study drug 
discontinuation, all-cause mortality. Descriptive statistics, including number and percentage for the 
categorical variables, will be provided by groups. 
Clinical failure at Day 70 will be analyzed using generalized estimating equations (GEE) assuming 
an unstructured correlation structure, including clinical failure at Day 42 (explanatory analysis time 
point). The difference in proportions of clinical failure between the two groups at Day 70 will be 
calculated with the corresponding 2-sided 95% confidence interval. As a sensitivity analysis, 
generalized linear mixed model (GLMM) approach will be used to analyze clinical failure. 
10.5.5.3 
Additional Efficacy Parameters 
 QoL score – QoL will be assessed using the ARLG Bloodstream Infection QoL Measure for the 
primary and exploratory endpoints (Appendix C). Two additional comparator measures (EQ-5D-
5L, https://euroqol.org/eq-5d-instruments/sample-demo/ and PROMIS Global Health short form, 
http://www.healthmeasures.net/administrator/components/com_instruments/uploads/Global%20
Health%20Scale%20v1.2%2008.22.2016.pdf) will also be collected and will be used in 
exploratory analyses only.  
 Desirability of Outcome Ranking (DOOR) (Evans 2015) endpoint results at Day 42. 
For the additional efficacy endpoints, descriptive statistics will be provided by treatment group. 
Continuous variables will be summarized by number of patients and mean, SD, median, minimum, 
and maximum values by treatment group. Categorical variables will be summarized by number and 
percentage of patients by treatment group. For QoL measures, the descriptive statistics will be 
presented by item as well.  

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Descriptive statistics for the DOOR endpoint will be provided by treatment group and summarized 
by number of patients and mean, SD, median, minimum, and maximum values; p-values will be 
determined using the Wilcoxon-rank sum test for continuous variables. 
 
Safety Analyses 
Safety analyses will be based on the safety population. Safety will be assessed using descriptive 
statistics of AEs, vital signs, and laboratory tests by treatment group. For each safety parameter, the 
last assessment made before the first dose of study product will be used as the baseline for all 
analyses of that safety parameter. 
10.5.6.1 
Adverse Events 
An AE (classified by preferred term) that occurs during the treatment period will be considered a 
treatment-emergent AE if it was not present before the first dose of study product or was present 
before the first dose of study product and increased in severity during the treatment period.  
The number and percentage of patients reporting treatment-emergent AEs in each treatment group 
will be tabulated by system organ class and preferred term; by system organ class, preferred term, 
and severity; and by system organ class, preferred term, and causal relationship to the study product. 
If more than one AE is coded to the same preferred term for the same subject, the subject will be 
counted only once for that preferred term using the most severe and most related occurrence for the 
summarization by severity and by causal relationship to the study product. 
The distribution of treatment-emergent AEs and AESIs by severity and causal relationship to the 
study product will be summarized by treatment group.  
The incidence of common (≥ 2% of patients in any treatment group) treatment-emergent AEs, on-
therapy SAEs, AESIs, and AEs leading to premature discontinuation of the study product will be 
summarized by preferred term and treatment group and will be sorted by decreasing frequency for 
the study product. In addition, the incidence of fatal on-therapy SAEs (i.e., events that caused death) 
will be summarized separately by treatment group and preferred term. An SAE will be defined as an 
on-therapy SAE if it occurred during or after the first infusion of study product. 
Listings will be presented for subjects with SAEs, AESIs, subjects with AEs leading to 
discontinuation, and subjects who die (if any). 
10.5.6.2 
Clinical Laboratory Parameters, and Vital Signs 
Descriptive statistics for clinical laboratory values and changes from the baseline values at each 
assessment time point will be presented by treatment group for each clinical laboratory parameter. 
Descriptive statistics for vital signs (e.g., pulse rate, systolic and diastolic BP) and changes from 
baseline values at each visit and at end of study will be presented by treatment group. 

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The number and percentage of subjects with potentially clinically significant (PCS) post-baseline 
clinical laboratory values will be tabulated by treatment group. The criteria for PCS laboratory 
values will be detailed in the statistical analysis plan. The percentages will be calculated relative to 
the number of subjects with available non-PCS baseline values and at least 1 post-baseline 
assessment. The numerator will be the total number of subjects with available non-PCS baseline 
values and at least 1 PCS post-baseline value. A supportive listing of subjects with PCS post-
baseline values will be provided, including the PID number, study center number, and baseline and 
post-baseline values. A listing of all AEs that occur in subjects who have PCS laboratory values or 
vital signs will also be provided. 
10.5.6.3 
Exploratory Dalbavancin Plasma Pharmacokinetic Analyses 
A range of exploratory analyses related to dalbavancin pharmacokinetics will be conducted among 
the subset of subjects receiving dalbavancin (n=100). The methodology used to evaluate PK 
parameters will be described in detail in the PK Plan and is reviewed briefly below.  
Pharmacokinetic Analysis 
Dalbavancin concentration-time data will be visualized using box and whisker plots, with 
investigation of any outliers for erroneous time or concentration data entry. Queries will be 
generated to resolve potential erroneous time or concentration data point entries due to transcription 
or measurement errors. Individual concentration-time plots will be generated on linear and semi-log 
scales to inform potentially optimal models for analysis. 
Non-Compartmental Pharmacokinetic Analysis  
Non-compartmental analysis (NCA) will serve as the initial approach to generate base PK parameter 
estimates for dalbavancin concentration-time data. These analyses will be conducted using an 
appropriate statistical package (e.g., Phoenix WinNonlin v8.2 or higher). This descriptive analysis 
will allow for comparison to previously published data.  The following PK exposures for 
concentration-time data will be calculated as appropriate and if possible depending upon samples 
collected: plasma concentration prior to dose, maximum plasma concentration (Cmax) after the first 
dose on Day 1, time to Cmax (Tmax), plasma concentration on Day 8 [C8day], plasma concentration on 
day 22 (C22day), concentration on day 42 (C42day), concentration on day 70 (C70day), area under the 
plasma concentration-time curve (AUC) from days 0-8 (AUC0-8days), AUC from days 0-22 (AUC0-
22days), AUC from days 0-42 (AUC0-42day), days 0-70 (AUC0-70days), AUC from days 8-22 (AUC8-
22days), AUC from days 22-42 (AUC22-42day), AUC from days 42-70 (AUC42-70day), AUC to the last 
quantifiable sample (AUC0–last), and AUC to infinity (AUC0–∞).   
Population Pharmacokinetic Analysis  
Population Pharmacokinetic Analysis. Population pharmacokinetic analysis provides a platform to 
identify patient covariates which can help explain a portion of the interindividual variability in 

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selected PK parameters. The non-linear mixed effects modeling software NONMEM Version 7.3 or 
higher (ICON Development Solutions, Ellicott City, MD) will be used to develop the population PK 
model for dalbavancin concentrations in plasma. The first-order conditional estimation method with 
interaction (FOCEI) will be utilized; other estimation methods such as expectation-maximization 
(e.g., SAEM) will also be considered. 
Structural PK model base development to model the plasma dalbavancin concentration-time data 
will be initiated using a linear three-compartment model with zero-order infusion as has been used 
previously (https://www.ncbi.nlm.nih.gov/pubmed/31087630).  Other model modifications will be 
considered as necessary.  Between-subject variability associated with model parameters and 
differing residual error structures will be tested. Model development will be guided by goodness of 
fit plots, plausibility of parameter estimates, reduction in inter-individual variability for structural 
and residual error parameters, as well as objective function and shrinkage values.   
Upon selection of an appropriate base structural PK model, covariate effects (e.g., age, gender, body 
size descriptors, creatinine clearance, albumin and IV drug use status) will be evaluated using 
stepwise forward selection followed by stepwise backward elimination processes. Model validation 
will be assessed through visual predictive checks as well as bootstrapping.  A listing of the 
individual PK parameters derived using the final population PK model will be provided for each 
patient.  The steady-state volume of distribution (Vss) will be calculated as the sum of the central 
(Vc) and peripheral volume terms (Vp1 and Vp2). The alpha-phase half-life (T1/2,α) beta-phase half-life 
(T1/2,β) and gamma-phase half-life (T1/2,γ) will be calculated for each patient using the individual 
post-hoc PK parameters.  Summary statistics (mean, standard deviation, median, minimum and 
maximum) will be calculated using CL, Vc, Vp1, Vp2, Vss, T1/2,α, T1/2,β, and T1/2,γ values. 
 
 

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Exposure-Response Relationship Analysis  
Using the final population PK model, individual post-hoc PK parameters, and the individual patient 
dosing histories, simulations will be performed to generate plasma dalbavancin concentration-time 
profiles and calculate plasma dalbavancin exposure measures for each study subject. The following 
exposure variables will be calculated for each patient: Cmax, C8day, C22day, C42day, C70day, AUC0-8days, 
AUC0-22days, AUC0-42day, AUC0-70days, AUC8-22days, AUC22-42day, AUC42-70day, and AUC to infinity 
(AUC0–∞).   The associations between each of the simulated dalbavancin exposures, as appropriate, 
and each outcome of interest will be explored using standard exposure-response methodologies.  
Only simulated exposures that occurred prior to the outcome of interest will be considered.  The 
outcomes evaluated will include (1) DOOR outcomes at day 42, mortality at day 42, infectious 
complications at day 42, adverse drug effects (grade 3 or higher) at day 42, late recurrence at 6 
months (within the subset having osteomyelitis), and occurrence of AST/ALT elevation >3x upper 
limit of normal during treatment.  Multivariable models will be used to estimate the effect of 
individual exposures measures on outcomes while accounting for relevant covariates.     
 

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SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
Each participating site will maintain appropriate medical and research records in compliance with 
ICH E6, Section 4.9 and regulatory and institutional requirements for the protection of 
confidentiality of subjects. Each site will permit authorized representatives of the DMID, its 
designees, and appropriate regulatory agencies to examine (and when required by applicable law, to 
copy) clinical records for the purposes of quality assurance reviews, audits, and evaluation of the 
study safety and progress. These representatives will be permitted access to all source data and 
source documents, which include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ memory aid or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, and subject files and records kept at the pharmacy, at the laboratories, and 
medico-technical departments involved in the clinical trial.  
 

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QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, each participating site(s) and its 
subcontractors are responsible for conducting routine quality assurance (QA) and quality control 
(QC) activities to internally monitor study progress and protocol compliance.  The site principal 
investigator will provide direct access to all study-related sites, source data/data collection forms, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities.  The site principal investigator will ensure all study personnel are 
appropriately trained and applicable documentations are maintained on site. 
The DCC will implement quality control procedures beginning with the data entry system and 
generate data quality control checks that will be run on the database.  Any missing data or data 
anomalies will be communicated to the participating site(s) for clarification and resolution. 

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DATA HANDLING AND RECORD KEEPING 
 
Data Management Responsibilities 
The investigator is responsible to ensure the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be completed in a neat, legible manner to ensure 
accurate interpretation of data.  Black or blue permanent ink is required to ensure clarity of 
reproduced copies.  When making changes or corrections, cross out the original entry with a single 
line, and initial and date the change.  DO NOT ERASE, OVERWRITE, OR USE CORRECTION 
FLUID OR TAPE ON THE ORIGINAL. 
Copies of the electronic CRF (eCRF) will be provided for use as source data collection forms and 
maintained for recording data for each subject enrolled in the study.  Data reported in the eCRF 
derived from source data collection forms should be consistent or the discrepancies should be 
explained. 
The sponsor and/or its designee will provide guidance to the site principal investigators and other 
study personnel on making corrections to the data collection forms and eCRF. 
 
Data Coordinating Center/Biostatistician Responsibilities 
Data collection is the responsibility of the study personnel at the participating clinical study site 
under the supervision of the site principal investigator.  During the study, the site principal 
investigator must maintain complete and accurate documentation for the study. 
The data coordinating center for this study, the Emmes Company, will be responsible for data 
management, quality review, analysis, and reporting of the study data. 
 
Data Capture Methods 
Clinical data (including, but not limited to, AE/SAEs, concomitant medications, medical history, 
physical assessments, and clinical laboratory values) will be collected on data collection forms by 
study personnel then entered into eCRFs via a 21 CFR Part 11-compliant internet data entry system 
provided by the study data coordinating center.  The data system includes password protection and 
internal quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate.   
 
Types of Data 
Data for this trial will include clinical, safety, and outcome measures (e.g., clinical laboratory 
values). 

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Study Records Retention 
Study records and reports including, but not limited to, eCRFs, source documents, ICFs, laboratory 
test results, and study drug disposition records will be retained for 2 years after a marketing 
application is approved for the study product for the indication for which it is being investigated; or, 
if no application is to be filed or if the application is not approved for the study product, until 2 years 
after the investigation is discontinued and the FDA has been notified. These documents will be 
retained for a longer period, however, if required by local regulations. ICFs for future use will be 
maintained as long as the sample/specimen exists. 
No records will be destroyed without the written consent of the sponsor. It is the responsibility of the 
sponsor to inform the site principal investigator when these documents no longer need to be retained.  
 

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CLINICAL MONITORING 
Site monitoring is conducted to ensure that the human subjects’ protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality and 
meet sponsor, ICH/GCP guidelines and applicable regulations, and that this trial is conducted in 
accordance with the protocol, protocol-specific MOP and applicable sponsor standard operating 
procedures.  DMID, the sponsoring agency, or its designee will conduct site-monitoring visits as 
detailed in the clinical monitoring plan. 
Site visits will be made at standard intervals as defined by DMID and may be made more frequently 
as directed by DMID.  Monitoring visits will include, but are not limited to, review of regulatory 
files, accountability records, eCRFs, informed consent forms, medical and laboratory reports, and 
protocol and GCP compliance.  Site monitors will have access to each participating site, study 
personnel, and all study documentation according to the DMID-approved site monitoring plan.  
Study monitors will meet with site principal investigators to discuss any problems and actions to be 
taken, and will document site visit findings and discussions. 
 

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PUBLICATION POLICY 
Following completion of the study, the lead Principal Investigator is expected to publish the results 
of this research in a scientific journal.  All investigators funded by the NIH must submit or have 
submitted for them to the National Library of Medicine’s PubMed Central 
(http://www.ncbi.nlm.nih.gov/pmc/) an electronic version of their final, peer-reviewed manuscripts 
upon acceptance for publication, to be made publicly available no later than 12 months after the 
official date of publication.  The NIH Public Access Policy ensures the public has access to the 
published results of NIH funded research.  It requires investigators to submit final peer-reviewed 
journal manuscripts that arise from NIH funds to the digital archive PubMed Central upon 
acceptance for publication.  Further, the policy stipulates that these papers must be accessible to the 
public on PubMed Central no later than 12 months after publication. 
Refer to: 
• NIH Public Access Policy, http://publicaccess.nih.gov/ 
• NIH Office of Extramural Research (OER) Grants and Funding, 
http://grants.nih.gov/grants/oer.htm 
As of January 2018, all clinical trials supported by the NIH must be registered on ClinicalTrials.gov, 
no later than 21 days after the enrollment of the first subject. Results of all clinical trials supported 
by the NIH, generally, need to be submitted no later than 12 months following the primary 
completion date. A delay of up to 2 years is available for trials that meet certain criteria and have 
applied for certification of delayed posting. 
As part of the result posting a copy of this protocol (and its amendments) and a copy of the 
Statistical Analysis Plan will be posted on ClincialTrials.gov. 
For this trial the responsible party is NIH/NIAID/DMID which will register the trial and post results.   
The responsible party does not plan to request certification of delayed posting. 
Refer to: 
• Public Law 110-85, Section 801, Clinical Trial Databases 
• 42CFR11 
• NIH NOT-OD-16-149 

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LITERATURE REFERENCES 
 Van Hal SJ, Jensen SO, Vaska VL, Espedido BA, Paterson DL, Gosbell IB. Predictors of 
mortality in Staphylococcus aureus Bacteremia. Clin Microbiol Rev. 2012;25(2):362-386. 
 
 Tong SY, Davis JS, Eichenberger E, Holland TL, Fowler VG, Jr. Staphylococcus aureus 
infections: epidemiology, pathophysiology, clinical manifestations, and management. Clin 
Microbiol Rev. 2015;28(3):603-661. 
 
 Thuny F, Di Salvo G, Belliard O, et al. Risk of embolism and death in infective endocarditis: 
prognostic value of echocardiography: a prospective multicenter study. Circulation. 
2005;112(1):69-75. 
 
 Murdoch DR, Corey GR, Hoen B, et al. Clinical presentation, etiology, and outcome of infective 
endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective 
Cohort Study. Arch Intern Med. 2009;169(5):463-473. 
 
 Selton-Suty C, Celard M, Le Moing V, et al. Preeminence of Staphylococcus aureus in infective 
endocarditis: a 1-year population-based survey. Clin Infect Dis. 2012;54(9):1230-1239. 
 
 Keller SC, Williams D, Rock C, Deol S, Trexler P, Cosgrove SE. A new frontier: Central line-
associated bloodstream infection surveillance in home infusion therapy. Am J Infect Control. 
2018;46(12):1419-1421. 
 
 Lefort A, Pavie J, Garry L, Chau F, Fantin B. Activities of dalbavancin in vitro and in a rabbit 
model of experimental endocarditis due to Staphylococcus aureus with or without reduced 
susceptibility to vancomycin and teicoplanin. Antimicrob Agents Chemother. 2004;48(3):1061-
1064. 
 
 Candiani G, Abbondi M, Borgonovi M, Romano G, Parenti F. In-vitro and in-vivo antibacterial 
activity of BI 397, a new semi-synthetic glycopeptide antibiotic. J Antimicrob Chemother. 
1999;44(2):179-192. 
 
 Raad I, Darouiche R, Vazquez J, et al. Efficacy and safety of weekly dalbavancin therapy for 
catheter-related bloodstream infection caused by gram-positive pathogens. Clin Infect Dis. 
2005;40(3):374-380. 
 

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 Dunne MW, Puttagunta S, Giordano P, Krievins D, Zelasky M, Baldassarre J. A Randomized 
Clinical Trial of Single-Dose Versus Weekly Dalbavancin for Treatment of Acute Bacterial Skin 
and Skin Structure Infection. Clinical infectious diseases : an official publication of the 
Infectious Diseases Society of America. 2016;62(5):545-551. 
 
 Seltzer E, Dorr MB, Goldstein BP, Perry M, Dowell JA, Henkel T. Once-weekly dalbavancin 
versus standard-of-care antimicrobial regimens for treatment of skin and soft-tissue infections. 
Clinical infectious diseases : an official publication of the Infectious Diseases Society of 
America. 2003;37(10):1298-1303. 
 
 Jauregui LE, Babazadeh S, Seltzer E, et al. Randomized, double-blind comparison of once-
weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated skin 
and skin structure infections. Clinical infectious diseases : an official publication of the 
Infectious Diseases Society of America. 2005;41(10):1407-1415. 
 
 Boucher HW, Wilcox M, Talbot GH, Puttagunta S, Das AF, Dunne MW. Once-weekly 
dalbavancin versus daily conventional therapy for skin infection. N Engl J Med. 
2014;370(23):2169-2179. 
 
 Holland TL, Raad I, Boucher HW, et al. Effect of Algorithm-Based Therapy vs Usual Care on 
Clinical Success and Serious Adverse Events in Patients with Staphylococcal Bacteremia: A 
Randomized Clinical Trial. Jama. 2018;320(12):1249-1258. 
 
 Baddour LM, Wilson WR, Bayer AS, et al. Infective Endocarditis in Adults: Diagnosis, 
Antimicrobial Therapy, and Management of Complications: A Scientific Statement for 
Healthcare Professionals from the American Heart Association. Circulation. 2015;132(15):1435-
1486. 
 
 Corey GR. Staphylococcus aureus bloodstream infections: definitions and treatment. Clin Infect 
Dis. 2009;48 Suppl 4:S254-259. 
 
 Lepak A, Marchillo K, VanHecker J, Andes D. Impact of Glycopeptide Resistance in 
Staphylococcus aureus on the Dalbavancin In Vivo Pharmacodynamic Target. Antimicrob 
Agents Chemother. 2015;59(12):7833-7836. 
 
 Andes D, Craig WA. In vivo pharmacodynamic activity of the glycopeptide dalbavancin. 
Antimicrob Agents Chemother. 2007;51(5):1633-1642. 
 

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 Marbury T, Dowell JA, Seltzer E, Buckwalter M. Pharmacokinetics of dalbavancin in patients 
with renal or hepatic impairment. J Clin Pharmacol. 2009;49(4):465-476. 
 
 Dorr MB, Jabes D, Cavaleri M, et al. Human pharmacokinetics and rationale for once-weekly 
dosing of dalbavancin, a semi-synthetic glycopeptide. J Antimicrob Chemother. 2005;55 Suppl 
2:ii25-30. 
 
 Carrothers TJ, Chittenden JT, Critchley I. Dalbavancin Population Pharmacokinetic Modeling 
and Target Attainment Analysis. Clin Pharmacol Drug Dev. 2020;9(1):21- 
 
 Evans SR, Rubin D, Follmann D, et al. Desirability of Outcome Ranking (DOOR) and Response 
Adjusted for Duration of Antibiotic Risk (RADAR). Clin Infect Dis. 2015;61(5):800-806. 
 
 Dalvance (dalbavancin) [product insert]. Madison, NJ: Allergan USA, Inc.; 2018. 
 
 Fowler VG, Jr., Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for 
bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006;355(7):653-
665. 
 
 Hamed K, Engelhardt M, Jones ME, et al. Ceftobiprole versus daptomycin in Staphylococcus 
aureus bacteremia: a novel protocol for a double-blind, Phase III trial. Future Microbiol. 
2020;15(1):35-48. 
 
 Lachin JL. Introduction to Sample Size Determination and Power Analysis for Clinical   Trials. 
Controlled Clinical Trials 198; 2:93-113 
 
 King HA, Doernberg SB, Miller J, et al. Patients’ experiences with Staphylococcus aureus and 
Gram-negative bacterial bloodstream infections: A qualitative descriptive study and concept 
elicitation phase to inform measurement of patient-reported quality of life. Clin Infect Dis 2020; 
Accepted, available epub ahead of print at: https://doi.org/10.1093/cid/ciaa611 
 
 DALVANCETM Dalbavancin for Injection [Investigator’s Brochure]. Madison, NJ: Allergan 
USA, Inc.; 2020 August. 

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APPENDICES 
 
 

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 Schedule of Events  
 
 
 
Induction 
Period 
Screening/ 
Enrollment Open Label Treatment Period 
Post-treatment  
Follow-up Period 
Visit 0 
(Pre-
Screening,  
Day -10 to 
Day 1) 
Visit 1 (Day 
–1 to Day 1) 
Visit 2  
(Baseline, 
Day 1) 
Visit 3 
(Day 8 
± 1 
day) 
Visit 4 
(Day 
22 
± 2 
days) 
Visit 5 
(Day 42 
± 3 
days) 
Visit 6 
(TOC, 
Day 
70 
± 7 
days)a ETb 
Visit 7 (Day 
180 ± 14 days, 
Osteomyelitis 
group)a 
Informed Consent 
 
X 
 
 
 
 
 
 
 
Dalbavancinc 
 
 
X 
X 
 
 
 
 
 
Standard of care 
antibiotic therapyc  
X 
X 
X (Duration 28-56 days) 
 
 
 
Medical historyd 
 
X 
X 
 
 
X 
X 
X 
 
Medication historye  
 
X 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
AEs/AESIs/SAEs 
 
 
X 
X 
X 
X 
X 
X 
 
Hematology and 
serum chemistry 
blood samplingf 
 
X 
 
Xg 
X 
X 
 
 
 
Coagulation lab 
testsf 
 
X 
 
 
 
 
 
 
 

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Induction 
Period 
Screening/ 
Enrollment Open Label Treatment Period 
Post-treatment  
Follow-up Period 
Visit 0 
(Pre-
Screening,  
Day -10 to 
Day 1) 
Visit 1 (Day 
–1 to Day 1) 
Visit 2  
(Baseline, 
Day 1) 
Visit 3 
(Day 8 
± 1 
day) 
Visit 4 
(Day 
22 
± 2 
days) 
Visit 5 
(Day 42 
± 3 
days) 
Visit 6 
(TOC, 
Day 
70 
± 7 
days)a ETb 
Visit 7 (Day 
180 ± 14 days, 
Osteomyelitis 
group)a 
Pregnancy testh 
 
X 
 
 
 
 
 
 
 
 PK samplingi  
 
 
X 
X 
X 
X 
X 
X 
 
Vital signsj 
 
X 
X 
Xk 
X 
X 
X 
X 
X 
Physical 
examinationl 
 
X 
X 
X 
X 
X 
X 
X 
X 
Echocardiogramm 
 
X 
 
 
 
 
 
 
 
Investigator 
assessment of 
efficacy  
 
 
 
 
 
X 
X 
X 
X 
Concomitant 
medicationsn 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
nondrug 
interventions 
 
X 
X 
X 
X 
X 
X 
X 
X 
QoL assessmento 
 
 
X 
X 
X 
X 
X 
X 
X 
 
AEs = adverse events; AESIs = adverse events of special interest; eCRF = electronic case report form; ET = Early 
Termination; PK = pharmacokinetic; SAE = serious adverse events  
aTelephone visit permissible if in-person visit is not possible; in person visit still preferred.  
bPatients who prematurely discontinue therapy should have an ET Visit within 72 hours.  
cAll subjects will be receiving standard of care prior to randomization; after randomization, subjects will receive either 
dalbavancin or standard of care based on their assigned treatment group.   
dIncludes targeted/pertinent medical and surgical history only  
eA complete medication history will be completed through 30 days prior to ICF signing; an extended 60 day review will 
be conducted for dalbavancin and oritavancin given the long half-lives of both drugs. 
fVisit 1 hematology, coagulation lab tests (PT, PTT,  and/or INR) and serum chemistry will be done in order to qualify 
the patient for the study, if not already collected per standard of care within 48 hours prior to randomization.  
gA serum creatinine assessment will be required within the 72 hours prior to the 2nd (Day 8) dalbavancin dose. Whether a 
serum creatinine must be repeated on Day 8 will be at the discretion of the site investigator based upon stability of 
the serum creatinine in the preceding 72 hours and whether the serum creatinine is near the threshold where dose 
adjustment would be necessary (e.g., near 30 mL/min).  

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hWomen of childbearing potential only, if not already performed (see Appendix B, Definitions); ensure test is negative 
within 48 hours before randomization. If the serum test results cannot be obtained before randomization, a urine 
pregnancy test may be used for enrollment.  
iDalbavancin PK samples will be drawn only for subjects receiving dalbvacancin. PK samples will be drawn at Day 1 
prior to dose, at end of infusion ± 10 minutes, 6 ± 2 hours post end of dose, 12 ± 4 hours post end of dose, 24 ± 6 
hours post end of dose), Day 8 (prior to 2nd dose), Day 22 ± 2 days (at time of clinic visit), day 42 ± 3 days, day 70 
± 7 days, and with any ET visit. Each sample must be accompanied by draw time and date.   
jVital signs include blood pressure, respiration rate, pulse rate, and temperature. 
kDay 8 vital signs not required for subjects receiving SOC antibiotics if discharge occurs prior to day 8. 
lA physical examination (including general appearance, examination of head, eyes, ears, nose, throat, neck, skin, heart, 
lungs, abdomen, neurologic system, musculoskeletal system, extremities, height, and body weight) will be done at 
Screening (Visit 1). If height or weight is not obtainable (eg, patient is immobilized), use the last known or stated 
height and weight. At subsequent visits, targeted physical exams will focus on changes from prior exams and on the 
evaluation of newly reported symptoms.  
mTransthoracic echocardiogram or, if clinically indicated, transesophageal echocardiogram to be performed (local 
laboratory), unless one has been performed as standard of care for this episode of bacteremia/endocarditis  
nAll concomitant medications from Screening (Visit 1) through Day 42 (± 3 days) (Visit 5) must be recorded in the 
patient’s medical record and on the eCRFs. Between the Day 42 Visit and Day 70 Visit, all concomitant medications 
for an AE or any antibacterial therapy should be recorded in the patient’s medical record and on the eCRF. 
oQoL assessments include the ARLG Bloodstream Infection QoL Measure (Appendix C), the EQ-5D-5L 
(https://euroqol.org/eq-5d-instruments/sample-demo/), and the PROMIS Global Health Short Form 
(http://www.healthmeasures.net/administrator/components/com_instruments/uploads/Global%20Health%20Scale%
20v1.2%2008.22.2016.pdf). 

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 Definitions 
Childbearing Potential: a woman is considered of childbearing potential unless post-
menopausal [≥1 year of spontaneous amenorrhea] or permanently surgically sterilized [bilateral 
oophorectomy, salpingectomy, hysterectomy, tubal ligation]. 
Effective Contraception: Must include at least one of the following: non-male sexual 
relationships only, abstinence from sexual intercourse with a male partner, monogamous 
relationship with a vasectomized partner who has been vasectomized ≥180 days before the 
subject received the first dose of study drug, barrier methods such as condoms or diaphragms, 
effective intrauterine devices (IUDs), NuvaRing®, or licensed hormonal methods such as 
implants, injectables, or oral contraceptives. 
Uncomplicated Staphylococcus aureus Bacteremia: defined as all of the following: exclusion 
of endocarditis by echocardiography; catheter‑associated bacteremia and removal of catheter; no 
implanted prostheses; follow-up blood cultures drawn within 48 hours after initial set that do not 
grow screening pathogen and all follow‑up blood cultures thereafter do not grow the screening 
pathogen; defervescence within 72 hours of initiating effective therapy; and no evidence of 
metastatic sites of infection.  
Complicated S. aureus Bacteremia:  
The following are examples of complicated S. aureus bacteremia. This is not an exhaustive list. 
If a patient’s infection does not meet the definition of uncomplicated bacteremia above, then that 
patient has complicated bacteremia.  
Positive follow-up blood cultures: blood cultures positive for S. aureus drawn at least 24 hours 
after the initial qualifying blood culture 
Persistent fever: oral temperature ≥38.0C for >72 hours after the initial positive blood culture for 
S. aureus 
Endocarditis:  
These criteria have been adjusted to be specific to S. aureus bacteremia, i.e. microbiological 
criteria related to organisms other than S. aureus have been removed. In addition, references to 
prosthetic valve infections have been removed, as these patients will be excluded from the study.  
According to modified Duke Criteria, diagnosis of IE can be definite, possible, or rejected. A 
diagnosis of IE is definite if either the following pathological or clinical criteria are met:  

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Pathologic criteria:  
• pathologic lesions: vegetation or intracardiac abscess demonstrating active endocarditis on 
histology, or  
• microorganism: demonstrated by culture or histology of a vegetation or intracardiac abscess  
 
One of these combinations of clinical criteria (see definitions below):  
• two major clinical criteria  
• one major and three minor criteria  
• five minor criteria  
 
Diagnosis of IE is possible if one of the following combinations of clinical criteria (see 
definitions below) are met:  
• one major and one minor criteria  
• three minor criteria are fulfilled  
  
Diagnosis of IE is rejected if one of the following criteria are met:  
• a firm alternate diagnosis is made  
• resolution of clinical manifestations after ≤ 4 days of antibacterial treatment  
• no pathological evidence of IE is found at surgery or autopsy after antibacterial treatment 
therapy for ≤ 4 days  
• clinical criteria for possible or definite IE are not met 
  
Major criteria for the diagnosis of infective endocarditis:  
 Positive blood culture with S. aureus from two separate blood cultures 
 Evidence of endocardial involvement with positive echocardiogram defined as 
 oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets 
in the absence of an alternative anatomic explanation  
 abscess  
 new valvular regurgitation (worsening or changing of preexisting murmur not sufficient)  
  
Minor criteria for the diagnosis of infective endocarditis:  

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 Predisposing factor: intravenous drug use or presence of a predisposing heart condition (a 
valve lesion associated with significant regurgitation or turbulence of blood flow)  
 Fever ≥38°C (100.4 °F)  
 Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, 
intracranial hemorrhage, conjunctival hemorrhages or Janeway lesions  
 Immunological phenomena: glomerulonephritis, Osler's nodes, Roth's spots, Rheumatoid 
factor  
 A single positive blood culture with S. aureus  
  
Visceral Abscess (e.g. liver, spleen, kidney, etc.) – either of the following: 
• Abscess visualized on radiographic exam, or 
• Isolation of S. aureus from culture of abscess contents 
  
Pleuropulmonary Infection – one of the following: 
 Pulmonary infiltrate consistent with pneumonia in patients with S. aureus bacteremia 
 S. aureus in pleural fluid, needle aspirate biopsy, or growth from bronchoalveolar lavage 
(BAL)/protected specimen brush (PSB) 
 Clinical evidence of pneumonia (e.g. increased O2, increased respiratory rate, cough, 
mechanical ventilation, purulent sputum, etc.) 
  
Osteomyelitis - Either of the following:  
 Radiographic evidence of bone lesion consistent with osteomyelitis/discitis; or  
 Culture of bone yields S. aureus.  
  
Pyomyositis – Either of the following:  
 Radiographic evidence consistent with pyomyositis; or  
 Culture of abscess contents yields S. aureus.  
  
Septic Arthritis – Either of the following:  
• S. aureus in culture of synovial fluid; or  
• Positive Gram stain of synovial fluid for Gram positive cocci AND synovial fluid cell count 
≥20,000 WBC/mL without alternate explanation  

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Septic Thrombophlebitis – Either of the following:  
• Palpable venous cord  
• Evidence of thrombosis on radiologic exam 
 
Relapsing Bacteremia:  Relapsing bacteremia is defined as a S. aureus that:  
• Represents the same bacterial strain as the Baseline Infecting Pathogen (based on bacterial 
speciation, antibiotic susceptibility testing, and/or genotyping tests, as appropriate);  
• Is documented by a blood culture yielding S. aureus obtained after randomization 
 
Source Control Procedure: a procedure intended to treat S. aureus infection. Examples include, 
but are not limited to, surgical debridement or amputations, drainage of infected spaces, and 
removal of prosthetic material 
Vascular Access Procedures: insertion or removal of vascular catheters 
Microbiologic Success: no post-randomization growth of the baseline pathogen from blood 
cultures or another sterile body site 
Blood Culture Contaminant: the following organisms may be considered a contaminant if 
grown from only one blood culture (either alone or in addition to S. aureus isolated from the 
same blood culture): Cutibacterium species, Micrococcus species, viridans-group streptococcus, 
coagulase-negative staphylococci, Corynebacterium species, Bacillus species other than B. 
anthracis, or enterococcus species. 
 
 

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 ARLG Bloodstream Infection Quality of Life Measure 
Please respond to each item by marking 
one box per row. 
  
  
  
  
  
Global  
Excellent 
Very Good 
Good 
Fair 
Poor 
Global01 
1 In general, would you say 
your health is: 
 
 
 
 
 
Global02 
2 In general, would you say 
your quality of life is: 
 
 
 
 
 
Thinking of your bloodstream infection, please answer the following questions to best capture your experiences. 
Fatigue 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
HI7 
3 During the past 7 days, I 
feel fatigued 
 
 
 
 
 
AN3 
4 
During the past 7 days, I 
have trouble starting things 
because I am tired 
 
 
 
 
 
FATEXP41 
5 
In the past 7 days, how run-
down did you feel on 
average?  
 
 
 
 
 
FATEXP40 
6 
In the past 7 days, how 
fatigued were you on 
average?  
 
 
 
 
 
Gastrointestinal Nausea and Vomiting 
Never  
Rarely 
Sometimes 
Often 
Always 
GISX49 
7 
In the past 7 days, how 
often did you have 
nausea—that is, a feeling 
 
 
 
 
 

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like you could vomit? (If 
never, skip to 9) 
GISX52 
8 
In the past 7 days, how 
often did you know that you 
would have nausea before it 
happened? 
 
 
 
 
 
GISX55 
9 
In the past 7 days, how 
often did you have a poor 
appetite? 
 
 
 
 
 
  
  
  
Never 
One day 
2-6 days 
Once a day 
More than 
once a day 
GISX59 
10 
In the past 7 days, how 
often did you throw up or 
vomit? 
 
 
 
 
 
Pain Intensity 
Had no pain 
Mild 
Moderate 
Severe 
Very severe 
PAINQU6 
11 
In the past 7 days, how 
intense was your pain at its 
worst? 
 
 
 
 
 
PAINQU8 
12 
In the past 7 days, how 
intense was your average 
pain? 
 
 
 
 
 
  
  
  
No pain 
Mild 
Moderate 
Severe 
Very severe 
PAINQU21 13 What is your level of pain 
right now? 
 
 
 
 
 
Sleep Disturbance 
Very poor 
Poor 
Fair 
Good 
Very Good 
Sleep109 
14 In the past 7 days, my sleep 
quality was 
 
 
 
 
 

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Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
Sleep116 
15 In the past 7 days, my sleep 
was refreshing 
 
 
 
 
 
Sleep20 
16 In the past 7 days, I had a 
problem with my sleep 
 
 
 
 
 
Sleep44 
17 In the past 7 days, I had 
difficulty falling asleep  
 
 
 
 
 
Emotional Distress - Depression 
Never  
Rarely 
Sometimes 
Often 
Always 
EDDEP04 
18 In the past 7 days, I felt 
worthless 
 
 
 
 
 
EDDEP06 
19 In the past 7 days, I felt 
helpless 
 
 
 
 
 
EDDEP29 
20 In the past 7 days, I felt 
depressed 
 
 
 
 
 
EDDEP41 
21 In the past 7 days, I felt 
hopeless 
 
 
 
 
 
Emotional Distress - Anxiety 
Never  
Rarely 
Sometimes 
Often 
Always 
EDANX01 
22 In the past 7 days, I felt 
fearful 
 
 
 
 
 
EDANX40 
23 
In the past 7 days, I found it 
hard to focus on anything 
other than my anxiety 
 
 
 
 
 
EDANX41 
24 In the past 7 days, my 
worries overwhelmed me 
 
 
 
 
 
EDANX53 
25 In the past 7 days, I felt 
uneasy 
 
 
 
 
 

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Cognitive Function - Abilities 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
PC43_2r 
26 In the past 7 days, my mind 
has been as sharp as usual 
 
 
 
 
 
PC44_2r 
27 
In the past 7 days, my 
memory has been as good 
as usual 
 
 
 
 
 
PC45_2r 
28 
In the past 7 days, my 
thinking has been as fast as 
usual 
 
 
 
 
 
PC47_2r 
29 
In the past 7 days, I have 
been able to keep track of 
what I am doing, even if I 
am interrupted 
 
 
 
 
 
Physical Function 
Without any 
difficulty 
With a little 
difficulty 
With some 
difficulty 
With much 
difficulty 
Unable to do 
PFA11 
30 
Are you able to do chores 
such as vacuuming or yard 
work? 
 
 
 
 
 
PFA21 
31 
Are you able to go up and 
down stairs at a normal 
pace? 
 
 
 
 
 
PFA23 
32 Are you able to go for a 
walk of at least 15 minutes? 
 
 
 
 
 
PFA53 
33 Are you able to run errands 
and shop? 
 
 
 
 
 
  
Not at all 
Very little 
Somewhat 
Quite a lot 
Cannot do 

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PFC12 
34 
Does your health now limit 
you in doing two hours of 
physical labor? 
 
 
 
 
 
PFB1 
35 
Does your health now limit 
you in doing moderate work 
around the house like 
vacuuming, sweeping floors 
or carrying in groceries? 
 
 
 
 
 
Ability to Participate in Social Roles and 
Activities 
Never  
Rarely 
Sometimes 
Often 
Always 
SRPPER11
_CaPS 
36 
I have trouble doing all of 
my regular leisure activities 
with others 
 
 
 
 
 
SRPPER18
_CaPS 
37 
I have trouble doing all of 
the family activities that I 
want to do 
 
 
 
 
 
SRPPER23
_CaPS 
38 
I have trouble doing all of 
my usual work (include 
work at home) 
 
 
 
 
 
SRPPER46
_CaPS 
39 
I have trouble doing all of 
the activities with friends 
that I want to do 
 
 
 
 
 
  
Excellent 
Very Good 
Good 
Fair 
Poor 
  
40 
Because of your 
bloodstream infection, 
would you say your health 
is.. 
 
 
 
 
 

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41 
Because of your 
bloodstream infection, 
would you say your quality 
of life is.. 
 
 
 
 
