Conditions: Acute Bacterial Skin and Skin Structure Infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 102
Healthy volunteers: no

Brief summary:
This study is being conducted to evaluate the pharmacokinetic (PK) and safety of Kimyrsa versus the approved oritavancin formulation in subjects with acute bacterial skin and skin structure infection (ABSSSI). Kimyrsa adjusts the infusion time, concentration and reconstitution/administration solutions of a single 1200 mg intravenous (IV) infusion of oritavancin

Detailed description:
Single IV dose oritavancin (1200 mg) has been approved in the U.S. for the treatment of adult patients with ABSSSI caused or suspected to be caused by Gram-positive microorganisms. The current study is being conducted to evaluate the relative exposure, PK and safety of a new formulation of oritavancin, Kimyrsa, by adjusting infusion time, concentration and reconstitution/administration solutions of a single 1200 mg IV infusion of oritavancin in adult subjects with ABSSSI.

Fifty (50) subjects will be administered the currently approved formulation of oritavancin, using the approved dosing regimen in which Sterile Water for Injection (SWFI) is the reconstituting agent and Dextrose 5% in Water (D5W) is used for further dilution to a total volume of 1000 mL. This formulation will be infused per the approved label over 3 hours. An additional 50 subjects will be administered Kimyrsa which contains hydroxypropyl-β-cyclodextrin (HPβCD). This formulation will be reconstituted with SWFI and further diluted in 0.9% sodium chloride (saline) to a total volume of 250 mL. This formulation will be infused over 60 minutes.

Arms:
arm 1: Three single-use vials, each containing 400 mg (1200 mg total) of oritavancin diphosphate (as the free base) and the inactive component mannitol. Oritavancin vials will be reconstituted with SWFI and further diluted in D5W for a total volume of 1000 mL and infused intravenously over 3 hours. arm 2: A single vial containing 1200 mg of oritavancin, HPβCD, and mannitol. Kimyrsa vials will be reconstituted with SWFI and further diluted with 0.9% sodium chloride for a total volume of 250 mL and infused intravenously over 1 hour.

Interventions: intervention 1: Current Formulation of Oritavancin intervention 2: Kimyrsa
Intervention descriptions: intervention 1: Current formulation of oritavancin (3 hour infusion of 1200 mg in 1000 ml of D5W) intervention 2: New formulation of oritavancin (1 hour infusion of 1200 mg in 250 ml of saline)

Protocol document:
Prot_001.pdf: 
 
 
Initial U.S. Approval: 2014 
ORBACTIV® (oritavancin) 
A Randomized, Open-label, Pharmacokinetics and Safety Study to Evaluate 
the Relative Exposure and Safety of a New Formulation Versus the Approved 
Formulation of a Single 1200 mg Intravenous (IV) Dose of ORBACTIV® 
(oritavancin) in Subjects Being Treated for Acute Bacterial Skin and Skin 
Structure Infection (ABSSSI) 
Protocol Number.:  ML-ORI-102 
U.S. IND Number: 51,292 
EudraCT Number.: Not Applicable 
  
 
Development Phase: 
Phase 1 
 
 
Sponsor: 
Melinta Therapeutics, Inc.  
 
300 Tri-State International 
Suite 272 
Lincolnshire, IL  60069 
 
 
Sponsor Contacts: 
 
Medical Monitor: 
Name: 
Silvia Helou, MD 
Sr. Medical Director 
 
Project Director: 
Name: 
Karen Fusaro 
Sr. Director, Clinical Operations 
 
Global Safety Officer: 
Name: 
Isabelle Degeyter, MD 
Sr. Director, Global Pharmacovigilance  
 
 
 
 
 
Version/Date: 
Date: 
Original Protocol dated 16 April 2019 
 
This document is a confidential communication from Melinta Therapeutics. Acceptance of this document constitutes 
an agreement by the recipient(s) that no information contained herein will be published or disclosed without prior 
written approval from Melinta, except that this document may be disclosed to appropriate Institutional Review 
Boards or Independent Ethics Committees under the condition that they are also required to maintain confidentiality. 


Oritavancin diphosphate 
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1. 
SIGNATURE PAGE 
Clinical Study Protocol ML-ORI-102 
Version Date: 16 April 2019 
The signature of the Investigator below constitutes his/her approval of this protocol and provides 
the necessary assurances that this study will be conducted according to all stipulations of the 
protocol as specified in both the clinical and administrative sections, including all statements 
regarding confidentiality. This trial will be conducted in compliance with the protocol and all 
applicable regulatory requirements, in accordance with Good Clinical Practices (GCPs), 
including International Conference on Harmonization (ICH) Guidelines, and in general 
conformity with the most recent version of the Declaration of Helsinki. 
Principal Investigator 
Signature 
Date 
Representatives of Melinta Therapeutics who agree to the terms and conditions of this protocol 
include: 
Melinta Medical Monitor 
Confidential 
Page 2of58 


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2. 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company:  Melinta Therapeutics, Inc. 
Name of Study Drug:  ORBACTIV® (oritavancin) 
Title of Study:  A Randomized, Open-label, Pharmacokinetics and Safety Study to Evaluate the Relative 
Exposure and Safety of a New Formulation Versus the Approved Formulation of a Single 1200 mg Intravenous 
(IV) Dose of ORBACTIV® (oritavancin) in Subjects Being Treated for Acute Bacterial Skin and Skin Structure 
Infection (ABSSSI) 
Phase of Development:  1 
Planned Number of Investigational Sites:  Multi-center study in approximately 5 centers in the United States. 
Number of Subjects:  Approximately 100 subjects will be randomized in a 1:1 ratio to the currently approved 
formulation of oritavancin versus a new formulation containing hydroxypropyl-β-cyclodextrin (HPβCD) 
Study Period:  The estimated study period for the study will be approximately 5 months from the time the first 
subject is enrolled until the last subject is completed.   
Rationale:  Single IV dose oritavancin (1200 mg) has been approved in the U.S. for the treatment of adult 
patients with ABSSSI caused or suspected to be caused by Gram-positive microorganisms. The current study is 
being conducted to evaluate the relative exposure, pharmacokinetics (PK) and safety of a new formulation of 
oritavancin by adjusting infusion time, concentration and reconstitution/administration solutions, of a single 1200 
mg IV infusion of oritavancin in adult subjects with ABSSSI. 
The approved formulation of oritavancin requires reconstitution of oritavancin for injection with Sterile Water for 
Injection (SWFI) and then further dilution in dextrose 5% in Water (D5W) prior to infusing a total volume of 
1000 mL over 3 hours. The outcome of this study will provide data to determine whether oritavancin can be 
infused in less than 3 hours, in a reduced volume, with potential to use normal saline or D5W for dilution. This 
would reduce the burden for patients by shortening infusion time and allowing flexibility for pharmacies to use 
D5W or normal saline. By decreasing the volume from 1000 ml to 250 ml, it reduces the amount of fluid that is 
given to the patient, which is especially important for renally impaired patients or patients with compromised 
cardiac function. 
Objectives:  To compare the relative AUC exposure, safety and tolerability of the new formulation to the 
approved formulation of oritavancin, with both administered as a single 1200 mg IV infusion in subjects with 
ABSSSI.   
Methodology:  This is a Phase 1 randomized, open-label, multi-center, study evaluating the PK and safety of a 
new formulation versus the approved oritavancin formulation. The new formulation enables a shorter infusion 
time and a smaller volume for reconstitution/administration of a single 1200 mg IV infusion of oritavancin in 
subjects with ABSSSI. 
Fifty (50) subjects will be administered the currently approved formulation of oritavancin, using the approved 
dosing regimen in which SWFI is the reconstituting agent and D5W is used for further dilution for a total volume 
of 1000 mL. This formulation will be infused per the approved label over 3 hours. An additional 50 subjects will 
be administered a new formulation of oritavancin which contains HPβCD. This formulation will be reconstituted 
with SWFI and further diluted in 0.9% sodium chloride (saline) for a total volume of 250 mL. This formulation 
will be infused over 60 minutes. 
Subject Participation:  Subjects will be screened up to 48 hours prior to the initiation of study drug. Oritavancin 
will be administered on Day 1. The total duration of the study is up to approximately 17 days, including the Post-
treatment follow-up. 
• 
Screening:  ≤ 48 hours prior to first dose 
• 
Treatment:  Day 1 
• 
Follow-up Visits:  Day 2, Day 4, Day 8 and End of Study Day 15 


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Diagnosis and Main Criteria for Selection: 
Subjects may be included in the study if they meet all of the following criteria: 
1. Subject must be 18 years of age or older, male or female, and of any race. 
2. Subject must give written informed consent before initiation of any study-related procedures. 
3. Diagnosis of ABSSSI (wound infections, cellulitis/erysipelas, or cutaneous abscess) suspected or 
confirmed to be caused by a Gram-positive pathogen requiring IV therapy. 
4. If female, the subject is surgically sterile, postmenopausal, or, if of childbearing potential, agrees to use 
at least 2 highly effective methods of birth control (e.g. prescription oral contraceptives, contraceptive 
injections, contraceptive patch, intrauterine device, barrier methods, abstinence) for the duration of the 
study until 60 days after study drug administration, or male partner sterilization alone. 
5. Subject must express a commitment to comply with all study visits, procedures and requirements for the 
duration of the study. 
Subjects will be excluded from the study if any of the following exclusion criteria apply prior to randomization: 
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 only Gram-negative pathogens (i.e., infections 
acquired during prolonged admission in hospital or long-term care facilities). 
b. Diabetic foot infections (infection extending distal to the malleoli in a subject with diabetes mellitus 
and peripheral neuropathy and/or vascular insufficiency or any ulceration of their foot). 
c. 
Concomitant infection at another site not including a secondary ABSSSI lesion (e.g., septic arthritis, 
endocarditis, osteomyelitis). 
d. Infected burns. 
e. 
A primary infection secondary to a pre-existing skin disease with associated inflammatory changes 
such as atopic dermatitis, eczema, or hidradenitis suppurativa. 
f. 
Decubitus or chronic skin ulcer, or ischemic ulcer due to peripheral vascular disease (arterial or 
venous). 
g. 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). 
h. Infections known to be caused by an organism resistant to oritavancin. 
i. 
Catheter site infections. 
5. Treatment with investigational medicinal product within 30 days or 5 half-lives, whichever is longer, 
before enrollment and for the duration of the study. 
6. Subjects currently receiving anticoagulant therapy.   
7. Known liver function tests (LFTs) ≥ 3 times the upper limit of normal (ULN) or total bilirubin ≥ 2 times 
ULN. 


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8. Any medical condition, which in the judgment of the Investigator, might interfere with the 
pharmacokinetics, distribution, metabolism, or excretion of the study drug. 
9. Any planned, major surgical procedure during the study period (Day 15).  
10. Subject is the Investigator or his/her deputy, research assistant, pharmacist, study coordinator, other staff 
or relative thereof directly involved in the conduct of the study. 
11. Known hypersensitivity to oritavancin, glycopeptides or HPβCD. 
12. Female subject who has a positive pregnancy test or is breastfeeding. 
13. Previous use of oritavancin or anticipated need to use a long acting glycopeptide during the study.  
Subjects excluded for any of the above reasons may be re-screened for participation at any time if the exclusion 
characteristic has changed. 
Investigational Product, Dose and Mode of Administration, Batch Number(s): 
One of two formulations of oritavancin diphosphate (oritavancin) will be administered intravenously to all 
subjects.  
Current Formulation: Composed of 3 single-use vials, each containing 400 mg of oritavancin and the inactive 
component mannitol. Oritavancin vials will be reconstituted with SWFI and further diluted in D5W for a total 
volume of 1000 mL and infused intravenously over 3 hours. Oritavancin Batch Number 00018 will be used. 
New Formulation: Composed of a single vial containing 1200 mg of oritavancin, HPβCD, and mannitol. 
Oritavancin vials will be reconstituted with SWFI and further diluted with 0.9% sodium chloride (saline) for a 
total volume of 250 mL and infused intravenously over 1 hour. Oritavancin Batch Number 00003 will be used.  
No other material or diluent may be substituted or concomitantly infused through the same IV line. 
Duration of Treatment: 
The dosing period is either three hours (Current Formulation) or one hour (New Formulation). 
Criteria for Evaluation: 
Primary endpoint: 
• 
Relative exposure of AUC of the new formulation to the approved formulation of oritavancin based on 
area under the plasma concentration-time curve from time zero to 72 hr (AUC0-72) and time zero to 
168 hr (AUC0-168). 
Secondary endpoint:  
• 
Safety and tolerability of the new formulation of oritavancin assessed according to adverse events (AEs) 
and serious adverse events (SAEs), clinical laboratory parameters (including Direct and Indirect Coombs 
development and oritavancin antibody assay as applicable), and vital signs. 
Exploratory endpoint: 
• 
Pharmacokinetic parameters (including, but not limited to: Cmax, Tmax, AUC, and, where they can be 
calculated, elimination half-life [t½], volume of distribution [Vd], and clearance). 
Pharmacology:  Blood samples for the analysis of oritavancin in plasma will be collected on Day 1 pre-dose and 
at the end of infusion (1 hour or 3 hours), and then 3 hours (for 1 hour infusions), 6 hours, 12 hours, 24 hours, 
72 hours, and 168 hours after the start of the infusion. 
Statistical Methods and Data Analysis:  Descriptive statistics include means, medians, standard deviations and 
ranges for continuous variables, as well as frequency and percentage for categorical variables. Descriptive 
statistics will be provided for demographic, baseline characteristics, and prior and concomitant medications. 
Summary tables and listings of safety data, including AEs, laboratory results (including Direct and Indirect 
Coombs) and vital signs will be provided for the Safety Population. 


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A general linear model will be used to evaluate the relative AUC exposure of the new formulation (test) relative 
to the approved formulation (reference) based on a two-group parallel design. The primary PK parameters 
(AUC0-72 and AUC0-168) will be natural-logarithmically transformed and used as the dependent variable. The 
independent variable includes formulation. For each PK parameter, the estimate of the treatment difference (test 
minus reference) and the upper/lower bound of its 90% confidence interval (CI) will be obtained from the general 
linear model, and then exponentiated to obtain the ratio of the geometric means and its 90% CI in the original 
scale.  
Sample size:  Using combined results from selected Phase 1 studies on oritavancin pharmacokinetics with the 
approved formulation (MDCO-ORI-14-01, MDCO-ORI-14-02, MDCO-ORI-15-01, MDCO-ORI-15-02), the 
observed coefficients of variation (CV) of AUC0-72 and AUC0-168 were 25.4% and 26.3%, respectively. Using a 
slightly larger CV value of 30% to be conservative, the table below shows estimated power values in a parallel 
study design to demonstrate equivalence of AUC of the new formulation (test, T) relative to the approved 
formulation (reference, R), assuming various true T/R ratios of geometric means of AUC0-72 and AUC0-168. The 
table uses a sample size of 100 subjects randomized in 1:1 ratio to the test and reference groups, and uses the 
standard 80% to 125% equivalence limits. A study design of 50 subjects in each of the test and reference groups 
should have ≥ ~90% power to demonstrate AUC equivalence, if the true T/R ratios are within 0.95 to 1.05. 
True T/R Ratio 
Power 
0.95 
89.5% 
1.0 
96.7% 
1.05 
90.2% 
Analysis population:  The subject populations are defined as follows:  
Intent-to-Treat (ITT) Population:  The ITT population will include all subjects randomized. 
Pharmacokinetics (PK) Population: All subjects who received the full dose of oritavancin and have any valid 
samples measured for study drug levels. The PK population will be the primary population for the PK analysis. 
Safety Population: All subjects who received any amount of IV oritavancin. The safety population will be the 
primary population for all the safety analyses. 
 
 


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3. 
TABLE OF CONTENTS 
1. 
SIGNATURE PAGE ..............................................................................................................2 
2. 
PROTOCOL SYNOPSIS........................................................................................................3 
3. 
TABLE OF CONTENTS ........................................................................................................7 
4. 
LIST OF ABBREVIATIONS ...............................................................................................11 
5. 
INTRODUCTION ................................................................................................................13 
5.1. 
Background on Oritavancin ........................................................................................13 
5.2. 
Nonclinical Studies .....................................................................................................14 
5.2.1. 
HPβCD Nonclinical Summary ......................................................................14 
5.2.2. 
PK and Toxicity of Oritavancin with HPβCD (Study SR15-030) ................15 
5.3. 
Summary of Clinical Pharmacology ..........................................................................15 
5.3.1. 
Currently Approved Formulation of Oritavancin .........................................15 
5.3.2. 
New Formulation of Oritavancin ..................................................................16 
5.4. 
Clinical .......................................................................................................................18 
5.4.1. 
Currently Approved Formulation of Oritavancin .........................................18 
5.4.2. 
New Formulation of Oritavancin ..................................................................19 
5.5. 
Rationale for the Present Study ..................................................................................22 
5.6. 
Study Population ........................................................................................................22 
6. 
STUDY OBJECTIVES .........................................................................................................23 
6.1. 
Primary Objective .......................................................................................................23 
6.2. 
Secondary Objective ...................................................................................................23 
6.3. 
Exploratory Objectives ...............................................................................................23 
7. 
STUDY DESIGN..................................................................................................................24 
7.1. 
Primary Endpoint(s) ...................................................................................................24 
7.2. 
Secondary Endpoint(s) ...............................................................................................24 
7.3. 
Exploratory Endpoint(s) .............................................................................................24 
7.4. 
Measures to Minimize/Avoid Bias .............................................................................25 
8. 
SELECTION OF SUBJECT POPULATION .......................................................................26 
8.1. 
Inclusion Criteria ........................................................................................................26 
8.2. 
Exclusion Criteria .......................................................................................................26 
8.3. 
Prior and Concomitant Treatment ..............................................................................27 
8.3.1. 
Permitted Adjunctive Therapies ...................................................................27 
8.3.2. 
Prohibited Medications .................................................................................28 
9. 
STUDY DRUGS ...................................................................................................................29 
9.1. 
Method of Assigning Subjects to Treatment Groups .................................................29 
9.2. 
Treatments Administered ...........................................................................................29 
9.2.1. 
Current Oritavancin Formulation ..................................................................29 
9.2.2. 
New Oritavancin Formulation ......................................................................29 


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9.3. 
Packaging and Labeling .............................................................................................29 
9.4. 
Study Drug Storage Conditions ..................................................................................29 
9.5. 
Blinding ......................................................................................................................30 
9.6. 
Receipt of Supplies .....................................................................................................30 
9.7. 
Study Drug Accountability .........................................................................................30 
9.8. 
Study Drug Handling and Return ...............................................................................30 
9.9. 
Product Complaints ....................................................................................................30 
10. SCHEDULE OF ASSESSMENTS AND PROCEDURES ..................................................32 
10.1. Schedule of Events/Assessments ................................................................................32 
10.2. Screening Period (Within 48 Hours Prior to Day 1) ..................................................35 
10.3. Randomization ............................................................................................................35 
10.4. Day 1 (Pre-Dose) ........................................................................................................35 
10.5. Day 1 (Dosing) ...........................................................................................................35 
10.6. Day 1 (Post-Dose) ......................................................................................................36 
10.7. Follow-up Visits Day 2 (24 Hours) and Day 4 (72 Hours) ........................................36 
10.8. Follow-up Visit Day 8 (168 Hours) ...........................................................................36 
10.9. End of Study (Day 15/Early Termination Visit) ........................................................36 
10.10. Unscheduled Visit ......................................................................................................37 
11. PROTOCOL ASSESSMENTS .............................................................................................38 
11.1. Demographic Data/Medical History ..........................................................................38 
11.2. Adverse Events ...........................................................................................................38 
11.3. Vital Signs ..................................................................................................................38 
11.4. Physical Examination .................................................................................................38 
11.5. Laboratory Assessments .............................................................................................38 
11.6. Assessment of Pharmacodynamics ............................................................................39 
11.7. Assessment of Pharmacokinetics ...............................................................................39 
12. STUDY AND SUBJECT DISCONTINUATION ................................................................41 
12.1. Screening Failures ......................................................................................................41 
12.2. Premature Discontinuation from Study Drug .............................................................41 
12.3. Premature Discontinuation from Study ......................................................................41 
12.4. Study Site Discontinuation .........................................................................................42 
13. ADVERSE EVENTS ............................................................................................................43 
13.1. Definitions ..................................................................................................................43 
13.1.1. Adverse Event ...............................................................................................43 
13.1.2. Serious Adverse Event ..................................................................................43 
13.1.3. Adverse Event of Special Interest (AESI) ....................................................44 
13.1.4. Special Situations ..........................................................................................44 


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13.2. Collection and Assessment of Data Evaluating Adverse Events ...............................44 
13.2.1. Pre-existing Conditions .................................................................................44 
13.2.2. AE Severity ...................................................................................................44 
13.2.3. Relationship Assessment ..............................................................................45 
13.3. Study Specific Safety Requirements for Additional Collection of Safety Data .........45 
13.3.1. Adverse Events of Special Interest (AESIs) .................................................45 
13.3.2. Special Situations ..........................................................................................45 
13.4. Procedure for Adverse Event Recording ....................................................................46 
13.4.1. Serious Adverse Events (SAEs) ....................................................................46 
13.4.2. Non-Serious AEs ..........................................................................................46 
13.4.3. Laboratory Abnormalities .............................................................................46 
13.4.4. Adverse Events of Special Interest (AESIs) .................................................46 
13.4.5. Special Situations ..........................................................................................47 
13.5. Expectedness ..............................................................................................................48 
14. STATISTICAL PLAN ..........................................................................................................49 
14.1. Sample Size ................................................................................................................49 
14.2. Randomization ............................................................................................................49 
14.3. General Statistical Considerations and Definitions ....................................................49 
14.3.1. General Statistical Methods ..........................................................................49 
14.3.2. Analysis Population ......................................................................................49 
14.3.3. Missing Data Handling .................................................................................50 
14.4. Statistical Analyses .....................................................................................................50 
14.4.1. Demographic and Background Characteristics .............................................50 
14.4.2. Study Drug and Concomitant Medications ...................................................50 
14.4.3. Safety Analysis .............................................................................................50 
14.4.4. Pharmacokinetic Parameters .........................................................................51 
15. QUALITY CONTROL AND QUALITY ASSURANCE ....................................................52 
15.1. Monitoring ..................................................................................................................52 
15.2. Auditing ......................................................................................................................52 
15.3. Protocol Deviations ....................................................................................................52 
16. ADMINISTRATIVE ASPECTS ..........................................................................................53 
16.1. Ethics and Responsibility ...........................................................................................53 
16.2. Institutional Review Board or Independent Ethics Committee Approval ..................53 
16.3. Informed Consent .......................................................................................................53 
16.4. Confidentiality ............................................................................................................53 
16.5. Compensation, Insurance and Indemnity ...................................................................53 
16.6. Protocol Amendment ..................................................................................................53 


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16.7. Data Collection ...........................................................................................................54 
16.7.1. Case Report Forms: Electronic .....................................................................54 
16.7.2. Source Document Maintenance ....................................................................54 
16.8. Study Monitoring Requirements ................................................................................54 
16.9. Study File Management ..............................................................................................55 
16.10. Study Completion .......................................................................................................56 
16.11. Audits .........................................................................................................................56 
16.12. Retention of Records ..................................................................................................56 
16.13. Disclosure of Data ......................................................................................................56 
16.14. Financial Disclosure ...................................................................................................57 
16.15. Publication Policy .......................................................................................................57 
17. REFERENCES .....................................................................................................................58 
 
 
LIST OF TABLES 
Table 1: 
Mean Pharmacokinetic Parameters for ABSSSI Subjects Receiving a Single 
1200 mg Dose (n = 297) .............................................................................................16 
Table 2: 
Summary of Mean (CV%) Oritavancin PK Parameters in Healthy Adult 
Subjects by Cohort (PK Population; Study MDCO-ORI-15-01) ...............................17 
Table 3: 
Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term (Safety Population; Study MDCO-ORI-15-01) ................................................20 
Table 4: 
Schedule of Events/Assessments ................................................................................33 
Table 5: 
PK Blood Draw Schedule ...........................................................................................39 


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4. 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ABSSSI 
Acute bacterial skin and skin structure infection 
ADL 
Activities of daily living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AUC 
Area under the curve of plasma concentrations 
CDAD 
Clostridium difficile-associated diarrhea 
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Maximal plasma concentrations 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
D5W 
Dextrose 5% in water 
EC 
Ethics Committee 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLM 
General linear model 
GPV 
Global Pharmacovigilance 
HPβCD 
Hydroxypropyl-β-cyclodextrin  
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
Intravenous 
hr 
Hour 
LFT 
Liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
MIC 
Minimum inhibitory concentration 


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Abbreviation 
Definition 
min 
Minute(s) 
NOAEL 
No-observed-adverse-effect level 
PK 
Pharmacokinetic 
PCS 
Potentially clinical significant 
PT 
Prothrombin time 
RSI 
Reference safety information 
s 
Second(s) 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SOP 
Standard operating procedure 
SWFI 
Sterile water for injection 
t½ 
Half-life 
TEAE 
Treatment emergent adverse event 
Tmax 
Time of observed Cmax 
TMF 
Trial Master File 
ULN 
Upper limit of normal 
Vd 
Volume of distribution 
Vz 
Volume of distribution 
WHO 
World Health Organization 
y 
Year 


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5. 
INTRODUCTION 
This protocol describes a randomized, open-label, multi-center, study evaluating the 
pharmacokinetic (PK) and safety of a new formulation versus the approved oritavancin 
formulation in subjects with acute bacterial skin and skin structure infection (ABSSSI). The new 
formulation adjusts the infusion time, concentration and reconstitution/administration solutions 
of a single 1200 mg intravenous (IV) infusion of oritavancin. 
Oritavancin has been approved in the United States for the treatment of adult patients with 
ABSSSI 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 3198 oritavancin-treated subjects from 
29 completed clinical trials in adults, including two Phase 4 studies, four Phase 3 studies, four 
Phase 2 studies, 19 Phase 1 studies and one ongoing Phase 1 trial in pediatrics. 
Oritavancin has been well tolerated in these studies. More details may be found in the 
Investigator’s Brochure (Oritavancin Investigator’s Brochure Edition 12.0). 
In a previous study (MDCO-ORI-15-01), the area under the curve (AUC) generated with a single 
1200 mg dose of the new formulation of oritavancin administered as an IV infusion over 30, 60, 
90 minutes, or 2 hours in healthy volunteers was comparable with previous exposure data with a 
1200 mg dose of the approved formulation of oritavancin administered over 3 hours. The 
purpose of the current study is to determine the (a) relative AUC exposure (b) safety and 
tolerability and (c) pharmacokinetic profile using the new single vial formulation of oritavancin 
following a single IV dose in subjects with ABSSSI. 
5.1. 
Background on Oritavancin 
Oritavancin is a novel semi-synthetic, lipoglycopeptide antibiotic that has three principal 
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 US Food and Drug Administration (FDA) for the 
treatment of adult patients with acute bacterial skin and skin structure infections caused or 
suspected to be caused by susceptible isolates of Gram-positive microorganisms including 
Staphylococcus aureus (including methicillin-susceptible and methicillin–resistant isolates), 
Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus 
anginosus group (includes S. anginosus, S. intermedius, and S. constellatus), and Enterococcus 
faecalis (vancomycin-susceptible isolates only) (ORBACTIV® Package Insert 2018). The 
currently approved formulation of oritavancin is obtained by reconstitution and dilution of three 
ORBACTIV® 400 mg vials to prepare a single 1200 mg intravenous dose. Reconstitution is by 
sterile water for injection (SWFI), and dilution is by dextrose 5% in water (D5W), yielding a 
final concentration of 1.2 mg/ml. The currently approved formulation of oritavancin is infused 
over 3 hours.  
This new formulation is reconstituted using a combination of hydroxypropyl-β-cyclodextrin 
(HPβCD) in SWFI instead of SWFI only. Hydroxypropyl-β-cyclodextrin is the most widely used 


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modified cyclodextrin and has been shown to change the physicochemical properties of 
lipophilic and other insoluble compounds when co-formulated in combination. HPβCD functions 
by forming an inclusion complex with the active pharmaceutical agent that increases aqueous 
solubility and stability (Loftsson 2005). Solutions of cyclodextrin-drug complexes may be 
lyophilized to produce freely soluble powders as drug products. 
The current formulation of oritavancin has limited solubility in solutions containing sodium 
chloride and must be diluted in 1000 mL of D5W and infused over 3 hours. As HPβCD has been 
shown to improve the solubility and formulation characteristics of numerous compounds 
including anti-infectives such as Sporanox® (itraconazole) and Vibativ® (telavancin), this 
excipient was tested with oritavancin. In HPβCD, oritavancin is significantly more soluble at 
physiologic pH and in 0.9% sodium chloride (normal saline) (MDCO Internal Report 
SR15-30 2015), allowing for smaller infusion volumes using in diluents other than D5W. 
5.2. 
Nonclinical Studies 
Oritavancin has been extensively studied pre-clinically. The results from the safety, toxicology, 
pharmacokinetic, and pharmacodynamic studies demonstrate that oritavancin does not appear to 
induce any biologically significant toxicity. An overview of relevant nonclinical study results is 
presented in the Investigator’s Brochure (Oritavancin Investigator’s Brochure Edition 12.0). 
5.2.1. 
HPβCD Nonclinical Summary 
HPβCD is quickly cleared after parenteral administration. After a single intravenous dose of 14C 
labeled HPβCD, the half-life in plasma was 0.4 and 0.8 hours in rats and dogs, respectively. The 
plasma clearance (CL) was 0.51 and 0.19 L/hr/kg in rats and dogs, respectively (Gould 2005). 
In acute toxicology studies in rats, there was no toxicity at 2 g/kg. In cynomolgus monkeys, a 
single dose of 10 g/kg was tolerated (Gould 2005). 
In sub-acute toxicity studies in rats over 90 days with doses of 50, 100, or 400 mg/kg, the no-
observed-adverse-effect-level (NOAEL) was 50 mg/kg/day. At 100 mg/kg/day, there were 
minimal histological changes in the epithelial cells of the bladder, changes in tubular cells of the 
kidney and in the liver. At 400 mg/kg/day, there were decreases in body weight and food 
consumption, changes in some clinical chemistry parameters and some increases in organ 
weights. These changes were reversible after one month (Gould 2005).  
In a second sub-acute toxicity study in rats over 90 days with every other day dosing at 
200 mg/kg/dose there was no toxicity observed (Gould 2005). 
In sub-acute toxicity studies in dogs over 90 days with doses of 50, 100, or 400 mg/kg, the 
NOAEL was 100 mg/kg/day. At 400 mg/kg/day, there were histological changes in the lung and 
epithelial cells of the bladder and renal pelvis. All changes were reversible after one month 
(Gould 2005). 
In a second sub-acute toxicity study in dogs over 90 days at doses of 700 – 1000 mg/kg, the only 
signs of toxicity were vacuolation of renal tubular cells which was reversible (Gould 2005). 
In a sub-acute toxicity study in cynomolgus monkeys with 200 mg/kg dosing every other day for 
91 days, there was no toxicity observed (Gould 2005). 


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5.2.2. 
PK and Toxicity of Oritavancin with HPβCD (Study SR15-030) 
The pharmacokinetics of oritavancin formulated in D5W or HPβCD in normal saline were 
compared after a one-hour intravenous infusion of 50 or 100 mg/kg in male Sprague-Dawley 
rats. Data indicate that the formulation does not have an impact on the pharmacokinetics of 
oritavancin. Rats infused with 50 mg/kg of oritavancin in D5W or HPβCD had maximum 
concentrations (Cmax) of 160 and 138 mg/L, respectively. Rats infused with 100 mg/kg of 
oritavancin in D5W or HPβCD had Cmax of 244 and 280 mg/L, respectively. The whole blood 
AUCs at 100 mg/kg were 1992.15 and 1964.47 mg*hr/L and the estimated plasma AUCs at 
100 mg/kg were 3172.21 and 3128.14 mg*hr/L for oritavancin in D5W and HPβCD, 
respectively. The concentrations of oritavancin in both formulations increased proportionally 
with dose.  
In the toxicity study, there were no clinical observations, hematology or clinical chemistry 
changes due to oritavancin formulated in D5W or in HPβCD over 8 days following single 1-hour 
intravenous infusions of 50 or 100 mg/kg. There was no treatment related macroscopic or 
microscopic changes in tissues collected at any dose with either formulation. 
Based on the lack of any significant findings with either formulation of oritavancin, the NOAEL 
for oritavancin in D5W or in HPβCD in normal saline was found to be ≥ 100 mg/kg following a 
single 1-hour infusion. 
The plasma AUC of oritavancin formulated in HPβCD in the rat following a 100 mg/kg dose 
was 3128.14 mg*h/L. This exposure level is roughly equivalent to a 1200 mg dose in man 
(~2800 mg*h/L). 
The dose of HPβCD in the control group and the 100 mg/kg oritavancin in HPβCD group was 
400 mg/kg. There were no adverse findings associated with either group.  
5.3. 
Summary of Clinical Pharmacology 
5.3.1. 
Currently Approved Formulation of Oritavancin 
The pharmacokinetics of a single 1200 mg dose of oritavancin in ABSSSI subjects were 
determined using the currently approved formulation from population pharmacokinetic analysis 
of pooled data from 297 adult subjects, and are presented in Table 1. 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. 


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Table 1: 
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 (h*µg/mL) 
1110 
(33.9%) 
AUC0-72 (h*µg/mL) 
1530 
(36.9%) 
AUC0-∞ (h*µg/mL) 
2800 
(28.6%) 
t½α (h) 
2.29 
(49.8%) 
t½β (h) 
13.4 
(10.5%) 
t½γ (h) 
245 
(14.9%) 
Abbreviations: 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; AUC0-72 = Area under the plasma concentration-time curve from 
time zero to 72 hours; AUC0-∞ = Area under the plasma concentration time curve from time zero to infinity; t½α = Half-life for the 
alpha phase; t½β = Half-life for the beta phase; t½γ = Half-life for the gamma phase; CV% = Percent coefficient of variation 
5.3.2. 
New Formulation of Oritavancin 
A multi-vial version of the new formulation (HPβCD solution was provided as a diluent) was 
tested in Study MDCO-ORI-15-01 to determine whether oritavancin could be infused in less 
than 3 hours, in a reduced volume, with potential to use normal saline instead of D5W for 
dilution. 
Study MDCO-ORI-15-01 was a Phase 1, single-center, double-blind cohort study evaluating the 
pharmacokinetics and safety of a new formulation of oritavancin by adjusting infusion time, 
concentration, and reconstitution/administration solutions, of a single 1200 mg IV infusion of 
oritavancin in healthy adult subjects. Fifty-six (56) subjects (46 received oritavancin and 
10 received placebo) with a median age of 40.5 years (range: 19-65 years) participated in the 
study. The study consisted of six cohorts (subjects in Cohort 6 received the new formulation over 
60 minutes using normal saline as the diluent, which is the formulation which will be studied in 
this trial). Oritavancin Cmax generally increased as the infusion duration decreased from 3 hours 
to 60 minutes, while the mean AUC, CL, and volume of distribution (Vz) estimates were 
comparable between the approved formulation and the new formulation (Table 2). 


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Table 2: 
Summary of Mean (CV%) Oritavancin PK Parameters in Healthy Adult 
Subjects by Cohort (PK Population; Study MDCO-ORI-15-01) 
PK Parameter 
(units) 
Cohort 1 
(n = 6) 
Cohort 2 
(n = 8) 
Cohort 3 
(n = 8) 
Cohort 4 
(n = 8) 
Cohort 5 
(n = 8) 
Cohort 6* 
(n = 8) 
IV infusion duration: 
3 hours 
2 hours 
90 minutes 60 minutes 
30 minutes 
60 minutes 
AUC0-last  
(h*µg/mL) 
3278 
(18.6) 
2377 
(22.7) 
2509 
(29.0) 
2535 
(32.2) 
2807 
(14.7) 
2719 
(20.5) 
AUC0-inf 
(h*µg/mL) 
3537 
(16.7) 
2617 
(23.9) 
2727 
(28.0) 
2756 
(31.1) 
3063 
(14.3) 
2962 
(20.7) 
Cmax 
(µg/mL) 
182.8 
(11.4) 
152.5 
(17.5) 
176.8 
(15.5) 
201.9 
(20.5) 
199.1 
(11.8) 
205.8 
(7.3) 
Tmax 
(h) 
3.040 
(3.00-3.08) 
2.000 
(2.00-2.02) 
1.465 
(1.44-1.51) 
1.025 
(1.00-1.04) 
0.490 
(0.48-0.51) 
0.970 
(0.96-1.00) 
t½ 
(h) 
47.807 
(32.6) 
60.694 
(14.6) 
61.264 
(21.7) 
62.968 
(24.7) 
57.479 
(14.7) 
52.608 
(19.5) 
CL 
(L/h) 
0.3483 
(18.6) 
0.4871 
(29.0) 
0.4729 
(29.3) 
0.4783 
(33.7) 
0.3988 
(14.2) 
0.4238 
(24.9) 
Vz 
(L) 
24.00 
(40.7) 
42.13 
(26.0) 
42.01 
(36.1) 
45.63 
(57.9) 
33.24 
(24.4) 
32.49 
(32.9) 
Abbreviations: CV% = percent coefficient of variation; h = hour(s); IV = intravenous; PK = pharmacokinetic; CL = clearance; 
Cmax = Maximum plasma concentration; AUC0-last = Area under the plasma concentration time curve from time zero to the time 
of the last measurable concentration; AUC0-∞ = Area under the plasma concentration time curve from time zero to infinity; 
t½, = Half-life; Tmax = Time of observed Cmax; Vz = volume of distribution  
Cohort 1: 1200 mg of oritavancin diluted in 1000 mL of dextrose 5% in water (D5W). 
Cohort 2: 1200 mg of oritavancin diluted in 250 mL of D5W with hydroxypropyl-β-cyclodextrin (HPβCD) or placebo of 250 mL 
of D5W. 
Cohort 3: 1200 mg of oritavancin diluted in 250 mL of D5W with HPβCD or placebo of 250 mL of D5W. 
Cohort 4: 1200 mg of oritavancin diluted in 250 mL of D5W with HPβCD or placebo of 250 mL of D5W. 
Cohort 5: 1200 mg of oritavancin diluted in 250 mL of D5W with HPβCD or placebo of 250 mL of D5W. 
*Cohort 6 differs from Cohort 4 as this cohort administered a 60-minute infusion diluted in 250 mL of normal saline instead of 
D5W. 
Note: Tmax reported as median (minimum-maximum). 
Source: MDCO-ORI-15-01 
For Cohort 1, the currently approved formulation, the mean Cmax was 182.8 µg/mL with a 
coefficient of variation (CV)% of 11.4%. The mean AUC0-last and AUC0-inf values were 3278 and 
3537 h*µg/mL, respectively, which were higher (approximately 1.2- to 1.4-fold) than the AUC 
values for all other cohorts and the AUC0-inf estimate listed in the product label (2800 h*µg/mL). 
Compared with Cohorts 2 through 6, the mean CL and Vz for Cohort 1 were slightly lower 
(approximately 0.5- to 0.8-fold). 
For Cohorts 2 through 5, the mean Cmax generally increased as the infusion duration decreased, 
as would be expected. The mean Cmax estimates for Cohorts 2 through 5 were 152.5, 176.8, 
201.9, and 199.1 µg/mL, respectively, and the CV% ranged from 11.8% to 20.5%. The mean 
AUC0-last and AUC0-inf values were similar across Cohorts 2 through 5, ranging from 
2377 h*µg/mL to 2807 h*µg/mL for AUC0-last and 2617 h*µg/mL to 3063 h*µg/mL for 
AUC0-inf. The mean CL, and Vz estimates were also similar across Cohorts 2 through 5. 


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For Cohort 6, the new formulation in 0.9% sodium chloride instead of D5W, the mean Cmax was 
205.8 µg/mL, which was comparable to the mean Cmax for Cohort 4 (201.9 µg/mL). The mean 
AUC0-last and AUC0-inf values were 2719 and 2962 h*µg/mL, respectively, which were also 
similar to the mean AUC0-last and AUC0-inf values for Cohort 4. 
The oritavancin plasma exposures following 60-minute infusions of the new formulation 
(Cohorts 4 and 6) from Study MDCO-ORI-15-01 were compared to the plasma exposures 
following 3-hour infusions of the currently approved formulation from completed Phase 1 and 
ABSSSI studies. The results of this analysis found that oritavancin exposures, as measured by 
AUC, were comparable between the two formulations.  
5.4. 
Clinical 
5.4.1. 
Currently Approved Formulation of Oritavancin 
As of 12 March 2019, oritavancin has been studied in 3198 oritavancin-treated subjects from 
29 completed clinical trials in adults, including two Phase 4 studies, four Phase 3 studies, four 
Phase 2 studies, 19 Phase 1 studies and one ongoing Phase 1 trial in pediatrics. 
5.4.1.1. 
Known and Potential Risks from Phase 3 ABSSSI Clinical Trials 
In the pooled ABSSSI clinical trials, there were 540 (55.3%) subjects in the oritavancin arm and 
559 (56.9%) subjects in the vancomycin arm, who reported ≥ 1 adverse reaction. Serious adverse 
reactions were reported in 57/976 (5.8%) subjects treated with oritavancin and 58/983 (5.9%) 
treated with vancomycin. The most commonly reported serious adverse reaction was cellulitis in 
both treatment groups: 11/976 (1.1%) in oritavancin and 12/983 (1.2%) in the vancomycin arms, 
respectively. 
The most commonly reported adverse reactions (≥ 3%) in subjects receiving a single 1200 mg 
dose of oritavancin in the pooled ABSSSI clinical trials were: nausea, headache, vomiting, limb 
and subcutaneous abscesses, and diarrhea. 
In the pooled ABSSSI clinical trials, oritavancin was discontinued due to adverse reactions in 
36/976 (3.7%) of subjects; the most common reported reactions leading to discontinuation were 
cellulitis (4/976, 0.4%) and osteomyelitis (3/976, 0.3%) (Orbactiv® Package Insert 2018). 
5.4.1.2. 
Hypersensitivity and Infusion Related Reactions 
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 oritavancin infusion in patients with a history of 
glycopeptide allergy. In the Phase 3 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 have been reported with the glycopeptide class, including oritavancin. 
The reactions resemble "Red-man Syndrome", including pruritus, urticaria and/or rash and 
flushing of the upper body. If infusion-related reactions occur, slowing or interrupting the 
infusion could stop the reaction. 


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5.4.1.3. 
Other Potential Risks 
Oritavancin has been shown to artificially prolong prothrombin time (PT) and International 
Normalized Ratio (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 currently receiving 
anticoagulant therapy are excluded from this study at Screening.  
Infusing oritavancin in a shorter duration may result in a higher Cmax. A higher Cmax may produce 
adverse events (AEs) similar to those observed in the oritavancin cardiac safety study 
(MDCO-ORI-12-02) where 1600 mg infused over three hours was selected as the supra-
therapeutic dose. In this study, forty-eight healthy volunteers were administered the 1600 mg 
supratherapeutic oritavancin dose (current formulation) and seven reported oral paresthesia or 
oral hypoesthesia. They were of mild intensity as were most of the events reported from the 
1600 mg dose.  
There are no additional AEs expected from using HPβCD as the excipient in this trial. 
A complete description of relevant risks of oritavancin can be found in the Investigator’s 
Brochure (Oritavancin Investigator’s Brochure Edition 12.0). 
5.4.2. 
New Formulation of Oritavancin 
As described in Section 5.3.2, Study MDCO-ORI-15-01 was a Phase 1, single-center, double-
blind cohort study evaluating the pharmacokinetics and safety of a new formulation of 
oritavancin by adjusting infusion time, concentration, and reconstitution/administration 
solutions, of a single 1200 mg IV infusion of oritavancin in healthy adult subjects. The new 
formulation was well tolerated by the healthy male and female subjects with no evidence of an 
increase in incidence or severity of treatment-emergent adverse events (TEAEs) with shorter 
infusion times and new formulation. 
5.4.2.1. 
Safety in Study MDCO-ORI-15-01 with Oritavancin New Formulation 
Overall, 10 subjects (17.9%) reported at least one TEAE and 8 subjects (14.3%) reported a 
TEAE considered related to study drug. All TEAEs were mild in severity. There were no deaths, 
serious adverse events (SAEs), or TEAEs leading to study drug or study discontinuation. 
Overall, a higher percentage of subjects (4 subjects, 50.0%) reported TEAEs in Cohort 3 
(90-minute IV infusion) followed by subjects (3 subjects, 37.5%) in Cohort 4 (60-minute IV 
infusion). Similar percentages of subjects reported TEAEs considered related to study drug in 
Cohorts 3 and 4 (3 subjects each, 37.5%). No TEAEs were reported by subjects in Cohort 1 
(3-hour IV infusion) or Cohort 2 (2-hour IV infusion). There was no evidence of an increase or 
change in TEAEs with a decrease infusion time response in Cohorts 1 through 5, and no 
evidence of a response to switching to normal saline between Cohorts 4 and 6. 
TEAEs reported by more than 1 subject included diarrhea, oral paresthesia, and headache 
(2 subjects each, 3.6%) (Table 3). All TEAEs of oral paresthesia occurred in Cohort 4 
(60-minute IV infusion) and all TEAEs of headache occurred in Cohort 3 (90-minute IV 
infusion). The TEAEs of diarrhea occurred in Cohort 3 (90-minute IV infusion) and Cohort 6 
(60-minute IV infusion). All other TEAEs were reported by one subject (1.8%) each. Based on 
the findings in these studies and the safety of HPβCD in other formulations, there is limited 
safety risk with use with oritavancin and thus further evaluation in human trials is warranted.


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Table 3: 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
(Safety Population; Study MDCO-ORI-15-01) 
System Organ Class 
 Preferred Term 
Cohort 1 
(3-hour IV) 
(n = 6) 
n (%) 
Cohort 2 
(2-hour IV) 
(n = 8) 
n (%) 
Cohort 3 
(90-min IV) 
(n = 8) 
n (%) 
Cohort 4 
(60-min IV) 
(n = 8) 
n (%) 
Cohort 5 
(30-min IV) 
(n = 8) 
n (%) 
Cohort 6* 
(60-min IV) 
(n = 8) 
n (%) 
Placebo 
(n = 10) 
n (%) 
Overall 
(N = 56) 
n (%) 
Number of subjects with at least 1 TEAE 
0 
0 
4 (50.0) 
3 (37.5) 
1 (12.5) 
1 (12.5) 
1 (10.0) 
10 (17.9) 
Number of TEAEs 
0 
0 
7 
4 
4 
4 
1 
20 
Gastrointestinal disorders 
0 
0 
2 (25.0) 
2 (25.0) 
0 
1 (12.5) 
0 
5 (8.9) 
 Abdominal pain 
0 
0 
0 
0 
0 
1 (12.5) 
0 
1 (1.8) 
 Constipation 
0 
0 
1 (12.5) 
0 
0 
0 
0 
1 (1.8) 
 Diarrhea 
0 
0 
1 (12.5) 
0 
0 
1 (12.5) 
0 
2 (3.6) 
 Nausea 
0 
0 
0 
0 
0 
1 (12.5) 
0 
1 (1.8) 
 Paresthesia oral 
0 
0 
0 
2 (25.0) 
0 
0 
0 
2 (3.6) 
General disorders and administration site 
0 
0 
0 
2 (25.0) 
0 
0 
1 (10.0) 
3 (5.4) 
 Injection site injury 
0 
0 
0 
1 (12.5) 
0 
0 
0 
1 (1.8) 
 Injection site pain 
0 
0 
0 
1 (12.5) 
0 
0 
0 
1 (1.8) 
 Medical device reaction 
0 
0 
0 
0 
0 
0 
1 (10.0) 
1 (1.8) 
Infections and infestations 
0 
0 
1 (12.5) 
0 
0 
0 
0 
1 (1.8) 
 Pharyngitis 
0 
0 
1 (12.5) 
0 
0 
0 
0 
1 (1.8) 
Injury, poisoning, and procedural complications 
0 
0 
0 
0 
1 (12.5) 
0 
0 
1 (1.8) 
 Infusion related reaction 
0 
0 
0 
0 
1 (12.5) 
0 
0 
1 (1.8) 
Musculoskeletal and connective tissue disorders 
0 
0 
0 
0 
1 (12.5) 
0 
0 
1 (1.8) 
 Muscle tightness 
0 
0 
0 
0 
1 (12.5) 
0 
0 
1 (1.8) 
Nervous system disorders 
0 
0 
2 (25.0) 
0 
0 
1 (12.5) 
0 
3 (5.4) 
 Dizziness 
0 
0 
0 
0 
0 
1 (12.5) 
0 
1 (1.8) 
 Headache 
0 
0 
2 (25.0) 
0 
0 
0 
0 
2 (3.6) 


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System Organ Class 
 Preferred Term 
Cohort 1 
(3-hour IV) 
(n = 6) 
n (%) 
Cohort 2 
(2-hour IV) 
(n = 8) 
n (%) 
Cohort 3 
(90-min IV) 
(n = 8) 
n (%) 
Cohort 4 
(60-min IV) 
(n = 8) 
n (%) 
Cohort 5 
(30-min IV) 
(n = 8) 
n (%) 
Cohort 6* 
(60-min IV) 
(n = 8) 
n (%) 
Placebo 
(n = 10) 
n (%) 
Overall 
(N = 56) 
n (%) 
Psychiatric disorders 
0 
0 
0 
0 
1 (12.5) 
0 
0 
1 (1.8) 
 Anxiety 
0 
0 
0 
0 
1 (12.5) 
0 
0 
1 (1.8) 
Respiratory, thoracic, and mediastinal disorders 
0 
0 
2 (25.0) 
0 
0 
0 
0 
2 (3.6) 
 Nasal congestion 
0 
0 
1 (12.5) 
0 
0 
0 
0 
1 (1.8) 
 Pharyngeal inflammation 
0 
0 
1 (12.5) 
0 
0 
0 
0 
1 (1.8) 
Abbreviations: IV = intravenous; min = minute; TEAE = treatment-emergent adverse event 
Cohort 1: 1200 mg of oritavancin diluted in 1000 mL of dextrose 5% in water (D5W). 
Cohort 2: 1200 mg of oritavancin diluted in 250 mL of D5W with hydroxypropyl-β-cyclodextrin (HPβCD). 
Cohort 3: 1200 mg of oritavancin diluted in 250 mL of D5W with HPβCD or placebo of 250 mL of D5W. 
Cohort 4: 1200 mg of oritavancin diluted in 250 mL of D5W with HPβCD or placebo of 250 mL of D5W. 
Cohort 5: 1200 mg of oritavancin diluted in 250 mL of D5W with HPβCD or placebo of 250 mL of D5W. 
*Cohort 6 differs from Cohort 4 as this cohort administered a 60-minute infusion diluted in 250 mL of normal saline instead of D5W. 
Placebo: Cohorts 2-6 each had 2 subjects who were administered placebo (250 mL of normal saline). These subjects are pooled together in the placebo column. 
 
 


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5.5. 
Rationale for the Present Study 
Single IV dose oritavancin (1200 mg) has been approved in the U.S. for the treatment of adult 
patients with ABSSSI caused or suspected to be caused by Gram-positive microorganisms. The 
current study is being conducted to evaluate the relative exposure, PK and safety of a new 
formulation of oritavancin by adjusting infusion time, concentration and reconstitution/ 
administration solutions, of a single 1200 mg IV infusion of oritavancin in adult subjects with 
ABSSSI. 
The approved formulation of oritavancin requires reconstitution of oritavancin for injection with 
SWFI and then further dilution in D5W prior to infusing a total volume of 1000 mL over 
3 hours. The outcome of this study will provide data to determine whether oritavancin can be 
infused in less than 3 hours, in a reduced volume, with potential to use normal saline or D5W for 
dilution. This would reduce the burden for patients by shortening infusion time and give 
flexibility for pharmacies to use D5W or normal saline. By decreasing the volume from 1000 ml 
to 250 ml, it reduces the amount of fluid that is given to the patient, which is especially important 
for renally impaired patients or patients with compromised cardiac function. 
In a prior study (MDCO-ORI-15-02) using the current approved formulation, elevated 
immunoglobulin levels and a positive Indirect Coombs test were observed in several healthy 
volunteers after a second dose of oritavancin (two weeks apart). Another study 
(MDCO-ORI-16-02) was subsequently completed with ABSSSI patients who received two doses 
of oritavancin one week apart (also with the current approved formulation). None of the patients 
in that study had a positive Indirect Coombs result.  
As a result of these findings and to verify whether this might occur with the new formulation in 
ABSSSI patients, plasma will be collected from subjects in this study before and after 
oritavancin dosing to test for Direct and Indirect Coombs. 
5.6. 
Study Population 
Male or female subjects at least 18 years old (inclusive) with ABSSSI who meet all the inclusion 
and none of the exclusion criteria. 


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6. 
STUDY OBJECTIVES  
6.1. 
Primary Objective 
The primary objective is to determine the relative AUC exposure of the new formulation of 
oritavancin compared to the currently approved formulation based on area under the plasma 
concentration-time curve (AUC) after a single 1200 mg IV infusion of oritavancin in male and 
female subjects with ABSSSI. 
6.2. 
Secondary Objective 
The secondary objective is to evaluate the safety and tolerability of the new formulation of 
oritavancin by the incidence of AEs and SAEs, clinical laboratory abnormalities, including the 
results of Direct and Indirect Coombs test and oritavancin antibody assay as applicable, and by 
vital signs. 
Safety and tolerability assessments will be evaluated through Day 15 following the oritavancin 
infusion. 
6.3. 
Exploratory Objectives 
An exploratory objective is the evaluation of pharmacokinetic parameters (including, but not 
limited to: Cmax, time of observed Cmax (Tmax), AUC, and, where they can be calculated, 
elimination half-life [t½], volume of distribution [Vd], and CL) after a single 1200 mg IV infusion 
of oritavancin in male and female subjects with ABSSSI. 


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7. 
STUDY DESIGN 
This study will be a Phase 1, randomized, open-label, multi-center, study evaluating the PK and 
safety of the new formulation compared to the currently-approved formulation of oritavancin.  
Approximately 100 subjects at about five centers will be randomized in a 1:1 ratio to the 
currently approved formulation of oritavancin versus the new formulation. Fifty (50) subjects 
will be administered the currently approved formulation of oritavancin, using the approved 
dosing regimen in which SWFI is used for reconstitution and D5W is used for further dilution to 
a final volume of 1000 mL. This formulation will be infused over 3 hours per the approved label. 
An additional fifty (50) subjects will be administered the new formulation of oritavancin. This 
formulation will also be reconstituted with SWFI and further diluted in 0.9% sodium chloride to 
a final volume of 250 mL. This formulation will be infused over 60 minutes. 
Informed consent will be obtained from subjects before the initiation of any study-specific 
procedures. Subjects will be screened up to 48 hours prior to the initiation of study drug. 
Subjects will receive their dose of oritavancin on Day 1 and will be asked to return to the study 
center on Day 2, Day 4, Day 8 and Day 15 for collection of additional blood samples and 
procedure assessments. The subject’s participation is approximately 17 days. 
Safety of the new formulation of oritavancin will be assessed according to AEs and SAEs, 
clinical laboratory parameters (including Direct and Indirect Coombs development and 
oritavancin antibody assay as applicable), and vital signs. 
Detailed descriptions of the assessments are provided in Section 10. 
7.1. 
Primary Endpoint(s) 
The primary endpoint of this trial is: 
Relative AUC exposure of the new formulation of oritavancin to the approved formulation of 
oritavancin based on areas under the plasma concentration-time curve from time zero to 72 hr 
(AUC0-72) and time zero to 168 hr (AUC0-168). 
7.2. 
Secondary Endpoint(s) 
The secondary endpoints of this trial are: 
Safety and tolerability of the new formulation of oritavancin assessed according to AEs and 
SAEs, clinical laboratory parameters (including Direct and Indirect Coombs development and 
oritavancin antibody assay as applicable), and vital signs, through Day 15 following completion 
of study drug infusion. 
7.3. 
Exploratory Endpoint(s) 
The exploratory endpoints of this trial are: 
An evaluation of pharmacokinetic parameters (including, but not limited to: Cmax, Tmax, AUC, 
and, where they can be calculated, elimination half-life [t½], Vd, and CL) after a single 1200 mg 
IV infusion of oritavancin in male and female subjects with ABSSSI. 


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7.4. 
Measures to Minimize/Avoid Bias 
This is an unblinded, open label study. The primary endpoint is based on a pharmacokinetic 
assessment, a measurement that is not subject to interpretation bias. 


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8. 
SELECTION OF SUBJECT POPULATION 
The following criteria for enrollment must be followed explicitly. The subject will not be 
enrolled unless the inclusion/exclusion criteria are met. The Investigator or other study site 
personnel must document in the source documents that the informed consent form (ICF) was 
signed and dated prior to any study screening procedures. The presence of inclusion criteria and 
absence of exclusion criteria will be verified in the electronic case report form (eCRF).  
8.1. 
Inclusion Criteria 
Subjects may be included in the study if they meet all of the following criteria: 
1. Subject must be 18 years of age or older, male or female, and of any race. 
2. Subject must give written informed consent before initiation of any study-related 
procedures. 
3. Diagnosis of ABSSSI (wound infections, cellulitis/erysipelas, or cutaneous abscess) 
suspected or confirmed to be caused by a Gram-positive pathogen requiring IV therapy. 
4. If female, the subject is surgically sterile, postmenopausal, or, if of childbearing potential, 
agrees to use at least 2 highly effective methods of birth control (e.g. prescription oral 
contraceptives, contraceptive injections, contraceptive patch, intrauterine device, barrier 
methods, abstinence) for the duration of the study until 60 days after study drug 
administration, or male partner sterilization alone. 
5. Subject must express a commitment to comply with all study visits, procedures and 
requirements for the duration of the study. 
8.2. 
Exclusion Criteria 
Subjects will be excluded from the study if any of the following exclusion criteria apply prior to 
randomization: 
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 only Gram-negative pathogens 
(i.e., infections acquired during prolonged admission in hospital or long-term care 
facilities). 
b. Diabetic foot infections (infection extending distal to the malleoli in a subject with 
diabetes mellitus and peripheral neuropathy and/or vascular insufficiency or any 
ulceration of their foot). 
c. Concomitant infection at another site not including a secondary ABSSSI lesion (e.g., 
septic arthritis, endocarditis, osteomyelitis). 
d. Infected burns. 


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e. A primary infection secondary to a pre-existing skin disease with associated 
inflammatory changes such as atopic dermatitis, eczema, or hidradenitis suppurativa. 
f. Decubitus or chronic skin ulcer, or ischemic ulcer due to peripheral vascular disease 
(arterial or venous). 
g. 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). 
h. Infections known to be caused by an organism resistant to oritavancin. 
i. Catheter site infections. 
5. Treatment with investigational medicinal product within 30 days or 5 half-lives, 
whichever is longer, before enrollment and for the duration of the study. 
6. Subjects currently receiving anticoagulant therapy. 
7. Known liver function tests (LFTs) ≥ 3 times the upper limit of normal (ULN) or total 
bilirubin ≥ 2 times ULN. 
8. Any medical condition, which in the judgment of the Investigator, might interfere with 
the pharmacokinetics, distribution, metabolism, or excretion of the study drug. 
9. Any planned, major surgical procedure during the study period (Day 15). 
10. Subject is the Investigator or his/her deputy, research assistant, pharmacist, study 
coordinator, other staff or relative thereof directly involved in the conduct of the study. 
11. Known hypersensitivity to oritavancin, glycopeptides or HPβCD. 
12. Female subject who has a positive pregnancy test or is breastfeeding. 
13. Previous use of oritavancin or anticipated need to use a long acting glycopeptide during 
the study. 
Subjects excluded for any of the above reasons may be re-screened for participation at any time 
if the exclusion characteristic has changed. 
8.3. 
Prior and Concomitant Treatment 
Reasonable efforts will be made to determine all relevant treatment (concomitant medications, 
including all prescription/non-prescription medications, herbal medications, vitamin 
supplements, supportive therapies, and concomitant non-pharmacological treatments) received 
by the subject within 14 days before administration of the first dose of study drug through the 
last study visit. These medications/treatments will be recorded in the eCRF. The medication 
name, route of administration, dose, unit, frequency and indication and duration of the 
treatment/procedure (start and stop dates) will be recorded in the eCRF. 
8.3.1. 
Permitted Adjunctive Therapies 
Minor surgical or bedside procedures (including incision and drainage, aspiration, lavage, etc.) 
are allowed during the study. However, planned major surgical procedures during the study that 


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could incur blood loss or fluid shifts are not permitted as this may impact the safety and PK 
analysis. 
8.3.2. 
Prohibited Medications 
As the safety data collection in this trial is extremely important, use of additional antibiotics 
during the study period should be minimized unless the patient is a treatment failure requiring 
unexpected rescue antibiotics or requires additional antibiotics to treat a new infection during the 
study.  


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9. 
STUDY DRUGS 
9.1. 
Method of Assigning Subjects to Treatment Groups 
The study is randomized 1:1 (Current Formulation:New Formulation). Randomization will take 
place in the electronic data capture (EDC) system once the subject is screened and confirmed to 
be eligible for participation. 
9.2. 
Treatments Administered 
After randomization, dosing will be performed on Day 1. All participants will receive a single 
intravenous infusion of oritavancin, either the current formulation or the new formulation, 
diluted as indicated below. A pharmacist or qualified designee will prepare the study drug 
infusions. No other material or diluent may be substituted or concomitantly infused through the 
same IV line. Refer to the Pharmacy Manual for further details regarding dose preparation and 
administration. 
9.2.1. 
Current Oritavancin Formulation 
The currently approved formulation is composed of 3 single-use vials, each containing 400 mg 
of oritavancin diphosphate (as the free base) and the inactive component mannitol. Oritavancin 
vials will be reconstituted with SWFI and further diluted in D5W for a total volume of 1000 mL 
and infused intravenously over 3 hours. 
9.2.2. 
New Oritavancin Formulation 
The new formulation is composed of a single vial containing 1200 mg of oritavancin, HPβCD, 
and mannitol. Oritavancin vials will be reconstituted with SWFI and further diluted with 0.9% 
sodium chloride (saline) for a total volume of 250 mL and infused intravenously over 1 hour. 
9.3. 
Packaging and Labeling 
The Sponsor will provide the current and new formulation. Infusion bags of D5W and 0.9% 
sodium chloride will be provided by the study site pharmacy. 
Vial labels will comply with regulatory requirements. The storage conditions for each 
medication provided will be described on the medication label. 
This study is open-label and therefore, the site personnel and study subject will know which 
formulation they are receiving and the infusion duration (3 hours or 1 hour). The pharmacist will 
label the infusion bag with the oritavancin 1200 mg (new formulation or current approved 
formulation) and will include the infusion time (1 hour or 3 hours). 
9.4. 
Study Drug Storage Conditions 
Oritavancin lyophilized powder should be stored at controlled room temperature (20°C to 25°C; 
68°F to 77°F) in a secure cabinet. Diluted intravenous solution in an infusion bag should be used 
within 6 hours when stored at room temperature, or within 12 hours when refrigerated. 
The combined storage time (reconstituted solution in the vial and diluted solution in the bag) and 
infusion time should not exceed 6 hours at room temperature or 12 hours when refrigerated (see 
Pharmacy Manual). Access should be strictly limited to the study pharmacists and their 
designees. 


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9.5. 
Blinding 
The study is open-label and therefore, there is no blinding of the study drug or study drug 
infusion time. 
9.6. 
Receipt of Supplies  
Upon receipt of the investigational drug, the pharmacist or designated study site personnel will 
visually inspect the shipment and verify the drug information, quantity, and condition of the kits 
received. The Investigational Drug Transmittal and Receipt Form will be completed and signed 
by the pharmacist and retained in the pharmacy binder. In addition, receipt of the study drug 
shipment will be sent to Melinta for placement in the Trial Master File (TMF). 
9.7. 
Study Drug Accountability 
It is the responsibility of the Investigator to ensure that a current record of inventory/drug 
accountability is maintained. 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. Inventory records must be readily available for inspection 
by the study monitor and available to Regulatory Agencies for inspection at any time. 
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) will be kept until the monitor 
has reviewed the accountability records. If this is not permitted by the institution’s Standard 
Operating Procedures (SOP), this should be discussed with the monitor prior to study start. 
9.8. 
Study Drug Handling and Return  
Upon the completion or termination of the study, and upon written authorization from Melinta or 
its representative, all unused and/or partially used study drug should be returned or destroyed at 
the investigational site, as specified by Melinta. It is the Investigator’s responsibility to ensure 
that Melinta or its representative has provided written authorization that procedures for proper 
disposal of the study drug have been established, and that appropriate records of the disposal are 
documented and maintained. No unused study drug may be disposed until fully accounted for by 
the Melinta monitor (or designee). 
9.9. 
Product Complaints 
Sites are required to report any product complaints to Melinta immediately but no later than 
24 hours from the time of awareness, by phone or e-mail as follows: 
US Phone: 1-844-MED-MLNT (1-844-633-6569) 
Email: medinfo@melinta.com 
Product Complaint: Is defined as any written, electronic, or oral communication that alleges 
deficiencies related to the identity, durability, reliability, quality, safety, effectiveness or 


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performance of a product, after it is released for distribution (EU DIR 2001/83/EC). (Derived 
from Ref US 21 CFR 211.198) 
There are two types of Product Complaints: Technical Quality Complaints and Preference 
Complaints.  
Technical Quality Complaint: A report of dissatisfaction with the product with regard to its 
efficacy, strength, integrity, purity, or quality; thus, a potential failure to meet product 
specifications. Examples include: 
• An indication that there is an unexpected physical change in the drug product such as 
discoloration, change in shape of the drug product, presence of particulates or any 
other physical change that might indicate contamination, a manufacturing defect or 
any other event that might indicate a compromise in product quality. 
• An indication that the content does not meet its labeled volume, count, etc. 
• An indication that there is an unexpected physical change in any part of the container 
(this includes the bottle, any part of the seal, the cap or the label). 
• An indication that the product is mislabeled. 
• An indication that there is an unexpected physical change of the product or container 
once the product is diluted or reconstituted (the container includes the vial, bag, IV-
line, syringe or any other item that is in contact with the product). 
• An indication that the product is falsified, tampered with or adulterated. 
• An indication that the product did not meet its pharmacologic effect, i.e. lack of 
efficacy. 
Preference Complaints: A report of dissatisfaction with service, delivery, packaging or other 
preference. 


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10. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES 
This study will consist of three periods:  
1. Screening Period – within 48 hours prior to first dose 
2. Day 1 (pre-dose, dosing, post-dose)  
3. Follow-up Period – Day 2 through Day 15 (End of study visit)  
The subject’s participation from screening/informed consent to end of study will be up to 
approximately 17 days. 
10.1. 
Schedule of Events/Assessments 
The Schedule of Events/Assessments (Table 4) summarizes the study assessments by time point. 


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Table 4: 
Schedule of Events/Assessments 
1Vital signs include blood pressure, temperature, respiratory rate and heart rate. 
                                                 
 
 
Study Procedures 
Screening 
Day 1 
Follow-up Visit 
Unscheduled 
 
≤ 48 hrs 
prior to 
Day 1 
Pre-
Dose 
Dosing 
Post-Dose 
(1 hr or 
3 hrs) 
Day 2 
(24 hrs) 
Day 4 
(72 hrs) 
Day 8 
(168 hrs) 
Day 159 
(336 hrs) 
Unscheduled 
Visit 
Informed consent 
X 
 
 
 
 
 
 
 
 
Assess inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
Medical history, including 
microbiology results if available 
X 
 
 
 
 
 
 
 
 
Randomize subject 
 
X 
 
 
 
 
 
 
 
Physical exam including height 
& weight 
X 
 
 
 
 
 
 
 
X 
Vital signs1 
X 
X 
 
X 
 
 
X 
 
X 
Urine pregnancy test2 
X 
X 
 
 
 
 
 
X 
X 
Chemistry and hematology 
laboratory assessments3 
X 
 
 
 
 
 
X 
X 
X 
Record prior or concomitant 
medications and surgical 
procedures 
X 
X 
 
X 
X 
X 
X 
X 
X 
Administer IV oritavancin4 
 
 
X 
 
 
 
 
 
 
Direct & Indirect Coombs Test5 
 
X 
 
 
 
 
X 
X 
X 
Collect plasma for oritavancin 
antibody assay6 
 
X 
 
 
 
 
X 
X 
X 
Collect plasma for PK7 
 
X 
 
X 
X 
X 
X 
 
X 
Assessment of adverse events8 
 
 
X 
X 
X 
X 
X 
X 
X 


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2At Screening and Day 15, perform a local urine pregnancy test for female subjects of childbearing potential (may be omitted for females > 2 years postmenopausal or 
surgically sterile). A urine pregnancy test will be performed again on Day 1 for female subjects of childbearing potential if the screening pregnancy test was performed 
> 24 hours prior to dosing. 
3Unless otherwise indicated, all chemistry and hematology laboratory tests will be performed by the site’s local laboratory. 
4Start time of study drug infusion is Hour 0 (study drug will be administered over 1 hour or 3 hours) 
5Direct and Indirect Coombs testing will be done at the local laboratory. Samples will be collected at Day 1 (pre-dose), Day 8 and Day 15. If a subject has a change in Direct 
or Indirect Coombs results at Day 8, subjects may be asked to return for subsequent labs in order to investigate this change. Subjects with a positive Direct or Indirect Coombs 
test at the Day 15 visit must have the test repeated every 2 weeks until it returns to baseline or stabilizes. 
6Plasma samples will be stored and tested for oritavancin antibody only if the subject(s) experience unexpected adverse events that may be associated with antibody 
production. 
7Time points for PK sample collection are Day 1 pre-dose and at the end of infusion (1 hour or 3 hours), and then at 3 hours (for 1 hour infusions), 6 hours, 12 hours, 
24 hours, 72 hours, and 168 hours after the start of the infusion. See Table 5 for windows for PK draws and visits. 
8Adverse events and serious adverse events will be assessed from the time of study drug administration through Day 15 post administration of oritavancin. 
9If the subject is required to terminate the study early, the subject must complete the Day 15 assessments at the time of the Early Termination Visit. 
                                                 
 
 
 
 
 
 
 
 


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10.2. 
Screening Period (Within 48 Hours Prior to Day 1) 
The following procedures will be performed within 48 hours prior to study drug administration 
to assess subject eligibility for the study: 
1. Obtain written informed consent. 
2. Assess inclusion/exclusion criteria. 
3. Record medical history including microbiology results, if available. 
4. Perform a physical examination (including height and weight). 
5. Obtain vital sign measurements (blood pressure, heart rate, respiratory rate and 
temperature). 
6. A local urine pregnancy test will be performed for female subjects of childbearing 
potential (may be omitted for females > 2 years postmenopausal or surgically sterile). 
7. Collect blood specimens for hematology and serum chemistry tests. 
8. Record prior and concomitant medications and surgical procedures (this includes, but is 
not limited to, aspiration, debridement, incision and drainage). 
10.3. 
Randomization 
Randomization should only occur once subject eligibility criteria are confirmed (see Section 9.4). 
10.4. 
Day 1 (Pre-Dose) 
The following assessments will be performed on Day 1 prior to dosing: 
1. Assess inclusion/exclusion criteria. 
2. Obtain vital sign measurements (blood pressure, heart rate, respiratory rate and 
temperature). 
3. A local urine pregnancy test will be performed for female subjects of childbearing 
potential (may be omitted for females > 2 years postmenopausal or surgically sterile) if 
the screening pregnancy test was performed > 24 hours prior to dosing.  
4. Record prior and concomitant medications and surgical procedures (this includes, but is 
not limited to, aspiration, debridement, incision and drainage). 
5. Collect blood specimens for PK, Direct and Indirect Coombs testing and oritavancin 
antibody assay. 
10.5. 
Day 1 (Dosing) 
Oritavancin will be administered over 3 hours (if randomized to the current formulation) or over 
1 hour (if randomized to the new formulation). The start time of study drug administration is 
Day 1 (Hour 0), and all subsequent visits and PK draws will be calculated from this start time.  
All AEs and SAEs that occur during the infusion will be recorded. See Section 5.4.1.2 for 
guidance in the event a hypersensitivity or infusion-related reaction occurs during infusion. 


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10.6. 
Day 1 (Post-Dose) 
The following assessments will be performed on Day 1 after dosing: 
1. Obtain vital sign measurements (blood pressure, heart rate, respiratory rate and 
temperature). 
2. Collect plasma for PK at the end of infusion (1 hour or 3 hours), and then at 3 hours (for 
1 hour infusions), 6 hours, and 12 hours after the start of the infusion. 
3. Record concomitant medications and surgical procedures (this includes, but is not limited 
to, aspiration, debridement, incision and drainage). 
4. Assess AEs and SAEs. 
10.7. 
Follow-up Visits Day 2 (24 Hours) and Day 4 (72 Hours) 
The following assessments will be performed on follow-up visits at Day 2 and Day 4 (See 
Table 5 for the visit window for each visit): 
1. Collect plasma for PK at 24 hours (Day 2) and 72 hours (Day 4) after the start of the 
infusion. 
2. Record concomitant medications and surgical procedures (this includes, but is not limited 
to, aspiration, debridement, incision and drainage). 
3. Assess AEs and SAEs. 
10.8. 
Follow-up Visit Day 8 (168 Hours) 
The following assessments will be performed on the follow-up visit at Day 8 (See Table 5 for the 
visit window for Day 8): 
1. Obtain vital sign measurements (blood pressure, heart rate, respiratory rate and 
temperature). 
2. Collect blood specimens for hematology and serum chemistry tests. 
3. Record concomitant medications and surgical procedures (this includes, but is not limited 
to, aspiration, debridement, incision and drainage). 
4. Collect blood specimens for Direct and Indirect Coombs testing and oritavancin antibody 
assay. 
5. Collect plasma for PK at 168 hours after the start of the infusion. 
6. Assessment of AEs and SAEs. 
10.9. 
End of Study (Day 15/Early Termination Visit) 
The following assessments will be performed on follow-up visit at Day 15 or the Early 
Termination Visit (See Table 5 for the visit window for Day 15): 
1. A local urine pregnancy test will be performed for female subjects of childbearing 
potential (may be omitted for females > 2 years postmenopausal or surgically sterile). 


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2. Collect blood specimens for hematology and serum chemistry tests. 
3. Collect blood specimens for Direct and Indirect Coombs testing and oritavancin antibody 
assay. 
4. Record concomitant medications and surgical procedures (this includes, but is not limited 
to, aspiration, debridement, incision and drainage). 
5. Assessment of AEs and SAEs. 
A subject’s participation in the study is complete when the subject has completed the Day 15 
Visit or Early Termination Visit. However, if at this visit there is an ongoing SAE, or the subject 
has a positive Direct or Indirect Coombs test, then the SAE will be followed and/or Coombs test 
result will be repeated up to a return to baseline condition or stabilization.  
10.10. 
Unscheduled Visit 
If at any time the Investigator believes the subject requires additional testing/follow-up, an 
Unscheduled Visit may be performed. 


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11. 
PROTOCOL ASSESSMENTS 
11.1. 
Demographic Data/Medical History 
Demographic information will be recorded at Screening. A complete medical and surgical 
history, including past and current use/abuse of drugs, alcohol, and tobacco, and any available 
microbiology results, will be collected at Screening and reviewed for any changes at Day 1. The 
medical history should include clinically significant medical or surgical history ongoing at 
baseline or with onset in the previous 2 years. 
11.2. 
Adverse Events 
Subjects will be carefully monitored for AEs by the investigator during the designated study 
period (see Section 13 for details). 
11.3. 
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 (Section 10.1). Blood pressure 
and pulse must always be taken after the subject has been resting supine for 5 minutes. 
11.4. 
Physical Examination 
A complete physical examination, including height (cm) and weight (kg), will be performed at 
Screening. The complete physical examination will include the following organ or body system 
assessments: skin; head, neurological; lungs; cardiovascular; abdomen (liver, spleen); lymph 
nodes; and extremities. 
11.5. 
Laboratory Assessments 
Specimens will be obtained at the designated time periods as indicated in the Schedule of Events 
(Section 10.1). All safety laboratory assessments and Direct and Indirect Coombs Testing 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 until returning to normal or baseline, or to a level that is agreed upon 
by both the Principal Investigator and the Sponsor. Laboratory assessments include: 
• 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, Absolute reticulocyte count, 
Haptoglobin.  
• Pregnancy Test: A urine pregnancy test (human chorionic gonadotropin for female 
subjects of childbearing potential only) will be conducted at Screening (and possibly at 
Day 1 if the screening test was performed more than 24 hours prior to dosing) and Day 
15. For information about reporting occurrences of pregnancy in a study subject or a 


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study subject’s partner (to be followed until conclusion of pregnancy and reported on 
specific forms; see Section 13.4.5.2). 
• Direct and Indirect Coombs Test: Direct and Indirect Coombs Test will be conducted at 
Day 1 (pre-dose), Day 8 and Day 15. 
• Oritavancin Antibody Assay: Two plasma samples will be collected at each of the 
following time points: Day 1 (pre-dose), Day 8 and Day 15. These samples will be stored 
at the site, and sent to a Central Lab for oritavancin antibody testing only if the subject(s) 
experiences unexpected AEs that may be associated with antibody production. 
11.6. 
Assessment of Pharmacodynamics 
Pharmacodynamic assessments will not be performed in this study. 
11.7. 
Assessment of Pharmacokinetics 
Blood samples for the analysis of oritavancin in plasma will be collected on Day 1 pre-dose and 
at the end of infusion (1 hour or 3 hours), and then 3 hours (for 1 hour infusions), 6 hours, 
12 hours, 24 hours, 72 hours, and 168 hours after the start of the infusion. Every effort should be 
made to collect all PK samples at the optimal sample time (within the window in Table 5 below). 
The date and time of each PK sample will be recorded on the eCRF.  
Table 5: 
PK Blood Draw Schedule 
PK Blood Draw Schedule 
Optimal Sample Time from 
START of infusion 
Sample Time Window 
Lower Limit 
Upper Limit 
Pre-Dose 
(-30 minutes) 
Any time prior to 
dose administration 
Any time prior to 
dose administration 
1 hour (end of infusion) 
New Formulation Arm Only 
1 hr 
1 hr 5 min 
3 hours  
New Formulation Arm Only 
2 hrs 50 min 
3 hrs 10 min 
3 hours (end of infusion) 
Current Formulation Arm Only 
3 hrs 
3 hrs 5 min 
6 hours 
5 hrs 45 min 
6 hrs 15 min 
12 hours 
10 hrs 
14 hrs 
24 hours (Day 2) 
20 hrs 
28 hrs 
72 hours (Day 4) 
60 hrs 
84 hrs 
168 hours (Day 8) 
Day 7 
Day 9 
 
Detailed collection, processing, storage, and shipment procedures will be provided in PK sample 
collection laboratory manual. Samples will be sent to a central laboratory for analysis. Plasma 


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concentrations will be determined using liquid chromatography-tandem mass spectroscopy 
methods. 


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12. 
STUDY AND SUBJECT DISCONTINUATION 
A clear distinction will be made between subjects who discontinue study drug dosing and those 
who withdraw or are withdrawn from the study. Only those subjects who are lost to follow-up, 
are unwilling to comply with protocol procedures, or who withdraw consent and/or refuse any 
further contact with respect to the study will be withdrawn from the study. 
12.1. 
Screening Failures 
Subjects who sign and date the ICF but who fail to meet the inclusion and exclusion criteria are 
defined as screen failures. 
12.2. 
Premature Discontinuation from Study Drug  
All subjects have the right to withdraw at any point during treatment or study participation 
without prejudice. The investigator can discontinue study drug at any time if medically 
necessary. If for any subject, study treatment is discontinued, the reason will be recorded, and the 
Sponsor should be notified promptly. Reasons that a subject may discontinue treatment: 
• Adverse event(s) 
• Death 
• Subject wishes to withdraw consent 
• Subject non-compliance or unwillingness to comply with the procedures required by the 
protocol 
• Investigator discretion 
• Melinta Therapeutics request  
In the event that study drug is discontinued prematurely, it is imperative that all safety 
procedures are completed. 
12.3. 
Premature Discontinuation from Study  
All subjects have the right to withdraw at any point during the study participation without 
prejudice or may be discontinued from the study for any of the following reasons:  
• Adverse event(s) 
• Death 
• Subject wishes to withdraw consent 
• Subject non-compliance or unwillingness to comply with the procedures required by the 
protocol 
• Investigator discretion 
• Lost to follow-up 
• Melinta Therapeutics request  
In the event that a subject discontinues from the study, all data collected up until the time of 
study withdrawal is to be entered into the eCRF. Every attempt should be made to collect follow 
up information except for those subjects who specifically withdraw consent to release such 
information. 


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12.4. 
Study Site Discontinuation 
Reasons for discontinuation of the study at an investigational site may include, but are not 
limited to, the following: 
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects. 
• Subject enrollment is unsatisfactory. 
• Investigator request to withdraw from participation. 
• Melinta Therapeutics decision. 
• Serious and/or persistent non-compliance by the Investigator with the protocol, the 
clinical research agreement, and/or applicable regulatory guidelines in conducting 
the study. 
• Institutional Review Board (IRB)/Independent Ethics Committee (IEC) decision to 
terminate or suspend approval for the investigation or the Investigator. 
• Investigator fraud (altered data, omitted data, or manufactured data). 


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13. 
ADVERSE EVENTS 
13.1. 
Definitions 
13.1.1. 
Adverse Event  
Any untoward medical occurrence in a patient or clinical trial 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 (e.g. 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. 
13.1.2. 
Serious Adverse Event 
A serious AE (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-subject hospitalization or prolongs hospitalization (planned surgical 
procedures or hospitalization are NOT an SAE), 
• Is a congenital anomaly/birth defect, or 
• Is another medically significant event where medical and scientific judgment should be 
exercised in deciding whether other situations should be considered serious reactions, 
such as important medical events that might not be immediately life threatening or result 
in death or hospitalization, but might jeopardize the subject or might require intervention 
to prevent one of the other outcomes listed above. Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias 
or convulsions that do not result in hospitalization, or the development of dependency or 
abuse. Any suspected transmission via a medicinal product of an infectious agent is also 
considered a serious adverse reaction. 
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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13.1.3. 
Adverse Event of Special Interest (AESI) 
An AE of special interest (serious or non-serious) is one of scientific and medical interest 
specific to the Sponsor’s product or program. Ongoing monitoring and rapid communication to 
the Sponsor is requested as such an event might warrant further investigation in order to further 
characterize it. 
13.1.4. 
Special Situations 
Information that is not necessarily considered an AE, but which can possibly contribute to the 
overall knowledge concerning the safety of the compound. 
Examples include, but are not limited to, reports of pregnancy/lactation exposures with or 
without any AEs related to the parent or child; medication errors – actual and potential; 
accidental exposure; suspected transmission via an investigational product of an infectious agent; 
drug interaction. 
13.2. 
Collection and Assessment of Data Evaluating Adverse Events 
13.2.1. 
Pre-existing Conditions 
Preexisting conditions (present before the start of the AE collection period) are considered 
concurrent medical conditions and should not be recorded as AEs. However, if the subject 
experiences a worsening or complication of such a concurrent condition, the worsening or 
complication should be recorded as an AE. Investigators should ensure that the AE term 
recorded captures the change in the condition (e.g., “worsening of [condition]”). Planned hospital 
admissions and/or surgical procedures for an illness or disease that existed at baseline and did 
not aggravate during the study should not be reported as AEs. If the subject has a worsening of 
the Index Infection meeting the criteria for an AE during their study participation, the AE should 
be documented as ‘Worsening of the Index Infection’ and if a new infection develops, the AE 
term should be documented as ‘New Infection with the type and location specified’ (i.e., New 
Cellulitis on Right Arm).  
13.2.2. 
AE Severity 
The severity of an AE will be assessed by the Investigator using the grading system described 
below. 
Adverse events (AEs) will be graded using the 5-point Common Terminology Criteria for 
Adverse Events (CTCAE) criteria (Version 5). 
Grade 1 = Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2= Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL). 
Grade 3 = Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limited self-care ADL. 
Grade 4 = Life-threatening consequences; urgent intervention indicated. 
Grade 5 = Death related to AE. 


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For AE severity grading guidance organized by system organ class (SOC) refer to 
CTCAE (Version 5.0).  
For AEs not listed in the CTCAE guidance, grading should be assigned using the 3-point scale 
below: 
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. 
Immediately life-threatening SAEs and fatal SAEs will be assigned a grade 4 or grade 5 
respectively. 
13.2.3. 
Relationship Assessment 
For each AE, the Investigator must make an assessment of the relationship of the event to the 
study drug as:  
Unrelated: There is no reasonable possibility that the administration of the study drug caused 
the AE; there is no temporal relationship between the investigational product and event onset, or 
an alternative etiology has been established.  
Related: There is a reasonable possibility that the administration of the study drug caused the 
AE; there is evidence to suggest a causal relationship between the study drug and the AE. 
13.3. 
Study Specific Safety Requirements for Additional Collection of Safety Data 
13.3.1. 
Adverse Events of Special Interest (AESIs) 
The following AESIs have been identified for oritavancin in this protocol:  
• Hypersensitivity including Red Man Syndrome  
• Pseudomembranous colitis/Clostridium difficile-associated diarrhea (CDAD) 
• Osteomyelitis 
• Hemolytic anemia:  
For the purpose of this study, the subjects will be monitored for signs of hemolysis. 
Subjects presenting with clinical signs of anemia should undergo a work-up that includes 
investigations of hemolytic anemia (absolute reticulocyte count, serum bilirubin <total 
and indirect>, lactic dehydrogenase, haptoglobin, alanine aminotransferase and a Direct 
and Indirect Coombs test). 
13.3.2. 
Special Situations 
Special Situations designated for this study are the following: 
• Medication errors that fall into the following categories: 
− Wrong investigational product; 
− Wrong dose (including overdose, underdose, change in dosing regimen, strength, 
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− Wrong route of administration; 
− Wrong subject (i.e. not administered to the intended subject); 
− Accidental exposure 
• Pregnancy/lactation exposures with or without any AEs related to the parent or child  
• Suspected transmission via a medicinal product of an infectious agent  
• Drug interactions 
13.4. 
Procedure for Adverse Event Recording 
13.4.1. 
Serious Adverse Events (SAEs) 
All SAEs that occur during the designated study period (from the time of study drug initiation to 
Day 15) must be reported to the Sponsor’s Global Pharmacovigilance (GPV) Department within 
24 hours of awareness of the event using the provided study specific SAE/AESI Report Form. 
Each SAE/AESI must also be recorded on the source documents and on the appropriate page of 
the eCRF. 
The Investigator should provide any follow-up information for the event to the Sponsor on an 
updated SAE/AESI Report Form as soon as it becomes available. The Sponsor will contact the 
Investigator, if necessary, to clarify any of the event information or request additional 
information. All SAEs will be followed until satisfactory resolution or until the investigator or 
sub-investigator deems the event to be chronic or the subject to be stable. The timelines and 
procedure for follow-up reports are the same as those for the initial report.  
If the Investigator is notified of a SAE/AESI that occurs post-study period that he or she wishes 
to report to the Sponsor (e.g., an event suspected to be causally related to investigational 
product), the event should be reported through the process described above.  
Where appropriate, if required by local regulations or procedures, the Investigator should report 
these events to the IRB/Ethics Committee (EC) and/or national regulatory authority in addition 
to the Sponsor. 
13.4.2. 
Non-Serious AEs 
All non-serious AEs that occur during the designated study period from the time of study drug 
initiation to Day 15 must be assessed and recorded on the source documents and the eCRF, 
regardless of causal relationship to the investigational product. 
13.4.3. 
Laboratory Abnormalities 
Abnormal laboratory values or test results constitute AEs only if they induce clinical signs or 
symptoms, are considered clinically significant, require therapy or further diagnosis beyond 
repeat testing for confirmation alone. 
13.4.4. 
Adverse Events of Special Interest (AESIs) 
The SAE/AESI Report Form should be completed for reporting the AESI whether or not the 
event meets the criteria for a SAE. The SAE/AESI Report Form should indicate that the reported 


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event is an AESI. If applicable, the eCRF page or a targeted questionnaire associated with the 
AESI should also be completed and submitted with the SAE/AESI Report Form.  
Non-serious AESIs should be reported to the Sponsor within 72 hours and serious AESIs should 
be reported to the Sponsor within 24 hours. 
13.4.5. 
Special Situations 
13.4.5.1. Medication Errors 
Medication errors with or without an associated AE should be recorded as medication errors in 
the eCRF.  
Medication errors and an associated SAE should be recorded in the eCRF and also reported to 
the Sponsor’s GPV as described in Section 13.4.1. 
Medication errors and an associated non-serious AE should be recorded in the eCRF as described 
in Section 13.4.2. 
A mis-dosing protocol deviation (refer to Section 16.3) should be reported as a medication error 
if it was an “unintended error”. 
13.4.5.2. Pregnancy/Lactation Exposure 
Occurrences of pregnancy/lactation exposure in a study subject or study subject’s partner from 
the time of study drug initiation through the follow-up must be reported to the Sponsor within 
24 hours using the Pregnancy/Lactation Exposure Report Form.  
A subject becoming pregnant while on study drug will immediately be withdrawn from the study 
and early termination study procedures will be performed. 
The subject or partner should be followed by the Investigator until completion of the pregnancy. 
If the pregnancy ends for any reason before the anticipated date of delivery, the Investigator 
should notify Melinta Safety. At the completion of the pregnancy, the Investigator will document 
the outcome of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting an 
SAE. 
In cases where a pregnancy/lactation exposure occurs with a SAE and/or AESI, the SAE/AESI 
Report Form should be used to report the SAE and/or AESI and the Pregnancy/Lactation 
Exposure Report Form should be used to report the pregnancy/lactation exposure. When a 
pregnancy/lactation exposure occurs without any concurrent SAE or AESI, the 
Pregnancy/Lactation Exposure Report Form must be submitted alone.  
13.4.5.3. Suspected Transmission via a Medicinal Product of an Infectious Agent 
Any suspected transmission of an infectious agent via a medicinal product should be considered 
an SAE and reported in accordance with Section 13.4.1 (SAEs). 
If no other criterion is applicable, the seriousness of this report should be assessed as a 
‘medically significant event’.  


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13.4.5.4. Drug Interaction 
An AE that occurs due to a suspected drug interaction, either serious or non-serious, should be 
recorded on the AE eCRF form and reported to the Melinta GPV Department using the 
SAE/AESI Report Form. The SAE/AESI Report Form should detail the investigational product, 
the interacting product and include the description of the alleged drug interaction. 
13.5. 
Expectedness  
Melinta GPV will be responsible for determining whether an AE is expected or unexpected for 
the purpose of SUSAR reporting. An AE will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the safety information previously described for the 
investigational product in the Reference Safety Information (RSI). 
For the investigational product and the approved product, the RSI will be the Investigator’s 
Brochure current/approved at the time of expectedness assessment. 


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14. 
STATISTICAL PLAN 
14.1. 
Sample Size 
Using combined results from selected Phase 1 studies on oritavancin pharmacokinetics with the 
approved formulation (MDCO-ORI-14-01, MDCO-ORI-14-02, MDCO-ORI-15-01, 
MDCO-ORI-15-02), the observed CV of AUC0-72 and AUC0-168 were 25.4% and 26.3%, 
respectively. Using a slightly larger CV value of 30% to be conservative, the table below shows 
estimated power values in a parallel study design to demonstrate equivalence of AUC of the new 
formulation (test, T) relative to the approved formulation (reference, R), assuming various true 
T/R ratios of geometric means of AUC0-72 and AUC0-168. The table uses a sample size of 
100 subjects randomized in 1:1 ratio to the test and reference groups, and uses the standard 80% 
to 125% equivalence limits. A study design of 50 subjects in each of the test and reference 
groups should have ≥ ~90% power to demonstrate AUC equivalence, if the true T/R ratios are 
within 0.95 to 1.05. 
True T/R Ratio 
Power 
0.95 
89.5% 
1.0 
96.7% 
1.05 
90.2% 
14.2. 
Randomization 
With a sample size of approximately 100, subjects will be randomized in 1:1 ratio in a parallel 
fashion to the test (new formulation) and reference (approved formulation) groups. 
14.3. 
General Statistical Considerations and Definitions 
14.3.1. 
General Statistical Methods 
All study-collected data will be summarized by treatment group using descriptive statistics, 
graphs, and/or raw data listings. Unless otherwise specified, descriptive statistics for continuous 
variables will include number of subjects (n), mean, standard deviation (SD), median, quartiles 
(Q1 and Q3), minimum (min) and maximum (max) values. Analysis of categorical variables will 
include frequency and percentage. Descriptive statistics will be provided for demographic, 
baseline characteristics, and prior and concomitant medications. Summary tables and listings of 
safety data, including AEs, laboratory results (comprising results from Direct and Indirect 
Coombs and oritavancin antibody assay as applicable) and vital signs will be provided for the 
Safety Population. 
14.3.2. 
Analysis Population 
14.3.2.1. Intent-to-Treat (ITT) Population 
All subjects randomized. 


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14.3.2.2. Pharmacokinetics (PK) Population 
All subjects who have received the full dose of oritavancin and have any valid samples measured 
for study drug levels. The PK population will be the primary population for the PK analysis. 
14.3.2.3. Safety Population 
All subjects who have received any amount of IV oritavancin. The safety population will be the 
primary population for all the safety analyses. 
14.3.2.4. Analysis Windows and Baseline 
All data collected in the study will be included in the analysis. Unless otherwise specified, the 
last evaluation prior to the initiation of study drug will be considered the "Baseline" evaluation 
for analysis. 
14.3.3. 
Missing Data Handling 
Unless otherwise specified, missing data will not be imputed and will be excluded from the 
associated analysis. 
14.4. 
Statistical Analyses  
14.4.1. 
Demographic and Background Characteristics 
Subject demographics and baseline characteristics will be summarized by treatment using the 
ITT and safety populations. 
14.4.2. 
Study Drug and Concomitant Medications 
Summary of each prior (pre-baseline) medication and concomitant (baseline or later) medication 
will be provided by treatment for the safety population. Medication will be coded with World 
Health Organization (WHO) Drug Dictionary Enhanced. Subjects will be counted only once by 
medication. 
14.4.3. 
Safety Analysis 
14.4.3.1. Adverse Events  
The Medical Dictionary for Regulatory Activities (MedDRA) will be used for coding AEs. An 
AE (classified by preferred term) occurring from the start of study drug will be counted as a 
TEAE either if it was not present at baseline or if it was present at baseline but increased in 
severity during the period of observation.  
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 SAEs and AEs leading to treatment or study discontinuation will also be provided 
by system organ class and preferred term. 


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14.4.3.2. Laboratory Tests 
Laboratory values will be summarized by treatment group, including changes from baseline at 
each time point. Analyses will also be performed for each lab parameter by treatment group for 
incidence rates of potentially clinically significant (PCS) values for subjects without PCS value 
at baseline. PCS values will be defined in the Statistical Analysis Plan (SAP). 
14.4.3.3. Vital Signs 
Vital sign measurements and changes from baseline will be summarized descriptively at each 
scheduled timepoint by treatment. PCS changes will also be summarized by treatment group. 
14.4.4. 
Pharmacokinetic Parameters 
Plasma (blood) concentration versus time data will be analyzed using noncompartmental 
pharmacokinetic analysis. The following pharmacokinetic parameters will be estimated where 
possible (additional parameters may be calculated): 
• Area under the plasma concentration-time curve (AUC) from time zero to 72 hr 
(AUC0-72), time zero to 168 hr (AUC0-168), time zero to the time of the last measurable 
concentration (AUC0-last) and. where possible, AUC from time zero to infinity 
(AUC0-∞) 
• Maximum observed measured plasma concentration (Cmax) 
• Time of observed Cmax (Tmax) 
• Elimination half- life (t½) 
• Total body clearance (CL) 
• Volume of distribution at steady state (Vd) 
All concentration data will be presented descriptively for each formulation at each time point. 
All pharmacokinetic parameters will be descriptively analyzed by formulation for the PK 
population. Descriptive statistics comprise N, mean, geometric mean, SD, SEM, median, %CV, 
minimum and maximum. 
A general linear model (GLM) will be used to evaluate the relative AUC exposure of the new 
formulation (test) relative to the approved formulation (reference) based on a two-group parallel 
design. The primary PK parameters (AUC0-72 and AUC0-168) will be natural-logarithmically 
transformed and used as the dependent variable. The independent variable includes formulation. 
For each PK parameter, the estimate of the treatment difference (test minus reference) and the 
upper/lower bound of its 90% confidence interval (CI) will be obtained from the general linear 
model, and then exponentiated to obtain the ratio of the geometric means and its 90% CI in the 
original scale. 


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
15.1. 
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 Good Clinical Practice (GCP) requirements. 
As part of a concerted effort to fulfill these obligations, the Sponsor's monitor will visit the 
center(s) 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. 
15.2. 
Auditing 
The Sponsor may conduct audits at the study center(s). Audits will include, but not be limited to, 
study 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. 
15.3. 
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, or their 
agent, at the earliest possible time by telephone. 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 the IRB/EC established procedures. 
The following Protocol Deviations will require additional information in the eCRF explaining 
why the deviation occurred and what will be done to prevent it from re-occurring: 
• Any deviation in the Inclusion/Exclusion criteria. 
• Subject is given an incorrect dose(s) of oritavancin (greater than 120% or less 
than 80%). 
• If a subject misses 2 or more consecutive PK draws. 


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16. 
ADMINISTRATIVE ASPECTS 
16.1. 
Ethics and Responsibility 
This protocol will be conducted in compliance with the protocol and all regulatory requirements, 
in accordance with GCP, including International Conference on Harmonization (ICH) 
Guidelines, and in general conformity with the most recent version of the Declaration of 
Helsinki. 
16.2. 
Institutional Review Board or Independent Ethics Committee Approval 
This protocol, the ICF, and all relevant supporting data must be submitted to the IRB/IEC for 
approval. IRB/IEC approval of the protocol, ICF, and any advertisement used to recruit study 
subjects must be obtained before the study may be initiated. 
The Investigator is responsible for keeping the IRB/IEC advised of the progress of the study and 
of any changes made to the protocol as deemed appropriate, but in any case, at least once a year. 
The Investigator is also responsible for notifying the IRB/IEC of all unanticipated risks involving 
human subjects that occur during the study. 
16.3. 
Informed Consent 
It is the policy of Melinta Therapeutics that written informed consent is obtained from subjects. 
The ICF must be signed and dated prior to any study-related procedures being performed at 
screening/Baseline. The Investigator or designee must address all questions raised by the subject 
before the subject signs the consent form. The original signed ICF for each participating subject 
shall be filed with records kept by the Investigators(s). A copy of the ICF must be provided to 
the subject. Where applicable, it will be provided in a certified translation of the local language. 
16.4. 
Confidentiality 
Personal study subject data collected and processed for the purposes of this study should be 
managed by the Investigator and his/her staff with adequate precautions to ensure the 
confidentiality of those data, and in accordance with applicable national and/or local laws and 
regulations on personal data protection. 
Monitors, auditors and other authorized agents of Melinta Therapeutics, the IRB/IEC approving 
this research, and the US FDA, as well as any other applicable regulatory authorities, will be 
granted direct access to the study subjects’ original medical records for verification of clinical 
trial procedures and/or data, without violating the confidentiality of the subjects, to the extent 
permitted by the law and regulations. In any presentation of the results of this study at meetings 
or in publications, the subject identities will remain confidential.  
16.5. 
Compensation, Insurance and Indemnity 
Information regarding compensation, insurance, and indemnity is addressed in the Clinical Trial 
Research Agreement. 
16.6. 
Protocol Amendment 
If a protocol has been filed with regulatory agencies or submitted to an IRB/IEC, and requires 
changes, a protocol amendment must be written. Any changes to the protocol will be made by 


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the sponsor. All amendments will be sent to the study sites who are then responsible for 
submitting the amendment to their IRB/IECs for approval prior to implementing the amendment 
changes or enrolling subjects under the amended protocol. 
16.7. 
Data Collection 
16.7.1. 
Case Report Forms: Electronic 
For this trial, an EDC eCRF system which is 21 CFR Part 11 compliant will be used to record all 
subject data specified by this protocol. The eCRF must be completed by designated and trained 
study personnel. All users will be trained by qualified personnel on the technical features of the 
EDC, as well as the content of the eCRF, 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.  
It is the responsibility of the Principal Investigator to ensure the eCRFs are completed in an 
accurate and timely manner. The eCRF should be filled out by the site within 3 business days 
after a visit is completed (except for Randomization which needs to be completed in the eCRF 
prior to dosing in order to determine the treatment assignment and infusion time). 
Prior to the database being locked, the Principal Investigator or a designated Sub-Investigator 
(listed on the Form FDA 1572) will review, approve and electronically 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. 
The processing of eCRFs will include an audit trail (to include changes made, reason for change, 
date of change and person making change). After the end of the trial, a copy of the data will be 
provided to the site, with the per-subject eCRF in an individual subject profile on disk or another 
electronic medium. 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. 
16.7.2. 
Source Document Maintenance 
Source documents are defined as the results of original observations and activities of a clinical 
investigation. Source documents may include, but are not limited to, study progress notes, e-mail 
correspondence, computer printouts, laboratory data, and drug accountability records. All source 
documents produced in this study will be maintained by the Investigator(s) and made available 
for inspection by Melinta Therapeutics representatives, the FDA, or other regulatory authorities. 
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 Sponsor and documented in the site files. 
16.8. 
Study Monitoring Requirements 
Site visits will be conducted by an authorized Melinta Therapeutics representative (the monitor) 
to inspect study data, subject medical records, and eCRFs in accordance with ICH guidelines, 
GCPs, and the respective US or national regulations and guidelines, as applicable. It will be the 
monitor’s responsibility to inspect the eCRF at regular intervals throughout the study, to verify 
adherence to the protocol and the completeness, consistency and accuracy of the data being 
entered. The monitor should have access to laboratory test reports and other subject records 
needed to verify the entries on the eCRFs. 


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The Investigator will permit representatives of Melinta Therapeutics, the US FDA, and/or 
respective health authorities to inspect facilities and records relevant to this study. 
16.9. 
Study File Management 
It is the responsibility of the Investigator(s) to ensure that the study file at the site is maintained. 
The study file may contain, but not limited to: 
1. Investigator’s Brochure (including updated or revised versions) 
2. Final study protocol 
3. Protocol amendments (if applicable) 
4. Fully executed Clinical Trial Agreement 
5. ICF (blank) 
6. Revised ICFs and/or all addenda (blank) 
7. Copy of signed form(s) US FDA Form 1572  
8. A completed and signed Health Canada QIU Form (if applicable) 
9. DHHS number for IRB or other documentation of IRB/IEC compliance with FDA 
10. Curricula Vitae (CV) of Investigators and Sub-Investigators 
11. Financial disclosure information provided to the sponsors  
12. A list of the IRB/IEC members and their qualifications  
13. If the Investigator is a member of the IRB/IEC, documentation stating he/she did not vote on 
the study.  
14. Documentation of IRB/IEC approval of protocol, ICF, any protocol amendments and any 
ICF revisions 
15. Annual IRB/IEC updates and approvals 
16. All correspondence between the Investigator, IRB/IEC and Melinta Therapeutics (or 
designee) 
17. Copies of all Investigational New Drug (IND) Safety Reports submitted to the FDA or other 
regulatory agencies, and IRB/IEC correspondence documenting their submission (if 
applicable) 
18. Laboratory certifications/normal laboratory value ranges 
19. Screening log 
20. Monitoring log 
21. Drug accountability records and invoices for receipt/return of study drug 
22. Protocol Signature Page 
23. Laboratory Director’s CV and medical/professional license, if available 


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16.10. 
Study Completion 
Melinta Therapeutics requires that the following data and materials be on file at the study site 
before a study can be considered completed or terminated: 
1. Laboratory findings, clinical data, and all special test results from screening through the end 
of the study follow-up period 
2. eCRFs properly completed by appropriate study personnel and electronically signed and 
dated by the Investigator 
3. Complete Drug Accountability records (drug inventory log and an inventory of returned or 
destroyed clinical material) 
4. Copies of protocol amendments and IRB/IEC approval/notification if appropriate 
5. A summary of the study prepared by the Principal Investigator (an IRB/IEC summary letter 
is acceptable) 
16.11. 
Audits 
During the course of the study, or after completion of the study, each study site may be subject to 
an audit by a Melinta Therapeutics Quality Assurance Auditor (or an auditor appointed by 
Melinta Therapeutics or its authorized representative) and/or an inspector from the FDA and/or 
other regulatory authority. Every attempt will be made to notify the Investigator in writing in 
advance of the audit.  
16.12. 
Retention of Records 
Melinta Therapeutics follows US regulations and ICH guidelines in its retention policy. 
US IND regulations (21 CFR 312.62) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drugs including CRFs, consent 
forms, laboratory test results, and medication inventory records be kept on file by the Principal 
Investigator for 2 years after a marketing application is approved for the drug for the indication 
for which it is being studied. If no application is filed or approved, these records must be kept for 
2 years after the investigation has been discontinued and the FDA has been notified. ICH 
guidelines indicate that documents should 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. If there is a country or 
institutional policy that specific records and documents be retained for a longer period than 
described above, the applicable sites must comply with those policies in addition to US and ICH 
policies. No study records should be destroyed without prior authorization from Melinta 
Therapeutics. 
16.13. 
Disclosure of Data 
The Investigator agrees by his/her participation that the results of this study may be used for 
submission to national and/or international registration and supervising authorities. If required, 
these authorities will be provided with the names of Investigators, their addresses, qualifications 
and extent of involvement. It is understood that the Investigator is required to provide Melinta 
Therapeutics with all study data, complete reports, and access to all study records. 


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Data generated by this study must be available for inspection by the US FDA and other 
regulatory authorities, by Melinta Therapeutics, and the IRB as appropriate. At a subject’s 
request, medical information may be given to his or her personal physician or other appropriate 
medical personnel responsible for his or her welfare. Subject medical information obtained 
during the course of this study is confidential and disclosure to third parties other than those 
noted above is prohibited. 
16.14. 
Financial Disclosure 
The US FDA Financial Disclosure by Clinical Investigators (21 CFR 54) regulations require 
sponsors to obtain certain financial information from Investigators participating in covered 
clinical studies; each Principal Investigator and Sub-investigator is required to provide the 
required financial information before participating in the study and to promptly update Melinta 
Therapeutics with any relevant changes to this information throughout the course of the clinical 
study and for up to 1 year after its completion. This rule applies to all Investigators and Sub-
investigators participating in covered clinical studies to be submitted to the FDA in support of an 
application for marketing approval. 
16.15. 
Publication Policy 
The publication policy is outlined in the Clinical Trial Agreement. 


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17. 
REFERENCES 
Common Terminology Criteria for Adverse Events (CTCAE) v5.0. 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_5x7.pdf 
Gould S, Scott RC. (2005) 2-Hydroxypropyl-beta-Cyclodextrin (HP-beta-CD): A Toxicology 
Review. Food and Chemical Toxicology, 43, 1451-1459. 
Loftsson T, Jarho P, Másson M, Järvinen T. (2005) Cyclodextrins in drug delivery. Expert 
Opinion on Drug Delivery, 2:2, 335-351. 
ORBACTIV® (oritavancin) [package insert] Lincolnshire, IL: Melinta Therapeutics, Inc.; 2018. 
Oritavancin Investigator’s Brochure, Edition 12, May 2018. 
Report MDCO-ORI-12-02:  A double-blind, randomized, placebo-controlled, parallel-design 
study with an open-label positive control to assess the cardiac safety of oritavancin in healthy 
volunteers.  September 2013. 
Report MDCO-ORI-15-01:  A randomized, double-blind, single-center, cohort study to evaluate 
the safety, tolerability, and pharmacokinetics of a new formulation of a single 1200 mg iv dose 
of oritavancin in healthy volunteers.  July 2016. 
Report MDCO-ORI-15-02:  A Double-Blind Randomized Study to Evaluate the Safety, 
Tolerability and Pharmacokinetics of Multiple 1200 mg Dose Intravenous Oritavancin Infusions 
in Healthy Subjects.  January 2017. 
Report MDCO-ORI-16-02:  A double-blind, randomized study to evaluate the safety of either a 
single 1200 mg intravenous (iv) dose of ORBACTIV® (oritavancin) and placebo or two iv doses 
of ORBACTIV® in subjects being treated for acute bacterial skin and skin structure infection.  
September 2017. 
The Medicines Company Internal Report SR15-30, 2015. 

SAP_000.pdf: 
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Statistical Analysis Plan 
 
Initial U.S. Approval: 2014 
ORBACTIV® (oritavancin) 
A Randomized, Open-label, Pharmacokinetics and Safety Study to Evaluate 
the Relative Exposure and Safety of a New Formulation Versus the Approved 
Formulation of a Single 1200 mg Intravenous (IV) Dose of ORBACTIV® 
(oritavancin) in Subjects Being Treated for Acute Bacterial Skin and Skin 
Structure Infection (ABSSSI) 
Protocol Number.:  ML-ORI-102 
U.S. IND Number: 51,292 
EudraCT Number.: Not Applicable 
  
  
 
 
 
 
 
Development Phase: 
Phase I 
 
 
Sponsor: 
Melinta Therapeutics, Inc.  
300 Tri-State International 
Suite 272 
Lincolnshire, IL  60069 
 
 
 
Statistician: 
Junming Zhu 
Edetek, Inc 
 
 
Version 2.0 
October 7, 2019 
 
This document is a confidential communication from Melinta Therapeutics. Acceptance of this document constitutes 
an agreement by the recipient(s) that no information contained herein will be published or disclosed without prior 
written approval from Melinta, except that this document may be disclosed to appropriate Institutional Review 
Boards or Independent Ethics Committees under the condition that they are also required to maintain confidentiality. 




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2. 
TABLE OF CONTENTS 
1. SIGNATURE PAGE .................................................................................................................2 
2. TABLE OF CONTENTS ...........................................................................................................3 
3. LIST OF TABLES .....................................................................................................................4 
4. LIST OF ABBREVIATIONS ....................................................................................................5 
5. INTRODUCTION .....................................................................................................................7 
6. STUDY OBJECTIVES AND ENDPOINTS .............................................................................8 
6.1. Primary Objective .............................................................................................................8 
6.2. Secondary Objective .........................................................................................................8 
6.3. Exploratory Objectives .....................................................................................................8 
6.4. Primary Endpoint(s) ..........................................................................................................8 
6.5. Secondary Endpoint(s) ......................................................................................................8 
6.6. Exploratory Endpoint(s)....................................................................................................8 
7. STUDY DESIGN.......................................................................................................................9 
8. STATISTICAL PLAN .............................................................................................................13 
8.1. Sample Size Determination.............................................................................................13 
8.2. Randomization ................................................................................................................13 
8.3. Analysis Population ........................................................................................................13 
8.3.1. Intent-to-Treat (ITT) Population .........................................................................13 
8.3.2. Pharmacokinetics (PK) Population .....................................................................13 
8.3.3. Safety Population ................................................................................................13 
8.4. General Statistical Considerations and Definitions ........................................................14 
8.4.1. Software ..............................................................................................................14 
8.4.2. General Statistical Methods ................................................................................14 
8.4.3. Analysis Windows and Baseline .........................................................................14 
8.4.4. Missing Data Handling .......................................................................................14 
8.5. Statistical Analyses .........................................................................................................15 
8.5.1. Subject Disposition .............................................................................................15 
8.5.2. Demographic and Baseline Characteristics ........................................................15 
8.5.3. Prior and Concomitant Medications ...................................................................15 
8.5.4. Study Drug Exposure ..........................................................................................16 
8.5.5. Safety Analysis ...................................................................................................16 


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 Adverse Events ....................................................................................16 
 Laboratory Tests ..................................................................................17 
 Chemistry and Hematology Laboratory Parameters, ...........................17 
 Analysis of Coombs Test .....................................................................19 
 Vital Signs ............................................................................................19 
8.5.6. Pharmacokinetic Parameters ...............................................................................19 
8.5.7. Subgroup Analysis ..............................................................................................20 
8.5.8. Interim Analysis ..................................................................................................20 
9. REFERENCES ........................................................................................................................21 
10. PLANNED TABLES, LISTINGS, AND FIGURES ...............................................................22 
 
3. 
LIST OF TABLES 
Table 1: 
Schedule of Events/Assessments ................................................................................10 
Table 2: 
PK Blood Draw Schedule ...........................................................................................12 
Table 3: 
Criteria for Potentially Clinically Significant Abnormal Lab Tests ...........................18 
Table 4: 
Criteria for Potentially Clinically Significant Vital Signs Values ..............................19 
Table 5: 
Planned Tables ............................................................................................................22 
Table 6: 
Planned Listings ..........................................................................................................23 
Table 7: 
Planned Figures ..........................................................................................................24 


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4. 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ABSSSI 
Acute Bacterial Skin and Skin Structure Infection 
AE 
adverse event 
AESI 
Adverse Event of Special Interest 
AUC 
Area under the curve of plasma concentrations 
BE 
Bioequivalence 
CE 
Clinical Evaluable 
CI 
confidence interval 
CL 
clearance 
Cmax 
maximal plasma concentrations 
CV 
coefficient of variation 
D5W 
dextrose 5% in water 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLM 
General Linear Model 
HPβCD 
Hydroxypropyl-β-cyclodextrin  
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IV 
intravenous 
h 
hour 
kg 
kilograms(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
MIC 
minimum inhibitory concentration 
mg 
milligram(s) 
mL 
milliliter(s) 
mm 
millimeter(s) 


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min 
minute(s) 
NOAEL 
no-observed-adverse-effect level 
PK 
pharmacokinetic 
PCS 
potentially clinically significant 
s 
second(s) 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOP 
standard operating procedures 
SWFI 
sterile water for injection 
t ½ 
half-life 
TEAE 
treatment emergent AE 
ULN 
upper limit of normal 
Vss 
volume of distribution at steady state 
WHO 
World Health Organization 
y 
year 


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5. 
INTRODUCTION 
The statistical analysis plan (SAP) describes the statistical analysis methods and the planned 
deliverables for the ML-ORI-102 study. This protocol is a randomized, open-label, multi-center, 
study evaluating the pharmacokinetics (PK) and safety of a new formulation versus the approved 
oritavancin formulation in adult subjects with acute bacterial skin and skin structure infections 
(ABSSSI). The new formulation adjusts the infusion time, concentration and 
reconstitution/administration solutions of a single 1200 mg intravenous (IV) infusion of 
oritavancin. 


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Primary Objective 
The primary objective is to determine the relative AUC exposure of the new formulation of 
oritavancin compared to the currently approved formulation based on area under the plasma 
concentration-time curve (AUC) after a single 1200 mg IV infusion of oritavancin in male and 
female subjects with ABSSSI. 
6.2. 
Secondary Objective 
The secondary objective is to evaluate the safety and tolerability of the new formulation of 
oritavancin by the incidence of adverse events (AEs) and serious adverse events (SAEs), clinical 
laboratory abnormalities, including the results of Direct and Indirect Coombs test and oritavancin 
antibody assay as applicable, and by vital signs. 
Safety and tolerability assessments will be evaluated through Day 15 following the oritavancin 
infusion. 
6.3. 
Exploratory Objectives 
An exploratory objective is the evaluation of pharmacokinetic parameters (including, but not 
limited to: Cmax, time of observed Cmax (Tmax), AUC, and, where they can be calculated, 
elimination half-life [t½], volume of distribution at steady state [Vss], and CL) after a single 
1200 mg IV infusion of oritavancin in male and female subjects with ABSSSI. 
Correspondingly the study endpoints are defined below. 
6.4. 
Primary Endpoint(s) 
The primary endpoint of this trial is: 
Relative AUC exposure of the new formulation of oritavancin to the approved formulation of 
oritavancin based on areas under the plasma concentration-time curve from time zero to 72 hr 
(AUC0-72) and time zero to 168 hr (AUC0-168). 
6.5. 
Secondary Endpoint(s) 
The secondary endpoints of this trial are: 
Safety and tolerability of the new formulation of oritavancin assessed according to AEs and 
SAEs, clinical laboratory parameters (including Direct and Indirect Coombs development and 
oritavancin antibody assay as applicable), and vital signs, through Day 15 following completion 
of study drug infusion. 
6.6. 
Exploratory Endpoint(s) 
The exploratory endpoints of this trial are: 
An evaluation of pharmacokinetic parameters (including, but not limited to: Cmax, Tmax, AUC, 
and, where they can be calculated, elimination half-life [t½], Vss, and CL) after a single 1200 mg 
IV infusion of oritavancin in male and female subjects with ABSSSI. 


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7. 
STUDY DESIGN 
This study will be a randomized, open-label, multi-center, study evaluating the PK and safety of 
the new formulation compared to the currently-approved formulation of oritavancin.  
Approximately 100 subjects at about 5 centers will be randomized in a 1:1 ratio to the currently 
approved formulation of oritavancin versus the new formulation. Fifty (50) subjects will be 
administered the currently approved formulation of oritavancin, using the approved dosing 
regimen in which SWFI is used for reconstitution and D5W is used for further dilution to a final 
volume of 1000 mL. This formulation will be infused over 3 hours per the approved label. An 
additional fifty (50) subjects will be administered the new formulation of oritavancin. This 
formulation will also be reconstituted with SWFI and further diluted in 0.9% sodium chloride to 
a final volume of 250 mL. This formulation will be infused over 60 minutes. 
Informed consent will be obtained from subjects before the initiation of any study-specific 
procedures. Subjects will be screened up to 48 hours prior to the initiation of study drug. 
Subjects will receive their dose of oritavancin on Day 1 and will be asked to return to the study 
center on Day 2, Day 4, Day 8 and Day 15 for collection of additional blood samples and 
procedure assessments. The subject’s participation is approximately 17 days. 
Safety of the new formulation of oritavancin will be assessed according to AEs and SAEs, 
clinical laboratory parameters (including Direct and Indirect Coombs development and 
oritavancin antibody assay as applicable), and vital signs. 
This is an unblinded, open label study. The primary endpoint is based on a pharmacokinetic 
assessment, a measurement that is not subject to interpretation bias. 
The schedule of study assessments is provided in Table 1, and PK sampling time points are 
provided in Table 2. 


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Table 1: 
Schedule of Events/Assessments 
1. Vital signs include blood pressure, temperature, respiratory rate and heart rate. 
2. At Screening and Day 15, perform a local urine pregnancy test for female subjects of childbearing potential (may be omitted for females > 2 years postmenopausal or surgically 
sterile). A urine pregnancy test will be performed again on Day 1 for female subjects of childbearing potential if the screening pregnancy test was performed > 24 hours prior to 
dosing. 
3. Unless otherwise indicated, all chemistry and hematology laboratory tests will be performed by the site’s local laboratory. 
Study Procedures 
Screening 
Day 1 
Follow-up Visit 
Unscheduled 
 
≤ 48 hrs 
prior to 
Day 1 
Pre-
Dose 
Dosing 
Post-Dose 
(1 hr or 
3 hrs) 
Day 2 
(24 hrs) 
Day 4 
(72 hrs) 
Day 8 
(168 hrs) 
Day 159 
(336 hrs) 
Unscheduled 
Visit 
Informed consent 
X 
 
 
 
 
 
 
 
 
Assess inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
Medical history, including 
microbiology results if available 
X 
 
 
 
 
 
 
 
 
Randomize subject 
 
X 
 
 
 
 
 
 
 
Physical exam including height 
& weight 
X 
 
 
 
 
 
 
 
X 
Vital signs1 
X 
X 
 
X 
 
 
X 
 
X 
Urine pregnancy test2 
X 
X 
 
 
 
 
 
X 
X 
Chemistry and hematology 
laboratory assessments3 
X 
 
 
 
 
 
X 
X 
X 
Record prior or concomitant 
medications and surgical 
procedures 
X 
X 
 
X 
X 
X 
X 
X 
X 
Administer IV oritavancin4 
 
 
X 
 
 
 
 
 
 
Direct & Indirect Coombs Test5 
 
X 
 
 
 
 
X 
X 
X 
Collect serum for oritavancin 
antibody assay6 
 
X 
 
 
 
 
X 
X 
X 
Collect plasma for PK7 
 
X 
 
X 
X 
X 
X 
 
X 
Assessment of adverse events8 
 
 
X 
X 
X 
X 
X 
X 
X 


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4. Start time of study drug infusion is Hour 0 (study drug will be administered over 1 hour or 3 hours) 
5. Direct and Indirect Coombs testing will be done at the local laboratory. Samples will be collected at Day 1 (pre-dose), Day 8 and Day 15. If a subject has a change in Direct or 
Indirect Coombs results at Day 8, subjects may be asked to return for subsequent labs in order to investigate this change. Subjects with a positive Direct or Indirect Coombs test 
at the Day 15 visit must have the test repeated every 2 weeks until it returns to baseline or stabilizes. 
6. Serum samples will be stored and tested for oritavancin antibody only if the subject(s) experience unexpected adverse events that may be associated with antibody production. 
7. Time points for PK sample collection are Day 1 pre-dose and at the end of infusion (1 hour or 3 hours), and then at 3 hours (for 1 hour infusions), 6 hours, 12 hours, 24 hours, 
72 hours, and 168 hours after the start of the infusion. See Table 2 for windows for PK draws and visits. 
8. Adverse events and serious adverse events will be assessed from the time of study drug administration through Day 15 post administration of oritavancin. 
9. The Day 15 visit may be performed within a ± 3 day window. If the subject is required to terminate the study early, the subject must complete the Day 15 assessments at the 
time of the Early Termination Visit. 


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Table 2: 
PK Blood Draw Schedule 
PK Blood Draw Schedule 
Optimal Sample Time from 
START of infusion 
Sample Time Window 
Lower Limit 
Upper Limit 
Pre-Dose 
(-30 minutes) 
Any time prior to 
dose administration 
Any time prior to 
dose administration 
1 hour (end of infusion) 
New Formulation Arm Only 
End of Infusion 
End of Infusion + 5 min 
3 hours  
New Formulation Arm Only 
2 hrs 50 min 
3 hrs 10 min 
3 hours (end of infusion) 
Current Formulation Arm Only 
End of Infusion 
End of Infusion + 5 min 
6 hours 
5 hrs 45 min 
6 hrs 15 min 
12 hours 
10 hrs 
14 hrs 
24 hours (Day 2) 
20 hrs 
28 hrs 
72 hours (Day 4) 
60 hrs 
84 hrs 
168 hours (Day 8) 
Day 7 
Day 9 
 


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8. 
STATISTICAL PLAN 
8.1. 
Sample Size Determination 
Using combined results from selected Phase 1 studies on oritavancin pharmacokinetics with the 
approved formulation, the observed CV of AUC0-72 and AUC0-168 were 25.4% and 26.3%, 
respectively. Using a slightly larger CV value of 30% to be conservative, the table below shows 
estimated power values in a parallel study design to demonstrate equivalence of AUC of the new 
formulation (test, T) relative to the approved formulation (reference, R), assuming various true 
T/R ratios of geometric means of AUC0-72 and AUC0-168. The table uses a sample size of 
100 subjects randomized in 1:1 ratio to the test and reference groups and uses the standard 80% 
to 125% equivalence limits. A study design of 50 subjects in each of the test and reference 
groups should have ≥ ~90% power to demonstrate AUC equivalence, if the true T/R ratios are 
within 0.95 to 1.05. 
True T/R Ratio 
Power 
0.95 
89.5% 
1.0 
96.7% 
1.05 
90.2% 
8.2. 
Randomization 
With a sample size of approximately 100, subjects will be randomized in 1:1 ratio in a parallel 
fashion to the test (new formulation) and reference (approved formulation) groups. 
8.3. 
Analysis Population 
8.3.1. 
Intent-to-Treat (ITT) Population 
All subjects randomized will be analyzed according to the treatment arm to which they were 
randomized. Subject disposition, demographic, and baseline characteristics will be summarized 
by treatment using the ITT population 
8.3.2. 
Pharmacokinetics (PK) Population 
All subjects who have received the full dose of oritavancin and have one valid sample measured 
for study drug levels. The PK population will be the primary population for the PK analysis. 
8.3.3. 
Safety Population 
All subjects who have received any amount of IV oritavancin will be included in the safety 
population. Treatment group will use it as actually received. The safety population will be the 
primary population for all the safety analyses. 


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8.4. 
General Statistical Considerations and Definitions 
8.4.1. 
Software   
All data listings, summaries and statistical analyses will be generated using SAS® Version 9.4 or 
above, or equivalent statistical software. PK analysis (including the calculation of PK parameters 
such as AUC, Cmax, T1/2, etc.) will use WinNonlin or relevant software, and will be performed by 
PK vendor. 
8.4.2. 
General Statistical Methods 
All study-collected data will be summarized by treatment group using descriptive statistics, 
graphs, and/or raw data listings. Unless otherwise specified, descriptive statistics for continuous 
variables will include number of subjects (n), mean, standard deviation (SD), median, quartiles 
(Q1 and Q3), minimum (min) and maximum (max) values. Analysis of categorical variables will 
include frequency and percentage. For the summary by visit analysis, graphic display using box-
whisker or mean +/- standard error plot will be generated. 
8.4.3. 
Analysis Windows and Baseline 
All data collected in the study will be included in the analysis. Unless otherwise specified, the 
last evaluation prior to the initiation of study drug will be considered the "Baseline" evaluation 
for analysis. For microbiologic assessments, any pathogen identified from within 72 hours prior 
to screening up to and including Day 2 will be considered as baseline. 
8.4.4. 
Missing Data Handling 
Unless otherwise specified, missing data will not be imputed and will be excluded from the 
associated analysis. 
Partial dates:  Dates missing the day of the month, or both the day and month of the year will 
adhere to the following conventions:   
• The missing day of onset of an adverse event or start date of a concomitant medications 
will conservatively be set to the earlier of: 
 first day of the month that the event occurred, as long as it is after the date of the start 
of first treatment 
 one day after the first dose, if this is the same month that the event occurred 
• The missing day of resolution of an adverse event or end date of a concomitant 
medications will be set to the last day of the month of the occurrence.  
• If the onset date of an adverse event or start date of a concurrent therapy is missing both 
the day and month, the onset date will be set to the earliest of: 
 January 1 of the year of onset, as long as it is after the first dose 
 one day after the first treatment, if this is the same year that the event occurred 


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• If the resolution date of an adverse event or end date of a concomitant medications is 
missing both the day and month, the date will be set to: 
 December 31 of the year of occurrence, if the patient is continuing treatment 
 The date of patient discontinuation, if the event is not ongoing 
8.5. 
Statistical Analyses  
8.5.1. 
Subject Disposition 
A disposition table will summarize the number of patients screened, randomized, treated, 
discontinued from study treatment and reasons for discontinuation from study and study drug by 
treatment groups. The table will define the ITT, PK, and Safety Populations. Indicator variables 
(Yes/No) will be presented in listings to identify the population flag. The reason for 
discontinuation from study and study drug will be summarized using the categories specified in 
the case report form (CRF), by treatment group. 
8.5.2. 
Demographic and Baseline Characteristics 
Subject demographics and baseline characteristics will be summarized by treatment groups using 
the ITT population. Unless the PK, and Safety population is significantly different from the ITT 
population (> 5% in total number of patients), the demographic and baseline characteristics table 
will not be duplicated. 
Demographic and baseline variables will include: 
• Age  
• Sex 
• Race 
• Ethnicity 
• Height  
• Weight  
• BMI 
• ABSSSI Disease Status 
Baseline pathogens and medical/surgical history will also be summarized. 
8.5.3. 
Prior and Concomitant Medications 
Summary of each prior medication, and concomitant medication will be provided by treatment 
group separately for the safety population. Medication will be coded with World Health 
Organization Drug Dictionary Enhanced (WHODrug March 1, 2019)2 and summarized using 
ATC Level 4 and generic drug names. Subjects will be counted only once within each period by 
medication. 


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8.5.4. 
Study Drug Exposure 
Extent of exposure including dose amount and duration of treatment (minutes) will be 
summarized for the Safety population. The number and percentage of subjects who completed 
treatment, and who experienced dose interruptions and discontinuations will be summarized for 
the Safety population. 
All study drug administration data will be presented in a listing. 
8.5.5. 
Safety Analysis 
Safety will be assessed according to adverse clinical events, clinical laboratory evaluations 
(including Coombs anti-globulin tests and oritavancin antibody assay, as applicable), and vital 
signs. For each safety parameter, the last assessment made prior to the first dose of study drug 
will be used as the baseline value for all analyses. 
 
Adverse Events 
The MedDRA Version 22.03 or later will be used for coding AEs. Adverse events (AEs) will be 
graded using the 5-point Common Terminology Criteria for Adverse Events (CTCAE) criteria 
(Version 5)1. An AE (classified by preferred term) occurring from the start of study drug will be 
counted as treatment emergent AE (TEAE) either if it was not present at baseline or if it was 
present at baseline but increased in severity during the period of observation.  
An overall summary of subjects reporting a TEAE in each treatment group will be provided for 
the Safety population. This analysis will include: the number and percentage of subjects 
reporting any TEAE, any TEAE presented by maximum severity, any TEAE related to study 
drug, any SAE, any SAE related to study drug, any SAE leading to premature discontinuation of 
study drug, any SAE with an outcome of death, any TEAE leading to study discontinuation, any 
TEAE leading to study drug discontinuation or interruption, and any TEAE of special interest 
will be summarized for the Safety population. 
The number and (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. A summary of TEAEs occurring in ≥ 5% (or >=2 subjects) of 
either formulation group (based on MedDRA preferred term) sorted by decreasing frequency in 
the new formulation arm will also be provided. Likewise, the number and percentage of subjects 
reporting a serious TEAE and reporting a study-drug related SAE in each treatment group will be 
tabulated separately by system organ class and preferred term. Likewise, summaries of TEAEs 
leading to study discontinuation or study drug discontinuation or interruption will also be 
provided by system organ class and preferred term. For all analyses of TEAEs if the same event 
(based on preferred term) occurred for the same subject more than once, 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. 
A listing of all serious TEAEs will be provided and will include subject ID, study day(s) of 
event, duration of study drug administered prior to onset (minutes), system organ class, preferred 
term, verbatim term, severity, relationship to study drug, action taken with study drug, and 
outcome. 


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A listing of all TEAEs leading to study discontinuation, and all TEAEs leading to study drug 
discontinuation or interruption and will include subject ID, study day(s) of event, duration of 
study drug administered prior to onset (minutes), system organ class, preferred term, verbatim 
term, severity, relationship to study drug, action taken with study drug, and outcome. 
 
Laboratory Tests 
Laboratory values presented will include: serum chemistry, hematology, direct/indirect Coombs 
test, and oritavancin antibody assay. Descriptive statistics (number of subjects with a reported 
value, mean, SD, median, minimum, and maximum) will be presented for quantitative laboratory 
parameters. Laboratory data will be summarized by visit using descriptive statistics (including 
absolute values and change from baseline). For qualitative laboratory parameters, tables will 
display the number of subjects with a reported value and percentage in each category. Laboratory 
results will be classified as low (L), normal (N), or high (H) according to the laboratory-supplied 
reference ranges from the local laboratories. 
There will be separate data listings for each category of laboratory test results. Subjects with 
values above or below the reference range, regardless of clinical significance, will be identified 
in the data listings with flags for high and low values. Potentially clinically significant (PCS) 
values will be flagged in the listings of chemistry and hematology data. 
 
Chemistry and Hematology Laboratory Parameters,  
Laboratory values descriptive statistics will be summarized by treatment group, including 
absolute value and changes from baseline at each scheduled time point. Graphic display of 
change over time using box-whisker plot or mean +/- standard error by visit will be generated. A 
shift table from baseline to overall worst post-baseline (which will include values from 
unscheduled post-baseline visits) by category (low, normal, high) will be generated. Subjects 
with missing data for a given visit will not contribute to the summary statistics for that visit. 
Tables showing shift from baseline will also be presented. 
Analyses will also be performed for each lab parameter by treatment group for incidence rates of 
PCS values abnormalities for subjects without a PCS value at baseline. PCS values are defined in 
Table 3. Listings of subjects with treatment-emergent PCS (Grade 3 and 4) post-baseline 
laboratory abnormalities will be provided. 


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Table 3: 
Criteria for Potentially 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 × 109/L 
 
Neutrophil Count 
< 1.0 × 109/L 
 
Lymphocyte count  
< 0.5 × 109/L  
 
Hematocrit 
≤ 0.75 × LLN 
≥ 1.25 × 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 × 109/L 
≥ 700 × 109/L 
Absolute Reticulocyte Count1 
 
> ULN 
Serum Chemistry 
 
 
BUN 
 
≥ 10.7 mmol/L 
Calcium 
≤ 7.0 mg/dL 
≥ 15.5 mg/dL 
CPK 
 
≥ 3 × ULN 
Creatinine 
 
≥ 2.0 mg/dL 
Glucose  
≤ 50 mg/dL 
≥ 180 mg/dL  
Haptoglobin 
< LLN or decrease of 50% from Baseline 
Potassium 
≤ 3.0 mmol/L 
≥ 5.5 mmol/L 
Sodium 
≤ 125 mmol/L 
≥ 150 mmol/L 
Liver Function Tests (LFTs): 
 
Alanine Transaminase (ALT/SGPT)  
≥ 3×, 5×, 10× and 20× ULN 
Aspartate Transaminase (AST/SGOT)  
≥ 3×, 5×, 10× and 20× ULN 
ALT or AST  
≥ 3×, 5×, 10×, or 20× ULN 
Total bilirubin  
≥ 1.5× and 2× ULN 
Alkaline Phosphatase (ALP)  
≥ 1.5× and 3× ULN 
ALT/AST ≥ 3 × ULN and Total bilirubin ≥ 2 × ULN 
 
Potential Hy’s Law cases:  
ALT or AST ≥ 3 × ULN, Total bilirubin ≥ 2 × ULN, and 
ALP ≤ 2 × ULN 
1. If reticulocytes are reported in % by local laboratory, these results will be converted to absolute count in the 
unit of 1000/mcl for this analysis. 


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 Analysis of Coombs Test  
Coombs Test (Indirect and Direct) results (positive or negative) will be summarized by treatment 
group, including changes from baseline (negative to positive) at each scheduled time point. A 
shift table from baseline to worst change (negative to positive) post-baseline will be generated. 
Subjects with missing data for a given visit will not contribute to the summary statistics for that 
visit.  
 
Vital Signs 
Systolic and Diastolic blood pressure (mmHg), heart rate (beats/minute, bpm), respiratory rate 
(breaths/minute, rpm), and temperature (°F) will be collected at Screening/Baseline, Day 1 (post-
dose), Day 2, Day 4, and Day 8 and Day 15. Body height and weight will be collected at 
Screening/Baseline only. 
Vital sign measurements and changes from baseline will be summarized descriptively at each 
scheduled timepoint and overall worst post-baseline (maximum and/or minimum) by treatment 
group. The number and percentage of subjects with treatment-emergent PCS changes will also be 
summarized by treatment group at each scheduled time point and overall worst post-baseline 
(which will include values from unscheduled post-baseline visits). 
A treatment-emergent PCS vital sign is defined as: Baseline value is within the normal range and 
the post-Baseline value is PCS. Table 4 provides definitions for PCS vital sign values. For each 
treatment-emergent PCS vital sign, if criteria in both directions (low and high) are shown for a 
single parameter, then abnormalities in each direction will be summarized separately. 
Table 4: 
Criteria for Potentially Clinically Significant Vital Signs Values 
Vital Sign 
Direction Criterion 
Systolic blood pressure 
Low 
Value ≤ 90 mmHg and decreased ≥ 20 mmHg from Baseline value 
 
High 
Value ≥ 180 mmHg and increased ≥ 20 mmHg from Baseline value 
Diastolic blood pressure 
Low 
Value ≤ 50 mmHg and decreased ≥ 15 mmHg from Baseline value 
 
High 
Value ≥ 105 mmHg and increased ≥ 15 mmHg from Baseline value 
Heart Rate 
Low 
Value ≤ 45 bpm and decreased ≥ 10 bpm from Baseline value 
 
High 
Value ≥ 120 bpm and increased ≥ 15 bpm from Baseline value 
Respiratory Rate 
Low 
Decreased ≥ 6 rpm from Baseline value 
 
High 
Increased ≥ 6 rpm from Baseline value 
All vital sign data collected during the study will be presented in a listing including an indication 
of whether each value is PCS. 
8.5.6. 
Pharmacokinetic Parameters 
All the pharmacokinetic analyses including the calculation of PK parameters and comparison 
between the two formulations, will be performed by the Melinta designated vendors. This section 
will just show what PK analysis will be included, all the TFLs related to PK will be provided by 
a separate report from the vendor. 


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Oritavancin plasma (blood) concentration versus time data will be analyzed using 
noncompartmental pharmacokinetic analysis. The following pharmacokinetic parameters will be 
estimated where possible (additional parameters may be calculated): 
• Area under the plasma concentration-time curve (AUC) from time zero to 72 hr 
(AUC0-72), time zero to 168 hr (AUC0-168), time zero to the time of the last measurable 
concentration (AUC0-last) and, where possible, AUC from time zero to infinity (AUC0-inf) 
• Maximum observed measured plasma concentration (Cmax) 
• Time of observed Cmax (Tmax) 
• Elimination half- life (t½) 
• Total body clearance (CL) 
• Volume of distribution at steady state (Vss) 
All concentration data will be presented descriptively for each formulation at each time point. 
All pharmacokinetic parameters will be summarized by formulation for the PK population. 
Descriptive statistics comprise N, mean, geometric mean, SD, SEM, median, %CV, minimum 
and maximum. 
A general linear model (GLM) will be used to evaluate the relative AUC exposure of the new 
formulation (test) relative to the approved formulation (reference) based on a two-group parallel 
design. The primary PK parameters (AUC0-72 and AUC0-168) will be natural-logarithmically 
transformed and used as the dependent variable. The independent variable includes formulation. 
For each PK parameter, the estimate of the treatment difference (test minus reference) and the 
upper/lower bound of its 90% confidence interval (CI) will be obtained from the general linear 
model, and then exponentiated to obtain the ratio of the geometric means and its 90% CI in the 
original scale. 
Bioequivalence can be demonstrated if the 90% CI in the original scale is within the range of 
80% to 125%. 
8.5.7. 
Subgroup Analysis 
No subgroup analysis is planned. 
8.5.8. 
Interim Analysis 
No interim analysis is planned. 


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9. 
REFERENCES 
1. Common Terminology Criteria for Adverse Events (CTCAE) v5.0. 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick
_Reference_5x7.pdf 
2. WHODrug, March 1, 2019 
https://www.who-umc.org/whodrug/whodrug-portfolio/whodrug-global/ 
3. MEDDRA Version 22.0 
https://www.meddra.org/news-and-events/news/english-meddra-version-220-available-
download 


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10. 
PLANNED TABLES, LISTINGS, AND FIGURES 
Table 5: 
Planned Tables  
Table Number 
Table Title 
Table 14.1.1 
Subject Disposition and Analysis (ITT Population) 
Table 14.1.2 
Significant Protocol Deviations (ITT Population) 
Table 14.1.3.1  
Demographic and Baseline Characteristics (ITT Population) 
Table 14.1.3.2 
Baseline Pathogens (ITT Population) 
Table 14.1.3.3 
Medical and Surgical History by MedDRA SOC and Preferred Term (ITT 
Population) 
CSR Section 14.1.4 
Prior Medications (ITT Population) 
CSR Section 14.1.5 
Concomitant Medications (ITT Population) 
CSR Section 14.3.1 
Dose Administration and Extent of Exposure (Safety Population) 
CSR Section 14.3.2.1 
Summary of Treatment Emergent Adverse Events (Safety Population) 
CSR Section 14.3.2.2 
Treatment Emergent Adverse Events by SOC and Preferred Term (Safety 
Population) 
CSR Section 14.3.2.3 
Treatment Emergent AEs by Preferred Term with Frequency > 5% (Safety 
Population) 
CSR Section 14.3.2.4 
Treatment Emergent Adverse Events by Severity, SOC and Preferred Term 
(Safety Population) 
CSR Section 14.3.2.5 
Treatment Emergent Adverse Events by Relationship to Study Drug, SOC 
and Preferred Term (Safety Population) 
CSR Section 14.3.2.6 
Treatment Emergent Serious Adverse Events by SOC and Preferred Term 
(Safety Population) 
CSR Section 14.3.2.7 
Study Drug Related Serious Adverse Events by SOC and Preferred Term 
(Safety Population) 
CSR Section 14.3.2.8.1 
Listing of All Serious Treatment Emergent Adverse Events 
CSR Section 14.3.2.8.2 
Listing of Treatment Emergent Adverse Events Leading to Study Drug 
Discontinuation (Safety Population) 
CSR Section 14.3.2.8.3 
Listing of Treatment Emergent Adverse Events Resulting in Interruption of 
Study Drug (Safety Population) 
CSR Section 14.3.2.9 
Adverse Events of Special Interest (Safety Population) 
CSR Section 14.3.3.1 
Descriptive Statistics for Chemistry Local Laboratory Parameters and 
Change from Baseline (Safety Population) 
CSR Section 14.3.3.2 
Descriptive Statistics for Hematology Local Laboratory Parameters and 
Change from Baseline (Safety Population) 
CSR Section 14.3.3.3 
Shift Table on Lab Abnormalities for Clinical Chemistry Local Laboratory 
Parameters from Baseline to Worst Post-baseline 


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Table Number 
Table Title 
CSR Section 14.3.3.4 
Shift Table on Lab Abnormalities for Clinical Hematology Local 
Laboratory Parameters from Baseline to Worst Post-baseline 
CSR Section 14.3.3.5 
Incidence of PCS Graded Abnormalities for Chemistry Local Laboratory 
Parameters (Safety Population) 
CSR Section 14.3.3.6 
Incidence of PCS Graded Abnormalities for Hematology Local Laboratory 
Parameters (Safety Population) 
CSR Section 14.3.3.7 
Listing of Subjects with Treatment-Emergent PCS Local Laboratory 
Chemistry Abnormalities (Safety Population) 
CSR Section 14.3.3.8 
Listing of Subjects with Treatment-Emergent PCS Local Laboratory 
Hematology Abnormalities (Safety Population) 
CSR Section 14.3.4.1 
Summary of Direct and Indirect Coombs Anti-globulin Local Laboratory 
Tests (Safety Population) 
CSR Section 14.3.4.2 
Shift Table of Direct and Indirect Coombs Anti-globulin Local Laboratory 
Tests from Baseline to Post-baseline (Safety Population) 
CSR Section 14.3.5.1 
Incidence of Treatment-Emergent PCS Vital Signs (Safety Population) 
CSR Section 14.3.5.2 
Vital Signs and Changes from Baseline by Visit (Safety Population) 
 
Table 6: 
Planned Listings 
Listing Number 
Listing Title 
Listing 16.2.1.1 
Subject Disposition 
Listing 16.2.1.2 
Screen Failures (Eligibility Criteria Not Met)  
Listing 16.2.1.3 
Subject Inclusion for Analysis Sets and Reasons for Exclusion 
Listing 16.2.2 
Significant Protocol Deviations 
Listing 16.2.3.1 
Demographic and Baseline Characteristics 
Listing 16.2.3.2 
Microbiological Assessments 
Listing 16.2.3.3 
Prior and Concomitant Medications 
Listing 16.2.3.4 
Concomitant Surgical Procedures  
Listing 16.2.3.5 
Medical and Surgical History 
Listing 16.2.4 
Study Drug Administration 
Listing 16.2.5.1 
Plasma Oritavancin Concentration by Time Points 
Listing 16.2.5.2 
PK Parameters by Subject 
Listing 16.2.6.1 
Adverse Events by Subject 
Listing 16.2.6.2 
AE of Special Interest by Subject 
Listing 16.2.7.1 
Local Laboratory Results: Hematology  


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Listing Number 
Listing Title 
Listing 16.2.7.2 
Local Laboratory Results: Chemistry  
Listing 16.2.7.3 
Local Laboratory Results: Direct/Indirect Coombs Anti-globulin Test 
Listing 16.2.8 
Vital Signs 
 
Table 7: 
Planned Figures 
Figure Number 
Figure Title 
CSR Section Figure 14.3.1 
Clinical Chemistry Lab Mean +/- Standard Error Plot by Visit and Lab 
Parameters 
CSR Section Figure 14.3.2 
Clinical Hematology Lab Mean +/- Standard Error Plot by Visit and Lab 
Parameters 
CSR Section Figure 14.3.3 
Vital Signs Mean +/- Standard Error Plot by Visit and Parameters