Clinical trial NCT02519842
Conditions: Chemotherapy-induced Nausea and Vomiting
Sponsor: Merck Sharp & Dohme LLC
Start date: 2015-09-14; Completion date: 2017-02-24
Enrollment: 75 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of fosaprepitant (MK-0517) plus ondansetron versus ondansetron alone for the prevention of chemotherapy-induced nausea and vomiting (CINV) in pediatric participants scheduled to receive chemotherapeutic agent(s) associated with moderate or high risk of causing emesis (vomiting), or chemotherapy agent(s) not previously tolerated due to vomiting. The primary hypothesis is that a single dose of fosaprepitant in combination with ondansetron provides superior control of CINV compared to ondansetron alone as measured by the percentage of participants with a Complete Response (no vomiting, no retching, and no use of rescue medications) in the delayed phase (\>24 to 120 hours) following initiation of emetogneic chemotherapy in Cycle 1.

Detailed description:
In Cycle 1, participants will receive double-blind study drug (fosaprepitant plus ondansetron with or without dexamethasone OR placebo to fosaprepitant plus ondansetron with or without dexamethasone). Upon completion of Cycle 1, participants may have the option to continue for up to 5 additional open-label cycles, receiving fosaprepitant plus ondansetron with or without dexamethasone.

Arms: arm 1: Participants received a single dose of fosaprepitant 150 mg (or age-based adjustment) administered intravenously (IV) on Day 1 prior to chemotherapy plus ondansetron IV on Day 1 prior to chemotherapy and at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. Participants may have also received dexamethasone IV at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. arm 2: Participants received a single dose of matched placebo for fosaprepitant IV on Day 1 prior to chemotherapy plus ondansetron IV on Day 1 prior to chemotherapy and at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. Participants may have also received dexamethasone IV at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. arm 3: Participants received a single dose of fosaprepitant 150 mg (or age-based adjustment) IV on Day 1 prior to chemotherapy plus a 5-hydroxytryptamine 3 (5-HT3) antagonist on Day 1 prior to chemotherapy and per product label or standard of care. Participants may also have received dexamethasone IV at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy.
Interventions: intervention 1: Fosaprepitant intervention 2: Placebo for fosaprepitant intervention 3: Ondansetron intervention 4: Dexamethasone intervention 5: 5-HT3 antagonist
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Official Protocol Title: A Phase III, Randomized, Placebo-Controlled Clinical Trial to Study 
the Efficacy and Safety of MK-0517/Fosaprepitant and Ondansetron 
Versus Ondansetron for the Prevention of Chemotherapy-Induced 
Nausea and Vomiting (CINV) in Pediatric Subjects Receiving 
Emetogenic Chemotherapy 
NCT number: 
NCT02519842
Document Date: 
07-May-2015


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THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., WHITEHOUSE 
STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
A Phase III, Randomized, Placebo-Controlled Clinical Trial to Study the Efficacy and Safety
of MK-0517/Fosaprepitant and Ondansetron Versus Ondansetron for the Prevention of 
Chemotherapy-Induced Nausea and Vomiting (CINV) in Pediatric Subjects Receiving 
Emetogenic Chemotherapy
IND NUMBER:  48,924
EudraCT NUMBER:  2014-001783-34


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TABLE OF CONTENTS
1.0
TRIAL SUMMARY.................................................................................................. 10
2.0
TRIAL DESIGN........................................................................................................ 10
Trial Design ........................................................................................................... 10
2.1
Trial Diagram........................................................................................................ 12
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 12
Primary Objective(s) & Hypothesis(es) .............................................................. 12
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 13
3.2
Exploratory Objectives......................................................................................... 13
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 14
Background ........................................................................................................... 14
4.1
Pharmaceutical and Therapeutic Background .................................................... 14
4.1.1
Rationale................................................................................................................ 15
4.2
Rationale for the Trial and Selected Subject Population .................................... 15
4.2.1
Rationale for Dose Selection/Regimen/Emetogenic Classification of 
4.2.2
Chemotherapeutic Agents................................................................................... 15
4.2.2.1
Rationale for Dose Selection ....................................................................... 15
4.2.2.2
Rationale for the Use of Ondansetron for Antiemetic Prophylaxis ............. 17
4.2.2.3
Rationale for Optional Corticosteroid Use for Antiemetic Prophylaxis ...... 18
4.2.2.4
Rationale for Emetogenic Classification of Chemotherapeutic Agents ...... 18
Rationale for Endpoints ...................................................................................... 19
4.2.3
4.2.3.1
Efficacy Endpoints....................................................................................... 19
4.2.3.2
Pharmacokinetic Endpoints ......................................................................... 19
4.2.3.3
Future Biomedical Research........................................................................ 19
Benefit/Risk ........................................................................................................... 20
4.3
5.0
METHODOLOGY ................................................................................................... 21
Entry Criteria........................................................................................................ 21
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 21
5.1.1
Subject Inclusion Criteria.................................................................................... 21
5.1.2
5.1.2.1
Inclusion Criteria for Cycle 1 ...................................................................... 21
5.1.2.2
Inclusion Criteria for Optional Cycles 2 to 6............................................... 23


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Subject Exclusion Criteria .................................................................................. 23
5.1.3
5.1.3.1
Exclusion Criteria for Cycle 1 Only ............................................................ 23
5.1.3.2
Exclusion Criteria for Cycle 1 and Optional Cycles 2 to 6.......................... 24
Trial Treatment(s) ................................................................................................ 27
5.2
Dose Selection .................................................................................................... 28
5.2.1
5.2.1.1
Dose Selection (Preparation) ....................................................................... 28
5.2.1.1.1
Fosaprepitant – Cycle 1 (Treatment Group 1) and Optional Cycles 
2 to 6 ..................................................................................................... 28
5.2.1.1.2
Placebo for fosaprepitant (normal saline) – Cycle 1 (Treatment 
Group 2)................................................................................................ 29
5.2.1.1.3
Ondansetron (both treatment groups) - Cycle 1.................................... 29
5.2.1.1.4
5-HT3 Antagonist – Optional Cycles 2 to 6.......................................... 30
5.2.1.1.5
Dexamethasone (optional) - Cycle 1 and Optional Cycles 2 to 6......... 30
Timing of Dose Administration .......................................................................... 30
5.2.2
5.2.2.1
Fosaprepitant/Placebo for Fosaprepitant...................................................... 30
5.2.2.2
Ondansetron - Cycle 1 ................................................................................. 31
5.2.2.3
5-HT3 Antagonist - Optional Cycles 2-6 ..................................................... 31
5.2.2.4
Dexamethasone (optional) - Cycle 1 and Optional Cycles 2 to 6................ 31
Trial Blinding/Masking....................................................................................... 32
5.2.3
Randomization or Treatment Allocation............................................................ 32
5.3
Stratification.......................................................................................................... 32
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 32
5.5
Rescue Medications & Supportive Care............................................................. 33
5.6
Diet/Activity/Other Considerations..................................................................... 34
5.7
Subject Withdrawal/Discontinuation Criteria................................................... 34
5.8
Subject Replacement Strategy............................................................................. 34
5.9
Beginning and End of the Trial ........................................................................... 35
5.10
Clinical Criteria for Early Trial Termination ................................................... 35
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 36
7.0
TRIAL PROCEDURES ........................................................................................... 41
Trial Procedures ................................................................................................... 41
7.1
Administrative Procedures.................................................................................. 41
7.1.1


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7.1.1.1
Informed Consent/Assent............................................................................. 41
7.1.1.1.1
General Informed Consent/Assent........................................................ 41
7.1.1.1.2
Consent/Assent and 
Collection of 
Specimens 
for 
Future 
Biomedical Research ............................................................................ 42
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 42
7.1.1.3
Subject Identification Card (Clinical Trial Identification Card).................. 42
7.1.1.4
Medical History ........................................................................................... 42
7.1.1.5
Prior and Concomitant Medications Review ............................................... 43
7.1.1.5.1
Prior Medications.................................................................................. 43
7.1.1.5.2
Concomitant Medications..................................................................... 43
7.1.1.6
Assignment of Screening Number............................................................... 43
7.1.1.7
Assignment of Randomization Number....................................................... 43
7.1.1.8
Trial Compliance (Study Medication/Patient Diary)................................... 44
7.1.1.9
Patient Diary Education for Subject/Parent/Caregiver - Cycle 1 Only........ 44
7.1.1.10 Laboratory and ECG Safety Test Review.................................................... 45
7.1.1.11 Rescue Medication Prescription .................................................................. 46
7.1.1.12 Subject/Parent/Caregiver Diary Completion - Cycle 1 Only....................... 46
7.1.1.13 Telephone or Direct Contact (scripted questions) - Cycle 1 Only............... 46
7.1.1.14 Patient Diary Review/Collection (with Subject/Parent/Caregiver) -
Cycle 1 Only................................................................................................ 47
Clinical Procedures/Assessments........................................................................ 48
7.1.2
7.1.2.1
Full Physical Examination - Cycle 1 Only .................................................. 48
7.1.2.2
Directed Physical Examination.................................................................... 48
7.1.2.3
Height - Cycle 1 only................................................................................... 48
7.1.2.4
Weight.......................................................................................................... 48
7.1.2.5
Vital Signs.................................................................................................... 48
7.1.2.6
12-Lead Electrocardiogram - Cycle 1 only.................................................. 48
7.1.2.7
Lansky or Karnofsky Performance Status Evaluation - Cycle 1 only ......... 49
7.1.2.8
Fosaprepitant or Matching Placebo for Fosaprepitant Administration........ 49
7.1.2.9
IV Ondansetron Administration - Cycle 1 only........................................... 49
7.1.2.10 5-HT3 Antagonist Administration - Optional Cycles 2-6 ............................ 49
7.1.2.11 Optional Dexamethasone Administration.................................................... 49


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7.1.2.12 Chemotherapy Infusion................................................................................ 50
Laboratory Procedures/Assessments .................................................................. 50
7.1.3
7.1.3.1
Local Laboratory Safety Evaluations (Hematology, Chemistry) ................ 50
7.1.3.2
Pharmacokinetic (PK) Evaluations (Cycle 2 Only) ..................................... 52
7.1.3.3
Future Biomedical Research........................................................................ 52
Other Procedures................................................................................................. 52
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 52
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 53
7.1.4.2
Blinding/Unblinding .................................................................................... 53
7.1.4.3
Calibration of Critical Equipment................................................................ 54
Visit Requirements.............................................................................................. 54
7.1.5
7.1.5.1
Cycle 1 ......................................................................................................... 54
7.1.5.1.1
Screening (Visit 1)................................................................................ 54
7.1.5.1.2
Randomization (Visit 2)........................................................................ 55
7.1.5.1.3
Telephone/Direct Contact Visits........................................................... 55
7.1.5.1.4
Post-Treatment (Visit 3) ....................................................................... 56
7.1.5.1.5
Follow-Up/Discontinuation (Visit 4).................................................... 56
7.1.5.2
Optional Cycles 2 to 6.................................................................................. 56
7.1.5.2.1
Treatment Visit ..................................................................................... 56
7.1.5.2.2
Follow-Up/Discontinuation Visit ......................................................... 57
Assessing and Recording Adverse Events .......................................................... 57
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 58
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 59
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 59
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 59
7.2.3.2
Events of Clinical Interest............................................................................ 60
Evaluating Adverse Events ................................................................................. 61
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 64
7.2.5
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 64
Statistical Analysis Plan Summary ..................................................................... 64
8.1
Efficacy Analyses ............................................................................................... 64
8.1.1


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Safety Analysis ................................................................................................... 65
8.1.2
Power and Sample Size....................................................................................... 65
8.1.3
Statistical Analysis Plan ....................................................................................... 66
8.2
Responsibility for Analyses/In-House Blinding ................................................. 66
8.2.1
Hypotheses.......................................................................................................... 66
8.2.2
Analysis Endpoints ............................................................................................. 66
8.2.3
8.2.3.1
Efficacy Endpoints....................................................................................... 66
8.2.3.2
Safety Endpoints .......................................................................................... 67
8.2.3.3
Pharmacokinetic Endpoints ......................................................................... 67
Analysis Populations........................................................................................... 67
8.2.4
8.2.4.1
Efficacy Analysis Populations ..................................................................... 67
8.2.4.2
Safety Analysis Populations ........................................................................ 68
8.2.4.3
Pharmacokinetic Analysis Populations........................................................ 68
Statistical Methods.............................................................................................. 68
8.2.5
8.2.5.1
Statistical Methods for Efficacy Analyses ................................................... 68
8.2.5.2
Statistical Methods for Safety Analyses ...................................................... 71
8.2.5.3
Statistical Methods for Pharmacokinetics.................................................... 73
8.2.5.4
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses....................................................................................................... 73
Multiplicity ......................................................................................................... 73
8.2.6
Sample Size and Power Calculations.................................................................. 74
8.2.7
Subgroup Analyses and Effect of Baseline Factors ............................................ 74
8.2.8
Interim Analysis.................................................................................................. 75
8.2.9
Compliance (Medication Adherence) ................................................................. 75
8.2.10
Extent of Exposure.............................................................................................. 75
8.2.11
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 75
Investigational Product ........................................................................................ 75
9.1
Packaging and Labeling Information ................................................................. 76
9.2
Clinical Supplies Disclosure................................................................................. 76
9.3
Returns and Reconciliation.................................................................................. 77
9.4
Standard Policies................................................................................................... 77
9.5


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10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 77
Confidentiality....................................................................................................... 77
10.1
Confidentiality of Data ....................................................................................... 77
10.1.1
Confidentiality of Subject Records ..................................................................... 77
10.1.2
Confidentiality of Investigator Information........................................................ 78
10.1.3
Confidentiality of IRB/IEC Information............................................................. 78
10.1.4
Compliance with Financial Disclosure Requirements....................................... 78
10.2
Compliance with Law, Audit and Debarment ................................................... 79
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 81
10.4
Quality Management System............................................................................... 81
10.5
Data Management................................................................................................. 81
10.6
Publications ........................................................................................................... 81
10.7
11.0
LIST OF REFERENCES......................................................................................... 83
12.0
APPENDICES........................................................................................................... 85
Merck Code of Conduct for Clinical Trials........................................................ 85
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 87
Pharmacogenomics 
Informational 
Brochure 
for 
IRBs/IECs 
& 
12.3
Investigational Site Staff ...................................................................................... 93
Lansky and Karnofsky Performance Status Scales......................................... 102
12.4
Emetogenicity of Commonly Used Chemotherapeutic Agents....................... 103
12.5
Approximate Blood Volumes Drawn by Trial Visit and by Sample Types... 104
12.6
Abbreviations and Definitions ........................................................................... 105
12.7
13.0
SIGNATURES......................................................................................................... 107
Sponsor's Representative ................................................................................... 107
13.1
Investigator.......................................................................................................... 107
13.2


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LIST OF TABLES
Table 1 Other Excluded Medications ..................................................................................... 26
Table 2 Trial Treatments – Cycle 1 ........................................................................................ 27
Table 3 Trial Treatments – Cycles 2 to 6................................................................................ 28
Table 4 Fosaprepitant Dose for Each Age Group................................................................... 29
Table 5 Laboratory Tests ........................................................................................................ 51
Table 6 Evaluating Adverse Events........................................................................................ 62
Table 7 Summary of Analysis Strategy for Key Efficacy Endpoints ..................................... 65
Table 8 Summary of Analysis Strategy for Efficacy Endpoints............................................. 70
Table 9 Analysis Strategy for Key Safety Parameters............................................................ 72
Table 10 Product Descriptions................................................................................................ 75


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LIST OF FIGURES
Figure 1 – Trial Design........................................................................................................... 12


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1.0 TRIAL SUMMARY
Abbreviated Title
Single Dose of MK-0517 for Prevention of CINV in Pediatric Subjects
Trial Phase
III
Clinical Indication
Prevention of nausea and vomiting associated with initial and repeat 
courses of highly and moderately emetogenic chemotherapy in pediatric 
subjects
Trial Type
Interventional
Type of control
Placebo
Route of administration
Intravenous (IV)
Trial Blinding
Double-blind
Treatment Groups
Group 1: fosaprepitant  + ondansetron
Group 2: placebo for fosaprepitant + ondansetron
Number of trial subjects
Approximately 180 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 23 months
from the time the first subject signs the informed consent until the last 
subject’s last visit.
Duration of Participation
Each subject will participate in the trial for approximately 43 days from 
the time the subject/parent/guardian signs the Informed Consent/Assent
Form (ICF) through the final contact.  After a screening phase of up to 28 
days, each subject will be receiving assigned treatment for approximately 
1 day.  After the end of treatment each subject will be followed for 14
days.  Note: Subjects may have the option to participate in up to 5 
additional open-label cycles.  Each optional cycle will be approximately 
15 days.
Randomization Ratio
1:1
A list of abbreviations and definitions used in this document can be found in Section 12.7 -
Abbreviations and Definitions.
2.0 TRIAL DESIGN
Trial Design
2.1
This is a randomized, placebo-controlled, parallel-group, multi-site, double-blind trial to 
evaluate the efficacy and safety of fosaprepitant for the prevention of chemotherapy-induced 
nausea and vomiting (CINV). Subjects must be scheduled to receive chemotherapeutic 
agent(s) associated with moderate or high risk of emetogenicity, or chemotherapy agent(s)
not previously tolerated due to vomiting. This study is to be conducted in conformance with 
Good Clinical Practices.
This study will endeavor to enroll an approximately even distribution of subjects into the 
following four age groups, but final enrollment in age groups may differ: 

Birth to <2 years,


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
2 to <6 years,

6 to <12 years,

12 to 17 years.
Subjects <12 years of age will NOT be permitted to participate in the current study 
until Pharmacokinetic/Pharmacodynamic (PK/PD) and safety data from an ongoing 
PK/PD and safety study (MK-0517 Protocol 029) can be evaluated to confirm the 
planned dose adjustments for subjects <12 years of age.  Enrollment of subjects <12 
years of age will begin once the study sites are notified of the final dosing instructions 
via a written letter from the SPONSOR.  The age categories may be adjusted if PK/PD 
data from the ongoing Protocol 029 do not support opening enrollment for one or more 
age group(s).
This study will evaluate a single dose of fosaprepitant dimeglumine (EMEND® for 
Injection), hereafter referred to as ‘fosaprepitant’,
in combination with the 5-
hydroxytryptamine 3 (5-HT3) antagonist ondansetron.  Subjects will be randomized into 1 of 
2 treatment regimens with a 1:1 ratio and will receive either a single IV dose of fosaprepitant 
in combination with IV ondansetron beginning on Day 1 of emetogenic chemotherapy or IV 
ondansetron concomitantly with a matching placebo for fosaprepitant.  IV dexamethasone 
may be administered as part of the antiemetic regimen at the discretion of the investigator.  
Chemotherapy naïve and non-naïve subjects are permitted to participate in the study.
Randomization will be stratified by age, planned use of High Risk emetogenic chemotherapy 
agent in Cycle 1 and planned use of dexamethasone as an antiemetic in Cycle 1.
The main objectives of this study will be assessed during a single chemotherapy cycle (Cycle 
1), where study medication will be administered in a double-blind manner. Upon completion 
of Cycle 1, eligible subjects may be invited to participate in an open-label fosaprepitant 
treatment period for up to 5 more cycles of chemotherapy.  Participation in open-label Cycles 
2 to 6 is optional.  All subjects will be allowed a maximum of 6 months from the end of 
Cycle 1 to complete Cycles 2 to 6.  
In Cycle 1, subjects may be screened up to 28 days prior to randomization.  Eligible subjects 
will then enter the double-blind treatment period and will be required to complete a Patient 
Diary for the 120 hours following the start of emetogenic chemotherapy administration.  
Subjects will be followed for 14 days after treatment with fosaprepitant or placebo to 
fosaprepitant.  Subjects will have 4 clinic visits and phone/direct contact will be made on
Days 2-5 of Cycle 1.
Subjects will be re-evaluated before entering optional Cycles 2 to 6 to determine if entry
criteria have been met.  Subjects will be followed for 14 days after his/her treatment with 
fosaprepitant in the last study cycle.  There are 2 clinic visits during each optional cycle.


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Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
Trial Diagram
2.2
The trial design is depicted below in Figure 1.  
Figure 1 – Trial Design
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
1) Objective:  To compare the single IV dose of fosaprepitant (in combination with 
ondansetron) to the ondansetron alone regimen with respect to the efficacy endpoint 
of Complete Response in the delayed phase (>24 to 120 hours) following the 
initiation of emetogenic chemotherapy in Cycle 1.
Hypothesis:  The single IV dose of fosaprepitant in combination with ondansetron
with or without dexamethasone (hereafter referred to as the fosaprepitant regimen)
provides superior control of CINV compared to ondansetron alone with or without 
dexamethasone (hereafter referred to as the control regimen) as measured by the 


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proportion of subjects with Complete Response (no vomiting, no retching, and no use 
of rescue medication) in the delayed phase (>24 to 120 hours) following the initiation 
of emetogenic chemotherapy in Cycle 1.
2) Objective:  To assess the safety and tolerability of the fosaprepitant regimen in 
subjects birth to 17 years of age who are receiving emetogenic chemotherapy.
Secondary Objective(s) & Hypothesis(es)
3.2
1) Objective:  To compare the fosaprepitant regimen to the control regimen with respect 
to the efficacy endpoint of Complete Response in the acute phase (0 to 24 hours)
following the initiation of emetogenic chemotherapy in Cycle 1.
Hypothesis:  The fosaprepitant regimen is superior to the control regimen as 
measured by the proportion of subjects with Complete Response in the acute phase (0 
to 24 hours) following the initiation of emetogenic chemotherapy in Cycle 1.
2)
Objective:  To compare the fosaprepitant regimen to the control regimen with 
respect to the efficacy endpoint of Complete Response in the overall phase (0 to 120
hours) following the initiation of emetogenic chemotherapy in Cycle 1.
Hypothesis:  The fosaprepitant regimen is superior to the control regimen as 
measured by the proportion of subjects with Complete Response in the overall phase 
(0 to 120 hours) following the initiation of emetogenic chemotherapy in Cycle 1.
3) Objective:  To compare the fosaprepitant regimen to the control regimen with respect 
to the efficacy endpoint of No Vomiting, regardless of rescue medication use, in  the 
overall phase (0 to 120 hours) following the initiation of emetogenic chemotherapy in 
Cycle 1. 
Hypothesis:  The fosaprepitant regimen is superior to the control regimen as 
measured by the proportion of subjects with No Vomiting, regardless of rescue 
medication use, in the overall phase (0 to 120 hours) following the initiation of 
emetogenic chemotherapy in Cycle 1.
Exploratory Objectives 
3.3
1) To compare, in the 120 hours following initiation of emetogenic chemotherapy 
(overall phase) in Cycle 1, the fosaprepitant regimen to the control regimen with 
respect to:

The number of emetic episodes;

The number of subjects with no use of rescue medication;

The time to first rescue medication;


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
The time to first vomiting.
2) To explore the efficacy of the fosaprepitant regimen versus the control regimen using
alternatively defined acute (the period from the initiation of the first dose of 
emetogenic chemotherapy until 24 hours after initiation of the last dose of emetogenic 
chemotherapy) and delayed (end of the acute phase to 120 hours after the first dose of 
emetogenic chemotherapy) phases.
3) To compare
aprepitant plasma concentrations
profiles and pharmacokinetic 
parameters (e.g., AUC0-∞, AUC0-24, Cmax, Tmax, t1/2, CL/F, C24hr, and C48hr), in pediatric
subjects from birth to 17 years old enrolled in Optional Cycle 2 to historical 
pharmacokinetic parameters obtained in adults.
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB) and approved labeling for detailed background 
information on fosaprepitant dimeglumine /MK-0517.
Pharmaceutical and Therapeutic Background
4.1.1
Substance P belongs to a family of neuropeptides known as tachykinins and is the preferred 
agonist for NK1 receptors.  In experimental models, NK1-receptor antagonists have 
demonstrated potent, and usually long-lasting, anti-emetic activity against a broad spectrum 
of central and peripheral emetogens, whereas 5-HT3 receptor antagonists show a more 
limited spectrum of activity with efficacy mostly against peripheral emetogens [1-3].
Brain penetrant NK1-receptor antagonists, such as aprepitant, have been shown in multiple 
studies to be clinically effective in preventing nausea and vomiting associated with 
emetogenic chemotherapy [4-6]. Oral aprepitant (EMEND®) is a selective high-affinity 
antagonist of human substance P/NK1 receptors that, when used in combination with 5-HT3 
receptor antagonists and corticosteroids, is highly effective in the prevention of acute and 
delayed nausea and vomiting due to highly and moderately emetogenic chemotherapy [4-7].  
The use of aprepitant in adults has been approved for the prevention of acute and delayed 
nausea and vomiting associated with initial and repeat courses of HEC (March, 2003) and 
MEC (October, 2005).  Due to the consistent demonstration of clinical benefit, a regimen of
aprepitant administered as 125 mg on Day 1 followed by 80 mg on Days 2 and 3 is 
considered standard of care in adults for the prevention of nausea and vomiting associated 
with HEC and MEC [8-10].  Refer to the EMEND® Capsules prescribing information for 
more details.  Aprepitant is not yet approved for use in children.
Fosaprepitant is a phosphoryl prodrug that is systemically converted to aprepitant within 30 
minutes of intravenous administration.  Thus, the pharmacological effect of fosaprepitant is 
attributed to aprepitant.  A single IV dose of fosaprepitant 150 mg used concomitantly with a 
5-HT3 antagonist and a corticosteroid was demonstrated to be non- inferior to the 3-day oral 
aprepitant regimen in subjects receiving cisplatin-based HEC [11].  Based on these data, 


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fosaprepitant 150 mg has been approved in many countries as an alternative to the 3-day oral 
aprepitant regimen for the prevention of both HEC and MEC-associated CINV in adults; 
however, in some countries it has been approved for use only in HEC.  Refer to the 
EMEND® for Injection prescribing information for more details.  Fosaprepitant is not yet 
approved for use in children.
The aprepitant and fosaprepitant Investigator’s Brochures (IBs) contain information about 
the physical, chemical, pharmaceutical, and formulation properties; preclinical and first in 
humans studies, as well as clinical studies conducted with these compounds.
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
For children undergoing chemotherapy, the current Multinational Association of Supportive 
Care in Cancer (MASCC), European Society for Medical Oncology (ESMO), and American 
Society of Clinical Oncology (ASCO) guidelines recommend the use of 5-HT3 antagonists, 
such as ondansetron, and corticosteroids to alleviate nausea and vomiting associated with 
emetogenic chemotherapy [8; 10].  However, despite the widespread use of these agents, 
nausea and vomiting continue to occur and remain a major source of distress for children 
undergoing emetogenic chemotherapy [12-14].  Thus, there is an ongoing need to evaluate 
the role of new anti-emetic agents such as fosaprepitant for pediatric CINV.
This study will evaluate the efficacy and safety of a single dose of fosaprepitant when 
administered concomitantly with ondansetron, with or without dexamethasone, in subjects 
birth to 17 years of age receiving emetogenic chemotherapy for a documented malignancy.  
The fosaprepitant dose included in this study is within exposures previously shown to be safe 
and well-tolerated in adult and adolescent subjects.
Rationale 
for 
Dose 
Selection/Regimen/Emetogenic 
Classification 
of 
4.2.2
Chemotherapeutic Agents
4.2.2.1
Rationale for Dose Selection
The approved regimen for fosaprepitant in adults for the prevention of CINV is a single 
IV dose of 150 mg. To support dosing in pediatric subjects, pharmacokinetic (PK) data are 
available from (1) an ongoing PK/PD (pharmacodynamic) pediatric study evaluating 
multiple dose levels of fosaprepitant (MK-0517 Protocol 029) and (2) a recently completed
PK/PD pediatric study (MK-0869 Protocol 134) that included a cohort in which a single 
dose level of intravenous fosaprepitant was administered.  Data from these studies and the 
aprepitant pediatric development program suggest that in adolescents ages 12 to 17 years, 
the adult dose (150 mg) is likely to achieve similar aprepitant PK exposures as observed in 
adults, and combined with exploratory efficacy data, this dose is appropriate for further 
evaluation in this study.  In addition, no unexpected or concerning safety signals have 
emerged.  Therefore, in the current study, the 150-mg single IV dose of fosaprepitant
approved for adults was chosen as the dose for adolescent subjects. 


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Dosing for fosaprepitant in children < 12 years of age has also been evaluated in Protocols
134 and 029.  Analyses of aprepitant PK following a single dose of fosaprepitant (doses up to 
3 mg/kg) demonstrated lower aprepitant plasma exposures (AUC0-∞and Cmin) in children < 
12 years of age as compared to adolescents and adults.  These lower-than-expected PK 
exposures were particularly evident at extended time points (e.g., C48hr, C72hr). Although the 
exact mechanism for lower aprepitant plasma levels with decreasing age is not known, the 
data are consistent with previous studies that demonstrated increased hepatic clearance in 
younger children compared to adolescents and adults [15].
Further, exploratory data in children < 12 years of age suggest minimal if any incremental 
efficacy in the delayed phase following single fosaprepitant doses of 3 mg/kg given
concomitantly with a 5-HT3 antagonist, compared to a standard regimen of a 5-HT3
antagonist alone (Protocol 134).  Combined with the PK data described above, these data 
suggest that a single fosaprepitant dose greater than 3 mg/kg will be needed to obtain 
clinically meaningful efficacy for CINV, particularly in the delayed phase.
Based on additional modeling and simulation data, the Sponsor estimates that a fosaprepitant 
dose ~5.0 mg/kg (up to the maximum adult dose of 150 mg) will be needed to achieve 
aprepitant PK exposures and efficacy similar to that of adults.  This fosaprepitant dose is 
predicted to result in aprepitant Cmax levels of ~5000 ng/mL (for comparison, the aprepitant 
Cmax value following 150 mg IV fosaprepitant in adults was ~4200 ng/mL).  In early studies 
of healthy, young adults, aprepitant Cmax levels up to ~9000 ng/mL were well-tolerated and 
therefore provide an adequate safety margin for the proposed 5.0 mg/kg dose.  
Given these considerations, Protocol 029 was amended to allow confirmation of the expected 
PK and safety/tolerability  in  cohorts of children ages 0 to <2 years , 2 to < 6 years, and 6 to 
<12 years, prior to further evaluation in the current study (Protocol 044).  In subjects 6 
months to < 12 years of age the 5.0 mg/kg dose will be evaluated. Assuming there are no 
unexpected findings with respect to either PK or safety/tolerability, the current study will be 
opened for enrollment within each cohort as data become available.  However, this dose may 
be adjusted based on PK, efficacy and/or safety/tolerability data from Protocol 029, and/or 
based on input from regulatory health authorities.  
Neither aprepitant nor fosaprepitant have been evaluated in subjects younger than 6 months 
of age.  In Protocol 029, pediatric subjects younger than 6 months of age will be enrolled 
and administered doses with a target PK profile similar to 150 mg fosaprepitant in adults as 
detailed above.  The proposed doses for subjects younger than 4 months of age in Protocol 
029 are further modified to account for expected reduced clearance due to immature 
expression of cytochrome P450 isoenzyme 3A4 (CYP3A4), the enzyme responsible for 
aprepitant metabolism. CYP3A4 at birth has negligible expression, and expression matures 
to approximately half of adult levels at 4 months of age, and reaches full maturity gradually 
over the next several years.  Therefore, the dose adjustments used in older pediatric subjects 
are also appropriate for 4- to 6-month-olds, but should be reduced in subjects below 4 
months of age to account for reduced metabolism.  The proposed dose adjustment is to 
reduce the dose to half in subjects from 1 month up to 4 months of age, and reduce the dose 
to one fourth in subjects from birth to 1 month of age (Table 4).  While no data currently 


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exist with aprepitant or fosaprepitant in this population to confirm this dose adjustment, data 
from a drug-drug interaction study in healthy adults co-administered ketoconazole and 
aprepitant is illustrative and included in the EMEND® product label.  This approach will be 
verified with data from Protocol 029 for subjects birth to < 4 months old.
Subjects <12 years of age will NOT be permitted to participate in the current study 
until PK/PD and safety data from an ongoing PK/PD and safety study (MK-0517 
Protocol 029) can be evaluated to confirm the planned dose adjustments for the 
subjects <12 years of age.  Enrollment of subjects <12 years of age will begin once the 
study sites are notified of the final dosing instructions via a written letter from the 
SPONSOR.
4.2.2.2
Rationale for the Use of Ondansetron for Antiemetic Prophylaxis
IV ondansetron was chosen as the 5-HT3 antagonist for Cycle 1 of this study since it has 
been extensively studied in the pediatric population and is approved for pediatric use.  In 
clinical drug interaction studies, aprepitant did not have clinically important effects on the 
PK of ondansetron.  As dosing information is not available in the U.S. label for pediatric 
subjects <6 months of age, the dose of IV ondansetron in this age group should be 
administered according to local standard of care.  If ondansetron dosing for subjects less <6 
months of age is not established locally, refer to the “Pediatric Oncology Group of Ontario 
(POGO) Guideline for the Prevention of Acute Nausea and Vomiting due to Antineoplastic 
Medication in Pediatric Cancer Patients” for guidance.  Electronic source is available on the 
POGO website: http://www.pogo.ca/healthcare/practiceguidelines/. 
In order to mitigate variability, IV ondansetron is required for Cycle 1 in this study and will 
be provided for prophylaxis use only by the Sponsor to be used on days of emetogenic 
chemotherapy administration and up to 24 hours after chemotherapy.  
The prescribing information on Zofran®
(ondansetron hydrochloride) injection for 
intravenous use [16] indicates in the Warnings and Precautions section that “ECG changes 
including QT interval prolongation have been seen in subjects receiving ondansetron”, and 
recommend ECG monitoring in “subjects with electrolyte abnormalities (e.g., hypokalemia 
or hypomagnesemia), congestive heart failure, bradyarrhythmias, or subjects taking other 
medicinal products that lead to QT prolongation.”  As such, this study will exclude subjects 
with a known history of QT prolongation, congestive heart failure, bradyarrythmia, or 
subjects taking any medication that is known to lead to QT prolongation.  Additional ECG 
monitoring will be performed for those subjects with an electrolyte abnormality (i.e., 
hypokalemia or hypomagnesemia) at baseline by including an ECG at 2 hours after the first 
dose of ondansetron in Cycle 1.  It is advised that investigators should consider correction of 
known electrolyte abnormalities prior to administration of ondansetron, consistent with 
ondansetron labeling and local standards of care.  Refer to the Zofran® for injection 
prescribing information for more details.


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4.2.2.3
Rationale for Optional Corticosteroid Use for Antiemetic Prophylaxis
Dexamethasone is a corticosteroid that may be used for the prevention/treatment of CINV.  
As both aprepitant and dexamethasone are substrates of CYP3A4, the effect of aprepitant on 
oral dexamethasone PK was evaluated in one study (MK-0869 Protocol 041).  In this study, 
the coadministration of aprepitant resulted in a significant 2-fold increase in dexamethasone 
AUC and Cmax.  A study evaluating the effects of aprepitant on the PK of IV dexamethasone 
has, likewise, demonstrated comparable results [17].  Thus, based upon available data, if 
dexamethasone is administered as part of the standard antiemetic regimen for subjects 
receiving fosaprepitant 150 mg (or age-based adjustment), the dose of dexamethasone 
should be reduced to 50% of the prescribed dose when administered within 48 hours 
following administration of fosaprepitant.  This recommendation may be modified based on 
an ongoing pediatric PK study (Protocol 029) examining the interaction of dexamethasone 
and fosaprepitant in pediatric subjects birth to 1 years of age.  If indicated, a revised dose 
adjustment will be implemented and sites will be notified via a written letter from the 
Sponsor about the change in the dose adjustment.
4.2.2.4
Rationale for Emetogenic Classification of Chemotherapeutic Agents
A schema that appropriately classifies the emetogenic risk of chemotherapy regimens is 
important for at least two reasons: (1) to provide a framework for treatment guidelines in the 
clinical setting, and (2) to precisely define the emetogenic challenge administered in a 
clinical trial.  To address this need, a 4-level system that classifies chemotherapeutic agents 
by emetogenicity (high, moderate, low, and minimal) has been utilized by consensus groups 
in oncology, including ASCO, MASCC, the European Society for Medical Oncology 
(ESMO), and the National Comprehensive Cancer Network (NCCN) [8-10; 18].  However, 
this system has been developed based on adult experience and cannot easily be extrapolated 
to the pediatric population due to potential differences in drug metabolism and susceptibility 
to nausea and vomiting [19-20].
The Pediatric Oncology Group of Ontario (POGO) developed pediatric guidelines of 
commonly used antineoplastic agents by emetogenicity [21]. This schema ranks single and 
multiple agent antineoplastic therapy as high emetic risk (>90%), moderate emetic risk (30-
90%), low emetic risk (10-<30%) and minimal emetic risk (<10%) associated with the 
frequency of emesis in the absence of prophylaxis.
For this study, the classification criteria developed by POGO and endorsed by the Children’s 
Oncology Group (COG) will be used as a guide for subject enrollment. Subjects who are 
administered
a chemotherapeutic agent
associated with moderate
or high risk of 
emetogenicity based on the POGO criteria (see Section 12.5 – Emetogenicity of Commonly 
Used Chemotherapeutic Agents), or will be receiving a chemotherapeutic regimen that they 
have previously not been able to tolerate due to vomiting, will be eligible to enroll in this 
study.  If a planned chemotherapy agent is not listed in the Emetogenicity of Commonly 
Used Chemotherapeutic Agents table, the investigator is encouraged to discuss the 
emetogenic stratification with the Clinical Director.


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Rationale for Endpoints
4.2.3
4.2.3.1
Efficacy Endpoints
The efficacy endpoints assessed in the pediatric CINV studies were designed to capture 
different components of the symptoms associated with CINV.  These include direct 
measurement of vomiting, retching and a surrogate measure of nausea (rescue medication 
use) with complete response defined as no vomiting, no retching, and no use of rescue 
medication.  CINV has traditionally been measured in two distinct periods after the initiation 
of chemotherapy: the acute phase (0 to 24 hours) and the delayed phase (>24 to 120 hours).  
In order to assess the totality of the symptoms, the overall phase, which encompasses both 
phases over the 0 to 120 hour period, was also captured.
4.2.3.2
Pharmacokinetic Endpoints
To allow further characterization of aprepitant PK parameters in pediatric subjects, sparse PK 
samples will be collected in Optional Cycle 2.
Because of their comparatively smaller blood volumes, the opportunity to collect specimens 
for PK analyses in children is much more limited compared to adults.  In order to limit the 
burden on these subjects, a flexible sparse sampling scheme will be utilized.  
PK samples for aprepitant will be collected from all subjects participating in the optional 
Cycle 2 at two time points: Cycle 2, Day 1 at end of fosaprepitant infusion and 2 to 4 hours 
after completion of fosaprepitant infusion.  
If the subject is still at the site or is returning to the site on Cycle 2 Days 2 or 3 (e.g., to 
receive additional chemotherapy), additional PK sample(s) will be collected at up to two
additional time points:  Cycle 2, Day 2 (ideally ~23 to 25 hours after fosaprepitant infusion
on Cycle 2, Day 1); and Cycle 2, Day 3 (ideally ~46 to 50 hours after fosaprepitant infusion
on Cycle 2, Day 1).  Subjects who will not be at the site on Cycle 2, Days 2 and 3 do not 
need to return for PK sampling.  
4.2.3.3
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on DNA (buccal swab) specimens 
collected during this clinical trial.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis 


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and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. The overarching goal is to use such 
information to develop safer, more effective drugs/vaccines, and/or to ensure that subjects 
receive the correct dose of the correct drug/vaccine at the correct time.  The details of this 
Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
4.3
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Based on the ongoing need for treatment options for the prevention of pediatric CINV, and 
the consistent efficacy and tolerability demonstrated by fosaprepitant and oral aprepitant in 
adults, the benefit-to-risk assessment for conducting MK-0517 Protocol 044 is favorable.
In completed and ongoing aprepitant and fosaprepitant studies in pediatric subjects in the 
development program (Protocols 097, 134, 208, 029), aprepitant/fosaprepitant was generally 
safe and well tolerated and the overall adverse experience profile for aprepitant/fosaprepitant 
has been similar to that reported previously in adult studies.  Peripheral catheter infusion site 
reactions seen in the adult studies will not be an issue in this study due to the use of a central 
venous catheter for study drug administration.
The pediatric studies, which are designed to match the exposures of aprepitant and 
fosaprepitant in pediatric subjects to those in adults, have demonstrated a safety profile that is 
generally similar to that seen in prior clinical trials in adults. Thus, there is no expectation of 
increased safety risk for subjects enrolled in this study.
Beneficial effects of aprepitant have been seen in 2 pediatric trials.  Efficacy was 
demonstrated in an aprepitant study in adolescents 12 to 17 years of age (Protocol 097) and a 
pediatric aprepitant study in patients 6 months to 17 years of age (Protocol 208). In these 
studies, a dose of aprepitant that approximated the demonstrated efficacious dose in adults 
provided better control of CINV over the control regimen.  These data are described in the 
aprepitant Investigator’s Brochure and support the conclusion that response to NK1 blockade 
in children is similar to that in adults, and that matching systemic exposure between the adult 
and pediatric population is an appropriate approach for developing NK 1 antagonists 
(including aprepitant and its pro-drug fosaprepitant) for use in the pediatric CINV 
population.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the Investigators Brochure (IB) and Informed Consent and 
Assent documents.


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5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male and female subjects between the ages of birth and 17 years (inclusive) with a 
documented malignancy who are scheduled to receive chemotherapeutic agent(s) associated 
with moderate or high risk of emetogenicity will be enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
5.1.2.1
Inclusion Criteria for Cycle 1
1. have parent/legal guardian (legally authorized representative) agreement to the 
subject’s participation as indicated by parent/legal guardian signature on the informed 
consent form.  Subject 12 to 17 years of age, or as required by local regulation,
assents and has the ability to understand the nature and intent of the study including 
the ability to comply with study procedures, complete study diary, and is willing to 
keep scheduled study visits.  The parent/legal guardian or subject may also provide 
consent/assent for Future Biomedical Research (FBR).  However, the subject may 
participate in the main trial without participating in the FBR.
2. be 0 (at least 37 weeks gestation) to 17 years of age at time of randomization.
3. have a Lansky Play Performance score ≥60 (subjects ≤16 years of age) or a Karnofsky 
score ≥60 (subjects >16 years of age) as defined in Section 12.4 – Lansky and 
Karnofsky Performance Status Scales.
4. have a predicted life expectancy ≥3 months.
5. be receiving chemotherapeutic agent(s) associated with moderate or high risk of 
emetogenicity for a documented malignancy, or a chemotherapy regimen not 
previously tolerated due to vomiting.  See Section 12.5 – Emetogenicity of 
Commonly Used Chemotherapeutic Agents, for guidance on the classification of 
chemotherapeutic agents.
Cycle 1 only: If a subject’s chemotherapy regimen has multiple chemotherapies with 
different emetogenic potential, then the most emetogenic agent must be part of the 
Day 1 regimen.
6. have a preexisting functional central venous catheter available for study drug 
administration.
7. meet one of the following categories:


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a) The subject is a male. 
b) The subject is a female who is not of reproductive potential, defined as a female 
who either: (1) has not begun menses; (2) has had a hysterectomy and/or bilateral 
oophorectomy, bilateral salpingectomy, or bilateral tubal ligation/occlusion at 
least 6 weeks prior to screening; OR (3) has a congenital or acquired condition 
that prevents childbearing.
c) The subject is a female who is of reproductive potential and agrees to avoid 
becoming pregnant# in the 28 days prior to receiving study drug, while receiving 
study drug and for at least 30 days (or local standard of care if longer) after the 
last dose of study drug (including the optional cycles) by complying with one of 
the following: (1) practice abstinence† from heterosexual activity OR (2) use (or 
have her partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):

non-hormonal intrauterine device (IUD)

vasectomy of a female subject’s male partner
Combination method (requires use of two of the following):

diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)

cervical cap with spermicide (nulliparous women only)

contraceptive sponge (nulliparous women only)

male condom or female condom (cannot be used together)

hormonal contraceptive (oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection); subjects must agree to add a barrier form 
of contraception during treatment with and for 1 month following the last dose of 
fosaprepitant (or local standard of care if longer).
# Female of child bearing potential is required to have a negative pregnancy test prior 
to start of fosaprepitant dosing in a cycle.
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception. 


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‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region.
5.1.2.2
Inclusion Criteria for Optional Cycles 2 to 6
In order to be eligible for participation in an optional cycle, the subject must meet 
inclusion criteria 5, 6, and 7 above in addition to the two criteria below.
8. have completed the preceding study cycle and related study procedures satisfactorily, 
have no unresolved drug related adverse events and continued participation in an 
optional cycle poses no unwarranted risk to the subject as determined by the 
investigator.  
9. have parent/legal guardian (legally authorized representative) or subject (if subject is 
18 years old) agreement to the subject’s participation as indicated by parent/legal 
guardian or subject (if subject is 18 years old) signature on the informed consent form 
for the optional cycles.  Subject 12 to 17 years of age, or as required by local 
regulation, assents and has the ability to understand the nature and intent of the study 
including the ability to comply with study procedures and is willing to keep 
scheduled study visits.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
5.1.3.1
Exclusion Criteria for Cycle 1 Only
1. has vomited in the 24 hours prior to chemotherapy initiation on Treatment Day 1.
2. has a symptomatic primary or metastatic central nervous system (CNS) malignancy 
with nausea and/or vomiting.  Subject who is asymptomatic is allowed to participate.
3. has abnormal laboratory values as follows:

peripheral absolute neutrophil count (ANC) <1000/mm3

platelet count <75,000/mm3

aspartate aminotransferase (AST) >5.0 x upper limit of normal (ULN) for age

alanine aminotransferase (ALT) >5.0 x ULN for age

bilirubin >1.5 x ULN for age

creatinine >1.5 x ULN for age


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4. will be receiving stem cell rescue therapy in conjunction with study related course of 
emetogenic chemotherapy or during the 14 days following administration of 
fosaprepitant/placebo for fosaprepitant. 
5. has received or will receive total body irradiation or radiation therapy to the abdomen 
(includes the level of the diaphragm and below) or pelvis in the week prior to 
Treatment Day 1 and/or during the diary reporting period (120 hours following
initiation of chemotherapy).
6. has had benzodiazepine (potential to alleviate nausea and vomiting), opioid or opioid 
like (e.g., tramadol hydrochloride) therapy (potential to enhance nausea and 
vomiting) initiated within 48 hours prior to study drug administration, or is expected 
to receive within 120 hours following initiation of chemotherapy, except for single 
daily doses of midazolam, temazepam or triazolam. 

Continuation of chronic benzodiazepine, opioid or opioid like therapy is permitted 
provided it was initiated at least 48 hours prior to study drug administration.
7. has been started on systemic corticosteroid therapy within 72 hours prior to study 
drug administration or is expected to receive a corticosteroid as part of the 
chemotherapy regimen.
Exceptions:

subject who is receiving chronic (>72 hours), daily steroid therapy can be enrolled 
provided the steroid dose is not >0.14 mg/kg (up to 10 mg) of prednisone daily or 
equivalent.

for supportive care, subject is permitted to receive a single dose of corticosteroid 
within 3 days prior (but not on the day of study drug administration) provided it is 
less than the equivalent of 20 mg of prednisone.
8. is currently taking, or has taken within 48 hours of Treatment Day 1 the following 
drugs with antiemetic properties: 5-HT3 antagonists (e.g., ondansetron), benzamides
(e.g., metoclopramide), butyrophenones (e.g., haloperidol), cyclizine, domperidone, 
herbal therapies with potential antiemetic properties, olanzapine, phenothiazines (e.g., 
prochlorpenzine), scopolamine.  Note: This is not an exhaustive list. The Sponsor
should be consulted in individual cases where the subject is taking an antiemetic not 
listed above.
5.1.3.2
Exclusion Criteria for Cycle 1 and Optional Cycles 2 to 6  
9. is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.


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10. is currently a user of any recreational or illicit drugs (including marijuana) or has 
current evidence of drug or alcohol abuse or dependence as determined by the 
investigator.
11. is mentally incapacitated or has a significant emotional or psychiatric disorder that, in 
the opinion of the investigator, precludes study entry.
12. is pregnant or breast feeding.  
13. is allergic to fosaprepitant, aprepitant, ondansetron, or any other 5-HT3 antagonist.
14. has a known history of QT prolongation or is taking any medication that is known to 
lead to QT prolongation.  A list of many drugs known to cause QT prolongation will 
be provided in a separate document in the Investigator Trial File Binder (or
equivalent).  This may not be a comprehensive list.
15. has an active infection (e.g., pneumonia), congestive heart failure, bradyarrythmia, 
any uncontrolled disease (e.g., diabetic ketoacidosis, gastrointestinal obstruction) 
except for malignancy, or has any illness which in the opinion of the investigator, 
might confound the results of the study or pose unwarranted risk in administering 
study drug or concomitant therapy to the subject.
16. has ever participated in a previous study of aprepitant or fosaprepitant or has taken a 
non-approved (investigational) drug within the last 4 weeks.  Note: Subjects in 
investigational studies with marketed chemotherapeutic agents (whether explicitly for 
children or only marketed for adults and usually administered in children with the 
appropriate dose adjustments) are allowed to enroll if they fulfill all other entry 
criteria.  Previous or current participation in an observational study is acceptable.
17. has received any medication within the timeframes listed in Table 1 or needs to 
receive any medication listed in Table 1 during the time period specified relative to 
initiation of chemotherapy.
Note: The list of CYP3A4 medications listed in Table 1 is not exhaustive.  The 
Sponsor should be consulted in individual cases where the subject is taking a 
moderate to strong CYP3A4 inducer/substrate/inhibitor (not including chemotherapy 
agents) not listed in Table 1.


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Table 1 Other Excluded Medications
Subject is currently taking, 
or has taken within 30 days 
of Treatment Day 1 or is 
expected to receive within 
120 hours following 
initiation of chemotherapy
Subject is currently taking, or 
has taken within 7 days of 
Treatment Day 1 or is expected 
to receive within 120 hours
following 
initiation 
of 
chemotherapy
Subject is currently taking or is 
expected to receive within 2 
weeks following initiation of 
chemotherapy
CYP3A4 
Inducers
barbiturates,
carbamazepine,
phenytoin,
rifampicin,
rifabutin, 
St. John’s Wort
CYP3A4 
Substrates
amifostine,
astemizole,
cisapride,
marinol,
pimozide,
terfenadine
CYP3A4 
InhibitorsA
amprenavir,
aprepitant,
atazanavir,
boceprevir,
ciprofloxacin,
clarithromycin,
conivaptan,
crizotinib, 
darunavir/ritonavir,
diltiazem,
erythromycin,
fluconazole, 
fosamprenavir,
imatinib,
indinavir, 
itraconazole, 
ketoconazole, 
lopinavir/ritonavir,  
mibefradil, 
nefazodone, 
nelfinavir, 
posaconazole, 
ritonavir, 
saquinavir,  
telaprevir, 
telithromycin, 
verapamil, 
voriconazole
CYP2C9 
Substrates
warfarin
AAzithromycin is a macrolide antibiotic that is permitted during the study period.


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Trial Treatment(s)
5.2
The treatment(s) to be used in this trial are outlined below in Table 2 and Table 3.
Table 2 Trial Treatments – Cycle 1
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Treatment 
Period
Use
fosaprepitant
150 mg or 
age-based 
adjustment
single dose
IV
Day 1 
experimental
placebo for
fosaprepitant
(normal saline)
0 mg
single dose
IV
Day 1 
placebo
ondansetron 
per product 
label or 
standard of 
care 
one dose 
prior to 
chemotherapy 
infusion 
required, then 
per product 
label or 
standard of 
care
IV
Day 1 and at 
investigator’s 
discretion on
the day(s) of 
chemotherapy 
and up to 24 
hours after 
chemotherapy
standard of 
care/
prophylaxis
dexamethasone
(optional)
per product 
label or 
standard of 
care *
per product 
label or 
standard of 
care
IV
at 
investigator’s 
discretion on
the day(s) of 
chemotherapy 
and up to 24 
hours after 
chemotherapy
prophylaxis
* For subjects receiving fosaprepitant, the dose of dexamethasone should be reduced to 50% of the 
prescribed dose when administered within 48 hours following administration of fosaprepitant.  Dose 
reduction applies to both dexamethasone used prophylactically and as rescue medication. No dose 
adjustment to dexamethasone will be made for subjects receiving placebo for fosaprepitant.


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Table 3 Trial Treatments – Cycles 2 to 6
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Treatment 
Period
Use
fosaprepitant
150 mg or 
age-based 
adjustment
single dose
IV
Day 1 
experimental
5-HT3 antagonist
per product 
label or 
standard of 
care 
one dose 
prior to 
chemotherapy 
infusion 
required, then 
per product 
label or 
standard of 
care
any route of 
administration
Day 1 and per 
product label 
or standard of 
care
standard of 
care/
prophylaxis
dexamethasone 
(optional)
per product 
label or 
standard of 
care *
per product 
label or 
standard of 
care
at 
investigator’s 
discretion 
at 
investigator’s 
discretion
prophylaxis
* The dose of dexamethasone should be reduced to 50% of the prescribed dose when administered 
within 48 hours following administration of fosaprepitant.  Dose reduction applies to both 
dexamethasone used prophylactically and as rescue medication. 
Trial treatment should begin on the day of randomization or as close as possible to the date 
on which the subject is allocated/assigned.
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 trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection
5.2.1
5.2.1.1
Dose Selection (Preparation)
5.2.1.1.1 Fosaprepitant – Cycle 1 (Treatment Group 1) and Optional Cycles 2 to 6
Open-label fosaprepitant (MK-0517) will be supplied by the Sponsor as a 150-mg vial of 
lyophilized powder.  The site will supply its own source of normal saline to be utilized in the 
preparation of fosaprepitant.  It will be prepared in Cycle 1 in a blinded manner by an 
unblinded pharmacist or qualified trial site personnel.
Subjects in Treatment Group 1 of 
Cycle 1 and those subjects participating in an optional, open-label cycle will receive 150 mg 
(or age-based dose adjustment not to exceed 150 mg) of fosaprepitant.
The individual 
fosaprepitant doses for each age group are summarized in Table 4 – Fosaprepitant Dose for 
Each Age Group. 


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The age-based dosing for subjects birth to <12 years of age may be modified, as needed, 
based on PK, efficacy and/or safety/tolerability data from Protocol 029, and/or based on 
input from regulatory health authorities.  If indicated, a revised dose adjustment will be 
implemented and sites will be notified via a written letter from the Sponsor if there are 
changes to the age-specific dose.
Table 4 Fosaprepitant Dose for Each Age Group
Age-Specific Dose Adjustments*
0-<2 years
2 to < 6
years
6 to <12
years
12 to 17
years
0 to <1 
month
1 to < 4 
months
4 months to 
<2 years
1.25 mg/kg
2.5 mg/kg
5.0 mg/kg
5.0 mg/kg
5.0 mg/kg
150 mg
* not to exceed 150 mg
Specific instructions on the preparation of fosaprepitant will be provided in a separate 
document. 
Note: Fosaprepitant is incompatible with any solutions containing divalent 
cations (e.g., Ca++, Mg++), including Lactated Ringer’s Solution and Hartmann’s Solution.
5.2.1.1.2 Placebo for fosaprepitant (normal saline) – Cycle 1 (Treatment Group 2)
Subjects in the control regimen (Treatment Group 2) will receive placebo for fosaprepitant
(normal saline).  To maintain blinding, placebo for fosaprepitant will be prepared in a blinded 
manner by the unblinded study pharmacist or qualified trial site personnel. The placebo for 
fosaprepitant will be prepared using a volume of normal saline matching the volume that 
would be used to prepare fosaprepitant as detailed in Table 4 – Fosaprepitant Dose for Each 
Age Group.  The site will supply its own source of normal saline to be utilized as placebo for
fosaprepitant.   
Specific instructions on the preparation of placebo for fosaprepitant will be provided in a 
separate document.
5.2.1.1.3 Ondansetron (both treatment groups) - Cycle 1
Ondansetron is the only 5-HT3 antagonist that may be used as part of the preventative 
antiemetic regimen in Cycle 1.  IV ondansetron is required for Cycle 1 of this study and will 
be supplied for prophylaxis use only by the Sponsor to be used on days of chemotherapy 
administration and up to 24 hours after chemotherapy.   
Ondansetron will be prepared per product label or based on local standard of care not to 
exceed the maximum single dose specified for pediatric use.


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5.2.1.1.4 5-HT3 Antagonist – Optional Cycles 2 to 6
Any 5-HT3 antagonist may be used as part of the preventative antiemetic regimen in Cycles 2 
to 6. The 5-HT3 antagonist will be supplied by the study site.   
The 5-HT3 antagonist will be prepared per product label or based on local standard of care
not to exceed the maximum single dose specified for pediatric use.
5.2.1.1.5 Dexamethasone (optional) - Cycle 1 and Optional Cycles 2 to 6
Dexamethasone may be administered as part of the antiemetic regimen at the discretion of 
the investigator.  In Cycle 1, it can be used prophylactically only on days of chemotherapy 
administration and up to 24 hours after chemotherapy.  If dexamethasone is used, it will be 
supplied locally by the study site.  In Cycle 1, IV dexamethasone must be used and prepared 
by the unblinded pharmacist or qualified trial site personnel to allow for dose reduction and 
to maintain the blind.  In Cycles 2 to 6, other dosage forms can be used as long as the dosage 
form can be reduced appropriately (see dose reduction below).  
For any subject receiving fosaprepitant, whether receiving the full dose or an age-based 
adjustment, the dose of dexamethasone should be reduced to 50% of the prescribed 
dose when administered within 48 hours following administration of fosaprepitant.  No 
dose adjustment of dexamethasone will be made for subjects allocated to the control regimen 
in Cycle 1.  
Cycle 1 only
In order to maintain the study blind during Cycle 1, the unblinded pharmacist or qualified 
trial site personnel should ensure that dexamethasone is prepared in a manner that maintains
masking of the drug dose and allows for the site personnel administering the corticosteroid 
to remain blinded.  For this study, unblinded Merck personnel will be designated to work 
with the unblinded pharmacist or qualified trial site personnel as needed.  
An unblinded pharmacist or qualified trial site personnel is required for Cycle 1 only.
Note: The dose adjustment recommendation for IV dexamethasone in subjects birth to 1 
year of age receiving fosaprepitant may be modified, as needed, based on an ongoing 
pediatric pharmacokinetic study (Protocol 029) examining the interaction of dexamethasone 
and fosaprepitant in pediatric subjects.  If indicated, a revised dose adjustment will be 
implemented and sites will be notified via a written letter from the Sponsor about the change 
in the dose adjustment.
Timing of Dose Administration
5.2.2
5.2.2.1
Fosaprepitant/Placebo for Fosaprepitant
Age 0 to <12 years: At approximately 90 minutes prior to initiation of the first emetogenic 
chemotherapy, subjects will be administered fosaprepitant or placebo, via a central venous 


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catheter, over a period of approximately 60 minutes.  The infusion will be complete 
approximately 30 minutes prior to chemotherapy initiation.
The use of a longer infusion time for the younger children is to mitigate the predicted higher
Cmax to AUC ratio in young children compared to adults.  It is expected that extending
the infusion duration to 60 minutes for these younger children (<12 years of age) would 
reduce the predicted peak aprepitant concentrations to levels similar to that of adults. 
Age 12 to 17 years: At approximately 60 minutes prior to initiation of the first emetogenic
chemotherapy, subjects will be administered fosaprepitant or placebo, via a central venous 
catheter, over a period of approximately 30 minutes.  The infusion will be complete 
approximately 30 minutes prior to chemotherapy initiation.
5.2.2.2
Ondansetron - Cycle 1
Ondansetron will be administered per product label or based on local standard of care.  For 
subjects 6 months to 17 years old, the first dose on Day 1 should be no later than 30 minutes 
prior to initiation of the first emetogenic chemotherapy.  The timing of the first dose of 
ondansetron administration for subjects <6 months old should be scheduled according to 
local standard of care. Additional doses of IV ondansetron on Day 1 should be administered 
according to local standard of care.  
Subjects receiving multi-day chemotherapy regimens are permitted to receive preventative 
antiemetic treatment with IV ondansetron after Day 1, with or without IV dexamethasone, if 
clinically indicated and consistent with local standard of care; however, only on the day(s) 
of chemotherapy administration and up to 24 hours after chemotherapy.  
5.2.2.3
5-HT3 Antagonist - Optional Cycles 2-6
The 5-HT3 antagonist will be administered per product label or local standard of care with 
the first dose administered prior to initiation of chemotherapy.
5.2.2.4
Dexamethasone (optional) - Cycle 1 and Optional Cycles 2 to 6
Dexamethasone will be administered per product label or local standard of care.  In Cycle 1 it
should be administered intravenously no later than 30 minutes prior to initiation of the first 
emetogenic chemotherapy.  Subjects receiving multi-day chemotherapy regimens are 
permitted to receive preventative antiemetic treatment with IV dexamethasone after Day 1, if 
clinically indicated and consistent with local standard of care; however, only on the day(s) 
of chemotherapy administration and up to 24 hours after chemotherapy.  In optional 
Cycles 2 to 6, dexamethasone may be administered as part of an anti-emetic regimen based 
on local standard of care.
See section 5.2.1.1.5, Dexamethasone (optional) - Cycle 1 and Optional Cycles 2 to 6, for 
dose reduction instructions.


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Trial Blinding/Masking
5.2.3
A double-blind/masking technique will be used.  Fosaprepitant, placebo for fosaprepitant and 
dexamethasone (if prescribed) in Cycle 1 will be prepared and dispensed in a blinded fashion 
by an unblinded pharmacist or qualified trial site personnel who are not involved in the 
treatment or clinical evaluation of the subjects.  The subject, the investigator and Sponsor 
personnel or delegate(s) who are involved in the treatment or clinical evaluation of the 
subjects are unaware of the group assignments.
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
Randomization or Treatment Allocation
5.3
Randomization will occur centrally using an interactive voice response system / integrated 
web response system (IVRS/IWRS). There are 2 treatment arms.  Subjects will be assigned 
randomly in a 1:1 ratio to fosaprepitant + ondansetron or placebo for fosaprepitant + 
ondansetron respectively once the answers to the stratification questions defined below are 
provided to the system.  See Section 7.1.1.7, Assignment of Randomization Number, for 
additional details on the assignment of the randomization number.
Stratification
5.4
Randomization will be stratified according to the following factors:
1. Age on Day 1 of emetogenic chemotherapy in Cycle 1 (0 to <2 years, 2 to <6 years, 6 to 
<12 years, 12 to 17 years).
2. Planned use of a chemotherapy agent associated with High Risk of emetogenicity in 
Cycle 1 (Yes or No).  
3. Planned use of dexamethasone as an antiemetic in Cycle 1 (Yes or No).
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
If there is a clinical indication for any medication specifically prohibited during the trial, 
discontinuation from trial therapy may be required.  The investigator should discuss any 
questions regarding this with the Sponsor Clinical Director.  The final decision on any 
supportive therapy rests with the investigator and/or the subject's primary physician.  
However, the decision to continue the subject on trial therapy requires the mutual agreement 
of the investigator, and the Sponsor, and the subject/parent/legal guardian.
Listed below are specific restrictions for concomitant therapy during the course of the trial:
1. A list of medications that are prohibited prior to and during the trial are identified in 
Section 5.1.3. Subject Exclusion Criteria.


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2. No drug or herbal therapy of any type is to be initiated during a study cycle without the 
knowledge of the investigator, unless required to treat an adverse event.
Rescue Medications & Supportive Care
5.6
Rescue medication is defined as any medication used to relieve symptoms of established 
nausea or vomiting.  The definition of rescue medication will be explained to the 
subject/parent/caregiver.  Rescue medication should not be taken to prevent nausea or 
vomiting.  Continuous administration of rescue antiemetic medications such as via a 
transdermal patch is not permitted.  Subjects will be instructed that they are allowed to take 
rescue medication if needed for established nausea or vomiting.  
In Cycle 1, subjects will be provided with a prescription for rescue medication according to 
investigator preference.  Permitted rescue medications are:

5-HT3
antagonists (dolasetron, granisetron, ondansetron, palononsetron or 
tropisetron) 

Benzamides (e.g., alizapride or metoclopramide)

Benzodiazepines

Butyrophenones (e.g., droperidol or haloperidol)

Cannabinoids (e.g., nabilone)

Cyclizine

Dexamethasone*

Domperidone

Herbal therapies with potential antiemetic properties

Methylprednisolone

Phenothiazines 
(e.g., 
chlorpromazine, 
fluphenazine, 
perphenazine, 
prochlorperazine, or thiethylperazine)

Scopolamine
The Patient Diary will be used to record the date, time, and type of rescue medication used
during Cycle 1.
In optional Cycles 2 to 6, the subject can be provided with a prescription for rescue 
medication according to investigator preference.
* If dexamethasone is used as rescue medication in Cycle 1, IV dexamethasone must be used
and prepared by the unblinded pharmacist or qualified trial site personnel to allow for dose 
reduction and to maintain the blind.  In Cycles 2 to 6, other dosage forms can be used as 
long as the dosage form can be reduced appropriately (see dose reduction below).  


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For any subject receiving fosaprepitant, whether receiving the full dose or an age-based 
adjustment, the dose of dexamethasone should be reduced to 50% of the prescribed
dose when administered within 48 hours following administration of fosaprepitant.
Diet/Activity/Other Considerations
5.7
There are no diet or activity restrictions.
Subject Withdrawal/Discontinuation Criteria
5.8
Subject/parent/legal guardian may withdraw consent and/or assent (as applicable) at any time 
for any reason or be dropped from the trial at the discretion of the investigator should any 
untoward effect occur.  In addition, a subject may be withdrawn by the investigator or the 
Sponsor if enrollment into the trial is inappropriate, the trial plan is violated, or for 
administrative and/or other safety reasons.  Specific details regarding discontinuation or 
withdrawal procedures; including specific details regarding withdrawal from Future 
Biomedical Research, are provided in Section 7.1.4 – Other Procedures.
Discontinuation from treatment is “permanent”.  Once a subject is discontinued, he/she shall 
not be allowed to restart treatment.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.

The subject withdraws assent.

The subject has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, places the subject at unnecessary risk through 
continued participation in the trial or does not allow the subject to adhere to the 
requirements of the protocol.

The subject has a positive pregnancy test.  The pregnancy will be followed to 
resolution.
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons:

Pregnancy

Any drug-related serious AE (SAE) or any SAE which might affect the ability of the 
subject to safely continue in the trial or provide reliable efficacy measurements.
Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced.


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Beginning and End of the Trial
5.10
The overall trial begins when the first subject/parent/legal guardian signs the informed 
consent form.  The overall trial ends when the last subject completes the last study-related 
phone call or visit, discontinues from the trial or is lost to follow-up (i.e. the subject is unable 
to be contacted by the investigator).
Clinical Criteria for Early Trial Termination
5.11
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, GCP and/or other 
applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.


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6.0 TRIAL FLOW CHART
Cycle 1
Study Day and Time are relative to initiation of the first emetogenic chemotherapy infusion (Tzero).
Trial Period
Screening
Treatment
Post-Treatment
Visit Number/Title:
1
Screening
2
Randomization
Telephone/ Direct
Contact
3
Post-Treatment
4
Follow-Up/
Discontinuation
Study Day
-28 to 1 A
1
2 to 5B
6 to 9 C
15 to 20 C
Administrative Procedures
Informed Consent and Assent (if applicable)
XD
Informed Consent and Assent (if applicable) for Future 
Biomedical Research
XE
Inclusion/Exclusion Criteria
X
X
Subject Identification Card
X (dispense)
X (collect) F
Medical History
X
X
Prior Medication Review
X
X
Concomitant Medication Review
X
X
X
Register Study Visit/Assignment of Screening & Randomization 
Numbers and/or Dispense Study Therapy via IVRS/IWRS
X
X
X G
Patient Diary Education for Subject/Parent/Caregiver and dispense 
diary
X H
Laboratory and/or ECG Safety Test Review
X
X
X
Rescue Medication Prescription
X
Subject/Parent/Caregiver Diary Completion
X----------------------------------X
Telephone/Direct Contact (scripted questions)
X B
X B
Patient Diary Review/Collection (with Subject/Parent/Caregiver)
X
Clinical Procedures/Assessments
Full Physical Examination 
X I
Directed Physical Examination
X
Height
X
Weight
X
Vital Signs (blood pressure, heart rate, respiratory rate, 
axillary/oral/ rectal/temporal/tympanic temperature)
X
X J
X
X
12-Lead Electrocardiogram (ECG)
X K
X L
X
Lansky or Karnofsky Performance Status Evaluation
X
Fosaprepitant or Matching Placebo Administration
X M
IV Ondansetron Administration
XN
Optional Dexamethasone Administration
X O
Chemotherapy Infusion
X P
Adverse Event Monitoring
X----------------------------------------------------------------------------------X


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Cycle 1
Study Day and Time are relative to initiation of the first emetogenic chemotherapy infusion (Tzero).
Trial Period
Screening
Treatment
Post-Treatment
Visit Number/Title:
1
Screening
2
Randomization
Telephone/ Direct
Contact
3
Post-Treatment
4
Follow-Up/
Discontinuation
Study Day
-28 to 1 A
1
2 to 5B
6 to 9 C
15 to 20 C
Laboratory Procedures/Assessments
Laboratory Safety Evaluations (Hematology, Chemistry)
X K
X
Ionized Calcium evaluation
XQ
XQ
Urine Pregnancy Test – if applicable 
X KR
Buccal swab samples for Future Biomedical Research 
XS
A The Screening and Randomization visits can occur on the same day as long as all study procedures are completed and subject eligibility is confirmed.
B Telephone or direct contact must be made daily on Days 2, 3, 4, and 5.  Telephone/direct contact must also be made on Day 6 if the Post Treatment visit is not on Day 6.
C One visit occurs during the designated period of study days.  The Follow-Up Visit can be scheduled to coincide with the start of the next study cycle provided that the next round 
of chemotherapy is 14-19 days after Treatment Day 1 (study days 15 to 20).
D Informed consent/assent MUST be obtained prior to any Visit 1 procedures.  
E Subject participation in Future Biomedical Research is optional.
F A reasonable attempt should be made to collect the Subject Identification Card if subject discontinues during Cycle 1 or if subject is not participating in optional cycle(s).   
G Register study discontinuation visit in IVRS/IWRS if subject discontinues during Cycle 1 or if subject is not participating in optional cycle(s).
H The Subject/Parent/Caregiver should be educated on the use of the Patient Diary prior to the start of emetogenic chemotherapy.
I Full physical exam (excluding breast, rectal, and urogenital, unless clinically indicated).
J All vital sign measurements will be obtained prior to fosaprepitant infusion.  Blood pressure and heart rate will be measured again ~ 15 minutes after completion of fosaprepitant 
infusion, prior to the start of chemotherapy.  
K ECG, Laboratory Safety Evaluations and Urine Pregnancy Test must be completed within 7 days prior to initiation of study medication. See Section 7.1.3.1 – Local Laboratory 
Safety Evaluations for the list of Laboratory Tests.
L This ECG is obtained ~2 (no later than 3) hours after initial administration of IV ondansetron in those subjects with a baseline potassium and/or magnesium level below the 
normal range for the subject’s age.
M Fosaprepitant or matching placebo dose is initiated at ~90 minutes prior to initiation of the first emetogenic chemotherapy and administered via a central venous catheter over a 
period of ~60 minutes for subjects <12 years old and ~60 minutes prior to initiation of the first emetogenic chemotherapy and administered over a period of ~30 minutes for 
subjects 12 to 17 years old.  The infusion will be complete ~30 minutes prior to chemotherapy initiation.
N IV ondansetron is required for Cycle 1 and will be supplied for prophylaxis use only by the Sponsor to be used on days of chemotherapy administration and up to 24 hours after 
chemotherapy.  For subjects 6 months to 17 years old, the first dose on Day 1 should be no later than 30 minutes prior to initiation of the first emetogenic chemotherapy. The 
timing of the first dose of ondansetron administration for subjects <6 months old should be scheduled according to local standard of care.  Additional doses of IV ondansetron on
Day 1 should be administered according to local standard of care.  For multi-dose chemotherapy regimens, IV ondansetron can be administered on subsequent days if clinically 
warranted and per local standard of care; however, it should only be administered on the day(s) of chemotherapy administration and up to 24 hours after chemotherapy 
administration.


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O IV dexamethasone may be administered as part of an anti-emetic regimen based on local standard of care, but no later than 30 minutes prior to initiation of the first emetogenic 
chemotherapy.  For subjects receiving fosaprepitant, the dose of dexamethasone should be reduced to 50% of the prescribed dose when administered within 48 hours following 
administration of fosaprepitant.  Dose reduction applies to dexamethasone used prophylactically and as rescue medication.  No dose adjustment will be made for subjects 
receiving placebo for fosaprepitant.  For multi-dose chemotherapy regimens, IV dexamethasone can be administered on subsequent days if clinically warranted and per local 
standard of care; however, it should only be administered on the day(s) of chemotherapy administration and up to 24 hours after chemotherapy administration.
P The time of initiation of the first emetogenic chemotherapy infusion will be recorded by the site staff on the front page of the Patient Diary.  This date and time will be 
designated as Tzero (0 hour) for the study cycle.
Q At selected sites, blood samples for ionized calcium will be drawn at the screening visit and at the randomization visit ~15 minutes after completion of fosaprepitant/placebo
infusion, prior to the start of chemotherapy.  
R Applies to female subjects of reproductive potential only.  If a female subject reaches menarche (menstruates for the first time), a urine pregnancy test must be done.  Post-
menarche female subjects must have a negative urine pregnancy test at Screening.  Results must be obtained prior to study drug administration.  Urine pregnancy testing should 
be repeated at subsequent visits if the subject reports non-compliance to birth control methods, if there is a question about potential pregnancy or as required by local guidelines.  
Note: a serum pregnancy test can be performed instead of the urine test per local regulatory requirements or standard of care.
S Informed consent/assent for future biomedical research must be obtained before the buccal swab DNA samples are collected.  The buccal swab DNA samples should be obtained 
predose on Day 1, on randomized subjects only, or at a later date as soon as the informed consent/assent is obtained.


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Cycles 2-6
Study Day and Time are relative to initiation of the first emetogenic chemotherapy infusion (Tzero).
Trial Period
Treatment
Post-Treatment
Visit Title:
Treatment
Follow-Up/
Discontinuation
Study Day
1
15 to 20A
Administrative Procedures
Informed Consent and Assent (if applicable)
XB
Inclusion/Exclusion Criteria
X
Subject Identification Card
X (collect) C
Concomitant Medication Review
X
X
Register Study Visit and/or Dispense Study Therapy via IVRS/IWRS
X
XD
Rescue Medication Prescription (optional)
X
Clinical Procedures/Assessments
Directed Physical Examination
X
X
Weight
X
Vital Signs (blood pressure, heart rate, respiratory rate, 
axillary/oral/rectal/temporal/tympanic temperature)
XE
X
Fosaprepitant Administration
XF
5-HT3 Antagonist Administration
XG
Optional Dexamethasone Administration
XH
Chemotherapy Infusion
X
Adverse Event Monitoring
X-------------------------X 
Laboratory Procedures/Assessments
Urine Pregnancy Test – if applicable 
XIJ
Pharmacokinetic (PK) Evaluations (Cycle 2 Only)
XK


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A One visit occurs during the designated period of study days.  The Follow-Up Visit can be scheduled to coincide with 
the start of the next chemotherapy cycle provided that the next round of chemotherapy is 14-19 days after Treatment 
Day 1 (study days 15 to 20) of the current chemotherapy cycle.
B Informed consent/assent MUST be obtained prior to any procedures being performed in Cycle 2.
C A reasonable attempt should be made to collect the Subject Identification Card when subject discontinues/completes 
the study.
D Register study discontinuation visit when subject discontinues from the study.
E All vital sign measurements will be obtained prior to fosaprepitant infusion.  Blood pressure and heart rate will be 
measured again ~ 15 minutes after completion of fosaprepitant infusion, prior to the start of chemotherapy.  
F Fosaprepitant dose is initiated at ~90 minutes prior to initiation of the first emetogenic chemotherapy and 
administered via a central venous catheter over a period of ~60 minutes for subjects <12 years old and ~60 minutes 
prior to initiation of the first emetogenic chemotherapy and administered over a period of ~30 minutes for subjects 
12 to 17 years old.  The infusion will be complete ~30 minutes prior to chemotherapy initiation.
G The 5-HT3 antagonist will be supplied by the Site and will be administered per product label or local standard of care 
prior to initiation of the first emetogenic chemotherapy.
H Dexamethasone may be administered as part of an anti-emetic regimen based on local standard of care.  The dose of
dexamethasone should be reduced to 50% of the prescribed dose when administered within 48 hours following 
administration of fosaprepitant.  Dose reduction applies to dexamethasone used prophylactically and as rescue 
medication.
I
Urine Pregnancy Test must be completed within 7 days prior to initiation of study medication.    
J
Applies to female subjects of reproductive potential only.  If a female subject reaches menarche (menstruates for the 
first time), a urine pregnancy test must be done.  Results must be obtained prior to study drug administration. Urine 
pregnancy testing should be repeated at subsequent visits if the subject reports non-compliance to birth control 
methods, if there is a question about potential pregnancy or as required by local guidelines.  Note: a serum pregnancy 
test can be performed instead of the urine test per local regulatory requirements or standard of care.
K Cycle 2 Only: PK samples for aprepitant to be collected from all subjects at two time points: Cycle 2, Day 1 at end 
of fosaprepitant infusion and 2 to 4 hours after (completion) of fosaprepitant infusion.  If the subject is still at the site 
or is returning to the site on Cycle 2 Days 2 or 3 (e.g., to receive additional chemotherapy), additional PK sample(s) 
will be collected at up to two additional time points:  Cycle 2, Day 2 (ideally ~23 to 25 hours after fosaprepitant 
infusion on Cycle 2, Day 1); and Cycle 2, Day 3 (ideally ~46 to 50 hours after fosaprepitant infusion on Cycle 2, Day 
1).  Subjects who will not be at the site on Cycle 2, Days 2 and 3 do not need to return for PK sampling


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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent and/or assent (if applicable) be obtained from 
the subject/parent/legal guardian.  In these cases, such evaluations/testing will be performed 
in accordance with those regulations.
Administrative Procedures
7.1.1
7.1.1.1
Informed Consent/Assent
The investigator or qualified designee must obtain documented consent and/or assent (if 
applicable) from each potential subject or each subject’s legally acceptable representative
prior to participating in a clinical trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent/Assent
Consent/assent must be documented by the subject’s dated signature or by the subject’s 
legally acceptable representative’s dated signature on a consent 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 subject before 
participation in the trial.
The initial informed consent/assent form, any subsequent revised written informed 
consent/assent form and any written information provided to the subject must receive the 
IRB/ERC’s approval/favorable opinion in advance of use.  The subject or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the subject’s willingness to continue participation in the 
trial.  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 
subject’s dated signature or by the subject’s legally acceptable representative’s dated 
signature.
Specifics about a trial and the trial population will be added to the consent/assent form 
template at the protocol level.  


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The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.  The assent, as applicable, will adhere to IRB/ERC requirements, 
applicable laws and regulations and Sponsor requirements.
7.1.1.1.2 Consent/Assent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
and/or assent (if applicable) to the subject/parent/legal guardian, answer all of his/her 
questions, and obtain written informed consent and/or assent (if applicable) before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent/assent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card (Clinical Trial Identification Card)
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the 
subject/parent/legal guardian provides written informed consent and/or assent, as applicable.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.  Specific 
medical history information will be reviewed and documented prior to treatment and will 
include:

Date/type of cancer diagnosis

History of CINV

History of motion sickness

History of morning sickness during pregnancy, if applicable

History of QT prolongation

Allergies to fosaprepitant aprepitant, ondansetron, or any other 5-HT3 antagonist


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
All active conditions

All inactive conditions diagnosed within the previous 5 years
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review and record prior medication taken by the 
subject in the preceding 30 days prior to entering the study.  The doses will not be recorded.  
For subjects hospitalized during this period, only the discharge medications will be recorded.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
starting on Day 1 of a study cycle through 14 days following the dose of 
fosaprepitant/placebo for fosaprepitant.  This will include the name of the medication, date(s)
of use and reason for use.  In addition, for chemotherapy medications, the dose will be 
recorded along with the start and stop times of chemotherapy.
A list of medications that are prohibited prior to and during the trial are identified in Section 
5.1.3. Subject Exclusion Criteria.  If there is a clinical indication for any medications 
specified in Section 5.1.3, refer to Section 5.5 Concomitant Medications/Vaccinations for 
further guidance.
7.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or allocation.  Each subject 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
The subject identification card will be updated with the screening number.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.1 - Screening.    
7.1.1.7
Assignment of Randomization Number
All eligible subjects will be randomly allocated and will receive a randomization number.  
The randomization number identifies the subject for all procedures occurring after 
randomization.  Once a randomization number is assigned to a subject, it can never be re-
assigned to another subject.


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A single subject cannot be assigned more than 1 randomization number.
After all required study screening procedures have been completed and subject’s eligibility 
has been confirmed, the randomization visit will be registered in IVRS/IWRS.
The subject identification card will be updated with the randomization number.
The date of treatment assignment should generally correspond to the date of randomization.  
However, for investigational sites unable to logistically prepare the fosaprepitant/placebo for
fosaprepitant on Day 1 that have obtained written permission from the Sponsor to prepare the 
fosaprepitant/placebo for
fosaprepitant
on Day
-1, the date of study medication 
administration will differ from the date of IVRS/IWRS treatment assignment.  If the 
fosaprepitant is prepared on Day -1, the timing of the fosaprepitant administration must be 
carefully monitored to ensure it is administered to the subject within 24 hours of preparation 
since reconstituted fosaprepitant may become unstable after 24 hours.
Sites contacting the IVRS/IWRS on Day -1 must verify and document that the subject 
continues to meet the eligibility criteria before administering the first dose of assigned study 
medication on Day 1.  
7.1.1.8
Trial Compliance (Study Medication/Patient Diary)
Administration of fosaprepitant/placebo for fosaprepitant will be witnessed by the 
investigator and/or trial staff.  The total volume of fosaprepitant infused will be compared to 
the total volume prepared to determine compliance with study dosing.
The site staff will give the subject/parent/caregiver a paper Patient Diary at the 
Randomization Visit.  Sites will be trained on the use of the diary by the Sponsor and are 
expected to subsequently train the subject/parent/caregiver on how to complete the diary. To 
ensure ongoing subject compliance with diary reporting, site staff will contact the 
subject/parent/caregiver on Days 2 to 5 and on Day 6, if the subject’s post-treatment visit is 
not scheduled for that day, to remind him/her to record episodes of vomiting/dry heaves and 
use of medication for vomiting or nausea in the Patient Diary. The site staff will review the 
Patient Diary in detail with the subject/parent/caregiver at the Post-Treatment Visit.
Interruptions from the protocol specified treatment plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
subject management.
7.1.1.9
Patient Diary Education for Subject/Parent/Caregiver - Cycle 1 Only
At the Randomization Visit, the subject/parent/caregiver will be given one diary for the use 
in pediatric subjects (birth to <12 years) or one for use in adolescent subjects (12 to 17 
years).  The diaries are identical except that the pediatric diary poses efficacy questions and 
provides instructions for completion to the subject’s parent/caregiver whereas the adolescent 
diary poses the questions and provides instructions for completion to the subject.  The diaries 


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will collect rescue medications and vomiting episodes for a 5-day period (120 hours), starting 
on Day 1.
Assessment of efficacy will begin at the initiation of the first emetogenic chemotherapy 
infusion (Tzero) and will end 120 hours later.  Efficacy will be assessed in Cycle 1 only using 
the Patient Diary.
The site staff will instruct the subject/parent/caregiver on the use of the Patient Diary by 
reviewing 
the 
“Instructions 
for 
Completing 
This
Diary” 
page 
with 
the 
subject/parent/caregiver ensuring he/she understands the definitions for vomiting and dry 
heaves.  In addition, the subject/parent/caregiver should be told that nausea is defined as 
“feeling the need to vomit”.  Distinct vomiting episodes are, by definition, separated by the 
absence of vomiting or dry heaves for at least one minute.  The subject/parent/caregiver will 
be instructed to record the date and time of any episodes of vomiting/dry heaves and use of 
any medication for vomiting or nausea in the diary at the time the episode occurs or the 
medication is taken.
The site staff will complete the shaded areas of the diary.  The subject/parent/caregiver will
record each time the subject vomits, has dry heaves or has to take medication for vomiting or 
nausea. Subjects (or their parent/caregiver) must continue to fill out the diary even if the 
subject has episodes of vomiting or dry heaves or requires use of medication for vomiting or 
nausea at any time during the diary reporting period.
The subject/parent/caregiver will be told that he/she will be contacted daily on Days 2 to 5 
and on Day 6, if the subject’s post-treatment visit is not scheduled for that day, to remind 
him/her to record episodes of vomiting/dry heaves and use of medication for vomiting or 
nausea in the diary.  Episodes of vomiting/dry heaves and use of medication for vomiting or 
nausea that occur on Day 6 (within the 120 hours) will be recorded on Day 5 of the Patient 
Diary.  The subject/parent/caregiver will be instructed to return the completed diary at the 
Post-Treatment Visit. 
7.1.1.10 Laboratory and ECG Safety Test Review
ECG and laboratory safety tests results, including urine pregnancy test (for females of 
reproductive potential), will be reviewed prior to randomization/treatment to confirm that the 
results are clinically acceptable and the subject meets the study requirements.  If the subject’s 
ECG, and blood and urine laboratory tests were not done within the preceding 7 days to the 
Randomization/Treatment Visit, they will be repeated.  Any results found clinically 
unacceptable may be repeated.  
It is advised that investigators consider correction of known electrolyte abnormalities prior to 
administration of ondansetron, consistent with ondansetron labeling and local standard of 
care.


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Clinically significant findings from the screening laboratory safety tests and/or ECG should 
be recorded as medical history. For laboratory safety tests and/or ECG performed after 
treatment, any clinically significant changes should be recorded as AEs.
7.1.1.11 Rescue Medication Prescription
In Cycle 1, subjects will be provided with a prescription for rescue medication according to 
investigator preference.  Permitted rescue medications are listed in Section 5.6 – Rescue 
Medications & Supportive Care.  Subject/parent/caregiver will be instructed that the subject 
is allowed to take medication if needed for established nausea or vomiting, but should not 
take the medication to prevent nausea or vomiting.  Subject/parent/caregiver will be 
instructed on how to record any medication taken for vomiting or nausea in the Patient Diary.
See section 7.1.1.9 - Patient Diary Education for Subject/Parent/Caregiver.  
In optional Cycles 2 to 6, the subject may be provided with a prescription for rescue 
medication according to investigator preference.
7.1.1.12 Subject/Parent/Caregiver Diary Completion - Cycle 1 Only
The subject/parent/caregiver will record the date and time of any episodes of vomiting/dry 
heaves and use of medication for vomiting or nausea in the Patient Diary.  The diary will be 
completed on Days 1 to 6 (for 120 hours after initiation of first emetogenic chemotherapy).  
7.1.1.13 Telephone or Direct Contact (scripted questions) - Cycle 1 Only
Site staff will contact (either telephone or in person) the subject/parent/caregiver on Days 2 
to 5 and on Day 6, if the subject’s post-treatment visit is not scheduled for that day, to remind 
him/her to record episodes of vomiting/dry heaves and use of medication for vomiting or 
nausea.  All attempted and completed telephone contacts will be documented by the trial site.  
The following questions, in the sequence listed, will be asked during each contact:
1. "Do you have your/your child’s diary with you?  If not, please obtain it and I will wait."
2. "Did you/your child have any episodes of vomiting/dry heaves in the last 24 hours?"
"If yes, how many times?  At what time(s)?  Did you record this in the diary?  If not, please 
record it now."
If the subject has had episodes of vomiting or dry heaves they should be reminded that they 
still need to complete the diary.
If the subject did not have any episodes of vomiting or dry heaves in the preceding 24 hours, 
they should be reminded to check the diary box for that day indicating that they did not have 
any episodes of vomiting or dry heaves.
3. "Did you/your child need medication to treat vomiting or nausea?"


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"If yes, how much?  At what time(s)?  Did you record this in the diary?  If not, please record 
it now."
If the subject has taken medication for vomiting or nausea, they should be reminded that they 
still need to complete the diary.
If the subject has not taken any medication for vomiting or nausea in the preceding 24 hours, 
they should be reminded to check the diary box for that day indicating that they did not take 
any medication for vomiting or nausea.
At each contact, the subject/parent/caregiver will be reminded that they/their child can still 
take medication if they have vomiting or nausea.
At the Day 6 contact (or Day 5 contact if Post-Treatment Visit is on Day 6), 
subject/parent/caregiver should be reminded to bring the completed diary to the next visit.
The questions relating to episodes of vomiting or dry heaves, and medications for vomiting 
or nausea are designed ONLY to assist subject/parent/caregiver in the proper completion of 
the Patient Diary.  The answers to questions about the endpoints of episodes of vomiting or 
dry heaves and medications for vomiting or nausea should NOT be recorded electronically 
by the person making the contact; rather the subject/parent/caregiver should be instructed to 
properly complete the diary.
During each contact, the subject/parent/caregiver will also be reminded to notify the 
investigator immediately of any adverse event.  
7.1.1.14 Patient Diary Review/Collection (with Subject/Parent/Caregiver) - Cycle 1 
Only
Subjects will return to the study site once during Day 6 to 9 and will bring the Patient Diary.

The site staff will review the Patient Diary in detail, making sure that there are no 
errors, ambiguities, or missing data.  All medications listed in the diary as 
medications for vomiting or nausea will be reviewed with the subject/parent/caregiver
to confirm that they were actually taken to treat established nausea, vomiting, or both.  
If an error is found, the subject/parent/caregiver will be instructed to cross out the 
first answer with a single line and to put his/her initials and date next to the correct
answer.

The diary will be initialed and dated by the subject/parent/caregiver (including 
relationship to patient, if applicable), in the presence of the investigator or his/her 
delegate, as verification of a true record. The site staff will collect the diary.


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Clinical Procedures/Assessments
7.1.2
7.1.2.1
Full Physical Examination - Cycle 1 Only
The investigator or qualified designee will perform a complete physical exam during the 
screening period according to local standard of care.  A complete physical examination may 
include the following assessments: general appearance, head, eyes, ears/nose/throat, neck, 
lymph nodes, skin, lungs, heart, abdomen, musculoskeletal, and neurologic evaluations. 
Breast, rectal, and genitourinary/pelvic exams should be performed when clinically indicated.  
Clinically significant abnormal findings should be recorded as medical history.  
7.1.2.2
Directed Physical Examination
Physical examinations after the Screening Visit will be directed exams. The investigator or 
qualified designee will perform a symptom-focused exam as clinically indicated.  New 
clinically significant abnormal findings found after receiving study therapy on Day 1 will be 
reported as adverse events.  If a randomized subject is discontinued for any reason, every 
attempt should be made to perform a final directed physical examination if indicated.
7.1.2.3
Height - Cycle 1 only
Height will be obtained with the subject’s shoes off.
7.1.2.4
Weight
Body weight will be obtained with the subject’s shoes off and jacket or coat removed.
7.1.2.5
Vital Signs
The investigator or qualified designee will assess vital signs as indicated in Section 6.0 -
Trial Flow Chart.  Vital signs include blood pressure, heart rate, respiratory rate and 
axillary/oral/rectal/temporal/tympanic temperature.  Blood pressure and heart-rate should be 
obtained with the subject in a seated, semi-recumbent, prone or supine position.  An 
appropriately sized blood pressure cuff will be used.  At the randomization/treatment visits, 
blood pressure and heart rate measurements will be taken prior to and ~15 minutes after 
fosaprepitant infusion, prior to chemotherapy infusion.  Every effort should be made to 
collect these measurements using the same arm and body position.   
7.1.2.6
12-Lead Electrocardiogram - Cycle 1 only
A screening 12-lead ECG will be obtained and read using local standard procedures.  If the 
subject’s ECG from the Screening Visit was not done within the preceding 7 days to the 
Randomization Visit, it will be repeated.


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In those subjects with a baseline potassium and/or magnesium level below the normal range 
for the subject’s age that were not corrected prior to randomization, another ECG will be 
obtained ~2 (no later than 3) hours after initial administration of ondansetron.
7.1.2.7
Lansky or Karnofsky Performance Status Evaluation - Cycle 1 only
The Lansky and Karnofsky Performance Status Scales (see Section 12.4 - Lansky and 
Karnofsky Performance Status Scales) will be used to evaluate if the subject meets the study 
inclusion criterion.  The Lansky Play-Performance Scale will be used to evaluate subjects
≤16 years of age.  The Karnofsky Performance Scale will be used to evaluate subjects >16 
years of age.  Subjects must have a score ≥60 to participate in this study (see Section 5.1.2–
Subject Inclusion Criteria).
7.1.2.8
Fosaprepitant or Matching Placebo for Fosaprepitant Administration
Fosaprepitant or matching placebo dose is initiated at ~90 minutes prior to initiation of the 
first emetogenic chemotherapy and administered via a central venous catheter over a period 
of ~60 minutes for subjects <12 years old and ~60 minutes prior to initiation of the first 
emetogenic chemotherapy and administered via a central venous catheter over a period of 
~30 minutes for subjects 12 to 17 years old.  The infusion will be complete ~30 minutes prior 
to chemotherapy initiation.
7.1.2.9
IV Ondansetron Administration - Cycle 1 only
IV ondansetron is required for Cycle 1 and will be supplied for prophylaxis use only by the 
Sponsor to be used on days of chemotherapy administration and up to 24 hours after 
chemotherapy.  For subjects 6 months to 17 years old, the first dose on Day 1 will be 
administered no later than 30 minutes prior to initiation of the first emetogenic 
chemotherapy. The timing of the first dose of ondansetron administration for subjects <6 
months old should be scheduled according to local standard of care.  Additional doses of IV 
ondansetron on Day 1 will be administered according to local standard of care.  For multi-
dose chemotherapy regimens, IV ondansetron can be administered on subsequent days if 
clinically warranted and per local standard of care; however, it should only be administered 
on the day(s) of chemotherapy administration and up to 24 hours after chemotherapy 
administration.
7.1.2.10 5-HT3 Antagonist Administration - Optional Cycles 2-6
For optional Cycles 2 to 6, any commercially available 5-HT3 antagonist may be used as part 
of the antiemetic regimen and will be supplied locally by the study site.  The 5-HT3
antagonist will be administered per product label or local standard of care with the first dose 
administered prior to initiation of chemotherapy.
7.1.2.11 Optional Dexamethasone Administration
Dexamethasone may be administered as part of an anti-emetic regimen based on local 
standard of care, but no later than 30 minutes prior to initiation of the first emetogenic 


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chemotherapy.  For subjects receiving fosaprepitant, the dose of dexamethasone should be 
reduced to 50% of the prescribed dose when administered within 48 hours following 
administration of fosaprepitant.  Dose reduction applies to dexamethasone used 
prophylactically and as rescue medication. No dose adjustment will be made for subjects 
receiving placebo for fosaprepitant.
In Cycle 1, for multi-dose chemotherapy regimens, IV dexamethasone can be administered 
on subsequent days if clinically warranted and per local standard of care; however, it should 
only be administered on the day(s) of chemotherapy administration and up to 24 hours after 
chemotherapy administration.
7.1.2.12 Chemotherapy Infusion
Subjects will receive at least one chemotherapeutic agent associated with moderate or high 
risk of emetogenicity for a documented malignancy, or a chemotherapy regimen not 
previously tolerated due to vomiting.  See Section 12.5, Emetogenicity of Commonly Used 
Chemotherapeutic Agents, for guidance on the classification of chemotherapy agents.
The chemotherapy regimen will be infused per the local standard of care.  The date and time 
of initiation of the first emetogenic chemotherapy infusion will be designated as Tzero (0 
hour) for the cycle. In Cycle 1, this date and time will be recorded by the site staff on the 
front page of the Patient Diary.
The dose, start and stop date/time for all chemotherapy agents will be recorded.
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood to be drawn over the course of the trial, including 
approximate blood volumes drawn by visit and by sample type per subject can be found in 
Section 12.6 – Approximate Blood Volumes Drawn by Trial Visit and by Sample Types.
7.1.3.1
Local Laboratory Safety Evaluations (Hematology, Chemistry)
Laboratory tests for hematology and chemistry are specified in Table 5.


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Table 5 Laboratory Tests
Hematology
Chemistry (serum/plasma)
Other
Hematocrit
Albumin
Urine Pregnancy Test -
females of childbearing 
potential 
Hemoglobin
Alkaline phosphatase
Serum Pregnancy Test, 
if per local standard of 
care or if indicated
Platelet count
Alanine aminotransferase 
(ALT)
White Blood 
Cell (WBC) 
total and 
differential
Aspartate aminotransferase 
(AST)
Bicarbonate
Calcium, Total 
Calcium, Ionized* (whole 
blood, plasma or serum)
Chloride
Creatinine
Glucose
Magnesium
Potassium
Sodium
Total Bilirubin  
Urea/Blood Urea Nitrogen
* At selected sites, blood samples for ionized calcium will be drawn in Cycle 1 only at the 
screening visit and at the randomization visit ~ 15 minutes after completion of 
fosaprepitant/placebo infusion, prior to the start of chemotherapy.  Ionized calcium will not be 
drawn at any other time points. 
Laboratory safety evaluations and Urine Pregnancy Test will be performed by the local 
laboratory according to local procedures and results will be documented on the subject’s 
chart.  Pre-dose testing that are conducted more than 7 days prior to dosing will be repeated 
and reviewed prior to fosaprepitant dosing in a cycle.
If a female subject reaches menarche (menstruates for the first time), a urine pregnancy test 
must be performed.  Results must be obtained prior to study drug administration. Urine 
pregnancy testing should be repeated at subsequent visits if the subject reports non-
compliance to birth control methods, if there is a question about potential pregnancy or as 


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required by local guidelines.  Note: a serum pregnancy test can be performed instead of the 
urine test per local regulatory requirements or standard of care.
7.1.3.2
Pharmacokinetic (PK) Evaluations (Cycle 2 Only)
PK samples for aprepitant will be collected from all subjects participating in optional Cycle 2
at two time points: Day 1, end of fosaprepitant infusion and approximately 2 to 4 hours after 
(completion) of fosaprepitant infusion.  
If the subject is still at the site or is returning to the site on Cycle 2 Day 2 or 3 (e.g., to 
receive additional chemotherapy), PK sample(s) will be collected at up to two additional time 
points:  Cycle 2, Day 2 (ideally ~23 to 25 hours after fosaprepitant infusion on Cycle 2, Day 
1); and Cycle 2, Day 3 (ideally ~46 to 50 hours after fosaprepitant infusion on Cycle 2, Day 
1).  Subjects who will not be at the site on Cycle 2, Days 2 and 3 do not need to return for PK 
sampling.
Subjects who have a multi-lumen central venous catheter will have one line designated 
strictly for the infusion of fosaprepitant and another line designated for the collection of PK.  
To avoid the potential of cross contamination, a subject that has fosaprepitant administered 
through a single lumen central venous catheter cannot have PK samples drawn from that 
same line on the day of fosaprepitant administration.  To obtain PK samples on the day of 
fosaprepitant administration, a peripheral line should be inserted to perform blood draws at 
the specified time points.  A single lumen catheter can be used to draw PK samples on Cycle 
2, Day 2 and Cycle 2, Day 3.  Venipuncture may be performed when clinically indicated.
Sample collection, storage and shipment instructions for the PK samples will be provided in 
the operations/laboratory manual.
7.1.3.3
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Buccal swab for future biomedical research.
Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment prior to completion of the treatment
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the Follow-Up/Discontinuation visit for the applicable cycle should be 
performed at the time of discontinuation.  Any adverse events which are present at the time 
of discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 7.2 - Assessing and Recording Adverse Events.  Subjects who 
discontinue will be instructed to come in for a Discontinuation Visit within 72 hours and 


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complete all discontinuation procedures.  See the required procedures for the Follow-
Up/Discontinuation Visit in Section 6.0 - Trial Flow Chart.  If the subject discontinues from 
Cycle 1 prior to the Post Treatment Visit, the subject/parent/caregiver will be asked if the 
subject experienced any episodes of vomiting/dry heaves since the previous visit/phone 
contact and if medication was taken to treat established nausea and/or vomiting. The 
subject/parent/caregiver will be asked to update the diary with the information, if not already 
recorded.  In addition, the site staff will review the Patient Diary in detail with the 
subject/parent/caregiver as detailed in Section 7.1.1.14 – Patient Diary Review/Collection
(with Subject/Parent/Caregiver).
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subject/parent/legal guardian may withdraw consent and/or assent (if applicable) for Future 
Biomedical Research and have their specimens and all derivatives destroyed.   
Subject/parent/legal guardian may withdraw consent and/or assent (if applicable) at any time 
by contacting the principal investigator for the main trial.  If medical records for the main 
trial are still available, the investigator will contact the Sponsor using the designated mailbox 
 and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
When the investigator or sub-investigator needs to identify the drug used by a subject and the 
dosage administered in case of emergency e.g., the occurrence of serious adverse 
experiences, he/she will contact the emergency unblinding call center by telephone and make 
a request for emergency unblinding.  As requested by the investigator or sub-investigator the 
emergency unblinding call center will provide the information to him/her promptly and 
report unblinding to the sponsor.  The emergency unblinding call center will make a record 
promptly however, the investigator or sub-investigator must enter the toxicity grade of the 
adverse experiences observed,   their relation to study drug, the reason thereof, etc., in the 
medical chart etc., before unblinding is performed.  
Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition.  In the event that the emergency unblinding call 
PPD


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center is not available for a given site in this trial, IVRS/IWRS should be used for emergency 
unblinding in the event that this is required for subject safety.
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible.  Only the principal investigator or delegate and the respective subject’s 
code should be unblinded.  Trial site personnel and Sponsor personnel directly associated 
with the conduct of the trial should not be unblinded.
7.1.4.3
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:

Laboratory/ECG equipment – as required for inclusion labs and trial assessments
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1
Cycle 1
7.1.5.1.1 Screening (Visit 1)
Up to 28 days prior to randomization, a potential subject will be evaluated to determine that 
he/she fulfills the entry requirements as set forth in Section 5.1, Entry Criteria.  The 
Screening Visit can occur the same day as the Randomization Visit (Day 1), as long as all 
required trial procedures for both visits are completed/reviewed prior to study drug 
administration and subject eligibility is confirmed.
Written consent and assent (if applicable) must be obtained prior to performing any protocol-
specific procedure.  Results of a test performed prior to the subject/parent/guardian signing 
consent/assent that are part of routine clinical management are acceptable in lieu of a 
screening test if performed within the specified time frame and the consent form indicates 
that such test results may be used.  
Screening procedures are to be completed within 28 days prior to the first dose of trial 
treatment except for the following:


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
Laboratory Safety (including ionized calcium at selected sites), Urine Pregnancy and 
ECG testing must be completed within 7 days prior to initiation of study medication.
A subject may be rescreened after initially failing to meet the inclusion/exclusion criteria.  
Results from assessments performed during the initial screening period are acceptable in lieu 
of repeating a screening test if performed within the specified time frame and the results meet 
the inclusion/exclusion criteria.
If a subject/parent/legal guardian has signed an informed consent/assent but the subject is not 
randomized into the study, the investigator will collect information at the Screening visit, 
including: basic demographics, inclusion/exclusion criteria, subject disposition, laboratory
data and adverse event information, as applicable.  Unless otherwise directed, no other data 
need to be collected for these subjects.
7.1.5.1.2 Randomization (Visit 2)
The subject will be required to return to the study site approximately 2.5 hours prior to 
initiation of emetogenic chemotherapy in order to allow adequate time to perform all study 
required procedures.
The subject/parent/caregiver will be asked by the site staff: “Did you (or your child) have any 
episodes of vomiting or dry heaves in the last 24 hours?”  Any subject who has vomited 
within the 24 hours prior to the scheduled start of emetogenic chemotherapy will not be 
permitted to participate in the study on that day.  The subject may be re-evaluated for study 
participation on a subsequent day if initiation of emetogenic chemotherapy is also delayed. 
If chemotherapy is not delayed, subject may be re-evaluated at a subsequent cycle.
The subject/parent/caregiver will be asked if the subject has had any changes in their health 
or taken any medications since the previous visit and the information will be recorded.  The 
subject must continue to fulfill the inclusion and exclusion criteria in order to be randomized.
Preliminary screening laboratory test results will be reviewed.  If the subject’s screening 
laboratory tests and ECG were obtained within the preceding 7 days, they will only need to 
be repeated if the subject’s clinical status has changed.  If the screening laboratory tests and 
ECG were completed >7 days prior to Day 1, then they will be repeated.
Prior to the initiation of the first emetogenic chemotherapy, the subject/parent/caregiver will 
be given a Patient Diary and will be educated on the appropriate completion of the diary.
At selected sites, a blood sample for ionized calcium will be collected ~15 minutes after 
completion of fosaprepitant/placebo infusion, prior to the start of chemotherapy.  
7.1.5.1.3 Telephone/Direct Contact Visits 
The site staff will contact the subject/parent/caregiver daily on Days 2 to 5 and on Day 6, if 
the subject’s post-treatment visit is not scheduled for that day, to ensure the diary is being 
completed.  Telephone or direct contact will be made based on subject location.  See Section 


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7.1.1.13, Telephone or Direct Contact (scripted questions) for details on questions to ask 
during each contact. 
Note:  Site staff must make every effort to make contact with the subject/parent/caregiver on 
all diary days (including weekends) in order to ensure compliance with diary completion.  
All attempted and completed telephone contacts will be documented by the trial site.
The subject/parent/caregiver will be reminded to bring the Patient Diary to the next visit.
7.1.5.1.4 Post-Treatment (Visit 3)
The subject will be required to return to the study site with the Patient Diary once during 
study Day 6 to 9 after the diary reporting period has been completed.  The diary will be 
reviewed with the subject as defined in Section 7.1.1.14 - Patient Diary Review/Collection
(with Subject/Parent/Caregiver).
7.1.5.1.5 Follow-Up/Discontinuation (Visit 4)
The subject will be required to return to the study site once during study Day 15 to 20 (14 to 
19 days following Treatment Day 1).  For subjects who elect to participate in Optional Cycle 
2, this visit can be scheduled to coincide with the start of the next chemotherapy cycle 
provided that the next round of chemotherapy is 14 to 19 days after Treatment Day 1.  
If there has been an interval hospitalization, only the discharge medications will be recorded. 
If a subject does not elect to participate in the Optional Cycles 2 to 6, a discontinuation visit 
will be registered in IVRS/IWRS and reasonable effort should be made to collect the subject 
identification card.
7.1.5.2
Optional Cycles 2 to 6
A subject who completes Cycle 1 may be invited to participate in optional Cycles 2 to 6.  A 
subject may participate in a total of 5 optional cycles.  Each subject will be allowed a 
maximum of 6 months from the end of Cycle 1 to complete the optional cycles.  
A minimum of 14 days is required between Day 1 in a cycle and Day 1 in a subsequent cycle.
7.1.5.2.1 Treatment Visit
Parent/legal guardian of subjects < 18 years old or subjects 18 years of age participating in 
the optional cycles must provide documented consent prior to the start of Cycle 2.  Written 
assent from subjects 12 to 17 years of age, or as required per local institutional guidelines, 
will also be collected.  
After all required study procedures have been completed and subject’s eligibility has been 
confirmed, the treatment visit will be registered in IVRS/IWRS for study drug component ID 
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The subject will receive open-label fosaprepitant.  Any commercially available 5-HT3
antagonist may be used as part of the antiemetic regimen with or without dexamethasone.  
Subjects may be provided with a prescription for rescue medication according to investigator 
preference.
In Cycle 2 only, PK samples for aprepitant will be collected as described in Section 7.1.3.2 -
Pharmacokinetic (PK) Evaluations.
7.1.5.2.2 Follow-Up/Discontinuation Visit
The subject will be required to return to the study site once during study Day 15 to 20 (14 to 
19 days following Treatment Day 1) of an optional cycle.  For subjects who elect to 
participate in the next optional cycle, this visit can be scheduled to coincide with the start of 
the next chemotherapy cycle provided that the next round of chemotherapy is 14 to 19 days 
after Treatment Day 1 of the current cycle.  
If there has been an interval hospitalization, only the discharge medications will be recorded. 
If a subject does not elect to participate in any additional optional cycles, a discontinuation 
visit will be registered in IVRS/IWRS. A subject who has completed the 5 optional cycles 
will have completed the study.  Reasonable effort should be made to collect the subject 
identification card when a subject discontinues from or completes the trial.  
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.


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All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
In Cycle 1, from the time of treatment allocation/randomization through 14 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
Events related to vomiting and dry heaves/retching are not defined as adverse events during 
the diary reporting period (120 hours following chemotherapy infusion) unless they meet the 
definition of a serious adverse event as described in Section 7.2.3.1 – Serious Adverse 
Events.  Beyond this period, vomiting and dry heaves/retching will be considered as adverse 
events. 
In Cycles 2 to 6, all serious adverse event(s), non-serious drug-related adverse event(s), and 
adverse event(s) leading to discontinuation from the study will be recorded.  This includes 
the time period from the completion of Cycle 1 through 14 days following treatment in the 
last optional cycle and at each examination.
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
In this trial, an overdose is defined as a single dose of study medication that exceeds the 
prescribed dose for each age range.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).


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Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 14 days following cessation of Sponsor’s product must be 
reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event. 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 6 for additional details regarding each of the above criteria.


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For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause, whether or not related to the Sponsor's product, must 
be reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI)  and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 


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upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent).
Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 6 and according to the NCI Common Terminology for 
Adverse Events (CTCAE), version 4.0. Any adverse event which changes CTCAE grade 
over the course of a given episode will have each change of grade recorded on the adverse 
event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the investigator’s opinion, there is sufficient data to support 
full attribution of the adverse experience to the single agent.
The NCI Common Terminology for Adverse Events (CTCAE), version 4.0 will be used to 
grade all adverse events.  The criteria will be provided in the Investigator Trial File Binder 
(or equivalent) and can be accessed electronically on the following website: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.


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Table 6 Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor's 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the Sponsor’s product?
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors


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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this 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 trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)


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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
8.0 STATISTICAL ANALYSIS PLAN
Statistical Analysis Plan Summary
8.1
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 8.2).
Efficacy Analyses
8.1.1
The primary and secondary endpoints, primary analysis population, and statistical methods 
that will be employed for the efficacy analyses are presented in Table 7 below. 
The primary hypothesis will be evaluated by comparing the fosaprepitant regimen to the 
control regimen with respect to the proportion of subjects reporting Complete Response in 
the delayed phase (>24 to 120 hours) following initiation of emetogenic chemotherapy in 
Cycle 1. 
The three secondary hypotheses will be evaluated by comparing the fosaprepitant regimen to 
the control regimen with respect to the proportion of subjects reporting Complete Response 
in the acute phase (0 to 24 hours), in the overall phase (0 to 120 hours) and No Vomiting in 
the overall phase (0 to 120 hours).
The multiplicity strategy described in Section 8.2.6 will be used to control Type I error rate 
when testing the primary and 3 secondary hypotheses.


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Table 7 Summary of Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Objective
Proportion of subjects with 
complete response from >24 to 120 
hours following initiation of 
emetogenic chemotherapy
P
CMH exact test ‡
ITT
Missing is treated 
as failure
Secondary Objectives
Proportion of subjects with 
complete response from 0 to 24 
hours following initiation of 
emetogenic chemotherapy
P
CMH exact test 
ITT
Missing is treated 
as failure
Proportion of subjects with 
complete response from 0 to 120 
hours following initiation of 
emetogenic chemotherapy
P
CMH exact test 
ITT
Missing is treated 
as failure
Proportion of subjects with no 
vomiting from 0 to 120 hours 
following initiation of emetogenic 
chemotherapy
P
CMH exact test 
ITT
Missing is treated 
as failure
†    P=Primary approach.
‡    Stratified by age (<2 years, 2 to 17 years), receipt of High Risk emetogenic chemotherapy agent in Cycle 1 (yes, 
no) and use of dexamethasone as an antiemetic in Cycle 1 (yes, no); CMH = .Cochran-Mantel-Haenszel
Safety Analysis
8.1.2
The All-Subjects-as-Treated (ASaT) population will be employed for safety analyses.  
For this study, there are no pre-specified events of interest, i.e., no Tier-1 events.
Power and Sample Size
8.1.3
The study intends to enroll approximately 180 subjects with 1:1 randomization to the 
fosaprepitant regimen and the control regimen, to achieve 80% power (1-sided, α=0.025) to 
demonstrate the primary hypothesis that the fosaprepitant regimen is superior to the control 
regimen as measured by the proportion of subjects with Complete Response from >24 to 120 
hours following initiation of emetogenic chemotherapy. This is based on the assumption of 
an underlying treatment difference of 20% across all age groups.
We assume that the 
response rate for the control regimen will be approximately 25% (similar to the observed 
response rate for Complete Response Delayed in the oral study Protocol 208) and the 
response rate for the fosaprepitant regimen is 45%.
If PK/PD data from the ongoing Protocol 029 do not support opening enrollment for one or 
more age group(s), the sample size and underlying treatment difference assumption may be 
adjusted, but the overall power of the study will be maintained.  


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Statistical Analysis Plan
8.2
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, but prior to any unblinding, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E-9).  Changes to exploratory or 
other non-confirmatory analyses made after the protocol has been finalized, along with an 
explanation as to when and why they occurred, will be listed in the Clinical Study Report 
(CSR) for the study.  Post hoc exploratory analyses will be clearly identified in the CSR.  No 
separate Statistical Analysis Plan (SAP) will be issued for this study.
Responsibility for Analyses/In-House Blinding
8.2.1
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
Cycle 1 of this study will be conducted as a double-blind study under in-house blinding 
procedures.  Additional chemotherapy cycles will be conducted as a fosaprepitant open-label 
study.  The official, final database for Cycle 1 will not be unblinded until medical/scientific 
review has been performed, protocol violators have been identified, and data have been 
declared final and complete.  Results from additional cycles of chemotherapy will be 
presented along with those of Cycle 1 in the CSR.
The Clinical Biostatistics department will generate the randomization schedule(s) for study 
treatment assignment.  Randomization will be implemented using an interactive voice 
response system / integrated web response system (IVRS/IWRS).
Hypotheses
8.2.2
Objectives and hypotheses of the study are stated in Section 3.0. The null hypothesis is that 
the fosaprepitant regimen is not superior to the control regimen.
Analysis Endpoints
8.2.3
Efficacy and safety endpoints that will be evaluated for between-treatment differences are
listed below, followed by the descriptions of the derivations of selected endpoints. Efficacy 
data will not be collected during Cycles 2 to 6.  PK data will be evaluated in Cycle 2 only 
and safety data will be evaluated in all cycles.
8.2.3.1
Efficacy Endpoints
The primary efficacy endpoint will be the proportion of subjects with Complete Response in 
the >24 to 120 hours following initiation of emetogenic chemotherapy.
The secondary efficacy endpoints will be: the proportion of subjects with Complete Response 
in the 0 to 24 hours following initiation of emetogenic chemotherapy; the proportion of 
subjects with Complete Response in the 0 to 120 hours following initiation of emetogenic 


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chemotherapy; and the proportion of subjects with No Vomiting, irrespective of use of rescue 
medication, in the 120 hours following initiation of emetogenic chemotherapy.
In addition to the above mentioned efficacy endpoints, the exploratory endpoints of the 
number of emetic episodes, the number of subjects with no use of rescue medication, the 
time to first rescue medication, and the time to first vomiting in the 120 hours following 
initiation of emetogenic chemotherapy, and the Complete Response using an alternative 
definition of “acute” and “delayed” phases will be assessed and presented.
8.2.3.2
Safety Endpoints
There are no pre-specified events of interest for this study (i.e. no Tier 1 events).
Safety endpoints that will be assessed include clinical and laboratory adverse events that are 
considered drug-related, serious, serious drug-related, or lead to discontinuation from the
study.
8.2.3.3
Pharmacokinetic Endpoints
The sparse PK samples may be used to calculate the PK endpoints for aprepitant (e.g. AUC0-
∞, AUC0-24, Cmax, Tmax, t1/2, CL/F, C24hr, and C48hr).
Analysis Populations
8.2.4
8.2.4.1
Efficacy Analysis Populations
The Intent-to-Treat (ITT) population which consists of all subjects (in the group they were) 
randomized and who received any study drug will serve as the primary population for the 
analysis of efficacy data in this study. A supportive analysis will be performed for the 
primary efficacy endpoint using the Full Analysis Set (FAS) population. 
The FAS 
population is a subset of all randomized subjects including all subjects who have received 
chemotherapy, received a dose of study drug and have at least one post-treatment efficacy 
assessment. Subjects excluded from the FAS will be considered as having an unfavorable 
response in the ITT analysis.
An additional supportive analysis using the Per-Protocol (PP) population will be performed 
for the primary efficacy endpoint.  The Per-Protocol population excludes subjects due to 
important deviations from the protocol that may substantially affect the result of the primary 
efficacy endpoint. The final determination on protocol violations/deviations, and thereby the 
composition of the Per-Protocol population, will be made prior to the final unblinding of the 
database and will be documented in a separate memo and/or listing.  
Details on the approach to handling missing data are provided in Section 8.2.5 Statistical 
Methods.


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8.2.4.2
Safety Analysis Populations
The All subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  The ASaT population consists of all randomized subjects who received at least 
one dose of any study drug. Subjects will be included in the treatment group corresponding 
to the study drug they actually received for the analysis of safety data using the ASaT 
population.  For most subjects this will be the treatment group to which they are randomized.  
Subjects who take incorrect study drug for the entire treatment period will be included in the 
treatment group corresponding to the study drug actually received. 
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study drug is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section 
8.2.5 Statistical Methods.
8.2.4.3
Pharmacokinetic Analysis Populations
The Per-Protocol population for PK will be those who participate in optional Cycle 2.  The 
Per-Protocol population for PK excludes subjects or specific PK samples from a subject due 
to important deviations from the protocol that may substantially affect the results of the PK 
endpoint.  
Statistical Methods
8.2.5
Statistical testing and inference for safety analyses are described in Section 8.2.5.2, Statistical 
Methods for Safety Analyses. Efficacy results that will be considered to be statistically 
significant after consideration of the strategy for controlling the Type I error are described in 
Section 8.2.6 Multiplicity. Nominal p-values may be computed for other efficacy analyses as 
a measure of strength of association between the endpoint and the treatment effect rather than 
formal tests of hypotheses.
8.2.5.1
Statistical Methods for Efficacy Analyses
The primary efficacy analysis will compare the fosaprepitant regimen to the control regimen
with respect to the proportion of subjects reporting Complete Response in the delayed phase 
(>24 to 120 hours) following initiation of emetogenic chemotherapy.
The secondary efficacy analyses will compare the fosaprepitant regimen to the control 
regimen with respect to the proportion of subjects reporting Complete Response (acute and 
overall) and the proportion of subjects reporting No Vomiting overall.
The treatment comparisons for Complete Response and No Vomiting will be made using the 
CMH Exact test with 3 strata defined as age (<2 years, 2 to 17 years), receipt of High Risk 
emetogenic chemotherapy agent in Cycle 1 (yes, no), and use of dexamethasone as an 


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antiemetic in Cycle 1 (yes, no). The superiority hypotheses will be evaluated by comparing 
the 1-tailed p-value to 0.025 and significance declared if this p-value is ≤0.025.  
A supportive analysis will be made using a logistic regression model that includes terms for 
treatment (fosaprepitant regimen, control regimen), age (<2 years, 2 to 17 years), receipt of a 
High Risk emetogenic chemotherapy agent in Cycle 1 (yes, no) and use of dexamethasone as 
an antiemetic in Cycle 1 (yes, no). 
The age category (<2 years, 2 to 17 years) in the analysis models may be adjusted if PK/PD 
data from the ongoing Protocol 029 do not support opening enrollment for one or more age 
group(s).
Any vomiting or use of rescue therapy within a phase will define a subject as having an 
unfavorable response for that phase for all 3 efficacy subject populations (ITT, FAS and PP).  
Subjects with missing binary data for the primary and secondary endpoints will be classified 
as non-responder/failure in both the ITT and FAS efficacy analyses.  In the PP population, 
any missing data will exclude the subject from the analysis within a phase.
For the exploratory analysis of time to first use of rescue medication, Kaplan-Meier curves 
depicting the percentage of subjects who did not use rescue medication, since the initiation of 
emetogenic chemotherapy, will be presented.  For the time to first vomiting analysis, Kaplan-
Meier curves depicting the percentage of subjects who are vomiting-free, ignoring rescue, 
since the initiation of emetogenic chemotherapy will also be presented. The Log-Rank test 
will be used for the treatment comparison. Descriptive summary will be made for number of 
episodes and number of subjects with no use of rescue medication in the overall phase.
Number and proportion of subjects with Complete Response using alternative definition of 
“acute” and “delayed” phase will be summarized. The alternative acute phase will be defined 
as the period from initiation of the first dose of emetogenic chemotherapy until 24 hours 
post-initiation of the last dose of emetogenic chemotherapy. The alternative delayed phase 
will be defined as the period from the end of the acute phase to 120 hours post-initiation of 
the first dose of emetogenic chemotherapy on day 1. Because of the expected variability in 
the number of days of emetogenic chemotherapy among subjects, the length of the alternative 
acute and delayed phases is also expected to vary. Therefore, to minimize this variability 
during the analyses, these alternative phases may also be evaluated using subgroups based on 
days of emetogenic chemotherapy.
Table 8 summarizes the key efficacy analyses.


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Table 8 Summary of Analysis Strategy for Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Objectives
Proportion of subjects with 
complete response from >24 to 120 
hours following initiation of 
emetogenic chemotherapy
P
CMH exact test ‡
ITT
Missing is treated 
as failure
Proportion of subjects with 
complete response from >24 to 120 
hours following initiation of 
emetogenic chemotherapy
S
CMH exact test 
FAS
Missing is treated 
as failure
Proportion of subjects with 
complete response from >24 to 120 
hours following initiation of 
emetogenic chemotherapy
S
CMH exact test 
PP
Excluded in the 
analysis
Proportion of subjects with 
complete response from >24 to 120 
hours following initiation of 
emetogenic chemotherapy
S
Logistic Regression 
Model
ITT
Missing is treated 
as failure
Secondary Objectives
Proportion of subjects with 
complete response from 0 to 24 
hours following initiation of 
emetogenic chemotherapy
P
CMH exact test 
ITT
Missing is treated 
as failure
Proportion of subjects with 
complete response from 0 to 24 
hours following initiation of 
emetogenic chemotherapy
S
Logistic Regression 
Model
ITT
Missing is treated 
as failure
Proportion of subjects with 
complete response from 0 to 120 
hours following initiation of 
emetogenic chemotherapy
P
CMH exact test 
ITT
Missing is treated 
as failure
Proportion of subjects with 
complete response from 0 to 120 
hours following initiation of 
emetogenic chemotherapy
S
Logistic Regression 
Model
ITT
Missing is treated 
as failure
Proportion of subjects with no 
vomiting from 0 to 120 hours 
following initiation of emetogenic 
chemotherapy
P
CMH exact test 
ITT
Missing is treated 
as failure
Proportion of subjects with no 
vomiting from 0 to 120 hours 
following initiation of emetogenic 
chemotherapy
S
Logistic Regression 
Model
ITT
Missing is treated 
as failure


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Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
Exploratory Objective
Time to first use of rescue  
medication
P
Kaplan-Meier curve and 
Log-Rank test
ITT
None
Time to first vomiting  in 120 
hours
P
Kaplan-Meier curve and 
Log-Rank test
ITT
None
Number of emetic episodes in 120 
hours
P
Descriptive Summary
ITT
Observed data
Number of subjects with no use of 
rescue medication in 120 hours
P
Descriptive Summary
ITT
Missing is treated 
as failure
Proportion of subjects with 
complete response using the 
alternative definition of “acute” 
and “delayed” phase.
S
Descriptive Summary
ITT
Missing is treated 
as failure
† P=Primary approach; S=Secondary approach.
‡ Stratified by age (<2 years, 2 to 17 years), receipt of High Risk emetogenic chemotherapy agent in Cycle 1 (yes, 
no) and use of dexamethasone as an antiemetic in Cycle 1 (yes, no); CMH = Cochran-Mantel-Haenszel
The strategy to address multiplicity issues with regard to multiple treatment comparisons, 
multiple efficacy endpoints, and/or multiple time points is described in Section 8.2.6, 
Multiplicity.
8.2.5.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events (AEs), laboratory tests, vital signs, and ECG measurements.
Cycle 1
The analysis of safety results will follow a tiered approach (Table 9). The tiers differ with 
respect to the analyses that will be performed.  Safety parameters or adverse experiences of 
special interest that are identified a priori constitute “Tier 1” safety endpoints that will be 
subject to inferential testing for statistical significance with p-values and 95% confidence 
intervals provided for between-group comparisons. This protocol does not have a Tier 1 
analysis. Other safety parameters will be considered Tier 2 or Tier 3.  Tier 2 parameters will 
be assessed via point estimates with 95% confidence intervals provided for between-group 
comparisons; only point estimates by treatment group are provided for Tier 3 safety 
parameters.
Adverse events (specific terms as well as system organ class terms) that are not pre-specified 
as Tier-1 endpoints will be classified as belonging to "Tier 2" or "Tier 3", based on the 
number of events observed.  Membership in Tier 2 requires that at least 4 subjects in any 
treatment group exhibit the event; all other adverse events and predefined limits of change 
will belong to Tier 3.


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The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences.  Because many 95% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in adverse events and 
predefined limits of change.
Continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters that are not pre-specified as Tier-1 endpoints will be considered Tier 3 safety 
parameters.  Summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format.  In addition, summary statistics for the 
difference between treatment groups will also be provided, along with nominal p-values for 
between-group differences.  
For this protocol, there are no prespecified events of interest (i.e. no Tier 1 events).  The 
broad clinical and laboratory AE categories consisting of the percentage of subjects with any 
AE, a drug related AE, a serious AE, an AE which is both drug-related and serious, and who 
discontinued due to an AE will be considered Tier 2 endpoints.  Ninety-five percent (95%) 
confidence intervals (Tier 2) will be provided for between-treatment differences in the 
percentage of subjects with events; these analyses will be performed using the Miettinen and 
Nurminen method [22], an unconditional, asymptotic method.
Table 9 Analysis Strategy for Key Safety Parameters
Safety Tier
Safety Endpoint†
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
None
--
--
--
Tier 2
Any AE
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Discontinuation due to AE
X
X
Discontinuation due to a Drug-Related AE
Specific AEs, SOCs‡ (incidence ≥4 in one of 
the treatment groups)
X
X
X
X
Tier 3
Specific AEs, SOCs‡ (incidence <4 of subjects 
in all of the treatment groups)
X
Change from Baseline Results (Labs, ECGs, 
Vital Signs) 
X
† Adverse Experience references refer to both Clinical and Laboratory AEs.
‡ Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier-2 endpoints.
NOTE: SOC= System Organ Class; X = results will be provided.


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Optional Cycles 2 to 6
For cycles 2 to 6, proportions will be displayed for serious adverse event(s), drug-related 
adverse event(s), and adverse event(s) leading to discontinuation from the study, which occur 
during the fosaprepitant treatment period plus 14 days post therapy. 
8.2.5.3
Statistical Methods for Pharmacokinetics
Population pharmacokinetic methods will be used to analyze the sparse plasma concentration 
results. Data from previous available CINV (MK-0869 Protocols 097 and 134; MK-0517-
029) and PONV (MK-0869 Protocol 148) pharmacokinetic studies conducted in pediatric 
subjects from birth to 17 years old will be evaluated for inclusion in the population modeling 
to further characterize the pharmacokinetic profile in pediatric subjects and support modeling 
the sparse data. 
Briefly, NONMEM software will be used to develop a population 
pharmacokinetic model that describes the plasma concentration-time data, with appropriate 
covariates such as body size and age included in the modeling. Model development will be 
guided by selection of models with parsimonious structure. This population model will be 
used to estimate the pharmacokinetic parameters of aprepitant (e.g., AUC0-∞, AUC0-24, 
Cmax, Tmax, t1/2, CL/F, C24hr, and C48hr) for pediatric subjects following administration of 
fosaprepitant.
8.2.5.4
Summaries of Baseline Characteristics, Demographics, and Other Analyses
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs.  No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of subjects screened, randomized, the primary 
reasons for screening failure, and the primary reasons for discontinuation will be displayed.  
Demographic variables (e.g., age) baseline characteristics, primary diagnosis, and prior and 
concomitant therapies will be summarized by treatment either by descriptive statistics or 
categorical tables.
Multiplicity
8.2.6
The following multiplicity strategy will be used to control Type I error in testing the primary 
and 3 secondary hypotheses. 
First, the primary hypothesis will be tested at alpha = 0.025, 1-tailed. If the testing on the 
primary hypothesis is significant, then Hochberg method will be used to test all 3 secondary 
hypotheses at total alpha = 0.025, 1-tailed.
To be more specific, for the three secondary null hypotheses, the following procedures will 
be taken if the primary hypothesis is significant:
1. The maximum of the three p-values (one-sided) is compared with 0.025.  If it is less than 
0.025 (1-sided), then all three null hypotheses are rejected and claim the statistical 
significance for all three endpoints.


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2. If the maximum of the three p-values is greater than 0.025, the null hypothesis associated 
with that p-value cannot be rejected (i.e. statistical significance cannot be claim for the 
corresponding endpoint). The next largest p-value will then be compared with alpha level 
of 0.025/2.  If it is less than 0.025/2, the remaining two null hypotheses are rejected. 
3. If the next largest p-value is greater than 0.025/2, the null hypothesis associated with this 
p-value cannot be rejected either. The smallest of the three p-values is then compared 
with alpha level of 0.025/3.  If it is less than 0.025/3, the null hypothesis associated with 
this p-value is rejected. If it is greater than 0.025/3, the null hypothesis associated with 
this p-value cannot be rejected. In this case, all three null hypotheses cannot be rejected.
Sample Size and Power Calculations
8.2.7
This study will randomize approximately 180 subjects with approximately 90 subjects into 
the fosaprepitant regimen group and 90 subjects into the control regimen group and has 80% 
power to demonstrate the superiority of the fosaprepitant regimen over the control regimen at 
an overall one-sided, 2.5% alpha-level, if the underlying treatment difference in Complete 
Response is 20%.  The power and sample size are based on the assumption of an underlying 
response rate of 25% for the control regimen (similar to the observed response rate for 
Complete Response Delayed in the oral aprepitant study Protocol 208) and of 45% for the 
fosaprepitant regimen.  The Complete Response calculation is based on an asymptotic 
method proposed by Farrington and Manning [23] with 90 subjects in the active control arm 
and 90 subjects in the fosaprepitant regimen arm expected to be included in the analysis and 
is carried out using SAS v9.1. The minimum criterion for success is that the one-sided p-
value < 0.025.
Subgroup Analyses and Effect of Baseline Factors
8.2.8
To explore whether the treatment effect is consistent across various subgroups, the estimate 
of the between-group treatment effect (with a nominal 95% CI) for the primary endpoint will 
be estimated within each category of the following classification variables:

Age category (birth to <2 years, 2 to <6 years, 6 to <12 years, and 12 to17 years).  
The category may be adjusted if PK/PD data from the ongoing Protocol 029 do not 
support opening enrollment for one or more age group(s).

Sex (Female, Male)

Race (American Indian or Alaska Native, Asian, Black or African American, 
Multiple, Native Hawaiian or Other Pacific Island and White)

Receipt of a High Risk emetogenic chemotherapy agent in Cycle 1 (Yes, No)

Use of Dexamethasone as an antiemetic in Cycle 1 (Yes, No)

Single versus multiple day chemotherapy


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In addition, a summary of count and percentage of all adverse events will be provided for 
each age category listed above.
Interim Analysis
8.2.9
No interim analyses are planned for this study.
Compliance (Medication Adherence)
8.2.10
Study medication will be administered in a supervised clinical setting and missed or incorrect 
dosing will be uncommon. Subjects who miss a dose or take an incorrect dose will be 
described in the CSR as to why the dose was missed or incorrect.
Extent of Exposure
8.2.11
The extent of exposure (dose and duration) to fosaprepitant will be summarized by the 
number of subjects exposed to fosaprepitant for defined periods of time.
In addition, the 
extent of exposure to ondansetron and dexamethasone will be summarized.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
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 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 10
Table 10 Product Descriptions
Product Name & Potency
Dosage Form
Fosaprepitant dimeglumine 150 mg
Lyophilized powder for injection
Ondansetron hydrochloride 2 mg/ml*
Solution for injection
*If ondansetron 2mg/ml supplies are not available, other formulations may be 
provided.  
All other supplies not indicated in Table 10 above will be provided centrally by the Sponsor 
or locally by the trial site, subsidiary or designee, depending on local country operational or 
regulatory requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 


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The trial site will be responsible for recording the lot number, manufacturer and expiry date 
of any locally purchased product.
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
For Cycle 1, the study site will receive open-label vials of fosaprepitant dimeglumine 150 
mg.  Ondansetron hydrochloride 2 mg/ml ampoules or vials will be received as open-label 
single units.  The study site will supply its own source of normal saline (0.9% sodium 
chloride) to prepare the study drug and to be utilized as needed for blinding purposes to 
match fosaprepitant dimeglumine.  
For the optional Cycles 2 to 6, open-label fosaprepitant dimeglumine will be packaged and 
supplied identical to Cycle 1. The 5-HT3 antagonist will be sourced by the study site.
Clinical Supplies Disclosure
9.3
The emergency unblinding call center will use the randomization schedule for the trial to 
unblind subjects and to unmask treatment identity. In the event that the emergency 
unblinding call center is not available for a given site in this trial, the central electronic 
randomization system (IVRS/IWRS) should be used in order to unblind subjects and to 
unmask treatment/vaccine identity.
The Sponsor will not provide random code/disclosure 
envelopes or lists with the clinical supplies.
Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the subject.  Every effort should be made not to unblind the subject unless necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible.  Only the principal investigator or delegate and the respective subject’s 
code should be unblinded.  Trial site personnel and Sponsor personnel directly associated 
with the conduct of the trial should not be unblinded.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.


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Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed and returned and the amount remaining 
at the conclusion of the trial. For all trial 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 investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
9.6
Trial site personnel will have access to a central electronic randomization system 
(IVRS/IWRS system) to allocate subjects, to assign treatment to subjects and to manage the 
distribution of clinical supplies. Each person accessing the IVRS system must be assigned an 
individual unique PIN.  They must use only their assigned PIN to access the system, and they 
must not share their assigned PIN with anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
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/ERC) 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 trial 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 Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent/assent form, the 
subject/parent/legal guardian agrees to this process.  If trial documents will be photocopied 
during the process of verifying worksheet/case report form information, the subject 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 subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.


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Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  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.
Compliance with Financial Disclosure Requirements
10.2
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 


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Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal 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.
Compliance with Law, Audit and Debarment
10.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., 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 trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 


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correspondence with regulatory authorities and IRBs/ERCs, consent and assent forms, 
investigator’s curricula vitae, monitor visit logs, laboratory reference ranges, laboratory 
certification or quality control procedures and laboratory director curriculum vitae.  By 
signing this protocol, the investigator agrees that documentation shall be retained until at 
least 2 years after the last approval of a marketing application in an ICH region or until there 
are no pending or contemplated marketing applications in an ICH region or until at least 2 
years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  Because the clinical development and marketing application process 
is variable, it is anticipated that the retention period can be up to 15 years or longer after 
protocol database lock. The Sponsor will determine the minimum retention period and notify 
the investigator when documents may be destroyed.  The Sponsor will determine the 
minimum retention period and upon request, will provide guidance to the investigator when 
documents no longer need to be retained.  The sponsor also recognizes that documents may 
need to be retained for a longer period if required by local regulatory requirements. All trial 
documents shall be made available if required by relevant regulatory authorities. The 
investigator must consult with and obtain written approval by the Sponsor prior to destroying 
trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate


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enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
Quality Management System
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 


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OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.


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11.0 LIST OF REFERENCES
1. Tattersall FD, Rycroft W, Francis B, Pearce D, Merchant K, MacLeod AM, et al. 
Tachykinin NK1 receptor antagonists act centrally to inhibit emesis induced by the 
chemotherapeutic agent cisplatin in ferrets. Neuropharmacol 1996;35(8):1121-9.
2. Tattersall FD, Rycroft W, Hill RG, Hargreaves RJ. Enantioselective inhibition of 
apomorphine-induced emesis in the ferret by the neurokinin1 receptor antagonist CP-
99,994. Neuropharmacol 1994;33(2):259-60.
3. Andrews PLR, Bhandari P. The 5-hydroxytryptamine receptor antagonists as antiemetics: 
preclinical evaluation and mechanism of action. Eur J Cancer 1993;29A(Suppl. 1):S11-
S16.
4. Hesketh PJ, Grunberg SM, Gralla RJ, Warr DG, Roila F, de Wit R, et al. The oral 
neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea 
and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in 
patients receiving high-dose cisplatin-the aprepitant protocol 052 study group. J Clin 
Oncol 2003;21(22):4112-9.
5. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, Ma GJ, Eldridge K, Hipple A, et al. 
Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy 
improves control of chemotherapy-induced nausea and vomiting: results from a 
randomized, double-blind, placebo-controlled trial in Latin America. Cancer 
2003;97(12):3090-8.
6. Warr DG, Hesketh PJ, Gralla RJ, Muss HB, Herrstedt J, Eisenberg PD, et al. Efficacy and 
tolerability of aprepitant for the prevention of chemotherapy-induced nausea and 
vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin 
Oncol 2005;23(12):2822-30.
7. Rapoport B, Jordan K, Boice JA, Taylor A, Brown C, Hardwick JS, et al. Aprepitant for 
the prevention of chemotherapy-induced nausea and vomiting associated with a broad 
range of moderately emetogenic chemotherapies and tumor types: a randomized, double-
blind study. Support Care Cancer 2010;18(4):423-31.
8. Multinational Association of Supportive Care in Cancer (MASCC). MASCC/ESMO 
Antiemetic Guideline 2013.
9. National Comprehensive Cancer Network, Inc. NCCN Clinical practice guidelines in 
oncology: Antiemesis (Version 1.2014).
10. Basch E, Prestrud A, Hesketh P, Kris M, Feyer P, Somerfield M, et al.  Anitemetics: 
American Society of Clinical Oncology (ASCO) Clinical Practice Guideline Update 2011
11. Gruberg S, Chua D, Maru A, Dinis Jose, DeVandry S, Boice J, et al.  Single-Dose 
Fosaprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting 


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Associated With Cisplatin Therapy: Randomized, Double-Blind Study Protocol - EASE.  
J Clin Oncol 2011; 29:1495-1501
12. Roila F, Feyer P, Maranzano E, Olver I, Clark-Snow R, Warr D, et al. Antiemetics in 
children receiving chemotherapy. Support Care Cancer 2005;13:129-31.
13. Small BE, Holdsworth MT, Raisch DW, Winter SS. Survey ranking of emetogenic 
control in children receiving chemotherapy. J Pediatr Hematol Oncol 2000;22(2):125-32.
14. Holdsworth MT, Raisch DW, Frost J. Acute and delayed nausea and emesis control in 
pediatric oncology patients. Cancer 2006;106(4):931-40.
15. Yanni SB, Annaert PP, Augustijns P, Ibrahim JG, Benjamin DK Jr, Thakker DR. In vitro 
hepatic metabolism explains higher clearance of voriconazole in children versus adults: 
role of CYP2C19 and flavin-containing monooxygenase 3. Drug Metab Dispos 
2010;38(1):25-31.
16. USA 
Package 
Circular. 
Highlights 
of 
Prescribing 
Information: 
ZOFRAN®
(GlaxoSmithKline) (ondansetron hydrochloride) injection for intravenous use: 2013.
17. Nakade S, Ohno T, Kitagawa J, Hashimoto Y, Katayama M, Awata H, et al. Population 
pharmacokinetics of aprepitant and dexamethasone in the prevention of chemotherapy-
induced nausea and vomiting. Cancer Chemother Pharmacol 2008; 63:75-83.
18. Roila F, Herrstedt J, Aapro M, Gralla RJ, Einhorn LH, Ballatori E, et al. Guideline update 
for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced 
nausea and vomiting: results of the Perugia consensus conference. Ann Oncol 
2010;21(suppl 5):v232-43.
19. Culy CR, Bhana N, Plosker GL. Ondansetron: a review of its use as an antiemetic in 
children. Paediatr Drugs 2001;3(6):441-79.
20. Antonarakis ES, Evans JL, Heard GF, Noonan LM, Pizer BL, Hain RDW. Prophylaxis of 
acute chemotherapy-induced nausea and vomiting in children with cancer: What is the 
evidence? Pediatr Blood Cancer 2004;43:651-8.
21. Dupuis LL, Boodhan S, Holdsworth M, Robinson PD, Hain R, Portwine C, 
O’Shaughnessy E and Sung L. Guideline for the Prevention of Acute Nausea and 
Vomiting due to Antineoplastic Medication in Pediatric Cancer Patients. Pediatric 
Oncology Group of Ontario; Toronto. 2012.
22. Miettinen OS, Nurminen M. Comparative analysis of two rates. Stat Med 1985;4:213-26.
23. Farrington CP, Manning G. Test statistics and sample size formulae for comparative 
binomial trials with null hypothesis of non-zero risk difference or non-unity relative risk. 
Stat Med 1990;9:1447-54.


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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
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 subject 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 (e.g., 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 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects 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 subjects, 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. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent/assent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects 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.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed 
consent/assent for participation.  Subjects 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 subject 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 subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent/assent 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 subjects 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 subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent/assent 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/ERC 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 (e.g., 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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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease.  A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The buccal specimen(s) collected in the current trial will be used to study various causes 
for how subjects may respond to a drug/vaccine.  The buccal specimen(s) will be stored 
to provide a resource for future trials conducted by Merck focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease.  The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent and/or Assent (if applicable)
Informed consent/assent for specimens (i.e., DNA, RNA, protein, etc.) will be
obtained during screening for protocol enrollment from all subjects or legal 
guardians, at a trial visit by the investigator or his or her designate.  Informed 
consent/assent for Future Biomedical Research should be presented to the subjects on 
Visit 1.  If delayed, present consent/assent at next possible Subject Visit. Informed 
consent/assent must be obtained prior to collection of all Future Biomedical Research 
specimens.  Consent/assent forms signed by the subject will be kept at the clinical 
trial site under secure storage for regulatory reasons.  Information contained on the 


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consent/assent form alone cannot be traced to any specimens, test results, or medical 
information once the specimens have been rendered de-identified.
Subjects are not required to participate in the Future Biomedical Research sub-trial in 
order to participate in the main trial. Subjects who decline to sign the Future 
Biomedical Research informed consent/assent will not have the specimen collected 
nor will they be discontinued from the main trial.
A template of each trial site’s approved informed consent/assent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Buccal swab specimens for DNA isolation will be obtained at a time when the subject 
is having other trial procedures conducted. Specimens like tissue and bone marrow 
will usually be obtained at a time when the subject is having such a procedure for 
clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  


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This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in this sub-trial.  Future Biomedical Research 
specimens remaining with the third party after the specific analysis is performed will be 
returned to the sponsor or destroyed and documentation of destruction will be reported to 
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6. Withdrawal From Future Biomedical Research 
Subject/parent/legal guardian may withdraw consent and/or assent (if applicable) for 
Future Biomedical Research and have their specimens and all derivatives destroyed.   
Subject/parent/legal guardian may withdraw consent and/or assent (if applicable) at any 
time by contacting the principal investigator for the main trial.  If medical records for the 
main trial are still available, the investigator will contact Merck using the designated 
mailbox 
 and a form will be provided by 
Merck to obtain appropriate information to complete specimen withdrawal.  
Subsequently, the subject's specimens will be removed from the biorepository and be 
destroyed. A letter will be sent from Merck to the investigator confirming the destruction. 
It is the responsibility of the investigator to inform the subject of completion of 
destruction.  Any analyses in progress at the time of request for destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research trial data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  Specimens may be stored for longer if a 
regulatory or governmental authority has active questions that are being answered.  In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Merck designated biorepository.  The specimens will be stored under strict 
supervision in a limited access facility which operates to assure the integrity of the 
specimens.  Specimens will be destroyed according to Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database 
thereby maintaining a separation of subject number and these results.  The separate 
databases are accessible only to the authorized Sponsor and the designated trial 
administrator research personnel and/or collaborators.  Database user authentication is 
highly secure, and is accomplished using network security policies and practices based in 
international standards (e.g., ISO17799) to protect against unauthorized access.  The 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
PPD


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data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender,
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized.  Buccal swab 
specimens will be collected inside the cheek with no associated venipuncture to obtain 
the specimen. Therefore, there will not be an additional risk for the subject.
Merck has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure Merck database, and all 


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specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
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Pharmacogenomics Informational Brochure for IRBs/IECs & Investigational Site Staff
12.3


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Lansky and Karnofsky Performance Status Scales
12.4
Score
Lansky Play-Performance Scale 
Definitions 
(subjects ≤16)
Karnofsky Performance Scale  
     Definitions 
(subjects > 16)
100
Fully active, normal
Normal; no complaints; no evidence of disease
90
Minor restrictions in physically strenuous 
activity
Able to carry on normal activity; minor signs or 
symptoms of disease
80
Active, but tires more quickly
Normal activity with effort; some signs or symptoms 
of disease
70
Both greater restriction of, and less time 
spent in, active play
Care of self; unable to carry on normal activity or to 
do active work
60
Up and around, but minimal active play; 
keeps busy with quieter activities
Requires occasional assistance but is able to care for 
most of his needs
50
Gets dressed but lies around much of the 
day, no active play;  able to participate in 
all quiet play and activities
Requires considerable assistance and frequent medical 
care
40
Mostly in bed; participates in quiet play 
activities
Disabled; requires special care and assistance
30
In bed; needs assistance even for quiet 
play
Severely disabled; hospitalization is indicated although
death not imminent
20
Often sleeping; play entirely limited to 
very passive activities
Hospitalization necessary, very sick active supportive 
treatment necessary
10
No play; does not get out of bed
Moribund; fatal processes progressing rapidly
0
Unresponsive
Dead


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Emetogenicity of Commonly Used Chemotherapeutic Agents
12.5
MINIMAL RISK
(<10% frequency)
LOW RISK
(10-<30% frequency)
MODERATE RISK
(30-90% frequency)
HIGH RISK*
(>90% frequency)
Alemtuzumab 
Amifostine ≤ 300 mg/m2
Aldesleukin > 12 to 15 million 
units/ m2
Single agent antineoplastic 
therapy
Alpha interferon 
Amsacrine
Amifostine >300 mg/m2
Altretamine
Aspagarinase (IM or IV) 
Bexarotene
Arsenic trioxide
Carboplatin
Bevacizumab 
Busulfan (oral)
Azacitidine
Carmustine >250 mg/m2
Bleomycin 
Capecitabine
Bendamustine
Cisplatin 
Bortezomib 
Cytarabine ≤ 200 mg
Busulfan
Cyclophosphamide  ≥1 g/m2
Cetuximab 
Docetaxel
Carmustine ≤ 250 mg/m2
Cytarabine 3 g/m2/dose
Chlorambucil (oral) 
Doxorubicin (liposomal)
Clofarabine
Dacarbazine 
Cladribine (2-
chlorodeoxyadenosine) 
Etoposide
Cyclophosphamide
  <1 g/m2
Dactinomycin
Dasatinib 
Fludarabine (oral)
Cyclophosphamide (oral)
Mechlorethamine
Decitabine 
5-Fluorouracil
Cytarabine > 200 mg to <3 g/m2
Methotrexate ≥12 g/m2
Denileukin diftitox 
Gemcitabine
Daunorubicin 
Procarbazine (oral)
Dexrazoxane 
Ixabepilone
Doxorubicin
Streptozocin 
Erlotinib 
Methotrexate >50 mg/m2 to 
<250 mg/m2
Epirubicin
Thiotepa ≥ 300 mg/ m2
Fludarabine 
Mitomycin
Etoposide (oral)
Multiple agent antineoplastic 
therapy
Gefitinib 
Mitoxantrone
Idarubicin
Cyclophosphamide + anthracycline
Gemtuzumab ozogamicin 
Nilotinib
Ifosfamide
Cyclophosphamide  + doxorubicin  
Hydroxyurea (oral) 
Paclitaxel
Imatinib (oral)
Cyclophosphamide + epirubicin
Lapatinib 
Paclitaxel-albumin
Intrathecal therapy 
(methotrexate, hydrocortisone 
& cytarabine)
Cyclophosphamide + etoposide
Lenalidomide 
Pemetrexed
Irinotecan
Cytarabine 150-200 mg/ m2 + 
daunorubicin
Melphalan (oral low-dose) Teniposide
Lomustine
Cytarabine 300 mg/ m2 + etoposide
Mercaptopurine (oral) 
Thiotepa < 300 mg/ m2
Melphalan > 50 mg/ m2
Cytarabine 300 mg/ m2 + 
teniposide
Methotrexate ≤ 50 mg/ m2
Topotecan
Methotrexate ≥ 250 mg/m2 to  
<12 g/m2
Doxorubicin + ifosfamide  
Nelarabine 
Vorinostat
Oxaliplatin  >75 mg/m2
Doxorubicin + methotrexate 5 g/ 
m2
Panitumumab 
Temozolomide (oral)
Etoposide + ifosfamide
Pentostatin 
Vinorelbine (oral)
Rituximab 
Sorafenib 
Sunitinib 
Temsirolimus
Thalidomide 
Thioguanine (oral) 
Trastuzumab 
Valrubicin 
Vinblastine 
Vincristine 
Vindesine 
* Except for combinations of agents listed below, emetogenicity is classified based on the most 
highly emetogenic agent. 
Vinorelbine 
Note: All agents given intravenously (IV) unless stated otherwise.
Adapted from Dupuis, L et al Guideline for the Prevention of Acute Nausea and Vomiting due to Antineoplastic Medication 
in Pediatric Cancer Patients. Pediatric Oncology Group of Ontario;Toronto. 2012.


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Approximate Blood Volumes Drawn by Trial Visit and by Sample Types
12.6
Cycle 1
Cycle 2
Trial Visit:
Screening
Visit 1
Randomization
Visit 2
Follow-
Up/Disc.
Visit 4
Treatment
Blood Parameter 
Approximate Blood Volume (mL)
Hematology
~0.5
~ 0.5
Chemistry
~0.6
~0.6
Ionized Calcium 
(at selected sites)
(~0.6)
(~0.6)
PK for aprepitant
~2.0 (~0.5 at 
4 time 
points)
Expected 
Total 
(mL)
~1.1 (~1.7)
(~0.6)
~1.1
~2.0


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Abbreviations and Definitions
12.7
Abbreviation
Definition
Acute Phase
0 to 24 hours following initiation of emetogenic chemotherapy
5-HT3
5-hydroxytryptamine 3
AE
Adverse event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUC0-∞
Area under the concentration-time curve from time 0 to infinity
CINV
Chemotherapy-induced nausea and vomiting
Cmax
Maximum observed plasma concentration
CMH
Cochran-Mantel-Haenszel
CNS
Central nervous system
Complete Response
No vomiting, no retching, and no use of rescue medication
CRF
Case report form
CSR
Clinical study report
CYP
Cytochrome P450
Delayed Phase
>24 to 120 hours following initiation of chemotherapy infusion
DNA
Deoxyribonucleic acid
Dry Heaves
When the subject tries to vomit and nothing comes up (as defined 
in the Patient Diary); Used synonymously with retching
ECG
Electrocardiogram
ECI
Event of clinical interest
eCRF
Electronic case report form
ERC
Ethics Review Committee
ESMO
European Society for Medical Oncology
FAS
Full analysis set
FDA
Food and Drug Administration
FDAMA
Food and Drug Administration Modernization Act
GCP
Good clinical practice
HEC
Highly emetogenic chemotherapy
IB
Investigator's brochure
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ITT
Intent to treat
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Integrated Web Response System
MASCC
Multinational Association of Supportive Care in Cancer
MEC
Moderately emetogenic chemotherapy
Nausea
feeling the need to vomit


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Abbreviation
Definition
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NK1
Neurokinin-1
No Rescue
Medication
Subject did not use medication to relieve symptoms of nausea or 
vomiting
No Vomiting
No vomiting and no retching/dry heaves (regardless of use of 
rescue medication)
Overall Phase
0 to 120 hours following initiation of emetogenic chemotherapy
PD
Pharmacodynamic(s)
PGt
Pharmacogenetic
PK
Pharmacokinetic(s)
PONV
Post-operative nausea and vomiting
PP
Per protocol
Prophylactic 
Medication
Medication to prevent symptoms of anticipated nausea and 
vomiting
QT
QT interval (interval between the Q and T waves in an 
electrocardiogram)
Rescue Medication
Medication to relieve symptoms of established nausea or 
vomiting
Retching
When subject tries to vomit and nothing comes up; Used 
synonymously with dry heaves
RNA
Ribonucleic acid
SAP
Statistical analysis plan
SAE
Serious Adverse Event
SOC
System organ class
Tzero
Start date and time of chemotherapy infusion
ULN
Upper limit of normal
Vomiting
When the contents of the stomach come up and out through the 
mouth (as defined in the Patient Diary)


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13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED