Conditions: Gram-Positive Bacterial Infections
Keywords: Gram positive bacteria Telavancin VIBATIV Pediatric Pharmacokinetics
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 22
Healthy volunteers: no

Brief summary:
This is a multicenter, open-label, single-dose pharmacokinetic (PK) study. Infants, children, and adolescents will receive a single 10 mg/kg dose of telavancin infused intravenously (IV) over 60 minutes

Detailed description:
This is a multicenter, open-label, single-dose pharmacokinetic (PK) study. Infants, children, and adolescents will receive a single 10 mg/kg dose of telavancin infused intravenously (IV) over 60 minutes in male or female infants, children, and adolescents (\> 12 months to 17 years, inclusive) who require systemic antibiotic therapy for the treatment or prevention of a known or suspected bacterial infection.

Blood samples for PK assessment will be taken as follows: 1.0 hour (±5 min), 1.5 hours (±5 min), 2 hours (±5 min), 6 hours (±30 min), 12 hours (±30 min) and 24 hours (±30 minutes) after the beginning of the infusion. The timing of PK sampling may be optimized after the completion of the older age groups (Cohorts 1-3) to assure that the minimum numbers of samples are collected in the youngest age group \> 12months to \< 24 months. Plasma exposures that will be compared to adult exposures are the primary assessment for this study.

Subject safety will be monitored during the study using standard measures, including physical examinations, vital signs, 12-lead ECGs, clinical laboratory assessments, urinalysis, concomitant medication usage, and adverse event reporting.

Arms:
arm 1: Telavancin 10 mg/kg IV administered over approximately 60 minutes one time.

Interventions: intervention 1: Telavancin
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
Protocol 0101, Amendment 5                                                                                                26Aug2019 
Telavancin 
Page 1 
 
  
CLINICAL STUDY PROTOCOL 
Study Title: 
An Open-Label Study of the Pharmacokinetics of a Single 
Dose of Telavancin in Pediatric Subjects Aged 12 months to 
17 Years 
Study Short Title: 
Telavancin Pediatric PK Study (Ages > 12 months to 17 
Years) 
Sponsor Study No.: 
0101 
ClinicalTrials.gov No.: 
NCT02013141 
Date: 
26 August 2019, Amendment 5 
31 January 2019, Amendment 4  
20 September 2016, Amendment 3, Version 1.0  
25 August 2015, Amendment 2 
18 April 2014, Amendment 1 
04 December 2013, Original Protocol 
 
 
Test Product: 
Telavancin 
US IND: 
[REDACTED] 
Sponsor: 
Cumberland Pharmaceuticals Inc. 
2525 West End Avenue, Suite 950 
Nashville, TN 37203 USA 
 
 
 
 
 
 
 
This study will be conducted according to the principles of Good Clinical Practice. 
 


Protocol 0101, Amendment 5                                                                                                26Aug2019 
Telavancin 
Page 2 
 
 
PROTOCOL SYNOPSIS 
 
Study Number and Title:  Study 0101: An Open-Label Study of the Pharmacokinetics of a 
Single Dose of Telavancin in Pediatric Subjects Aged > 12 months to 17 Years 
Study Short Title:  Telavancin Pediatric PK Study (Ages > 12 months to 17 Years) 
Estimated Number of Study Centers and Countries or Regions:  At approximately 
10 sites in the United States (US) 
Background and Rationale:   
Telavancin is a rapidly bactericidal, injectable antibiotic with concentration-dependent 
activity against clinically important Gram-positive pathogens. Telavancin is approved in the 
US for treatment, in adults, of complicated skin and skin structure infections and 
hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) caused by 
susceptible isolates of Staphylococcus aureus. This study is designed to evaluate the 
single-dose pharmacokinetics (PK) of telavancin in pediatric subjects to support 
development of a dosing algorithm that will deliver exposures similar to those found to be 
safe and effective in adults. 
The most common adverse events, which occurred in ≥10% of telavancin-treated patients 
in Phase 3 studies of complicated skin and skin structure infections (cSSSI), were taste 
disturbance, nausea, headache, vomiting, foamy urine, and insomnia. In these studies, 
telavancin was compared in a blinded manner to vancomycin. Serious adverse events 
were reported in 7% of patients treated with telavancin, and the most common included 
renal, respiratory, and cardiac events. Treatment discontinuations due to adverse events 
occurred in 8% of patients treated with telavancin, the most common events being nausea 
and rash. The incidence of adverse events indicative of renal impairment (increased serum 
creatinine, renal insufficiency, and renal failure) was 3% of telavancin-treated patients, and 
serious adverse events indicative of renal impairment occurred in 1% of telavancin-treated 
patients.  
Telavancin has also been evaluated in two Phase 3 trials in adults for hospital-acquired 
bacterial pneumonia and ventilator-associated bacterial pneumonia, again in a blinded 
comparison with vancomycin. Serious adverse events were reported in 31% of patients 
treated with telavancin. Treatment discontinuations due to adverse events occurred in 8% 
of patients who received telavancin, with the most common events being acute renal failure 
and QTc interval prolongation. Treatment-emergent adverse events reported in 5% or more 
of telavancin-treated patients included nausea, vomiting, and acute renal failure. The 
incidence of adverse events indicative of renal impairment (acute renal failure and 
increased serum creatinine) was 10% of telavancin-treated patients, and serious adverse 
events indicative of renal impairment occurred in 2% of telavancin-treated patients.  
Telavancin has linear, predictable PK in the adult population. Mean plasma clearance after 
multiple dosing of 10 mg/kg every 24 hours in adults is 13.1 mL/hr/kg; the mean volume of 
distribution at steady state is 133 mL/kg, and the mean elimination half-life is 8.1 hours. 
Approximately 90% of telavancin is bound to plasma proteins, primarily albumin. 
Telavancin is predominantly eliminated renally, with approximately 60% of the dose 
excreted unchanged in urine over 48 hours. 
 


Protocol 0101, Amendment 5                                                                                                26Aug2019 
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PROTOCOL SYNOPSIS (CONTINUED) 
 
 
Objectives:   
Primary: 
• 
To characterize the pharmacokinetics of telavancin after a single dose in pediatric 
subjects (>12 months to 17 years inclusive) who require systemic antibiotic therapy for 
the treatment or prevention of a known or suspected bacterial infection 
Secondary: 
• 
To assess the safety and tolerability of telavancin after a single dose in pediatric 
subjects (> 12 months to 17 years inclusive) who require systemic antibiotic therapy for 
the treatment or prevention of a known or suspected bacterial infection 
Study Design:  This is a multicenter, open-label, single-dose pharmacokinetic (PK) study. 
Infants, children, and adolescents will receive a single dose of telavancin infused 
intravenously (IV) over approximately 60 minutes. 
Duration of Study Participation:  Up to 9 days 
Number of Subjects per Group: 
In total, approximately 30 male and female infants, children, and adolescents will be 
enrolled into the study, as follows: 
1. Adolescents (12 to 17 years), N = 8 
2. Older Children (6 to 11 years), N = 8 
3. Younger Children (2 to 5 years), N = 8 
4. Infants >12 and < 24 months, N = 6 
Cohorts 1, 2, 3 and 4 will be enrolled in parallel (simultaneously).  
Study Population: 
Male or female infants, children, and adolescents (> 12 months to 17 years, inclusive) who 
require systemic antibiotic therapy for the treatment or prevention of a known or suspected 
bacterial infection.  
Inclusion Criteria: 
Subjects who meet all of the following criteria will be eligible for study enrollment: 
1. Subject is > 12 months to 17 years of age (inclusive) 
2. Subject’s weight is within the 3rd to 97th percentile (inclusive) for age and sex. Refer to 
Appendix 1 through Appendix 4.  
3. Written informed consent and assent (if appropriate for older age groups) has been 
obtained per institutional review board (IRB) policy and requirements, consistent with 
ICH guidelines.  
4. Male and female subjects of reproductive potential (i.e., post-pubertal males and 
post-menarche females) must agree to use a highly effective method of contraception 


Protocol 0101, Amendment 5                                                                                                26Aug2019 
Telavancin 
Page 4 
 
PROTOCOL SYNOPSIS (CONTINUED) 
 
 
throughout study period and for 30 days after administration of study drug. A highly 
effective method of birth control is defined as one that results in a low failure rate 
(i.e., <1% per year) when used consistently and correctly, such as condom + 
diaphragm, condom + spermicide, diaphragm + spermicide; or intrauterine device 
(IUD) with documented failure rate of <1% per year; or oral/injectable/implanted 
hormonal contraceptives used in combination with an additional double-barrier 
method; or sexual abstinence. 
5. Female subjects who are post menarche are required to have a negative serum 
pregnancy test before the administration of study drug. 
6. Subject requires or recently completed systemic antibiotic therapy for the treatment or 
prevention of a known or suspected bacterial infection.  If completed, the last 
administered dose of systemic antibiotic must be within 24 hours of enrollment. 
Exclusion Criteria: 
1. Subject has an estimated creatinine clearance <50 mL/min/1.73 m2 (Schwartz 
equation). 
2. Any clinically significant abnormal laboratory value, including hematology, chemistry, or 
urinalysis that in the judgement of the investigator would make it difficult to assess the 
pharmacokinetic profile and safety of a single dose of telavancin or would compromise 
the safety of the subject. 
3. Any clinically significant medical history, abnormal physical examination finding, or vital 
sign measurement, including evidence of hemodynamic instability or significant 
collections of fluid outside normal vascular and tissue compartments (e.g., large pleural 
effusions, ascites), that in the judgement of the investigator would make it difficult to 
assess the pharmacokinetic profile or safety of a single dose of telavancin or would 
compromise the safety of the subject. 
4. Subject has clinically relevant cardiac abnormality, in the opinion of the investigator, 
such as: 
a. A mean QTcF >440 msec, congenital long QT syndrome, second or third 
degree heart block at rest.  
b. Hemodynamically significant heart disease, eg, hemodynamically unstable 
congenital heart defect, uncompensated heart failure, uncorrected abnormal 
calcium, hyperkalemia, or any other unstable cardiac condition.  
c. An arrhythmic heart condition requiring medical therapy 
5. Subject is receiving an anticoagulant AND requires specific coagulation testing 
(Prothrombin Time/International Normalized Ratio, Activated Partial Thromboplastin 
Time, Activated Clotting Time, or Coagulation Based Factor X Activity Assay) within 
24 hours of receiving the telavancin dose.  NOTE: Although telavancin does not 
interfere with coagulation, it interferes with some assays used to monitor coagulation. 
6. Subjects who are receiving concomitant vancomycin treatment should not be assessed 
for vancomycin serum concentrations within 24 hours of receiving the Telavancin dose.  
NOTE: Telavancin might interfere with some Vancomycin therapeutic drug monitoring 


Protocol 0101, Amendment 5                                                                                                26Aug2019 
Telavancin 
Page 5 
 
PROTOCOL SYNOPSIS (CONTINUED) 
 
 
assays. Caution should be exercised when interpreting vancomycin drug monitoring 
levels in the presence of telavancin.  
7. Subject has a history of allergies or hypersensitivities to glycopeptide antibiotics 
(e.g., vancomycin), telavancin, or the formulation excipients. 
8. Subject requires, or is anticipated to require, concomitant [within 24 hours before or 
24 hours following the single dose of study medication (telavancin)] administration of 
agents that in the clinical judgment of the investigator increase the risk of torsade de 
pointes.  
9. Subject is considered unlikely to comply with the study procedures. 
10. Subject was treated with an investigational drug within 30 days or five half-lives, 
whichever is longer, before study entry. 
11. Subject has any other condition that, in the opinion of an investigator, would confound 
or interfere with evaluation of safety of the investigational drug, or prevent compliance 
with the study protocol. 
Test Product, Dose, and Route of Administration; Regimen; Duration of Treatment:  
Telavancin 10 mg/kg will be administered as a single IV infusion over approximately 
60 minutes to children in the 3 older age groups: Adolescents (12 to17 years), Older 
Children (6 to 11 years), Younger Children (2 to 5 years).  The appropriateness of the 
dose(s) used in children > 12 months to < 24 months will be assessed during interim PK 
analyses of telavancin concentration-time data, including PK exposure estimates. The 
pediatric exposure estimates will be compared to historical data in adults to facilitate 
adjustment of the dose for the youngest age group. Pharmacokinetic results completed to 
date indicate that telavancin exposure is consistent with initial modeling projections; 
exposure was observed to decrease with decreasing body weight. 
Reference Therapy, Dose, and Route of Administration; Regimen; Duration of 
Treatment:  Not applicable 
Study Evaluations 
Safety Assessments: 
Subject safety will be monitored during the study using standard measures, including 
physical examinations, vital signs, 12-lead ECGs, clinical laboratory assessments, 
urinalysis, concomitant medication usage, and adverse event reporting. 
Pharmacokinetic Assessments: 
Blood samples for PK assessment will be taken as follows: 1.0 hour (±5 min), 1.5 hours 
(±5 min), 2 hours (±5 min), 6 hours (±30 min), 12 hours (±30 min) and 24 hours 
(±30 minutes) after the beginning of the infusion. The timing of PK sampling may be 
optimized after the completion of the older age groups (Cohorts 1-3) to assure that the 
minimum numbers of samples are collected in the youngest age group > 12months to < 24 
months.  Plasma exposures that will be compared to adult exposures are the primary 
assessment for this study.   
 


Protocol 0101, Amendment 5                                                                                                26Aug2019 
Telavancin 
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PROTOCOL SYNOPSIS (CONTINUED) 
 
 
Plasma will be assayed for the determination of telavancin and the primary metabolite 
(AMI-11352). 
Statistical Methods: 
Sample Size: 
The standard regulatory requirement for sample size in pediatric studies is to prospectively 
power to target a 95% confidence interval within 60% and 140% of the geometric mean 
estimates of clearance (CLp) and volume of distribution (Vdss) in each pediatric age 
subgroup with at least 80% power. 
Approximately 30 male and female infants, children, and adolescents will be enrolled into 
the study.  
The subjects entered will be stratified by age: 
• 
Adolescents (12 to 17 years), N= 8  
• 
Older Children (6 to11 years), N = 8  
• 
Younger Children (2 to 5 years), N = 8  
• 
Infants > 12 and < 24 months, N = 6 
Sample size for each pediatric age subgroup was determined on the basis of the variability 
in telavancin PK parameters from adult data. 
Study Endpoints: 
The primary study analysis variables are the telavancin PK parameters: Cmax, Tmax, AUC0−t, 
AUC0-inf, and t1/2 (as appropriate) derived from plasma concentration-time data.  
The secondary endpoints are safety variables (see Safety Assessments above). 
Analysis: 
Noncompartmental and/or population PK methods will be used for determination of plasma 
PK parameters. All PK parameters will be presented by individual listings and summary 
statistics according to age stratification, including mean, geometric mean, median, 
standard deviation, 95% confidence interval, and coefficients of variation, minimum, 
maximum and number of subjects. Further analyses of the potential relationship between 
PK parameters and subject age may be performed. Plasma concentration data may also 
be utilized for development of a pediatric population PK model.  
Safety information gathered will be tabulated and descriptively summarized. 


Protocol 0101, Amendment 4 DRAFT 
 
Protocol 0101, Amendment 5                                                                                                                                                                        26Aug2019 
Telavancin 
Page 7 
 
 
SCHEDULE OF STUDY PROCEDURES 
 
Table 1: 
Schedule of Assessments 
Procedure 
Screening 
(Up to 48 Hours 
Before Dosing) 
Day 1 
Day 2 
Follow Up  
(Day 8 ± 1 Day)h 
Assent if appropriate and Informed Consent 
X 
 
 
 
Review Inclusion/Exclusion Criteria 
X 
X 
 
 
Medication and Medical History 
X 
 
 
 
Weight and Height/Length 
X 
 
 
 
Vital Signsa 
X 
X 
X 
 
ECG (12-lead)b 
X 
X 
 
 
Physical Examination 
X 
 
 
 
Serum Pregnancy Testc 
X 
 
 
 
Hematology, Serum Chemistry, Urinalysisd 
 Xd 
 
 Xd 
 
Telavancin Drug Dosing 
 
X 
 
 
Plasma PK Samplinge 
 
X 
X 
 
Concomitant Medications 
X 
X 
X 
Xg 
Adverse Events 
X 
X 
X 
Xg 
Abbreviations: ECG, electrocardiogram; PK, pharmacokinetic 
a Vital signs (Heart rate [HR], blood pressure [BP], respiratory rate [RR] and body temperature) will be measured following dosing as outlined in Table 2. HR and 
BP will be measured after a subject has rested for at least 5 minutes in the seated or supine position. 
b ECGs (12-lead) will be recorded after a subject has rested for at least 10 minutes in the supine position.  If the screening ECG is collected less than 24 hours 
before study drug dosing, the ECG prior to dosing may be omitted. The ECG on Day 1 may be collected between 1.5 and 2.5 hours (±10 minutes) after 
commencement of the telavancin infusion. 
c Pregnancy tests will be performed on female patients who are post menarche. 
d If standard clinical laboratory tests have been performed within the protocol-specified windows for laboratory testing at screening and Day 2, the results may be 
used to avoid excessive blood draws. Only hematology and chemistry laboratory testing is required on Day 2. 


Protocol 0101, Amendment 5                                                                                                                                                                       26Aug2019 
Telavancin 
Page 8 
 
SCHEDULE OF STUDY PROCEDURES (CONTINUED) 
 
 
e Blood samples for plasma PK analysis of telavancin will be collected as outlined in Table 2.  
f 
May be either an office visit or a telephone call, at the Investigator’s discretion. 
 
 


Protocol 0101, Amendment 5                                                                                                                                                                       26Aug2019 
Telavancin 
Page 9 
 
SCHEDULE OF STUDY PROCEDURES (CONTINUED) 
 
 
Table 2: 
Schedule of Procedures and Blood PK Collections 
Sample or Procedure 
Sampling Time Points (hours) relative to the start of the infusion  
1.0b 
1.5b 
2 b 
6 b 
12 b 
24 b 
Heart Rate and Blood Pressurea 
Xc 
 
 
 
 
X 
Respiratory Rate and 
Temperaturea 
Xc 
 
 
 
 
X 
Pharmacokinetic Sampling 
(Blood) 
Xc 
X 
X 
X 
X 
X 
a Heart rate [HR], blood pressure [BP], respiratory rate [RR] and body temperature will be measured after a subject has rested for at least 5 minutes in the 
seated or supine position.  
b Collect PK sample at 1, 1.5 and 2 h (±5 minutes) and samples at 6, 12, and 24 h (±30 minutes). 
c  To be collected relative to the start of the infusion 
Note:  For procedures scheduled to be performed at common times, priority is to be given to collection of the PK samples at the designated time.  
 
 


Protocol 0101, Amendment 5                                                                                                26Aug2019 
Telavancin 
Page 10 
 
 
TABLE OF CONTENTS 
 
PAGE 
 
PROTOCOL SYNOPSIS ....................................................................................................... 2 
SCHEDULE OF STUDY PROCEDURES .............................................................................. 7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................ 13 
1 
INTRODUCTION ..................................................................................................... 15 
1.1 
Background and Rationale ........................................................................... 15 
1.2 
Nonclinical Profile ......................................................................................... 16 
1.2.1 Pharmacology................................................................................... 16 
1.2.2 Toxicology ........................................................................................ 16 
1.2.3 Pharmacokinetics ............................................................................. 16 
1.3 
Clinical Experience ....................................................................................... 16 
1.4 
Risks and Benefits ....................................................................................... 17 
1.4.1 Red Man Syndrome .......................................................................... 18 
1.4.2 Subjects of Childbearing Potential .................................................... 18 
2 
OBJECTIVES .......................................................................................................... 19 
3 
STUDY DESIGN ...................................................................................................... 20 
3.1 
Overview ...................................................................................................... 20 
3.2 
Rationale for Study Design ........................................................................... 21 
3.3 
Selection of Dose and Duration of Treatment ............................................... 21 
3.4 
Study Endpoints ........................................................................................... 23 
3.5 
Minimization of Bias ..................................................................................... 23 
3.5.1 Blinding............................................................................................. 23 
3.5.2 Treatment Assignment ...................................................................... 24 
4 
STUDY POPULATION ............................................................................................ 25 
4.1 
Inclusion Criteria .......................................................................................... 25 
4.2 
Exclusion Criteria ......................................................................................... 25 
5 
STUDY DRUGS ...................................................................................................... 27 
5.1 
Description of Study Drug ............................................................................ 27 
5.2 
Dosage and Administration .......................................................................... 27 
5.3 
Treatment Compliance ................................................................................. 28 
5.4 
Drug Accountability and Reconciliation ........................................................ 28 
6 
STUDY PROCEDURES .......................................................................................... 29 
6.1 
Schedule of Study Procedures ..................................................................... 29 
6.2 
Total Blood Volume ...................................................................................... 29 
6.3 
Procedures by Visit ...................................................................................... 29 
6.3.1 Screening ......................................................................................... 29 
6.3.2 Day 1 (see Table 1) .......................................................................... 30 
6.3.3 Day 2 (Day of Discharge) ................................................................. 31 
6.3.4 Day 8 (±1 day)/Follow-Up ................................................................. 31 
6.3.5 Study Termination ............................................................................ 32 
6.3.6 Pregnancy Reporting ........................................................................ 32 
6.4 
Description of Study Assessments ............................................................... 32 
6.4.1 Demographic and Baseline Assessments ......................................... 32 
6.4.1.1 
Demographic Information ................................................ 32 


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TABLE OF CONTENTS (CONTINUED) 
 
PAGE 
 
 
6.4.1.2 
Height and Weight Measurements .................................. 32 
6.4.2 Pharmacokinetic Assessments ......................................................... 32 
6.4.3 Safety Assessments ......................................................................... 33 
6.4.3.1 
Adverse Events ............................................................... 33 
6.4.3.2 
Medical History ................................................................ 33 
6.4.3.3 
Medication History ........................................................... 33 
6.4.3.4 
Physical Examination ...................................................... 33 
6.4.3.5 
Vital Signs ....................................................................... 34 
6.4.3.6 
Electrocardiograms ......................................................... 34 
6.4.3.7 
Laboratory Tests ............................................................. 34 
6.5 
Safety Data Review Committee .................................................................... 35 
6.6 
Concomitant Medications ............................................................................. 37 
6.7 
Discontinuation ............................................................................................ 38 
6.7.1 Subject Discontinuation .................................................................... 38 
6.7.2 Subject Replacement ........................................................................ 39 
6.7.3 Study Discontinuation ....................................................................... 39 
6.8 
Pregnancy .................................................................................................... 39 
7 
ADVERSE EVENTS ................................................................................................ 40 
7.1 
Regulatory Definition of an Adverse Event ................................................... 40 
7.2 
Adverse Event Definition for the Purposes of This Study .............................. 40 
7.3 
Assessment of Adverse Events .................................................................... 41 
7.4 
Serious Adverse Events ............................................................................... 41 
7.5 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as Adverse Events or Serious Adverse Events ............................................ 42 
7.6 
Serious Adverse Event Reporting ................................................................ 43 
7.7 
Adverse Event Follow-up ............................................................................. 43 
8 
STATISTICAL CONSIDERATIONS ......................................................................... 45 
8.1 
Analysis Objectives ...................................................................................... 45 
8.2 
Sample Size and Power ............................................................................... 45 
8.3 
Enrollment .................................................................................................... 46 
8.4 
Endpoints ..................................................................................................... 46 
8.4.1 Safety Endpoints .............................................................................. 46 
8.4.2 Pharmacokinetic Endpoints .............................................................. 46 
8.5 
Statistical Analysis ....................................................................................... 46 
8.5.1 General Considerations .................................................................... 46 
8.5.2 Handling of Missing Data .................................................................. 47 
8.5.3 Analysis Populations......................................................................... 47 
8.5.4 Demographics, Baseline Characteristics and Patient 
Disposition ........................................................................................ 47 
8.5.5 Safety ............................................................................................... 47 
8.5.6 Analysis of Pharmacokinetics ........................................................... 48 
8.6 
Data Monitoring Committees ........................................................................ 49 
9 
STUDY ADMINISTRATION ..................................................................................... 50 
9.1 
Principal Investigator Responsibilities .......................................................... 50 
9.2 
Institutional Review Board/Independent Ethics Committee ........................... 51 


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TABLE OF CONTENTS (CONTINUED) 
 
PAGE 
 
 
9.3 
Informed Consent ......................................................................................... 51 
9.4 
Data Recording and Quality Assurance ........................................................ 52 
9.5 
Document Retention .................................................................................... 53 
9.6 
Confidentiality .............................................................................................. 53 
9.7 
Access to Data and Documents ................................................................... 54 
9.8 
Quality Control: Study Monitoring and Auditing ............................................ 54 
9.9 
Publication ................................................................................................... 55 
10 
REFERENCES ........................................................................................................ 56 
11 
APPENDICES ......................................................................................................... 57 
 
LIST OF TABLES 
 
Table 1: 
Schedule of Assessments .................................................................. 7 
Table 2: 
Schedule of Procedures and Blood Collections .................................. 9 
Table 3: 
Exposures to Telavancin Based on a Population 
Pharmacokinetic Model in Pediatric (Predicted) and Adult 
(Actual) Subjects .............................................................................. 23 
Table 4: 
Stopping Rules ................................................................................. 37 
 
LIST OF APPENDICES 
 
Appendix 1: 
Growth Charts for Boys, Birth to 36 Months ...................................... 58 
Appendix 2: 
Growth Charts for Girls, Birth to 36 Months ...................................... 59 
Appendix 3: 
Weight-for-Age Percentiles (5th to 95th Percentiles) for Boys, 
2−20 Years ....................................................................................... 60 
Appendix 4: 
Weight-for-Age Percentiles (5th to 95th Percentiles) for Girls, 
2−20 Years ....................................................................................... 61 
Appendix 5: 
Schwartz Equation for Estimated Creatinine Clearance .................... 62 
Appendix 6: 
Severity Grading for Red Man Syndrome ......................................... 63 
Appendix 7: 
Number of Samples and Approximate Amount of Blood to Be 
Collected from Each Subject ............................................................. 64 
Appendix 8: 
Maximum Allowable Total Blood Volumes to Be Collected from 
Each Subject .................................................................................... 65 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Description 
Ae 
amount excreted 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC0-t 
area under the concentration-time curve from time zero to the last 
measurable concentration 
AUC0-inf 
area under the concentration-time curve from time zero extrapolated to 
infinity 
BMI 
body mass index 
BP 
blood pressure 
BSA 
body surface area 
BSV 
between-subject variability 
CFR 
(United States) Code of Federal Regulations 
CDC 
Centers for Disease Control and Prevention 
CLp 
plasma clearance 
CLr 
renal clearance 
Cmax 
maximum concentration 
CrCL 
creatinine clearance 
CRF 
case report form 
cSSSI 
complicated skin and skin structure infection(s) 
cSSTI 
complicated skin and soft tissue infection(s) 
ECG 
Electrocardiogram 
EDC 
electronic data capture 
Fe 
fraction excreted 
GCP 
Good Clinical Practice 
HABP 
hospital-acquired bacterial pneumonia 
HIV 
human immunodeficiency virus 
HR 
heart rate 
IB 
Investigator's Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IV 
Intravenous 


Protocol 0101, Amendment 5                                                                                                26Aug2019 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Description 
LAR 
legally authorized representative 
MedDRA 
Medical Dictionary for Regulatory Activities (MedDRA®) 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QTc 
corrected QT interval 
QTcF 
Fridericia-Corrected QT Interval 
REB 
Research Ethics Board 
RR 
respiratory rate 
SAE 
serious adverse event 
SD 
standard deviation 
SDRC 
Safety Data Review Committee 
SOP 
standard operating procedure 
t1/2 
half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
time of maximum concentration 
US 
United States 
VABP 
ventilator-associated bacterial pneumonia 
Vd 
volume of distribution 
Vdss 
volume of distribution at steady-state  
 


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1 
INTRODUCTION 
1.1 
Background and Rationale 
Telavancin is a rapidly bactericidal, injectable antibiotic with concentration-dependent 
activity against clinically important Gram-positive pathogens. Telavancin is approved in the 
United States (US) for treatment, in adults, of complicated skin and skin structure infections 
and hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) caused 
by susceptible isolates of Staphylococcus aureus.  
The most common adverse events (AEs), which occurred in ≥10% of telavancin-treated 
patients in Phase 3 studies of complicated skin and skin structure infections (cSSSI) were 
taste disturbance, nausea, headache, vomiting, foamy urine, and insomnia. In these studies, 
telavancin was compared in a blinded manner to vancomycin. Serious adverse events 
(SAEs) were reported in 7% of patients treated with telavancin, and the most common 
included renal, respiratory, and cardiac events. Treatment discontinuations due to adverse 
events occurred in 8% of patients treated with telavancin, the most common events being 
nausea and rash. The incidence of adverse events indicative of renal impairment (increased 
serum creatinine, renal insufficiency, and renal failure) was 3% of telavancin-treated 
patients, and serious adverse events indicative of renal impairment occurred in 1% of 
telavancin-treated patients.  
Telavancin has also been evaluated in two Phase 3 trials for hospital-acquired bacterial 
pneumonia and ventilator-associated bacterial pneumonia, again in a blinded comparison 
with vancomycin. Serious adverse events were reported in 31% of patients treated with 
telavancin. Treatment discontinuations due to adverse events occurred in 8% of patients 
who received telavancin, with the most common events being acute renal failure and 
corrected QT (QTc) interval prolongation. Treatment-emergent adverse events (TEAEs) 
reported in 5% or more of telavancin-treated patients included nausea, vomiting, and acute 
renal failure. The incidence of adverse events indicative of renal impairment (acute renal 
failure and increased serum creatinine) was 10% of telavancin-treated patients, and serious 
adverse events indicative of renal impairment occurred in 2% of telavancin-treated patients.  
Telavancin has linear, predictable PK in the adult population. Mean plasma clearance after 
multiple dosing of 10 mg/kg every 24 hours in adults is 13.1 mL/hr/kg; the mean volume of 
distribution at steady state is 133 mL/kg, and the mean elimination half-life is 8.1 hours. 


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Approximately 90% of telavancin is bound to plasma proteins, primarily albumin. Telavancin 
is predominantly eliminated renally, with approximately 60% of the dose excreted 
unchanged in urine over 48 hours. 
This study is designed to evaluate the single-dose PK of telavancin in pediatric subjects to 
support development of a dosing algorithm that will deliver exposures similar to those found 
to be safe and effective in adults. 
1.2 
Nonclinical Profile 
A review of the nonclinical profile of telavancin can be found in the current version of the 
telavancin Investigator’s Brochure (IB).  
1.2.1 Pharmacology 
The summary of pharmacology data can be found in the current version of the telavancin IB.  
1.2.2 Toxicology 
The summary of toxicology data can be found in the current version of the telavancin IB. 
Studies in juvenile rats demonstrated that adverse effects and doses at which these effects 
were observed were similar in adult and juvenile rats.  
1.2.3 Pharmacokinetics 
The pharmacokinetics, excretion, metabolism, and tissue distribution of telavancin has been 
studied in animals. Findings of note include linear kinetics, urinary excretion as the primary 
route of elimination and little or no in vitro metabolism. 
Further information can be found in the telavancin IB. 
1.3 
Clinical Experience 
Details of clinical data obtained from completed studies to date may be found in the 
telavancin IB.  
The PK, safety, and tolerability of telavancin administered intravenously in humans have 
been evaluated in 14 Phase 1 studies. The 14 studies were conducted in 484 subjects, 
including 18 healthy elderly subjects, 16 subjects with moderate hepatic impairment, and 
79 subjects with various degrees of renal impairment. In addition, two drug-interaction 


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studies, a thorough QTc study, a study of telavancin PK after intravenous administration of 
single and multiple doses to healthy Japanese and white subjects, and a metabolism and 
excretion study using [14C] telavancin have been completed in healthy subjects.  
The safety and efficacy of telavancin have been evaluated in two Phase 2 studies. In one 
study, 184 patients with cSSSI were exposed to telavancin and in another study, 29 patients 
with bacteremia were exposed to telavancin. The safety and efficacy of telavancin have also 
been evaluated in four Phase 3 studies with vancomycin as a comparator, in which a total of 
929 patients with cSSSI and a total of 751 patients with hospital-acquired bacterial 
pneumonia (HABP) were exposed to telavancin.  
1.4 
Risks and Benefits 
The efficacy of telavancin has been demonstrated in Phase 3 studies of adult patients 
suspected to be caused by Gram-positive bacterial pathogens, in which telavancin 
demonstrated noninferiority to vancomycin. Because the current study will be evaluating 
single doses of telavancin in this pediatric population, no benefits are anticipated.  
In single-dose studies of telavancin, the following adverse events have been reported:  taste 
disturbance, headache, pruritus/urticaria, flushing, red man syndrome, hypersensitivity, 
constipation, transient elevated coagulation parameters, injection site pain, nausea, foamy 
urine, fatigue, somnolence, vasovagal syncope, decreased serum potassium, increased 
serum lactic dehydrogenase, and QT prolongation.  
In Phase 2 and Phase 3 studies in which multiple doses of telavancin were administered, 
the following adverse events were reported: infusion-related reactions, urticaria, rash, 
pruritus, dermatitis, red man syndrome, renal insufficiency, QTc prolongation, ototoxicity, 
superinfection, and antibiotic-associated colitis/ pseudomembranous colitis. Laboratory 
abnormalities included elevations in serum creatinine and urea. In addition, increases in 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed 
infrequently with no evidence of a relationship to telavancin dose. 
Telavancin may pose a risk to fetuses, based on nonclinical data, and should be avoided 
during pregnancy unless the potential benefit outweighs the potential risks. 
C. difficile-associated colitis is a potential adverse reaction and should be considered in 
subjects with diarrhea subsequent to drug administration. 


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1.4.1 Red Man Syndrome 
Administration of glycopeptide antibiotics like telavancin may be associated with histamine 
release during the infusion and for a limited period thereafter. The syndrome is more 
prominent when the infusion is rapid, hence the use of a 1-hour infusion in this study. In 
extreme cases (eg, clinically severe symptoms including, for example, dyspnea, or 
angioedema), antihistamines may be necessary to alleviate the symptoms of red man 
syndrome and should be available for such an occurrence. In most cases, symptoms 
resolve without treatment within 15 to 30 minutes of onset. Refer to the IB for further details.  
1.4.2 Subjects of Childbearing Potential 
Adverse developmental outcomes were observed in three animal species at clinically 
relevant telavancin doses. This raises concerns about potential adverse developmental 
outcomes in humans (Section 5.4 of VIBATIV® prescribing information). Thus, female 
subjects who are post menarche are required to have a negative serum pregnancy test 
before the administration of study drug (Section 4). Females who are post menarche should 
be apprised of the animal teratology findings observed with the administration of telavancin. 
Males should be apprised of the effects on sperm count, motility, and morphology that were 
noted in animals exposed to telavancin.  
Females of childbearing potential (defined as females who are post menarche) and sexually 
active males participating in telavancin studies must agree to use appropriate contraceptive 
measures for at least 30 days after the single dose of telavancin. Medically acceptable 
contraceptives include surgical sterilization; approved hormonal contraceptives (i.e., birth 
control pills, Depo-Provera®, or Lupron Depot®); barrier methods (i.e., condom, diaphragm) 
used with a spermicide; or an intrauterine device. Abstinence is a valid form of 
contraception. Study participants should be advised to inform the study physician 
immediately if they become pregnant, or their partner becomes pregnant, while participating 
in the study. 


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2 
OBJECTIVES 
The primary objective of the study is as follows: 
• 
To characterize the pharmacokinetics of telavancin after a single dose in pediatric 
subjects (> 12 months to 17 years inclusive) who require systemic antibiotic therapy for 
the treatment or prevention of a known or suspected bacterial infection 
The secondary objective of the study is as follows: 
• 
To assess the safety and tolerability of telavancin after a single dose in pediatric 
subjects (> 12 months to 17 years inclusive) who require systemic antibiotic therapy for 
the treatment or prevention of a known or suspected bacterial infection 


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3 
STUDY DESIGN 
3.1 
Overview 
This is an open-label study of the pharmacokinetics and safety of a single intravenous dose 
of telavancin in pediatric subjects, aged > 12 months to 17 years, who require systemic 
antibiotic therapy or prophylaxis for a known or suspected bacterial infection. Pediatric 
subjects will be enrolled by age as follows: 
1. Adolescents (12 to 17 years)  
2. Older Children (6 to11 years)  
3. Younger Children (2 to 5 years)  
4. Infants (>12 and < 24 months) 
Subjects’ age will be based on their last birthday. 
• 
Approximately eight subjects will be enrolled in Cohorts 1, 2 and 3 and approximately 6 
subjects will be enrolled in Cohort 4. All 4 cohorts will be enrolled in parallel 
(simultaneously). The first eight (8) subjects (Cohort 1) will receive a single 10 mg/kg 
dose of IV administered telavancin.  After the enrollment of the first 8 subjects and 
respective data are available, the population PK model will be refined and estimates of 
telavancin PK exposure will be generated for each subject. These estimates will then be 
compared to those observed historically in adults to facilitate adjustment of the pediatric 
dosing strategy, as necessary. PK data in patients recruited to date indicate that exposure 
to telavancin is consistent with initial modeling analysis and decreases with decreasing 
body weight. Therefore, the current dose is not expected to result in increased exposure 
in younger subjects with lower body weights. The Safety Data Review Committee 
(SDRC, Section 6.5) will make an integrated assessment of the safety, tolerability and 
available PK data after enrollment of approximately every 8 subjects for Cohorts 1-3 and 
after approximately 6 subjects for Cohort 4.  . 
Once a subject meets protocol eligibility, a single intravenous dose of telavancin will be 
administered over approximately 60 minutes on Day 1. Subjects will be followed for 
24 hours for PK and safety assessments and will complete the study after a safety follow-up 
evaluation on Day 8 (± 1 day).  


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3.2 
Rationale for Study Design 
This study is designed as a multicenter, open-label study to evaluate the single-dose PK 
and safety of telavancin in pediatric subjects (> 12 months to 17 years). Because the 
primary objective of this study is characterization of PK, it has been designed as an open-
label study. Approximately 30 male and female infants, children and adolescents will be 
enrolled. A single dose of 10 mg/kg has been selected for the first eight subjects in this 
study because it is the dose that has been previously evaluated and demonstrated to be 
safe and efficacious in adult patients.  
In adults, telavancin exhibits a linear and predictable PK profile. The elimination t1/2 of 
telavancin in adults with normal renal function is approximately 8.1 hours. PK 
measurements in this initial pediatric study will be assessed over 24 hours to ensure 
adequate characterization of the plasma PK profile in this population while minimizing 
unnecessary blood collections and hospitalization on the part of the subjects.  
In adults, telavancin is primarily eliminated unchanged in the urine. Urinary excretion and 
the renal clearance of telavancin in the pediatric population will be assessed over 24 hours. 
Pediatric patients with estimated creatinine clearance <50 mL/min/1.73 m2 will be excluded 
from the trial. 
3.3 
Selection of Dose and Duration of Treatment 
Infants, children, and adolescents will receive a single intravenous (IV) telavancin dose 
infused over approximately 60 minutes. The initial starting dose of 10 mg/kg for the first 
eight subjects is the approved dose for treatment of complicated skin and skin structure 
infections (cSSSI) and treatment of hospital-acquired and ventilator-associated bacterial 
pneumonia (HABP/VABP) caused by susceptible isolates of Staphylococcus aureus in adult 
patients with creatinine clearance >50 mL/min. 
Dose selection for the current study was based upon the current approved dose in adults 
(10 mg/kg), preclinical data, and simulations of the anticipated plasma exposure to 
telavancin in pediatric patients based on the adult telavancin population PK model and 
allometric scaling of telavancin clearance and volume of distribution to pediatric patients.  
The effect of telavancin was evaluated in juvenile rats in a repeated-dose toxicity study. 
Based on these results, the effects of telavancin on juvenile animals did not differ 


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substantively from the effects in adults. A summary of the juvenile toxicology data may be 
found in the current version of the telavancin IB.  
Clearance and volume of distribution were scaled allometrically from the adult population PK 
model across the pediatric age and weight range on the basis of an assumed allometric 
exponent of 0.75 (clearance) and 1.0 (volume of distribution), respectively.  
Pediatric PK simulations were conducted utilizing a uniform distribution of body weights 
between 9.6 kg (average weight of a 1-year old child, based on WHO growth standards) and 
70 kg. The distribution of creatinine clearance (CrCL) values was taken from the observed 
distribution of subjects in the adult population PK model and constrained to ≥50 mL/min in 
accordance with the study protocol. The age of each subject in the simulations was 
estimated by utilizing the average weight vs. age from the Centers of Disease Control and 
Prevention (CDC) growth charts for children in the United States {3}. Additionally, the values 
of CrCL for subjects 1 to 2 years of age were reduced by 15% to reflect dependence of renal 
function on size, organ maturation, and body composition {4}. 
PK simulations for a pediatric dataset of 1500 subjects (n = 200 simulations per subject) and 
dose of 10 mg/kg were conducted using the population PK model and categorized by the 
age stratification that is defined in the protocol (Table 3). The mean and standard deviation 
of exposures (area under the curve [AUC]) in the pediatric population are anticipated to be 
lower than the 864 ± 285 μg•hr/mL observed at day 4 in the Phase 3 adult population 
(Studies 0015, 0017, 0018, and 0019) after a dose of 10 mg/kg (18 to 65 years of age, 
n = 393).  
The selected dose level (10 mg/kg) is therefore anticipated to maintain plasma exposure to 
telavancin at comparable or lower levels than previously observed in the adult population. 
The results of this study will be utilized to design dosing algorithms in pediatric patients 
intended to maintain comparable exposures to the approved dose in adults.  The 
appropriateness of the 10 mg/kg dose will be evaluated after enrollment of Cohorts 1-4. 
 


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Table 3: 
Exposures to Telavancin Based on a Population Pharmacokinetic Model in 
Pediatric (Predicted) and Adult (Actual) Subjects 
Age Range 
Estimated AUC0-24 (μg•hr/mL) 
(Mean ± SD) 
Adult* 
864 ± 285* 
12 – 17 years 
628 ± 214 
6 – 11 years 
537 ± 185 
2 – 5 years 
457 ± 160 
1 – 2 years 
433 ± 155 
* 
Observed exposure on day 4 from Phase 3 clinical data 
(n = 393) 
Note: Simulations based on a total of 300,000 simulated 
subjects at a telavancin dose of 10 mg/kg 
 
3.4 
Study Endpoints 
The primary study analysis variables are the plasma PK parameters for telavancin. The 
following will be derived from plasma concentration-time data:  
• 
Maximum observed plasma concentration (Cmax) 
• 
Time to reach maximum observed plasma concentration (Tmax) 
• 
Area under the plasma concentration versus time curve from time 0 to the last 
sample with measurable analyte concentration (AUC0-t) 
• 
Area under the concentration versus time curve extrapolated to infinity (AUC0-inf) 
• 
Terminal elimination half-life (t1/2) 
The secondary endpoints are safety and tolerability which will be monitored during the study 
using standard measures including physical exams, vital signs, 12-lead ECGs, clinical 
laboratory assessments, urinalysis, concomitant medication usage and adverse event 
monitoring (Safety Assessments, Section 6.4.3). An exploratory endpoint is the qualitative 
assessment of plasma concentrations for the metabolite AMI-11352. 
3.5 
Minimization of Bias 
Since the primary objective of this study is characterization of PK, an open-label design is 
deemed appropriate. 
3.5.1 Blinding 
This is an open-label study. 


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3.5.2 Treatment Assignment 
All subjects will receive a single dose of telavancin. See Section 5.2 for information 
regarding dose administration. 
 


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4 
STUDY POPULATION 
Approximately 30 male and female infant, child, and adolescent subjects’ ages > 12 months 
to 17 years, inclusive, who require systemic antibiotic therapy for the treatment or prevention 
of a known or suspected bacterial infection will be enrolled in this study. Subjects will be 
enrolled by age into one of four subgroups: 
1. Adolescents (12 to 17 years), N = 8 
2. Older Children (6 to 11 years), N = 8 
3. Younger Children (2 to 5 years), N = 8 
4. Infants >12 and < 24 months, N = 6 
4.1 
Inclusion Criteria 
Subjects who meet all of the following criteria will be eligible for study enrollment: 
1. Subject is > 12 months to 17 years (inclusive) 
2. Subject has a weight within the 3rd to 97th percentile (inclusive) for age and sex. Refer to 
Appendix 1 through Appendix 4.  
3. Written informed consent and assent (if appropriate for older age groups) has been 
obtained per institutional review board (IRB) policy and requirements, consistent with 
ICH guidelines.  
4. Male and female subjects of reproductive potential (ie, post-pubertal males and 
post-menarche females) must agree to use a highly effective method of contraception 
throughout study period and for 30 days after administration of study drug. A highly 
effective method of birth control is defined as one that results in a low failure rate 
(ie, <1% per year) when used consistently and correctly, such as condom + diaphragm, 
condom + spermicide, diaphragm + spermicide; or intrauterine device (IUD) with 
documented failure rate of <1% per year; or oral/injectable/implanted hormonal 
contraceptives used in combination with an additional double-barrier method; or sexual 
abstinence. 
5. Female subjects who are post menarche are required to have a negative serum 
pregnancy test before the administration of study drug. 
6. Subject requires or recently completed systemic antibiotic therapy for the treatment or 
prevention of a known or suspected bacterial infection.  If completed, the last 
administered dose of systemic antibiotic must be within 24 hours of enrollment.  
 
4.2 
Exclusion Criteria 
Subjects who satisfy any of the following criteria are not eligible for study enrollment: 
1. Subject has an estimated creatinine clearance <50 mL/min/1.73 m2 (Schwartz equation).  
2. Any clinically significant abnormal laboratory value, including hematology, chemistry, or 
urinalysis that in the judgement of the investigator would make it difficult to assess the 
pharmacokinetic profile and safety of a single dose of telavancin or would compromise 
the safety of the subject. 


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3. Any clinically significant medical history, abnormal physical examination finding, or vital 
sign measurement, including evidence of hemodynamic instability, that in the judgement 
of the investigator would make it difficult to assess the pharmacokinetic profile or safety 
of a single dose of telavancin or would compromise the safety of the subject. 
4. Subject has clinically relevant cardiac abnormality, in the opinion of the investigator, 
such as: 
a. A mean QTcF >440 msec, congenital long QT syndrome, second or third degree 
heart block at rest.  
b. Hemodynamically significant heart disease, eg, hemodynamically unstable 
congenital heart defect, uncompensated heart failure, uncorrected abnormal 
calcium, hyperkalemia, or any other unstable cardiac condition 
c. An arrhythmic heart condition requiring medical therapy 
5. Subject is receiving an anticoagulant AND requires specific coagulation testing 
(Prothrombin Time/International Normalized Ratio, Activated Partial Thromboplastin 
Time, Activated Clotting Time, or Coagulation Based Factor X Activity Assay) within 
24 hours of receiving the Telavancin dose. NOTE: Although Telavancin does not 
interfere with coagulation, it interferes with some assays used to monitor coagulation. 
6. Subject is receiving concomitant vancomycin treatment AND requires vancomycin drug 
monitoring levels within 24 hours of receiving the Telavancin dose.  NOTE: Telavancin 
might interfere with some Vancomycin therapeutic drug monitoring assays. Caution 
should be exercised when interpreting vancomycin drug monitoring levels in the 
presence of telavancin. NOTE: A subject who is receiving concomitant vancomycin and 
does not require vancomycin monitoring within the specified window would be eligible for 
enrollment. 
7. Subject has a history of allergies or hypersensitivities to glycopeptide antibiotics 
(eg, vancomycin), telavancin, or the formulation excipients. 
8. Subject requires, or is anticipated to require, concomitant (within 24 hours before or 
24 hours following telavancin administration, administration of agents that are associated 
with torsade de pointes. 
9. Subject is considered unlikely to comply with the study procedures. 
10. Subject was treated with an investigational drug within 30 days or five half-lives, 
whichever is longer, before study entry. 
11. Subject has any other condition that, in the opinion of an investigator, would confound or 
interfere with evaluation of safety of the investigational drug, or prevent compliance with 
the study protocol. 


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5 
STUDY DRUGS 
All study drug supplied by the Sponsor must be stored in a secure location accessible only 
to designated study personnel. 
5.1 
Description of Study Drug 
Telavancin drug substance is manufactured as telavancin hydrochloride and is marketed as 
VIBATIV®. Telavancin hydrochloride is a lipoglycopeptide antibacterial that is a synthetic 
derivative of vancomycin. Telavancin is supplied in single-use vials containing 750 mg 
telavancin as a sterile, preservative-free lyophilized powder. Inactive ingredients are 
hydroxypropylbetadex, mannitol, and sodium hydroxide and hydrochloric acid used in 
minimal quantities for pH adjustment. 
Telavancin is to be stored at refrigerated temperatures of 2°C to 8°C (35°F to 46°F). 
Excursions to room temperatures (up to 25°C [77°F]) for up to 7 days are acceptable. 
Refer to the telavancin pharmacy manual for details on handling, reconstitution, dilution, and 
administration. 
5.2 
Dosage and Administration 
Telavancin will be administered by qualified study site personnel as a single IV infusion 
using an IV pump over approximately 60 minutes.  Telavancin may be administered without 
regard to meals. The first eight (8) subjects will receive a single dose of telavancin 
(10 mg/kg). The appropriateness of the 10 mg/kg dose will be evaluated after completion of 
a total of approximately 8, 16, 24, and 30 subjects in Cohorts 1- 4 using PK methods as 
described in Section 3.1.  
The start time, stop time, and rate of each infusion will be recorded in the source documents 
for all subjects. Should red man syndrome (Section 1.4.1) occur in association with the 
infusion, the infusion should be stopped and not resumed. If the infusion is stopped for any 
reason, the following must be recorded in the source documents: the reason for stopping the 
infusion, the stop time of the infusion, and the rate of infusion just prior to being stopped. 
These data will be used to calculate the total amount of telavancin infused into the subject. 
All remaining study procedures should be completed for the subject.  


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5.3 
Treatment Compliance 
Subjects will receive a single IV dose of telavancin administered by qualified study 
personnel at the study site. Compliance with the dosing regimen will be assessed by 
reconciliation of used and unused study drug. Any discrepancies will be reviewed with the 
site staff and retraining on proper dosing will occur as needed. 
5.4 
Drug Accountability and Reconciliation 
The investigator or designee is responsible for maintaining accountability records for all 
study drug(s) received from the Sponsor, in accordance with applicable government 
regulations and study procedures. The accountability records for study medication 
(telavancin) will be maintained in a secure location, accessible only to authorized staff 
members. The accountability record will include entries for receipt, distribution or dispensing, 
and destruction of the material(s). 
Unused and expired study drugs will be disposed of in accordance with written instructions 
from the Sponsor. Copies of the study medication accountability records will be provided to 
the Sponsor at completion of the study and will be made available for review by the site 
monitor during the course of the study. 


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6 
STUDY PROCEDURES 
6.1 
Schedule of Study Procedures 
The schedule of study procedures is summarized in Table 1 and Table 2. 
6.2 
Total Blood Volume 
The total volume of blood to be drawn from each subject for PK and safety laboratory 
assessments is approximately 15 mL for females who are post menarche and 14.0 mL for 
males and pre-menarchal females as outlined in Appendix 7.  Additional safety laboratory 
tests may be drawn, as required for safety assessments.  Exact volumes will depend on 
individual sample volumes required at each institution. Blood sample volume must not 
exceed 5% of total blood volume (TBV) over 24 hours and up to 10% of TBV over 8 weeks. 
The investigator must ensure that the total volume of blood drawn does not exceed 5% of 
total blood volume especially in the youngest cohort. References for safe limits for a 
maximum blood volume to be drawn can be found in Appendix 8. 
6.3 
Procedures by Visit 
Written assent, if applicable, and written informed consent must be obtained before any 
protocol specific procedures are performed.  
The site should make every effort to perform procedures at the scheduled times, and the 
actual time should be recorded in the source documents and case report forms. When 
multiple assessments are scheduled at the same nominal time, PK sample collections 
should occur as close as possible to the scheduled nominal time. ECGs and vital signs may 
be collected prior to the PK sample collection. 
6.3.1 Screening 
The screening visit will be performed within 48 hours before planned dosing. Screening 
activities will comprise the following: 
• 
Written, signed, and dated informed consent must be obtained after the nature of the 
study has been explained to the legally authorized representative and subject, if 
applicable, and before any study procedures are performed. Where applicable, assent 
will also be obtained based on local IRB requirements. 
• 
Review of inclusion and exclusion criteria (Subjects will be eligible for enrollment only if 
they meet all the inclusion and none of the exclusion criteria) 
• 
Medication and medical history 


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• 
Height and weight 
• 
Vital signs 
o Heart rate (HR) and blood pressure (BP) 
o Respiratory Rate (RR) and body temperature 
• 
ECG (12-lead) 
• 
Physical examination as outlined in Section 6.4.3.4 
• 
Blood collection (NOTE: If standard clinical laboratory tests have been performed within 
the protocol-specified windows for laboratory testing at screening, the results may be 
used to avoid excessive blood draws.) 
o Hematology 
o Serum chemistry 
o Serum pregnancy test (for females who are post menarche) 
• 
Urine collection for urinalysis 
• 
Concomitant medications 
• 
Adverse events 
6.3.2 Day 1 (see Table 1) 
The following procedures will be performed on Day 1: 
Pre-Dose Procedures: 
• 
Review of inclusion and exclusion criteria (Subjects will be eligible for enrollment only if 
they meet all the inclusion and none of the exclusion criteria) 
• 
Vital signs  
o HR and BP 
o RR and body temperature 
• 
ECG (12-lead), (if not done within the past 24 hours) 
 
Dosing: 
• 
Study medication (telavancin) dosing, IV over 60 minutes (± 5 minutes) 
 
 


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Post dose Procedures: 
• 
Vital signs at 1 (± 20 minutes) and 4 hours (± 20 minutes) after the start of the telavancin 
infusion 
o HR and BP 
o RR and body temperature 
• 
ECG (12-lead), to be recorded between 1.5 and 2.5 hours (± 10 minutes) after the start 
of the telavancin infusion 
• 
Blood collection 
o PK samples will be collected at 1 hour (± 5 min), 1.5 hours (± 5 min), 2 hours (± 
5 min), 6 hours (± 30 min), and 12 hours (± 30 min), after the start of the telavancin 
infusion 
• 
Adverse events 
• 
Concomitant medications 
6.3.3 Day 2 (Day of Discharge) 
The following procedures will be performed on Day 2: 
• 
Vital signs at 24 hours (± 2 hours) after the start of the telavancin infusion  
o HR and BP at 24 hours (± 2 hours) after the start of the telavancin infusion 
o RR and body temperature 
• 
Blood collection  
o PK samples will be collected at 24 hours (± 30 minutes) after the start of the 
telavancin infusion  
o Hematology and serum chemistry laboratory testing. (NOTE: If standard clinical 
laboratory tests have been performed within the protocol-specified windows for 
laboratory testing on Day 2 (same calendar day), the results may be used to avoid 
excessive blood draws.) 
o Adverse events 
• 
Concomitant medications 
6.3.4 Day 8 (±1 day)/Follow-Up  
The following procedures will be performed at the Follow-Up (Day 8 ±1 day), which should 
occur 7 days after dosing. At the discretion of the Investigator, the Follow-Up Visit may be 
either a clinic visit or telephone call: 
• 
Adverse events 
• 
Concomitant medications 


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6.3.5 Study Termination 
Study termination will be considered the date that the subject withdraws from or completes 
the study, even if that date does not correspond to a protocol-specific visit.  
6.3.6 Pregnancy Reporting 
Study participants should be advised to inform the study physician immediately if they 
become pregnant, or their partner becomes pregnant, while participating in the study 
(Section 1.4.2). 
6.4 
Description of Study Assessments 
6.4.1 Demographic and Baseline Assessments 
6.4.1.1 Demographic Information 
Demographic information to be collected will include: date of birth, sex, race, and ethnicity.  
6.4.1.2 Height and Weight Measurements 
Height and weight will be measured and recorded as outlined in Table 1. The subject’s 
weight must be within the 3rd and 97th percentile (inclusive) for age and sex. For subjects 
aged > 12 months to <24 months, the charts in Appendix 1 and Appendix 2 should be used.  
For subjects age 2 to 17 years, Appendix 3 and Appendix 4 should be used. 
Height or length (in centimeters) and weight (in kilograms) should be measured with the 
subject’s shoes off. The body weight from Screening will be used to calculate the telavancin 
dose. 
6.4.2 Pharmacokinetic Assessments 
Blood samples for plasma PK assessments will be collected and processed according to 
instructions specified in the Pharmacokinetic Sample Collection Manual separate from this 
document. The total blood volume for PK is discussed in Section 6.2 and is outlined in 
Appendix 7. 
Blood samples for PK assessment will be collected as follows:  
• 
After the start of infusion: 1.0 hour (±5 min), 1.5 hours (±5 min), 2 hours (±5 min), 6 
hours (±30 min), 12 hours (±30 min), and 24 hours (±30 minutes after the beginning 
of the telavancin infusion.   


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The actual time of collection must be recorded for each sample. Note that the PK sampling 
scheme may be optimized after the completion of each interim analysis to assure that the 
minimum number of samples are used in each subsequent set of six or eight subjects. 
Refer to the Pharmacokinetic Sample Collection Manual for specific information on the 
collection and processing of PK plasma samples.  
6.4.3 Safety Assessments 
6.4.3.1 Adverse Events 
Adverse events (AEs) will be recorded from the time of consent through the follow-up visit 
for each subject. AEs may be observed by the site study personnel or spontaneously 
reported by the subject or reported in response to a standard question from site study 
personnel and include any protocol-related event.  
6.4.3.2 Medical History 
A complete medical history will be taken during the Screening Visit and will include 
evaluation for past and present cardiovascular, respiratory, gastrointestinal, renal, hepatic, 
neurological, endocrine, lymphatic, hematologic, immunologic, dermatologic, psychiatric, 
and genitourinary diseases, surgical history, or any other diseases or disorders. Medical 
events or conditions that arise or worsen in severity or frequency following telavancin 
administration will be recorded as a (Treatment Emergent Adverse Event) TEAE. 
6.4.3.3 Medication History 
All medications used within the past 30 days will be recorded. 
6.4.3.4 Physical Examination 
The physical examination at Screening will be performed by an appropriately qualified 
individual (e.g., physician or nurse practitioner or physician’s assistant or equivalent under 
the supervision and/or delegation of a physician) and will include examination of the 
following: general appearance; head, ears, eyes, nose, and throat; neck, skin/dermatologic 
system; cardiovascular system; respiratory system; abdomen/gastrointestinal system; 
genitourinary system, lymphatic system; musculoskeletal system; and nervous system. Post 
screening examinations will be abbreviated and based on symptomatology, largely focused 
on evaluation of AEs, if any, and any abnormalities identified on the Screening examination.  


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6.4.3.5 Vital Signs 
Heart rate, systolic and diastolic blood pressure, respiratory rate, and body temperature will 
be taken as outlined in Table 1 and Table 2.  
Blood pressure and heart rate will be measured after the subject has been resting for at 
least 5 minutes in the seated or supine position. Blood pressure will be measured using a 
calibrated manual or automatic blood pressure device. Heart rate will be recorded by 
palpation of the radial pulse over a 60-second period or by the automated blood pressure 
device. 
Body temperature will be measured (oral, tympanic, or axillary) using a digital thermometer 
and recorded in degrees Celsius.  
Any screening or pre-dose vital sign outside the normal range may be repeated once at the 
discretion of the investigator. 
6.4.3.6 Electrocardiograms 
Twelve-lead ECGs will be collected at each scheduled time point as specified in the Table 1 
after the subject has been resting in the supine position for at least 10 minutes.  If the 
screening ECGs are collected less than 24 hours before study drug dosing, the ECG prior to 
dosing may be omitted. 
6.4.3.7 Laboratory Tests 
The following laboratory assessments will be performed as specified in Table 1 and Table 2. 
Refer to the Laboratory Manual for specific information on the collection and processing of 
laboratory tests. 
Additional and repeat laboratory safety testing for the evaluation of abnormal results and/or 
adverse events during the study may be performed at the discretion of the Investigator or 
upon request of the Sponsor. Repeat laboratory testing of abnormal potentially clinically 
significant or clinically significant results for the Screening evaluation of the subject may be 
repeated once at the discretion of the Investigator. 
All laboratory safety testing will be performed by the local laboratory. These local laboratory 
safety test results will be used to determine a subject’s eligibility for entry into the study.  
Study specific lab results will be entered into the case report form.  If standard clinical 


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laboratory tests have been performed within the protocol-specified windows for laboratory 
testing at screening or Day 2, the results may be used to avoid excessive blood draws. 
6.4.3.7.1 Hematology 
Hematology samples will be analyzed for the following: hematocrit and hemoglobin; red 
blood cell count; white blood cell count, including automatic differential count (percent and 
absolute) of neutrophils, eosinophils, basophils, monocytes, lymphocytes; mean corpuscular 
volume; mean corpuscular hemoglobin; mean corpuscular hemoglobin concentration; and 
platelet count. 
6.4.3.7.2 Serum Chemistry 
Serum chemistry samples will be analyzed for the following: albumin, sodium, potassium, 
calcium, chloride, bicarbonate, glucose, BUN, creatinine, total bilirubin, alkaline 
phosphatase, lactate dehydrogenase, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), and gamma-glutamyl transferase. 
6.4.3.7.3 Urinalysis 
Urinalysis includes determination of pH; specific gravity; presence of blood, glucose, protein, 
ketones, bilirubin, urobilinogen, nitrite, and leukocytes; and microscopic examination of 
sediment, if clinically indicated. 
6.4.3.7.4 Pregnancy Tests 
Serum β-human chorionic gonadotropin pregnancy tests will be performed for all females 
who are post menarche.  
6.5 
Safety Data Review Committee 
A Safety Data Review Committee (SDRC) will be composed of internal Sponsor personnel 
only, including the Cumberland Clinical Study Director, the Medical Monitor, the statistician 
and the PK scientist. Additional members may be added as needed at the discretion of the 
Clinical Study Director.  
An SDRC meeting will be held after the enrollment of approximately every 8 subjects for 
Cohorts 1-3 and after approximately 6 subjects for Cohort 4.  Data from these subjects has 
to be completed and available before the meeting.  The SDRC will also meet if a Stopping 
Rule is met (Table 4). Available safety data, including demographic data, ECG results, vital 


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signs, adverse events, and laboratory results, and any available PK data will be reviewed at 
each meeting. Additional meetings will be scheduled as needed to review safety and 
available PK data. 
As enrollment in Cohorts 1, 2, 3 and 4 may be ongoing during the SDRC, the SDRC may 
recommend that the study continues without modification; dosing adjustments; a cohort be 
expanded; or that dosing be discontinued.  
 
 


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Table 4: 
Stopping Rules 
Scenario 
Action 
Any occurrence of a suspected 
telavancin-related moderate adverse 
drug reaction of the same system 
class (eg, cardiovascular) observed 
in two or more subjects  
 
* Exception: red man syndrome, local 
site reactions,  
• 
Stop dosing additional subjects and convene 
SDRC (if event occurs outside the regularly 
scheduled review).  
• 
Review AE and all relevant safety data for 
evidence of relationship to treatment and 
clinical or medical significance.  
• 
Upon unanimous decision by the SDRC, one 
of the following decisions may be made:  
– Discontinue enrollment  
– Continue enrollment  
** If moderate red man syndrome is observed in 
at least two subjects, then the rate of 
telavancin infusion will be decreased by 50% 
for subsequent subjects  
Any occurrence of a suspected 
telavancin-related severe or serious 
adverse drug reaction  
• 
Stop dosing additional subjects and convene 
SDRC (if event occurs outside the regularly 
scheduled SDRC).  
• 
Review AE and all relevant safety data for 
evidence of relationship to treatment and 
clinical or medical significance.  
• 
If a severe or serious adverse event is 
determined by the SDRC to be related to 
study drug and clinically or medically 
significant, no further administration at this 
dose should occur. Enrollment of the study 
may continue at a lower dose upon 
unanimous decision of the SDRC.  
6.6 
Concomitant Medications 
Concomitant use of other antibiotics for bacterial infections, prophylaxis, or empiric therapy 
for a suspected bacterial infection are allowed during the study.  
Subjects cannot participate in the study if they are:  
• 
Receiving concomitant vancomycin treatment AND require vancomycin drug 
monitoring levels within 24 hours of receiving the telavancin dose. NOTE: Telavancin 
might interfere with some Vancomycin therapeutic drug monitoring assays. Caution 
should be exercised when interpreting vancomycin drug monitoring levels in the 
presence of telavancin.  


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• 
Subject requires, or is anticipated to require, concomitant (within 24 hours before or 
24 hours following telavancin administration), administration of agents that are 
associated with torsade de pointes. 
Additional prescription and over-the-counter medications are permitted. Any addition or 
change in regimen of concomitant medications should be recorded in the source documents 
and the eCRF. Medications taken from 30 days before enrollment through Follow-Up should 
be recorded in the source documents and eCRF.  
6.7 
Discontinuation 
6.7.1 Subject Discontinuation 
Any subject (or his or her legally authorized representative) may withdraw their consent to 
participate in the study at any time without prejudice. The investigator must withdraw from 
the study any subject who requests to be withdrawn. A subject’s participation in the study 
may be discontinued at any time at the discretion of the investigator and in accordance with 
his or her clinical judgment. When possible, the tests and evaluations listed for the early 
termination visit should be carried out. If a subject withdraws before completing the study, 
the reason for withdrawal is to be documented on the CRF. 
The Sponsor will be notified of all subject withdrawals. 
Reasons for which the investigator or the Sponsor may withdraw a subject from the study or 
a subject may choose to terminate participation before completion of the study include, but 
are not limited to, the following: 
• 
Adverse event 
• 
Subject choice 
• 
Major violation of the protocol 
• 
Termination of the study by the Sponsor 
• 
Other 
Subjects who discontinue study drug early due to an adverse reaction or any other reason 
(other than withdrawal of consent) should be encouraged to continue their participation in 
the follow-up safety assessments. If a subject fails to return for scheduled visits, a 
documented effort (e.g., at least 2 phone calls to the subject and a certified letter) must be 
made to determine the reason. 


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6.7.2 Subject Replacement 
Subjects who discontinue the study due to an AE will not be replaced. Subjects with serious 
protocol violations where PK is not evaluable will be replaced. Subjects discontinued for 
other reasons may be replaced at the Sponsor’s discretion.  
6.7.3 Study Discontinuation 
The Sponsor reserves the right to discontinue this study at any time for any reason. 
6.8 
Pregnancy 
If a female subject or partner of a male subject becomes pregnant during the study, the 
Sponsor clinical study director (or designee) must be notified immediately. Follow-up 
information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required. 


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7 
ADVERSE EVENTS 
7.1 
Regulatory Definition of an Adverse Event 
In the International Conference on Harmonization (ICH) E6 Guideline for Good Clinical 
Practice, Section 1.2 defines an adverse event (AE) as any untoward medical occurrence in 
a patient or clinical investigation subject administered a pharmaceutical product and which 
does not necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not considered related to the medicinal (investigational) product. 
7.2 
Adverse Event Definition for the Purposes of This Study 
For the purposes of this the Sponsor clinical study, adverse events will be defined as 
follows:  
An adverse event (AE) is any untoward medical occurrence in a subject who has signed an 
informed consent form and is participating in a clinical investigation. An AE can be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease, whether or not considered related to the study drug (investigational product). 
Preexisting events that increase in frequency or severity or change in nature during or as a 
consequence of participation in clinical studies will also be considered as adverse events. 
An AE may also include pre- or post-treatment complications that occur as a result of a 
protocol-mandated procedure (such as a biopsy). 
Any medical condition or clinically significant laboratory abnormality with an onset date prior 
to the time the subject signed the informed consent form is considered to be preexisting and 
should be documented in the medical history CRF, if applicable for the study. 
Whenever possible, the diagnosis (rather than a series of terms related to a diagnosis) 
should be recorded as the AE term. 
An AE does not include the following: 
• 
Medical or surgical procedures (such as surgery, endoscopy, tooth extraction, or 
transfusion); the condition that leads to the procedure is an adverse event 
• 
Preexisting diseases or conditions present or detected before signing an informed 
consent form that do not worsen 


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• 
Situations where an untoward medical occurrence has not occurred (such as 
hospitalization for elective surgery or social and/or convenience admissions) 
• 
Overdose of either study drug or concomitant medication without any signs or 
symptoms, unless the subject is hospitalized for observation 
 
7.3 
Assessment of Adverse Events 
All AEs will be assessed by the investigator and recorded in the case report form, including 
the dates of onset and resolution, severity, relationship to study drug, outcome, and action 
taken with study medication. 
Clinical severity should be recorded and graded using mild, moderate or severe as 
described below. 
Mild 
= Awareness of signs or symptoms, but easily tolerated 
Moderate 
= Discomfort sufficient to cause interference with usual activities 
Severe 
= Incapacitation with inability to work or perform usual activities 
The relationship to study drug therapy should be assessed using the following definitions: 
• 
Not Related:  Evidence exists that the adverse event has an etiology other than the 
study drug (such as a preexisting condition, underlying disease, intercurrent illness, or 
concomitant medication). 
• 
Possibly/Probably Related: A temporal relationship exists between the event onset 
and administration of the study drug. It cannot be readily explained by the subject’s 
clinical state or concomitant therapies and appears with some degree of certainty to 
be related based on the known therapeutic and pharmacologic actions of the drug. In 
case of cessation or reduction of the dose, the event abates or resolves and reappears 
upon rechallenge. It should be emphasized that ineffective treatment should not be 
considered as causally related in the context of adverse event reporting. 
These criteria in addition to good clinical judgment should be used as a guide for 
determining the causal assessment. If it is felt that the event is not related to study drug 
therapy, then an alternative explanation should be provided. 
7.4 
Serious Adverse Events 
A serious adverse event (SAE) is defined as any adverse drug experience occurring at any 
dose that results in any of the following outcomes: 
• 
Death 
• 
Life-threatening situation (subject is at immediate risk of death) 


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• 
Inpatient hospitalization or prolongation of existing hospitalization (excluding those for 
study therapy or placement of an indwelling catheter, unless associated with other 
serious events) 
• 
Congenital anomaly/birth defect in the offspring of a subject who received study drug 
• 
Other: Important medical events that may not result in death, be immediately 
life-threatening, or require hospitalization, may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. Examples 
of such events are as follows: 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias or convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse 
Additional Considerations for Serious Adverse Events 
• 
Death is an outcome of an adverse event and not an adverse event in itself. In reports of 
death due to disease progression, where no other information is provided, the death will 
be assumed to have resulted from progression of the disease being treated with the 
study drug(s). 
• 
All deaths, regardless of cause, must be reported for subjects if the death occurs while 
the subject is participating in the study. 
• 
“Occurring at any dose” does not imply that the subject is receiving study drug at the 
time of the event; dosing may have been given as treatment cycles or interrupted 
temporarily before the onset of the SAE, but may have contributed to the event. 
• 
“Life-threatening” means that the subject was at immediate risk of death from the event 
as it occurred. This does not include an event that might have led to death, if it had 
occurred with greater severity. 
• 
Complications that occur during hospitalizations are AEs. If a complication prolongs 
hospitalization, it is an SAE. 
• 
“Inpatient hospitalization” means the subject has been formally admitted to a hospital for 
medical reasons, for any length of time. This may or may not be overnight. It does not 
include presentation and care within an emergency department. 
• 
The investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and/or SAE and not the individual signs/symptoms. 
7.5 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events 
Abnormal laboratory findings (such as clinical chemistry, hematology, or urinalysis) or other 
abnormal assessments (such as electrocardiograms [ECGs], X-rays, or vital signs) that are 
associated with signs and/or symptoms or are considered clinically significant in the 
judgment of the investigator must be recorded as AEs or SAEs if they meet the definition of 


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an adverse event (or serious adverse event), as described in Sections 7.2 (Adverse Event 
Definition for the Purposes of This Study) and 7.4 (Serious Adverse Events). 
If there are any AE questions, the investigator is encouraged to contact the Sponsor clinical 
study director or medical monitor to discuss. 
7.6 
Serious Adverse Event Reporting 
Any SAE that occurs after a subject signs an informed consent form through the follow-up 
visit (or at the time a subject is determined to be ineligible for the study or who does not 
enroll in the study), regardless of causal relationship, must be reported to the Sponsor within 
24 hours of the investigator’s knowledge of the event.  
To report an SAE, complete and fax the Serious Adverse Event Report Form to the 
following: 
[REDACTED] 
 
For medical questions regarding an SAE, contact the Sponsor medical monitor by telephone 
as follows: 
[REDACTED] 
 
For fatal or life-threatening events, also fax copies of hospital case reports, autopsy reports, 
and other documents when requested. Additional information may be requested from the 
investigator to ensure the timely completion of accurate safety reports. 
An SAE may qualify for reporting to regulatory authorities if the SAE is possibly attributable 
to the study drug and is unexpected/unlisted based on the current Telavancin Investigator’s 
Brochure. In this case, all investigators will receive notification of the event. The investigator 
is responsible for notifying the Institutional Review Board or Ethics Committee and 
documenting the notification, as required by local regulatory authorities and in accordance 
with the local institutional policy. 
7.7 
Adverse Event Follow-up 
A subject experiencing an AE or SAE will be followed by the investigator or his/her trained 
delegate(s) through the follow-up visit or until the investigator and/or the Sponsor has 
determined that the AE or SAE has resolved or a stable clinical endpoint is reached, 


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whichever is longer. The Sponsor may request follow-up of certain adverse events until 
resolution and documentation of assessments made during this period. 
The investigator must take all therapeutic measures necessary for resolution of an SAE. Any 
medications necessary for treatment of the SAE must be recorded in the concomitant 
medication section of the case report form. 


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8 
STATISTICAL CONSIDERATIONS 
8.1 
Analysis Objectives 
The principal objectives of this study are to characterize the PK and assess the safety and 
tolerability of telavancin after a single dose in pediatric subjects (> 12 months to 17 years). 
8.2 
Sample Size and Power 
The standard regulatory requirement for sample size in pediatric studies is to prospectively 
power to target a 95% confidence interval within 60% and 140% of the geometric mean 
estimates of clearance (CLp) and the volume of distribution (Vdss) in each pediatric 
subgroup with at least 80% power. 
Sample size for each pediatric age subgroup was determined on the basis of the variability 
in telavancin PK parameters from adult data. Data from all Phase 1 telavancin studies (eight 
studies, which included a total of 236 healthy subjects without infection) conducted by the 
Sponsor were used to estimate variability using two different methods (based on either a 
noncompartmental analysis or a population PK modeling approach), as outlined in Wang et 
al {1}. The corresponding sample size intended for PK analysis was calculated using the 
estimated variability. 
1) Based on noncompartmental analysis:  Determine variability from any prior relevant 
study by calculating the standard deviation (SD) of the natural log–transformed 
individual clearance (CL) and volume of distribution at steady state (Vdss). 
Noncompartmental analysis of data from the Phase 1 trials resulted in SDs of 0.27 
and 0.21 for CL and Vdss, respectively. 
2) Based on population PK modeling:  Estimate the SD based upon the 
between-subject variability (BSV) found in the population PK model. The BSVs in the 
population PK model {2} were used, ie, 29% and 23% for CL and V1, respectively. 
The corresponding estimates of the SDs derived from the BSVs were 0.284 and 
0.227 for CL and V1, respectively. 
Using the most conservative estimate of SD (0.284 for CL derived from the population PK 
model), a sample size of seven per age subgroup is deemed sufficient to meet the 
aforementioned requirements with at least 80% power. In anticipation of possible drop-outs 
or missing samples, eight subjects will be enrolled in each age subgroup, which will result in 


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a total of approximately 30 male and female infants, children and adolescents participating 
in this study:  
• 
Adolescents (12-17 years), N=8  
• 
Older Children (6-11 years), N = 8  
• 
Younger Children (2-5 years), N = 8  
• 
Infants >12 and < 24 months, N = 6 
 
8.3 
Enrollment 
This is an open-label study and parallel (simultaneous) enrollment is allowed for all Cohorts.  
8.4 
Endpoints 
8.4.1 Safety Endpoints 
Safety endpoints include adverse events, concomitant medications, laboratory 
measurements, ECGs, physical examinations, and vital signs. 
8.4.2 Pharmacokinetic Endpoints 
The primary study analysis variables are the telavancin PK parameters: Cmax, Tmax, AUC0−t, 
AUC0-inf, and t1/2 (as appropriate) derived from the plasma concentration-time data. 
8.5 
Statistical Analysis 
8.5.1 General Considerations 
Unless otherwise specified, results will be tabulated and summarized descriptively; all 
individual subject data will be fully listed.  
The number and percentage of patients will be presented for categorical variables while 
mean, median, standard deviation and range (minimum and maximum) will be presented for 
continuous variables.  
The statistical package SAS (C 
ary, North Carolina) will be used to produce summary tables and subject listings related to 
demographics, baseline characteristics, patient disposition and safety assessment. 


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8.5.2 Handling of Missing Data 
Unless otherwise specified, missing values will not be imputed. 
8.5.3 Analysis Populations 
Two analysis populations will be defined: 
• 
Safety population: all subjects who receive any amount of study drug.  
• 
PK population: all subjects who receive any amount of study drug and who provide PK 
data from at least one post-dose plasma sample. 
8.5.4 Demographics, Baseline Characteristics and Patient Disposition 
Summary of demographics and baseline characteristics will include all subjects from the 
Safety population. The number of subjects discontinuing the study prematurely and the 
reason for discontinuing will be summarized based on the Safety population. 
8.5.5 Safety 
All safety assessments will be conducted on the Safety population.  
Treatment-emergent adverse events (TEAEs) are defined as AEs with onset on or after 
initiation of study medication. The number and percentage of patients reporting TEAEs will 
be tabulated by Medical Dictionary for Regulatory Activities (MedDRA®, version 16 or a 
more recent version) system organ class and preferred term, severity, and relationship to 
study medication. Serious TEAEs and TEAEs resulting in discontinuation of study drug will 
be summarized separately. 
Concomitant medications will be mapped using the WHODRUG dictionary (WHODDE B2 
format, March 2013 or a more recent version). The number and percentage of patients 
taking each concomitant medication will be tabulated. 
Analysis of laboratory results will be based on those reported by the local laboratory. 
Continuous laboratory measurements will be descriptively summarized at each visit for 
observed values and changes from baseline. Categorical laboratory measurements will be 
summarized by the number and percentage of patients with low, normal and high values 
based upon the normal ranges provided by each local laboratory. If a normal range is 
missing for a particular local laboratory then the normal “textbook range” will be used. A shift 


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table of laboratory measurements comparing pre- and post-treatment values relative to 
normal ranges (for example, normal to low, normal to normal, or normal to high) will also be 
summarized. 
Vital signs and ECG parameters (based on average of multiple measurements if measured) 
will be summarized at each visit for observed values and changes from baseline. In addition, 
QT and QTc intervals will be summarized categorically as number and percentage of 
patients with abnormal values or increases. 
8.5.6 Analysis of Pharmacokinetics 
For all PK data analyses, the PK population will be used. 
Individual and mean drug concentration versus time curves for telavancin and its metabolite, 
AMI-11352, will be presented by subgroup. Summary statistics (mean, standard deviation, 
minimum, maximum, number of subjects, and coefficient of variation) will be calculated for 
plasma concentrations for each time point and pediatric age subgroup. 
Plasma telavancin concentration-time data will be used to obtain Tmax, Cmax, AUC0-t, AUC0-inf, 
and t1/2 (as appropriate).  
Noncompartmental and/or population PK modeling methods will be used for determination 
of plasma PK parameters. All PK parameters will be presented by individual listings and 
summary statistics according to age stratification (e.g., mean, geometric mean, median, 
standard deviation, 95% confidence interval, coefficients of variation, minimum, maximum, 
and number of subjects). Further analysis of the potential relationship between PK 
parameters and subject age may be performed.  Plasma concentration data may also be 
utilized for development of a pediatric population PK model. 
In the first step of the population PK model development for this analysis, the full population 
PK model from adults will be modified to incorporate the expected alteration in renal function 
with age in the pediatric population {6}. This modified model will then be used to simulate 
expected telavancin concentration-time profiles in adolescent patients receiving the planned 
dose of 10 mg/kg in order to ensure that the resultant PK exposures (Cmax and AUC) are 
consistent with those observed in adult patients administered telavancin in previous clinical 
studies. Once the study has begun enrollment, a modified population PK model will be fit to 
the telavancin plasma concentration-time data from the first set of eight subjects in order to 


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assess the applicability of the model and to verify that dosing of the next set of eight 
subjects at 10 mg/kg remains appropriate. Further modifications to the model will be made if 
an adequate fit to the data is not obtained using the previous population PK model. These 
may include: 1) changes to the residual error model; 2) addition or deletion of inter-individual 
variability terms; and/or 3) modifications to the covariate relationships. The basic structural 
model (2 compartments, linear elimination) will not be modified. This process will be 
repeated for each successive set of eight subjects by fitting the model to all of the available 
data from the study at the time of the interim analysis. 
At study completion, the telavancin population PK model in children will be completed by 
fitting the model to the final, locked data from the protocol. In addition to confirming the 
covariate relationships identified in the iterative process described above, the model will be 
qualified using accepted pharmacometric techniques. The methods and results of the 
population PK analysis of data from this pediatric study will be reported separately from the 
clinical study report. 
Preliminary metabolite profiling of plasma may be conducted. 
8.6 
Data Monitoring Committees 
No data monitoring committee independent of the Sponsor is planned for this study. Refer to 
Section 6.5 for details regarding the Safety Data Review Committee comprised of internal  
Sponsor personnel only. 


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9 
STUDY ADMINISTRATION 
This study will be conducted in compliance with all applicable regulations. 
9.1 
Principal Investigator Responsibilities 
Before beginning the study, the principal investigator (PI) at each site must provide to the 
Sponsor or its designee a fully executed and signed Form FDA 1572 and, if applicable, a 
financial disclosure form. For applicable studies, financial disclosure forms must also be 
completed for all sub-investigators who will be directly involved in the treatment or 
evaluation of research subjects in this study. (A sub-investigator is defined in ICH E6 as any 
individual member of the clinical study team designated and supervised by the investigator 
at a study site to perform critical study-related procedures and/or to make important study-
related decisions [e.g., associates, residents, research fellows].) 
The PI will ensure the following: 
• 
He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when necessary 
to protect the safety, rights, or welfare of subjects. 
• 
He or she will personally conduct or supervise the study. 
• 
He or she will inform any potential subjects, or any persons used as controls, that the 
drugs are being used for investigational purposes and he or she will ensure that the 
requirements relating to obtaining informed consent in 21 CFR Part 50 and institutional 
review board (IRB) review and approval in 21 CFR Part 56 are met.  
• 
He or she will report to the sponsor adverse experiences that occur in the course of the 
investigation in accordance with 21 CFR 312.64. 
• 
He or she has read and understands the information in the Telavancin Investigator’s 
Brochure, including potential risks and side effects of the drug. 
• 
His or her staff and all persons who assist in the conduct of the study are informed about 
their obligations in meeting the above commitments 
• 
He or she will ensure that adequate and accurate records in accordance with 
21 CFR 312.62 and to make those records available for inspection in accordance with 
21 CFR 312.68. 
• 
He or she will ensure that the IRB/Independent Ethics Committee (IEC) complies with 
the requirements of 21 CFR Part 56, and other applicable regulations, and conducts 
initial and ongoing reviews and approvals of the study. He or she will also ensure that 
any change in research activity and all problems involving risks to human subjects or 
others are reported to the IRB/IEC. Additionally, he or she will not make any changes in 
the research without IRB/IEC approval, except where necessary to eliminate apparent 
immediate hazards to human subjects. 
• 
He or she agrees to comply with all other requirements regarding the obligations of 
clinical investigators and all other pertinent requirements in 21 CFR Part 312. 


Protocol 0101, Amendment 5                                                                                                26Aug2019 
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9.2 
Institutional Review Board/Independent Ethics Committee 
Before beginning study-specific research, the investigator will obtain written confirmation 
that the IRB, IEC, or Research Ethics Board (REB) is properly constituted and compliant 
with ICH and Good Clinical Practice (GCP) requirements, applicable laws, and local 
regulations. A copy of the confirmation from the IRB/IEC/REB will be provided to the 
Sponsor or its designee. The protocol, informed consent form (ICF), IB, and any other 
appropriate written information provided to the subjects that the IRB/IEC/REB may require to 
fulfill its responsibilities will be submitted to the IRB/IEC/REB in advance of the study. The 
Sponsor or its designee must approve the ICF and all subject recruitment materials before 
they are submitted to the IRB/IEC/REB. The study will not proceed until appropriate 
documents from the IRB/IEC/REB confirming unconditional approval of the protocol and the 
ICF are obtained by the investigator and copies are received by The Sponsor or its 
designee. If possible, the approval document should refer to the study by study protocol title 
and the Sponsor study number, identify the documents reviewed, and include the date of the 
review and approval. The written approval of the IRB/IEC/REB will be retained as part of the 
study file. The study may proceed before approval of consent forms and other study 
documents translated to a language other than the native language of the clinical site, 
provided that written IRB/IEC/REB approval of the translated documents is obtained before 
they are used. Any amendments to the protocol should be reviewed promptly. 
The investigator must provide the appropriate periodic reports on the progress of the study 
to the IRB/IEC/REB and the Sponsor in accordance with local IRB/IEC/REB requirements 
and applicable governmental regulations, whichever is strictest. 
9.3 
Informed Consent 
A properly written and executed ICF, in compliance with ICH E6 (GCP Guideline, 
Section 4.8), 21 CFR §50, and other applicable local regulations, will be obtained for each 
subject before enrollment of the subject into the study. The investigator will prepare the ICF 
or revise the template ICF and provide the documents to the Sponsor (or designee) for 
approval before submission to the IRB/IEC/REB. The Sponsor and the IRB/IEC/REB must 
approve the documents before they are implemented. 


Protocol 0101, Amendment 5                                                                                                26Aug2019 
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For studies in which a legally authorized representative (LAR) provides informed consent on 
behalf of the subject, documentation will also be required to indicate the relationship of the 
LAR to the subject. 
The investigator will provide copies of the signed ICF to each subject (or the subject’s legally 
authorized representative) and will maintain the original in the subject’s record file. 
9.4 
Data Recording and Quality Assurance 
As used in this protocol, the term case report form (CRF) should be understood to refer to 
either a paper form or an electronic data record or both, depending on the data collection 
method used. 
Electronic data capture (EDC) technology will be used for this study. All clinical information 
requested in this protocol will be recorded on the electronic case report forms approved by 
the Sponsor, or via other data collection methods, eg, electronic laboratory data transfer. 
Study site personnel will enter (in English) study data into the CRFs for each randomized 
subject. Training on the EDC application will be completed and documented before access 
to the EDC system is given. 
In the event of a CRF data change (eg, correction of an error or addition of new information), 
corrections will be made to the CRF. Corrections to the CRFs, including the reason for 
change, will be automatically documented through the EDC system’s audit trail. 
The investigator is responsible for reviewing all CRFs, verifying them for accuracy, and 
approving them via an electronic signature. The investigator is designated as the signatory 
coordinating investigator. 
An electronic copy of the CRF casebooks will be sent to the site for retention with other 
study documents after full completion of the study, ie, after database lock. 
The investigator is responsible for maintaining accurate, authentic, complete, and up-to-date 
records for each subject. The investigator is also responsible for ensuring the availability of 
any original source documentation related to the study (including any films, tracings, 
computer discs, tapes, and worksheets). In most cases the source is the subject’s medical 
record. Data collected on the CRFs must match the source documents. 


Protocol 0101, Amendment 5                                                                                                26Aug2019 
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In some cases, the CRF may also serve as the source document. In these cases, a 
document should be available at the investigator’s site and clearly identify those data that 
will be recorded in the CRF and for which the CRF will stand as the source document. 
9.5 
Document Retention 
Until otherwise notified by the Sponsor, an investigative site must retain in a controlled 
manner all study documents required by the Sponsor and by the applicable regulations. The 
investigative site must take measures to prevent accidental or premature destruction of 
essential documents, that is, documents that individually and collectively permit evaluation 
of the conduct of a study and the quality of the data produced, including paper copies of 
study records (e.g., subject charts) and any original source documents that are electronic, 
as required by applicable regulations. 
The investigator must consult the Sponsor representative before disposal of any study 
records and must notify the Sponsor of any change in the location or disposition of the study 
files. If an investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study documents, custody must be transferred to a person who 
will accept the responsibility. The Sponsor must be notified in writing of the name and 
address of the new custodian and must approve this transfer of responsibility. 
9.6 
Confidentiality 
The investigator or designee must explain to each subject, before enrollment into the study, 
that, for evaluation of study results, the subject’s confidential medical information obtained 
during the study may be shared with the study sponsor, regulatory agencies, and the 
institutional review board (IRB) or independent ethics committee (IEC). The investigator 
(or designee) is responsible for obtaining written permission to use confidential medical 
information in accordance with country-specific regulations (such as the Health Insurance 
Portability and Accountability Act in the United States) from each subject or, if appropriate, 
the subject’s legally authorized representative. If permission to use confidential medical 
information is withdrawn, the investigator is responsible for documenting that no further data 
from the subject will be collected. 
Subject medical information obtained during this study is confidential, and disclosure to 
unauthorized third parties is prohibited. The pertinent sections of data protection laws will be 
complied with in full. Study records containing subject information will only be identified by 


Protocol 0101, Amendment 5                                                                                                26Aug2019 
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the subject identification number, subject initials, date of birth, and study number, and not by 
the subject’s full name, except the subject consent form, which is archived at the study 
center only. The subject’s name will not be used in any public report of the study. 
During the course of the study, a confidential subject identification list will be maintained by 
the investigator and archived at the investigative site. 
Before and during the conduct of the study, no study-related details may be disclosed, 
ie, placed on the internet, published, or otherwise publicized, or provided to a third party 
without prior written permission from the Sponsor. The policy for publication of data after 
completion of the study is described in Section 9.9 (Publication). 
9.7 
Access to Data and Documents 
Upon receipt of the subject’s permission, medical information may be given to his or her 
personal physician or other appropriate medical personnel responsible for his or her welfare. 
Study data recorded on the CRFs must be verifiable to the source data. All original 
recordings, laboratory reports, and subject records generated by this study must be 
available to the Sponsor, representatives of the Sponsor, the IRB/IEC/REB, and applicable 
regulatory authorities, and they may be used for submission to regulatory authorities. In 
addition, all source data should be attributable (signed and dated), consistent with local 
medical practice. The investigator must therefore agree to allow direct access to all source 
data. Subjects (or their legally authorized representatives) must also allow access to their 
medical records, and subjects will be informed of this and will confirm their agreement when 
giving informed consent. 
9.8 
Quality Control: Study Monitoring and Auditing 
Qualified individuals designated by the Sponsor will monitor all aspects of the study 
according to GCP and standard operating procedures (SOPs) for compliance with 
applicable government regulations. The investigator agrees to allow these monitors direct 
access to the clinical data and supplies, dispensing, and storage areas and, if requested, 
agrees to assist the monitors. The investigator and staff are responsible for being present or 
available for consultation during routinely scheduled site visits conducted by the Sponsor or 
its designees. 


Protocol 0101, Amendment 5                                                                                                26Aug2019 
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Members of the Sponsor’s GCP Quality Assurance Department or designees may conduct 
an audit of a clinical site at any time during or after completion of the study. The investigator 
will be informed if an audit is to take place and advised as to the scope of the audit. 
Inspections and audits are typically carried out during the clinical and reporting phases of 
this study to ensure that the study is conducted and data are generated, documented, and 
reported in compliance with the protocol, GCP, written SOPs and applicable laws, rules, and 
regulations. 
Representatives of the FDA or other Regulatory Agencies, including IRB/IEC 
representatives may also conduct an audit of the study. If informed of such an inspection, 
the investigator should notify the Sponsor immediately. The investigator will ensure that the 
auditors have access to the clinical supplies, study site facilities, laboratory and all data 
(including original source documentation) and all study files are available, if requested. 
Noncompliance with the protocol, ICH, GCP, or local regulatory requirements by an 
investigator, institution, institution staff, or representatives of the Sponsor will lead to prompt 
action by the Sponsor to secure compliance. Continued noncompliance may result in 
termination of the investigator’s involvement in the study. The IRB/IEC/REB and relevant 
regulatory authority will be informed. 
9.9 
Publication 
The Sponsor recognizes the importance of communicating medical study data and therefore 
encourages their publication in reputable scientific journals and presentation at seminars or 
conferences. The Sponsor will retain the ownership of the data collected in this study. The 
investigator will provide any proposed manuscript or abstract to the Sponsor before 
submission for publication or presentation of any results or data obtained in this study. 
Additional details of the processes of producing and reviewing reports, manuscripts, and 
presentations based on the data from this study will be described in the Clinical Study 
Agreement between the Sponsor and the investigator. 


Protocol 0101, Amendment 5                                                                                                26Aug2019 
Telavancin 
Page 56 
 
 
10 
REFERENCES 
The following references are available upon request. 
1. 
Wang Y, Jadhav PR, Lala M, Gobburu, JV. Clarification on precision criteria to derive 
sample size when designing pediatric pharmacokinetic studies. J Clin Pharmacol. 
2012;52:1601-6. 
2. 
Samara E, Shaw JP, Barriere SL, Wong SL, Worboys P. Population 
pharmacokinetics of telavancin in healthy subjects and patients with infections. 
Antimicrob Agents Chemother. 2012;56(4):2067-73. 
3. 
Developed by the National Center for Health Statistics in collaboration with the 
national Center for Chronic Disease Prevention and Health Promotion (2000). 
http://www.cdc.gov/growthcharts 
4. 
Holford N. Dosing in children. Clin Pharmacol Ther. 2010 Mar;87(3):367-70. 
5. 
Beers, MH. The Merck Manual of Diagnosis and Therapy, Nineteenth Edition. The 
Merck Publishing Group, Rahway, NJ: Merck & Co, Inc., 2011. 
6. 
Rhodin MM et al. Human renal function maturation: a quantitative description using 
weight and postmenstrual age. Pediatr. Nephrol. 24, 67–76 (2009 
7. 
Schwartz G. Measurement and estimation of GFR in children and adolescents. Clin J 
Am Soc Nephrol. 2009 Nov;4(11):1832-43. 
8. 
Sahai, J, Healy DP, Shelton MJ, Miller JS, Ruberg SJ, Polk R. Comparison of 
vancomycin and teicoplanin-induced histamine release and “red man syndrome”. 
Antimicrob. Agents Chemother. 1990, 34(5):765-9. 
 


Protocol 0101, Amendment 5                                                                                                26Aug2019 
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Page 57 
 
 
11 
APPENDICES 
 


Protocol 0101, Amendment 5                                                                                                26Aug2019 
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Page 58 
 
 
Appendix 1: 
Growth Charts for Boys, Birth to 36 Months 
 


Protocol 0101, Amendment 5                                                                                                26Aug2019 
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Page 59 
 
 
Appendix 2: 
Growth Charts for Girls, Birth to 36 Months 
 


Protocol 0101, Amendment 5                                                                                                26Aug2019 
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Page 60 
 
 
Appendix 3: 
Weight-for-Age Percentiles (5th to 95th Percentiles) for Boys, 
2−20 Years 
 


Protocol 0101, Amendment 5                                                                                                26Aug2019 
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Appendix 4: 
Weight-for-Age Percentiles (5th to 95th Percentiles) for Girls, 
2−20 Years 
 


Protocol 0101, Amendment 5                                                                                                26Aug2019 
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Page 62 
 
 
Appendix 5: 
Schwartz Equation for Estimated Creatinine Clearance 
The estimated creatinine clearance will be calculated using the Schwartz equation {5, 7} as 
follows:   
creatinine clearance (mL/min/1.73m2) = 
k × height or length (in cm) 
serum creatinine (in mg/dL) 
 
 
 
Where k = constant of proportionality that is age-specific: 
 
k = 0.55 for subjects 1 to 12 years 
k = 0.55 for female subjects >12 years  
k = 0.70 for male subjects >12 years  
 
 
 


Protocol 0101, Amendment 5                                                                                                26Aug2019 
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Page 63 
 
 
Appendix 6: 
Severity Grading for Red Man Syndrome 
 
No Reaction 
Mild 
Moderate 
Severea 
Erythema 
0 
(<1% BSA) 
1 
(1 - 5% BSA) 
2 
(5 - 10% BSA) 
3 
(>10% BSA) 
Pruritus 
0 
1 
2 
3 
Global Severity 
(Calculated from the sum of 
the individual scores for 
erythema and pruritus) 
0 
1-2 
3-4 
5-6 
BSA – body surface area 
a 
Red man syndrome may also meet severe criteria if muscle spasm, chest pain, dyspnea, or 
hypotension is present. 
Source: Sahai, et al {7} 
 
 
 


Protocol 0101, Amendment 5                                                                                                                                                                        26Aug2019 
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Appendix 7: 
Number of Samples and Approximate Amount of Blood to Be Collected from Each Subject 
Blood Draws for Study 0101 
 
Prestudy 
Screen 
Day 1 
Day 2 
Total # 
Blood 
Draws 
Approximate blood 
Volume Per Drawa 
(mL) 
Subtotal mL of 
Blood 
Hours post dose 
1 
1.5 
2 
6 
12 
24 
 
 
 
Pregnancy Test* 
1 
 
 
 
 
 
 
1 
1 
1 
Hematology 
1 
 
 
 
 
 
1 
2 
2 
4 
Chemistry 
1 
 
 
 
 
 
1 
2 
3.5 
7 
Plasma PK 
 
1 
1 
1 
1 
1 
1 
6 
0.5 
3 
Total / study day 
2-3* 
5 
3 
8 
 
 
 
Total volume needed (mL) 
14.0-15.0 mL*a 
* 1.0 mL required for those not requiring a pregnancy test; pregnancy test done only on females who have reached menarche 
a. Actual blood volume will vary by institution, but will not exceed not exceed 5% of total blood volume (TBV) over 24 hours and up to 10% of TBV over 8 weeks 
(see Section 6.2).  


Protocol 0101, Amendment 5                                                                                                                                                                        26Aug2019 
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Appendix 8: 
Maximum Allowable Total Blood Volumes to Be Collected from Each Subject 
CMRC IRB MAXIMUM ALLOWABLE TOTAL BLOOD DRAW VOLUMES (CLINICAL + RESEARCH) 
Body Wt (Kg) 
Body Wt 
(lbs) 
Total blood 
volume (mL) 
Maximum allowable volume 
(mL) in one blood draw 
(= 2.5% of total blood 
volume) 
Total volume (clinical + 
research) maximum 
volume (mL) drawn in a 
30-day period 
Minimum 
Hgb required 
at time of 
blood draw 
Minimum Hgb required at 
time of blood draw if 
subject has respiratory/CV 
compromise 
1 
2.2 
100 
2.5 
5 
7.0 
9.0 -10.0 
2 
4.4 
200 
5 
10 
7.0 
9.0-10.0 
3 
6.3 
240 
6 
12 
7.0 
9.0-10.0 
4 
8.8 
320 
8 
16 
7.0 
9.0-10.0 
5 
11 
400 
10 
20 
7.0 
9.0-10.0 
6 
13.2 
480 
12 
24 
7.0 
9.0-10.0 
7 
15.4 
560 
14 
28 
7.0 
9.0-10.0 
8 
17.6 
640 
16 
32 
7.0 
9.0-10.0 
9 
19.8 
720 
18 
36 
7.0 
9.0-10.0 
10 
22 
800 
20 
40 
7.0 
9.0-10.0 
11-15 
24-33 
880-1200 
22-30 
44-60 
7.0 
9.0-10.0 
16-20 
35-44 
1280-1600 
32-40 
64-80 
7.0 
9.0-10.0 
21-25 
46-55 
1680-2000 
42-50 
64-100 
7.0 
9.0-10.0 
26-30 
57-66 
2080-2400 
52-60 
104-120 
7.0 
9.0-10.0 
31-35 
68-77 
2480-2800 
62-70 
124-140 
7.0 
9.0-10.0 
36-40 
79-88 
2880-3200 
72-80 
144-160 
7.0 
9.0-10.0 
41-45 
90-99 
3280-3600 
82-90 
164-180 
7.0 
9.0-10.0 
46-50 
101-110 
3680-4000 
92-100 
184-200 
7.0 
9.0-10.0 
51-55 
112-121 
4080-4400 
102-110 
204-220 
7.0 
9.0-10.0 
56-60 
123-132 
4480-4800 
112-120 
224-240 
7.0 
9.0-10.0 
61-65 
134-143 
4880-5200 
122-130 
244-260 
7.0 
9.0-10.0 
68-70 
145-154 
5280-5600 
132-140 
264-280 
7.0 
9.0-10.0 
71-75 
156-185 
5680-6000 
142-150 
284-300 
7.0 
9.0-10.0 
76-80 
167-176 
6080-6400 
152-160 
304-360 
7.0 
9.0-10.0 
81-85 
178-187 
6480-6800 
162-170 
324-340 
7.0 
9.0-10.0 
86-90 
189-198 
6880-7200 
172-180 
344-360 
7.0 
9.0-10.0 
91-95 
200-209 
7280-7600 
182-190 
364-380 
7.0 
9.0-10.0 
96-100 
211-220 
7680-8000 
192-200 
384-400 
7.0 
9.0-10.0