A Phase 2, Single-center, Open-label, Randomized, Comparator-controlled Trial of the Safety and Efficacy of Dalbavancin Versus Active Comparator in Adult Patients With Osteomyelitis Known or Suspected to be Due to Gram-Positive Organisms
Phase: PHASE2
Conditions: Osteomyelitis
Sponsor: Durata Therapeutics Inc., an affiliate of Allergan plc

NCT02685033 
 
Study ID: DAL‐MD‐04 
 
Title:  A Phase 2, Single‐center, Open‐label, Randomized, Comparator‐Controlled Trial of 
the Safety and Efficacy of Dalbavancin versus Active Comparator in Adult Patients 
with Osteomyelitis Known or Suspected to be due to Gram‐Positive Organisms 
 
 
Protocol Date: 23 Jun 2015 

1.0
TITLE PAGE
Durata Therapeutics International BV (an Affiliate of Actavis, Inc.)
Spaces Zuidas II
Barbara Strozzilaan 101, 1083HN, Amsterdam
The Netherlands
A Phase 2, Single-center, Open-label, Randomized, Comparator-Controlled Trial of 
the Safety and Efficacy of Dalbavancin versus Active Comparator in Adult Patients
with Osteomyelitis Known or Suspected to be due to Gram-Positive Organisms
DAL-MD-04
Dalbavancin
IND # 60,613
Original Protocol Date:
23 Jun 2015
Confidentiality Statement
This document is the property of Durata Therapeutics, Inc., (an affiliate of Actavis, Inc.) 
and may not—in full or part—be passed on, reproduced, published, distributed, or 
submitted to any regulatory authority without the express written permission of Durata 
Therapeutics, Inc.
 
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2.0
SYNOPSIS AND SCHEDULE OF EVALUATIONS
CLINICAL STUDY SYNOPSIS: Study DAL-MD-04
Title of Study
A Phase 2, Single-center, Open-label, Randomized, Comparator-controlled 
Trial of the Safety and Efficacy of Dalbavancin versus Active Comparator in 
Adult Subjects with Osteomyelitis Known or Suspected to be due to Gram-
Positive Organisms
Study Centers (Country)
1 (Ukraine)
Development Phase
2
Objectives
Primary-

To determine the efficacy of dalbavancin for the treatment of the first 
episode of osteomyelitis known or suspected to be caused by Gram-
positive pathogens in adults
Secondary-

To assess the safety and tolerability of dalbavancin in adult patients with 
osteomyelitis.

To estimate clinical response rate per pathogen in the dalbavancin group
at the end of therapy (Day 42) and Day 180

To estimate clinical response rate in the dalbavancin group at Day 21, 
Day 180 and Day 365

 
Methodology
Single-center, open-label, parallel-arm, randomized, efficacy and safety study
Number of Patients
Approximately 80 (70 in the dalbavancin treatment group and 10 in the 
comparator treatment group)
Diagnosis and 
Main Criteria for Inclusion
Male and female patients who are ≥ 18 years of age that meet the diagnostic 
criteria for osteomyelitis defined as pain or point tenderness upon palpation or 
probing to bone, and either radiological findings consistent with a diagnosis of 
osteomyelitis or a bone specimen with Gram-positive cocci on a baseline 
Gram-stain
Test Product, Dosage, and Mode of 
Administration
Dalbavancin 1500 mg IV over 30 minutes on Day 1 and Day 8 (if creatinine 
clearance ≥ 30 mL/min or if on regular hemodialysis or peritoneal dialysis)

Dose reduction if creatinine clearance < 30 mL/min (and not receiving 
regular hemodialysis or peritoneal dialysis): Dalbavancin 1000 mg IV 
over 30 minutes on Day 1 and Day 8
Duration of Treatment
Treatment: 2 doses of dalbavancin 1 week apart, 4-6 weeks comparator
Follow up: 365 days from the start of therapy
Reference Therapy, Dosage, and 
Mode of Administration
Standard of care antibiotic (oral or intravenous) for the treatment of 
osteomyelitis based on the judgment of the study physician
Drugs allowed as concomitant medications

Aztreonam may be administered at randomization for presumed co-
infection with a Gram-negative pathogen and could be discontinued if a 
Gram-negative pathogen is not documented by culture results. A switch 
to an oral antibiotic for coverage of Gram-negative pathogens is 
allowed once evidence of clinical improvement has been established.

Metronidazole (IV or oral) or oral vancomycin may be used for 
Clostridium difficile infections.

Other antibiotics that do not achieve significant therapeutic
concentrations in the serum (eg, nitrofurantoin) may be considered for 
treatment of other concomitant infections. Close consultation with the 
medical monitor is advised prior to use of these antibiotics.
Surgical debridement should be performed on any patient if clinically 
indicated.
 
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Criteria for Evaluation
Primary Outcome Measure
Clinical response at Day 42 in the Clinically Evaluable (CE) population
Secondary Outcome Measures

Clinical improvement at Day 21 in the mITT and CE Populations

Clinical response (cure, failure, or indeterminate) at Day 42 in the mITT
and micro-mITT Populations

Clinical response (cure, failure, or indeterminate) at Day 180 in the mITT
and CE Populations

Clinical response (cure, failure, or indeterminate) at Day 365 in the mITT
and CE Populations

Clinical response (cure, failure, or indeterminate) by pathogen at Day 42
and Day 180 in the CE Population
 
Pharmacokinetic Measures
Not Applicable
Statistical Methods
The study is exploratory in nature. Descriptive statistics, including the 
numbers and percentages for categorical variables, and the numbers, means, 
standard deviations, medians, minimums, and maximums for continuous 
variables will be provided.  Listings of individual patient’s data will be 
produced.
 
 
 
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3.1 TABLE OF CONTENTS 
 
 
Page
1.0 TITLE PAGE ..............................................................................................
 
2.0 SYNOPSIS AND SCHEDULE OF EVALUATIONS ...............................
 
3.0 TABLE OF CONTENTS AND TABLES 
 
3.1 TABLE OF CONTENTS .........................................................................
 
3.2 LIST OF IN-TEXT TABLES ..................................................................
 
4.0 LIST OF ABBREVIATIONS .....................................................................
 
5.0 ETHICAL CONSIDERATIONS ................................................................
 
5.1 INDEPENDENT ETHICS COMMITTEE ..............................................
 
5.2 ETHICAL CONDUCT OF THE STUDY...............................................
 
5.3 PATIENT INFORMATION AND INFORMED CONSENT.................
 
6.0 INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE ...................................................................................................
 
7.0 INTRODUCTION ......................................................................................
 
8.0 STUDY OBJECTIVES ...............................................................................
 
9.0 INVESTIGATIONAL PLAN .....................................................................
 
9.1 OVERALL STUDY DESIGN AND PLAN: DESCRIPTION ...............
 
9.2 DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE 
OF CONTROL GROUPS .............................................................................
 
9.3 SELECTION OF STUDY POPULATION .............................................
 
9.3.1 Inclusion Criteria ...............................................................................
 
9.3.2 Exclusion Criteria ..............................................................................
 
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9.3.3 Removal of Patients From Therapy or Study Assessment ................
 
9.3.3.1 Premature Discontinuation From Study Drug ............................
 
9.3.3.2 Withdrawal From Study ..............................................................
 
9.3.4 Patient Replacement Procedures .......................................................
 
9.4 TREATMENTS .......................................................................................
 
9.4.1 Treatments Administered ..................................................................
 
9.4.1.1 Dalbavancin Treatment Group ....................................................
 
9.4.1.2 Standard of Care Treatment Group .............................................
 
9.4.1.3 Other Additional Antibacterial Therapy .....................................
 
9.4.1.4 Duration of Treatment.................................................................
 
9.4.2 Identity of Investigational Products ..................................................
 
9.4.3 Method of Assigning Patients to Treatment Groups .........................
 
9.4.4 Selection of Dosages in the Study .....................................................
 
9.4.4.1 Dose Adjustments - Dalbavancin ................................................
 
9.4.4.2 Dose Adjustments - Other Investigational Products ...................
 
9.4.5 Blinding .............................................................................................
 
9.4.6 Unblinding .........................................................................................
 
9.4.7 Prior and Concomitant Therapy ........................................................
 
9.4.8 Monitoring Treatment Compliance ...................................................
 
9.5 EFFICACY AND SAFETY VARIABLES .............................................
 
9.5.1 Efficacy Assessments ........................................................................
 
9.5.1.1 Primary and Secondary Efficacy Assessments ...........................
 
9.5.1.1.1 Primary Efficacy Assessment ...............................................
 
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9.5.1.1.2 Secondary Efficacy Assessments .........................................
 
9.5.1.2 Microbiological Assessments .....................................................
 
9.5.1.2.1 Blood Samples for Culture ...................................................
 
9.5.2 Safety Assessments ...........................................................................
 
9.5.2.1 Adverse Events ...........................................................................
 
9.5.2.1.1 Abnormal Test Findings .......................................................
 
9.5.2.2 Causality Assessment..................................................................
 
9.5.2.3 Severity Assessment ...................................................................
 
9.5.2.4 Serious Adverse Events ..............................................................
 
9.5.2.4.1 Hospitalization ......................................................................
 
9.5.2.5 Reporting Adverse Events and Serious Adverse Events ............
 
9.5.2.6 Immediate Reporting of Serious Adverse Events and Events 
of Special Interest ...................................................................................
 
9.5.2.7 Reporting of Pregnancies Occurring During the Study ..............
 
9.5.2.8 Potential Hy’s Law Cases ...........................................................
 
9.5.2.9 Clinical Laboratory Determinations ...........................................
 
9.5.2.9.1 Potential Drug-Induced Liver Injury/Hy’s Law ...................
 
9.5.2.10 Vital Signs, Body Weight, and Height......................................
 
9.5.2.11 Physical Examination................................................................
 
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9.6 DATA QUALITY ASSURANCE ..........................................................
 
9.6.1 Data Recording and Documentation .................................................
 
9.6.2 Data Monitoring ................................................................................
 
9.7 STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE ..............................................................................................
 
9.7.1 Analysis Populations .........................................................................
 
9.7.1.1 Screened Population ....................................................................
 
9.7.1.2 Intent-to-Treat Population ...........................................................
 
9.7.1.3 Safety Population ........................................................................
 
9.7.1.4 Modified Intent-to-Treat Population ...........................................
 
9.7.1.5 Clinically Evaluable Population .................................................
 
9.7.1.6 Microbiological mITT Population ..............................................
 
9.7.2 Patient Disposition ............................................................................
 
9.7.3 Demographics and Other Baseline Characteristics ...........................
 
9.7.4 Extent of Exposure and Treatment Compliance ...............................
 
9.7.4.1 Extent of Exposure ......................................................................
 
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9.7.4.2 Measurement of Treatment Compliance .....................................
 
9.7.5 Efficacy Analyses ..............................................................................
 
9.7.5.1 Primary Efficacy Parameter ........................................................
 
9.7.5.2 Secondary Efficacy Parameters ..................................................
 
 
9.7.6.1 Adverse Events ...........................................................................
 
9.7.6.2 Clinical Laboratory Parameters ..................................................
 
9.7.6.3 Vital Signs ...................................................................................
 
 ......................
 
9.7.8 Interim Analysis ................................................................................
 
9.7.9 Determination of Sample Size ...........................................................
 
9.7.10 Computer Methods ..........................................................................
 
9.8 CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES ..................................................................................................
 
9.9 PROTOCOL DEVIATIONS ...................................................................
 
10.0 STUDY SPONSORSHIP..........................................................................
 
10.1 STUDY TERMINATION .....................................................................
 
10.2 REPORTING AND PUBLICATION ...................................................
 
11.0 INVESTIGATOR OBLIGATIONS .........................................................
 
11.1 DOCUMENTATION ............................................................................
 
11.2 PERFORMANCE ..................................................................................
 
11.3 USE OF INVESTIGATIONAL MATERIALS ....................................
 
11.4 CASE REPORT FORMS ......................................................................
 
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11.5 RETENTION AND REVIEW OF RECORDS .....................................
 
11.6 PATIENT CONFIDENTIALITY .........................................................
 
12.0 INVESTIGATOR’S STATEMENT .........................................................
 
13.0 APPENDICES ..........................................................................................
 
APPENDIX I. ELEMENTS OF INFORMED CONSENT ...........................
 
 ..............................................
 
APPENDIX III. POTENTIAL DRUG-INDUCED LIVER 
INJURY/HY’S LAW ....................................................................................
 
 
14.0 LITERATURE CITED .............................................................................
 
 
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3.2 LIST OF IN-TEXT TABLES 
 
 
Page
 
Table 9.4.4.1–1. Dalbavancin Dosage Adjustments for Renal Impairment .....
 
 
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4.0
LIST OF ABBREVIATIONS
ABSSSI
acute bacterial skin and skin structure infection
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase 
AST
aspartate aminotransferase
AUC
area under curve
CA-MRSA
community-acquired methicillin-resistant staphylococcus aureus
CFR
Code of Federal Regulations
CFU
colony-forming units
CRP
C-reactive protein
cSSSI
complicated skin and skin structure infection
eCRF
electronic case report form
EDC
electronic data capture
EOIV
end of intravenous
ESR
erythrocyte sedimentation rate
FDA
US Food and Drug Administration
FR
Federal Register
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act of 1996
ICF
informed consent form
ICH
International Conference on Harmonisation
IND
Investigational New Drug
IRB
Institutional Review Board
ITT
intent-to-treat
 
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IV
intravenous, intravenously
LAR
legally authorized representative
MedDRA
Medical Dictionary for Regulatory Activities
MIC90
minimum inhibitory concentration 90
MITT
modified intent-to-treat
Micro-mITT
microbiological modified intent-to-treat
MRI
magnetic resonance imaging
MRSA
methicillin-resistant Staphylococcus aureus
PCS
potentially clinically significant
PHL
potential Hy’s Law
RSM
Regional Site Manager
SAE
serious adverse event
SOC
standard of care
TEAE
treatment-emergent adverse event
TOC
test-of-cure
ULN
upper limit of normal
 
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5.0
ETHICAL CONSIDERATIONS
5.1
INDEPENDENT ETHICS COMMITTEE
This study will be carried out in full compliance with the guidelines of the independent 
ethics committee (IEC) and government agencies of the Ukraine as well as the European 
Union Clinical Trial Directive (Directive 2001/20/EC), where applicable. Before the 
study begins, the site will require approval from an IEC and government agency. During 
the course of the study, the Sponsor or authorized representative will provide timely and 
accurate reports to the IEC on the progress of the study, at intervals not exceeding 1 year 
(or as appropriate) and will notify the IEC of SAEs or other significant safety findings. 
The study protocol, Informed Consent Form (ICF), information sheet advertisements, and 
amendments (if any) will be approved by the IEC at the study site in conformance with 
CFR, Title 21, Part 56, the European Union Clinical Trial Directive (Directive 
2001/20/EC), and local regulations.
5.2
ETHICAL CONDUCT OF THE STUDY
This clinical study will be conducted in accordance with the ethical principles that have 
their origins in the Declaration of Helsinki.
This clinical study will comply with ICH Guidance on General Considerations for 
Clinical Trials (ICH-E8; 62 FR 66113, 17 Dec 1997) and Good Clinical Practice 
(ICH-E6; 62 FR 25692, 09 May 1997), as well as Part 312 of the CFR.
5.3
PATIENT INFORMATION AND INFORMED CONSENT
Patients, after being given an explanation of the study, will give voluntary and written 
informed consent before participating in any study-related procedures.
Each patient (or his or her legally authorized representative) will read, assent to an
understanding of, and sign an instrument of ICF after having had an opportunity to 
discuss it with the study staff before signing; each patient will be made aware that he or 
she may withdraw from the study at any time.
The informed consent statement contains all the elements of informed consent listed in 
Appendix I of this protocol. Signed copies of the ICF will be given to the patient, and 
both documents will be placed in the Investigator’s study files. 
 
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6.0
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE
This study will be performed at 1 study center in the Ukraine.
The Investigator is responsible for ensuring that the study is conducted according to the 
signed Investigator statement, the investigational plan, GCP guidelines, and applicable 
regulations; for protecting the rights, safety, and welfare of patients under the 
Investigator’s care; and for the control of investigational products under investigation. An 
Investigator shall obtain the informed consent of each human patient prior to the patient
enrolling in the study and/or prior to participating in any study-related activity. 
The Investigator must meet his or her obligations to the patients, ethics committee, 
Sponsor, and regulatory authorities by maintaining oversight and control of the study’s 
conduct and the study staff. It is the responsibility of the Investigator to ensure that any 
and all delegated duties be assigned to qualified staff by education, experience, and 
licensure (in accordance with local regulations) and that the Investigator oversight is
documented and assessment of their capabilities and performance consistent with the
study investigational plan. The Investigator will be responsible for the management of the 
study, including maintaining the study file and the patient records, corresponding with the 
IEC, and completing the electronic case report forms (eCRFs).
 
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7.0
INTRODUCTION
Osteomyelitis is an infection of bone that can occur as a result of hematogenous seeding 
(transmitted via blood), contiguous spread of infection to bone from adjacent soft tissues 
and joints (eg, cellulitis, septic arthritis), or direct inoculation of infection into the bone as 
a result of trauma or surgery (Fritz and McDonald, 2008). Hematogenous osteomyelitis is 
usually monomicrobial, while osteomyelitis due to contiguous spread or direct 
inoculation is usually polymicrobial. Staphylococcus aureus (S. aureus) is the organism 
most commonly isolated from all forms of osteomyelitis (Calhoun et al, 2009).
Standard treatment for osteomyelitis requires prolonged antibiotic therapy (4-6 weeks) 
and may require surgical debridement (removal of infected tissue). Whenever possible, 
antibiotic therapy should be tailored to culture and susceptibility findings. Antimicrobials 
with activity against the most commonly isolated organism, S. aureus, are routinely used. 
These include anti-staphylococcal penicillins (nafcillin/oxacillin), clindamycin, first-
generation cephalosporins (cefazolin), and vancomycin. With the increasing incidence of 
community-acquired-methicillin-resistant S. aureus (CA-MRSA), vancomycin has 
become the primary choice for therapy when that organism is suspected. Vancomycin or 
clindamycin are used when 10% or more of community S. aureus isolates are known to 
be methicillin resistant (Liu et al, 2011). However, presence of inducible resistance to 
clindamycin limits its use and vancomycin requires careful dose adjustments to maintain 
appropriate concentrations in the blood. Clearly, the seriousness of the condition, with its 
potential for limb-threatening outcomes, strongly suggests a need for the development of 
additional antimicrobial agents. 
Dalbavancin is a lipoglycopeptide which is highly active against Gram-positive bacteria, 
including streptococci, S. pneumoniae and S. aureus, including MRSA; the MIC90 for 
S. aureus is 0.06 μg/mL. In addition, dalbavancin has a half-life of approximately 
14 days, allowing for once weekly dosing. In adults, dalbavancin (given as 1000 mg on 
Day 1 followed by 500 mg on Day 8), has been shown to be non-inferior both to linezolid 
alone and to a comparator regimen including vancomycin and linezolid in the treatment 
of acute bacterial skin and skin structure infections (ABSSSI)/complicated skin and skin 
structure infections (cSSSI) in multiple randomized, double-blinded studies (VER001-9, 
DUR001-301 and DUR001-302). Dalbavancin was well tolerated in these studies, with a 
higher proportion of patients in the comparator group reporting an adverse event (AE) as 
compared with dalbavancin. The most common AEs reported with dalbavancin were 
gastrointestinal complaints (nausea, diarrhea) and headache.
 
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Pharmacokinetics in Bone and Related Tissue
The pharmacokinetics of dalbavancin in bone and synovial tissue have been studied in a 
Phase 1 study in adults undergoing elective orthopedic surgery (DUR001-105). Adults 
scheduled for elective orthopedic surgery were assigned to one of 6 cohorts, for tissue 
sampling at 12 hours, 24 hours, 72 hours, 168 hours, 240 hours or 336 hours post dose. 
Enrolled subjects received a single 1000 mg dose of dalbavancin at the appropriate time 
point prior to scheduled surgery. Thirty-one subjects received dalbavancin in order to 
obtain 30 evaluable bone samples. The mean concentration of dalbavancin in bone at 
12 hours post dose was 6.3 ± 3.2 μg/g, and remained > 10-fold above the MIC90 of 
S. aureus through the final sample collection at 336 hours (14 days) (see Table below). 
The mean bone:plasma AUC penetration ratio was 13.9%. The concentration of 
dalbavancin in synovial fluid at 12 hours post dose was 22.9 μg/mL and also remained 
above MIC90 of S.aureus through final sample collection. Similar values were seen in 
synovial tissue.
Table: Dalbavancin tissue concentrations in DUR001-105 (Dunne et al)
Animal model of osteomyelitis 
Dalbavancin was studied in a rat model of S. aureus sternal osteomyelitis. Rats with 
S. aureus sternal osteomyelitis were treated with one of 3 regimens: dalbavancin 
(20 mg/kg loading dose followed by 10 mg/kg daily), vancomycin (given IP, 50 mg/kg, 
q12h) or saline treatment for 7 days and 14 days; efficacy in reducing sternal bone 
bacterial counts was assessed. Dalbavancin showed superiority compared to saline at 
7 days (0.75 log reduction in bone CFU) and at 14 days treatment (> 3-log reduction in 
bone CFU). Treatment with 7 days of dalbavancin reduced systemic dissemination of 
MRSA compared to saline (5% vs 33%). Results were similar to those achieved by 
vancomycin therapy. This study demonstrated the effectiveness of dalbavancin using 
doses mimicking human PK in the treatment of MRSA rat sternal osteomyelitis and 
confirms that dalbavancin in bone is available for the killing of bacterial pathogens.
 
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The prolonged half-life of dalbavancin, which allows for once weekly dosing, maintains
serum concentrations above the MIC90 for most Gram-positive pathogens, including 
S. aureus. The demonstrated distribution of dalbavancin into bone and related tissues is 
also reassuring. The 2-dose, once weekly dosing regimen offers advantages to patients 
and physicians regarding the need for prolonged intravenous access and compliance with 
an anti-infective treatment course for a disease with a treatment duration of 4-6 weeks.
More complete information about dalbavancin is found in the current Investigator's 
Brochure.
 
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8.0
STUDY OBJECTIVES
Primary-

To determine the efficacy of dalbavancin for the treatment of the first episode of 
osteomyelitis known or suspected to be caused by Gram-positive pathogens in adults
Secondary-

To assess the safety and tolerability of dalbavancin in adult patients with 
osteomyelitis

To estimate the clinical response rate per pathogen in the dalbavancin group at the 
end of therapy (Day 42) and Day 180

To estimate the clinical response rate in the dalbavancin group at Day 21, Day 180 
and Day 365

 
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9.0
INVESTIGATIONAL PLAN
9.1
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION
This clinical study will be a single-center, randomized, open-label, active-controlled,
parallel-group study comparing dalbavancin to standard of care (SOC) therapy in 
osteomyelitis. Patients randomized to the dalbavancin treatment group will receive 
2 doses of dalbavancin 1 week apart and patients in the SOC treatment group will receive 
SOC therapy for 4 to 6 weeks of treatment with SOC therapy. Patients will then be 
followed up for a period of 365 days.
The Schedule of Assessments and Procedures is presented in Section 2.0. Detailed 
descriptions of each study visit can be found in Section 9.5.1.
9.2
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE 
OF CONTROL GROUPS
An open-label, randomized, parallel-arm study design was chosen because of the 
challenges with conducting a blinded study with various treatment options and dosing 
schedules.
There will be 2 open-label treatment groups: dalbavancin 1500 mg IV on Day 1 and 
Day 8, and oral or IV SOC antibiotic for osteomyelitis based on investigator judgment for 
4-6 weeks. The 2 groups will be randomized in a 7:1 ratio (70 patients in the dalbavancin 
treatment group and 10 patients in the SOC treatment group).
The SOC treatment group will serve as a contemporaneous illustration of typical SOC 
regimens used at the study site, and to help assess generalizability of study findings, since 
the study will be done in a single site in the Ukraine. A small comparator group (n = 10) 
is preferred over extrapolating from historical controls that may be very different from 
study cohort, and would likely lack efficacy data and inflammatory markers at the same 
time points as the dalbavancin treatment group.
9.3
SELECTION OF STUDY POPULATION
9.3.1
Inclusion Criteria
To be eligible to participate in the study, a patient must meet the following criteria:
1. Male or female, ≥18 years old
 
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2. A diagnosis of osteomyelitis (first episode) defined by:

Pain or point tenderness upon palpation or probing to bone

Plain radiograph or MRI consistent with osteomyelitis (indistinctly 
marginated edema-like pattern of bone marrow hypointensity on 
unenhanced T1-weighted sequences, hyperintensity on fat-saturated 
T2-weighted and STIR sequences and/or abnormal enhancement on 
gadolinium-enhanced fat-saturated T2-weighted sequences, with or 
without visible periostitis or cortical bone destruction)
OR
Gram-positive cocci documented on a baseline Gram-stain from a bone 
specimen 

Elevated CRP (low sensitivity) above the upper limit of normal (ULN) 
(reference range for low sensitivity CRP is 3-10 mg/L)
3. A signed and dated written informed consent document indicating that the subject 
(or a legally authorized representative) has been informed of all pertinent aspects 
of the study.
4. Subjects must be willing and able, if discharged from the hospital, to return to the 
hospital or a designated clinic for scheduled visits, treatment, laboratory tests, and 
other outpatient procedures as required by the protocol.
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will not be eligible to participate in the 
study:
1. Treatment with an investigational drug within 30 days preceding the first dose of 
investigational product.
2. Receipt of > 24 hours of potentially effective IV antibacterial therapy for 
osteomyelitis within 96 hours of randomization, unless the pathogen isolated was 
documented to be MRSA that was resistant to the administered antibiotic.
3. A prior episode of osteomyelitis, or a failed course of therapy for osteomyelitis.
4. Infection associated with a burn wound, with a sacral decubitus ulcer, or with 
multiple sites of osteomyelitis.
 
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5. Septic arthritis that is non-contiguous to osteomyelitis, as diagnosed by isolation 
of a pathogen from synovial fluid culture.
6. Immunosuppression/immune deficiency, including hematologic malignancy, 
recent bone marrow transplant (in post-transplant hospital stay), absolute 
neutrophil count < 500 cells/mm3, receiving immunosuppressant drugs after organ 
transplantation, receiving oral steroids for an extended period of time (> 20 mg 
prednisolone per day or equivalent),  chronic granulomatous disease, and known 
or suspected human immunodeficiency virus (HIV) infection with a CD4 cell 
count < 200 cells/mm3 or with a past or current acquired immunodeficiency 
syndrome (AIDS)-defining condition and unknown CD4 count.
7. Evidence of Gram-negative bacteria by Gram stain in the absence of 
Gram-positive organisms.
8. Gram-negative bacteremia, even in the presence of Gram-positive infection or
Gram- positive bacteremia. Note: If a Gram-negative bacteremia develops during
the study, or is subsequently found to have been present at Baseline, the patient 
should be removed from study treatment and receive appropriate antibiotic(s) to 
treat the Gram-negative bacteremia.
9. Evidence of fungus or mycobacteria at baseline 
10. Patients with concomitant endocarditis, necrotizing fasciitis, or prosthetic material 
at the site of infection at the time of study initiation.
11. Patients with an infection involving a limb with evidence of critical ischemia 
defined as any of the following criteria: absent or abnormal Doppler wave forms, 
toe blood pressure of < 45 mm Hg, ankle brachial index < 0.5, and/or critical 
ischemia as assessed by a vascular surgeon.
12. Infection due to an organism known prior to study entry to not be susceptible to 
dalbavancin (dalbavancin mean inhibitory concentration [MIC] > 0.12 μg/mL) or 
vancomycin (vancomycin MIC > 2 μg/mL).
13. Concomitant systemic antibacterial therapy for Gram-positive infections 
(eg, rifampin, gentamicin).
14. Concomitant condition requiring any antibiotic therapy that would interfere with 
the assessment of study drug for the condition under study.
15. Known or suspected hypersensitivity to glycopeptide antibiotics.
16. Patients with a rapidly fatal illness, who are not expected to survive for 3 months.
 
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17. Pregnant or nursing females; positive urine (or serum) pregnancy test at Screening 
(pre-menopausal females only) or after admission (prior to dosing)
18. Sexually active females of childbearing potential who are unwilling or unable to 
use an acceptable method of contraception from at least the first dose of study 
drug until the last pregnancy test.
19. Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the Investigator, would make the patient 
inappropriate for entry into this study.
20. Unwilling or unable to follow study procedures.
21. Employee or immediate relative of an employee of Durata Therapeutics, Inc., any 
of its affiliates or partners, or the study site.
9.3.3
Removal of Patients From Therapy or Study Assessment
Patients should be encouraged to complete all study assessments. However, a patient may 
be discontinued from study drug therapy or may withdraw consent to participate in this 
study at any time without penalty or loss of benefits to which the patient is otherwise 
entitled. 
A premature discontinuation from the study will occur when a patient who signed the 
ICF, regardless of circumstances, ceases participation in the study, before the completion 
of all study assessments (ie, before completing all protocol-stipulated activities).
Follow-up of patients prematurely discontinued from study drug or withdrawn from the 
study will be conducted as described below.
9.3.3.1
Premature Discontinuation From Study Drug
Reasons: Possible reasons for premature discontinuation from study drug administration 
include, but are not limited to:

Occurrence of an AE that, in the opinion of the Investigator, warrants the patient’s 
permanent discontinuation from IV study drug

Known pregnancy or breastfeeding during the study therapy administration period. A 
female patient whose pregnancy test is positive at Day 28 or 42 must be followed 
through the immediate postnatal period or until termination of the pregnancy. Study 
center personnel must report every pregnancy as soon as possible (within 24 hours of 
learning of the pregnancy; as described in Section 9.5.2.7).
 
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
The patient meets criteria for drug-induced liver injury per Appendix III, at the 
discretion of the Investigator

Patient has an insufficient therapeutic response to study drug. 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 therapy.

If a Gram-negative bacteremia or fungemia develops during the study, or is 
subsequently found to have been present at Baseline, the patient should be removed 
from study treatment and receive appropriate antibiotic(s) to treat the Gram-negative 
bacteremia.

Patients from whom only a Gram-negative pathogen is isolated from blood and/or 
bone culture should be removed from study treatment and receive appropriate 
antibiotic(s) to treat the Gram-negative infection.

Investigator determines that it is in the best interest of the patient to discontinue study 
drug, due to reasons other than an AE
Assessments and Procedures: A patient who is prematurely discontinued from study 
drug should have the assessments for premature discontinuation conducted at the time of 
discontinuation as outlined in Table 2-1. A clear description of reason for premature 
discontinuation from study drug must be documented. If a patient is discontinued from 
study drug due to insufficient therapeutic effect and is switched to an alternative 
antibiotic, that therapy should be recorded. The reasons for premature discontinuation 
from study drug will be reflected on the relevant disposition page of the eCRF. Patients 
who discontinue from study therapy should continue to have follow-up safety visits.
9.3.3.2
Withdrawal From Study 
Reasons: Possible reasons for withdrawal from study depend on the timing of the 
withdrawal, and include, but are not limited to:

Screen failure (failure to meet inclusion/exclusion criteria) (before administration of 
first dose of study therapy)

Withdrawal of consent (a clear reason must be documented)

AE (before administration of first dose of study therapy)

Protocol deviation/violation, including lack of compliance 
 
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
Lost to follow-up (every effort must be made to contact the patient; a certified letter 
must be sent)

Study or site prematurely terminated by Sponsor for any reason 
An AE should not be a reason for withdrawal from study after study drug has been 
administered. The patient may be discontinued from study drug due to an AE, in which 
case they should be encouraged to stay in the study for follow-up safety assessments. 
Note: If death was due to an AE, then the AE is the reason for discontinuing study drug 
and death is the reason for withdrawal from study. If the death is due to lack of efficacy, 
then lack of efficacy is the reason for discontinuing study drug, and death is the reason 
for withdrawal from study.
Assessments and Procedures: Patients may withdraw from the study, or be withdrawn 
at the request of the Investigator or Sponsor. A patient who is withdrawn from the study 
should be encouraged to undergo the assessments for premature discontinuation 
conducted as outlined in Table 2-1 on the day of withdrawal. Patients who do not 
complete all scheduled visits/procedures must be requested in writing to come in for a 
premature discontinuation visit and to return any unused investigational product. A copy 
of the letter, together with the source documentation, will be kept by the Investigator. A 
clear description of reason for withdrawal from study must be documented. The reasons 
for withdrawal from the study will be reflected on the relevant disposition page of the 
eCRF.
9.3.4
Patient Replacement Procedures
Randomized patients who are withdrawn will not be replaced.
 
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9.4
TREATMENTS
9.4.1
Treatments Administered
9.4.1.1
Dalbavancin Treatment Group
Patients randomized to the dalbavancin treatment group will receive treatment as follows:

Normal renal function (and patients receiving regular hemodialysis or peritoneal 
dialysis): dalbavancin 1500 mg IV over 30 (± 5) minutes on Day 1 and Day 8. 

Chronic renal insufficiency (with a serum creatinine clearance of < 30 mL/min and 
not receiving regular hemodialysis): dalbavancin 1000 mg IV over 30 (± 5) minutes
on Day 1 and Day 8
9.4.1.2
Standard of Care Treatment Group
Patients randomized to the SOC comparator treatment group will receive an antibiotic 
consistent with SOC for osteomyelitis based on Investigator judgment. The duration of 
treatment will be 4-6 weeks.
9.4.1.3
Other Additional Antibacterial Therapy
Aztreonam may be administered at randomization for presumed co-infection with a 
Gram-negative pathogen and could be discontinued if a Gram-negative pathogen is not 
documented by culture results. A switch to an oral antibiotic for coverage of 
Gram-negative pathogens is allowed once evidence of clinical improvement has been 
established.
Metronidazole (IV or oral) or oral vancomycin may be used for Clostridium difficile
infections.
Other antibiotics that do not achieve significant therapeutic concentrations in the serum 
(eg, nitrofurantoin) may be considered for the treatment of other concomitant infections. 
Close consultation with the medical monitor is advised prior to use of these antibiotics.
9.4.1.4
Duration of Treatment
The total duration of study therapy will be 2 doses of dalbavancin given 1 week apart, 
and 4 to 6 weeks of comparator treatment.
 
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9.4.2
Identity of Investigational Products
Dalbavancin for Injection is supplied as a single-use vial of sterile, lyophilized 
preservative-free powder containing dalbavancin hydrochloride equivalent to 500 mg of 
dalbavancin. Each vial should be reconstituted and further diluted prior to administration 
by addition of 5% dextrose (5% glucose) solution (D5W) in accordance with the study 
pharmacy manual. The study center is responsible for providing the appropriate 
commercially available diluents required for preparation and administration of 
IV infusion.
Investigational dalbavancin will be labeled based on local regulations. Immediately 
before dispensing investigational dalbavancin, the Investigator will write the patient 
identification number, patient’s initials, and date on the label. 
With the exception of dalbavancin, all other study drugs (oral or parenteral) will be 
commercially labeled and supplied by the study site. If aztreonam is not available locally, 
it will also be labeled and supplied by the Sponsor. All study drugs should be kept in a 
secure place under appropriate storage conditions, as specified on the drug labeling and 
package insert.
The Investigator or designee is responsible for recording the receipt and use of all 
investigational products supplied and for ensuring the supervision of the storage and 
allocation of these supplies. Upon completion of the study or termination of the site, all 
unused study drugs that were not dispensed will be shipped to a site designated by the 
Sponsor. 
Refer to the Pharmacy Manual for additional information.
9.4.3
Method of Assigning Patients to Treatment Groups
Patients will be randomly assigned 7:1 to the dalbavancin or SOC treatment group.
At the time of signing the ICF and consenting to participate in this study, each patient
will be assigned a unique 8-digit patient identification number consisting of a 3-digit 
study center number followed by a 2-digit protocol number and then a 3-digit unique 
patient number for the study center. The first patient to sign the ICF at the study center 
will be assigned the first number in the sequence by the study center, and each 
subsequent patient will be assigned the next sequential number. This patient identification
number will be used to identify the patient at all phases of the study. 
 
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A list of patient randomization numbers will be generated by Statistical Programming at 
Actavis. The study center will be provided with the list of randomization numbers and the 
corresponding treatment group assignment (dalbavancin or SOC comparator). 
Randomization numbers will be assigned consecutively (eg, 1, 2, 3,…) by the 
Investigator (or appropriately trained designee) at the time the patient is randomized into 
the treatment group (ie, the first patient randomized will be assigned to the first number 
in the sequence and assigned to the associated treatment group). The treatment group 
assignment will be blinded until the time of randomization.
Refer to the Pharmacy Manual for additional information.
9.4.4
Selection of Dosages in the Study
A 2-dose regimen of 1500 mg of dalbavancin administered 1 week apart is proposed for 
treatment of osteomyelitis in adults for the following reasons:

The safety of a single 1500 mg dose has been previously evaluated in approximately 
60 healthy adult volunteers. The single 1500 mg dose was also administered (over 
30 minutes) to over 300 patients with ABSSSI in the recently completed Phase 3 trial 
DUR001-303, with comparable safety and efficacy to the two-dose regimen (1000 mg 
on Day 1, followed by 500 mg on Day 8). While a 25 mg/kg dose was also studied in 
a small number of children and was also well tolerated, it was only studied in children 
< 6 years of age.

A total dose of 4500 mg over 8 weeks was safely administered and well-tolerated in a
phase 1 study of extended duration dosing (DUR001-104), with no apparent 
accumulation (1000 mg of dalbavancin on Day 1 followed by 500 mg weekly for 
7 additional weeks) (Dunne, 2015).

The 2-dose regimen of 1500 mg of dalbavancin administered 1 week apart was 
derived from data from the bone penetration study (DUR001-105) and extended 
duration dosing study (DUR001-104), along with population PK modeling 
(Dunne, 2015). 

The pharmacokinetic/pharmacodynamic parameter that correlated best with 
dalbavancin’s efficacy is AUC/MIC. The 2-dose regimen of 1500 mg administered 
1 week apart is expected to achieve an AUC similar to that for a 1000 mg initial dose, 
followed by 4 subsequent 500 mg weekly doses (Dunne, 2015). 
 
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
In animal models (Andes, 2007), delivery of the same total dose of dalbavancin
earlier in the course of therapy was associated with a better likelihood of success 
relative to the same total dose given in smaller amounts over longer periods of time. 
Assuming these findings in animals pertain to human infection, 2 doses of 
dalbavancin within the first 8 days may be more likely to be effective relative to the 
same total dose over approximately 6 weeks.

The proposed dose will also provide dalbavancin exposures in plasma which exceed 
the MIC90 for S. aureus for greater than 42 days (6 weeks).

Delivery of only 2 doses of dalbavancin avoids the need for a central catheter and the 
need for delivery of intravenous medications at home.
The dosing regimen for the SOC comparators will be based on the relevant prescribing 
information for those medications and standard clinical care for patients with 
osteomyelitis.  The total treatment duration for patients in the SOC treatment group is 
expected to be 4-6 weeks.
9.4.4.1
Dose Adjustments - Dalbavancin
In the case of renal impairment, at any time, the dose of dalbavancin (including the initial 
dose) may be adjusted by the pharmacist or designee per the dosage regimen in
Table 9.4.4.1–1. At any time, the dose of dalbavancin may be readjusted to the 
appropriate dosage when renal function improves. 
 
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Table 9.4.4.1–1.
Dalbavancin Dosage Adjustments for Renal Impairment
Estimated Creatinine Clearance (mL/min)a
Recommended Dosage Regimen
≥30
and patients receiving regular hemodialysis 
or peritoneal dialysis
No adjustment: 1500 mg IV (over 30 minutes) on Day 1 and 
Day 8
< 30
1000 mg IV (over 30 minutes) on Day 1 and Day 8
a
As calculated using the Cockcroft-Gault formula.
IV = intravenously.
Estimate CrCl using the following Cockcroft-Gault formula, based on serum 
creatinine concentrations obtained at Baseline and Day 8, and using ideal body 
weight instead of actual weight.
Males:
CrCl =
(140 - age in years) × Ideal body weight (kg)
72 × serum creatinine (mg/dL)
Females:
CrCl =
(140 - age in years) × Ideal body weight (kg)
× 0.85
72 × serum creatinine (mg/dL)
Ideal body weight is calculated as:
Males:
If height (H) > 152.5 cm
Ideal body weight = 50 + [(H –152.4) x 0.89]
If H < 152.5 cm
Ideal body weight = 50 – [(152.4 – H) x 0.89]
Females: 
If H > 152.5 cm
Ideal body weight = 45.4 + [(H –152.4) x 0.89]
If H < 152.5 cm
Ideal body weight = 45.4 – [(152.4 – H) x 0.89]
9.4.4.2
Dose Adjustments - Other Investigational Products 
For all other investigational products, appropriate dosage modifications for renal function 
will be made per the respective package insert or institutional guidelines.
9.4.5
Blinding
This study will be conducted as an open-label investigation; no blinding of assigned 
treatment will occur.
9.4.6
Unblinding
Not applicable
 
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9.4.7
Prior and Concomitant Therapy
Receipt of more than 24 hours of potentially effective intravenous antibacterial therapy 
for osteomyelitis within 96 hours of randomization is not allowed (unless the pathogen 
isolated was documented to be MRSA that was resistant to the administered antibiotic).
Treatment with an investigational drug within 30 days prior to the first dose of study 
medication is not allowed. A patient who has had a prior failed course of therapy for 
osteomyelitis should not be enrolled.
Drugs Not Allowed as Concomitant Medications (up to Day 42)-

Systemic antibacterial therapy for Gram-positive infections (eg, rifampin, 
gentamicin).

Concomitant antibiotic therapy that would interfere with the assessment of study drug
Drugs Allowed as Concomitant Medications-

Aztreonam may be administered at randomization for presumed co-infection with a 
Gram-negative pathogen and could be discontinued if a Gram-negative pathogen is 
not documented by culture results. A switch to an oral antibiotic for coverage of 
Gram-negative pathogens is allowed once evidence of clinical improvement has been 
established.

Metronidazole (IV or oral) or oral vancomycin may be used for Clostridium difficile
infections.

Other antibiotics that do not achieve significant therapeutic concentrations in the 
serum (eg, nitrofurantoin) may be considered for treatment of other concomitant 
infections. Close consultation with the medical monitor is advised prior to use of 
these antibiotics.
Surgical debridement should be performed on any patient if clinically indicated.
9.4.8
Monitoring Treatment Compliance
Treatment compliance will be closely monitored by recording the date, time, and whether 
or not each dose of IV study drug was completely infused and, if applicable, whether or 
not each intended dose of oral therapy was taken. 
 
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9.5
EFFICACY AND SAFETY VARIABLES
9.5.1
Efficacy Assessments
9.5.1.1
Primary and Secondary Efficacy Assessments
9.5.1.1.1
Primary Efficacy Assessment
Clinical response at Day 42 in the Clinically Evaluable (CE) population.
Clinical response can be either cure, failure, or indeterminate:

Cure is defined as recovery without need for additional antibiotic therapy. 

Failure is defined as:
○
Requirement of additional antibiotic therapy for no response or worsening after 
improvement
○
New purulence
○
Amputation due to progression of infection (from initiation of study drug to 
outcome assessment visit).
○
Requiring > 6 weeks of antibiotic therapy for patients in the comparator arm
○
Death (for any reason). 

Indeterminate is defined as:
○
Lost to follow-up
○
Amputation due to vascular insufficiency (from initiation of study drug to 
outcome assessment visit).
9.5.1.1.2
Secondary Efficacy Assessments

Clinical improvement at Day 21 in the modified ITT (mITT) and CE populations
○
Clinical improvement at Day 21 is defined as no worsening of pain from baseline 
(if present at baseline) (subjective pain and/or point tenderness) and improvement 
in inflammation (as measured by C-reactive protein).

Clinical response (cure, failure, or indeterminate) at Day 42 in the mITT and micro-
mITT populations
 
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
Clinical response (cure, failure, or indeterminate) at Day 180 in the mITT and CE 
Populations

Clinical response (cure, failure, or indeterminate) at Day 365 in the mITT and CE
Populations

Clinical response (cure, failure, or indeterminate) by pathogen at Day 42 and Day 180 
in the CE Population
9.5.1.2
Microbiological Assessments
9.5.1.2.1
Blood Samples for Culture
Peripheral blood culture must be drawn at Baseline (prior to study drug treatment), not 
through an existing intravascular line. If blood cultures are positive at Baseline, they 
should be repeated once every 24 hours until negative. At the Day 8 visit, results of all 
prior blood cultures should be checked and blood cultures should be repeated if previous 
blood cultures were positive. 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 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 to all study drugs used at the 
study site.
Microbiological specimens and isolates will be collected, processed, and stored in 
accordance with local procedures (refer to Microbiology Manual).
9.5.2
Safety Assessments
Patients must be evaluated by a physician or an appropriately trained health care 
professional at every visit, and the evaluation must be documented. 
 
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9.5.2.1
Adverse Events
An AE is any untoward medical occurrence in a patient or clinical investigation patient
administered a pharmaceutical product, unless the event is captured in the study endpoint, 
as defined below; the event need not necessarily have a causal relationship with this
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal 
product (ICH-E2A). For all AEs, the investigator must pursue and obtain adequate 
information both to determine the outcome of the AE and to assess whether it meets the 
criteria for classification as a serious AE (SAE) requiring immediate notification to the 
Sponsor. All AEs will be followed up by the investigator until the event or its sequel 
resolve or stabilize at a level acceptable to the investigator, and the Sponsor concurs with 
that assessment.
For the purpose of the site’s data collection responsibilities, all AEs should be recorded 
on the CRF from the time the patient signed the ICF until the final protocol-defined study 
visit.
An event would be considered as adequately captured in the study endpoint if it is 
accurately and fully represented by a protocol-defined reason for clinical failure (other 
than mortality) or relapse. Such an event should not be reported as an adverse event 
unless it is a serious adverse event as defined in this protocol (Section 9.5.2.4). Events 
represented by the study endpoints include all of the following:

Increase or no change in pain and/or point tenderness (compared with baseline)

Increase or no change in CRP (compared with highest value)

Requirement of additional antibiotic therapy for no response or worsening after 
improvement

New purulence

Amputation due to progression of infection (from initiation of study drug to outcome 
timepoint).

Requiring > 6 weeks of antibiotic therapy for patients in the comparator arm

Lost to follow-up

Amputation due to vascular insufficiency (from initiation of study drug to outcome 
timepoint)
 
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Except for circumstances as defined above, examples of AEs include but are not limited 
to:

Abnormal test findings (see Section 9.5.2.1.1)

Clinically significant signs and symptoms

Changes in physical examination findings

Hypersensitivity

Progression/worsening of underlying disease
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug abuse;

Drug misuse; 

Drug interactions;

Drug dependency;

Extravasation of study drug;

Exposure during Pregnancy
Please note medical procedures scheduled prior to consenting, 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.
Pregnancies should not be automatically assessed as AEs (Section 9.5.2.7).
9.5.2.1.1
Abnormal Test Findings
An abnormal objective test finding (e.g., an abnormal liver function test result) should be 
reported as an AE if the following conditions apply: 

Test result is associated with accompanying symptoms and/or signs, constituting a 
clinical syndrome (e.g., abnormal liver function test results, jaundice, and hepatic 
tenderness suggesting a diagnosis of hepatitis), and/or
 
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
Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or

Test result leads to a change in study dosing or withdrawal from the study, significant 
additional concomitant drug treatment, or other therapy.
Merely repeating an abnormal test, in the absence of any of the above conditions, does 
not define the abnormal objective test finding as an AE. 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 adverse event due to 
an abnormal lab test finding should be noted in the CRF.
9.5.2.2
Causality Assessment
For each AE (serious and non-serious), the Investigator must provide an assessment of 
causal relationship to the investigational product. For all AEs, sufficient information 
should be obtained by the investigator to determine the causality of the AE. The causality 
assessment must be recorded on the appropriate AE reporting page of the patient’s eCRF. 
An investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that the investigational product caused or contributed to an AE. If 
the investigator does not know whether or not investigational product caused the event, 
then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the Sponsor.  If the investigator's causality assessment is 
"unknown but not related to investigational product", this should be clearly documented 
on study records.  Specifically, the investigator will choose whether the AE is unrelated, 
unlikely related, possibly related or probably related to the investigational product.
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
The Investigator will assess causality of the event in relation to dalbavancin based on the 
following defined criteria: 

UNRELATED: No relationship between the event and medicinal product

UNLIKELY: Event or laboratory test abnormality, with a time to drug intake that 
makes a relationship improbable (but not impossible); disease or other drugs provide 
plausible explanations
 
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
POSSIBLY: Event or laboratory test abnormality, with reasonable time relationship 
to drug intake; could also be explained by disease or other drugs; information on drug 
withdrawal may be lacking or unclear

PROBABLY: Event or laboratory test abnormality, with reasonable time relationship 
to drug intake; unlikely to be attributed to disease or other drugs; response to 
withdrawal clinically reasonable; rechallenge not required
9.5.2.3
Severity Assessment
The Investigator will provide an assessment of the severity of each AE by recording a 
severity rating on the appropriate AE reporting page of the patient’s eCRF. 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 9.5.2.4). Severity will be assessed 
according to the following scale:
Mild:
Does not interfere with the patient’s usual function.
Moderate:
Interferes to some extent with the patient’s usual function.
Severe:
Interferes significantly with the patient’s usual function.
9.5.2.4
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:

Results in death

Is life threatening (immediate risk of death)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity, or

Is a congenital anomaly/birth defect
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based on 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 patient
hospitalization, or the development of investigational product dependency or drug abuse.
 
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Emergency room visits that do not result in hospitalization should be evaluated for one of 
the other serious outcomes to determine whether they qualify as SAEs.
Preplanned hospitalizations (eg, elective procedures for preexisting conditions that did 
not worsen, such as cosmetic surgery and hysterectomy) are excluded from SAE 
reporting.
For SAEs, the reporting period to the Sponsor begins from the time that the patient 
provides informed consent, i.e., prior to undergoing any study-related procedure and/or 
receiving investigational product, through the Final Visit. Any SAE occurring any time 
after the reporting period must be promptly reported if a causal relationship to 
investigational product is suspected. 
9.5.2.4.1
Hospitalization
Adverse events associated with hospitalization or prolongations of hospitalization are 
considered serious.  Any initial admission to a healthcare facility meets these criteria. 
Admission also includes transfer within the hospital to an acute/intensive care unit 
(e.g., from the psychiatric wing to a medical floor, medical floor to a coronary care unit, 
neurological floor to a tuberculosis unit).
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (e.g., caregiver relief);

Skilled nursing facilities;

Nursing homes;

Routine emergency room admissions;

Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, 
clinical AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (e.g., for 
work-up of persistent pre-treatment laboratory abnormality);

Social admission (e.g., patient has no place to sleep);
 
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
Administrative admission (e.g., for yearly physical exam);

Protocol-specified admission during a study (e.g., for a procedure required by the 
study protocol);

Optional admission not associated with a precipitating clinical AE (e.g., for elective 
cosmetic surgery). Pre-planned treatments or surgical procedures should be noted in 
the baseline documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should 
not be reported as an AE. However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an AE. For example, an acute 
appendicitis that begins during the AE reporting period should be reported as the AE and 
the resulting appendectomy should be recorded as treatment of the AE.
9.5.2.5
Reporting Adverse Events and Serious Adverse Events
At each visit, patients are to be queried regarding any AEs or SAEs that have occurred 
since the previous visit. Patients will be asked to volunteer information with a nonleading 
question such as, “How do you feel since your last visit?” Study site personnel will 
record all pertinent information in the patient’s eCRF. 
All AEs must be recorded on the appropriate AE reporting page of the patient’s eCRF
whether or not they are considered causally related to the investigational product.
For every AE, the Investigator must:

Provide an assessment of the seriousness of the event (ie, is it an SAE?), as well as 
the severity and causal relationship

Document all actions taken with regard to the investigational product

Detail any other treatment measures taken for the AE

Document the outcome of the AE
In addition, patients are to be reminded, as described in the ICF and in accordance with 
Section 9.5.2.1, to notify site personnel of any AEs occurring from the time the patient 
signed the ICF until the final protocol defined study visit.
 
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Any AEs that are ongoing at the time of the final protocol-defined study visit will be 
followed until the condition returns to prestudy status, has resolved or stabilized, or can 
be explained as being unrelated to the investigational product. If a follow-up visit is 
deemed necessary for appropriate safety surveillance, it will take place within 30 days of 
the final protocol-defined study visit.
For SAEs, the reporting period to the Sponsor begins from the time that the patient 
provides informed consent, i.e., prior to undergoing any study-related procedure and/or 
receiving investigational product, through the Final Visit. Any SAE occurring any time 
after the reporting period must be promptly reported if a causal relationship to 
investigational product is suspected. 
9.5.2.6
Immediate Reporting of Serious Adverse Events and Events of 
Special Interest
The Sponsor is required to inform worldwide regulatory authorities of SAEs that meet 
specific criteria. Therefore, the Sponsor must be notified immediately regarding any SAE 
that occurs after informed consent is obtained.
Within 24 hours of learning of any AE that meets one of the criteria for an SAE, the 
study site personnel must report the event to Actavis Global Drug Safety on the SAE 
Form for Clinical Trials. The Sponsor’s Study Physician may also be notified by 
telephone.
If, during follow-up, any nonserious AE worsens and eventually meets the criteria for an 
SAE, that AE should be recorded as a new SAE.
The site must transmit the SAE Form for Clinical Trials to the SAE fax number shown 
below. Even if an initial report is made by telephone, the SAE Form for Clinical Trials 
completed with all available details must still be faxed within 24 hours of knowledge of 
the event at the study site.
Supplemental information should be submitted as soon as available and may include 
laboratory results, radiology reports, progress notes, hospital admission and emergency 
room notes, holding and observation notes, discharge summaries, autopsy reports, and 
death certificates.
The Investigator is expected to take all therapeutic measures necessary for resolution of 
the SAE. Any medications or procedures necessary for treatment of the SAE must be 
recorded on the appropriate pages of the patient’s eCRF. All SAEs are to be followed by 
the study staff until resolution or until the SAE is deemed stable. The Sponsor may 
contact the study site to solicit additional information or follow up on the event.
 
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Fax the SAE Form for Clinical Trials to Actavis, Inc.
9.5.2.7
Reporting of Pregnancies Occurring During the Study
An exposure during pregnancy occurs if a female becomes, or is found to be, pregnant 
either while receiving or having been directly exposed to (e.g., environmental exposure) 
the investigational product, or the female becomes, or is found to be, pregnant after 
discontinuing and/or being directly exposed to the investigational product (maternal 
exposure). Within 24 hours of learning of the pregnancy, the study site personnel must 
report the event to Actavis Global Drug Safety on the Clinical Trial Pregnancy Form and 
fax it to the SAE/Pregnancy fax number stated in Section 9.5.2.6, even if no AE has 
occurred. Pregnancies in female partners of male patients occurring during the time frame 
described above must also be reported. 
The pregnancy must be followed to term and the outcome reported by completing a 
follow-up a Clinical Trial Pregnancy Form. If the pregnancy is associated with an SAE 
(eg, if the mother is hospitalized for hemorrhage), a separate SAE Form for Clinical 
Trials must be filed as described in Section 9.5.2.6 with the appropriate serious criterion 
(eg, hospitalization) indicated in addition to the Pregnancy Form.
9.5.2.8
Potential Hy’s Law Cases
Criteria for potential Hy’s Law cases are as follows: 

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 × ULN 
AND 

Total bilirubin ≥2 × ULN AND 

Alkaline phosphatase (ALP) < 2 × ULN
Study site personnel must report every patient who meets these criteria. Typically, all 
3 analytes will be obtained from the same sample, but they may come from multiple 
samples taken within a 24 hour period. This requirement applies from the time the patient
signs the ICF for the study until the final protocol-defined study visit.
 
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The Investigator must notify the Sponsor immediately when the above criteria have been 
met. A potential Hy’s law case must be faxed to the Sponsor on an AE of Special Interest 
Form as soon as possible (within 24 hours of learning of the potential Hy’s law) to the 
SAE/Pregnancy fax number stated in Section 9.5.2.6, even if no AE has occurred. The 
eCRF for potential Hy’s law cases must be completed within 7 calendar days. Every 
effort to determine the cause of the liver enzyme abnormalities must be made, and close 
monitoring should be initiated in conjunction with the Study Physician and in accordance 
with FDA guidance (US Food and Drug Administration, 2009).
9.5.2.9
Clinical Laboratory Determinations
Blood and urine samples for clinical laboratory tests will be collected according to the 
Schedule of Assessments and Procedures (Table 2-1). 
Women of childbearing potential (including those who are fewer than 2 years 
postmenopausal) will be required to have a serum pregnancy test at baseline. The test 
must be negative before randomization. If the serum test results cannot be obtained 
before randomization, a urine pregnancy test may be used for enrollment.
The following clinical laboratory levels will be measured:
Hematology: Basophils (absolute count and %), eosinophils (absolute count and %), 
erythrocyte count, hematocrit, hemoglobin, lymphocytes (absolute count 
and %), monocytes (absolute count and %), neutrophils (absolute count 
and %), immature neutrophils (bands; %), platelet count
Chemistry:
Albumin, ALP, AST, ALT, bilirubin (total and direct), blood urea 
nitrogen, calcium, creatinine, electrolytes (ie, bicarbonate, chloride, 
potassium, sodium), gamma-glutamyl transferase, glucose (nonfasting),
lactate dehydrogenase, magnesium, protein (total)
Other:
CRP, ESR, pregnancy test
The site’s local laboratory will be used to evaluate all laboratory samples.
Results from unscheduled laboratory tests will not be collected, unless associated with an 
SAE or AE leading to discontinuation of IV study drug.
Any abnormal laboratory test possibly attributable to IV study drugs, or of clinical 
significance, will be repeated at appropriate intervals until stabilization; results from 
these unscheduled laboratory tests should be collected.
9.5.2.9.1
Potential Drug-Induced Liver Injury/Hy’s Law
See Section 9.5.2.8.
 
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9.5.2.10
Vital Signs, Body Weight, and Height
Vital signs will be recorded at every visit; the parameters are:

Blood pressure: systolic and diastolic - to be taken after the patient has been sitting 
for 5 minutes

Pulse rate: to be taken after the patient has been sitting for 5 minutes

Respiratory rate

Temperature (oral, rectal, or tympanic): if taken multiple times, record the highest 
daily temperature
Body weight and height will be measured at baseline. If height or weight is not obtainable 
(eg, patient is immobilized), the last known or stated height and weight may be used.
9.5.2.11
Physical Examination
A complete physical examination (including targeted examination of the infection site) 
will be conducted at Baseline by a professionally trained physician or health professional 
licensed to perform physical examinations.
A targeted examination of the infection site will be performed at Day 8, 21, 28, 42, 180, 
and 365 as well as upon premature discontinuation.  
The same medically trained individual should perform all assessments, if possible. 
Patients may not receive pain medication, including ibuprofen and acetaminophen, within 
the 4 hours preceding the assessments.
 
 
 
 
 
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9
1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9
3
 
 
 
 
 
9
4
 
 
 
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9
5
 
 
 
 
 
 
 
9
6
 
 
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9
7
 
 
 
 
 
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9.6
DATA QUALITY ASSURANCE
9.6.1
Data Recording and Documentation
Data collection will involve the use of the Actavis electronic data capture (EDC) system, 
to which only authorized personnel will have access. Patient’s data are to be entered into 
the EDC system by the Investigator or designee using their assigned EDC user account.
After data entry into the EDC system by the Investigator or designee, a combination of 
manual and programmatic edit checks will be used to review the data for completeness, 
logic, and adherence to study protocol. As a result of these edit checks, data monitoring 
and reviews, queries may be electronically issued to the site and should be answered 
electronically via the EDC system.
Each query will carry identifying information (assigned username, date, and time) to 
assist the Sponsor and the Investigator on the origin of the data clarification request and 
the response provided by the Investigator. All data changes made to the patient’s data via 
a data query will be approved by the Investigator prior to final database lock.
After all data have been reviewed and all issues have been resolved, the database will be 
locked.
All data collected in the context of this study will be stored and evaluated per regulatory 
requirements and applicable guidance for electronic records. Also, data will be stored and 
evaluated in such a way as to guarantee patient confidentiality in accordance with the 
legal stipulations applying to confidentiality of data. Study records (eg, copies of eCRFs, 
laboratory reports, patient diaries, regulatory documents, etc) will be retained at the site, 
along with adequate source documentation, according to regulatory requirements. All 
study records must be available for inspection by the Sponsor, its authorized 
representatives, and regulatory or other health authorities.
 
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9.6.2
Data Monitoring
Before any patient enters the study, a representative of the Sponsor will meet with the 
Investigator and the study site staff to review the procedures to be followed during the 
study. EDC functionality training is provided via computer-based training to train 
investigators and authorized designees on recording the data in the eCRFs using the EDC 
system. After the first patient is enrolled, the Sponsor representative, a Regional Site 
Manager (RSM) or designee, will periodically monitor the progress of the study by 
conducting on-site visits. This RSM or designee will review query statuses remotely, 
possibly warranting more frequent communication and/or site visits with the Investigator 
and the study site staff. The Investigator will make available to the RSM or designee 
source documents (written notes and electronic medical records, if used), signed consent 
forms, and all other study-related documents. The Investigator and the study site staff 
will be responsible for data entry of patient data into the eCRFs via the EDC system, 
resolving data queries generated via the EDC system and providing missing or corrected 
data. The Investigator or designee will be responsible for approving all changes 
performed on the data, and endorsing the patient data within the EDC system. This 
approval method will include applying an electronic signature linked to a uniquely 
assigned username and password that together will represent a traditional handwritten 
signature used in the past.
9.7
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
9.7.1
Analysis Populations
Analysis Populations are described below.
9.7.1.1
Screened Population
The Screened Population will consist of all patients who undergo the Baseline Visit and 
receive a patient identification number.
9.7.1.2
Intent-to-Treat Population
The Intent-to-Treat Population will consist of all patients in the Screened Population who 
are randomized to a treatment group in the study.
9.7.1.3
Safety Population
The Safety Population will be a subset of the ITT Population and will include all 
randomized patients who receive any amount of randomized medication. Patients will be 
analyzed according to the treatment actually received.  
 
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9.7.1.4
Modified Intent-to-Treat Population
The mITT Population will be a subset of the ITT Population and will include all 
randomized patients who receive any amount of randomized medication and meet the 
criteria for known or suspected Gram-positive osteomyelitis (Inclusion Criterion 2). 
Patients from whom only a Gram-negative pathogen is isolated from blood and/or bone 
culture will be excluded from the mITT. Patients whose cultures include both a 
Gram-positive and a Gram-negative pathogen will remain in the mITT. Patients will be 
analyzed according to randomized treatment group, regardless of treatment received. 
9.7.1.5
Clinically Evaluable Population
The CE Population will be a subset of the mITT Population and will include patients who 
meet both of the following specific conditions for evaluability:

For patients randomized to receive dalbavancin, received at least 1 dose of active 
study medication.  For patients randomized to comparator, received at least 2 weeks 
of study medication

Received no more than 1 dose of another (non-study) systemic antibacterial therapy 
with documented activity against the causative organism, from study drug initiation 
until the outcome assessment visit, for an indication other than osteomyelitis. [Note: 
patients receiving a non-study systemic antibacterial treatment for the treatment of 
osteomyelitis from initiation of study drug through the outcome assessment visit will 
be assessed as EVALUABLE FAILURES]
9.7.1.6
Microbiological mITT Population
The microbiological mITT (micro-mITT) population will be a subset of the mITT 
population and will include patients with a Gram-positive pathogen isolated from blood 
and/or bone specimen. Patients whose cultures include both a Gram-positive and a Gram-
negative pathogen will remain in the micro-mITT.
9.7.2
Patient Disposition
Patient disposition (enrollment, discontinuations from study drug and the study) by 
treatment group will be provided based on the ITT Population. Reasons for exclusion 
from study populations will be summarized for the ITT Population.
The number of patients in the Safety and ITT Populations will be summarized by 
treatment group; the Screened Analysis Set will only be summarized overall.
Screen failures (ie, patients screened but not randomized) and the associated reasons for 
failure will be tabulated overall. 
 
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The number and percentage of patients who complete the treatment period and of patients 
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 from the treatment period as recorded on the termination pages
of the eCRF will be summarized (number and percentage) by treatment group for all 
randomized patients. 
9.7.3
Demographics and Other Baseline Characteristics
Demographics (eg, age, race, gender, body mass index), medical and surgical history, 
description of the infection by pathogen, markers of disease severity and co-morbidities 
(eg, presence of bacteremia, renal impairment), baseline assessment of the clinical signs 
and symptoms, and microbiological assessment of the infection site will be summarized 
by treatment group in the mITT Population.
Prior medication is defined as any medication taken before the date of the first dose of 
investigational product. Concomitant medication is defined as any medication started on 
or after the date of the first dose of investigational product. Any prior medications 
stopped more than 3 days before the date of the first dose of investigational product and 
any concomitant medications started after the date of the last dose of investigational 
product will not be presented in the summary tables, but will be included in the patient
data listings. Medications that are ongoing at the time of first dose of randomized 
medication will be counted both as prior and concomitant. 
Both prior and concomitant medication use will be summarized by the number and 
proportion of patients in each treatment group receiving each medication within each 
therapeutic class for the Safety Population. Multiple administrations of the same 
medication to a patient will be counted only once for the given patient. Medication-
related summaries will be presented separately by “systemic antimicrobial medications” 
and “other medications not in this class” subgroups.
9.7.4
Extent of Exposure and Treatment Compliance
9.7.4.1
Extent of Exposure
Exposure to study drug will be summarized by treatment group for the Safety Population. 
Calendar days of exposure will be calculated as the number of calendar days on study 
drug. For each type of exposure descriptive statistics (number of patients, mean, SD, 
median, minimum, and maximum) will be presented.
 
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9.7.4.2
Measurement of Treatment Compliance
Each patient’s compliance with study therapy will be calculated based on the number of 
doses of study drug the patient would have been expected to receive based on the number 
of treatment days, the specific dosing regimen indicated for the given drug, and the start 
and stop date and times of the first and last dose of each study drug. Treatment 
compliance is defined as the number of doses actually received divided by the number of 
doses expected (× 100) over the time period of first dosing date and time to last dosing 
date and time. 
9.7.5
Efficacy Analyses
Efficacy analyses will be based on the mITT analysis set. Baseline for efficacy is defined 
as the last measurement collected just before the first dose of randomized study drug. All 
confidence intervals will be 2-sided 95% confidence intervals, unless stated otherwise.
For each efficacy parameter listed below, number and proportion of patients with 
categories of clinical responses will be presented by treatment groups, and the 2-sided 
95% confidence intervals for the percentage of patients with favorable response will be 
obtained using the Clopper-Pearson method (Clopper and Pearson, 1934) for each 
treatment group unless stated otherwise. Due to the small sample size of comparator 
treatment arm, the between treatment comparison will not be provided.
9.7.5.1
Primary Efficacy Parameter
The primary efficacy parameter is the clinical response at Day 42 in the CE population. 
Clinical response can be either cure, failure, or indeterminate, as defined in 
Section 9.5.1.1.1. For calculation of the 95% confidence interval for the percentage of 
patients with response of cure, the indeterminate responses will be treated as failures.
9.7.5.2
Secondary Efficacy Parameters
The following are the secondary efficacy parameters:

Clinical improvement at Day 21 in the mITT and CE Populations
○
Clinical improvement at Day 21 is defined as no worsening of pain from baseline 
(if present at baseline) (subjective pain and/or point tenderness) and improvement 
in inflammation (as measured by CRP).

Clinical response (cure, failure, or indeterminate) at Day 42 in the mITT and 
micro-mITT Populations
 
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
Clinical response (cure, failure, or indeterminate) at Day 180 in the mITT and CE 
Populations

Clinical response (cure, failure, or indeterminate) at Day 365 in the mITT and CE 
Populations

Clinical response (cure, failure, or indeterminate) by pathogen at Day 42 and Day 180 
in the CE Population.
Clinical responses at Days 180 and 365 are defined and handled in the same way as the 
primary parameter. For clinical response by pathogen, 95% confidence intervals will be 
calculated only for pathogens for which sample sizes are greater than 10 in the 
dalbavancin group.
  
 
 
 
 
 
 
9.7.6.1
Adverse Events
An AE (classified by preferred term) that occurs during the treatment period will be 
considered a TEAE if it was not present before the date of the first dose of investigational 
product or was present before the date of the first dose of investigational product and
increased in severity during the treatment period. If more than 1 AE is reported before the 
date of the first dose of investigational product and coded to the same preferred term, the 
AE with the greatest severity will be used as the benchmark for comparison with the AEs 
occurring during the treatment period that were also coded to that preferred term. 
 
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The number and percentage of patients reporting TEAEs 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 investigational product. If more than 1 AE is coded to the same preferred term for the 
same patient, the patient 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 investigational product.
The distribution of TEAEs by severity and causal relationship to the investigational 
product will be summarized by treatment group.
The incidence of common (eg, ≥ 2% of patients in any treatment group) TEAEs, 
on-therapy SAEs, and AEs leading to premature discontinuation of the investigational 
product will be summarized by preferred term and treatment group and will be sorted by 
decreasing frequency for the test treatment. In addition, the incidence of fatal on-therapy 
SAEs (ie, events that caused death) will be summarized separately by treatment group 
and preferred term. 
Listings will be presented for patients with SAEs, patients with AEs leading to
discontinuation, and patients who die (if any).
9.7.6.2
Clinical Laboratory Parameters
Descriptive statistics for clinical laboratory values (in SI units) and changes from the 
baseline values at each assessment time point will be presented by treatment group for 
each clinical laboratory parameter.
The number and percentage of patients with PCS postbaseline 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 patients with available non-PCS baseline values and at least 1 postbaseline
assessment. The numerator will be the total number of patients with available non-PCS 
baseline values and at least 1 PCS postbaseline value. A supportive listing of patients 
with PCS postbaseline values will be provided, including the patient identification
number, study center number, and baseline and postbaseline values. A listing of all AEs 
that occur in patients who have PCS laboratory values will also be provided.
Patients who meet the potential Hy’s law criteria will be summarized for the Safety 
Population. Supportive tabular displays will also be provided.
 
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9.7.6.3
Vital Signs
Descriptive statistics for vital signs (ie, systolic and diastolic blood pressure, pulse rate, 
respiratory rate, temperature) and changes from baseline values at each visit and at end of 
study will be presented by treatment group.
Vital sign values will be PCS if they meet both the observed-value criteria and the change 
from baseline–value criteria detailed in the statistical analysis plan. The percentages will 
be calculated relative to the number of patients with baseline values and at least 1
postbaseline assessment. The numerator will be the total number of patients with 
available baseline values and at least 1 PCS postbaseline value. A supportive listing of 
patients with PCS postbaseline values will be provided, including the patient 
identification number, and baseline and postbaseline values. A listing of all AEs that 
occur in patients who have PCS vital sign values will also be provided.
 
 
 
9.7.8
Interim Analysis
No interim analysis is planned for this study.
9.7.9
Determination of Sample Size
This study is not powered for comparative inferential statistical analyses.
The planned enrollment of 70 patients in the dalbavancin treatment arm will result in a 
2-sided 95% confidence interval with the approximate half-width of 11% for the 
proportion of patients with a clinical cure when the expected proportion is 65%. Higher 
observed favorable response rates will result in improved precision. The precision for the 
comparator arm is not estimated due to the small sample size. The comparator arm is 
intended to provide information on SOC treatment regimens and overall generalizability 
of study findings, and is not intended to provide a statistically powered comparison of 
efficacy.
9.7.10
Computer Methods
Statistical analyses will be performed using SAS version 9.3 or higher.
 
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9.8
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES
Any amendment to this protocol will be provided to the Investigator in writing by the 
Sponsor. No protocol amendment may be implemented (with the exceptions noted below) 
before it has been approved by the IEC and the signature page, signed by the Investigator, 
has been received by the Sponsor. If the protocol is amended to eliminate or reduce the 
risk to patients, the amendment may be implemented before IEC review and approval. 
However, the IEC must be informed in writing of such an amendment, and approval must 
be obtained within reasonable time limits. 
9.9
PROTOCOL DEVIATIONS
A protocol deviation is any change, divergence, or departure from the study design or 
procedures that is under the Investigator’s responsibility and oversight (as defined by 
regulations) without prior written IEC approval or favorable opinion of an appropriate 
amendment and that does not have a major impact on the patient’s rights, safety, or 
well-being, or on the integrity and authenticity of the study data. Deviations may include, 
but are not limited to, departure from inclusion/exclusion criteria, allowed concomitant 
medications, dosing or duration of treatment, failure to follow withdrawal criteria or
perform the required assessments at specified time points, and scheduling of visits not in 
accordance with specifications.
Deviating from the protocol is permitted only if absolutely necessary for the safety or 
clinical management of the patients and must immediately be reported to the Sponsor.
Protocol deviations must be reported to the Sponsor (either verbally or electronically) in a 
timely manner from the date of discovery.
Protocol deviations that may impact patient’s rights (eg, failure to obtain informed 
consent prior to initiating study procedures); safety or well-being (eg, deviations that 
resulted in an SAE, exposure during pregnancy); or the integrity and authenticity of the 
study data should be reported to the Sponsor within 24 hours, if possible. 
The IEC must be notified according to the criteria and time period dictated by the IEC
associated with this study. 
 
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10.0
STUDY SPONSORSHIP
This study is sponsored by Durata Therapeutics International BV, an affiliate of Actavis,
Inc.
10.1
STUDY TERMINATION
The Sponsor reserves the right to terminate the study in its entirety or at a specific study 
center before study completion. 
10.2
REPORTING AND PUBLICATION
All data generated in this study are the property of the Sponsor. An integrated clinical and 
statistical report will be prepared at the completion of the study.
Publication of the results by the Investigator will be subject to mutual agreement between 
the Investigator and the Sponsor, and will follow the Sponsor’s Standard Operating 
Procedures on publications.
 
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11.0
INVESTIGATOR OBLIGATIONS
11.1
DOCUMENTATION
The Investigator must provide the following to Durata Therapeutics (an affiliate of 
Actavis, Inc.), before the start of the study:

A fully executed contract

The curricula vitae for the Investigator and all Sub-Investigators, including a copy of 
each physician’s license

A copy of the original IEC approval for conducting the study. If the study is ongoing, 
renewals must be submitted at yearly intervals. All subsequent modifications must be 
submitted and approved by the IEC, as stated in Section 9.8.

A copy of the IEC-approved ICF and any supplemental privacy form, if applicable

A list of the IEC members 

A copy of the laboratory certifications and reference ranges

The Investigator’s Statement page in this protocol signed and dated by the 
Investigator

Financial disclosure agreement completed and signed by the Investigator and all 
Sub-Investigators. The Investigator and all Sub-Investigators will provide an updated 
financial disclosure agreement to the Sponsor 1 year after the completion of the study.
11.2
PERFORMANCE
The Investigator must demonstrate reasonable efforts to obtain qualified patients for the 
study.
 
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11.3
USE OF INVESTIGATIONAL MATERIALS
The Investigator will acknowledge that the investigational product supplies are 
investigational and as such must be used strictly in accordance with the protocol and only 
under the supervision of the Investigator or Sub-Investigators. The investigational 
products must be stored in a secured place and must be locked. At study initiation, a 
representative from the Sponsor will inventory the investigational products at the site. 
The Investigator must maintain adequate records documenting the receipt and disposition 
of all study supplies. The Sponsor will supply forms on which to record the date the 
investigational products were received and a dispensing record in which to record each 
patient’s use. All unused investigational products must be returned to the Sponsor. It is 
the Investigator’s responsibility to ensure that patients return their investigational 
product.
11.4
CASE REPORT FORMS
All patient data relating to the study will be recorded on eCRFs to be provided by the 
Sponsor, through the EDC system. The Investigator is responsible for verifying that all 
data entries in the eCRFs are accurate and correct by electronically signing the completed 
eCRF casebook submitted to the Sponsor. The Investigator must maintain and retain 
accurate documentation that supports the information entered into the EDC system for 
source document verification and possible regulatory inspection.
11.5
RETENTION AND REVIEW OF RECORDS
Records and documents pertaining to the conduct of this study, including eCRFs, source 
documents, consent forms, regulatory documents, clinical laboratory results, calibration 
logs, or reports (including, but not limited to, all local laboratory results), and medication 
inventory records in all formats (including, but not limited to, written, electronic, 
magnetic, and optical records, and scans, x-rays) must be retained by the Investigator for 
a period of at least 15 years after study completion unless local regulations or institutional 
policies require a longer retention period or otherwise notified in writing by the Sponsor. 
No study records shall be destroyed without notifying the Sponsor and providing the 
Sponsor the opportunity to arrange long-term storage for such study records or 
authorizing in writing the destruction of records after the required retention period.
The Investigator must permit access to any documentation relating to the study upon 
request of the Sponsor or applicable regulatory authorities. If the Investigator for the 
study retires, relocates, or for other reasons withdraws from the responsibility of keeping 
the study records, custody must be transferred to a suitable alternate custodian employee 
of the institution or to a suitably qualified and responsible third party. The Sponsor must 
be notified in writing of the name and address of the new custodian in advance of the 
transfer.
 
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11.6
PATIENT CONFIDENTIALITY
All patient records will only be identified by initials and patient identification number. 
Patients’ names are not to be transmitted to the Sponsor. The Investigator will keep a 
master patient list on which the patient identification number and the full name, address, 
and telephone number of each patient are listed.
 
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12.0
INVESTIGATOR’S STATEMENT
I agree to conduct the study in accordance with this protocol (DAL-MD-04, dated 
23 Jun 2015) and with all applicable government regulations and good clinical practice 
guidance.
_______________________________________
_____/_____/______
Investigator’s Signature
Date
_______________________________________
Investigator’s Name
 
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13.0
APPENDICES
APPENDIX I.
ELEMENTS OF INFORMED CONSENT
Procedures will comply with 21 CFR, Parts 50 and 312. Signed informed consent will be 
obtained from each patient participating in a clinical research study or from the patient’s 
legally authorized representative. This consent must include the following items:

A statement that the study involves research and an explanation of the purposes of the 
research; a description of the procedures to be followed and the identification of any 
procedures that are experimental; and the expected duration of the patient’s 
participation

A description of any reasonably foreseeable risks or discomforts to the patient

A description of any benefits to the patient or to others that may reasonably be 
expected from the research. If the patient is to be paid for participating in the study, 
the consent form must state the amount that he/she will receive and the schedule of 
payment (to ensure neither coercion nor undue influence).

A disclosure of appropriate alternative procedures or courses of treatment, if any, that 
might be advantageous to the patient

A statement describing the extent, if any, to which confidentiality of records 
identifying the patient will be maintained and noting the possibility that the FDA; the 
Sponsor; the IEC; another regulatory agency or an authorized contract research 
organization may inspect the records

For research involving more than minimal risk, an explanation of whether any 
medical treatment is available if injury occurs and, if so, what it consists of or where 
further information may be obtained

An explanation of whom to contact, including the relevant telephone number, for 
answers to pertinent questions about the research and the research patient’s rights and 
whom to contact in the event of a research-related injury to the patient. (Note: In 
some cases, it may be necessary to identify a person other than the Investigator as the 
contact. The guidance of the IEC may be required)

A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the patient is otherwise entitled, and that the 
patient may discontinue participation at any time without penalty or loss of benefits to 
which the patient is otherwise entitled
 
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
A statement that the particular treatment or procedures may involve risks to the 
patient (or to the embryo or fetus if the patient is, or may become, pregnant) that are 
at present unforeseeable

The expected circumstances for which the patient’s participation may be terminated 
by the Investigator without regard to the patient’s consent

Any additional costs to the patient that may result from participation in the research

The consequences of a patient’s decision to withdraw from the research and 
procedures for an orderly termination of the patient’s participation

A statement that significant new findings developed during the course of the research 
that may relate to the patient’s willingness to continue participation will be provided 
to the patient

The approximate number of patients involved in the study

A statement of consent (eg, “I agree to participate . . .”)

A place for the patient’s signature and date of signing

A statement indicating that information about this study has been, or will be, entered 
into a databank that is publicly accessible at www.ClinicalTrials.gov.
A copy of the signed consent form must be given to the patient.
 
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APPENDIX III.
POTENTIAL DRUG-INDUCED LIVER INJURY/HY’S LAW
IDENTIFICATION
The Investigator is responsible for determining whether a patient meets the following 
potential Hy’s law (PHL) criteria at any point after initiation of study therapy (IV or 
oral). For a PHL case to meet Hy’s Law, the increases from baseline in AST or ALT and
total bilirubin values, in the Investigator’s clinical judgment, should be temporally related 
to one another and to the administration of study drug, without an alternative explanation.
PHL 
AST or ALT ≥ 3 × ULN and total bilirubin ≥ 2 × ULN and ALP < 2 × ULN
If there are increases from baseline in AST or ALT ≥ 3 × ULN and total 
bilirubin ≥2 × ULN:

The Investigator must follow the instructions in this appendix

The investigative site must complete the appropriate screen(s) of the eCRF with the 
local laboratory test results
FOLLOW-UP AND REPORTING 
If the Investigator determines that the patient has not met PHL criteria (has not had 
increases from baseline in AST or ALT ≥3 × ULN and total bilirubin ≥ 2 × ULN and
ALP < 2 × ULN, at any point after initiation of study drug), the Investigator is to perform 
follow-up on subsequent laboratory results as required for patient care and per protocol 
Section 9.5.2.9.1.
If the Investigator determines that the patient has met PHL criteria (has had AST or 
ALT ≥3 × ULN and total bilirubin ≥2 × ULN, and ALP < 2 × ULN, elevated from 
baseline at any point after initiation of study drug):

The Investigator should review the criteria for premature discontinuation of study 
drug due to elevated liver chemistry values, per protocol Section 9.3.3

Any PHL case should be handled as an SAE associated with the use of the drug and 
reported as an SAE per protocol Section 9.5.2.5 (ie, even before all other possible 
causes of liver injury have been excluded). It should be promptly reported before 
doing a full workup on the patient to rule out other etiologies 
 
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
The Investigator will investigate the etiology of the event and establish if another 
explanation/alternative cause other than drug-induced liver injury caused by the study 
drug is possible. The Sponsor may be contacted to discuss the work-up. 

The investigative site must complete the appropriate screens of the eCRF.
If there is an alternative explanation or the liver chemistry values increased from baseline 
are not temporally related to one another and to the initiation of study drug, the 
Investigator should update the PHL SAE to reflect the attributed underlying illness and 
reassign an appropriate causality assessment, per protocol Sections 9.5.2.5 and 9.5.2.2, 
respectively. 
If there is no alternative explanation and the liver chemistry values increased from 
baseline are temporally related to one another and to the initiation of study drug, the 
Investigator should update the PHL SAE to a Hy’s Law case (reported term ‘Hy’s Law’) 
and reassign a causality assessment of “related.”
If, despite the Investigator’s attempts to conduct follow-up and the guidance provided in 
this appendix, there is an unavoidable delay of > 3 weeks in obtaining the information 
necessary to assess whether or not the case meets the criteria for a Hy’s case, then it is 
assumed that there is no alternative explanation until such time as an informed decision 
can be made.
REFERENCE
US Food and Drug Administration. Guidance for Industry. Drug-induced liver injury: 
Premarketing clinical evaluation. 2009 Jul. Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM174090.pdf. Accessed 2014 Oct 28.
 
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14.0
LITERATURE CITED
Andes D, Craig WA. In vivo pharmacodynamic activity of the glycopeptide dalbavancin. 
Antimicrob Agents Chemother. 2007 May;51(5):1633-42.
Calhoun J, Manring M, Shirtliff M. Osteomyelitis of the long bones. Semin Plast Surg 
2009;23:59-72.
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika 1934;26:404–13.
Dunne MW, Puttagunta S, Sprenger CR, Rubino C, Van Wart S, Baldassarre J.
Extended-duration dosing and distribution of dalbavancin into bone and articular tissue. 
Antimicrob Agents Chemother. 2015 Apr;59(4):1849-55. 
Fritz J, McDonald J. Osteomyelitis: approach to diagnosis and treatment. Phys Sportsmed 
2008;36(1)
Liu C, Baker A, Cosgrove SE, et al. Clinical Practice Guidelines by the Infectious 
Diseases Society of America for the treatment of methicillin-resistant Staphylococcus 
aureus infections in adults and children. Clin Infect Dis 2011;52:1-38.
US Food and Drug Administration. Guidance for Industry. Drug-induced liver injury: 
Premarketing clinical evaluation. 2009 Jul. Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM174090.pdf. Accessed 2014 Oct 28.
 
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