Conditions: Bacteremia Soft Tissue Infections Skin Diseases, Infectious
Keywords: methicillin-resistant S. aureus (MRSA) infections complicated skin and soft tissue infections (cSSTI)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 18
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the safety, efficacy and pharmacokinetic (PK) parameters of daptomycin for injection in Japanese pediatric participants aged 1 to 17 years with complicated skin and soft tissue infection (cSSTI) or bacteremia caused by gram-positive cocci.

Detailed description:

Arms:
arm 1: Participants aged 1 to 17 years old with cSSTI or bacteremia will receive daptomycin intravenously every 24 hours for either 5-14 days for cSSTI or for 5-42 days for bacteremia.

Interventions: intervention 1: Daptomycin for Injection
Intervention descriptions: intervention 1: Once daily administration of 5, 7, 9, 10, or 12 mg/kg intravenous (IV) daptomycin infused with 25-50 mL saline over 30-60 minutes depending upon infection type and age level.

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03643952 
Document Date: 
03-Jun-2020
A Phase II Open-Label, Single-arm Clinical Trial to Study the 
Safety, Efficacy and Pharmacokinetics of MK-3009 (Daptomycin) in 
Japanese Pediatric Participants Aged 1 to 17 Years with Complicated 
Skin and Soft Tissue Infections or Bacteremia caused by Gram-
positive cocci


Product:  MK-3009
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Protocol/Amendment No.: 029-01 
MK-3009-029-01 Final Protocol
03-Jun-2020
Confidential
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A.
(MSD).
Protocol Title: A Phase II Open-Label, Single-arm Clinical Trial to Study the Safety, 
Efficacy and Pharmacokinetics of MK-3009 (Daptomycin) in Japanese Pediatric Participants 
Aged 1 to 17 Years with Complicated Skin and Soft Tissue Infections or Bacteremia caused 
by Gram-positive cocci
Protocol Number: 029-01
Compound Number: MK-3009
Sponsor Name and Legal Registered Address: 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or MSD)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
Not Applicable
EudraCT NUMBER: Not Applicable
Approval Date:  03 June 2020
 
 
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor Contact information can be found in the Investigator Trial 
File Binder (or equivalent). 
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 01
03-JUN-2020
In the section 5.3 Beginning and End of Study Definition, the definition of the overall 
study ends was amended.
Original Protocol
09-APR-2018
Not applicable
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment : 01
Overall Rationale for the Amendment:
Pharmacokinetic analysis and central microbiology reference laboratory analysis are key secondary endpoints in the study; the study is 
not considered complete until all key data are available for planned endpoint analyses, and these data will only become available 2-3 
months after the last patient last visit date.
Summary of Changes Table:
Primary reason(s) for this amendment:
Section # and Name
Description of Change
Brief Rationale
5.3 Beginning and End of 
Study Definition
The following sentence is added: For purposes of 
analysis and reporting, the overall study ends 
when the Sponsor receives the last 
pharmacokinetic analysis and central 
microbiology reference laboratory analysis results.
Pharmacokinetic analysis and central 
microbiology reference laboratory analysis are 
key secondary endpoints in the study; the study 
is not considered complete until all key data are 
available for planned endpoint analyses, and 
these data will only become available 2-3 
months after the last patient last visit date.
 
 
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Additional change(s) for this amendment:
Section # and Name
Description of Change
Brief Rationale
2 Schedule of Activities 
(SoA)
Japanese Version Only: To delete the footnote b of 
‘Clinical Assessment of Infection Site’ at Visit 1.
Change based on Protocol Clarification Letter 
(PCL) on July 12, 2018: corrected minor error.
3.1 Study Rationale
Update the status of pediatric indication in EU 
(underlined);
Daptomycin is also indicated in the EU for adult 
and pediatric (1 to 17 years of age) patients with S. 
aureus bacteremia (SAB). In adults, use in 
bacteremia should be associated with RIE or with 
cSSTI, while in pediatric patients, use in 
bacteremia should be associated with cSSTI.
Change based on PCL on July 12, 2018: Update 
the information.
3.1 Study Rationale
English Version Only:
To change as follows (underlined); ‘Target 
pathogens: daptomycin susceptible MRSA’
Change based on PCL on July 12, 2018: 
corrected minor error.
7.1 Treatments 
Administered
To change the Study Treatment Name to 
‘Daptomycin for injection’ in Table 1.
Change based on PCL on July 12, 2018: updated 
based on Clinical Supplies Specification.
9 Study Assessments and 
Procedures
To add the amount of blood collection for 
analyzing plasma daptomycin concentration as 
follows;
The amount of blood collected from each 
participant for analyzing plasma daptomycin 
concentration will be approximately 5 mL total (1 
mL per each sampling point).
Change based on PCL on July 12, 2018: 
determined the procedures for details.
 
 
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Section # and Name
Description of Change
Brief Rationale
9.1.8 Treatment 
Administration
English Version Only:
To change as follows (underlined); over 60 
minutes +/- 10 minutes（1 to 6 years old）
Change based on PCL on July 12, 2018: 
corrected minor error.
9.2.2 Microbiological 
Response
Japanese Version Only: To correct the typo in the 
section title.
Change based on PCL on July 12, 2018: 
corrected minor error.
9.2.2.1 Pathogen-level 
microbiological response
9.2.2.2 Subject-level 
microbiological response
10.4.1 Efficacy / 
Pharmacokinetic Endpoints
To change the wording from ’gram positive 
pathogen(s)’ and ‘gram-positive’ to ‘gram-positive 
cocci’.
Change based on PCL on July 12, 2018: clarified 
the wording about infecting pathogen.
9.5.4 Neurological 
Examination
To change the assessment partially as follows;
Neurological Examination should be performed 
according to section 2.
The investigators will perform an age appropriate 
neurological examination including assessments of 
Mental Status, Cranial Nerve, Muscle Tone (Leg 
and Arm), Muscle Strength (Leg and Arm),
Reflexes (Ankle, Biceps, Knee and Babinski), 
Coordination and Gait (Finger-to-Nose), Sensory 
(light touch sense-Forearms and Legs) and Tremor 
(Upper Extremities). All assessments will be 
evaluated as normal or abnormal (grading of 
abnormal and so on if applicable).
Change based on PCL on July 12, 2018 and Nov 
1, 2018: update the wording and such during 
EDC construction.
 
 
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Section # and Name
Description of Change
Brief Rationale
9.5.7.2 Collection of blood
To change the blood culture as follows 
(underlined);
At EOT (Visit 4), blood culture is required even if 
the blood cultures until 2 sequential cultures 
demonstrate no growth is confirmed.
Change based on PCL on July 12, 2018: 
corrected minor error.
9.5.7.3 Gram stain
To change as follows;
Gram stain should be performed at Visit 1, using 
the collected specimen (infection site) or the 
bacteria from the specimen culture (Infection site 
or blood). If the pathogen species are identified by 
other methods, gram stain is not necessary. Gram 
stain may be performed at the same day of 
screening period as the first dose of study drug 
administration (i.e. Before the first dose of study 
drug).
Change based on PCL on July 12, 2018: 
reflected the notes in Section 2 and clarified the 
requirement of gram stain.
9.5.8 Clinical Assessment 
of Infection Site
To add the procedures as follows;
The investigators will evaluate the clinical 
assessment of signs and symptoms of cSSTI 
according to section 2. The signs and symptoms 
(Erythema, Swelling/Edema, Induration, Localized 
Warmth, Tenderness on Palpation, Drainage, 
Fluctuance, Ulceration, Necrotic Tissue, Localized 
Pain, Redness, Chills and Fever) will be examined 
and will be evaluated as "Yes” or “No”, and grade 
(Mild, Moderate or Severe, if applicable).
Change based on PCL on July 12, 2018: 
described the procedures for details based on 
Section 2.
 
 
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Section # and Name
Description of Change
Brief Rationale
10.6.3 Summaries of 
Baseline Characteristics, 
Demographics, and Other 
Analyses
English Version Only:
To add the sentence as follows (underlined);
Population PK analysis may be conducted if 
needed. If population PK analysis will be 
conducted, PK data and analysis will be reported 
separately in a population PK report.
Change based on PCL on July 12, 2018: 
described population PK analysis for details.
12.4 Appendix 4: Clinical
Laboratory Tests
English Version Only:
To change about Hematology in table 13 
(underlined);
WBC count with Differential includes 
‘Neutrophils, Lymphocytes, Monocytes, 
Eosinophils and Basophils’. 
Change based on PCL on July 12, 2018: 
corrected minor error.
12.4 Appendix 4: Clinical
Laboratory Tests 
To change the Laboratory Assessments in table 13 
as follows (underlined);
Note: 1. Direct bilirubin is tested with blood 
drawing again if total bilirubin is elevated above 
the upper limit of normal and the investigator 
needs further assessments.
Change based on PCL on Nov 1, 2018: clarified 
the wording about the procedure.
 
 
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1.
Synopsis.......................................................................................................................16
2.
Schedule of Activities (SoA)......................................................................................19
3.
Introduction................................................................................................................23
Study Rationale .......................................................................................................23
Background..............................................................................................................24
Pharmaceutical and Therapeutic Background .....................................................24
Benefit/Risk Assessment.........................................................................................25
4.
Objectives/Hypotheses and Endpoints.....................................................................25
5.
Study Design...............................................................................................................26
Overall Design .........................................................................................................26
Study Diagram .....................................................................................................27
Number of Participants ..........................................................................................28
Beginning and End of Study Definition ................................................................28
Clinical Criteria for Early Study Termination .....................................................28
Scientific Rationale for Study Design....................................................................28
Rationale for Population ......................................................................................28
Rationale for Endpoints .......................................................................................28
Safety Endpoints...........................................................................................28
Efficacy Endpoints........................................................................................29
Pharmacokinetic Endpoints ..........................................................................29
Rationale for population ......................................................................................29
Justification for Dose ..............................................................................................29
6.
Study Population........................................................................................................30
Inclusion Criteria....................................................................................................30
Exclusion Criteria ...................................................................................................32
 
 
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Lifestyle Restrictions...............................................................................................33
Meals and Dietary Restrictions............................................................................33
Caffeine Alcohol, and Tobacco Restrictions .......................................................33
Activity ................................................................................................................33
Screen Failures ........................................................................................................33
Participant Replacement Strategy.........................................................................33
7.
Treatments..................................................................................................................33
Treatments Administered.......................................................................................34
Method of Treatment Assignment.........................................................................34
Stratification.........................................................................................................34
Blinding....................................................................................................................34
Preparation/Handling/Storage/Accountability ....................................................35
Dose Preparation..................................................................................................35
Handling, Storage and Accountability.................................................................35
Treatment Compliance...........................................................................................36
Concomitant Therapy.............................................................................................36
Rescue Medications and Supportive Care ...........................................................36
Treatment After the End of the Study ..................................................................36
Clinical Supplies Disclosure...................................................................................37
8.
Discontinuation/Withdrawal Criteria......................................................................37
Discontinuation of Study Treatment.....................................................................37
Withdrawal from the Study ...................................................................................38
Lost to Follow Up....................................................................................................38
9.
Study Assessments and Procedures..........................................................................38
Administrative and General Procedures ..............................................................39
Informed Consent/Assent.....................................................................................39
General Informed Consent/Assent................................................................39
Inclusion/Exclusion Criteria ................................................................................40
Participant Identification Card.............................................................................40
Medical History ...................................................................................................40
Prior and Concomitant Medications Review .......................................................40
 
 
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Prior Medications..........................................................................................40
Concomitant Medications.............................................................................40
Assignment of Screening Number.......................................................................40
Assignment of Treatment/Randomization Number.............................................41
Treatment Administration....................................................................................41
Timing of Dose Administration....................................................................41
Discontinuation and Withdrawal .........................................................................41
Participant Blinding/Unblinding..........................................................................41
Calibration of Equipment.....................................................................................42
Efficacy Assessments...............................................................................................42
Clinical Response.................................................................................................42
Microbiological Response....................................................................................42
Pathogen-level microbiological response .....................................................42
Subject-level microbiological response ........................................................43
Adverse Events (AE), Serious Adverse Events (SAE) and Other 
Reportable Safety Events .......................................................................................44
Time Period and Frequency for Collecting AE, SAE and Other 
Reportable Safety Event Information ..................................................................44
Method of Detecting AE, SAE and Other Reportable Safety Events..................46
Follow-up of AE, SAE and Other Reportable Safety Event Information............46
Regulatory Reporting Requirements for SAE .....................................................46
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..................................................................................47
Pregnancy and Exposure During Breastfeeding ..................................................47
Events of Clinical Interest (ECI)..........................................................................47
Treatment of Overdose...........................................................................................48
Safety........................................................................................................................48
Physical Examinations.........................................................................................48
Vital Signs............................................................................................................49
Height and weight................................................................................................49
Neurological Examination ...................................................................................49
Assessment of Motor Developmental Skills........................................................50
Clinical Safety Laboratory Assessments..............................................................50
 
 
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Microbiological Culture.......................................................................................50
Collection of Infection-Site Specimens ........................................................51
Collection of blood .......................................................................................51
Gram stain.....................................................................................................51
Clinical Assessment of Infection Site..................................................................52
Pharmacokinetics....................................................................................................52
Blood Collection for Plasma daptomycin ............................................................52
Pharmacodynamics.................................................................................................53
Biomarkers ..............................................................................................................53
Future Biomedical Research Sample Collection..................................................53
Visit Requirements..................................................................................................53
Screening..............................................................................................................53
Treatment Period..................................................................................................53
Follow up period (Post-treatment).......................................................................53
10.
Statistical Analysis Plan ............................................................................................54
Statistical Analysis Plan Summary........................................................................54
Responsibility for Analyses/In-House Blinding....................................................55
Hypotheses/Estimation ...........................................................................................55
Analysis Endpoints..................................................................................................55
Efficacy / Pharmacokinetic Endpoints.................................................................55
Safety Endpoints ..................................................................................................56
Analysis Populations...............................................................................................56
Efficacy / Pharmacokinetics Analysis Populations..............................................56
Safety Analysis Populations ................................................................................56
Statistical Methods..................................................................................................56
Statistical Methods for Efficacy Analysis............................................................56
Statistical Methods for Safety Analysis...............................................................57
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses...............................................................................................................57
Interim Analyses .....................................................................................................58
Multiplicity ..............................................................................................................58
Sample Size and Power Calculations ....................................................................58
 
 
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Subgroup Analyses..................................................................................................59
Compliance (Medication Adherence)....................................................................59
Extent of Exposure..................................................................................................59
11.
References...................................................................................................................59
12.
Appendices..................................................................................................................60
Appendix 1: Study Governance Considerations ..................................................60
Merck Code of Conduct for Clinical Trials .....................................................................60
Financial Disclosure.........................................................................................................62
Data Protection.................................................................................................................62
Confidentiality of Data ....................................................................................................62
Confidentiality of Participant Records.............................................................................62
Confidentiality of IRB/IEC Information..........................................................................63
Publication Policy............................................................................................................63
Compliance with Study Registration and Results Posting Requirements .......................63
Compliance with Law, Audit and Debarment .................................................................64
Data Quality Assurance ...................................................................................................64
Source Documents ...........................................................................................................65
Study and Site Closure.....................................................................................................65
Appendix 2: Contraceptive Guidance and Pregnancy Testing...........................66
Definitions........................................................................................................................66
Contraception Requirements............................................................................................66
Pregnancy Testing............................................................................................................68
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting..............................................69
Definition of AE ..............................................................................................................69
Definition of SAE ............................................................................................................70
Additional Events Reported.............................................................................................71
Recording AE and SAE ...................................................................................................71
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor..................74
Appendix 4: Clinical Laboratory Tests.................................................................76
 
 
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LIST OF TABLES
    
Table 1
Study Treatment....................................................................................................34
Table 2
Dose Preparation...................................................................................................35
Table 3
Definition of clinical assessment..........................................................................42
Table 4
Definition of pathogen-level microbiological response .......................................43
Table 5
Definition of Super infection and new infection ..................................................43
Table 6
Definition of subject-level microbiological response...........................................43
Table 7
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events......................................................................................45
Table 8
Blood sampling points and their allowances ........................................................52
Table 9
List of efficacy endpoints .....................................................................................55
Table 10
Analysis Strategy for Key Efficacy Variables......................................................57
Table 11
Precision estimates for efficacy analysis ..............................................................58
Table 12
Contraceptive Methods.........................................................................................67
Table 13
Protocol-Required Safety Laboratory Assessments .............................................76
 
 
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LIST OF FIGURES
Figure 1
Trial Design ..........................................................................................................27
 
 
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1. Synopsis
Protocol Title:  
A Phase II Open-Label, Single-arm Clinical Trial to Study the Safety, Efficacy 
and Pharmacokinetics of MK-3009 (Daptomycin) in Japanese Pediatric 
Participants Aged 1 to 17 Years with Complicated Skin and Soft Tissue Infections 
or Bacteremia caused by Gram-positive cocci
Short Title: 
PII Trial of Daptomycin (MK-3009) in Japanese Pediatric Subjects with cSSTI & 
Bacteremia
Objectives/Hypotheses and Endpoints:
In Japanese pediatric participants aged 1 to 17 years old with complicated skin and soft 
tissue infection (cSSTI) or bacteremia caused by Gram-positive cocci:
Objective
Endpoint
Primary

To assess the safety and tolerability 
of daptomycin.

Adverse Events (AEs)
-
Participant experiencing AE
-
Participant discontinuing study 
treatment due to AEs
Secondary

To assess the efficacy of 
administration of daptomycin in 
participants with methicillin-
resistant S. aureus (MRSA) 
infections.

Clinical response at Test of Cure (TOC) 
visit

Subject-level microbiological response 
at Test of Cure (TOC) visit

To evaluate steady state 
pharmacokinetics of administration 
of daptomycin.

Pharmacokinetic parameters such as 
AUC0-24 , Cmax, tmax, CLss, Vss, t1/2 will 
be evaluated if evaluable data is 
obtained.
 
 
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Overall Design:
Study Phase
Phase II
Clinical Indication
Treatment of cSSTI and bacteremia caused by MRSA
Population
Patients with cSSTI or bacteremia
Study Type
Interventional
Type of Design
Single treatment group (Non-Randomized)
(including 4 age sub-groups in each primary disease 
category)
Type of Control
No treatment control
Study Blinding
Unblinded Open-label
Estimated Duration 
of Study
The Sponsor estimates that the study will require 
approximately 2 and a half years from the time the first 
participant signs the informed consent/assent until the last 
participant’s last study-related phone call or visit.  
Number of Participants:
Approximately20 participants will be enrolled.
Treatment Groups and Duration:
Treatment Groups
All age groups: daptomycin intravenous (IV)
cSSTI
(Treatment period: 
5-14 days)
Bacteremia
(Treatment period: 
5-42 days)
12-17 years old
5 mg/kg q 24 hrs 
infused over 30 
minutes
7 mg/kg q 24 hrs 
infused over 30 
minutes
7-11 years old
7 mg/kg q 24 hrs 
infused over 30 
minutes
9 mg/kg q 24 hrs 
infused over 30 
minutes
2-6 years old
9 mg/kg q 24 hrs 
infused over 60 
minutes
12 mg/kg q 24 hrs 
infused over 60 
minutes
1  to < 2 years
old
10 mg/kg q 24 hrs 
infused over 60 
minutes
12 mg/kg q 24 hrs 
infused over 60 
minutes
 
 
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Duration of 
Participation
Each participant will participate in the study for 
approximately 31 days (cSSTI) or approximately 59 days 
(bacteremia) from the time the participant signs the 
Informed Consent Form (ICF) through the final contact.  
Within 72 hours of the screening visit, each participant will 
be allocated to treatment for approximately 5 to up to 14 
days (cSSTI) or 42 days (bacteremia).  After the end of IV 
therapy, each participant will be followed for 14 days.
Study governance considerations are outlined in Section 12.1.
 
 
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2. Schedule of Activities (SoA)
Study Period
Screening
Treatment
Follow up
Notes
Visit Number/Title:
Visit 1
Screening
Visit 2
Initiation of 
Therapy
Visit 3
On Therapy
Visit 4
End of 
Therapy
（EOT）
Visit 5
Test of 
Cure
（TOC）
Visit 6
Follow Up
（FU）
Scheduled Study Day of Visit:
≤ 72 hours 
from first 
dose of study 
medication
Day 1
Day 3
Day 4 -
Day 
before 
EOT
Day 5 - 14 a
Day 5 - 42 a
7 days 
following 
EOT
14 days 
following 
EOT
Window for Scheduled Visit:
+ 1 Day
+ 1 Day
± 3 Days
+ 3 Days
Administrative Procedures
Informed Consent
X
Participant Identification Card
X
Inclusion/Exclusion Criteria
X
Medical History
X
Prior/Concomitant Medication 
Review
X
X
X
X
X
X
X
Treatment Allocation
X
MK-3009 (daptomycin) 
Administration e
X (q 24 hours)
Efficacy Procedures
Clinical Response Assessment
X
X
For procedure, see Section 
9.2.1.
Microbiological Response Rating
X
X
For procedure, see Section 
9.2.2.
Safety Procedures
Full physical examination
X
X
Directed physical examination 
X
X
Twice a 
week h
X
X
Emphasis on evaluation of 
weakness, muscle pain, and 
signs and symptoms related to 
source of infection.
Height
X
Weight
X
X
Measure weight if a clinically 
significant weight change 
occurred in study therapy.
 
 
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Study Period
Screening
Treatment
Follow up
Notes
Visit Number/Title:
Visit 1
Screening
Visit 2
Initiation of 
Therapy
Visit 3
On Therapy
Visit 4
End of 
Therapy
（EOT）
Visit 5
Test of 
Cure
（TOC）
Visit 6
Follow Up
（FU）
Scheduled Study Day of Visit:
≤ 72 hours 
from first 
dose of study 
medication
Day 1
Day 3
Day 4 -
Day 
before 
EOT
Day 5 - 14 a
Day 5 - 42 a
7 days 
following 
EOT
14 days 
following 
EOT
Window for Scheduled Visit:
+ 1 Day
+ 1 Day
± 3 Days
+ 3 Days
Vital Signs (heart rate, blood 
pressure, respiratory rate, oral 
body temperature)
X
X (Daily) c
X
X
If the participant’s oral body 
temperature cannot be 
measured, then it is acceptable 
to measure the body 
temperature via non-oral 
methods, e.g. rectal, forehead, 
or aural. However, for each 
participant, the method by 
which body temperature is 
measured should be the same 
throughout the study.
Neurological Examination
X
X
Twice a 
week h
X
X
Assessment of Motor 
Developmental Skills
X
X
Only for participants who are  ≤ 
6 years old.
Clinical Assessment of Infection 
Site
X
X
X
Once a 
week h
X
X
Only 
for 
participants 
with 
cSSTI.
AE Monitoring
X (Daily)
X
X
Blood for hematology
X b
X c
Once a 
week h
X c
X
Blood for chemistry
X b
X c
Once a 
week h
X c
X
 
 
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Study Period
Screening
Treatment
Follow up
Notes
Visit Number/Title:
Visit 1
Screening
Visit 2
Initiation of 
Therapy
Visit 3
On Therapy
Visit 4
End of 
Therapy
（EOT）
Visit 5
Test of 
Cure
（TOC）
Visit 6
Follow Up
（FU）
Scheduled Study Day of Visit:
≤ 72 hours 
from first 
dose of study 
medication
Day 1
Day 3
Day 4 -
Day 
before 
EOT
Day 5 - 14 a
Day 5 - 42 a
7 days 
following 
EOT
14 days 
following 
EOT
Window for Scheduled Visit:
+ 1 Day
+ 1 Day
± 3 Days
+ 3 Days
Serum CPK
X b
X c
X c
Once a 
week h
X c
X
Urine for urinalysis
X b
X
Only if the urine sample cannot 
be collected because of 
participant’s clinical condition, 
then it is acceptable not to 
conduct this test.
Urine pregnancy test
(β-hCG; Woman of Childbearing 
Potential only)
X
Serum β-hCG should be 
measured if the urine pregnancy 
test is positive.
Infection Site Specimen for 
Culture
X d
X
X
X
Only for participants with 
cSSTI. For participants in 
which infection site specimen 
collection is not medically 
acceptable, follow up specimen 
is not required.
Blood Specimen for Culture e
X d
X
X f
X
X
X
At Visit 6 (FU), not necessary if 
the result at Visit 5 (TOC) is 
negative.
Gram stain
X
If the pathogen species are 
identified by other methods, 
gram stain is not necessary.
 
 
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Study Period
Screening
Treatment
Follow up
Notes
Visit Number/Title:
Visit 1
Screening
Visit 2
Initiation of 
Therapy
Visit 3
On Therapy
Visit 4
End of 
Therapy
（EOT）
Visit 5
Test of 
Cure
（TOC）
Visit 6
Follow Up
（FU）
Scheduled Study Day of Visit:
≤ 72 hours 
from first 
dose of study 
medication
Day 1
Day 3
Day 4 -
Day 
before 
EOT
Day 5 - 14 a
Day 5 - 42 a
7 days 
following 
EOT
14 days 
following 
EOT
Window for Scheduled Visit:
+ 1 Day
+ 1 Day
± 3 Days
+ 3 Days
Pharmacokinetics
Blood 
to 
collect 
plasma 
for 
daptomycin PK Analysis
X g
a.
IV study therapy for cSSTI and/or bacteremia should be administered for a minimum of 5 full days. The total duration of IV study therapy should not exceed 14 days for 
cSSTI, and should not exceed 42 days for bacteremia.
b.
It is acceptable to use local laboratory data for enrollment criteria of laboratory test. The samples for laboratory tests at baseline are collected separately and sent to a 
central Laboratory as needed.
c.
Prior to administration of the study medication.
d.
It is acceptable to use a culture sample collected within 120 hours before first study medication.
e.
If the blood culture for participant with cSSTI is positive after allocation through the study (including at Visit 1), the participant could continue the study therapy with 
change of dose regimen for cSSTI to bacteremia upon consultation/discussion with sponsor.
f.
After Day 3, performed as clinically indicated or, if pre-study blood culture was positive, repeat blood culture until confirmed negative. For details about blood culture, 
see Section 9.5.7.2.
g.
Perform on the day following the administration of IV study medication for at least 2 consecutive days before blood collection (i.e., PK sampling on the 3rd day of 
consecutive administration of IV study medication). Only in cases where it is unavoidable, blood should be collected beyond the allowance of visit 3. In all, Sampling at 5 
timepoints will occur: Pre-dose, 15 minutes after IV study medication infusion, and at 1 hour post-infusion, 4 hours post infusion, and12 hours post IV study medication 
infusion.
h.
Weekly basis is considered as ‘Day 8 – Day 14’, ‘Day 15 – Day 21’, ‘Day 22 – Day 28’, ‘Day 29 – Day 35’, ‘Day 36 – Day 42’.
 
 
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3. Introduction
Daptomycin (MK-3009) is a cyclic lipopeptide that represents the class of antibiotics derived 
from the fermentation of a strain of Streptomyces roseosporus.
Study Rationale 
Throughout the world, Staphylococcus aureus (including methicillin-resistant S. aureus; 
MRSA) causes a number of invasive diseases, including complicated skin and soft tissue 
infections (cSSTI) and bacteremia in adult and pediatric populations.  Antibacterial agents to 
treat cSSTI and bacteremia especially caused by MRSA remain as unmet medical needs, 
especially for the pediatric population.  
As of Aug 2017, daptomycin is currently approved for marketing in 62 countries, including 
the United States (US), the European Union (EU), and Japan.
In the US and the EU, daptomycin is indicated for the treatment of adult and pediatric (1 to 
17 years of age) patients with cSSTI caused by gram positive pathogens respectively.
Daptomycin is indicated in the US for the treatment of Staphylococcus aureus (S aureus) 
bloodstream infections (bacteremia), including those with right-sided infective endocarditis 
(RIE) in adult patients and S aureus bloodstream infections (bacteremia) in pediatric patients 
(1 to 17 years of age). Daptomycin is also indicated in the EU for adult and pediatric (1 to 17 
years of age) patients with S. aureus bacteremia (SAB). In adults, use in bacteremia should 
be associated with RIE or with cSSTI, while in pediatric patients, use in bacteremia should 
be associated with cSSTI.
In Japan, daptomycin is currently indicated the treatment of the infection in adult listed 
below.
Target pathogens: daptomycin susceptible MRSA
Target indications: Septicemia, right-sided infective endocarditis, deep skin infections, 
secondary infections such as Secondary infections such as trauma, burns and surgical 
wounds, and secondary infections of erosions and ulcers
Therefore, this study is conducted in Japanese pediatric patients based on the dose regimen in 
non-Japanese pediatric patients that shows the efficacy of daptomycin in clinical studies.
Of the 5 drugs (vancomycin, teicoplanin, arbekacin, linezolid and daptomycin) currently 
approved in Japan for infection due to S. aureus (including MRSA), all except for 
daptomycin have been indicated for use in the pediatric population.  However, these 4 drugs 
are either recommended to be administered with therapeutic drug monitoring (TDM) (eg, 
vancomycin) and/or require multiple doses per day (eg, 2-4 times a day). Given the once-
daily dosing regimen of daptomycin, the absence of a need for TDM during daptomycin 
therapy, and the extensive safety and efficacy of daptomycin use in the adult population, the 
Sponsor is pursuing the clinical development of daptomycin for use in the Japanese pediatric 
population.
 
 
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Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3009(daptomycin).
Pharmaceutical and Therapeutic Background
Daptomycin binds preferentially to Gram-positive bacterial membranes, inserts into the 
membrane and causes a rapid depolarization of membrane potential, which results in 
inhibition of protein, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis, 
and consequently, bacterial cell death.
Daptomycin for pediatric patients is approved in the US and EU (See Section 3.1) based on 
the results of safety, efficacy and pharmacokinetics that are provided from pivotal studies as 
below.
In pediatric patients with cSSTI, P017(DAP-PEDS-07-03) study was conducted to assess the 
safety, efficacy, and PK of daptomycin  versus SOC comparator antibiotics in pediatric 
subjects between the ages of 1 to 17 years, inclusive, with cSSTI caused by Gram-positive 
pathogens. A total of 389 participants were treated in the study (257 participants randomized 
to daptomycin treatment and 132 participants randomized to SOC treatment. In conclusion, 
Daptomycin administered at doses of 5, 7, 9, or 10 mg/kg for up to 14 days to pediatric 
subjects with cSSTI aged 12 to 17 years, 7 to 11 years, 2 to 6 years, and 1 to < 2 years, 
respectively, was shown to be safe and well tolerated and was as effective as SOC therapy.
The P005 (DAP-PEDBAC-11-02) study was conducted to assess the safety, efficacy, and PK 
of IV daptomycin  versus SOC comparator antibiotics in pediatric subjects between the ages 
of 1 to 17 years, inclusive, with S. aureus bacteremia (SAB). A total of 82 subjects were 
randomized into the study (55 subjects were randomized to daptomycin treatment and 27 
subjects were randomized to comparator treatment.  Daptomycin administered intravenously 
at doses of 7, 9, or 12 mg/kg for up to approximately 6 weeks to pediatric subjects with S. 
aureus bacteremia aged 12 to 17 years, 7 to 11 years, and 1 to 6 years respectively, was 
shown to be safe and well tolerated and was as effective as the comparator.  No subject < 2 
years of age was enrolled.  Although not directly studied, simulations based on the pediatric 
population PK model indicated that doses of 12 mg/kg administered to those 1-2 years of age 
in bacteremia would result in comparable exposures to pediatric patients 2 to <18 years 
receiving the age-specific, weight-based doses.  Therefore, efficacy and safety from pediatric 
patients 2 to <18 years can be extended to pediatric patients 1 to <2 years.
In Japan, the clinical study in pediatrics has not been conducted, though phase III study in 
adults patients (P002) was conducted (with the proportion of participants with infections by 
Gram-positive coccus was 94.2% [114 of 121 participants] and with infections by MRSA 
was 64.5% [78 of 121 participants]).
Based on the Phase I study in Japan (P001) and the Phase I studies in the non-Japanese 
population conducted by Cubist (Protocol DAP-00-02 and DAP-ADT-04-02), the 
pharmacokinetics in Japanese healthy participants were considered to be similar to non-
Japanese healthy participants. Also, the same result about pharmacokinetics in Japanese 
patients is provided from the Phase III study in Japan (P002). Therefore, it is anticipated that 
the exposures in Japanese pediatric patients with cSSTI following daptomycin administration 
 
 
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at the evaluated dosing regimens in this study (P029) are comparable to the exposures in non-
Japanese pediatric patients with cSSTI (P017) and with SAB (P005) in whom efficacy and 
safety were established previously.  Overall, the dosing regimens evaluated in this study 
(P029) are appropriate for Japanese pediatric patients with cSSTI or bacteremia.
The purpose of this study is to assess the safety, efficacy and PK of daptomycin in Japanese 
pediatric participants aged 1 to 17 years with cSSTI or bacteremia.
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
The overall benefit-risk of daptomycin use in the pediatric population has been demonstrated 
in the non-Japanese pediatric cSSTI and bacteremia studies (Refer to Section 3.2.1).
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying Investigators Brochure (IB) and Informed 
Consent documents.
4. Objectives/Hypotheses and Endpoints
In Japanese pediatric participants aged 1 to 17 years old with cSSTI or bacteremia caused by 
Gram-positive cocci:
Objective
Endpoint
Primary

To assess the safety and tolerability 
of daptomycin.

Adverse Events (AEs)
-
Participant experiencing AE
-
Participant discontinuing study 
treatment due to AEs
Secondary

To assess the efficacy of 
administration of daptomycin in 
participants with MRSA infections.

Clinical response at Test of Cure (TOC) 
visit

Subject-level microbiological response at 
Test of Cure (TOC) visit

To evaluate steady state 
pharmacokinetics administration of 
daptomycin.

Pharmacokinetic parameters such as 
AUC0-24 , Cmax, tmax, CLss, Vss, t1/2 will be 
evaluated if evaluable data is obtained.
 
 
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Objective
Endpoint
Exploratory

To assess the efficacy of 
administration of daptomycin in 
participants with MRSA infections.

Clinical response at End Of Therapy 
(EOT) visit

Subject-level microbiological response at 
End Of Therapy (EOT) visit

To assess the efficacy of 
administration of daptomycin.

Clinical response at EOT and TOC visit

Subject-level microbiological response at 
EOT and TOC visit

To assess the microbiological 
efficacy of administration of 
daptomycin per pathogen(s).

Pathogen-level microbiological response 
per pathogen(s) at EOT and TOC visit
5. Study Design 
Overall Design 
This is an open-label, single-arm study of daptomycin (MK-3009) in Japanese pediatric 
participants with cSSTI or bacteremia caused by Gram-positive cocci.
Approximately 20 Japanese pediatric participants aged 1 to 17 years old with cSSTI or 
bacteremia caused by Gram-positive cocci as a infection type will be enrolled into this study. 
The study enrollment will be stopped when a total of 20 participants are enrolled. Details 
regarding enrollment distribution by age and diagnoses are provided in Section 5.2.
After a maximum duration of 72-hour screening period, eligible participants will receive a 
minimum of 5 days to up to a maximum of 14 days (cSSTI) or 42 days (bacteremia) of IV 
study therapy. While on study therapy, study visits will be performed on Day 1 (initiation of 
IV study drug), Day 3 (on therapy visit), and at end of therapy (EOT) (Administration of 
study medication will be witnessed by investigator or qualified designee in the study site, but 
hospitalization in the treatment period is not mandatory). At Day 3, blood sampling for 
analyzing plasma daptomycin concentration is conducted from 5 timepoints will occur: Pre-
dose, 15 minutes after IV study medication infusion, and at 1 hour post-infusion, 4 hours post 
infusion, and12 hours post IV study medication infusion. Following the completion of IV 
study therapy, all participants will be evaluated 7 days following completion of therapy (at 
test of cure, TOC visit). In addition, a Follow up (FU) visit will be performed in all 
participants at 14 days after completion of IV study therapy. All participants will remain in 
the study for a total of up to 31 days (cSSTI) or 59 days (bacteremia).
Safety and tolerability will be carefully monitored throughout the study by the Sponsor in 
accordance with standard procedures.
 
 
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Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the Study SoA - Section 2. Details of each 
procedure are provided in Section 9 – Study Assessments and Procedures.
Study Diagram
The study design is depicted in Figure 1.
Trial Design for cSSTI
Trial Design for bacteremia
Figure 1
Trial Design
 
 
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Number of Participants
Approximately 20 participants will be allocated.
The study will target enrollment of the following minimum number of participants in each 
infection type category and age groups (see below), but the study enrollment would be 
stopped when a total of 20 participants are enrolled regardless of enrollment status of each 
infection type or age groups:
・6 participants with bacteremia
・1 participant of 1to < 2 years old and 3 participants each for the higher age categories, 
regardless of the infection type.
Beginning and End of Study Definition
The overall study begins when the first participant signs the informed consent/assent form.  
The overall study ends when the last participant completes the last study-related phone-call 
or visit, withdraws from the study or is lost to follow-up (ie, the participant is unable to be 
contacted by the investigator).  
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last pharmacokinetic analysis and central microbiology reference laboratory analysis results.
Clinical Criteria for Early Study Termination
There are no pre-specified criteria for terminating the study early.
Scientific Rationale for Study Design 
Rationale for Population
The Japanese pediatric (1-17 years of age) population will be studied to support the planned 
licensing of daptomycin for treating cSSTI or bacteremia caused by Gram-positive cocci in 
Japan.
For the age of participants, same with the studies in non-Japanese pediatric, patients younger 
than 12 months are excluded from this study due to the risk of potential effects on muscular, 
neuromuscular, and/or nervous systems (either peripheral and/or central) observed in 
neonatal dogs with intravenous daptomycin.
Rationale for Endpoints
Safety Endpoints
As the primary objective of this study, the safety and tolerability of daptomycin will be 
assessed by clinical evaluation of adverse events and inspection of other study parameters 
including vital sign, physical examinations, and standard laboratory safety tests at time points 
specified in Section 2. Adverse events are graded and recorded according to Section 9.3. 
Participants may be asked to return for unscheduled visits in order to perform additional 
safety monitoring.
 
 
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Other assessments of neurology and motor development are conducted in this study. The 
safety of daptomycin in the pediatric population in studies conducted outside Japan appears 
to be comparable to that observed in adults. The main safety concerns for this product 
include the important identified risks of severe skeletal muscle toxicity, peripheral 
neuropathy, development of resistance among S. aureus isolates during therapy, severe 
allergic reactions (including pulmonary eosinophilia and severe cutaneous reactions such as 
DRESS [Drug rash with Eosinophilia and Systemic Symptoms]) and eosinophilic 
pneumonia; the important potential risks associated with daptomycin include bone marrow 
toxicity, severe hepatic toxicity, and dysregulation of in vivo coagulation. Therefore, these 
safety concerns will be monitored closely in this study through clinical assessments and 
laboratory testing.
Efficacy Endpoints
A secondary objective of this study is to assess the efficacy of daptomycin in participants 
with MRSA infections that is the target pathogen of the Japanese adult indication. Because 
the targeted infections in this study, i.e. cSSTI and bacteremia, are serious illnesses, the 
efficacy of treatment should take into account responses in terms of both clinical signs and 
symptoms and microbiological results. Clinical response and microbiological response are 
both defined as the efficacy endpoints in this study.
Pharmacokinetic Endpoints
A secondary objective of this study is to characterize the PK profile of daptomycin in 
Japanese pediatric patients. The plasma concentration will be used to determine PK 
parameters (eg. Cmax, tmax, AUC0-24, CLss and Vss, t1/2 will be assessed if evaluable data is 
obtained) for daptomycin.
Rationale for population
The Japanese pediatric (1-17 years of age) population will be studied to support the planned 
licensing of daptomycin for treating cSSTI or bacteremia caused by Gram-positive cocci in 
Japan.
As was the case for the pediatric daptomycin cSSTI and bacteremia studies in non-Japanese 
pediatric, patients younger than 12 months are excluded from this study due to the risk of 
potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral 
and/or central) observed in neonatal dogs with intravenous daptomycin.
Justification for Dose 
Dosing regimens in Japanese pediatric patients were selected based on matching AUC with 
adult Japanese patients at the approved 4 mg/kg (cSSTI) or 6 mg/kg (bacteremia) doses.  
These doses have been demonstrated to be safe and efficacious in Japanese and non-Japanese 
adult Ph3 studies. In addition, owing to the lack of a role of drug metabolizing enzymes and 
transporters in daptomycin disposition, ontogenic changes are not expected to influence on 
PK of daptomycin in pediatric.
Pharmacokinetic assessments in non-Japanese pediatric subjects demonstrated that, in 
general, body weight-normalized total body clearance in pediatric patients was higher than in 
 
 
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adults and increased with a decrease in age, whereas elimination half-life tends to decrease 
with a decrease in age.  These observations support age-specific, weight-based dosing 
regimens outlined in the table (see Section 7.4.1).  These dosing regimens have been 
evaluated in non-Japanese pediatric cSSTI or bacteremia safety/efficacy/PK studies and were 
shown to have comparable safety and efficacy profiles observed in adults, and achieved 
comparable AUC distribution to those in adult patient populations.  Although not directly 
studied, simulations based on the pediatric population PK model indicated that doses of 12 
mg/kg administered to those 1-2 years of age in bacteremia would result in comparable 
exposures to those 2-6 years. 
There is no difference in daptomycin PK between Japanese and non-Japanese (healthy or 
patients adult).
These results together support the appropriateness of the age-specific, weight-based dosing 
regimens evaluated in P017 and P005 in Japanese pediatric patients with cSSTI or 
bacteremia in the current study. See Section 7.4.1 for recommended dosing.
6. Study Population
Male/Female Japanese participants with cSSTI or bacteremia caused by Gram-positive cocci 
between the ages of 1 to 17 years will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
1. Require treatment for cSSTI or bacteremia.
NOTE: Participants have to meet the following diagnostic criteria (either for cSSTI or 
bacteremia). If the participant meets both criteria for cSSTI and bacteremia, the 
participant must be allocated to group of bacteremia.
For participant with cSSTI;
The participant must meet the following two criteria.
I.
Has cSSTI known or suspected to be caused by Gram-positive cocci that requires 
intravenous antibiotic treatment and diagnosed with either Gram stain or culture.
Complicated infections are defined as infections either involving deep soft tissue 
or requiring significant surgical intervention (e.g. cellulitis, erysipelas, infected 
ulcers, burns, and major abscesses), or skin and soft tissue infections accompanied 
by systemic signs and/or symptoms where intravenous antibiotic therapy is 
warranted. 
II. Has at least 3 of the following clinical signs and symptoms associated with the 
cSSTI: 
a.
Pain; 
 
 
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b.
Tenderness to palpation; 
c.
Temperature >37.0°C axillary or >37.5°C oral or >38.0° C rectal, forehead, 
or aural; 
d.
White blood count (WBC) >12,000/mm3 or ≥10% bands; 
e.
Swelling and/or induration; 
f.
Erythema (>1cm beyond edge of wound or abscess); 
g.
Pus formation. 
h.
CRP > Upper Limited of Normal.
For participant with bacteremia:
Have proven or probable Gram-positive coccus bacteremia defined as follows:
Proven
Participants with proven bacteremia are those with pathogen identification of Gram-
positive cocci at least one blood culture bottle by conventional culture methods or by 
a rapid diagnostic test in screening period.
Probable
Participants with probable bacteremia are those with a blood culture result 
demonstrating Gram-positive cocci by Gram stain in screening period.
Demographics
2. Be male or female Japanese aged ≥ 1 to ≤ 17 years on the day of signing informed 
consent.
Male participants:
3. A male participant must agree to use contraception as detailed in Section 12.2 during 
the treatment period and for at least 14 days, after the last dose of study treatment and 
refrain from donating sperm during this period.
Female participants:
4. A female participant is eligible to participate if she is not pregnant (see Section 12.2), 
not breastfeeding, and at least one of the following conditions applies: 
a.) Not a woman of childbearing potential (WOCBP) as defined in Section 12.2
OR 
b.) A WOCBP who agrees to follow the contraceptive guidance in Section 12.2
during the treatment period and for at least 14 days after the last dose of study 
treatment.
Informed Consent/Assent
5. The parent of participant (or a legally acceptable representative if applicable) 
provides written informed consent for the trial with understanding the study 
procedures, alternative treatments available, and risks involved with the study, and 
voluntarily agreement to participate. The participant can provide written assent if 
participant can do.
 
 
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Others
6. Agree to allow any bacterial isolates obtained from protocol-required specimens
related to the current infection to be provided the Central Microbiology Reference
Laboratory for study-related microbiological testing, long-term storage, and other 
future testing.
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Prior/Concomitant Therapy
1. Has received previous systemic antimicrobial therapy that is effective against Gram 
positive cocci and exceeding 72 hours duration administered at anytime during the 96 
hours prior to the first dose of study drug;
Exception: participant is eligible if the antibiotic is known to be not effective against 
the causative pathogen (includes clinical failure evaluated by investigator) or if the 
culture data demonstrate in vitro resistance to prior i.v. antibiotic.
Medical Conditions
2. Has a known infection caused solely by Gram-negative pathogen(s), fungus(i) or 
virus(es).
3. Has pneumonia (septic emboli in the lung is not an exclusion if clear evidence of 
source of infection is other than lungs), empyema, meningitis, endocarditis, or 
osteoarticular infection.
4. Has a history of or current rhabdomyolysis.
5. Is anticipated to require non-study systemic antibiotics that may be potentially 
effective against Gram-positive pathogen(s).
6. Has shock or hypotension unresponsive to fluids or vasopressors for ≥4 hours.
7. Has significant allergy/hypersensitivity or intolerance to daptomycin.
8. Has renal insufficiency (i.e. estimated glomerular filtration rate (eGFR) < 50 
mL/min/1.73m2). The calculus equation of eGFR is referred to section 12.4.
9. Has Creatine Phosphokinase (CPK) elevation ≥ 10 X ULN (upper limit of normal) 
without symptoms or ≥ 5 X ULN with symptoms such as myalgia, muscle stiffness, 
muscle weakness at screening.
10. Has a history of clinically significant (as assessed by the Investigator) muscular 
disease, nervous system or seizure disorder, including unexplained muscular 
weakness, history of peripheral neuropathy, Guillain-Barre or spinal cord injury; 
previous uncomplicated febrile seizure allowed.
11. Has a history or current evidence of any condition, therapy, lab abnormality or other 
circumstance that might expose the participant to risk by participating in the trial, 
confound the results of the trial, or interfere with the participant’s participation for the 
full duration of the trial.
 
 
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12. Is a female who is pregnant or is expecting to conceive (or is a male partner of a 
female who is expecting to conceive), is breastfeeding, or plans to breastfeed prior to 
completion of the study.
Prior/Concurrent Clinical Study Experience
13. Is currently participating in, or has participated in, any other clinical study involving
the administration of investigational or experimental medication (not licensed by
regulatory agencies) at the time of the presentation or during the previous 30 days
prior to screening or is anticipated to participate in such a clinical study during the
course of this trial.
14. Has previously participated in this study at any time.
15. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this study.
Lifestyle Restrictions
Meals and Dietary Restrictions
There are no restrictions in diet or meal.
Caffeine Alcohol, and Tobacco Restrictions
Alcohol and tobacco consumption are not permitted during the entire study period.
Activity
There are no restrictions in activity.
Screen Failures
Screen failures are defined as participants who consent/assent to participate in the clinical 
study but are not subsequently entered in the study.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any adverse events or serious adverse events 
(SAE) meeting reporting requirements as outlined in the data entry guidelines.
Participant Replacement Strategy
A participant who discontinues from the study will not be replaced.
7. Treatments
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo,
or medical device(s) intended to be administered to a study participant according to the study 
protocol.
 
 
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Clinical supplies [study treatment(s) provided by the Sponsor] will be packaged to support 
enrollment as required.  Clinical supplies will be affixed with a clinical label in accordance 
with regulatory requirements.
Treatments Administered
The study treatment to be used in this study is outlined below in Table 1 Study Treatment.
Table 1
Study Treatment
Study Treatment 
Name:
Daptomycin for injection
Dosage Formulation:
Lyophilized powder 
Unit Dose Strength(s):
500mg
Dosage Level(s):
Once daily administration of 5, 7, 9, 10, or  12mg/kg per 
infection types and age levels  [See Section 7.4.1] 
Route of 
Administration:
IV infusion
Sourcing:
Provided centrally by the Sponsor
All supplies indicated in Table 1 will be provided per the ‘Sourcing’ row depending upon 
local country operational requirements.  Every attempt should be made to source these 
supplies from a single lot/batch number. The study site is responsible for recording the lot 
number, manufacturer, and expiry date for any locally purchased product as per local 
guidelines unless otherwise instructed by the Sponsor.
Refer to Section 9.1.8 for details regarding administration of the study treatment.
Method of Treatment Assignment 
Participants participating in this trial will be allocated by non-random assignment.
Stratification
For this single treatment group design, eligible participants will be pre-stratified by age 
category (12-17, 7-11, 2-6 and 1 to <2 years of age) and infection type (cSSTI, bacteremia) 
prior to treatment assignment.  The target number of participants for age categories and 
bacteremia as outlined in Section 5.2.
Blinding 
This study is an open-label study; therefore, the Sponsor, investigator and participant will 
know the treatment administered.
 
 
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Preparation/Handling/Storage/Accountability
Dose Preparation
The dose is assigned according to weight and infection type in each age group as Table 2.
Table 2
Dose Preparation
cSSTI
Bacteremia
Infusion 
Volume
Infusion 
Duration
12-17 years old
5 mg/kg q 24 hrs
7 mg/kg q 24 hrs
50 mL saline
30 minutes
7-11 years old
7 mg/kg q 24 hrs
9 mg/kg q 24 hrs
50 mL saline
30 minutes
2-6 years old
9 mg/kg q 24 hrs
12 mg/kg q 24 hrs
25 mL saline
60 minutes
1 to < 2 years old
10 mg/kg q 24 hrs
12 mg/kg q 24 hrs
25 mL saline
60 minutes
Time window for dosing interval (q 24 hours): +/- 2 hours
Time window for infusion duration: +/- 5 minutes for 30 minutes, +/- 10 minutes for 60 
minutes
The dose of each participant should be determined based on the body weight measured at 
Visit 1. If the body weight fluctuates by more than 10% during the treatment period and the 
investigator determines that it is a clinically significant fluctuation, the dose may be 
recalculated and modified.
If a participant with cSSTI is diagnosed with bacteremia after allocation (i.e. the blood 
culture for participant with cSSTI is positive after allocation through the study [including at 
Visit 1]), the participant could continue the study treatment with change of dose regimen 
from dosing for cSSTI to dosing for bacteremia upon consultation/discussion with sponsor.
Handling, Storage and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate.  Where local discard and destruction is appropriate, the 
 
 
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investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the
Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of study 
treatments in accordance with the protocol and any applicable laws and regulations.
Treatment Compliance
Interruptions from the protocol specified treatment plan for compliance < 80% (actual 
number of study administration is < 80% of actual number of days for treatment period)
require consultation between the investigator and the Sponsor and written documentation of 
the collaborative decision on participant management.
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study.  If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study therapy or vaccination may be required.  
The investigator should discuss any questions regarding this with the Sponsor Clinical 
Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician. However, the decision to continue 
the participant on study treatment requires the mutual agreement of the investigator, the 
Sponsor and the participant.
The following concomitant medications/therapies are prohibited in this study:
(From first study drug administration to TOC)
•
Non-study systemic (oral, intravenous or suppository) antibacterial treatments with 
indications for Gram-positive coccus identified as baseline causative pathogen.
•
Any medication administration via intramuscular (IM) injection.
Aztreonam as adjunctive antimicrobial therapy for Gram-negative aerobic pathogens may be 
initiated at the discretion of the investigator depending on the clinical circumstances and the 
likely or proven pathogens at a given site.
Rescue Medications and Supportive Care
No rescue or supportive medications are specified to be used in this study.
Treatment After the End of the Study 
There is no study-specified treatment following the end of the study.
 
 
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Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor 
and/or designee are not blinded. Study treatment (name, strength or potency) is included in 
the label text; random code/disclosure envelopes or lists are not provided.
8. Discontinuation/Withdrawal Criteria 
Discontinuation of Study Treatment 
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment discontinuation may be important 
to the study, they must be collected through the participant’s last scheduled follow-up, even 
if the participant has discontinued study treatment.  Therefore, all participants who 
discontinue study treatment prior to completion of the protocol-specified treatment period
will still continue to participate in the study as specified in Section 2.
Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur. In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the study plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 9.1.9.
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons:
○
The participant or participant’s legally acceptable representative requests to discontinue 
study treatment.
o
The participant or participant’s legally acceptable representative requests to discontinue 
study treatment.
o
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or sponsor, placed the participant at unnecessary risk from continued 
administration of study treatment.
o
The participant has a confirmed positive serum pregnancy test.
o
Non-compliance, such that the Investigator did not permit further study participation.
o
Rhabdomyolysis with or without renal failure not attributed to known causes such as 
trauma or burns.
o
Guillain-Barre syndrome.
o
Elevated blood creatine phosphokinase (CPK) to levels ≥ 10X ULN not related to trauma, 
burns or muscle infection.
o
Elevated blood creatine phosphokinase (CPK) to levels ≥ 5X ULN with muscle 
symptoms such
as but not limited to weakness or myalgia not related to an underlying 
disease (e.g. muscle infection).
 
 
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o
Decreased renal function (eGFR is < 30 mL/min/1.73m2) at any time after screening. The 
calculus equation of eGFR is referred to section 12.4.
For participants who are discontinued from study treatment but continue to be monitored in 
the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study treatment is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study treatment. 
Withdrawal from the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will not receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study are outlined in Section 9.1.9.  The procedures to be performed should a participant 
repeatedly fail to return for scheduled visits and/or if the study site is unable to contact the 
participant are outlined in Section 8.3.
Lost to Follow Up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
●
The site must attempt to contact the participant and reschedule the missed visit.  If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
●
The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (eg, phone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the participant’s medical record.
●
Note:  A participant is not considered lost to follow-up until the last scheduled visit 
for the individual participant.  The missing data for the participant will be managed 
via the pre-specified statistical data handling and analysis guidelines.
9. Study Assessments and Procedures
●
Study procedures and their timing are summarized in the SoA. 
●
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
●
The Investigator is responsible for assuring that procedures are conducted by 
appropriately qualified or trained staff.  Delegation of study site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
●
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
 
 
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to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
●
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
●
Additional evaluations/testing may be deemed necessary by the investigator and or 
the Sponsor for reasons related to participant safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (eg, HIV, Hepatitis C, etc.), 
and thus local regulations may require that additional informed consent, and assent if 
applicable, be obtained from the participant.  In these cases, such evaluations/testing 
will be performed in accordance with those regulations.
The amount of blood collected from each participant for clinical safety laboratory assessment 
over the duration of the study will be approximately 13mL to 33mL depending on the 
treatment period of each participant. The amount of blood collected from each participant for 
analyzing plasma daptomycin concentration will be approximately 5 mL total (1 mL per each 
sampling point).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
Administrative and General Procedures
Informed Consent/Assent
The investigator or qualified designee must obtain documented consent, and assent if 
applicable, from each potential participant or each participant’s legally acceptable 
representative prior to participating in a clinical study. If there are changes to the 
participant’s status during the study (eg, health or age of majority requirements), the 
investigator or qualified designee must ensure the appropriate consent/assent is in place. 
General Informed Consent/Assent
Consent/assent must be documented by the participant’s dated signature or by the 
participant’s legally acceptable representative’s dated signature on a consent/assent form 
along with the dated signature of the person conducting the consent discussion. 
A copy of the signed and dated consent/assent form should be given to the participant before 
participation in the study.
The initial informed consent/assent, any subsequent revised written informed consent/assent
and any written information provided to the participant must receive the IRB/IEC’s 
approval/favorable opinion in advance of use.  The participant or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the participant’s willingness to continue participation in the study.  
The communication of this information will be provided and documented via a revised 
consent/assent form or addendum to the original consent/assent form that captures the 
 
 
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participant’s dated signature or by the participant’s legally acceptable representative’s dated 
signature.
Specifics about a study and the study population will be added to the consent/assent form 
template at the protocol level.  
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations 
and Sponsor requirements. The assent, as applicable will adhere to IRB/IEC requirements, 
applicable laws and regulations and Sponsor requirements.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the study.
Participant Identification Card
All participants will be given a Participant Identification Card identifying them as 
participants in a research study. The card will contain study site contact information 
(including direct telephone numbers) to be utilized in the event of an emergency. The 
investigator or qualified designee will provide the participant with a Participant Identification 
Card immediately after the participant provides written informed consent/assent. At the time 
of treatment allocation/randomization, site personnel will add the treatment/randomization 
number to the Participant Identification Card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
treatment in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained and the evaluation of a participant’s medical history in 
terms of study eligibility will be evaluated by the investigator or qualified. All medical 
conditions including infections will be documented at Visit1 on the appropriate eCRF.
Prior and Concomitant Medications Review
Prior Medications
The investigator or qualified designee will review prior medication use, and record prior 
medication taken by the participant within 30 days before starting the study.
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to treatment allocation.  Each 
 
 
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participant will be assigned only one screening number.  Screening numbers must not be re-
used for different participants.
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by non-random assignment, and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization.   Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
Treatment Administration
Trial dosage and regimen of study drug are described in Section 7.4.1. The first dose will be 
administered at Visit 2.
All IV study therapy infusions should be administered over 30 minutes +/- 5 minutes (7 to 17 
years old) or 60 minutes +/- 10 minutes (1 to 6 years old). The IV study therapy must NOT 
be administered simultaneously through the same infusion line/lumen with any other drugs. 
If another IV drug is required either prior to or after study drug and only 1 line is available, 
an appropriate volume of saline flush must be used between IV infusions. Administration of 
study medication will be witnessed by the investigator and/or qualified designee.
IV study therapy should be administered for a minimum of 5 days to up to a maximum of 14 
days (cSSTI) or 42 days (bacteremia). Administration of trial medication will be witnessed 
by the investigator and/or qualified designee.
Further details on the preparation, storage, and administration of the intravenous study 
antibiotics are provided in a separate Pharmacy Binder.
Timing of Dose Administration
The IV study drug infusion will be administrated once daily every 24 (+/- 2) hours.
Discontinuation and Withdrawal
Participants who discontinue study treatment prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities
scheduled for the final study visit should be performed (at the time of withdrawal).  Any 
adverse events which are present at the time of withdrawal should be followed in accordance 
with the safety requirements outlined in Section 9.3.
Participant Blinding/Unblinding
This is an open label study; there is no blinding for this study.
 
 
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Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible.  
Documentation of equipment calibration must be retained as source documentation at the 
study site.
Efficacy Assessments 
Clinical Response
At the EOT and TOC, the investigator will determine the subject’s clinical response based on 
consideration of the subject's signs and symptoms compared with those present at baseline 
using the following categories as Table 3:
Table 3
Definition of clinical assessment
Cure
Resolution of clinically significant signs and symptoms associated 
with admission infection (i.e., return to pre-infection Baseline). No 
further antibiotic therapy required for the infection type under study.
Improvement
Partial resolution of clinical signs or symptoms of infection such that 
no further antibiotic therapy is required for the infection type under 
study. 
Failure
Inadequate clinical response to therapy – additional antibiotic therapy 
required for infection type under study.
Not evaluable
None of the above. (e.g. Subject was not available to be examined and 
assessed.)
"Cure" and "Improved" will be considered a “Clinical success” (satisfactory clinical 
responses).
Any subjects who still require further antibiotic therapy at TOC will be considered a 
"Failure".
For subjects whose clinical course cannot be clearly defined as “Improved”, a clinical 
outcome of “Failure” will be rendered. Subjects who discontinue study drug therapy before 
Day 3 will be considered “Not evaluable” unless otherwise deemed a clinical “failure”. 
“Clinical failure” will be carried through as “failure” for purposes of evaluation.
Microbiological Response
Pathogen-level microbiological response
At the EOT and TOC, Each subject’s Baseline Infecting Pathogen(s) will be assessed by 
investigator according to the following criteria, which are hierarchical and mutually 
exclusive as Table 4:
 
 
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Table 4
Definition of pathogen-level microbiological response
Eradication
Absence of the Baseline Infecting Pathogen
Presumed
eradication
Absence of material to culture in a subject deemed a clinical cure 
(cSSTI only)
Persistent
Continued presence of the Baseline Infecting Pathogen
Presumed
persistent
Absence of material to culture in a subject deemed a clinical failure 
(cSSTI only)
Not evaluable
None of the above (e.g. Study data are not available)
Proportion of the microbiological success per pathogen will be analyzed based on these 
results (see stat section 10.6).
Super infection and new infection will be also assessed by investigator separately from the 
baseline infection evaluation as Table 5.
Table 5
Definition of Super infection and new infection
Super infection
Presence of new gram-positive cocci pathogen(s) other than baseline 
infecting pathogen during treatment period
New infection
Presence of new gram-positive cocci pathogen other than baseline 
infecting pathogen or superinfecting pathogen after EOT
Subject-level microbiological response
At the EOT and TOC, the Subject’s Microbiological Response will be derived from the 
Pathogen-Level Microbiological Response for all of the subject’s Baseline Infecting 
Pathogens and from the presence or absence of a Superinfecting Pathogen or New infecting 
pathogen (gram-positive cocci). The Subject’s Microbiological Response will be categorized 
as Table 6:
Table 6
Definition of subject-level microbiological response
Success
Absence or presumed absence* of the ALL Baseline Infecting 
Pathogen(s)
And
No gram-positive cocci superinfection (EOT) or gram-positive new 
infection (TOC) 
Failure
Presence of any Baseline Infecting Pathogen(s)
Or
Gram-positive cocci superinfection (EOT) or gram-positive new infection 
(TOC)
Not evaluable
None of the above (e.g. Study data are not available)
*: Only applicable for cSSTI
 
 
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Adverse Events (AE), Serious Adverse Events (SAE) and Other Reportable Safety 
Events 
The definitions of an adverse event (AE) or serious adverse event (SAE), as well as the 
method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting AE, SAE and other reportable safety event reports can be 
found in Section 12.3
AE, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 
The investigator, who is a qualified physician, and any designees are responsible for 
detecting, assessing, documenting, and reporting events that meet the definition of an AE or 
SAE as well as other reportable safety events. Investigators remain responsible for following 
up AE, SAEs and other reportable safety events for outcome according to Section 9.3.3.
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
Safety Event Information 
All AEs, SAEs and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event causes the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure. 
From the time of treatment allocation/randomization through 14 days following cessation of 
treatment, all AEs, SAEs and other reportable safety events must be reported by the 
investigator. 
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph must be reported immediately to the Sponsor 
if the event is considered to be drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the sponsor.
All initial and follow-up AEs, SAEs and other reportable safety events will be recorded and 
reported to the sponsor or designee within the timeframes as indicated in Table 7.
 
 
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Table 7
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
Specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol 
Specified Follow-up 
Period
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to 
SPONSOR:
Non-Serious 
Adverse Event 
(NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data 
entry 
guidelines
Serious Adverse 
Event (SAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- Potential DILI
- Require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (Do not 
require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar 
days of 
learning of 
event
Cancer
Report if:
- due to 
intervention
- causes exclusion
Report all
Not required
Within 5 
calendar 
days of 
learning of 
event
 
 
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
Specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol 
Specified Follow-up 
Period
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to 
SPONSOR:
Overdose
Report if:
- receiving placebo 
run-in or other 
run-in medication 
Report all
Not required
Within 5 
calendar 
days of 
learning of 
event
Method of Detecting AE, SAE and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and non-leading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
Follow-up of AE, SAE and Other Reportable Safety Event Information 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE and other reportable safety events 
including pregnancy and exposure during breastfeeding, ECI, Cancer and Overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 8.3). In addition, the investigator will 
make every attempt to follow all non-serious AEs that occur in randomized participants for 
outcome.  Further information on follow-up procedures is given in Section 12.3.
Regulatory Reporting Requirements for SAE
●
Prompt notification (within 24 hours) by the investigator to the sponsor of SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are met. 
●
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. All Adverse Events will be reported to regulatory authorities, IRB/IECs 
and investigators in accordance with all applicable global laws and regulations, ie, per 
ICH Topic E6 (R1) Guidelines for Good Clinical Practice.
●
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
●
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the sponsor will file 
 
 
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it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements.
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered adverse 
events, any pregnancy or infant exposure during breastfeeding in a participant (spontaneously 
reported to the investigator or their designee) that occurs during the study are reportable to 
the Sponsor.
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, 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.
Events of Clinical Interest (ECI)
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
Events of clinical interest for this study include: 
1. 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 study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent).
If laboratory tests meet this ECI criteria above in patients BEFORE receiving MK-3009, 
investigators need to report that as ECI within 24 hours of leaning the event to the 
SPONSOR, however the process to identify the etiology (stage 1 and stage 2 testing) 
should be evaluated as clinically indicated. Instead, the Liver Functional Test in the 
participant should be periodically monitored and discontinuation of MK-3009 should be 
considered if necessary.
 
 
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Treatment of Overdose
In this study, an overdose is defined as follows.
Dose regimen: more than once daily, or the administration interval is less than 12 hours even 
once daily
Dosage: more than the protocol-specified dose of study medication. (Please see Table 2)
If overdose is suspected, carefully observe the condition of the participant and provide 
supportive treatment as necessary. In adults, daptomycin is slowly removed from the body by 
hemodialysis (about 15% removal of the dose in 4 hours) or peritoneal dialysis (about 11% 
removal in 48 hours).
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor based on the clinical finding of the participant.
Safety 
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below. The clinical laboratory test can be found in Section 12.4.
Planned time points for all safety assessments are provided in the SoA.
Physical Examinations
All physical examinations must be performed by the investigators.
A full physical examination, performed at Visit1 and Visit6 includes the following 
assessments:

general appearance

head

eyes

ears/nose/ throat

neck

lymph nodes

skin

lungs

heart

abdomen

musculoskeletal

neurologic evaluations
 
 
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(If clinically indicated) 

Breast

rectal

genitourinary/pelvic exams
Directed physical examination, performed at Visit2, Visit4, Visit5 and in treatment period 
(twice a week) includes the following assessments:
Emphasis on evaluation of:

weakness

muscle pain

signs and symptoms related to source of infection.
Any abnormal or clinically significant findings from the physical examinations must be 
recorded on the appropriate eCRF.
Vital Signs
Blood pressure (systolic/diastolic), pulse rate, respiratory rate and oral temperature will be 
assessed.
•
If the participant’s oral body temperature cannot be measured, then it is acceptable to 
measure the body temperature via non-oral methods, e.g. rectal, forehead, or aural. 
However, for each participant, the method by which body temperature is measured 
should be the same throughout the study.
•
Participants should be resting in a seated or semi-recumbent position for at least 10 
minutes prior to having vital sign measurements obtained. And clinical laboratory test 
should be performed after the measurement of vital signs.
•
Vital signs should be measured prior to administration of the study medication.
Height and weight
The height should be measured at Visit1.
The weight should be measured at Visit1 and Visit3. And the weight should be measured and 
recorded if a clinically significant weight change occurred in study therapy.
Neurological Examination
Neurological Examination should be performed according to section 2.
The investigators will perform an age appropriate neurological examination including 
assessments of Mental Status, Cranial Nerve, Muscle Tone (Leg and Arm), Muscle Strength 
(Leg and Arm), Reflexes (Ankle, Biceps, Knee and Babinski), Coordination and Gait 
(Finger-to-Nose), Sensory (light touch sense-Forearms and Legs) and Tremor (Upper 
Extremities). All assessments will be evaluated as normal or abnormal (grading of abnormal 
and so on if applicable).
 
 
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Assessment of Motor Developmental Skills
Motor developmental skills should be assessed for the participants 6 years and under.
The investigators will perform an assessment of motor developmental skills using the 
questionnaire (e.g. washes and dries hands, balances on one foot for 2 seconds. Reference: 
American Academy of Pediatrics’ Bright Futures). For the assessment at Visit1, the 
investigators may assess based on the information on developmental skills immediately prior 
to cSSTI or bacteremia provided by participant’s parents.
Clinical Safety Laboratory Assessments
Refer to Section 12.4 for the list of clinical laboratory tests to be performed and to the SoA 
for the timing and frequency. 
●
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the participant's condition.
●
All protocol-required laboratory assessments, as defined in Section 12.4, must be 
conducted in accordance with the laboratory manual and Section 2.
●
If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in study participant management or 
are considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
●
For any laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 14 days after the last dose of study 
treatment, every attempt should be made to perform repeat assessments until the 
values return to normal or baseline or if a new baseline is established as determined 
by the investigator. 

In cases of technical difficulties or age of participant, it is acceptable that the 
laboratory tests of urinalysis is not conducted according to the determines of 
investigators.
Microbiological Culture
All microbiological Cultures should be performed at the local microbiology laboratory 
according to recognized methods and per each laboratory's standard procedures according to 
section 2.
Any suspected causative bacterial pathogens that are isolated from local microbiological 
cultures must be collected and available for submission to the Central Microbiology 
Reference Laboratory. Suspected causative bacterial pathogens should also be stored at the 
local microbiology laboratory if possible future testing is needed. Relevant culture data, 
including date of collection, specimen type (including method of collection), and pathogen 
 
 
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identification (to the species level, if identified) must be collected on the appropriate eCRF. 
Submission of suspected causative bacterial pathogen is needed for allocated participant only.
Additional details regarding bacterial specimen collection, processing, handling, and 
shipment will be provided by the Sponsor in a separate microbiology laboratory manual.
Collection of Infection-Site Specimens
Infection-site specimens for culture should be obtained from the participant with cSSTI 
specified in protocol (refer to Section 2). For collection of infection-site specimen at Visit 1, 
if the culture specimen collected within 120 hours before the first administration of study 
drug already exists, the same specimen may be used. For participants in which infection site 
specimen collection is not medically acceptable, follow up specimen is not required.
All specimens collected for culture must be collected via valid sampling technique (aspirate, 
biopsy, deep swab, etc; superficial swab not acceptable) by investigators or qualified 
designee, and specimens should be collected as much as possible. If there is no appropriate 
site to collect the specimens (e.g. cellulitis) specimens are to be collected according to 
standard practice at the site.
In addition, the data regarding to surgical intervention and indwelling/replacement/removal 
of prosthetic object (e.g. catheter, stent) should be recorded and collected on the appropriate 
eCRF. Additional unscheduled cultures should also be performed for obtained specimen at 
the time of any surgical intervention.
Collection of blood
For each blood culture collection, two sets of blood cultures (total 4 bottles: 2 for aerobic 
culture and 2 for anaerobic culture), i.e., one set each from two separate venipuncture (or 1 
venipuncture and 1 catheter) sites are recommended. However, if in the opinion of the 
investigator and owing to the safety of the participant or age of participant, it is acceptable 
that the number of sets or bottles for blood culture is not satisfied with protocol.
At Visit1, blood culture is required in all participants. For blood collection at Visit 1, if the 
culture specimen collected within 120 hours before the first administration of study drug 
already exists, the same specimen may be used. At EOT (Visit 4), blood culture is required 
even if the blood cultures until 2 sequential cultures demonstrate no growth is confirmed. In 
the follow-up period, blood cultures are performed at TOC (Visit 5) and FU (Visit 6), but if 
the result is negative at TOC (Visit 5), blood culture should not be required at FU (Visit 6).
Participants with positive blood cultures at Visit1 (screening) should have follow-up blood 
cultures until 2 sequential cultures demonstrate no growth is confirmed.
For participants with negative blood cultures at Visit1 (screening), i.e. participants with no 
evidence of bacteremia, the follow-up blood culture is not required and should also be 
performed at the investigator discretion as clinically indicated.
Gram stain
Gram stain should be performed at Visit 1, using the collected specimen (infection site) or 
the bacteria from the specimen culture (Infection site or blood). If the pathogen species are 
identified by other methods, gram stain is not necessary. Gram stain may be performed at the 
 
 
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same day of screening period as the first dose of study drug administration (i.e. Before the 
first dose of study drug).
Clinical Assessment of Infection Site
The investigators will evaluate the clinical assessment of signs and symptoms of cSSTI 
according to section 2. The signs and symptoms (Erythema, Swelling/Edema, Induration, 
Localized Warmth, Tenderness on Palpation, Drainage, Fluctuance, Ulceration, Necrotic 
Tissue, Localized Pain, Redness, Chills and Fever) will be examined and will be evaluated as 
"Yes” or “No”, and grade (Mild, Moderate or Severe, if applicable).
Pharmacokinetics
Blood Collection for Plasma daptomycin
Blood sampling for analyzing plasma daptomycin concentration is conducted on Visit 3. And 
blood sampling is performed after at least 2 consecutive daptomycin dosing. In order to avoid 
the missing of collecting the blood sample, it is acceptable to collect the blood sample 
beyond the allowance of Visit 3 (+1 day). 
Total 5 points of blood sampling is recommended for all age groups as Table 8.
Table 8
Blood sampling points and their allowances
Blood sampling points
Allowance
Pre-dose
Within 2 hours prior of daptomycin 
dosing
15 min after the end of infusion
+/- 5 min
1 hour after the end of infusion
+/- 10 min
4 hours after the end of infusion
+/- 30 min
12 hours after the end of infusion
- 2 hours
However, if in the opinion of the investigator and owing to the safety of the participant or age 
of participant, number of blood samples as below may be collected to support PK analysis 
with consultation with the Sponsor.

7 to 17 years old participants: All 5 points.

1 to 6 years old participants: At least 3 points at 15 minutes, 1 or 4 hours and 12 
hours post-infusion
The blood sample for daptomycin PK evaluation is collected through a separate line in a 
contralateral arm/leg from the infusion line/lumen used for study drug or infusion solution 
dosing.
If the blood sample should be collected through the same infusion line/lumen used for study 
drug or infusion solution dosing due to the subject condition, the infusion line/lumen is 
required to be flushed by the appropriate volume of saline solution. 
 
 
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The sample collection, storage and shipment instructions of the plasma sample are referred to 
the operations/laboratory manual.
Pharmacodynamics
Pharmacodynamics will not be evaluated in this study. 
Biomarkers
Biomarkers are not evaluated in this study.
Future Biomedical Research Sample Collection 
Future Biomedical Research Samples will not be collected in this study.
Visit Requirements
Visit requirements are outlined in Section 2 – Schedule of Activities (SoA).  Specific 
procedure-related details are provided above in Section 9 – Study Assessments and 
Procedures.
Screening
Approximately 72 hours prior to first dose, potential participants will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 6.1 and 6.2. 
Regarding the evaluation and procedures prescribed in Section 2, if there is data obtained in 
the screening period (72 hours before the first dose of study administration), even if the data 
obtained before obtaining the consent of participating in the trial, eligibility may be evaluated 
using such data. Screening procedures before allocation may be repeated multiple times after 
consultation with the Sponsor.
Treatment Period
IV study therapy should be administered for a minimum of 5 days, i.e., 5 dose of daptomycin 
based on the q24h dosing regimen. The total duration of IV study therapy should NOT 
exceed 14 days (cSSTI) or 42 days (bacteremia).
Assessments and procedures while on IV study therapy will be completed at the indicated 
times and intervals as per the Schedule of Activities (Section 2). All study assessments are 
recommended to be performed at approximately the same time of day for the study 
participant (e.g. every morning) for each calendar day.
The EOT visit will be completed within 1 day after the last dose of IV study therapy.
Follow up period (Post-treatment)
TOC visit [7 (+/-3) days after completion of IV study therapy] and FU visit [14 (+3) days 
after completion of IV study therapy] must be completed for each participant.
 
 
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10. Statistical Analysis Plan 
This section outlines the statistical analysis strategy and procedures for the study.  Changes 
to analyses made after the protocol has been finalized, but prior to the database lock, will be 
documented in a supplemental SAP (sSAP) and referenced in the Clinical Study Report 
(CSR) for the study.  Post hoc exploratory analyses will be clearly identified in the CSR.
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 10.2-10.12.
Study Design Overview
An open-label, single-arm phase II study to assess safety, efficacy and 
pharmacokinetics of daptomycin in Japanese pediatric participants with cSSTI or
bacteremia
Treatment Assignment
All participants enrolled in the treatment period will receive open-label treatment 
with daptomycin. The dose level will vary depending on the age category and 
infection type of individual participants (See Section 7.4.1).
Analysis Populations
The primary analysis populations for efficacy, pharmacokinetics and safety are as 
follows.
Efficacy
Modified intent-to-treat population with positive culture of MRSA at baseline 
(MITT-MRSA)
Pharmacokinetics
Pharmacokinetics (PK) population
Safety
All Participants as Treated (APaT) population
Primary Endpoint(s)
Safety parameters including AEs, laboratory tests, vital signs
Secondary Endpoint(s)
1.
Clinical response to daptomycin at the TOC visit
2.
Subject-level microbiological response to daptomycin at the TOC visit
3.
Pharmacokinetic parameters of daptomycin
Statistical Methods for 
Key Efficacy and 
Pharmacokinetics 
Analyses
Efficacy
The proportions of participants achieving clinical success and microbiological 
success, respectively, will be calculated by visit, along with corresponding 95% 
confidence intervals (CIs) by the method of Clopper and Pearson [1]. The 
analysis will be performed separately by infection type (cSSTI, bacteremia). 
Participants who have both cSSTI and bacteremia will be included in the analysis 
of both infection types. The analysis of the proportion of participants in the 
MITT-MRSA population achieving clinical success at the TOC visit is of 
primary interest for efficacy.
Pharmacokinetics
Descriptive statistics of pharmacokinetic parameters will be provided.
Statistical Methods for 
Key Safety Analyses
The proportions of participants will be calculated for broad clinical and 
laboratory AE categories [e.g., any AE, a drug-related AE, a serious AE (SAE), a 
drug-related SAE, discontinuation of study treatment due to an AE], as well as 
specific AEs (system organ classes and preferred terms). Change from baseline in 
laboratory tests and vital signs will be summarized.
Interim Analyses
No interim analysis is planned.
Multiplicity
No multiplicity adjustment is planned.
Sample Size and Power
A total of 20 participants will be enrolled in the treatment period. If a particular 
AE or other safety event of interest is not observed in any of the 20 participants, 
then the true incidence of that event is 11% or less with 90% confidence.
 
 
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Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor. This trial is being conducted as a non-
randomized, open-label study, i.e., participants, investigators, and Sponsor personnel will be 
aware of participant treatment assignments after each participant is enrolled and treatment is 
assigned.
Hypotheses/Estimation
The objectives of the study are stated in Section 4. 
Analysis Endpoints
Efficacy, pharmacokinetics and safety endpoints that will be evaluated in the study are listed 
below.
Efficacy / Pharmacokinetic Endpoints
Efficacy
The efficacy endpoints will be clinical response and microbiological response at the EOT and 
TOC visits. At a particular visit, clinical success and microbiological success for a participant 
will be defined as follows.
Clinical success: a clinical response of “Cure” or “Improvement” at that visit.
Microbiological success (subject-level): microbiological responses of “Eradication” or 
“Presumed Eradication” (i.e., pathogen-level microbiological success) at that visit for all 
pathogens identified at baseline, without any superinfection or new infection by gram-
positive cocci pathogen(s).
A list of efficacy endpoints is provided below.
Table 9
List of efficacy endpoints
Secondary
The following endpoints in the MITT-MRSA population:

Clinical response at the TOC visit

subject-level microbiological response at the TOC visit
Exploratory
1.
The following endpoints in the MITT-MRSA population:

Clinical response at the EOT visit

Subject-level microbiological response at the EOT visit
2.
The following endpoints in the MITT and MITT Gram-Positive 
populations

Clinical response at the EOT and TOC visits

Subject-level microbiological response at the EOT and TOC visits
3.
By-pathogen microbiological response at EOT and TOC visits in the 
MITT, MITT Gram-Positive and MITT-MRSA populations
Further details are in Section 9.2.
 
 
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Pharmacokinetics
Pharmacokinetic endpoints include the following pharmacokinetic parameters: AUC0-24, Cmax, 
tmax, CLss, Vss, t1/2 if evaluable data is obtained.
Safety Endpoints
Refer to Section 5.4.2.1.
Analysis Populations
The analysis populations for efficacy, pharmacokinetics and safety are defined below. The 
composition of the respective populations will be made and documented in a separate memo 
prior to the database lock.
Efficacy / Pharmacokinetics Analysis Populations
Efficacy
The modified intent-to-treat (MITT) population, which consists of all enrolled participants 
who receive at least one dose of study treatment, will be used for the analysis of efficacy data 
in this study. Subsets of the MITT population consisting of those participants with positive 
culture of any Gram-positive coccus (cocci) and MRSA at baseline will be defined as the 
MITT-Gram Positive and MITT-MRSA populations, respectively. The primary population 
for efficacy analysis will be the MITT-MRSA population.
Pharmacokinetics
The Pharmacokinetics (PK) population will be used for the analysis of pharmacokinetic data 
in the study. The PK population consists of all enrolled participants who meet the following:

The participant receives at least 3 consecutive IV infusions of study treatment

The participant has at least 1 PK sample following study drug administration on the PK 
sampling day

The participant does not have any major protocol violation affecting the PK profile.
Safety Analysis Populations
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all enrolled participants who receive at least one dose of study 
treatment.
Statistical Methods
Statistical Methods for Efficacy Analysis
The proportions of participants achieving clinical success and microbiological success, 
respectively, will be calculated by visit, along with corresponding 95% CIs by the method of 
Clopper and Pearson. The analysis will be performed separately by infection type (cSSTI, 
bacteremia). Participants who have both cSSTI and bacteremia will be included in the 
analysis of both infection types.
 
 
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Missing data and the assessment of “Not Evaluable” will be considered failure. The 
exception to this will be:

[cSSTI only] Even if culture is missing at a particular timepoint, microbiological 
success will be presumed from clinical success (i.e., presumed eradication)
A clinical response of “Failure” at the EOT visit will be carried forward to the TOC visit. A 
microbiological response of “Persistent” at the EOT visit will be carried forward to the TOC 
visit.
Table 10 summarizes key efficacy analysis.
Table 10
Analysis Strategy for Key Efficacy Variables
Endpoint / Variable
(Description / Timepoint)
Statistical Method
Analysis 
Population
Missing Data Approach
Secondary objectives
Clinical success at the TOC visit
Clopper-Pearson
MITT-MRSA
Missing = Failure†
Microbiological success at the TOC visit
Clopper-Pearson
MITT-MRSA
Missing = Failure†
† [cSSTI only] Even if culture is missing at a particular timepoint, microbiological success will be presumed from
clinical success (i.e., presumed eradication)
Statistical Methods for Safety Analysis
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, vital signs and laboratory tests.
The proportions of participants will be calculated for broad clinical and laboratory AE 
categories [e.g., any AE, a drug-related AE, a serious AE (SAE), a drug-related SAE, 
discontinuation of study treatment due to an AE], specific AEs (system organ classes and 
preferred terms) and participants whose laboratory measurement exceeds predefined limits of 
change.
Summary statistics for baseline, on-treatment, and change from baseline values will be 
provided for continuous measures such as vital signs and laboratory tests.
The analysis of safety data will include all enrolled participants regardless of the infection 
type. A supplemental analysis by infection type will also be performed; in this analysis, those 
participants who have both cSSTI and bacteremia and treated with the daptomycin dose for 
bacteremia will be considered to be participants with bacteremia.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic and baseline characteristics
The number and percentage of participants screened, enrolled, the primary reasons for 
screening failure, and the primary reason for study/study therapy discontinuation will be 
displayed. Demographic variables (e.g., age, gender), primary and secondary diagnoses, and 
prior and concomitant therapies will be summarized by descriptive statistics or categorical 
tables.
 
 
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Pharmacokinetics
PK parameters of daptomycin obtained from individual participants will be listed. 
The following PK parameters of daptomycin (AUC0-24, Cmax, tmax, CLss, Vss and t1/2 if 
evaluable data is obtained) will be determined by non-compartmental PK analysis if at least 3 
PK samples are available, and these PK parameters will be summarized by descriptive 
statistics. If less than 3 PK samples are available, the plasma concentration including Cmax (or 
end of infusion) will be described. The derived PK parameters of daptomycin will be 
reported for each infection type and age categories.  Population PK analysis may be 
conducted if needed. If population PK analysis will be conducted, PK data and analysis will 
be reported separately in a population PK report.
Interim Analyses
No interim analysis is planned.
Multiplicity
No multiplicity adjustment is planned.
Sample Size and Power Calculations
A total of 20 participants will be enrolled in the treatment period. If a particular AE or other 
safety event of interest is not observed in any of the 20 participants, then the true incidence of 
that event is 11% or less with 90% confidence.
In order to collect data from the broadest range of categories of participants possible, the 
study will target enrollment of the following minimum number of participants in each 
category:

6 participants with bacteremia

1 participant of 1 to <2 years old and 3 participants each for the higher age categories, 
regardless of the infection type.
The recruitment will continue until a total of 20 participants have been enrolled in the 
treatment period regardless of the age category or infection type.
The 95% CIs for efficacy analysis under various sample sizes are shown below.
Table 11
Precision estimates for efficacy analysis
Number of participants
included in analysis
Number of participants
achieving success
95% CI of percentage of participants 
achieving success
5
3
4
(14.7%, 94.7%)
(28.4%, 99.5%)
10
6
7
8
9
(26.2%, 87.8%)
(34.8%, 93.3%)
(44.4%, 97.5%)
(55.5%, 99.7%)
15
9
10
11
12
13
14
(32.3%, 83.7%)
(38.4%, 88.2%)
(44.9%, 92.2%)
(51.9%, 95.7%)
(59.5%, 98.3%)
(68.1%, 99.8%)
 
 
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Subgroup Analyses
No subgroup analysis is planned.
Compliance (Medication Adherence)
For each subject, treatment compliance will be calculated as follows.
Compliance (%) =
Number of completed IV doses
x100
Number of expected IV doses
Descriptive statistics of treatment compliance will be calculated for the respective efficacy 
analysis populations.
Extent of Exposure
The extent (number of days) of exposure to study treatment will be evaluated for the APaT 
population.
11. References
1.
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
the Binomial. Biometrika; 26: 404-13.
2.
The Guidance of renal function evaluation for pediatric Chronic Kidney Disease. Labor 
and Welfare Research grant subsidy Overcoming research project on refractory diseases, 
the year 2013 (Japan Pediatric CKD Research Group). Feb 28, 2014.
 
 
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12. Appendices
Appendix 1: Study Governance Considerations
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of participant safety is the overriding concern 
in the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the
party (parties) employed for their execution (eg, contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
participant preferences, etc.  
The design (ie, participant population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial 
initiation, sites are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Participant Protection
A. IRB/IEC review
All clinical trials will be reviewed and approved by an independent IRB/IEC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/IEC prior to implementation, except that 
changes required urgently to protect participant safety and well-being may be enacted in anticipation of IRB/IEC 
approval. For each site, the IRB/IEC and Merck will approve the participant informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance.  
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a 
minimum, trial designs will take into account the local standard of care.  Participants are never denied access to 
appropriate medical care based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Participants are enrolled only after providing informed consent 
for participation.  Participants may withdraw from a Merck trial at any time, without any influence on their access to,
or receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding participant confidentiality, to the greatest extent possible.  Unless required by 
law, only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential 
medical records that might identify the research participant by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.  Merck does not pay incentives to 
enroll participants in its trials.  However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
Merck does not pay for participant referrals.  However, Merck may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/IEC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Data Protection
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/IEC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this study will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents in 
order to verify worksheet/case report form data.  By signing the consent form, the participant 
agrees to this process.  If study documents will be photocopied during the process of 
 
 
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verifying worksheet/case report form information, the participant will be identified by unique 
code only; full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Publication Policy
The results of this study may be published or presented at scientific meetings. The sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the sponsor before submission.  This allows the sponsor to protect 
proprietary information and to provide comments.  
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and site contact information.  
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
 
 
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Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good
Clinical Practice (eg, International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated 
Guideline and other generally accepted standards of good clinical practice); and all 
applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Merck Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers or from government programs for procedures included as part of the study
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The Investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection, and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator or 
qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
 
 
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regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or regulatory authority as a result of an audit or inspection to cure 
deficiencies in the study documentation and worksheets/case report forms.
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Study and Site Closure
The sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP. 
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
 
 
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Appendix 2: Contraceptive Guidance and Pregnancy Testing
Definitions 
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
●
Postmenopausal female
○
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
▪
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required. 
○
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
Contraception Requirements
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following during the protocol defined time frame in section 6.1: 
●
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent.
●
Use a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a woman of childbearing potential who is not currently 
pregnant.
o
The following are not acceptable methods of contraception:
 
 
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▪
Periodic abstinence (calendar, symptothermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method (LAM).
▪
Male and female condom cannot be used together.
○
A combination of male condom with either cap, diaphragm or sponge with 
spermicide are considered acceptable, but not highly effective, birth control methods.
○
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration.
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use 
one of the contraception methods described in Table 12 consistently and correctly during the 
protocol-defined time frame in Section 6.1.
Table 12
Contraceptive Methods
Acceptable Contraceptive Methods  
Failure rate of >1% per year when used consistently and correctly. 
●
Male or female condom with or without spermicide
●
Cervical cap, diaphragm or sponge with spermicide
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen- containing ) hormonal contraception b
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●
Progestogen-only hormonal contraception b
○
Oral 
○
Injectable 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen- only contraceptive implant b, c 
●
Intrauterine hormone-releasing system (IUS) b
●
Intrauterine device (IUD)
●
Bilateral tubal occlusion
●
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
 
 
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●
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.) 
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods 
for participants of clinical studies.
a) Typical use failure rates are lower than perfect-use failure rates (ie, when used 
consistently and correctly). 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study 
treatment, condoms must be used in addition to the hormonal contraception during the 
treatment period and for at least [X days, corresponding to time needed to eliminate study 
treatment plus 30 days for study treatments with genotoxic potential]  after the last dose of 
study treatment .
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) 
guidelines, acceptable hormonal contraceptives are limited to those which inhibit ovulation. 
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
 
 
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Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment.
●
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
●
NOTE: for purposes of AE definition, study treatment (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, manufactured by, licensed by, 
provided by or distributed by the sponsor for human use in this study.
Events Meeting the AE Definition 
●
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, or are considered clinically significant in the 
medical and scientific judgment of the investigator.
●
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
●
New conditions detected or diagnosed after study treatment administration even though 
it may have been present before the start of the study.
●
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
●
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. 
●
For all reports of overdose (whether accidental or intentional) with an associated 
adverse event, the AE term should reflect the clinical symptoms or abnormal test result.  
An overdose of study treatment without any associated clinical symptoms or abnormal 
laboratory results is reported using the terminology “accidental or intentional overdose 
without adverse effect.”
●
Any new cancer or progression of existing cancer.
 
 
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Events NOT Meeting the AE Definition 
●
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads 
to the procedure is the AE.
●
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
●
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
●
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
●
Refer to section 9.3.5 for protocol specific exceptions
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met 
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
●
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing 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 an MSD product and is documented in the patient’s 
medical history.
d. Results in persistent or significant disability/incapacity
●
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
●
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
 
 
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e.
Is a congenital anomaly/birth defect
●
in offspring of participant taking the product regardless of time to diagnosis
f.
Other important medical events:
●
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Additional Events Reported
Additional Events which require reporting 
●
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.
●
Is a cancer;
●
Is associated with an overdose.
Recording AE and SAE
AE and SAE Recording
●
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related 
to the event.
●
The investigator will record all relevant AE/SAE information on the Adverse Event 
case report forms/worksheets at each examination.
●
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
●
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor. In this case, all participant identifiers, with the exception of the 
participant number, will be blinded on the copies of the medical records before 
submission to the Sponsor.
●
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
 
 
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Assessment of Intensity
●
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
●
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories: 
●
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.  (for pediatric studies, 
awareness of symptoms, but easily tolerated)
●
Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities. (for pediatric studies, definitely acting like something is wrong)
●
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe 
(for pediatric studies, extremely distressed or unable to do usual activities).
Assessment of Causality
●
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 product 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 participant 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 studies with investigational 
medicinal product)?
●
Likely Cause:  Is the AE not reasonably explained by another etiology such as 
 
 
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underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
●
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 study is a single-dose drug study); or (4) Sponsor's 
product(s) is/are only used one time.)
●
Rechallenge:  Was the participant re-exposed to the Sponsor's product in this 
study?
●
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 study is a single-dose drug study); 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 PARTICIPANT THEN 
THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR, AND IF REQUIRED, THE INSTITUTIONAL REVIEW 
BOARD/INDEPENDENT ETHICS COMMITTEE.
●
Consistency with Study 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.
●
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. 
 
 
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Product:  MK-3009
74
Protocol/Amendment No.: 029-01 
MK-3009-029-01 Final Protocol
03-Jun-2020
Confidential
●
No, there is not a reasonable possibility of Sponsor's product relationship:
Participant 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 participant with overdose without an associated AE.)
●
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
●
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the Sponsor.
●
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
●
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements
Follow-up of AE and SAE
●
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
●
New or updated information will be recorded in the CRF.
●
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor 
AE, SAE, and Other Reportable Safety Event Reporting to Sponsor via Electronic 
Data Collection Tool
●
The primary mechanism for reporting to the Sponsor will be the electronic data 
collection (EDC) tool.  
●
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
●
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.  
●
Reference section 9.3.1 – Time Period and Frequency for Collecting AE and 
SAE and Other Reportable Safety Event Information for reporting time 
requirements 
 
 
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Product:  MK-3009
75
Protocol/Amendment No.: 029-01 
MK-3009-029-01 Final Protocol
03-Jun-2020
Confidential
●
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
●
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.
●
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form or by 
telephone (see next section).
●
Contacts for SAE reporting can be found in the Investigator Trial File Binder (or 
equivalent).
SAE Reporting to the Sponsor via Paper CRF
●
If the electronic data collection tool is not operational, facsimile transmission or secure 
e-mail of the SAE paper CRF is the preferred method to transmit this information to 
the Sponsor.
●
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
●
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
●
Contacts and instructions for SAE reporting and paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
 
 
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Product:  MK-3009
76
Protocol/Amendment No.: 029-01 
MK-3009-029-01 Final Protocol
03-Jun-2020
Confidential
Appendix 4: Clinical Laboratory Tests 
•
The tests detailed in Table 13 will be performed by the central laboratory (chemistry) 
or local laboratory (hematology and urinalysis). (Chemistry at Visit1 only, there is 
possibility that the tests will also be performed by the local laboratory). 
•
If the test for chemistry is performed by local laboratory at Visit 1 to confirm the 
eligibility before Visit 2, it is recommended that the sample for central analysis is 
obtained at the same time.
•
The local laboratory results of hematology and urinalysis must be entered into the 
CRF.
•
If the local laboratory results are used to make either a study treatment decision or 
response evaluation, the results must be entered into the CRF.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 6.1 and 6.2 of the protocol.
•
Additional tests (by the local or central laboratory) may be performed at any time 
during the study as determined necessary by the investigator to assess the clinical 
conditions of participant or required by local regulations.
Table 13
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
WBC count with Differential:
RBC Count
Neutrophils
Eosinophils
Hemoglobin
Lymphocytes
Basophils
Hematocrit
Monocytes
Chemistry
Aspartate
aminotransferase 
(AST)
Alanine 
aminotransferase
(ALT)
Alkaline 
phosphatase (ALP)
Total bilirubin
Direct bilirubin 1
Sodium (Na)
Potassium (K)
Chloride (Cl)
Calcium (Ca)
Glucose 2
Blood Urea 
Nitrogen (BUN)
Creatinine
Creatine 
Phosphokinase  
(CPK)
Total Protein
Albumin
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood
Other Screening 
Tests

[Serum or urine] β human chorionic gonadotropin (β hCG) pregnancy test (as 
needed for women of childbearing potential). Serum β hCG is tested only 
when the result of urine β hCG pregnancy test is positive.
Note:
1.
Direct bilirubin is tested with blood drawing again if total bilirubin is elevated above the upper limit of normal and 
the investigator needs further assessments.
2.
Indicate if fasting, or nonfasting at blood drawing. Blood glucose meter at bedside could be used to measure 
glucose depending on a participants’ condition. However, for each participant, the method by which glucose is 
measured should be the same throughout the study.
 
 
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Product:  MK-3009
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Protocol/Amendment No.: 029-01 
MK-3009-029-01 Final Protocol
03-Jun-2020
Confidential
Investigators must document their review of each laboratory safety report.
eGFR is calculated basically refer to the equation as follows [2].
eGFR=110.2*(y/serum Cr)+2.93
boys: y=-1.259*H5+7.815*H4-18.57*H3+21.39*H2-11.71*H+2.628
girls: y=-4.536*H5+27.16*H4-63.47*H3+72.43*H2-40.06*H+8.778
 
 
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