Conditions: Acute Bacterial Skin and Skin Structure Infection
Keywords: skin infection
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 17
Healthy volunteers: no

Brief summary:
This was a Phase 4, multicenter, open-label safety study of a single 1200 milligrams (mg) IV infusion of oritavancin in adult participants on chronic warfarin with acute bacterial skin and skin structure infection (ABSSSI) suspected or proven to be caused by Gram-positive pathogens.

An additional group of participants with ABSSSI, who were not on concomitant warfarin therapy, were also enrolled to obtain additional information following a single dose of oritavancin administration.

Detailed description:

Arms:
arm 1: Oritavancin as a single 1200 mg IV dose administered over 3 hours in participants with ABSSSI who were not on concomitant warfarin therapy arm 2: Oritavancin as a single 1200 mg IV dose administered over 3 hours in participants with ABSSSI who were on concomitant warfarin therapy at a standard dose and dosing schedule

Interventions: intervention 1: Oritavancin intervention 2: Warfarin
Intervention descriptions: intervention 1: Administered intravenously intervention 2: Administered as a concomitant medication at a standard dose and dosing schedule

Protocol document:
Prot_000.pdf: 
The Medicines Company 
Final 17 March 2016 
Initial U.S. Approval: 2014 
ORBACTIV™ (oritavancin) 
AN OPEN-LABEL STUDY TO EVALUATE THE SAFETY OF A SINGLE 1200 MG IV 
DOSE OF ORBACTIV (ORITAVANCIN) IN PATIENTS ON CONCOMITANT 
CHRONIC WARFARIN THERAPY BEING TREATED FOR ACUTE BACTERIAL 
SKIN AND SKIN STRUCTURE INFECTION 
Protocol No.: MDCO-ORI-14-03 
U.S. IND No.: 51,292 
EuDRACT No.: Not Applicable 
PROTOCOL VERSION:  3.0 
Drug Development Phase: 
IV 
Sponsor: 
The Medicines Company 
8 Sylvan Way 
Parsippany, NJ 07054 
Sponsor Representatives: 
Medical Director: 
Name: 
 
Project Manager: 
Name: 
 
Drug Safety Officer: 
Name: 
 
Issue Date: 
 17 March 2016 
CONFIDENTIAL 
Property of The Medicines Company 
May not be used, divulged, published or otherwise disclosed without the consent of 
The Medicines Company 
This study will be conducted in compliance with Good Clinical Practice (GCP) and protection of the subject as required 
by the regulations and directives in operation at this time. 
NCT #: NCT02452918


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PROCEDURES IN CASE OF EMERGENCY 
 
Emergency Contact Information 
Role in Study 
Name 
Telephone Number 
Medical Director 
 
 
Drug Safety Physician 
 
 
Study Manager 
 
 
 


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PROTOCOL SYNOPSIS 
Name of Sponsor/Company: The Medicines Company 
Name of Finished Product: ORBACTIV™ (oritavancin) 
Name of Active Ingredient: oritavancin diphosphate 
Title of Study: An Open-Label Study to Evaluate the Safety of a Single 1200 mg IV Dose of Orbactiv 
(oritavancin) in Subjects on Concomitant Chronic Warfarin Therapy Being Treated For Acute Bacterial Skin 
and Skin Structure Infection (ABSSSI) 
Study Centers: Multicenter, at up to 10 centers in the United States 
Phase of Development: IV 
Objective:    
Assess the safety and tolerability when a single 1200 mg IV infusion of oritavancin is given concomitantly in 
subjects on chronic warfarin therapy with ABSSSI.  
Methodology: This is a Phase IV, multicenter, open-label safety study of a single 1200 mg intravenous (IV) 
infusion of oritavancin in adult subjects on chronic warfarin with acute bacterial skin and skin structure 
infection (ABSSSI) suspected or proven to be caused by Gram-positive pathogens. ABSSSI includes wound 
infections, infective cellulitis, and major cutaneous abscesses.  
An additional group of patients with ABSSSI, who are not on concomitant warfarin therapy, will also be 
enrolled to obtain information regarding the potential for antibody production following a single dose of 
oritavancin administration in patients.   
Subjects providing informed consent and meeting all study eligibility criteria will be enrolled in the study and 
will receive one 1200 mg dose of IV oritavancin.   
Number of Subjects: Approximately 25 subjects on concomitant warfarin therapy will be enrolled in this study.  
An additional group of 15 patients with ABSSSI, who are not on warfarin, will also be enrolled. 
Diagnosis and Main Criteria for Inclusion: 
Subjects who meet all of the following inclusion criteria are eligible for the study: 
1. Males or females ≥18 years old 
2. Diagnosis of ABSSSI (wound infection, cellulitis/erysipelas, or cutaneous abscess) suspected or 
confirmed to be caused by a Gram-positive pathogen requiring IV therapy  
3. Must be currently being treated with chronic warfarin therapy*: 
a. 
Warfarin therapy must have been initiated a minimum of 30 days prior to enrollment 
b. Current warfarin dosage must be stable for at least 14 days prior to enrollment 
c. 
At least one documented INR between 1.5 and 3.0 in the 30 days prior to screening 
d. The INR value at Screening must fall within 1.5 and 3.0 and also be within 25% of the prior 
documented value 
4. Able to give informed consent and willing to comply with all required study procedures  
*Patients in the non-warfarin group are not required to be on chronic warfarin therapy 
 
Subjects who meet any of the following criteria are not eligible to participate in this study: 
1. Infections associated with, or in close proximity to, a prosthetic device 
2. Severe sepsis or refractory shock 
3. Known or suspected bacteremia at time of screening 
4. ABSSSI due to or associated with any of the following: 


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a. 
Infections suspected or documented to be caused by Gram-negative pathogens (i.e., human or 
animal bites, injuries contaminated with fresh or salt water, external malignant otitis) 
b. Wound infections (surgical or traumatic) and abscesses with only Gram-negative pathogens  
c. 
Diabetic foot infections (infection extending distal to the malleoli in a patient with diabetes 
mellitus and peripheral neuropathy and/or vascular insufficiency or any ulceration of their 
foot)  
d. Concomitant infection at another site not including a secondary ABSSSI lesion (e.g.,  septic 
arthritis, endocarditis, osteomyelitis) 
e. 
Infected burns 
f. 
A primary infection secondary to a pre-existing skin disease with associated inflammatory 
changes such as atopic dermatitis, eczema or hidradenitis suppurativa  
g. Decubitus or chronic skin ulcer, or ischemic ulcer due to peripheral vascular disease (arterial 
or venous) 
h. Any evolving necrotizing process (i.e. necrotizing fasciitis), gangrene or infection suspected 
or proven to be caused by Clostridium species (e.g., crepitance on examination of the ABSSSI 
site and/or surrounding tissue(s) or radiographic evidence of subcutaneous gas in proximity to 
the infection) 
i. 
Infections known to be caused by a Gram-positive organism with a vancomycin minimum 
inhibitory concentration (MIC) >2 μg/mL or clinically failing prior therapy with glycopeptides  
j. 
Catheter site infections 
5. Currently receiving chronic systemic immunosuppressive therapy such as chemotherapy or prednisone  
(prednisone at non-immunosuppressive doses of ≤15 mg/day is permitted) 
6. Subjects who are likely to need treatment with intravenous unfractionated heparin sodium within 48 
hours after oritavancin administration 
7. Last known cluster of differentiation 4 (CD4) count <200 cells/mm3 in subjects with known human 
immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) 
8. Neutropenia with absolute neutrophil count (ANC) <500 cells/mm3 
9. Significant or life-threatening condition (e.g., endocarditis) that would confound or interfere with the 
assessment of safety 
10. Women who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least 
2 acceptable methods of birth control: (e.g., prescription oral contraceptives, contraceptive injections, 
contraceptive patch, intrauterine device, barrier method(s) or male partner sterilization). Women 
≥2 years postmenopausal or surgically sterile are exempt from this exclusion 
11. History of immune-related hypersensitivity reaction to glycopeptides (such as vancomycin, televancin, 
daptomycin, or dalbavancin) or any of their excipients. Note: subjects who have had histamine-like 
infusion reactions to a glycopeptide are not excluded 
12. Subjects unwilling to forego blood and/or blood product donation for at least 1 month from initiation of 
oritavancin dose  
13. Treatment with investigational medicinal product within 30 days or 5 half-lives, whichever is longer, 
before enrollment and for the duration of the study 
14. Investigational device present, or removed within 30 days before enrollment, or presence of device-
related infection  
15. Significant change of any medications over the preceding 7 days that could interfere with the 
metabolism of warfarin (if patient is on chronic warfarin therapy) 
16. Subjects who the investigator considers unlikely to adhere to the protocol, comply with oritavancin 
administration, or complete the clinical study (e.g., unlikely to survive 90 days from initiation of 
oritavancin dosing) 


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Test Product, Dose and Mode of Administration: 
The investigational drug oritavancin diphosphate (oritavancin) will be administered intravenously to all subjects. 
The dose is made up of three single-use vials, each containing 400 mg of oritavancin and the inactive 
component mannitol. At the time of use, each vial should be reconstituted by adding 40 mL of Sterile Water for 
Injection, United States Pharmacopeia (USP). After reconstitution, oritavancin should be further diluted in 
approximately 1000 mL of 5% Dextrose Injection (D5W).  
On Day 1 of the study, subjects will be administered a single 1200 mg IV dose of oritavancin in 1000 mL D5W. 
Oritavancin must be infused over 3 hours.  No other material or diluent may be substituted or concomitantly 
infused through the same IV line. 
Duration of Treatment: Intravenous oritavancin will be administered in a single 1200mg intravenous dose.  
Reference Therapy, Dose, and Mode of Administration: Not applicable. 
Criteria for Evaluation:  
Primary outcome: 
 
Safety of the administration of oritavancin in subjects on chronic warfarin will be assessed according to 
vital signs, laboratory abnormalities, and the incidence of Adverse Events (AEs) and Serious Adverse 
Events (SAEs) 
Additional Safety Evaluation: 
Any changes in warfarin dosing (for patients on warfarin therapy), based on the PT/INR results or safety data 
will be recorded. If the PT/INR has not returned to therapeutic baseline by Day 14, patient will be referred to 
and followed by their primary physician responsible for their PT/INR monitoring. 
Secondary outcomes:  
 
Clinical cure as an assessment of efficacy, determined by the investigator at 48-72 hours after start of 
oritavancin dose and at Day 7 
Exploratory Outcome: 
 
Potential for antibody development following a single dose oritavancin administration 
Clinical evaluation time points: 
 
Assessment of safety (adverse events and PT/INR testing) Days 1, 2, 3, 7 and 14 
 
Early clinical efficacy evaluation at 48 to 72 hours from start of oritavancin administration 
 
Post-therapy efficacy evaluation at Day 7   
Statistical Methods: Approximately 25 subjects on chronic warfarin therapy will be enrolled (ITT population).  
An additional group of 15 ABSSSI patients, who are not on chronic warfarin therapy, will also be enrolled. 
Sample size:  The sample size of 25 subjects is chosen based on feasibility and clinical judgment to provide 
adequate safety information on the administration of oritavancin to subjects with an ABSSSI who are on chronic 
warfarin. An additional group of 15 ABSSSI patients who are not on chronic warfarin therapy was added to 
obtain information regarding potential for antibody production related to oritavancin administration. 
Analysis population: The patient populations are defined as follows:  
 
Intent-to-Treat (ITT) Population: The ITT population will include all subjects screened and enrolled 
 
Safety Population: All subjects dosed with IV oritavancin. The safety population will be the primary 
population for all the safety analyses 
Descriptive statistics will be provided for demographic, baseline characteristics, medical history, prior and 
concomitant medications.  Descriptive statistics include means, medians, standard deviations and ranges for 
continuous variables, as well as frequency and percentage for categorical variables.   
Summary tables and listings of safety data, including adverse events, laboratory results (prothrombin time 
(PT)/international normalized ratio (INR), direct and indirect Coombs, Immunoglobulin panel, oritavancin 


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antibody assay) and vital signs will be provided for the safety population. Summaries of clinical cure as assessed 
by the investigator at Day 3 and Day 7 will be provided for the ITT population. 


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Table 1: SCHEDULE OF EVENTS   
Study procedures 
SCREENING 
Pre-Dose 
Treatment 
FOLLOW UP 
 
≤24 hrs from 
1st dose 
Day 1 
Day 1 
Day 2 
Day 3 
Safety & 
Efficacy 
Visit 
Day 7 
Safety & 
Efficacy 
Visit 
Day 14 Follow 
up Visit 
(± 2 days)1 
Informed Consent 
x 
 
 
 
 
 
 
Assess Inclusion/Exclusion 
x 
x 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
Physical Exam (height and weight at Screening only) 
x 
 
 
 
 
 
 
Vital Signs2 
x 
x 
x 
 
x 
x 
x 
Pregnancy test3 
x 
 
 
 
 
x 
 
Record ABSSSI surgical procedures4 
x 
 
 
 
 
 
 
Safety laboratory assessments5 
x 
 
 
 
 
x 
x 
Microbiology testing6 
x 
 
 
 
 
 
 
Record prior or concomitant medications 
x 
x 
x 
x 
x 
x 
x 
Administer IV oritavancin 
 
 
x 
 
 
 
 
PT/INR Test7 
x 
 
 
x 
x 
x 
x 
Assess clinical cure8 
 
 
 
 
x 
x 
 
Immunoglobulin panel and plasma for oritavancin 
antibody assay 
x 
 
 
 
x 
x 
x 
Direct and Indirect Coombs Test9 
x 
 
 
 
x 
x 
x 
Assessment of adverse events10 
x 
x 
x 
x 
x 
x 
x 
Plasma Storage Samples for Drug Dependent Antibody 
Ex Vivo Study11 
 
 
x 
 
 
 
 
                                                          
1 If subject has abnormal laboratory values that have not returned to a therapeutic baseline by Day 14, additional follow up visits may be required. 
2 Vitals signs include blood pressure, temperature, respiratory rate and heart rate.  
3 Perform a local urine pregnancy test for female patients of childbearing potential (may be omitted for females > 2 years postmenopausal or surgically sterile). 
4 This includes but is not limited to aspiration, debridement, incision and drainage. 
5 Blood chemistry and hematology (Section 7.2.4 for listing of tests to be performed). Unless otherwise indicated all laboratory tests will be performed by site’s local laboratory. 
6 Microbiology testing should be performed per institutions Standard of Care (SOC). 
7 Patients on warfarin are required to have at least one documented INR between 1.5 and 3.0 in the 30 days prior to screening.  The INR value at Screening must fall within 1.5 and 3.0.  After dosing 
with oritavancin, the next PT/INR should be collected with 18-36 hours of start of oritavancin infusion. If PT/INR has not returned to baseline at Day 3, more frequent PT/INR testing prior to Day 7 may 
be required.  
8 Clinical cure should be assessed by investigator at Day 3 (48-72 hours after start of oritavancin administration) and at Day 7. 
9 Patients with a negative Coombs Test at Day 14 test must have test repeated every 2 weeks until return to baseline or stable. 
10 Adverse events and serious adverse events will be assessed from the time of informed consent through 14 days post first administration of Oritavancin.   
11 Blood will be collected immediately after the completion of the infusion to prepare three plasma sample for Ex Vivo Study investigating the effects of Oritavancin on Antibody Formation.  


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TABLE OF CONTENTS 
PROCEDURES IN CASE OF EMERGENCY .................................................................................. 2 
PROTOCOL SYNOPSIS .................................................................................................................. 3 
TABLE OF CONTENTS .................................................................................................................. 8 
LIST OF TABLES .......................................................................................................................... 11 
LIST OF ABBREVIATIONS .......................................................................................................... 12 
1. 
INTRODUCTION ................................................................................................................. 14 
1.1. 
Background ............................................................................................................. 14 
1.2. 
Oritavancin .............................................................................................................. 14 
1.2.1. 
Preclinical Studies ..................................................................................... 15 
1.2.2. 
Summary of Clinical Pharmacology ............................................................ 15 
1.2.3. 
Clinical Studies ......................................................................................... 15 
1.2.4. 
Known and Potential Risks and Benefits ...................................................... 17 
1.3. 
Study Rationale ........................................................................................................ 18 
1.4. 
Study Population ...................................................................................................... 19 
2. 
TRIAL OBJECTIVE AND PURPOSE .................................................................................. 19 
3. 
TRIAL DESIGN .................................................................................................................... 19 
3.1. 
Primary Outcome..................................................................................................... 19 
3.2. 
Secondary Outcome ................................................................................................. 19 
3.2.1. 
Exploratory Outcome: ................................................................................ 19 
3.3. 
Measures to Minimize/Avoid Bias ............................................................................ 20 
3.3.1. 
Unblinded Study ........................................................................................ 20 
3.4. 
Type/Design of Trial ................................................................................................. 20 
4. 
SUBJECT POPULATION .................................................................................................... 21 
4.1. 
Number of Subjects .................................................................................................. 21 
4.2. 
Inclusion Criteria ..................................................................................................... 21 
4.3. 
Exclusion Criteria .................................................................................................... 21 
4.4. 
Withdrawal Criteria................................................................................................. 23 
5. 
TREATMENT OF SUBJECTS ............................................................................................. 24 
5.1. 
Study Medications .................................................................................................... 24 
5.1.1. 
Oritavancin ............................................................................................... 24 
5.1.2. 
Packaging and Labeling ............................................................................. 24 
5.1.3. 
Storage ..................................................................................................... 24 
5.1.4. 
Accountability ........................................................................................... 25 
5.2. 
Concomitant Medications ......................................................................................... 25 


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5.2.1. 
Prohibited Concomitant Medications ........................................................... 25 
5.2.2. 
Permitted Concomitant Medications ............................................................ 25 
5.2.3. 
Warfarin Therapy ...................................................................................... 25 
5.3. 
Restrictions .............................................................................................................. 26 
6. 
SEQUENCE OF PROCEDURES .......................................................................................... 26 
6.1. 
General Conduct of the Trial.................................................................................... 26 
6.2. 
Screening Period (≤24 hrs prior to Day 1)................................................................. 26 
6.3. 
Day 1 Pre-dose ......................................................................................................... 27 
6.4. 
Treatment Period ..................................................................................................... 27 
6.4.1. 
Day 1 ........................................................................................................ 27 
6.5. 
FOLLOW UP ........................................................................................................... 27 
6.5.1. 
Day 2 ........................................................................................................ 27 
6.5.2. 
Day 3 ........................................................................................................ 28 
6.5.3. 
Day 7 ........................................................................................................ 28 
6.5.4. 
Day 14 (±2 days) ....................................................................................... 28 
7. 
PROTOCOL ASSESSMENTS .............................................................................................. 29 
7.1. 
Treatment, Day 1 ..................................................................................................... 29 
7.1.1. 
Medical management guidelines ................................................................. 29 
7.1.1.1. 
Gram-negative pathogen ABSSSI infections ............................ 29 
7.2. 
Assessment of Safety ................................................................................................ 29 
7.2.1. 
Adverse Events ......................................................................................... 29 
7.2.2. 
Physical Examinations ............................................................................... 29 
7.2.3. 
Vital signs ................................................................................................. 29 
7.2.4. 
Laboratory assessment ............................................................................... 30 
7.3. 
Assessment of efficacy .............................................................................................. 30 
8. 
ADVERSE EVENTS ............................................................................................................. 33 
8.1. 
Definitions ................................................................................................................ 33 
8.1.1. 
Adverse Event ........................................................................................... 33 
8.1.1.1. 
AE Severity ........................................................................... 33 
8.1.1.2. 
Study Drug Causality ............................................................. 33 
8.1.2. 
Serious Adverse Event ............................................................................... 34 
8.1.3. 
Medication Errors ...................................................................................... 35 
8.1.4. 
Reporting Medication Errors ...................................................................... 35 
8.1.5. 
Reporting Events of Pregnancy ................................................................... 36 
8.2. 
Procedure for Non-Serious Adverse Event Recording .............................................. 36 
8.3. 
Procedure for Serious Adverse Event Reporting ...................................................... 36 
9. 
DATA COLLECTION ........................................................................................................... 38 
10. 
STATISTICAL PLAN ........................................................................................................... 39 


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10.1. 
Sample Size .............................................................................................................. 39 
10.2. 
General Statistical Considerations and Definitions ................................................... 39 
10.2.1. 
General Statistical Methods ........................................................................ 39 
10.2.2. 
Analysis Population ................................................................................... 39 
10.2.2.1. 
Intent-to Treat (ITT) Population .............................................. 39 
10.2.2.2. 
Safety Population ................................................................... 39 
10.2.3. 
Analysis Windows and Baseline ................................................................. 39 
10.2.4. 
Missing Data Handling .............................................................................. 39 
10.3. 
Statistical Analyses ................................................................................................... 39 
10.3.1. 
Demographic and Background Characteristics ............................................. 40 
10.3.2. 
Prior and Concomitant Medications ............................................................ 40 
10.3.3. 
Safety Analysis ......................................................................................... 40 
10.3.3.1. 
Adverse Events ...................................................................... 40 
10.3.3.2. 
Clinical Safety Laboratory Tests .............................................. 40 
10.3.3.3. 
Vital Signs............................................................................. 40 
11. 
RECORDS RETENTION ..................................................................................................... 41 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................................ 42 
12.1. 
Monitoring ............................................................................................................... 42 
12.2. 
Auditing ................................................................................................................... 42 
12.3. 
Protocol Deviations .................................................................................................. 42 
13. 
ETHICS AND RESPONSIBILITY ........................................................................................ 44 
13.1. 
Informed Consent .................................................................................................... 44 
13.2. 
Ethics committee/Institutional Review Board ........................................................... 44 
14. 
CONFIDENTIALITY ........................................................................................................... 45 
15. 
INVESTIGATOR AGREEMENT ......................................................................................... 46 
16. 
REFERENCES ..................................................................................................................... 47 
16.1. 
Publications ............................................................................................................. 47 
16.2. 
Study Reports .......................................................................................................... 47 


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LIST OF TABLES 
Table 1:             SCHEDULE OF EVENTS   ....................................................................................................................... 7 
Table 2 
Mean Pharmacokinetic Parameters for ABSSSI Subjects Receiving a Single 1200 mg Dose (n = 297)
 ............................................................................................................................................................... 15 
Table 3 
Overview of Adverse Events from SOLO Pooled Data (Safety Population) ......................................... 16 
Table 4 
Adverse Events that Occurred in ≥3% of Subjects in the Oritavancin Treatment Group (Safety 
Population) ............................................................................................................................................. 17 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Explanation 
ABSSSI 
acute bacterial skin and skin structure infection 
AE 
adverse event 
AIDS 
Acquired Immune Deficiency Syndrome 
ANC 
absolute neutrophil count 
AUC 
area under the plasma concentration time curve  
AUC0-24 
Area under the drug concentration-time curve from time zero to 24 hours 
AUC0-∞ 
Area under the concentration-time curve from zero to infinity 
BMI 
body mass index 
CD4 
cluster of differentiation 4 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CrCl 
creatinine clearance 
CS 
clinically significant 
CV 
coefficient of variation 
CYP2C9 
Cytochrome P450 2C9 enzyme 
D5W 
5% dextrose in water 
EC 
Ethics Committee 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HEENT 
head, eyes, ears, nose, throat 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonisation 
IgA 
Immunoglobulin A 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
INR 
International Normalized Ratio 
IRB 
institutional review board 
ITT 
Intent-to-Treat 
IV 
intravenous 
MDCO 
The Medicines Company 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
MIC 
Minimum Inhibitory Concentration 
MRSA 
methicillin-resistant S. aureus 
No. 
Number 
OTC 
over the counter 
PK 
pharmacokinetic 
PT 
prothrombin time 


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Abbreviation 
Explanation 
Q1 
first quartile 
Q3 
third quartile 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
standard of care 
TEAE 
treatment-emergent adverse event 
T1/2 
Half-life 
T1/2,α 
Half-life for the alpha phase 
T1/2,β 
Half-life for the beta phase 
T1/2,γ 
Half-life for the gamma phase 
US 
United States 
USP 
United States Pharmacopeia 
USPI 
United States Package Insert 
Vss 
steady-state volume of distribution 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
This protocol describes a multicenter, open-label study to evaluate the safety of a single 1200 
mg IV dose of Orbactiv (oritavancin) for the treatment of subjects on concomitant chronic 
warfarin therapy being treated for an acute bacterial skin and skin structure infection 
(ABSSSI).  An additional group of fifteen patients will also be enrolled that are being treated 
for an ABSSSI and are NOT on concomitant chronic warfarin therapy. 
Oritavancin has been approved in the United States for the treatment of adult patients with 
acute bacterial skin and skin structure infections (ABSSSIs) caused or suspected to be caused 
by susceptible isolates of designated Gram-positive microorganisms. An extensive clinical 
development program has been conducted to evaluate the safety and effectiveness of 
oritavancin, comprising 4 Phase III studies, 4 Phase II studies and 15 Phase I studies completed 
in adults. A safety and pharmacokinetic study in the pediatric population is ongoing.  A total of 
3042 subjects have been exposed to oritavancin to date, including 1075 adult subjects with 
ABSSSI treated with a 1200 mg single dose regimen.  
1.1. 
BACKGROUND 
ABSSSIs are common infections that include cellulitis, major cutaneous abscesses, and 
wound infections. ABSSSIs are inflammatory microbial invasions of the epidermis, 
dermis and subcutaneous tissues [Dryden, 2009]. These infections are frequently 
caused by Gram-positive bacteria including methicillin-susceptible S. aureus, 
methicillin-resistant S. aureus (MRSA), Streptococcus pyogenes, and other β-hemolytic 
streptococcal species and enterococci.  The clinical complications of improperly treated 
or untreated ABSSSIs may include local expansion and spread, secondary bacteremia 
with potential for distant metastatic foci of infection, and systemic effects of bacterial 
infection. 
1.2. 
ORITAVANCIN 
Oritavancin is a novel semi-synthetic, lipoglycopeptide antibiotic that has three 
mechanisms of action: 1) inhibition of the transglycosylation (polymerization) step of 
cell wall biosynthesis by binding to the stem peptide of peptidoglycan precursors; 2) 
inhibition of the transpeptidation (crosslinking) step of cell wall biosynthesis by 
binding to the peptide bridging segments of the cell wall; and 3) disruption of bacterial 
membrane integrity, leading to depolarization, permeabilization, and rapid cell death. 
These multiple mechanisms contribute to the rapid, concentration-dependent 
bactericidal activity of oritavancin. 
Oritavancin has been approved by the Food and Drug Administration (FDA) for the 
treatment of adult subjects with ABSSSIs caused or suspected to be caused by 
susceptible isolates of designated Gram-positive microorganisms including methicillin 
resistant Staphylococcus aureus [ORBACTIV™ Package Insert 2014].   


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1.2.1. Preclinical Studies 
Oritavancin has been extensively studied pre-clinically. The results from the 
safety, toxicology, pharmacokinetic, and pharmacodynamic studies demonstrate 
that oritavancin does not induce any biologically significant toxicity.  An 
overview of relevant nonclinical study results is presented in the Investigator’s 
Brochure [Oritavancin Investigator’s Brochure Version 10].   
1.2.2. Summary of Clinical Pharmacology  
The pharmacokinetics of a single 1200 mg dose of oritavancin in ABSSSI 
subjects were determined from population pharmacokinetic analysis of pooled 
data from 297 adult subjects and are presented in Table 2. At steady state, 
oritavancin exhibits linear pharmacokinetics at a dose up to 1200 mg. The 
mean, population-predicted oritavancin concentration-time profile displays a 
multi- exponential decline and a long terminal half-life of 245 hours. Normal 
Healthy Volunteers administered a single 1200 mg dose of oritavancin 
experience higher oritavancin exposure when compared to patients; mean Cmax 
was approximately 25% higher in healthy volunteers and AUC0-∞ was 
approximately 40% higher in healthy volunteers when compared to patients. 
Table 2 Mean Pharmacokinetic Parameters for ABSSSI Subjects Receiving a Single 1200 mg Dose (n 
= 297)  
Parameter 
Mean (CV%) 
Vss (L) 
97.8 
(56.4%) 
Cmax (μg/mL) 
138 
(23.0%) 
AUC0-24 (μg•h/mL) 
1110 
(33.9%) 
AUC0-72 (g•h/mL) 
1530 
(36.9) 
AUC0-∞ (μg•h/mL) 
2800 
(28.6%) 
T1/2,α (h) 
2.29 
(49.8%) 
T1/2,β (h) 
13.4 
(10.5%) 
T1/2,γ (h) 
245 
(14.9%) 
Vss, Steady-state volume of distribution; Cmax, Maximum plasma concentration; AUC0-24, Area under the plasma 
concentration-time curve from time zero to 24 hours, AUC0-∞ = Area under the plasma concentration time curve from 
time zero to infinity; T1/2,α, Half-life for the alpha phase, T1/2,β, Half-life for the beta phase; T1/2,γ, Half-life for the gamma 
phase; CV% = Percent Coefficient of variation. 
 
1.2.3. Clinical Studies 
The clinical program of oritavancin comprises four completed Phase III studies, 
four Phase II studies, fourteen Phase I studies in healthy subjects, and 
one Phase I study in both healthy and hepatically-impaired subjects. Throughout 
the completed studies, IV oritavancin was administered to 3042 individuals 
(2632 subjects and 410 healthy subjects) [Oritavancin Investigator’s Brochure 
Version 10]. 


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Efficacy and safety findings of the intended treatment dose in adult subjects 
with ABSSSI are summarized below:  
Efficacy 
The results from SOLO I and SOLO II in 1959 adult patients demonstrate that a 
single 1200 mg IV dose of oritavancin is clinically non-inferior to 7 to 10 days 
of IV vancomycin (1 g or 15 mg/kg twice daily) using a pre-specified non-
inferiority margin of 10% for both early clinical response and clinical cure at 
post therapy evaluation. The subject population was representative of ABSSSIs 
with S. aureus the common causative pathogen isolated; a large subset of 
subjects (N=405) had documented MRSA infections. Efficacy in MRSA 
subjects was similar to that observed in the overall population for all endpoints. 
Safety 
The SOLO I and SOLO II studies demonstrated that a single 1200 mg IV dose 
of oritavancin is well tolerated and has a similar safety profile to 7 to 10 days of 
IV vancomycin treatment as demonstrated by the similar frequency and nature 
of treatment emergent adverse events, Serious Adverse Events (SAEs) and 
Adverse Events (AEs) leading to discontinuation reported by patients (Table 3).  
 
Table 3 
Overview of Adverse Events from SOLO Pooled Data (Safety Population)  
 
SOLO Pool 
Category 
Oritavancin 
(N=976) 
n (%) 
Vancomycin 
(N=983) 
n (%) 
No. of Subjects with any AE 
 540 (55.3%)  559 
(56.9%) 
No. of Subjects with any AE Leading to 
Study Drug Discontinuation 
  36 
(3.7%)   41 
(4.2%) 
No. of Subjects with SAE 
  57 
(5.8%)   58 
(5.9%) 
No. of Subjects with any AE Leading to 
Death 
   2 
(0.2%)    3 
(0.3%) 
 
 
AE = adverse event; SAE = serious adverse event. 
 
 
 


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Table 4 
Adverse Events that Occurred in ≥3% of Subjects in the Oritavancin Treatment Group 
(Safety Population) 
 
SOLO Pool 
Preferred Term 
Oritavancin 
(N=976) 
n (%) 
Vancomycin 
(N=983) 
n (%) 
 
 
 
Nausea 
97 (9.9%) 
103 
(10.5%) 
Headache 
69 (7.1%) 
66 
(6.7%) 
Vomiting 
45 (4.6%) 
46 
(4.7%) 
Cellulitis 
37 (3.8%) 
32 
(3.3%) 
Diarrhea 
36 (3.7%) 
32 
(3.3%) 
Constipation 
33 (3.4%) 
38 
(3.9%) 
Infusion site extravasation  
Pyrexia   
Pruritus 
33 (3.4%) 
30 (3.1%)  
29 (3.0%) 
33 
(3.4%)  
31 
(3.2%) 
73 
(7.4%) 
 
1.2.4. Known and Potential Risks and Benefits 
Twenty three clinical trials, including four Phase III, four Phase II, and fifteen 
Phase I studies have been completed to date, in which 3042 subjects were 
exposed to oritavancin. The most common adverse events (>3%) by preferred 
term in either treatment group, in the SOLO I or SOLO II studies were nausea, 
headache, vomiting, cellulitis, diarrhea, constipation, infusion site extravasation, 
pyrexia and pruritus, as outlined in Table 4.  
Serious hypersensitivity reactions have been reported with the use of 
oritavancin. If an acute hypersensitivity reaction occurs during oritavancin 
infusion, discontinue oritavancin immediately and institute appropriate 
supportive care. Due to the possibility of cross-sensitivity, carefully monitor for 
signs of hypersensitivity during ORBACTIV infusion in patients with a history 
of glycopeptide allergy. In the Phase III ABSSSI clinical trials, the median 
onset of hypersensitivity reactions in oritavancin -treated patients was 1.2 days 
and the median duration of these reactions was 2.4 days.    
Infusion related reactions or anaphylactoid reactions have been reported with 
oritavancin including pruritus, urticaria or flushing. If reactions do occur, 
slowing or interrupting the infusion should be considered to mitigate the 
reaction. 
Oritavancin is a mild inhibitor of Cytochrome P450 2C9 enzyme (CYP2C9), 
and therefore, has the potential to increase warfarin concentrations when 
administered concomitantly.  Oritavancin has been shown to artificially prolong 
PT and INR for up to 24 hours, making the monitoring of the anticoagulation 
effect of warfarin unreliable up to 24 hours after an oritavancin dose. Subjects 


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who are on warfarin (including all subjects in this trial) should be closely 
monitored for signs of bleeding. 
A complete description of relevant risks of oritavancin can be found in the 
investigator’s brochure [Oritavancin Investigator’s Brochure Version 10] and 
the United States Package Insert (USPI). 
1.3. 
STUDY RATIONALE 
As noted above, oritavancin is a weak inhibitor of CYP2C9 based on a 31% increase 
(90% confidence interval (CI) [1.294, 1.345]) in the systemic exposure of S warfarin 
(TMC-ORI-12-03). Two additional studies are ongoing; MDCO-ORI-14-01 is a Phase I 
study in healthy volunteers to assess the magnitude and duration of the effect of a single 
1200 mg intravenous dose on numerous coagulation tests, including PT/INR, and 
MDCO-ORI-14-02 which is an additional Phase I study in healthy volunteers assessing 
the magnitude and duration of the pharmacokinetic (PK) interaction between warfarin 
and oritavancin. Since warfarin is a drug with a narrow therapeutic index and some 
patients with ABSSSI may receive oritavancin while on warfarin treatment, this study 
is being conducted to characterize the effect of oritavancin on clinical care and warfarin 
dosing.  The intention is to determine the magnitude and duration, if any, of alterations 
to warfarin dosing or of clinically important consequences of dosing with oritavancin. 
In the SOLO and SIMPLIFI trials, a total of 16 patients with ABSSSI received 
concomitant warfarin while treated with a single 1200 mg dose of oritavancin.  Of these 
16 patients, 10 were on warfarin prior to starting oritavancin, 4 received warfarin 
therapy after starting oritavancin therapy and for 2 patients the timing of warfarin 
therapy is unknown.  None of these 16 patients discontinued from the study early due to 
adverse events.  One patient experienced an event of infusion site thrombosis 2 days 
prior to the administration of warfarin therapy but there were no other bleeding or 
thrombotic related events.  Additionally, no abnormal prothrombin time coagulation 
tests were reported in the oritavancin treated patients.   
This study will extend the above safety data in patients with ABSSSI when oritavancin 
and warfarin are given concomitantly.   
In addition, a group of patients with ABSSSI, who are not on concomitant warfarin 
therapy, have been added to this study to obtain information regarding the potential for 
antibody production following a single dose of oritavancin administration in patients.  
This has not been previously tested, therefore plasma will be collected at regular 
intervals after oritavancin dosing to test for immunoglobulins, direct and indirect 
Coombs, and presence of oritavancin antibodies.    
The 1200 mg dose of oritavancin is the United States (US) approved therapeutic dose. 


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This study will also be conducted in compliance with Good Clinical Practices (GCP) 
including the Declaration of Helsinki and all applicable regulatory requirements. 
 
1.4. 
STUDY POPULATION 
Subjects at least 18 years of age with an ABSSSI, on concomitant warfarin therapy, 
suspected or confirmed to be caused by Gram-positive pathogens. An ABSSSI includes 
the following infections: Wound infections, cellulitis/erysipelas and major cutaneous 
abscess. An additional group of patients with ABSSSI, who are not on concomitant 
warfarin therapy, will also be enrolled.  
 
2. 
TRIAL OBJECTIVE AND PURPOSE 
The primary objectives of this study are: 
 To assess the safety and tolerability when a single 1200 mg IV infusion of 
oritavancin is given concomitantly in subjects on chronic warfarin therapy with 
ABSSSI. 
 An additional group of patients with ABSSSI, who are not on concomitant warfarin 
therapy, will be enrolled to obtain information regarding the potential for antibody 
production following a single dose of oritavancin administration in patients. 
 
3. 
TRIAL DESIGN 
3.1. 
PRIMARY OUTCOME 
The primary outcome of this trial will be:  
 Safety of the administration of oritavancin in subjects on chronic warfarin will 
be assessed according to vital signs, laboratory abnormalities, and the incidence 
of AEs and SAEs. 
3.2. 
SECONDARY OUTCOME 
The secondary outcome of this trial will be: 
 Clinical cure determined by the Investigator at 48-72 hours after start of 
oritavancin dose and Day 7 visit. 
3.2.1. Exploratory Outcome: 
 An exploratory outcome of this trial is to evaluate the potential for antibody 
development following a single dose oritavancin administration. 


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3.3. 
MEASURES TO MINIMIZE/AVOID BIAS  
3.3.1. Unblinded Study 
This is an open label study.  The primary endpoints are safety and laboratory 
measurements, primarily change in PT/INR, which is not likely to be subject to 
interpretation bias.   
3.4. 
TYPE/DESIGN OF TRIAL 
This will be a Phase IV, open-label study evaluating the safety and tolerability when a 
single 1200 mg dose of oritavancin is given concomitantly in subjects on chronic 
warfarin therapy with ABSSSI.  An additional group of patients with ABSSSI, who are 
not on concomitant warfarin therapy, will also be enrolled. 
Up to 40 subjects will be enrolled at up to 10 centers in the United States.  Informed 
consent will be obtained from subjects meeting all inclusion and no exclusion criteria 
before the initiation of any study-specific procedures.   
Eligible subjects will be enrolled and receive a single 1200 mg dose of oritavancin IV.  
Adverse events and SAEs will be assessed from the time of informed consent through 
14 days post administration of oritavancin.  
A description of each study period and the assessments that will be performed at each 
time point is detailed in Section 6. 
 


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4. 
SUBJECT POPULATION 
4.1. 
NUMBER OF SUBJECTS 
Up to forty subjects will be enrolled at up to 10 centers in the US. Approximately 25 
subjects on concomitant warfarin therapy will be enrolled in this study.  An additional 
15 patients with ABSSSI, who are not on warfarin, will also be enrolled.  
4.2. 
INCLUSION CRITERIA 
Subjects may be included in the study if they meet all of the following criteria: 
1. Males or females ≥18 years old 
2. Diagnosis of ABSSSI (wound infections, Cellulitis/erysipelas, or cutaneous 
abscess) suspected or confirmed to be caused by a Gram-positive pathogen 
requiring IV therapy 
3. Must be currently being treated with chronic warfarin therapy*: 
a. Warfarin therapy must have been initiated a minimum of 30 days prior to 
enrollment  
b. Current warfarin dosage must be stable for at least 14 days prior to enrollment  
c. At least one documented INR between 1.5 and 3.0 in the 30 days prior to 
Screening 
d. The INR value at Screening must fall within 1.5 and 3.0 and also be within 25% 
of the prior documented value 
4. Able to give informed consent and willing to comply with all required study 
procedures 
*Patients in the non-warfarin sub-group are not required to be on chronic warfarin 
therapy 
4.3. 
EXCLUSION CRITERIA 
Subjects will be excluded from the study if any of the following exclusion criteria 
apply: 
1. Infections associated with, or in close proximity to, a prosthetic device 
2. Severe sepsis or refractory shock 
3. Known or suspected bacteremia at time of screening  
4. ABSSSI due to or associated with any of the following: 
a. Infections suspected or documented to be caused by Gram-negative pathogens 
(i.e., human or animal bites, injuries contaminated with fresh or salt water, 
external malignant otitis) 
b. Wound infections (surgical or traumatic) and abscesses with only Gram-
negative pathogens  


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c. Diabetic foot infections (infection extending distal to the malleoli in a patient 
with diabetes mellitus and peripheral neuropathy and/or vascular insufficiency 
or any ulceration of their foot)  
d. Concomitant infection at another site not including a secondary ABSSSI lesion 
(e.g., septic arthritis, endocarditis, osteomyelitis) 
e. Infected burns 
f. A primary infection secondary to a pre-existing skin disease with associated 
inflammatory changes such as atopic dermatitis, eczema or hidradenitis 
suppurativa  
g. Decubitus or chronic skin ulcer, or ischemic ulcer due to peripheral vascular 
disease (arterial or venous) 
h. Any evolving necrotizing process (i.e. necrotizing fasciitis), gangrene or 
infection suspected or proven to be caused by Clostridium species (e.g., 
crepitance on examination of the ABSSSI site and/or surrounding tissue(s) or 
radiographic evidence of subcutaneous gas in proximity to the infection) 
i. Infections known to be caused by a Gram-positive organism with a vancomycin 
minimum inhibitory concentration (MIC) >2 μg/mL or clinically failing prior 
therapy with glycopeptides  
j. Catheter site infections 
5. Currently receiving chronic systemic immunosuppressive therapy such as 
chemotherapy or prednisone  (prednisone at non-immunosuppressive doses of ≤15 
mg/day is permitted) 
6. Subjects who are likely to need treatment with intravenous unfractionated heparin 
sodium within 48 hours after oritavancin administration 
7. Last known cluster of differentiation 4 (CD4) count <200 cells/mm3 in subjects 
with known human immunodeficiency virus (HIV)/acquired immune deficiency 
syndrome (AIDS) 
8. Neutropenia with absolute neutrophil count (ANC) <500 cells/mm3 
9. Significant or life-threatening condition (e.g., endocarditis) that would confound or 
interfere with the assessment of safety 
10. Women who are pregnant or nursing, or who are of childbearing potential and 
unwilling to use at least 2 acceptable methods of birth control: (e.g., prescription 
oral contraceptives, contraceptive injections, contraceptive patch, intrauterine 
device, barrier method(s) or male partner sterilization). Women ≥2 years 
postmenopausal or surgically sterile are exempt from this exclusion 
11. History of immune-related hypersensitivity reaction to glycopeptides (such as 
vancomycin, televancin, daptomycin, or dalbavancin) or any of their excipients. 
Note: subjects who have had histamine-like infusion reactions to a glycopeptide are 
not excluded 
12. Subjects unwilling to forego blood and/or blood product donation for at least 1 
month from initiation of oritavancin dose 


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13. Treatment with investigational medicinal product within 30 days or 5 half-lives, 
whichever is longer, before enrollment and for the duration of the study 
14. Investigational device present, or removed within 30 days before enrollment, or 
presence of device-related infection  
15. Significant change of any medications over the preceding 7 days that could interfere 
with the metabolism of warfarin (if patient is on chronic warfarin therapy)  
16. Subjects who the investigator considers unlikely to adhere to the protocol, comply 
with oritavancin administration, or complete the clinical study (e.g., unlikely to 
survive 90 days from initiation of oritavancin dosing) 
Subjects excluded for any of the previous criteria may only be rescreened for participation after 
favorable discussion with sponsor and principal investigator 
4.4. 
WITHDRAWAL CRITERIA 
All subjects have the right to withdraw at any point during the study without prejudice. 
The investigator can discontinue any subject at any time if medically necessary. It will 
be documented whether or not each subject completes the clinical study. If for any 
reason study treatment or observations are discontinued, the reason will be recorded 
and the Sponsor should be notified. Reasons that a subject may discontinue 
participation in this clinical study include the following: 
 Adverse event(s) 
 Death 
 Withdrawal of consent by subject 
 Physician decision 
 Lost to follow-up 
It is imperative to obtain safety follow-up information for all subjects whether or not 
they discontinue oritavancin. Every attempt should be made to collect follow-up 
information except for those subjects who specifically withdraw consent for release of 
such information.  


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5. 
TREATMENT OF SUBJECTS 
5.1. 
STUDY MEDICATIONS 
Each subject will receive a single 1200 mg IV dose of oritavancin.  Oritavancin will be 
prepared by the study pharmacist/designee. 
5.1.1. Oritavancin 
Oritavancin will be supplied as a lyophilized powder in single-use glass vials. 
Each vial will contain 400 mg of oritavancin. 
Three 400-mg vials will be required for each subject receiving oritavancin. At 
the time of use, each vial will be reconstituted by adding 40 mL of Sterile Water 
for Injection, United States Pharmacopeia, to each 400-mg vial of oritavancin. 
Vials reconstituted in this manner will provide a 10 mg/mL solution. After 
reconstitution, oritavancin should be further diluted in 5% dextrose in water 
(D5W) to provide a total volume of approximately 1000 mL. Since the 
solubility of oritavancin is highly dependent upon pH, no other material or 
diluent may be substituted or concomitantly infused through the same IV line. 
The IV line should be flushed with D5W before and after; saline must not be 
used since it may cause precipitation. 
Each subject will receive a single oritavancin dose of 1200 mg in 1000 mL of 
D5W administered as a constant-rate IV infusion over 3 hours via a single 
dedicated peripheral IV line. Oritavancin must be infused over 3 hours 
(6.7 mg/minute) to reduce the potential for histamine-like infusion reactions or 
phlebitis. 
5.1.2. Packaging and Labeling 
Oritavancin will be provided by the Sponsor. Warfarin will be supplied by the 
site. Infusion bags of D5W will be provided by the study site pharmacy. 
Medication labels will comply with regulatory requirements. The storage 
conditions for each medication provided will be described on the medication 
label. 
5.1.3. Storage 
Oritavancin lyophilized powder should be stored in a secure cabinet or other 
enclosure at controlled room temperature (20°C to 25°C; 68°F to 77°F). Diluted 
intravenous solution in an infusion bag should be used within 6 hours when 
stored at room temperature, or used within 12 hours when refrigerated at 2 to 
8°C (36 to 46°F). The combined storage time (reconstituted solution in the vial 
and diluted solution in the bag) and 3 hour infusion time should not exceed 6 


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hours at room temperature or 12 hours if refrigerated (see Pharmacy Manual). 
Access should be strictly limited to the study pharmacists and their designees. 
5.1.4. Accountability 
The investigator or designee must maintain an inventory record of all study 
medications received and administered to assure the regulatory authorities and 
the Sponsor that the drug will not be dispensed to any person who is not a 
subject under the terms and conditions set forth in this protocol. Drug 
accountability forms and/or specific instructions can be found in the Pharmacy 
Manual. 
The oritavancin supplied for use in this study is to be prescribed only by the 
principal investigator or designated sub-investigators and may not be used for 
any purpose other than that outlined in this protocol. 
During the study, all used oritavancin containers (e.g., empty vials/bottles) will 
be kept until the monitor has reviewed the accountability records. 
All used and unused oritavancin supplied for this study will be destroyed on site 
once inventoried and the monitor has reviewed the accountability records. In the 
event that oritavancin needs to be returned for any other reason, the site will 
receive a written request listing the drug lot number(s) to be returned and the 
reason for the return request. 
5.2. 
CONCOMITANT MEDICATIONS 
5.2.1. Prohibited Concomitant Medications 
If possible, patients on chronic warfarin therapy should not take any new 
medications that could interfere with warfarin metabolism, other than 
oritavancin, during this study. Any concomitant medications will be recorded in 
the electronic case report form (eCRF) according to the Schedule of Events. 
5.2.2. Permitted Concomitant Medications 
Subjects enrolled and treated with oritavancin may receive additional antibiotic 
therapy with gram-negative coverage if necessary. 
5.2.3. Warfarin Therapy 
Any changes in warfarin dosing (for patients on concomitant chronic warfarin), 
based on the PT/INR results or safety data will be captured. 


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5.3. 
RESTRICTIONS 
Subjects will be encouraged to continue their usual diet and level of activity, as dictated 
by their clinical condition. Activities that would impact clinical outcome should be 
avoided during the study period. 
 
6. 
SEQUENCE OF PROCEDURES  
A summary of clinical assessments and procedures is provided before the contents in Schedule 
of Events. 
This study consists of four periods: Screening, Pre-Dose, Treatment, and Follow-up.  The 
maximum duration of a patient’s participation in this study is approximately 14 days post first 
administration of oritavancin. 
6.1. 
GENERAL CONDUCT OF THE TRIAL 
Written informed consent will be obtained from all subjects by the site staff member 
before any study-specific procedure is performed. 
6.2. 
SCREENING PERIOD (≤24 HRS PRIOR TO DAY 1) 
The following procedures will be performed ≤ 24 hours prior to Day 1 to establish each 
candidate's general health and qualifications for enrollment into the study: 
 Obtain written informed consent 
 Verify inclusion/exclusion criteria 
 Record medical history and demographics 
 Obtain height and weight to determine body mass index (BMI) 
 Perform a physical examination 
 Obtain vital sign measurements (blood pressure, heart rate, respiratory rate and 
temperature) 
 Collect blood specimens for hematology, serum chemistry, immunoglobulin panel, 
oritavancin antibody assay, PT/INR coagulation test, direct and indirect Coombs 
test 
 A urine pregnancy test will be performed for female subjects of childbearing 
potential. This test may be omitted for females >2 years postmenopausal or 
surgically sterile.  
 Microbiology samples, if obtained, per standard of care 
 Record medication history over the past 14 days, including over-the-counter (OTC), 
prescription drugs, vitamins and nutraceuticals (e.g., herbal supplements) 


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 Assessment of AEs and SAEs starting from the time the informed consent form is 
signed  
 Record planned ABSSI surgical procedures 
6.3. 
DAY 1 PRE-DOSE 
The following pre-dose procedures will be performed at Day 1 prior to administration 
of oritavancin: 
 Vital signs (blood pressure, heart rate, respiratory rate and temperature) 
 Confirm that the subject continues to meet inclusion and exclusion criteria 
including the verification of safety lab results 
 Collection of concomitant medication information 
 Assessment of AEs and SAEs 
 
6.4. 
TREATMENT PERIOD 
The enrollment process will be initiated only after confirmation of a subject’s 
eligibility. Each successive subject will be assigned a unique subject identification 
number. 
If a subject is found to be ineligible after signing the informed consent, but prior to 
dosing, he or she will be considered a screen failure, the subject will not be enrolled, 
and oritavancin will not be administered.   
6.4.1. Day 1  
Ideally, treatment should be initiated within 4 to 6 hours after the patient is first seen on 
Day 1. 
 Administer oritavancin as a single IV infusion of 1200 mg over 3 hours 
 Vital signs (blood pressure, heart rate, respiratory rate and temperature) 
 Collection of concomitant medication information 
 
Assessment of AEs and SAEs 
 
Collect blood sample for Drug Dependent Antibody Ex Vivo Study (immediately after the 
completion of the oritavancin infusion). 
6.5. 
FOLLOW UP 
6.5.1. Day 2 
 Collect blood sample for PT/INR coagulation test (window: 18-36 hours after the 
start of the oritavancin infusion). 
 


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6.5.2. Day 3 
 Vital signs (blood pressure, heart rate, respiratory rate and temperature) 
 Assessment of early clinical cure at 48-72 hours after start of infusion of 
Oritavancin 
 Assessment of AEs and SAEs 
 Collect blood specimens for immunoglobulin panel, oritavancin antibody assay, 
PT/INR coagulation test, direct and indirect Coombs test  
 Collection of concomitant medication information 
6.5.3. Day 7  
 Obtain vital sign measurements (blood pressure, heart rate, respiratory rate and 
temperature) 
 Collect blood specimens for hematology, serum chemistry, immunoglobulin panel, 
oritavancin antibody assay, PT/INR coagulation test, direct and indirect Coombs 
test 
 A urine pregnancy test will be performed for female subjects of childbearing 
potential. This test may be omitted for females >2 years postmenopausal or 
surgically sterile.  
 Assessment of clinical cure 
 Collection of concomitant medication information 
 Assessment of AEs and SAEs   
6.5.4. Day 14 (±2 days) 
 Vital signs (blood pressure, heart rate, respiratory rate and temperature) 
 Collection of concomitant medication information 
 Collect blood specimens for hematology, serum chemistry, immunoglobulin panel, 
oritavancin antibody assay, PT/INR coagulation test*, direct and indirect Coombs 
test  
• Assessment of AEs and SAEs 
• Patients with a negative Coombs Test at Day 14 test must have test repeated every 2 
weeks until return to baseline or stable. 
 
*If a subject’s PT/INR has not returned to therapeutic baseline by Day 14, patient will 
be referred to and followed by their primary physician responsible for their PT/INR 
monitoring. 
 


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7. 
PROTOCOL ASSESSMENTS 
7.1. 
TREATMENT, DAY 1 
7.1.1. Medical management guidelines 
Other interventions to optimize the care of subjects will be left to the discretion 
of the attending physician and investigator. These include surgical/nonsurgical 
debridement of devitalized tissue, removal of prosthetic material, incision and 
drainage, suture removal, percutaneous aspiration, packing, dressings, or 
irrigation with normal saline to remove superficial slough, excess exudate or 
visible debris. Standard of care therapy (such as daily superficial debridements 
and dressing changes) are allowed.  
If a patient has an infusion reaction with oritavancin the infusion may be slowed 
or stopped. The patient should be treated as necessary. The infusion may be 
resumed at half the previous infusion rate with continued monitoring for signs 
or symptoms of a histamine infusion reaction. 
If a patient is classified as a treatment failure by the investigator at any time, the 
patient may be administered alternative antibiotic therapy according to clinical 
judgment. 
7.1.1.1. 
Gram-negative pathogen ABSSSI infections 
Subjects enrolled and treated with oritavancin before culture results 
are available and found to have a Gram-negative pathogen may 
receive additional antibiotic therapy with gram-negative coverage.  
7.2. 
ASSESSMENT OF SAFETY  
When blood draws and vital signs are done at the same timepoint, the following 
sequence should be followed: 1) vital sign assessment 2) blood draw for lab tests. 
7.2.1. Adverse Events  
Subjects will be carefully monitored for adverse events by the investigator 
during the designated study period.   
7.2.2. Physical Examinations 
A physical exam will include head, eyes, ears, nose, throat (HEENT), heart, 
lungs, abdomen, skin, and extremities.  Body mass index (BMI) will be 
calculated based on height and weight collected at the Screening Visit. 
7.2.3. Vital signs 
Vital signs (blood pressure, heart rate, respiratory rate and temperature) will be 
assessed at the designated time periods as indicated in the Schedule of Events. 


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Blood pressure and pulse must always be taken after the subject has been resting 
supine for 5 minutes. 
7.2.4. Laboratory assessment 
Specimens will be obtained at the designated time periods as indicated in the 
Schedule of Events. All clinical laboratory assessments will be performed by 
the site’s local laboratory. Additional local laboratory testing may be performed 
at the discretion of the investigator.  Any clinically significant lab findings that 
occur during the study should be followed to resolution per the 
Investigator/Sponsor’s decision.  If the PT/INR has not returned to baseline by 
Day 14, patient will be followed until PT/INR has returned to therapeutic 
baseline. 
 Chemistry:  Blood urea nitrogen, Serum creatinine, Total bilirubin, Direct 
bilirubin, Alkaline phosphatase, Aspartate aminotransferase, Alanine 
aminotransferase, Albumin, Total protein, Glucose, Calcium, Chloride, 
Sodium, Magnesium, Potassium, Uric acid, Lactate dehydrogenase, 
Bicarbonate, Phosphorus  
 Hematology: Hemoglobin, Hematocrit, White blood cell count (with 
automated differential), Red blood cell count, Platelet count 
 Coagulation Tests: PT/INR 
 Urine Pregnancy Test 
 Direct and Indirect Coombs test 
 Immunoglobulin Panel Assays: Immunoglobulin M (IgM), 
Immunoglobulin G (IgG); Immunoglobulin E (IgE), Immunoglobulin A 
(IgA),  
 Assay for oritavancin antibodies 
 Plasma Storage Samples for Drug Dependent Antibody Ex Vivo Study 
  
7.3. 
ASSESSMENT OF EFFICACY 
Definition of clinical response: 
Assessment of clinical cure at 48 to 72 hours: 
A patient is classified as “success” if all of the following are met: 
 Cessation of spread or reduction of the lesion defined as: Cessation of spread 
of the redness, edema, and/or induration or reduction in size (length, width, 


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and area) of the redness, edema, and/or induration such that the size of the 
lesion is less than or equal to the size at baseline 
 
Resolution (absence) of fever (temperature <37.7°C)  
 
No rescue antibiotic medication 
A patient cannot be classified as a “success” at 48-72 hours (i.e., patient is a 
failure) if: 
 Death (all-cause mortality) from the start of oritavancin administration  
 Fever (one or more temperature readings of ≥37.7°C between 48 and 72 
hours) 
 Spread of lesion defined as an increase in size (length, width, or area) of the 
redness, edema, and/or induration such that the size of the lesion is greater 
than the size at baseline  
 Administration of rescue antibacterial drug therapy or any non-trial 
antibacterial drug therapy for the treatment of ABSSSI prior to the 48-72 
hours clinical cure evaluation 
 
Requires an additional unplanned surgical procedure after start of therapy as 
described below under: “A patient cannot be classified as clinical cure if” 
Investigator assessment of clinical cure:   
At Day 7:  Complete or nearly complete resolution of baseline signs and 
symptoms of the primary infection such that no further treatment with antibiotics 
is needed   
A patient cannot be classified as clinical cure if: 
 Patient did not fulfill criteria for clinical cure above 
 Investigator assignment of failure any time prior to Day 7 
 Patient dies (all-cause mortality) from the start of administration of 
oritavancin  
 Incision and drainage after 48 hours of treatment that was unplanned prior to 
enrollment, with the exception of cellulitis where there is a conversion into an 
abscess or when an extension of the original incision is indicated  
 Initiation of non-study antibacterial drugs for treatment of other infection 
unless antibiotic lacks efficacy in the treatment of ABSSSI 
 Subjects who otherwise do not meet the definition of clinical cure (e.g., lost to 
follow-up; oritavancin discontinued secondary to adverse reaction) 


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A patient who is not classified as clinical cure will be classified as failure. 


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8. 
ADVERSE EVENTS  
8.1. 
DEFINITIONS 
8.1.1. Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a 
subject or clinical investigation subject administered a medicinal product and 
which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with 
the use of a medicinal product, whether or not considered related to the 
medicinal product. 
Planned hospital admissions and/or surgical operations for an illness or disease 
that existed before the drug was given or the subject was enrolled in a clinical 
study are not to be considered AEs. 
Subjects experiencing adverse events should be followed clinically until their 
health has returned to baseline status or until all parameters have returned to 
normal or have otherwise been explained.  It is expected that the investigator 
will provide or arrange appropriate supportive care for the subject if necessary. 
8.1.1.1. AE Severity 
The severity of an AE will be assessed by the investigator.  The 
investigator should ensure that any subject experiencing an AE 
receives appropriate medical support until the event resolves. 
AEs will be graded on a 3-point scale and reported as indicated on the 
case report form.  The intensity of an AE is defined as follows: 
1 = Mild:  Discomfort noticed, but no disruption to daily activity. 
2 = Moderate:  Discomfort sufficient to reduce or affect normal daily 
activity. 
3 = Severe:  Inability to work or perform normal daily activity. 
8.1.1.2. Study Drug Causality 
The relationship of an AE to study treatment will be assessed with 
consideration to the following criteria: 
 Temporal relationship to the initiation of study medication 
 Response of the event to withdrawal of study medication 
 AE profile of concomitant therapies 
 Clinical circumstances during which the AE occurred 


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 Subject’s clinical condition and medical history  
Categorization of causality will be designated by the investigator as 
stated below: 
1. Unlikely related - Lack of reasonable possibility of a causal 
relationship - causal relationship between the event and the IMP. 
This means that there are little to no facts (evidence) or arguments 
to suggest a causal relationship. 
2. Reasonable Possibility - Reasonable possibility of a causal 
relationship - causal relationship between the event and the IMP. 
This means that there are facts (evidence) or arguments to suggest 
a causal relationship. 
8.1.2. Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence that at any 
dose: 
 Results in death, 
 Is life-threatening, i.e., the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred (it does not include an 
event that, had it occurred in a more severe form, might have caused death), 
 Results in a significant, persistent or permanent change, impairment, 
damage or disruption in the subject's body function/structure, physical 
activities and/or quality of life, 
 Requires in-patient hospitalization or prolongs hospitalization, 
 Is a congenital anomaly/birth defect, or 
 Is another medically significant event that, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above (e.g., allergic 
bronchospasm requiring intensive treatment in an emergency department or 
home, blood dyscrasias or convulsions that do not result in hospitalization, 
or the development of drug dependency or drug abuse). 
A distinction should be drawn between serious and severe AEs. Severity is an 
estimate or measure of the intensity of an AE, while the criteria for serious AEs 
are indications of adverse subject outcomes for regulatory reporting purposes. A 
severe AE need not necessarily be considered serious and a serious AE need not 
be considered severe. For example, nausea that persists for several hours may be 
considered severe nausea, but not an SAE. On the other hand, a myocardial 
infarction (MI) that may be considered minor could also be an SAE if it 
prolonged hospitalization. 


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When death occurs with an SAE, the cause of death must be reported as an 
SAE. “Fatal” will be reported as the outcome for these events. 
8.1.3. Medication Errors 
 Medication error refers to any unintended error in the dosing and 
administration of the study product as per instructions in the protocol.  
Medication Errors generally fall into 4 categories as follows: 
1. wrong medication 
2. wrong dose (including dosing regimen, strength, form, concentration, 
amount); 
3. wrong route of administration; 
4. wrong patient (i.e. not administered to the intended patient) 
Medication Errors include occurrences of overdose and underdose of the study 
product(s), and misuse. 
Overdose: Administration of a quantity of the study product given per 
administration or per day which is above the maximum recommended dose 
according to the reference safety information or protocol for the investigational 
product or comparator as applicable. This also takes into account cumulative 
effects due to overdose.  
Underdose: Administration of a quantity of the study product given per 
administration or per day which is under the minimum recommended dose 
according to the reference safety information or protocol for the investigational 
product.  
Misuse: Intentional and inappropriate use of a medicinal product not in 
accordance with the prescribed or authorised dose, route of administration, 
and/or the indication(s) or not within the legal status of its supply (e.g. without 
prescription for medicinal products subject to medical prescription). 
8.1.4. Reporting Medication Errors 
Medication errors with or without an associated AE need to be recorded as 
medication errors in the eCRF as described in Section 8.2. 
Medication errors with an associated SAE need to be recorded as medication 
errors in the eCRF and reported to MDCO Global Pharmacovigilance as 
described in Section 8.3. 
A mis-dosing protocol deviation (refer to Section 12.3) would need to be 
reported as a medication error if it was an “unintended error” as defined in 
Section 8.1.3. 


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8.1.5. Reporting Events of Pregnancy 
Occurrences of pregnancy in a study subject or study subject’s partner, 
including pregnancies detected anytime from administration of oritavancin until 
60 days after administration of oritavancin, must be reported within 24 hours 
using the Pregnancy Reporting form. In cases where a pregnancy occurs with a 
Serious Adverse Event, the Serious Adverse Event reporting form should be 
used to report the SAE and the Pregnancy Reporting form should be used to 
report the pregnancy. Any spontaneous abortion must be captured as a SAE.  
When a pregnancy occurs without any intercurrent SAE, the Pregnancy 
Reporting form may be submitted alone.  Follow-up through pregnancy 
outcome is required if a pregnancy is detected during this study.  
The Medicines Company or its designee will contact the investigator, if 
necessary, to clarify any of the pregnancy information. The investigator will 
provide follow-up information to MDCO or its designee as soon as it becomes 
available. Additionally, if required by local regulations or procedures, the 
investigator will report pregnancies to the Institutional Review Board 
(IRB)/Ethics Committee (EC) and/or national or local regulatory authorities. 
8.2. 
PROCEDURE FOR NON-SERIOUS ADVERSE EVENT RECORDING 
All non-serious AEs that occur during the designated study period (from signing the 
inform consent to 14 days following initial oritavancin administration) must be assessed 
and recorded on the source documents and eCRF, regardless of causal relationship to 
the study drug.   
8.3. 
PROCEDURE FOR SERIOUS ADVERSE EVENT REPORTING 
All SAEs that occur during the designated study period (from signing the informed 
consent to 14 days following initial warfarin administration) must be reported to The 
Medicines Company (MDCO) within 24 hours of awareness of the event using the 
provided study specific SAE Report Form. The completion and processing of the SAE 
Report Form (paper) should follow the instructions provided in the SAE Report Form 
completion guidelines.  In addition to completing the SAE Report Form, each SAE 
must be entered on the appropriate page of the eCRF.   
The investigator must assess the causality for each SAE. 
MDCO will contact the investigator, if necessary, to clarify any of the event 
information. The investigator should provide any follow-up information for the event to 
MDCO as soon as it becomes available. 
If the investigator is notified of an SAE that occurs during post-study period, that he or 
she wishes to report to the Sponsor (e.g., an event suspected to be causally related to 
study drug), the event should be reported through the process described above.  


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Where appropriate, if required by local regulations or procedures, the investigator 
should report these events to the Institutional Review Board (IRB)/Ethics Committee 
(EC) and/or national regulatory authority. 


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9. 
DATA COLLECTION 
An electronic data capture (EDC) system will be used for this trial.  All users will be trained on 
the technical features of the EDC as well as the content of the eCRF by qualified personnel 
prior to gaining access to the EDC.  A User ID/Password will be granted after training.  This 
ID is not to be shared amongst the study staff.  All users must have a unique account to enter or 
review data.  The eCRF should be filled out by the site 5 days after the Day 7 visit and 3 days 
after the Day 14 visit. It is not expected that the eCRF will serve as source for any data 
collected in this trial.  If there is a reason for a site to do so, it must be approved by MDCO and 
documented in the site files. 
Prior to the database being locked, the investigator or designee will review, approve and 
sign/date each completed eCRF.  This signature serves as attestation of the Investigator’s 
responsibility for ensuring that all data entered into the eCRF are complete, accurate and 
authentic. After the end of the trial, a copy of the data will be provided to the site.  This copy 
will contain the final data, an audit trail of activity on the data, and any queries and answers 
that were posted for data clarification. 


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10. STATISTICAL PLAN 
The primary objective of this study is to assess the safety and tolerability when a single 1200 mg 
infusion of oritavancin is given concomitantly in subjects on chronic warfarin with ABSSSI. 
Statistical methods and data presentation will be described in more detail in the Statistical Analysis 
Plan (SAP) document. 
10.1. SAMPLE SIZE 
The sample size of 25 subjects on concomitant warfarin therapy is chosen based on 
feasibility and clinical judgment to provide adequate safety information on the 
administration of oritavancin with an ABSSSI who are on chronic warfarin.  
An additional group of 15 ABSSSI patients, who are not on chronic warfarin therapy, 
was added to obtain information regarding potential for antibody production related to 
oritavancin administration. 
10.2. GENERAL STATISTICAL CONSIDERATIONS AND DEFINITIONS 
10.2.1. General Statistical Methods 
Continuous variables will be summarized using mean, standard deviation (SD), 
median, quartiles (Q1 and Q3), minimum, and maximum. Categorical variables 
will be summarized using frequency and percentage. 
10.2.2. Analysis Population 
Two populations will be used for data analyses and/or presentation. 
10.2.2.1. Intent-to Treat (ITT) Population 
The ITT population will include all subjects screened and enrolled. 
This will be the primary population for efficacy analysis. 
10.2.2.2. Safety Population 
The safety population will include all subjects who are dosed with IV 
oritavancin. This will be the primary population for safety analysis. 
10.2.3. Analysis Windows and Baseline 
Unless otherwise specified, the last evaluation prior to the initiation of dosing 
will be considered the “Baseline” evaluation for analysis of data. 
10.2.4. Missing Data Handling 
Unless otherwise specified, missing data will not be imputed and will be excluded 
from the associated analysis. 
10.3. STATISTICAL ANALYSES 
All summaries will be presented by group. 


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10.3.1. Demographic and Background Characteristics 
Subject demographics and baseline characteristics will be summarized using the 
safety population. 
10.3.2. Prior and Concomitant Medications 
Separate summaries of prior and concomitant medications will be provided for 
the safety population. Prior medications are those received before the initiation 
of dosing on Day 1 while concomitant medications are those received after. 
Medications will be coded with the World Health Organization (WHO) Drug 
Dictionary Enhanced.  
10.3.3. Safety Analysis 
10.3.3.1. Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) will be 
used for coding AEs. An AE (classified by system organ class and 
preferred term) that occurs during the treatment period will be counted 
as a treatment-emergent AE (TEAE) either if it is not present at 
Baseline or if it is present at Baseline but increased in severity during 
the treatment period or follow up period. 
The number (percentage) of subjects reporting TEAEs for each 
preferred term will be tabulated by system organ class, by system 
organ class and severity, and by system organ class and relationship to 
oritavancin. If more than 1 event occurred with the same preferred 
term for the same subject, the subject will be counted only once for 
that preferred term using the most severe or related occurrence for the 
summary by severity, or relationship to study drug, respectively. 
Listings of SAEs and AEs leading to treatment or study 
discontinuation will also be provided. 
10.3.3.2. Clinical Safety Laboratory Tests 
Clinical safety laboratory values and changes from Baseline, including 
prothrombin time (PT)/international normalized ratio (INR), direct and 
indirect Coombs, Immunoglobulin panel, oritavancin antibody assay,   
will be summarized descriptively. Clinically significant (CS) values 
will also be flagged in a listing. 
10.3.3.3. Vital Signs 
Vital sign measurements and changes from Baseline will be 
summarized descriptively at each scheduled time point. Potentially 
clinically significant changes will also be flagged in a listing. 


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11. RECORDS RETENTION 
Current Food and Drug Administration (FDA) regulations require all investigators 
participating in clinical drug trials to maintain detailed clinical data for one of the following 
periods: 
 At least 2 years following the date on which a New Drug Application is approved by the 
FDA, or 
 Two years after the Sponsor notifies the investigator that no further application is to be 
filed with the FDA 
Similarly, International Conference on Harmonization (ICH) guidelines require that essential 
documents be retained until at least 2 years after the last approval of a marketing application in 
an ICH region and until there are no pending or contemplated marketing applications in an 
ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. 
To comply with these requirements, the investigator will not dispose of any records relevant to 
this study without either (1) written permission from the Sponsor or (2) providing an 
opportunity for the Sponsor to collect such records. The investigator shall take responsibility 
for maintaining adequate and accurate hard copy source documents of all observations and data 
generated during this study, including any data clarification forms received from the Sponsor. 
Such documentation is subject to inspection by the Sponsor or its agents, the FDA and/or other 
regulatory agencies. 


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12. QUALITY CONTROL AND QUALITY ASSURANCE 
12.1. MONITORING 
The Sponsor has ethical, legal, and scientific obligations to carefully follow this study 
in accordance with established research principles and applicable regulations. The 
investigator, as part of his responsibilities, is expected to cooperate with the Sponsor in 
ensuring that the study adheres to the protocol and GCP requirements. 
As part of a concerted effort to fulfill these obligations, the Sponsor’s monitor will visit 
the study center during the study in accordance with the Monitoring Plan set forth for 
this trial. The investigator will permit the Sponsor to monitor the study as frequently as 
is deemed necessary and provide access to medical records/source documents to ensure 
that data are being recorded adequately, that data are verifiable, and that protocol 
adherence is satisfactory. 
12.2. AUDITING 
The Sponsor may conduct audits at the study centers. Audits will include, but will not 
be limited to, drug supply, presence of required documents, the informed consent 
process, and comparison of eCRFs with source documents. The investigator agrees to 
permit audits conducted at a reasonable time in a reasonable manner. 
Regulatory authorities worldwide may also inspect the investigator during or after the 
study. The investigator should contact the Sponsor immediately if this occurs, and must 
permit regulatory authority inspections. 
12.3. PROTOCOL DEVIATIONS 
This study will be conducted as described in this protocol, except for an emergency 
situation in which the protection, safety, and well-being of the subject requires 
immediate intervention, based on the judgment of the investigator (or a responsible, 
appropriately trained professional designated by the investigator). 
In the event of a significant deviation from the protocol due to an emergency, accident, 
or mistake, the investigator or designee must contact the Sponsor (Clinical Project 
Director, Medical Director or Clinical Research Associate) at the earliest possible time. 
This will allow an early joint decision regarding the subject’s continuation in the study. 
The investigator and the Sponsor will document this decision. 
The IRB/EC will be informed of all protocol changes by the investigator in accordance 
with the IRB/EC-established procedure. No deviations from the protocol of any type 
will be made without complying with all IRB/EC-established procedures. 
Any protocol deviations that will affect the subject’s safety or the study objectives may 
be considered a Major Protocol Deviation upon review by the Sponsor.  In addition, 
any of the following deviations will be considered Major Protocol Deviations: 


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Inclusion/Exclusion Criteria deviations: 
 Subject is < 18 years of age. 
 Subject has a condition, including findings in the medical history or in pre-study 
assessments that constitutes a risk or a contraindication for the participation in 
the study or completing the study. 
 Subject has a history of hypersensitivity to drugs with a similar chemical 
structure (i.e. glycopeptide antibiotics) to the investigational product or any of 
its excipients.  
Dosing deviation: 
 
Subject is given an incorrect dose of oritavancin. 
 


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13. ETHICS AND RESPONSIBILITY 
This study will be conducted in compliance with the protocol, the Sponsor’s standard operating 
procedures and/or guidelines, the United States regulations, the ICH GCP guidelines, the 
Declaration of Helsinki, and other local regulations, as applicable. 
13.1. INFORMED CONSENT 
Written informed consent will be obtained from all subjects or, as per IRB/EC 
guidelines, before any study-related procedures (including any pretreatment 
procedures) are performed. The investigator has both ethical and legal responsibilities 
to ensure that each subject being considered for inclusion in this study is given a full 
explanation of the protocol. This shall be documented on a written informed consent 
form, which shall be approved by the same IRB/EC responsible for approval of this 
protocol. Each informed consent form shall include the elements required by ICH, Part 
E6, Section 4.8 and any applicable local regulations. The investigator agrees to obtain 
approval from the Sponsor of any written informed consent form used in the study, 
preferably prior to submission to the IRB/EC. 
Once the appropriate essential information has been provided to the subject and fully 
explained by the investigators (or a qualified designee) and the subject indicates an 
understanding of the implications of participation, the subject and the investigator (or 
designee) shall sign the IRB/EC-approved written informed consent form. The subject 
shall be given a copy of the signed informed consent form and the original shall be filed 
appropriately, according to the institution. A second copy may be filed in the subject's 
medical record, if allowed by the institution. 
13.2. ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD 
This protocol, the written informed consent form, and any materials presented to 
subjects shall be submitted to the IRB/EC identified with this responsibility. 
Notification in writing of approval must come from the IRB/EC chairman or secretary, 
to the investigator, either as a letter or as a copy of the appropriate section of the 
IRB/EC meeting minutes where this protocol and associated informed consent form 
were discussed. The investigator will not participate in the decision. If the investigator 
is an IRB/EC member, the written approval must indicate such nonparticipation in the 
voting session. The investigator will submit status reports to the IRB/EC as required by 
the governing body. The IRB/EC must be notified by the investigator in writing of the 
interruption and/or completion of the study; the investigator must promptly report to the 
IRB/EC all changes in research (protocol amendments) and will not make such changes 
without IRB/EC approval, except where necessary to eliminate apparent immediate 
hazards to human subjects. In cases where it is necessary to eliminate immediate 
hazards to subjects, the IRB/EC must then be notified of the change as per local 
requirements. The investigator is required to maintain an accurate and complete record 


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of all written correspondence to and received from the IRB/EC and must agree to share 
all such documents and reports with the Sponsor. 
 
14. CONFIDENTIALITY 
All information generated in this study must be considered highly confidential and must not be 
disclosed to any persons not directly concerned with the study without written prior permission 
from the Sponsor. However, authorized regulatory officials and Sponsor personnel will be 
allowed full access to the records. All medications provided and subject bodily fluids and/or 
other materials collected shall be used solely in accordance with this protocol, unless otherwise 
agreed to in writing by the Sponsor. 
Only unique subject numbers in eCRFs will identify subjects. Their full names may, however, 
be made known to a product regulatory agency or other authorized official if necessary. 


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15. INVESTIGATOR AGREEMENT 
I have read and understand the protocol (including the Investigator’s Brochure Version 10) and 
agree that it contains all the ethical, legal, and scientific information necessary to conduct this 
study. I will personally conduct the study as described. 
I will provide copies of the protocol to all physicians, nurses and other professional personnel 
responsible to me who will participate in the study. I will discuss the protocol with them to 
assure myself that they are sufficiently informed regarding the investigational new drug 
oritavancin, the concurrent medications, and safety parameters and the conduct of the study in 
general. I am aware that this protocol must be approved by the IRB/EC responsible for such 
matters in the Clinical Study Facility where oritavancin will be tested prior to commencement 
of this study. I agree to adhere strictly to the attached protocol. I understand that this 
IRB/EC-approved protocol will be submitted to relevant regulatory authorities by the Sponsor, 
as appropriate. I agree that clinical data entered on case report forms by me and my staff will 
be utilized by the Sponsor in various ways such as for submission to governmental regulatory 
authorities and/or in combination with clinical data gathered from other research sites, 
whenever applicable. I agree to allow Sponsor monitors and auditors full access to all medical 
records/source documents at the research facility for subjects screened or enrolled in the study. 
I agree to provide all subjects with informed consent forms, as required by government and 
ICH regulations. I further agree to report to the Sponsor any adverse experiences in accordance 
with the terms of this protocol, ICH guideline Part E6, Section 4.11, and applicable local 
regulations. 
 
 
 
Principal Investigator (Signature) 
 
Date 
 
Principal Investigator (Printed Name) 
 
 
 
Institution Name 
 
 
 


Oritavancin diphosphate 
Clinical Study Protocol MDCO-ORI-14-03 Amendment 2 
Confidential 
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The Medicines Company 
 
Final 17 March 2016 
16. REFERENCES 
16.1. PUBLICATIONS 
Dryden MS. Skin and soft tissue infection: microbiology and epidemiology. Int J 
Antimicrob Agents. 2009;34 (Suppl 1):S2-7. 
ORBACTIV (oritavancin) [package insert] Parsippany, NJ: The Medicines Company; 
2014. 
Oritavancin Investigator’s Brochure, Edition 10, March 2015. 
16.2. STUDY REPORTS 
TMC-ORI-12-03: An Open Label Study Evaluating the Effects of a Single Oritavancin 
Infusion on Cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A, N-
Acetyltransferase-2, and Xanthine Oxidase Activities in Healthy Adults using the 
Cooperstown 5 + 1 Cocktail. 
 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
(SAP) 
AN OPEN-LABEL STUDY TO EVALUATE THE SAFETY OF A SINGLE 1200 MG IV 
DOSE OF ORBACTIV (ORITAVANCIN) IN PATIENTS ON CONCOMITANT 
CHRONIC WARFARIN THERAPY BEING TREATED FOR ACUTE BACTERIAL 
SKIN AND SKIN STRUCTURE INFECTION 
Protocol No.: MDCO-ORI-14-03 
U.S. IND No.: 51,292 
Version 1.0: 23 September 2016 
The Medicines Company 
8 Sylvan Way 
Parsippany, NJ 07054 
Confidentiality Statement 
This document is confidential. It contains proprietary information belonging to Rempex Pharmaceuticals, 
Inc. (Rempex). Any viewing or disclosure of such information that is not authorized in writing by 
Rempex is strictly prohibited. Such information may be used solely for the purpose of reviewing or 
performing this study. 
NCT #: NCT02452918


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TABLE OF CONTENTS 
Table of Contents .................................................................................................................2 
1 
Introduction ...................................................................................................................5 
2 
Objectives and Endpoints ..............................................................................................6 
2.1 Primary Objectives ..............................................................................................6 
2.2 Secondary Objective ............................................................................................6 
2.3 Endpoint 
....................................................................................................6 
2.3.1 Primary Endpoint ....................................................................................6 
2.3.2 Secondary Endpoint ................................................................................6 
2.3.3 Exploratory Endpoint: .............................................................................6 
3 
Study Design .................................................................................................................7 
3.1 Number of Subjects .............................................................................................7 
3.2 Sample Size Considerations ................................................................................7 
3.3 Study Design ....................................................................................................7 
4 
General Statistical Considerations ................................................................................9 
5 
Analysis Populations ...................................................................................................10 
5.1 Intent-to Treat (ITT) Population ........................................................................10 
5.2 Safety Population ..............................................................................................10 
5.3 Missing Data Handling ......................................................................................10 
5.4 Key Definitions .................................................................................................10 
6 
Subject Disposition and Baseline Characteristics .......................................................11 
6.1 Subject Discontinuation ....................................................................................11 
6.2 Demographics and Baseline Characteristics .....................................................11 
6.3  Study Drug and Concomitant Medications .......................................................11 
7  EFFICACY Analysis ..................................................................................................12 
8  Safety Analysis ............................................................................................................13 
8.1 Adverse Events ..................................................................................................13 
8.2 Clinical Laboratory Assessments ......................................................................13 
8.3 Vital Signs 
..................................................................................................14 
8.4 Extent of Exposure ............................................................................................15 
9 
Pharmacokinetic Analyses ..........................................................................................16 
10 Exploratory Analysis ...................................................................................................17 
11 References ...................................................................................................................18 
  


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LIST OF ABBREVIATIONS 
Abbreviation 
Explanation 
ABSSSI 
acute bacterial skin and skin structure infection 
AE 
adverse event 
AIDS 
Acquired Immune Deficiency Syndrome 
ANC 
absolute neutrophil count 
AUC 
area under the plasma concentration time curve  
AUC0-24 
Area under the drug concentration-time curve from time zero to 24 hours 
AUC0-∞ 
Area under the concentration-time curve from zero to infinity 
BMI 
body mass index 
CD4 
cluster of differentiation 4 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CrCl 
creatinine clearance 
CS 
clinically significant 
CV 
coefficient of variation 
CYP2C9 
DAT 
Cytochrome P450 2C9 enzyme 
Direct Coombs Test  
D5W 
5% dextrose in water 
EC 
Ethics Committee 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HEENT 
head, eyes, ears, nose, throat 
HIV 
IAT 
Human Immunodeficiency Virus 
Indirect Coombs Test (DAT) 
ICH 
International Conference on Harmonisation 
IgA 
Immunoglobulin A 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
INR 
International Normalized Ratio 
IRB 
institutional review board 
ITT 
Intent-to-Treat 
IV 
intravenous 
LLN 
lower limit of the standard reference (normal) range 
MDCO 
The Medicines Company 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
MIC 
Minimum Inhibitory Concentration 
MRSA 
methicillin-resistant S. aureus 
No. 
Number 


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Abbreviation 
Explanation 
OTC 
over the counterPotentially clinically significant (PCS) 
PCS 
Potentially clinically significant  
PK 
pharmacokinetic 
PT 
prothrombin time 
Q1 
first quartile 
Q3 
third quartile 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
standard of care 
TEAE 
treatment-emergent adverse event 
T1/2 
Half-life 
T1/2,α 
Half-life for the alpha phase 
T1/2,β 
Half-life for the beta phase 
T1/2,γ 
Half-life for the gamma phase 
ULN 
Upper limit of the standard reference (normal) range 
US 
United States 
USP 
United States Pharmacopeia 
USPI 
United States Package Insert 
Vss 
steady-state volume of distribution 
WHO 
World Health Organization 


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1 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentation to be used for the analysis and summarization of safety data from Protocol 
MDCO-ORI-14-03, Amendment 2 (17 March 2016).    
The analysis plan will be finalized prior to database lock, but may change due to 
unforeseen circumstances.  Any changes made after finalization of the analysis plan will 
be documented.  Related documents are the study protocol and electronic case report 
forms (eCRFs). 
 
 
 


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2 
OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objectives 
• 
To assess the safety and tolerability when a single 1200 mg intravenous (IV) 
infusion of oritavancin is given concomitantly in subjects on chronic warfarin 
therapy with acute bacterial skin and skin structure infection (ABSSSI). 
• 
An additional group of patients with ABSSSI, who are not on concomitant 
warfarin therapy, will be enrolled to obtain information regarding the potential for 
antibody production following a single dose of oritavancin administration in 
patients. 
2.2 
Secondary Objective 
Not applicable.  
 
2.3 
Endpoint 
2.3.1 
Primary Endpoint 
The primary endpoint of this trial is:  
• 
Safety of the administration of oritavancin in subjects on chronic warfarin will be 
assessed according to vital signs, laboratory abnormalities, and the incidence of 
AEs and SAEs. 
2.3.2 Secondary Endpoint 
The secondary endpoint of this trial is: 
• 
Clinical cure determined by the Investigator at 48-72 hours after start of 
oritavancin dose and Day 7 visit. 
2.3.3 Exploratory Endpoint: 
An exploratory outcome of this trial is to evaluate the potential for antibody development 
following a single dose oritavancin administration. 


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3 
STUDY DESIGN 
3.1 
Number of Subjects 
Up to forty subjects will be enrolled at up to 10 centers in the United States (US). 
Approximately 25 subjects on concomitant warfarin therapy will be enrolled in this 
study.  An additional 15 patients with ABSSSI, who are not on warfarin, will also be 
enrolled.  
3.2 
Sample Size Considerations 
The sample size of 25 subjects on concomitant warfarin therapy is chosen based on 
feasibility and clinical judgment to provide adequate safety information on the 
administration of oritavancin with an ABSSSI who are on chronic warfarin.  
An additional group of 15 ABSSSI patients, who are not on chronic warfarin therapy, 
was added to obtain information regarding potential for antibody production related to 
oritavancin administration. 
3.3 
Study Design 
This will be a Phase IV, open-label study evaluating the safety and tolerability when a 
single 1200 mg dose of oritavancin is given concomitantly in subjects on chronic 
warfarin therapy with ABSSSI.  An additional group of patients with ABSSSI, who are 
not on concomitant warfarin therapy, will also be enrolled. 
Up to 40 subjects will be enrolled at up to 10 centers in the United States.  Informed 
consent will be obtained from subjects meeting all inclusion and no exclusion criteria 
before the initiation of any study-specific procedures.   
Eligible subjects will be enrolled and receive a single 1200 mg dose of oritavancin IV.  
Adverse events and SAEs will be assessed from the time of informed consent through 14 
days post administration of oritavancin.  
The schedule of events is shown in Table 1.  This schedule is based on Protocol MDCO-
ORI-14-03, Amendment 2 (17 March 2016).  In Protocol Amendment 1 (dated 16 
December 2015), Direct Coombs Test (DAT) was added to the schedule of events; in 
Protocol Amendment 2, Indirect Coombs Test (IAT) and  the drug dependent antibody  
was  added to the schedule of events.  


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8 
     Table 1:    Schedule of Events   
Study procedures 
SCREENING 
Pre-Dose 
Treatment 
FOLLOW UP 
 
≤24 hrs from 
1st dose 
Day 1 
Day 1 
Day 2 
Day 3 
Safety & 
Efficacy 
Visit 
Day 7 
Safety & 
Efficacy 
Visit 
Day 14 Follow 
up Visit 
(± 2 days)1 
Informed Consent 
x 
 
 
 
 
 
 
Assess Inclusion/Exclusion 
x 
x 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
Physical Exam (height and weight at Screening only) 
x 
 
 
 
 
 
 
Vital Signs2 
x 
x 
x 
 
x 
x 
x 
Pregnancy test3 
x 
 
 
 
 
x 
 
Record ABSSSI surgical procedures4 
x 
 
 
 
 
 
 
Safety laboratory assessments5 
x 
 
 
 
 
x 
x 
Microbiology testing6 
x 
 
 
 
 
 
 
Record prior or concomitant medications 
x 
x 
x 
x 
x 
x 
x 
Administer IV oritavancin 
 
 
x 
 
 
 
 
PT/INR Test7 
x 
 
 
x 
x 
x 
x 
Assess clinical cure8 
 
 
 
 
x 
x 
 
Immunoglobulin panel and plasma for oritavancin 
antibody assay 
x 
 
 
 
x 
x 
x 
Direct and Indirect Coombs Test9 
x 
 
 
 
x 
x 
x 
Assessment of adverse events10 
x 
x 
x 
x 
x 
x 
x 
Plasma Storage Samples for Drug Dependent Antibody 
Ex Vivo Study11 
 
 
x 
 
 
 
 
 
1 If subject has abnormal laboratory values that have not returned to a therapeutic baseline by Day 14, additional follow up visits may be required. 
2 Vitals signs include blood pressure, temperature, respiratory rate and heart rate.  
3 Perform a local urine pregnancy test for female patients of childbearing potential (may be omitted for females > 2 years postmenopausal or surgically sterile). 
4 This includes but is not limited to aspiration, debridement, incision and drainage. 
5 Blood chemistry and hematology . Unless otherwise indicated all laboratory tests will be performed by site’s local laboratory. 
6 Microbiology testing should be performed per institutions Standard of Care (SOC). 
7 Patients on warfarin are required to have at least one documented International Normalized Ratio (INR) between 1.5 and 3.0 in the 30 days prior to screening. The INR value at Screening must fall 
within 1.5 and 3.0.  After dosing with oritavancin, the next Prothrombin Time/International Normalized Ratio (PT/INR) should be collected with 18-36 hours of start of oritavancin infusion. If PT/INR 
has not returned to baseline at Day 3, more frequent PT/INR testing prior to Day 7 may be required.  
8 Clinical cure should be assessed by investigator at Day 3 (48-72 hours after start of oritavancin administration) and at Day 7. 
9 Patients with a negative Coombs Test at Day 14 test must have test repeated every 2 weeks until return to baseline or stable. 
10 Adverse events and serious adverse events will be assessed from the time of informed consent through 14 days post first administration of Oritavancin.   
11 Blood will be collected immediately after the completion of the infusion to prepare three plasma sample for Ex Vivo Study investigating the effects of Oritavancin on Antibody Formation.  


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4 
GENERAL STATISTICAL CONSIDERATIONS 
All analyses described in this plan are considered a priori analyses in that they have been 
defined prior to database lock.  All other analyses, if any, designed subsequent to the 
database lock will be considered post hoc analyses and will be applied as exploratory 
methodology.  All post hoc analyses will be identified as such in the clinical study report. 
Continuous variables will be summarized using mean, standard deviation (SD), median, 
quartiles (Q1 and Q3), minimum, and maximum. Categorical variables will be 
summarized using frequency and percentage. 
Summary statistics will be presented as follows: number of observations will be 
presented without any decimal places, minimum/maximum in the same precision as 
reported values, arithmetic and geometric means/median to 1 more decimal place than the 
reported values, SD to 1 more decimal place than mean/median, and coefficient of 
variation (CV) to 1 decimal place.  
Data will be summarized by cohort. Summary tables will only be provided for cohorts 
with more than 4 subjects. For cohorts with no more than 4 subjects, only listings will be 
provided.  
All statistical analyses will be conducted using SAS version 9.3 or later using 
procedures appropriate for the particular analysis. 


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5 
ANALYSIS POPULATIONS 
Two populations will be used for data analyses and/or presentation. 
5.1 
Intent-to Treat (ITT) Population 
The ITT population will include all subjects screened and enrolled. This will be the 
primary population for efficacy analysis. 
5.2 
Safety Population 
The safety population will include all subjects who are dosed with IV oritavancin. This 
will be the primary population for safety analysis. 
5.3 
Missing Data Handling 
Unless otherwise specified, missing data will not be imputed and will be excluded from 
the associated analysis. 
5.4 
Key Definitions 
Unless otherwise specified, the last evaluation prior to the initiation of study drug will be 
considered the "Baseline" evaluation for analysis. 
 


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6 
SUBJECT DISPOSITION AND BASELINE 
CHARACTERISTICS 
6.1 
Subject Discontinuation 
The number of subjects who enroll in the study and the number and percentage of 
subjects who complete the study will be presented by cohort.  The frequency and 
percentage of subjects who withdraw or discontinue from the study and the reason for 
withdrawal or discontinuation will be summarized for the safety population. 
A data listing for subject disposition including study completion status and reason for 
study discontinuation will be provided. In addition, analysis populations and reasons for 
exclusion from the analysis population will be provided in a data listing. 
6.2 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be summarized by cohort for the 
safety populations. Descriptive statistics (i.e., mean, median, SD, minimum, and 
maximum) will be calculated for continuous demographic and baseline characteristic 
variables (age, weight, height, and body mass index [BMI]) and frequency counts will be 
tabulated for categorical demographic variables (sex, race, and ethnicity) for each cohort 
and overall.   
In addition to the summary tables, a data listing will be provided for all demographic 
data. The height, weight, and BMI will be provided in the vital sign data listing. 
6.3  
Study Drug and Concomitant Medications 
Separate summary of prior (pre-baseline) and concomitant (baseline or later) medications 
will be provided for the safety population. Medications will be coded with the World 
Health Organization (WHO) Drug Dictionary Enhanced. Subjects will be counted only 
once within each period by medication. 
Prior medications are those with a start date occurring before the initiation of study drug 
on Day 1. Concomitant medications are those with a start date occurring on or after the 
initiation of study drug on Day 1 or that have unknown or ongoing end dates.  In the 
event of a partial date, the medication will be classified as prior.  
Prior and concomitant medications will be provided in a data listing by subject. 
 
 
 


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7  
EFFICACY ANALYSIS 
Efficacy results for all subjects will be provided in data listings.  


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8  
SAFETY ANALYSIS 
8.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) dictionary version 18.0 or 
higher will be used for coding adverse events (AEs).  Each verbatim term will be mapped 
to a preferred term and system organ class (SOC). 
An AE (classified by system organ class and preferred term) that occurs during the 
treatment period will be counted as a treatment-emergent AE (TEAE) either if it is not 
present at Baseline or if it is present at Baseline but increased in severity during the 
treatment period or follow up period. 
The number (percentage) of subjects reporting TEAEs for each preferred term will be 
tabulated by system-organ class, by system-organ class and severity, and by system-
organ class and relationship to study drug.  If more than one event occurred with the 
same preferred term for the same subject, the subject will be counted only once for that 
preferred term using the most severe or related occurrence for the summary by severity, 
or relationship to study drug, respectively. 
Summaries of serious adverse events (SAEs) and AEs leading to study discontinuation 
will also be provided by system organ class and preferred term. Listings of SAEs and 
AEs leading to treatment or study discontinuation will also be provided. 
In the presentation, SOC and preferred term will be sorted in alphabetical order.  
All AEs captured in the database will be listed in by-subject data listings; however, only 
TEAEs will be summarized. 
MedDRA version will be footnoted in both tables and data listings.     
8.2 
Clinical Laboratory Assessments 
Clinical safety laboratory values and changes from baseline of hematology, serum 
chemistry, and urinalysis, including prothrombin time (PT)/international normalized ratio 
(INR), direct and indirect Coombs (DAT and IAT), Immunoglobulin panel, oritavancin 
antibody assay,    will be summarized descriptively. Potentially clinically significant (PCS) 
values will also be flagged in a listing. The criteria for potentially clinical significant liver 
function tests are displayed in Table 2.  
Unscheduled assessments that are not used for baseline will not be included in summary 
tables; however, all measurements will be listed. 
 


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Table 2: 
Criteria for Potential Clinically Significant Abnormal Lab Tests 
 
Parameter 
Lower limit 
Upper limit 
Hematology 
 
 
Red Blood Cell Count 
 0.75× LLN 
≥ 1.25×ULN 
WBC’s Count 
<2.0 x 109/L 
 
Hematocrit 
≤0.75x LLN 
≥1.25x ULN 
Hemoglobin 
≤11.5 g/dL Male 
≤9.5 g/dL Female 
≥18.0 g/dL Male 
≥16.0 g/dL Female 
Platelet count 
≤75 x 109/L 
 
≥700 x 109/L 
Serum Chemistry 
 
 
BUN 
 
≥10.7 mmol/L 
Calcium 
≤7.0 mg/dL 
≥15.5 mg/dL 
Creatinine 
 
≥2.0 mg/dL 
Glucose  
≤50 mg/dL 
≥180 mg/dL  
Potassium 
≤3.0 mmol/L 
≥5.5 mmol/L 
Sodium 
≤125 mmol/L 
≥150 mmol/L 
Liver Function Tests (LFTs) 
 
Alanine Transaminase (ALT/SGPT) ≥ 3x, 5x, 10x and 20x ULN 
Aspartate Transaminase (AST/SGOT) ≥ 3x, 5x, 10x and 20x ULN 
ALT or AST ≥ 3x, 5x, 10x, or 20x ULN 
Total bilirubin ≥ 1.5x and 2x ULN 
Alkaline Phosphatase (ALP) ≥ 1.5x and 3x ULN 
ALT/AST ≥ 3x ULN and Total bilirubin ≥ 2x ULN;  
Potential Hy’s Law cases: ALT or AST ≥3×ULN, Total bilirubin ≥2×ULN, and ALP ≤ 2×ULN 
 
 
LLN: lower limit of the standard reference (normal) range. 
ULN: upper limit of the standard reference (normal) range. 
 
 
8.3 
Vital Signs 


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Vital sign measurements and changes from baseline will be summarized descriptively at 
each scheduled timepoint. Potentially clinically significant changes will also be flagged 
in a listing based on the following thresholds: 
• Respiratory Rate ≤10 rpm; 
• Respiratory Rate ≥30 rpm; 
• Systolic blood pressure ≥180 mm Hg and increase ≥20 mm Hg from Baseline; 
• Diastolic blood pressure ≥110 mm Hg and increase ≥15 mm Hg from Baseline; 
• Systolic blood pressure ≤90 mm Hg and decrease ≥20 mm Hg from Baseline; 
• Diastolic blood pressure ≤50 mm Hg and decrease ≥15 mm Hg from Baseline; 
• Heart rate ≥120 bpm with increase ≥15 bpm from Baseline; 
• Heart Rate ≤50 bpm with decrease ≥15 bpm from Baseline. 
 
Unscheduled assessments that are not used for baseline will not be included in summary 
tables; however, all measurements will be listed. 
8.4 
Extent of Exposure 
Study drug administration dates and times will be provided in a data listing. 


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9 
PHARMACOKINETIC ANALYSES 
Not applicable as no pharmacokinetic sample was collected. 
 
 


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10 
EXPLORATORY ANALYSIS 
No exploratory analysis is planned.  
 
 
 


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11 
REFERENCES 
Not applicable