Clinical trial NCT02750761
Conditions: Gram-Positive Bacterial Infections
Sponsor: Merck Sharp & Dohme LLC
Start date: 2016-05-02; Completion date: 2018-12-21
Enrollment: 32 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study to assess the pharmacokinetics (PK) of tedizolid phosphate and its active metabolite, tedizolid, and the safety of tedizolid phosphate following administration of a single IV (Part A) or oral suspension (Part B) administration to hospitalized participants ages 6 to \<12 years (Groups 1 and 3, respectively), and 2 to \<6 years (Groups 2 and 4, respectively).

Detailed description:
Part A (IV):

* Group 1 (Cohort 1 and Cohort 2) (6 to \<12 years)
* Group 2 (Cohort 1 and Cohort 2) (2 to \<6 years)

Part B (Oral Suspension):

* Group 3 (6 to \<12 years)
* Group 4 (2 to \<6 years)

In Cohort 1 of Group 1 (IV) participants received a single administration of tedizolid phosphate at 5 mg/kg of total body weight. After all participants in Cohort 1 of Group 1 received study drug, a preliminary analysis of the safety and PK data was performed and results were used to select 4 mg/kg as the appropriate dose for Cohort 2 of Group 1 and Group 3, and to select 6 mg/kg as the starting dose for the younger participants, Cohort 1 of Group 2. After all participants in Cohort 1 of Group 2 receive study drug, another preliminary analysis of the safety and PK data will be performed and results will be used to confirm 6 mg/kg as the appropriate dose for Cohort 2 of Group 2. Similarly, the Group 4 dose will be confirmed after data review of Group 3 results.

Arms: arm 1: Participants 6 to \<12 years of age received a single intravenous infusion of tedizolid phosphate dosed at 5 mg/kg of total body weight. Maximum dose is 200 mg of tedizolid phosphate. arm 2: Participants 6 to \<12 years of age received a single intravenous infusion of tedizolid phosphate dosed at 4 mg/kg of total body weight. Maximum dose is 200 mg of tedizolid phosphate. arm 3: Participants 2 to \<6 years of age received a single intravenous infusion of tedizolid phosphate dosed at 6 mg/kg of total body weight. Maximum dose is 200 mg of tedizolid phosphate. arm 4: Participants 2 to \<6 years of age received a single intravenous infusion of tedizolid phosphate dosed at 3 mg/kg of total body weight. Maximum dose is 200 mg of tedizolid phosphate. arm 5: Participants 6 to \<12 years of age received a single dose of tedizolid phosphate oral suspension dosed at 4 mg/kg of total body weight. Maximum dose is 200 mg of tedizolid phosphate. arm 6: Participants 2 to \<6 years of age received a single dose of tedizolid phosphate oral suspension dosed at 3 mg/kg of total body weight. Maximum dose is 200 mg of tedizolid phosphate.
Interventions: intervention 1: Tedizolid Phosphate (IV) intervention 2: Tedizolid Phosphate (oral suspension)
Intervention descriptions: intervention 1: 200 mg/vial powder for injection intervention 2: Powder for oral suspension 20 mg/mL following reconstitution

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT02750761  
Document Date: 
23-Jun-2017
A Phase 1, Single-Administration Pharmacokinetic and Safety Study 
of Oral and IV Tedizolid Phosphate in Hospitalized Subjects 2 to 
<12 Years Old


Tedizolid Phosphate (MK-1986)
Protocol TR701-120/MK-1986-013, Amendment 4
1
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Confidential
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & DOHME 
CORP., A SUBSIDIARY OF MERCK & CO., INC., WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Cubist Pharmaceuticals, LLC,
A wholly-owned indirect subsidiary of 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
Weystrasse 20, Lucerne 6
Switzerland
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File Binder (or 
equivalent).
TITLE:
A Phase 1, Single-Administration Pharmacokinetic and Safety Study of Oral and IV Tedizolid 
Phosphate in Hospitalized Subjects 2 to <12 Years Old
IND NUMBER:  [106,307 (IV) and 125,076 (Oral Suspension)]
EudraCT NUMBER:  2015-004595-29
 
 
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SUMMARY OF CHANGES: TR701-120 Amendment 4
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section
Change
Rationale
1.0 Synopsis 
Methodology;
Investigational 
product, dosage and 
mode of 
administration         
6.1 Overall Study 
Design
Updated dose for 6 to <12 years from 5 mg/kg to 
4mg/kg, dose for 2 to <6 years from 5 mg/kg to 6 
mg/kg based on the data from interim safety and 
pharmacokinetic analyses; updated with alternative 
enrollment sequences for both older and younger 
age groups.
The dose level for the two age groups was adjusted 
based on the results of the first interim analysis of the 
safety and pharmacokinetic data. The new dose levels 
are expected to provide a closer match to the adult 
pharmacokinetic parameters. The order of dosing groups 
was also adjusted to allow the flexibility to enroll the 
second IV cohorts for each age group, wholly or in part, 
prior to initiation of the oral groups, in case there is a 
delay in the availability of the tedizolid phosphate oral 
suspension. This flexibility will minimize the duration 
of the trial and allow continued enrollment in the study 
since the initiation of other clinical trials is dependent
on the results of MK-1986-013, and does not impact the 
assessment of appropriate doses for subsequent age. 
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section
Change
Rationale
Title Page
Changed the sponsor address
Corrected business address (business address of Cubist, 
rather than Merck & Co.).
1.0 Synopsis  
Name of 
Sponsor/Company; 
Investigators
Updated the Sponsor name from “a wholly-owned 
subsidiary of Merck” to “a wholly-owned 
subsidiary of Merck Sharp & Dohme Corp”; 
remove row of Investigators.
Corrected Sponsor name; removed row of Investigators 
as this information is not necessary for the synopsis of 
the protocol.
3.0 List of 
Abbreviations and 
Definition of Terms
Added PfOS, Powder for Oral Suspension to the 
list.
Updated the list.
 
 
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Section
Change
Rationale
4.0 Introduction
Separated TR701-120 (MK-1986-013) from 
planned studies to ongoing studies in Table 2.
Reflected current studies’ status.
6.1 Overall Study 
Design
Added rescreening language.
Clarified if a subject does not meet certain entry criteria, 
rescreen is allowed.
8.2 Concomitant 
Medications
Added reference number of monoamine oxidase 
inhibitors or serotonergic agents.
Made it easier for reference.
9.2.1 Intravenous 
Tedizolid 
Phosphate
Removed “Calculations of” from “Calculations of 
dose allowable volumes, and infusion rate required 
are provided in the Pharmacy Manual”.
Site is not required to calculate the dose but should look 
for the dose provided in the pharmacy manual.
9.2.2 Oral Tedizolid 
Phosphate
Removed “Calculations of” from “Calculations of 
volume required is provided in the Pharmacy 
Manual.”
Site is not required to calculate the volume but should 
look for the volume provided in the pharmacy manual.
10.2.2 Definition of 
an Overdose for this 
Protocol and 
Reporting an 
Overdose to the 
Sponsor
Clarified the nominal dose used to report an 
overdose for this trial is based on age group and 
body weight.
Clarified the nominal dose to ensure accurate reporting 
of an overdose.
12.2 Samples
Updated “Part V” to “Part B” in Table 5 
Pharmacokinetic sampling scheme; added footnote 
stating if a subject vomits during and/or after oral 
dose administration within 1.5 hours, PK samples 
will not be collected. However, vomiting must be 
recorded as AE.
Corrected the typing error; subjects who vomit during 
oral dosing will not get the full dose of the study drug. 
Therefore, PK sample should not be collected. However, 
vomiting itself is considered as an adverse event, and 
should be reported as such.
 
 
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Section
Change
Rationale
19.0
Appendix D 
Schedule of Study 
Assessments
Updated footnote (b) to allow ECGs collected 
within the 30 days prior to screening to be used to 
satisfy the entry criterion; updated footnote (c) 
removed oral from the measurement of temperature
but added the consistent method should be used to 
obtain body temperature; removed “supine” from 
measurement of resting BP but added that it should 
be measured in the same position each time.;
updated footnote (f) from “HDYF inquiry 
performed at each vital signs measurement” to 
“HDYF inquiry performed at vital signs 
measurement, once daily”; added footnote (i) to 
clarify that safety labs collected as part of standard 
care can be used for screening if they are within the 
7 days prior to dosing.
Clarified prior ECG and safety laboratory collected 
prior to the study can be used to satisfy entry criteria if 
meets the required window; multiple methods of 
measuring temperature in children are standard and 
permissible; as long as resting BP is measured in a 
consistent fashion, it will allow for monitoring of 
changes.; HDYF is only intended to be asked once per 
day, rather than at every blood pressure measurement; 
allowance of prior lab values as long as they are within 
7 days prior to receipt of study drug minimizes blood 
sampling and stress/distress to the child.
19.0 
Appendix E
Examples of 
Prohibited 
Concomitant 
Medications
Added examples of prohibited medications related 
to exclusion criterion #11
Provided reference.
Global
Minor edits.
 
 
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INVESTIGATOR’S AGREEMENT
I have received and read the Investigator’s Brochure for tedizolid phosphate.  I have read the 
TR701-120 protocol and agree to conduct the study as outlined.  I will also ensure that sub-
investigator(s) and other relevant members of my staff have access to this protocol. I agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol.
Phase 1, Single-Administration Pharmacokinetic and Safety Study of Oral and IV Tedizolid
Phosphate in Hospitalized Subjects 2 to <12 Years Old
Printed Name of Investigator
Signature of Investigator
Date
 
 
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1.0
SYNOPSIS
Name of Sponsor/Company: Cubist Pharmaceuticals, LLC (Cubist), a wholly-owned 
subsidiary of Merck Sharp & Dohme Corp.
Name of Investigational Product:  Tedizolid Phosphate
Name of Active Ingredient:  tedizolid phosphate
Title of Study: Phase 1, Single-Administration Pharmacokinetic and Safety 
Study of Oral and IV Tedizolid Phosphate in Hospitalized Subjects 2 to <12 
Study center(s):  Approximately 20
Study period (years):
Estimated date first subject enrolled: May 2016
Estimated date last subject completed: April 2018
Phase of development: 1
Objectives:
Part A (Intravenous [IV] Study Drug Administration)
Primary objective:  To describe the single-administration pharmacokinetics (PK) of IV
tedizolid phosphate (TZD) and its active metabolite, tedizolid, in subjects ages 6 to <12 years
(Group 1) and 2 to <6 years (Group 2).
Secondary objective:  To evaluate the safety and tolerability of IV TZD administration in
subjects ages 6 to <12 years (Group 1) and 2 to <6 years (Group 2).
Part B (Oral Study Drug Administration)
Primary objective:  To describe the bioavailability of tedizolid following oral TZD 
administration to subjects ages 6 to <12 years (Group 3) and 2 to <6 years (Group 4).
Secondary objective:
•  To evaluate the safety and tolerability of oral TZD administration in subjects ages 6 to
<12 years (Group 3) and 2 to <6 years (Group 4).
•  To evaluate the palatability of oral TZD suspension in subjects ages 6 to <12 years
(Group 3) and 2 to <6 years (Group 4).
Study Rationale:  Safety and PK results will determine the appropriate dose for a
subsequent safety and efficacy study in children from 3 months to <12 years, and for PK
studies in younger children, i.e., preterm and full-term neonates, and infants/toddlers.
 
 
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Methodology: This is an open-label, multicenter, 2-part, single-administration study to
assess the PK of TZD and its active metabolite, tedizolid, and the safety of TZD following
administration of a single IV (Part A) or oral (Part B) administration to hospitalized subjects 
ages 6 to <12 years (Groups 1 and 3, respectively), and 2 to <6 years (Groups 2 and 4,
respectively). Subjects receiving prophylaxis for or being treated for a confirmed or 
suspected infection with Gram-positive bacteria will be enrolled. The IV groups will be split 
into 2 cohorts of 5 subjects each.
Prior to this amendment, 5 subjects ages 6 to <12 from 
Cohort 1 of Group 1 received the study drug at dose of 5 mg/kg of total body weight.  The 
table below summarizes the parts (administration route), groups (age), and cohorts (dose) of 
the amended study.
Part A – IV administration
Dose
Group 1: 6 to <12 years (N=10)
Cohort 1: 5 mg/kg (completed)
Cohort 2: 4 mg/kg 
Group 2: 2 to <6 years (N=10)
Cohort 1: 6 mg/kg 
Cohort 2: 6 mg/kg or modified
Part B – Oral administration
Group 3: 6 to <12 years (N=6)
4 mg/kg
Group 4: 2 to <6 years (N=6)
6 mg/kg or modified
TZD will be administered to subjects any time after antimicrobial administration with a non-
study antibiotic has been initiated.
Progression to younger ages will be conducted as follows:
The first group enrolled was Group 1 Cohort 1; following enrollment of all 5 patients in this 
cohort, a preliminary analysis took place to review the pharmacokinetic and safety data to 
confirm or adjust the dose for the remaining subjects in this age range (Group 1 Cohort 2 and 
Group 3). Analysis of the safety data indicate that the 5 mg/kg dose is well tolerated. 
Pharmacokinetic analyses indicated  the appropriate dose level for subjects 6 to < 12 years 
should be adjusted downward to 4 mg/kg, and for subjects 2 to <6 years old adjusted upward 
to 6 mg/kg, to better match to adult pharmacokinetic parameters and increase the likelihood 
of target attainment in later efficacy and safety studies. The modified dose level was 
communicated to sites via a memo and a revised Pharmacy Manual.
The younger age range will follow a similar sequence, with a preliminary analysis of PK and 
safety after the first cohort of Group 2 receiving 6 mg/kg IV has been enrolled, in order to 
confirm or adjust the dose for the remaining subjects in this age range (Group 2 Cohort 2 and 
Group 4).
In order to expedite the initiation of later studies that depend on oral and IV PK data, further 
enrollment in the 6 to <12 years age range was planned to initiate with Group 3 (oral), to 
evaluate bioavailability, prior to enrolling the remainder of the IV Group 1Cohort 2. A 
similar sequence of enrollment (IV Group 2 Cohort 1, Oral Group 4, and IV Group 2 Cohort 
2) is planned for enrollment of the lower age group.
However, it is not necessary to evaluate bioavailability prior to selecting an appropriate dose 
and proceeding with dosing in IV Group 1 Cohort 2 or Group 2 Cohort 2.  Under 
 
 
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Amendment 4, the order of dosing for either age group is now flexible and can be altered as 
follows. If the powder for oral suspension is not available at the time of planned oral group 
enrollment, enrollment of the second IV cohort may be initiated prior to enrollment of the 
oral cohort. In this case, enrollment of the oral dosing group will be initiated as soon as the 
oral suspension is available, whether the enrollment of the second IV cohort is completed or 
not.  If the oral group is started before the second IV cohort is completed, enrollment in the 
second IV cohort will be paused and second IV cohort will only be completed once the full
oral group is enrolled. A bioavailability assessment will also be performed following 
completion of Group 3; available PK data from all prior cohorts in the study will be used to 
inform the dose selection of Group 4.
In addition to safety (clinical laboratory evaluations; physical, examinations; adverse 
events), palatability will be assessed in oral TZD suspension in subjects ages 6 to <12 years
(Group 3) and 2 to <6 years (Group 4). Subjects will receive study drug on Day 1, with 
study visits on Day 2 and Day 8. The Day 8 Visit may be a telephone contact.
Number of subjects (planned): At least 32 subjects will be enrolled in this study to ensure at 
least 28 subjects with complete PK profiles.
Part A: At least 20 subjects will be enrolled to receive IV TZD (10 subjects in Groups 1 and 
10 subjects in Group 2 [5 subjects in each of 2 cohorts]).
Part B: At least 12 subjects will be enrolled to receive oral TZD (6 subjects in Group 3 and 6 
subjects in Group 4).
Criteria for Inclusion:
1. Aged 2 to <12 years at the time of consent
2. Receiving prophylaxis for or with a confirmed or suspected infection with Gram-
positive bacteria and receiving concurrent antibiotic treatment with Gram-positive 
antibacterial activity
3. Weight >5th percentile and <95th percentile based on age
(http://www.cdc.gov/growthcharts/clinical_charts.htm)
4. Stable condition as determined from medical history, physical examination,
electrocardiogram
(minimally 5-lead), vital signs, and clinical laboratory evaluations
5. No clinically significant ECG abnormalities in the judgment of the Investigator
6. Serum creatinine within 1.5 × upper limit of reference range based on age
7. Females must be pre-menarchal, abstinent, or practicing an effective method of birth 
control
8. Negative blood or urine beta-human chorionic gonadotropin pregnancy test (if urine test
is used, it must be high sensitivity [i.e., able to detect 10 mIU/mL β-hCG]) at the
Screening Visit (post-menarchal females only)
9. Subjects and parents must be willing to adhere to the prohibitions and restrictions 
specified in this protocol
10. Parents or subjects’ legally authorized representative (LAR) able to give informed
consent and willing and able to comply with all required study procedures. Assent is 
also required of children capable of understanding the nature of the study (typically ≥7
years old)
 
 
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Criteria for Exclusion:
1. History of seizures, other than febrile seizures, clinically significant cardiac 
arrhythmia, cystic fibrosis, moderate or severe renal impairment, or any physical 
condition that could interfere with the interpretation of the study results, as
determined by the Investigator
2. Use of rifampin within, 14 days prior to study drug administration
3. Use of ranitidine, cimetidine, and antacids for subjects in Part B (oral 
administration) from 24 hours prior to study drug administration and throughout the 
study
4. Recent (3 month) history or current infection with viral hepatitis or other significant 
hepatic disease
5. History of drug allergy or hypersensitivity to oxazolidinones
6. Pregnant or breast feeding
7. Significant blood loss (≥5% of total blood volume) within 60 days before the 
Screening Visit
8. Any acute or chronic condition that, in the opinion of the Investigator, would limit 
the subject’s ability to complete and/or participate in this clinical study
9. Treatment with investigational medicinal product within 30 days before the 
infusion/dose of study drug
10. Need for oral administration of methotrexate, topotecan, irinotecan or rosuvastatin, 
during administration of oral study drug. (Administration during the follow-up 
period is allowed, as is administration during treatment with IV study drug.)
11. Use of monoamine oxidase inhibitors or serotonergic agents including tricyclic 
antidepressants, selective serotonin reuptake inhibitors, and serotonin 5 
hydroxytryptamine receptor agonists (triptans), meperidine, or buspirone within,14 
days prior to study, or planned use while on study
Investigational product, dosage and mode of administration:
Five subjects of Group 1 Cohort 1 received a single dose of 5 mg/kg dose prior to this 
amendment.  
Under this amendment, subjects 6 to <12 years of age will receive a single 4 mg/kg dose TZD, 
and subjects 2 to <6 years of age will receive a 6 mg/kg dose (with possible adjustment based 
on data from preliminary analyses), as either an IV infusion (Tedizolid Phosphate for Injection,
200 mg/vial diluted into sterile saline for injection; infused at a rate to deliver the desired dose 
in 60 minutes [up to 200 mg]; Part A) or an oral suspension (Part B). See Pharmacy Manual 
for instructions, including allowable IV volumes.
Duration of study:  Enrollment will be completed within approximately 2 years.  The overall 
duration of the study will be up to 11 days from the Screening Visit through the last visit (Day
8), unless a subject is being monitored for an a serious adverse event (SAE).  Subjects will be 
monitored for AEs through 7 days after study drug administration and SAEs will be followed 
until stabilization, resolution/death, or consent/assent is withdrawn.
 
 
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Criteria for evaluation: Safety
Safety evaluations will include laboratory evaluations (hematology, serum chemistry, and 
urinalysis; see APPENDIX A. CLINICAL LABORATORY EVALUATIONS), pregnancy 
testing (for females of childbearing potential in Groups 1 and 3), vital signs, physical 
examinations, monitoring of AEs, recording of concomitant medications, and monitoring of
venous tolerability (for subjects who receive IV drug).
PK
Plasma samples will be analyzed for concentrations of TZD and its active metabolite, tedizolid. 
Based on the individual plasma concentration-time data, using actual sampling times, PK
parameters for tedizolid and TZD
including the following will be determined:
•  maximum observed drug concentration in plasma (Cmax)
•  time to reach peak plasma concentration (tmax)
•  area under the plasma concentration-time curve (AUC)
•  terminal elimination half-life (t½)
•  clearance after oral and IV administration (CL/F and CL, respectively)
Palatability: Palatability will be assessed using a hedonic scale (see APPENDIX B. 
PALATABILITY ASSESSMENT) and spontaneous verbal judgment.
Analysis Sets:
The Intent to Treat analysis set will consist of data from all enrolled subjects. 
Enrolled subjects include all subjects whose designee signs the Informed Consent 
Form.
The Safety analysis set will consist of data from subjects who receive any study drug.
The PK analysis set will consist of data from subjects who receive study drug and have 
at least 1 quantifiable post-administration concentration.
 
 
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Statistical methods:
No formal statistical tests are planned.  The planned sample size is not based on a
power calculation; sample size is similar to other pediatric PK studies.
Study data will be presented using summary statistics by group (Groups 1-4). Continuous
study data will be summarized with the number of subjects, mean standard deviation,
median, minimum, and maximum. Categorical data will be summarized with the number
and percentage in each category. Demographic information and baseline characteristics 
will be summarized by age group and dose cohort. For PK summaries, geometric means 
and coefficients of variation will be calculated, as appropriate.
PK analyses
Descriptive statistics will be presented for tedizolid and TZD plasma concentrations by 
group.  Mean and individual plasma concentration-time profiles will be plotted in linear
and semilogarithmic scales.  All TZD and tedizolid PK parameters will be summarized by 
treatment using summary statistics.
Safety data
Safety data will be tabulated and summarized separately for each age group and dose cohort.
The number and percentage of subjects reporting treatment-emergent AEs (TEAEs) will be
presented by System Organ Class (SOC) and preferred term according to the Medical
Dictionary for Regulatory Activities (MedDRA), by relationship to the study drug 
administration and by severity.
Hematology and chemistry laboratory data, and vital signs data will be summarized using
summary statistics. Changes from the Screening Visit to Day 2 will also be summarized for
laboratory and vital signs data.  All safety data will be listed.
Palatability assessments of oral suspension will be analyzed using descriptive statistics.
 
 
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2.0
TABLE OF CONTENTS AND LIST OF TABLES 
1.0
SYNOPSIS........................................................................................................................... 6
2.0
TABLE OF CONTENTS AND LIST OF TABLES.......................................................... 12
3.0
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.................................... 17
4.0
INTRODUCTION ............................................................................................................. 18
5.0
TRIAL OBJECTIVES AND PURPOSE ........................................................................... 20
Primary Objective .......................................................................................................... 20
5.1
Secondary Objective ...................................................................................................... 20
5.2
6.0
INVESTIGATIONALPLAN ............................................................................................ 20
Overall Study Design ..................................................................................................... 20
6.1
Number of Subjects........................................................................................................ 24
6.2
Treatment Assignment ................................................................................................... 24
6.3
7.0
SELECTION AND WITHDRAWAL OF SUBJECTS ..................................................... 24
Subject Inclusion Criteria............................................................................................... 24
7.1
Subject Exclusion Criteria.............................................................................................. 25
7.2
Subject Withdrawal Criteria ........................................................................................... 26
7.3
Subject Withdrawal from the Study........................................................................ 26
7.3.1
Study or Site Discontinuation ................................................................................. 26
7.3.2
8.0
TREATMENT OF SUBJECTS ......................................................................................... 26
Description of Study Drug.............................................................................................. 26
8.1
Concomitant Medications .............................................................................................. 26
8.2
Treatment Compliance ................................................................................................... 27
8.3
Randomization and Blinding.......................................................................................... 27
8.4
9.0
STUDY DRUG MATERIALS AND MANAGEMENT................................................... 27
Study Drug Formulation/Packagingand Labeling/Storage ............................................ 27
9.1
Administration................................................................................................................ 27
9.2
Intravenous Tedizolid Phosphate............................................................................ 28
9.2.1
Oral Tedizolid Phosphate........................................................................................ 28
9.2.2
Study Drug Accountability, Handling, and Disposal ..................................................... 28
9.3
10.0
ASSESSMENT OF SAFETY............................................................................................ 29
Safety Variables ............................................................................................................. 29
10.1
Assessing and Recording Adverse Events ..................................................................... 29
10.2
Definition of Adverse Events.................................................................................. 29
10.2.1
 
 
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Definition of an Overdose for this Protocol and Reporting of an Overdose to the 
10.2.2
Sponsor 30
Reporting of Pregnancy and Lactation to the Sponsor ........................................... 30
10.2.3
Immediate Reporting of Adverse Events to the Sponsor........................................ 31
10.2.4
10.2.4.1
Serious Adverse Events ..............................................................................................31
10.2.4.2
Events of Clinical Interest............................................................................................32
Evaluating Adverse Events..................................................................................... 33
10.2.5
Sponsor Responsibility for Reporting Adverse Events .......................................... 36
10.2.6
11.0
ASSESSMENT OF PALATABILITY.............................................................................. 36
12.0
PHARMACOKINETIC ASSESSMENT .......................................................................... 36
Assessment..................................................................................................................... 36
12.1
Samples .......................................................................................................................... 36
12.2
13.0
STATISTICAL METHODS.............................................................................................. 37
Analysis Sets .................................................................................................................. 37
13.1
Determination of Sample Size........................................................................................ 38
13.2
General Statistical Considerations.................................................................................. 38
13.3
Subject Enrollment and Disposition, and Protocol Violations/Deviations............. 38
13.3.1
Study Drug Exposure.............................................................................................. 39
13.3.2
Demographics and Baseline Characteristics........................................................... 39
13.3.3
Pharmacokinetic Analysis .............................................................................................. 39
13.4
Safety Analysis............................................................................................................... 39
13.5
Adverse Events ....................................................................................................... 39
13.5.1
Laboratory Evaluations........................................................................................... 40
13.5.2
Prior and Concomitant Medications ....................................................................... 40
13.5.3
Handling of Missing Data .............................................................................................. 41
13.6
14.0
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS................................................ 41
Study Monitoring ........................................................................................................... 41
14.1
Protocol Violations and Deviations ........................................................................ 42
14.1.1
15.0
ETHICS ............................................................................................................................. 42
Ethics Review................................................................................................................. 42
15.1
Written Informed Consent.............................................................................................. 43
15.2
Subject Confidentiality................................................................................................... 43
15.3
16.0
DATA HANDLING AND RECORDKEEPING............................................................... 44
Case Report Forms and Study Records .......................................................................... 44
16.1
 
 
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Data Quality Assurance.................................................................................................. 44
16.2
Inspection of Records..................................................................................................... 45
16.3
Retention of Records...................................................................................................... 45
16.4
17.0
PUBLICATION POLICY ................................................................................................. 45
18.0
LIST OF REFERENCES................................................................................................... 45
19.0
APPENDICES ................................................................................................................... 46
APPENDIX A.  CLINICAL LABORATORY EVALUATIONS................................................ 47
APPENDIX B.  PALATABILITY ASSESSMENT..................................................................... 48
APPENDIX C.  PHARMACOKINETIC SAMPLING ................................................................ 49
APPENDIX D.   SCHEDULE OF STUDY ASSESSMENTS..................................................... 50
APPENDIX E.   Examples of Prohibited Concomitant Medications ........................................... 51
20.0
SIGNATURE..................................................................................................................... 52
 
 
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LIST OF TABLES
Table 1  Abbreviations and Specialist Terms ............................................................................... 17
Table 2  Pediatric Studies ............................................................................................................. 19
Table 3  Study TR701-120 Parts, Groups, and Cohorts ............................................................... 21
Table 4  Evaluating Adverse Events............................................................................................. 34
Table 5  Pharmacokinetic sampling scheme................................................................................. 37
 
 
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LIST OF FIGURES
Figure 1
Study Scheme for TR701-120.................................................................................... 23
Figure 2
Study Progression for TR701-120: Oral and IV administration................................. 23
 
 
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3.0
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Table 1  Abbreviations and Specialist Terms
Abbreviation or Specialist Term
Explanation
ABSSSI
Acute bacterial skin and skin structure infections
AE
Adverse event
AUC
Area under the plasma concentration-time curve
CFR
Code of Federal Regulations
CI
Confidence interval
CL
Clearance after IV administration
CL/F
Clearance after oral administration
Cmax
Maximum observed drug concentration in plasma
cSSTIs
Complicated skin and soft tissue infections
ECG
Electrocardiogram
e-CRF
Electronic case report form
GCP
Good Clinical Practice
ICF
Informed consent form
ICH
International Conference on Harmonisation
IRB
Institutional Review Board
ITT
Intent to treat
LAR
Legally authorized representative
MedDRA
Medical Dictionary for Regulatory Activities
PDCO
EMA/Paediatric Committee
PfOS
Powder for Oral Suspension
PK
Pharmacokinetics
SAE
Serious adverse event
SOC
System organ class
t½
Terminal elimination half-life
TEAE
Treatment-emergent adverse events
tmax
Time to reach peak plasma concentration
TZD
Tedizolid phosphate
WHO
World Health Organization
 
 
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4.0
INTRODUCTION
Tedizolid phosphate (Sivextro™, TR-701 FA, MK-1986) is a novel oxazolidinone prodrug 
antibiotic that is rapidly converted in vivo by phosphatases to the microbiologically active moiety 
tedizolid
(TR-700). Tedizolid is a protein synthesis inhibitor that interacts with the 50S subunit of the
bacterial ribosome.  Tedizolid has bacteriostatic activity against Gram-positive bacteria including 
common skin pathogens Staphylococcus aureus (both methicillin-sensitive and –resistant strains) 
and Streptococcus pyogenes, less common species causing acute bacterial skin and skin structure 
infections (ABSSSI), S. anginosus-milleri group and Enterococcus faecalis, and other Gram-
positive aerobes and anaerobes.  New drug applications for tedizolid phosphate for the indication 
of ABSSSI were approved by the Food and Drug Administration (FDA) 20 June 2014. A 
Marketing Authorization Application was approved by the European Medicines Agency (EMA) 
on 23 March 2015.
Two registrational Phase 3 studies in patients with ABSSSI found 6 days treatment with 200 mg 
per day tedizolid phosphate to be noninferior to 10 days treatment with 600 mg twice daily 
linezolid at 48 to 72 hours based on no increase in lesion area from baseline and no fever (Study 
TR701-112) or a 20% decrease in lesion area from baseline (TR701-113).  Patients in TR701-
112 were required to be at least 18 years of age, while patients in TR701-113 could be as young 
as 12 years; however, only 2 adolescents were enrolled in the trial. The change in the age criteria 
for eligibility from the TR701-112 study to the second TR701-113 study was based on PK and 
safety data from Study TR701-111 in adolescents.  One adolescent received tedizolid phosphate
in Study TR701-113 and was considered a clinical success and experienced no TEAEs.
In the Phase 1 Study TR701-111, 20 adolescents (12 to 17 years old) who were receiving 
prophylaxis for or had a confirmed or suspected Gram-positive infection for which they were 
receiving treatment with Gram-positive activity received tedizolid phosphate.  Results of the PK 
analysis showed that the mean Cmax and AUC∞for oral or IV administration of tedizolid 200 mg 
were similar in adolescent and in healthy adult subjects, thus the adult dose of 200 mg tedizolid 
phosphate is an appropriate dose to further evaluate in adolescents.  In this study, TEAEs were 
mild, no subjects discontinued treatment due to an AE, and no deaths or SAEs were reported. 
Clinical laboratory evaluations, vital sign measurements, physical examinations, and ECGs did 
not show clinically significant changes.
As with adults, S. aureus, Streptococcus A group, and Enterococcus species are the most 
common pathogens in pediatric ABSSSIs.  The recent emergence of community-acquired (CA) 
staphylococcal skin infections is particularly troublesome in the pediatric population, and both 
hospital-acquired and CA-MRSA (methicillin-resistant S. aureus) are more common among 
children in summer and autumn months than in winter or spring.  Antibiotic choices for ABSSSI 
in adults and children are similar, with the exception of linezolid, an oxazolidinone, which is not 
approved for pediatric use in the European Union.
The EMA/Paediatric Committee (PDCO) issued a Pediatric Investigation Plan Positive Opinion 
in October 2013 for the treatment of complicated skin and soft tissue infections (cSSTIs).  The 
 
 
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proposed FDA Pediatric Study Plan was submitted with the new drug applications in October
2013, and reflects the outcome of the EMA/PDCO discussions and meetings with the FDA. 
These studies are described in Table 2.
Table 2  Pediatric Studies
Study
Description
Completed
Phase 1 PK 
TR701-111
Open-label, multicenter, two-part, single-dose, parallel-design, safety, and 
pharmacokinetic study of oral and IV TR-701 FA in subjects 12 to 17 years
Ongoing
TR701-122
(MK-1986-012)
Phase 3 study of IV to oral 6-day tedizolid phosphate compared with 10-day
comparator in subjects 12 to <18 years with cSSTI
TR701-120
(MK-1986-013)
Phase 1, single-administration safety and pharmacokinetic study of oral and IV
tedizolid phosphate in hospitalized subjects 2 to <12 Years
Planned
TR701-128
(MK-1986-018)
Randomized, single-blind, safety and efficacy study of IV to oral tedizolid phosphate
and comparator for cSSTI in subjects >3 months to <12 years
TR701-121
(MK-1986-014)
Phase 1, single-dose safety and pharmacokinetic study of oral and IV tedizolid
phosphate in in-patients under 2 years
TR701-129
(MK-1986-021)
Open-label, multicenter, Phase 3 study of IV tedizolid phosphate 5 mg/kg once daily
for 10 to 14 days for hospital-acquired late-onset sepsis in preterm and term neonates
and infants aged 5 days to ≤3 months
Abbreviations: cSSTI=complicated skin and soft tissue infection; IV=intravenous.
Results of Study TR701-111 established that exposure was similar in adults and adolescents and 
that tedizolid phosphate was well-tolerated with no clinically significant safety findings in 20 
adolescent subjects. An initial adolescent population PK model was used to simulate concentrations 
for younger pediatric age groups using allometric scaling. These simulations support an estimated 
dose of 5 mg/kg tedizolid phosphate in the pediatric population.
The proposed study is a safety and PK study of single-administration oral or IV tedizolid 
phosphate in hospitalized subjects 2 to <12 years old receiving prophylaxis for or being treated for 
a confirmed or suspected infection with Gram-positive bacteria.  Safety and PK results from this 
study will determine the appropriate dose for a subsequent safety and efficacy study in children 3 
months to <12 years, and for PK studies in younger children (i.e., preterm and full-term neonates, 
and infants/toddlers).
 
 
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This study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with applicable United States FDA clinical trial 
regulations and guidelines, the International Conference of Harmonisation (ICH; E6) Good Clinical 
Practice (GCP) guidelines and E11 Clinical Investigation of Medicinal Products in the Paediatric 
Population, the EU Directive 2001/20/EC for clinical trials conducted in the EU, and the Institutional 
Review Board (IRB) and local legal requirements.
5.0
TRIAL OBJECTIVES AND PURPOSE
Primary Objective
5.1
Part A (IV Study Drug Administration)
To describe the single-administration PK of IV tedizolid phosphate and its active metabolite, 
tedizolid, in subjects ages 6 to <12 years (Group 1) and 2 to <6 years (Group 2).
Part B (Oral Study Drug Administration)
To describe the bioavailability of tedizolid following oral tedizolid phosphate administration to 
subjects ages 6 to <12 years (Group 3) and 2 to <6 years (Group 4).
Secondary Objective
5.2
Part A (IV Study Drug Administration)
To evaluate the safety and tolerability of IV tedizolid phosphate administration in subjects ages 
6 to <12 years (Group 1) and 2 to <6 years (Group 2).
Part B (Oral Study Drug Administration)
To evaluate the safety and tolerability of oral tedizolid phosphate administration in subjects ages
6 to <12 years (Group 3) and 2 to <6 years (Group 4).
To evaluate the palatability of oral tedizolid phosphate suspension in subjects ages 6 to <12 years
(Group 3) and 2 to <6 years (Group 4).
6.0
INVESTIGATIONALPLAN
Overall Study Design
6.1
This is an open-label, multicenter, 2-part, single-administration study to assess the PK of 
tedizolid phosphate and its active metabolite, tedizolid, and the safety of tedizolid phosphate 
following administration of a single IV (Part A) or oral (Part B) administration to hospitalized 
subjects ages 6 to <12 years (Groups 1 and 3, respectively), and 2 to <6 years (Groups 2 and 4, 
respectively).  Subjects receiving prophylaxis for or being treated for a confirmed or suspected 
infection with Gram-positive bacteria will be enrolled.  The IV groups will be split into 2 cohorts 
of 5 subjects each. Prior to this amendment, 5 subjects ages 6 to <12 from Cohort 1 of Group 1 
received the study drug at dose of 5 mg/kg of total body weight. Table 3 summarizes the parts
(administration route), groups (age), and cohorts (dose) of the amended study.
 
 
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Table 3  Study TR701-120 Parts, Groups, and Cohorts
Part A – IV administration
Dose
Group 1: 6 to <12 years (N=10)
Cohort 1: 5 mg/kg (completed)
Cohort 2: 4 mg/kg 
Group 2: 2 to <6 years (N=10)
Cohort 1: 6mg/kg 
Cohort 2: 6 mg/kg or modified
Part B – Oral administration
Group 3: 6 to <12 years (N=6)
4 mg/kg
Group 4: 2 to <6 years (N=6)
6 mg/kg or modified
Tedizolid phosphate will be administered to subjects any time after antimicrobial administration 
with a non-study antibiotic has been initiated.
Progression to younger ages will be conducted as follows:
The first group enrolled was Group 1 Cohort 1; following enrollment of all 5 patients in this 
cohort, a preliminary analysis took place to review the pharmacokinetic and safety data in order to 
confirm or adjust dose for the remaining subjects in this age range (Group 1 Cohort 2 and Group
3). Analysis of the safety data indicate that the 5 mg/kg dose is well tolerated. Pharmacokinetic 
analyses indicated the appropriate dose level for subjects 6 to < 12 years old should be adjusted
downward to 4 mg/kg, and for subjects 2 to <6 years old adjusted upward to 6 mg/kg, to better 
match to adult pharmacokinetic parameters and increased the likelihood of target attainment in 
later efficacy and safety studies. The modified dose level was communicated to sites via a memo 
and a revised Pharmacy Manual.
The younger age range will follow a similar sequence, with a preliminary analysis of PK and 
safety after the first cohort of Group 2 receiving 6 mg/kg IV has been enrolled, in order to 
confirm or adjust the dose for the remaining subjects in this age range (Group 2 cohort 2 and 
Group 4).
In order to expedite the initiation of later studies that depend on oral and IV PK data, further 
enrollment in the 6 to <12 years age range was planned to initiate with Group 3 (oral), to evaluate 
bioavailability  prior to enrolling the remainder of the IV Group 1Cohort 2. A similar sequence of 
enrollment (IV Group 2 Cohort 1, Oral Group 4, and IV Group 2 Cohort 2) was planned for 
enrollment of the lower age group. 
However, it is not necessary to evaluate bioavailability prior to selecting an appropriate dose and 
proceeding with dosing in IV Group 1 Cohort 2 or Group 2 Cohort 2.  Under Amendment 4, the 
order of dosing for either age group is now flexible and can be altered as follow. If the powder for 
oral suspension is not available at the time of planned oral group enrollment, enrollment of the 
second IV cohort may be initiated prior to enrollment of the oral cohort. In this case, enrollment of 
the oral dosing group will be initiated as soon as the oral suspension is available whether the 
 
 
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enrollment of the second IV cohort is completed or not.  If the oral group is started before the 
second IV cohort is completed, enrollment in the second IV cohort will be paused and the second 
IV cohort will only be completed once the full oral group is enrolled. A bioavailability assessment 
will also be performed following completion of Group 3; available PK data from all prior cohorts 
in the study will be used to inform the dose selection of Group 4.
In addition to safety (clinical laboratory evaluations; physical examinations; adverse events), 
palatability will be assessed in oral tedizolid phosphate suspension in subjects ages 6 to <12 years 
(Group 3) and 2 to <6 years (Group 4).  Subjects will receive study drug on Day 1, with study 
visits on Day 2 and Day 8.  The Day 8 Visit may be a telephone contact.
Study treatment may be discontinued at the subject’s/LAR’s request, in the case of unacceptable 
toxicity or pregnancy, or if the Investigator believes changing therapy would be in the best interest 
of the subject.
The overall duration of the study is expected to be approximately 24.5 months (24 months for 
enrollment, 11 days from the Screening Visit through last visit [Study Day 8]).  Subject 
participation may be extended if a subject is being monitored for an SAE. Subjects will be 
monitored for AEs through 7 days after study drug administration and SAEs will be followed until 
stabilization, resolution/death, or consent/assent is withdrawn.
Rescreen is permitted two times if a subject initially does not meet eligibility but later does.
A scheme showing the study visit schedule is presented in Figure 1, and enrollment progression in 
Figure 2. APPENDIX D SCHEDULE OF STUDY ASSESSMENTS presents the detailed 
schedule of assessments.
 
 
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Figure 1
Study Scheme for TR701-120
Figure 2
Study Progression for TR701-120: Oral and IV administration
*Oral suspension groups G3 and G4 will be prioritized over IV groups, G1C2 and G2C2, as soon as the Powder 
for Oral Suspension (PfOS) is available. If enrollment of G1C2 or G2C2 has not completed before PfOS 
availability (start of Oral enrollment); then G1C2 and/or G2C2 will resume enrollment after completion of the 
oral groups (G3 and G4).
Abbreviations: C=Cohort, G=Group, PK=pharmacokinetics
 
 
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Number of Subjects
6.2
At least 32 subjects will be enrolled in this study to ensure at least 28 subjects with complete PK
profiles.
Part A IV Administration: At least 20 (15 additional, as of amendment 3) subjects will be 
enrolled to receive IV tedizolid phosphate (10 subjects ages 6 to <12 years in Group 1, of which 
the first cohort of 5 subjects has been enrolled; and 10 subjects ages 2 to <6 years enrolled in 
Group 2 [5 subjects in each of 2 cohorts]; 9 completed in each Group).
Part B Oral Administration: At least 12 subjects will be enrolled to receive oral tedizolid 
phosphate (6 subjects ages 6 to <12 years enrolled in Group 3 and 6 subjects ages 2 to <6 years 
enrolled in Group 4; 5 completed in each Group).
Treatment Assignment
6.3
This study is an open-label study and thus no randomization to study treatment is required.
7.0
SELECTION AND WITHDRAWAL OF SUBJECTS
Subject Inclusion Criteria
7.1
1. Aged 2 to <12 years at the time of consent
2. Receiving prophylaxis for or with a confirmed or suspected infection with Gram-
positive bacteria and receiving concurrent antibiotic treatment with Gram-positive 
antibacterial activity
3. Weight >5th percentile and <95th percentile based on age
(http://www.cdc.gov/growthcharts/clinical_charts.htm)
4. Stable condition as determined from medical history, physical examination, ECG
(minimally 5-lead), vital signs, and clinical laboratory evaluations
5. No clinically significant ECG abnormalities in the judgment of the Investigator
6. Serum creatinine within 1.5 × upper limit of reference range based on age
7. Females must be pre-menarchal, abstinent, or practicing an effective method of
birth control
8. Negative blood or urine beta-human chorionic gonadotropin pregnancy test (if urine test 
is used, it must be high sensitivity [i.e., able to detect 10 mIU/mL β-hCG]) at the
Screening Visit (post-menarchal females only)
 
 
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9. Subjects and parents must be willing to adhere to the prohibitions and 
restrictions specified in this protocol
10. Parents or subjects’ LAR able to give informed consent and willing and able to comply 
with all required study procedures.  Assent is also required of children capable of 
understanding the nature of the study (typically ≥7 years old)
Subject Exclusion Criteria
7.2
1. History of seizures, other than febrile seizures, clinically significant cardiac arrhythmia, 
cystic fibrosis, moderate or severe renal impairment, or any physical condition that
could interfere with the interpretation of the study results, as determined by the
Investigator
2. Use of rifampin within 14 days prior to study drug administration
3. Use of ranitidine, cimetidine, and antacids for subjects in Part B (oral administration) 
from 24 hours prior to study drug administration and throughout the study
4. Recent (3 month) history or current infection with viral hepatitis or other significant 
hepatic disease
5. History of drug allergy or hypersensitivity to oxazolidinones
6. Pregnant or breast feeding
7. Significant blood loss (≥5% of total blood volume) within 60 days before the Screening
Visit
8. Any acute or chronic condition that, in the opinion of the Investigator, would limit the 
subject’s ability to complete and/or participate in this clinical study
9. Treatment with investigational medicinal product within 30 days before the 
infusion/dose of study drug
10. Need for oral administration of methotrexate, topotecan, irinotecan or rosuvastatin, 
during administration of oral study drug. (Administration during the follow-up period is 
allowed, as is administration during treatment with IV study drug.)
11. Use of monoamine oxidase inhibitors or serotonergic agents including tricyclic 
antidepressants, selective serotonin reuptake inhibitors, and serotonin 5 
hydroxytryptamine receptor agonists (triptans), meperidine, or buspirone within,14 
days prior to study, or planned use while on study
 
 
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Subject Withdrawal Criteria
7.3
Subject Withdrawal from the Study
7.3.1
Subjects may withdraw or be withdrawn from the study at any time.  Subjects may be 
withdrawn from the study at the request of the Investigator or Sponsor.  Reasonable efforts are
to be made to complete all protocol-specified assessments listed for the Day 2 Visit at the time 
of withdrawal and to perform follow-up safety assessments.
Study or Site Discontinuation
7.3.2
Sponsor reserves the option to terminate the study or discontinue site participation at any time. 
Reasons for terminating the study or discontinuing the participation of a specific site include, 
but are not limited to, the following:
•
The incidence or severity of AEs in this or other studies with the study drug indicates
a potential health hazard to subjects
•
Subject enrollment is unsatisfactory
•
Data recording are inaccurate or incomplete
•
The Investigator does not adhere to the protocol or applicable regulatory guidelines 
in conducting the study
•
The IRB decides to terminate or suspend approval for the study or the Investigator
•
The Investigator asks to withdraw from study participation
8.0
TREATMENT OF SUBJECTS
Description of Study Drug
8.1
The investigational study drug is tedizolid phosphate (Sivextro), also known by the investigational 
number TR-701 FA, and will be supplied for IV infusion and as an oral suspension. Additional 
information is provided in Section 9.1 and a complete list of ingredients is provided in the 
Pharmacy Manual.
Concomitant Medications
8.2
Use of monoamine oxidase inhibitors or serotonergic agents including tricyclic antidepressants, 
selective serotonin reuptake inhibitors, and serotonin 5-hydroxytryptamine receptor agonists 
(triptans), meperidine, or buspirone is not permitted while on study (refer to 19.0 Appendix E). 
 
 
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For subjects receiving oral tedizolid phosphate administration (Part B), ranitidine, cimetidine,
and antacid use is prohibited.
Treatment Compliance
8.3
No calculations of treatment compliance are planned.
Randomization and Blinding
8.4
This is an open-label study with no randomization or blinding procedures.
9.0
STUDY DRUG MATERIALS AND MANAGEMENT
Study Drug Formulation/Packaging and Labeling/Storage
9.1
The investigational study drug is Tedizolid Phosphate, also known as Sivextro, MK-1986, and 
TR-701 FA.
Intravenous Form
Tedizolid Phosphate is formulated as a sterile lyophilized powder for injection for IV 
administration.  Tedizolid Phosphate for Injection, 200 mg/vial, consists of Tedizolid 
Phosphate, mannitol, and sodium hydroxide that are lyophilized.  The resulting drug product is 
a white to off-white cake that results in a clear light-yellow solution after reconstitution.
Tedizolid Phosphate for Injection, 200 mg/vial will be manufactured according to Good 
Manufacturing Practice requirements.  Additional information is provided in the Pharmacy 
Manual.
Oral Form
Tedizolid Phosphate Powder for oral suspension is white to off-white powder for constitution 
into suspension for oral administration.  The product is supplied in clear Type III glass bottles. 
Following constitution, each 1 mL contains 20 mg Tedizolid Phosphate. Inactive ingredients are 
potassium sorbate, silicon dioxide, succinic acid, sucrose and xanthan gum. Additional 
information is provided in the Pharmacy Manual.
Store all study drugs in accordance with instructions provided in the label on the clinical supply.
Administration
9.2
Subjects of 6 to <12 years will receive 4mg/ tedizolid phosphate; and subjects of 2 to < 6 years 
will receive 6 mg/kg (with possible adjustment based on the data from the second preliminary 
analyses of safety and PK) tedizolid phosphate as either an IV infusion (Part A) or an oral 
 
 
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suspension (Part B). Regardless of body weight, the maximum dose is 200 mg of tedizolid 
phosphate.
Intravenous Tedizolid Phosphate
9.2.1
Flush the IV line before and after study drug administration, per standard of care. No other IV 
therapy should be administered concurrently with the study drug.
A detailed method for preparation of the IV dosing solution is provided in the Pharmacy Manual. 
Infuse the solution for injection at a rate to deliver the desired dose in 60±10 minutes.
Dose, allowable volumes, and infusion rate required are provided in the Pharmacy Manual.   
Record start and stop times in the source documents and electronic case report forms (e-CRFs).  
Monitor the subject for at least 30 minutes post-infusion.
Oral Tedizolid Phosphate
9.2.2
Oral tedizolid phosphate administration is to occur within 15-60 minutes following a meal.
The target dose for oral administration is based on body weight using the following formula: 
Target dose (mg/kg) × body weight (kg) = dose required (mg)
Dose required (mg)/suspension concentration (mg/mL) = target volume (mL)
Volume required is provided in the Pharmacy Manual.
Study Drug Accountability, Handling, and Disposal
9.3
All study drug required for completion of this study will be provided by Sponsor or Sponsor’s 
designee.  The recipient will acknowledge receipt of the drug indicating shipment content and 
condition. Damaged supplies will be replaced. Accurate records of all study drugs dispensed
from and returned to the study site are to be maintained.  A Study Monitor will be responsible 
for checking drug accountability at the study site.  Inventory records must be available for 
inspection by Sponsor, a designee of Sponsor, or Regulatory Authorities at any time.  The 
Investigator will be responsible for ensuring the study drug is used in accordance with this
protocol.
Additional information is provided in the Pharmacy Manual.
All unused study drug (IV and oral suspension) and unused and used packaging are to be retained 
at the study site until receipt of written instruction from Sponsor regarding disposition. All 
records related to study drug supply and disposition are to be maintained by the study site.
 
 
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10.0
ASSESSMENT OF SAFETY
Safety Variables
10.1
Safety will be assessed through summaries of TEAEs, laboratory evaluations (hematology and 
chemistry), vital signs, physical examinations,  and concomitant medications.  Adverse events 
will be collected from the time when the ICF is signed through 7 days after study drug 
administration.
Clinical laboratory evaluations are listed in APPENDIX A. CLINICAL LABORATORY 
EVALUATIONS.
Assessing and Recording Adverse Events
10.2
Definition of Adverse Events
10.2.1
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in frequency 
and/or intensity) of a preexisting condition that is temporally associated with the use of the 
Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples of 
this may include, but are not limited to, teething, typical crying in infants and children and onset 
of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
From the time of treatment allocation/randomization through 7 days after study drug 
administration, all adverse events must be reported by the investigator. Such events will be 
recorded at each examination on the Adverse Event case report forms/worksheets.  The reporting 
 
 
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timeframe for adverse events meeting any serious criteria is described in Section 10.2.4.1. The 
investigator will make every attempt to follow all subjects with non-serious adverse events for 
outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Definition of an Overdose for this Protocol and Reporting of an Overdose to the 
10.2.2
Sponsor 
In this trial, an overdose is any dose higher than 1.25x times the nominal dose of tedizolid 
phosphate (nominal dose is 4 mg/kg daily for subjects 6 to <12 years, and 6 mg/kg for subjects 2 
to <6 years, not to exceed the adult dose of 200 mg/day.)  This threshold was selected 
conservatively, as on a dosage expected to produce an exposure (AUC) that matches the 
exposure reached at the no-observable-adverse-effect level in juvenile rats after 6 weeks of 
dosing (rats dosed from post-natal day 7 through 54).
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental or 
intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the investigator 
within 24 hours to the Sponsor either by electronic media or paper. Electronic reporting 
procedures can be found in the EDC data entry guidelines. Paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
10.2.3
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously
reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.  
Pregnancies and lactations that occur from the time of treatment allocation/randomization through 7 
days after study drug administration must be reported by the investigator.  All reported pregnancies 
must be followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, 
 
 
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intrauterine death, miscarriage and stillbirth must be reported as serious events (Important Medical 
Events). If the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or paper. 
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
10.2.4
10.2.4.1 Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is another important medical event. 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe as 
SAEs to meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 4 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours to 
the Sponsor if it causes the subject to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 7 days after study 
drug administration, any serious adverse event, or follow up to a serious adverse event, including 
death due to any cause, whether or not related to the Sponsor's product, must be reported within 
24 hours to the Sponsor either by electronic media or paper. Electronic reporting procedures can 
be found in the EDC data entry guidelines. Paper reporting procedures can be found in the 
Investigator Trial File Binder (or equivalent).
 
 
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Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the investigator 
at any time outside of the time period specified in the previous paragraph also must be reported 
immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
10.2.4.2 Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, or is 
the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 7 days after study 
drug administration, any ECI, or follow up to an ECI, whether or not related to the Sponsor’s 
product, must be reported within 24 hours to the Sponsor, either by electronic media or paper.  
Electronic reporting procedures can be found in the EDC data entry guidelines.  Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Events of clinical interest for this trial include:
1. 
An overdose of Sponsor's product, as defined in Section 10.2.2 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results. 
2. 
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent).
3.
Severe or serious cases of C. difficile infection such as toxic megacolon or 
pseudomembranous colitis.
4.
Clinically significant hematologic adverse events defined as hemoglobin <8.5 g/dL,
platelet counts (<112 × 103/mm3) or absolute neutrophil counts (<0.8 × 103/mm3).
5.
Serotonin syndrome in patients receiving drugs with serotonergic potential.
 
 
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Evaluating Adverse Events
10.2.5
An investigator who is a qualified physician will evaluate all adverse events with respect to the 
elements outlined in Table 4. The investigator’s assessment of causality is required for each 
adverse event.  Refer to Table 4 for instructions in evaluating adverse events.
 
 
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Table 4  Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation.   (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for
collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 
hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor's product to be discontinued?
Relationship to 
Sponsor's 
Product
Did the Sponsor's product cause the adverse event?   The determination of the likelihood that the Sponsor's product caused the adverse event will be provided by an 
investigator who is a qualified physician.  The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done.  This initialed document must be retained for the required regulatory time frame.  The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information
The following components are to be used to assess the relationship between the Sponsor's product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor's product caused the adverse event:
Exposure
Is there evidence that the subject was actually exposed to the Sponsor's product such as:  reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the Sponsor's product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
 
 
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Relationship
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor's product discontinued or dose/exposure/frequency reduced?
      If yes, did the AE resolve or improve?
           If yes, this is a positive dechallenge.    If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite 
continuation of the Sponsor's product; (3) the trial is a single-dose drug trial); or (4) Sponsor's product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor's product in this trial?
      If yes, did the AE recur or worsen?
          If yes, this is a positive rechallenge.    If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); 
or (3) Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor's product or drug class 
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following:
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor's product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause. 
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without 
an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
10.2.6
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) Guidelines 
for Good Clinical Practice.
11.0
ASSESSMENT OF PALATABILITY
Palatability will be assessed in subjects participating in Part B, oral administration, using a hedonic 
method (see APPENDIX B.  PALATABILITY ASSESSMENT) and spontaneous verbal 
judgment.
12.0
PHARMACOKINETIC ASSESSMENT
Assessment
12.1
Plasma samples will be analyzed for concentrations of tedizolid phosphate and its active 
metabolite, tedizolid.  Based on the individual plasma concentration-time data, using actual 
sampling times, PK parameters for tedizolid and tedizolid phosphate including the following will 
be determined:
•  Cmax
•  tmax
•  AUC
•  t½
•  CL/F and CL, respectively
Samples
12.2
In Part A, blood samples for analysis of tedizolid phosphate and tedizolid will be collected at the 
following timepoints (shown in tabular format in Table 5): 
6 years to <12 years of age: immediately after the end of the 1 hour infusion, and at 1.5, 2, 3, 4, 6, 
12, and 24 hours after the start of infusion.
2 years to <6 years of age: immediately after the end of the 1 hour infusion, and at 3, 6, 12, 24, 
and 48 hours after the start of infusion (unless discharged after 24 hour sample)
In Part B, blood samples for analysis of tedizolid phosphate and tedizolid will be collected at the 
following timepoints: 
6 years to <12 years of age: 1, 2, 3, 4, 6, 8, 12, and 24 hours after study drug administration.
2 years to <6 years of age: 3, 6, 9, 12, 24, and 48 hours after study drug administration (unless 
discharged after 24 hour sample)
 
 
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Table 5  Pharmacokinetic sampling scheme.
Time after start of infusion (hours)
Part A (IV)
End of 
Infusio
n
1.5
2
3
4
6
12
24
48
6 to <12
years
X
X
X
X
X
X
X
X
2 to <6 
years
X
X
X
X
X
X
Time after administration (hours)
Part B*
(Oral)
1
2
3
4
6
8
9
12
24
48
6 to <12 
years
X
X
X
X
X
X
X
X
2 to <6 
years
X
X
X
X
X
X
Allowable windows on collection:
Timepoint
<2 hours
2 to <6 
hours
6 to 12 
hours
24 hours
48 hours
Window
±10 minutes
±15 minutes
±30 minutes
±2 hours
±2 hours
* If the subject vomits during and/or after oral dose administration within 1.5 hours, PK samples will not be 
collected. However, vomiting must be recorded as an AE.
Per individual, the trial-related blood loss (including any losses in the maneuver) will not exceed 3% 
of the total blood volume and will not exceed 1% at any single time.  The total volume of blood is 
estimated at 80 to 90 mL/kg body weight; 3% is 2.4 mL blood per kg body weight.
Detailed instructions on collecting and processing blood PK samples are provided in APPENDIX C. 
PHARMACOKINETIC SAMPLING and the Laboratory Manual.  Results of analysis will be
reported separately.
13.0
STATISTICAL METHODS
Analysis Sets
13.1
The Intent to Treat (ITT) analysis set will consist of data from all enrolled subjects. Enrolled 
subjects include all subjects whose LAR signs the Informed Consent Form.
The Safety analysis set will consist of data from subjects who receive any study drug. Subjects will 
be categorized to the actual treatment received.
 
 
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The PK analysis set will consist of data from subjects who receive study drug and have at least
one quantifiable post-administration concentration.
Determination of Sample Size
13.2
No formal statistical tests are planned and the planned sample size is not based on a power 
calculation. Previous studies indicated that plasma tedizolid AUC has an intersubject percent 
coefficient of variation of approximately 20%.
If pediatric AUC is similar to adult AUC (Sivextro prescribing information 2015), then N=5 
subjects per group affords 81% power to estimate group geometric mean AUC ratio and 
associated 90% confidence interval within the range of 0.5 to 2.0, which are boundaries that 
represent no clinically meaningful change for tedizolid plasma exposure (Flanagan 2014).
Six subjects will be enrolled per age group to assess bioavailability.
General Statistical Considerations
13.3
Continuous variables will be summarized with the number of subjects, mean, standard
deviation, median, minimum, and maximum by age group and dose group.  Categorical data 
will be summarized with the number and percentage in each category.   All comparisons will be 
by age group and dose cohort.
Medical history and AEs will be coded using the MedDRA. Medications will be coded using 
the World Health Organization (WHO) Drug Dictionary to classify medications by preferred 
term and WHO Anatomical Therapeutic Chemical classification of ingredients.
Statistical summaries (descriptive statistics and frequency tables) will be generated using 
SAS® Version 9.3 or later (SAS Institute Inc., Cary, NC, USA).  The statistical analysis plan 
will provide a detailed description of the statistical methods and will be finalized prior to
database lock.
For all analyses, baseline is defined as the most recent measurement prior to the first 
administration of study drug, unless otherwise specified.
No formal statistical hypotheses testing will be performed.  Therefore, multiplicity is not a 
concern.
Subject Enrollment and Disposition, and Protocol Violations/Deviations
13.3.1
Subject enrollment and disposition data will be summarized using all enrolled subjects in the
eCRF database.  This summary table will present the number of subjects who were enrolled in 
the study, received study drug, and completed the study for the ITT Analysis Set.
Protocol violations, deviations and inclusion/exclusion data will be summarized by age group and 
dose cohort by ITT Analysis Set
 
 
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Study Drug Exposure
13.3.2
A study drug administration summary by age group and dose cohort will be provided including 
the distribution of the total number subjects receiving IV study drug, drug interruptions, and 
the number of oral administrations in the Safety Analysis Set.
Palatability assessments of oral suspension will be analyzed using descriptive statistics.
Demographics and Baseline Characteristics
13.3.3
Demographic data and baseline characteristics including medical history and pregnancy 
test results will be summarized for the Safety Analysis Set.
Pharmacokinetic Analysis
13.4
Descriptive statistics will be presented for tedizolid and tedizolid phosphate plasma concentrations 
by age group and dose cohort.  Mean and individual plasma concentration-time profiles will be 
plotted in linear and semilogarithmic scales. All PK parameters will be summarized by age group 
and dose cohort using summary statistics.
The primary endpoint of the PK analysis is the geometric mean ratio of AUC (Part A Group 1 and 
Group 2) relative to adults, and bioavailability of tedizolid following oral tedizolid phosphate 
administration (Part B).
Safety Analysis
13.5
Safety will be assessed through summaries using descriptive statistics of TEAEs, laboratory 
evaluations, vital signs, physical examinations, and concomitant medications.
All safety analyses will be based on the Safety Analysis Set. Safety data will be summarized 
separately for each age group and dose cohort.
The number and percentage of subjects reporting will be presented by SOC and preferred term 
according to the MedDRA, by relationship to the study drug and by severity.
Adverse Events
13.5.1
All TEAEs will be recorded.  Events with onset date that could not be used to determine its 
TEAE status or completely missing will be considered TEAEs.  Treatment-emergent AEs, 
categorized by MedDRA system organ class and preferred term, will be summarized in tables. 
The tables will include the number of unique subjects experiencing each event, and percentage 
of subjects experiencing each event.
Treatment-emergent AEs will also be tabulated by the number and percentage of subjects 
experiencing events by severity and relationship to study drug.  In the tabulation by severity, a 
 
 
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subject with more than 1 event coded to the same preferred term will be classified according 
to the most severe event.  Similarly, in the tabulation by relationship, a subject will be 
classified according to the event with the strongest relationship to study drug.
Summaries of TEAEs leading to death and all SAEs will be provided.  All reported AEs will 
be presented by site and subject in a data listing including the verbatim term, preferred term, 
and MedDRA SOC.
The safety evaluation will be based on clinical review of the following safety parameters:
•  Incidence of AEs and SAEs
•  AEs and SAEs by relationship to study drug
•  AEs by severity
•  Deaths
•
Premature discontinuation from the study due to an AE, regardless of relationship 
to study medication
•  Clinical laboratory data
•  Vital signs
•  Concomitant medications
•  Physical examinations
Laboratory Evaluations
13.5.2
Hematology and chemistry laboratory data and vital signs data will be summarized using 
summary statistics.  Changes from the Screening Visit to Day 2 will be summarized for laboratory 
data and vital signs parameters.  The laboratory listings will provide a flag indicating all out-of-
range laboratory assessments.
Prior and Concomitant Medications
13.5.3
Prior medications are any medication received prior to and stopped before the subject received 
study drug. Concomitant medications are any medication received by the subject starting on or 
after the day the subject received study drug, or given prior to the subject receiving study drug and 
continuing to receive it during the study.  Only concomitant medications will be summarized.  All 
medications will be presented in the listing.
 
 
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Handling of Missing Data
13.6
Every effort should be made to collect all data at specified times, according to the schedule of 
study events.  For all data points, missing data will be handled as follows:
•
Missing values for individual data points will remain missing.  Missing values will 
not be imputed and only observed values will be used in data analyses and 
presentations
•
Where individual data points are missing, categorical data will be summarized based 
on reduced denominators (i.e., only subjects with data available will be included in 
the denominators)
The handling of missing AE data, partial and missing dates are presented in detail in
the statistical analysis plan.
14.0
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
Study Monitoring
14.1
Before an investigational site can enter a subject into the study, a representative of Sponsor will 
visit the investigational study site to determine the adequacy of the facilities and discuss with 
the Investigator(s) and other personnel their responsibilities and the responsibilities of Sponsor 
or its representatives.  This will be documented in a Clinical Study Agreement between Sponsor 
and the investigator.
During the study, a monitor from Sponsor or representative will have regular contacts with 
the investigational site including the following activities:
•  Provide information and support to the Investigator(s)
•  Confirm that facilities remain acceptable
•
Confirm that the investigational team is adhering to the protocol, e.g., data are being 
accurately recorded in the e-CRF, and that investigational product accountability
checks are being performed
•
Perform source data verification.  This includes a comparison of the data in the eCRF 
with the subject’s medical records at the hospital or practice, and other records relevant 
to the study.  This will require direct access to all original records for each subject (e.g.,
clinic charts)
•  Record and report any protocol deviations not previously sent to Sponsor
•
Confirm AEs and SAEs have been properly documented on e-CRFs and confirm any 
SAEs have been forwarded to Sponsor and those SAEs that met criteria for reporting 
have been forwarded to the IRB
 
 
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The monitor will be available between visits if the Investigator or other staff needs information or 
advice.
Sponsor personnel or their designee may perform an audit at any time during or after completion
of the clinical study, as defined in the Audit Plan.  All study-related documentation is to be made 
available to the designated auditor.  In addition, study site personnel are to be available to answer 
any questions.  The Investigator will permit authorized representatives of the Sponsor and the 
regulatory agencies or local health authorities to inspect facilities and records relevant to this 
study.
Protocol Violations and Deviations
14.1.1
A protocol deviation is any change, divergence, or departure from the study design or procedures 
defined in the protocol.  Important protocol deviations are a subset of protocol deviations that may 
significantly impact the completeness, accuracy, and/or reliability of the study data or that may 
significantly affect a subject's rights, safety, or well-being.  Deviations include, but are not limited 
to, the following:
•  those who entered the study even though they did not satisfy all entry criteria
•  those who developed withdrawal criteria during the study but were not withdrawn
•  those who received the wrong treatment or incorrect dose
•  those who received an excluded concomitant treatment
15.0
ETHICS
Ethics Review
15.1
This study will be conducted in accordance with applicable United States FDA clinical trial 
regulations and guidelines, the ICH (E6) GCP guidelines, the European Union Directive
2001/20/EC for clinical trials conducted in the European Union, and the IRB and local legal 
requirements, and is consistent with the ethical principles that have their origin in the Declaration 
of Helsinki.
In accordance with federal regulations and the ICH, the Investigator is responsible for submitting 
the study protocol, sample ICF, and any other documents that pertain to subject information (i.e., 
subject dosing diaries), recruitment methods such as advertisements, and any other information 
that may be requested to the IRB for review and approval prior to initiation of the study.  The IRB 
will provide the Investigator written assurance of compliance with ICH (E6) guidelines.
The Investigator shall obtain and maintain records for all written IRB approval documentation 
including reviews of any subsequent changes to the study (i.e., protocol amendment(s) or 
modifications to the ICF).  The Investigator will obtain annual IRB approval at appropriate 
intervals as required not to exceed 1 year and at the close of the study.
 
 
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The Investigator must report unanticipated problems involving risks to subjects or others, serious 
and/or continuing noncompliance, and any suspension or termination of Investigator participation
in the study to the IRB promptly according to the IRB requirements.
Written Informed Consent
15.2
The Investigator should use the Sponsor-approved ICF template to incorporate any site-
specific information.  No deletions or major deviations are to be made to the draft ICF without
prior written approval from Sponsor or designee.  Any changes required by the IRB will 
require Sponsor or designee review and agreement prior to use.  The Investigator provides
Sponsor with a copy of the consent/assent form which was reviewed and approved by the IRB.
The Investigator or designee is to explain the study and ICF to the subject and answer any 
questions in accordance with 21 CFR Part 50.  The person who conducts the informed 
consent/assent discussion is to sign and date the ICF and provide a fully executed copy to 
the subject.  If applicable, an IRB approved certified translation of the ICF in a language 
understandable to the subject will be provided.
The original signed and dated ICF is to remain in each subject’s study file and be available for 
review by study monitors or authorized regulatory representatives at any time.
Subject Confidentiality
15.3
The information obtained during the conduct of this clinical study is confidential, and disclosure 
to third parties other than those noted is prohibited.
Information obtained during the conduct of this study will be collected, processed, and transmitted
to or for the benefit of Sponsor in accordance with applicable law, as discussed below. 
Information contained therein will be maintained in accordance with applicable law protecting 
subject privacy and may be inspected by the clinical researcher, the researcher’s staff, Sponsor
and its representatives, to check, process, evaluate, and use the information collected during the
study.  Processing, evaluation, or use of the information will be performed by a health 
professional for medical purposes and/or by those operating under a duty of confidentiality that is 
equivalent to that of a health professional. Information will be transmitted and processed as 
Sponsor may direct, including to Sponsor and its representatives in the United States or 
elsewhere. Information obtained from the study will likely be used by Sponsor in connection with
study drug development, including possible filing of regulatory dossiers with governmental 
authorities for marketing approval, and for other pharmaceutical and medical research purposes.  
The Investigator is obliged to provide Sponsor with complete test results and all data developed in 
this study.  This information may be disclosed to other physicians who are conducting similar 
studies, to the FDA/applicable regulatory agencies as deemed necessary by Sponsor, or to local 
health authorities as required by law.  Subject-specific information may be provided to other 
appropriate medical personnel only with the subject’s permission.
 
 
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All Investigators and other research study personnel who process information from the study must 
take appropriate measures to prevent unauthorized or unlawful processing or disclosure of data.
16.0
DATA HANDLING AND RECORDKEEPING
Case Report Forms and Study Records
16.1
The site will use a web browser address for an Electronic Data Capture system database that has 
been fully validated and conforms to 21 CFR Part 11 and the Guidance for Industry on 
Computerized Systems Used in Clinical Trials requirements.  This study will be performed using 
an e-CRF.  The Investigator and study site staff will receive training and support on the use of
the e-CRF.  All e-CRF data are to be completed by the study coordinator or other designated site 
personnel. All data entry, modification, or deletion will be recorded automatically in the
electronic audit trail.  All data changes will be clearly indicated with a means to locate prior 
values. Informed consent, demography, inclusion/exclusion and end of study e-CRF pages are 
needed for patients who are enrolled but not treated.
All electronic data entered by the site (including the electronic audit trail) will be maintained or 
made available at the site in compliance with 21 CFR Part 11 and other applicable retention 
regulations. The computerized system is able to generate accurate and complete copies of 
records in paper or electronic form for inspection and review by applicable regulatory authorities, 
the IRB, and auditors or other designees authorized by Sponsor.
In addition to capturing the user identification as part of the audit trail for all data entry, the e-
CRF allows for application of electronic signatures.  The Investigator or designated 
subinvestigator, following review of the data in the e-CRF, will confirm the validity of each 
subject’s data by electronic signature.  This electronic signature will be certified as outlined in 21 
CFR Part 11.
Sponsor will retain the original e-CRF data and audit trail.  An electronic or certified paper copy 
of all completed e-CRF data, including query resolution correspondence, will be provided to the 
Investigator at the end of the study.
Data Quality Assurance
16.2
Training sessions, regular monitoring of investigators by Sponsor or designated personnel, 
instruction manuals, data verification, cross-checking and data audits will be performed to ensure 
quality of all study data. Investigator meetings and/or on-site site initiations will be performed to 
prepare investigators and other study personnel for appropriate collection of study data.
Audits for quality assurance of the database may be performed according to relevant procedures 
within the research organization or at the request of Sponsor’s Quality Assurance department.
 
 
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Inspection of Records
16.3
To ensure compliance with current Federal Regulations and the ICH GCP E6 guideline, data 
generated by this study including source documentation must be available for inspection upon 
request by representatives of the FDA, national and local health authorities, Sponsor, and the 
IRB for each study site.
Sponsor or designee will be allowed to conduct site visits to the investigation facilities for the 
purpose of monitoring any aspect of the study. The Investigator agrees to allow the monitor 
to inspect the drug storage area, study drug stocks, drug accountability records, subject charts 
and study source documents, and other records relative to study conduct.
Retention of Records
16.4
The Investigator is to retain records and documents pertaining to the conduct of this study 
including PDF copies of e-CRFs, source documents, ICFs, laboratory test results, and study 
medication inventory records for a period of at least 2 years after the last approval of a
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  No study records shall
be destroyed without prior authorization from the Sponsor.
17.0
PUBLICATION POLICY
Sponsor intends to pursue publication of the results of the study in cooperation with a lead 
Investigator, subject to the terms and conditions of the clinical study agreement between 
Sponsor and Investigators.  Sponsor written approval is required for publication of any data 
subsets.  Final authorship will be determined in accordance with the International Committee of
Medical Journal Editors definition of authorship (e.g., by contributions to study design, 
enrollment, data analysis, and/or interpretation of the results) (http://www.icmje.org/).  Subject 
names and other personal data relating to an identified or identifiable subject (such as 
photographs, audio, videotapes, or other factors specific to physical, physiological, mental, 
economic, cultural or social identity), may not be disclosed in any publication without prior 
written authorization from Sponsor and the subject.
18.0
LIST OF REFERENCES
Sivextro™US Prescribing Information.  Merck & Co., 2015. Accessed: Feb 2016. 
Available from: http://www.merck.com/product/usa/pi_circulars/s/sivextro/sivextro_pi.pdf
Flanagan S, Passarell J, Lu Q, Fiedler-Kelly J, Ludwig E, Prokocimer P.  Tedizolid Population
Pharmacokinetics, Exposure Response, and Target Attainment.  Antimicrob Agents Chemother.
2014;58(11):6462-70.
 
 
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19.0
APPENDICES
 
 
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APPENDIX A. CLINICAL LABORATORY EVALUATIONS
Clinical Laboratory Evaluations
Chemistry Panel 
Total Bilirubin
Direct Bilirubin
Indirect Bilirubin
Albumin
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
Gamma-glutamyl transpeptidase 
Lactate dehydrogenase
Urea nitrogen
Creatinine
Glucose
Uric Acid
Calcium
Phosphorus
Total Protein
Cholesterol
Creatine kinase/creatine phosphokinase
Sodium
Potassium
Bicarbonate
Chloride
Magnesium
Hematology/Differential Panel
Hemoglobin
Hematocrit
Red blood cell count 
White blood cell count
Neutrophils (%, absolute)
Lymphocytes (%, absolute)
Monocytes (%, absolute)
Eosinophils (%, absolute)
Basophils (%, absolute)
Bands (%, absolute), if available
Platelet count
Pregnancy Test (females of childbearing potential in Groups 1 
and 3); Serum or urine beta-human chorionic gonadotropin
(If urine test is used, it must be high sensitivity [i.e. able to 
detect 10 mIU/mL hCG])
Urine Panel (Screening only)
pH 
Bilirubin
Glucose
Ketones
Urobilinogen
 
 
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APPENDIX B. PALATABILITY ASSESSMENT
Palatability will be evaluated using a 5-point hedonic scale in subjects administered tedizolid 
phosphate oral suspension, using the tool shown below.  The facial score should be rated by the 
child, in verbal children of an age able to understand. (Ask the subject to rate the taste of
tedizolid phosphate suspension. The subject can respond orally and/or by pointing to a face). For 
preverbal children, the score should be assessed by the parent/caregiver, or study staff 
administering or witnessing administration of the study drug. 
Facial score from Sjovall J, Fogh A, Huitfeldt B, Karlsson G, Nylen O.  Methods for 
evaluating the taste of paediatric formulations in children:  A comparison between the facial 
hedonic method and the patients’ own spontaneous verbal judgment.  Eur J Pediatr.  
1984;141(4):243-7.
 
 
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APPENDIX C. PHARMACOKINETIC SAMPLING
Blood will be collected from subjects to evaluate the systemic plasma concentrations of
tedizolid and tedizolid phosphate after administration of tedizolid phosphate using a validated 
assay.
Per individual, the trial-related blood loss (including any losses in the maneuver) will not 
exceed 3% of the total blood volume and will not exceed 1% at any single time.  The total 
volume of blood is estimated at 80 to 90 mL/kg body weight; 3% is 2.4 mL blood per kg body 
weight.
Detailed information on sample collection and processing is provided in the 
Laboratory Manual. Perform the following:
1.   Collect blood (500 µL) in the tube provided by the Sponsor-designated central 
laboratory
2.   Slowly invert the tube at least 8 to 10 times
3.   Place the tube in an ice water bath until centrifugation
4.  Centrifuge the sample at 2000 × g at 5ºC for 15 minutes.  If a refrigerated centrifuge is
not available, place the tube in an ice bath immediately before and after the 
centrifugation for at least 5 minutes each time
5.   Collect supernatant (plasma) and split into 2 aliquots and store at -20ºC or colder
•  One aliquot will be shipped to the Sponsor-designated central laboratory
•
The other aliquot is to be stored at the study site as a back-up sample until notified 
by Sponsor or designee that the sample either is to be sent to the Sponsor-
designated central laboratory or is to be destroyed
 
 
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APPENDIX D.  SCHEDULE OF STUDY ASSESSMENTS
Assessment
Screening a
(Study
Day -3 to 1)
Study
Day 1
Study
Day 2
Study Day 8 
(±1 day; may 
be phone 
contact)
Informed Consent/Assent (before study 
X
Verify subject meets eligibility criteria
X
Record demographic data and medical
history (up to last 5 years)
X
Perform 12-lead electrocardiogram b
X
Record vital signs
X
X c
X
Record height and weight
X
Perform physical examination
X
X
Record prior and concomitant medications
X
X
X
Administer study drug d
X
Conduct palatability test e
X
Assess adverse events (collected from
signed ICF through 7 days after
administration)
X
X
X
X
Perform HDYF inquiry f
X
X
X
Collect blood samples for PK analysis g
X
X
Collect urine and blood samples for
urinalysis and chemistry and 
hematology analyses h
Xi
X (only if 
Screening 
Visit sample
>7 days prior)
X
(blood 
sample 
only)
Collect blood or urine sample for
pregnancy testj
X
Abbreviations:  HDYF=how do you feel; ICF=informed consent form; IV=intravenous; PK=pharmacokinetic
a
Screening procedures may be completed on Day 1.
b
Subjects will rest in the supine position 10 minutes prior to ECG recording, ECGs collected within 30 days prior to 
screening may be used to satisfy the screening requirement. If more than one ECG is available within the 30 days 
window, the most recent ECG should be used to satisfy the screening requirement.
c
For Day 1, record vital signs (including temperature, respiratory rate, and resting blood pressure and pulse) prior to 
study drug administration.  Also record resting blood pressure and pulse at 0.5, 1, 2, 3, 4, and 6 hours after study 
drug administration (relative to the start of infusion for IV administration). The consistent method should be used to 
measure body temperature, and the subject should be in the same position (e.g. supine) for all vital sign 
measurements.
d
Administer tedizolid phosphate as a 60-minute IV infusion (Part A) or oral suspension (Part B). Oral tedizolid
phosphate administration is to be given within 15-60 minutes following a meal
e
Palatability will be assessed following oral suspension administration (Part B).
f
HDYF inquiry performed at vital signs measurement, once daily.
g
Samples are to be collected at timepoints as described in Section 12.2.
h
Laboratory evaluations include serum chemistry and hematology panels, and urinalysis.
i
Pre-screening local laboratory test results that were collected as part of standard of care may be used if collected 
within 7 days prior to the dose of study medication.
j
Females of childbearing potential in Groups 1 and 3 only. If urine test is used, it must be high sensitivity (i.e. able to 
detect 10 mIU/mL hCG).
 
 
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APPENDIX E.  Examples of Prohibited Concomitant Medications
The following examples of prohibited concomitant medications are not all inclusive and should 
be used as a guide for exclusion from the protocol.
Receipt of the following medications is prohibited in the 2 weeks prior to study through the last 
visit.
Examples
Monoamine Oxidase Inhibitors
Iprindole
Moclobemide
Rasagiline
Iproniazid
Nialamide
Selegiline 
Iproclozide
Opipramol
Toloxatone 
Isocarboxazid
Phenelzine
Tranylcypromin
Selective Serotonin Reuptake Inhibitors
Citalopram
Fluoxetine 
Sertraline
Dapoxetine 
Fluvoxamine maleate
Vilazodone
Escitalopram oxalate
Paroxetine
Serotonin Norepinephrine Reuptake Inhibitors
Duloxetine
Desvenlaxifine
Venlafaxine
Tricyclic Antidepressants
Amitriptyline
Doxepin
Protriptyline
Clomipramine
Imipramine
Trimipramine
Desipramine
Lofepramine 
Dosulepin
Nortriptyline
Triptans and other medications with potential serotonergic activity
Amoxapine
Mirtazapine
Trazodone
Bupropion
Naratriptan
Trimeperidine
Buspirone 
Nefazodone
Zolmitriptan
Maprotiline
Rizatriptan
Meperidine
Sumatriptan
 
 
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20.0
SIGNATURE
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
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