Clinical trial NCT02279173
Conditions: Immune Thrombocytopenia
Keywords: Pediatric Immune Thrombocytopenia Amgen
Sponsor: Amgen
Start date: 2014-12-10; Completion date: 2019-08-08
Enrollment: 203 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase 3b single arm, open label, multicenter study describing the percentage of time pediatric participants with ITP have a platelet response while receiving romiplostim, defined as a platelet count ≥ 50 x 10\^9/L in the absence of ITP rescue medications for the past 4 weeks.

Detailed description:

Arms: arm 1: Participants received romiplostim administered weekly by subcutaneous injection for up to 3 years. The starting dose was 1 µg/kg titrated in 1 µg/kg increments up to a maximum of 10 µg/kg to reach a target platelet count ≥ 50 x 10⁹/L.
Interventions: intervention 1: Romiplostim
Intervention descriptions: intervention 1: Romiplostim subcutaneous weekly injection

Protocol documents:
Prot_000.pdf: 
16.1.1
Protocol and Amendments
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 1


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Product:  Romiplostim 
Protocol Number:  20101221 
Date:  15 August 2014 
Page 2 of 69 
Investigator’s Agreement 
I have read the attached protocol entitled A Single Arm, Open-label, Long-term Efficacy 
and Safety Study of Romiplostim in Thrombocytopenic Pediatric Subjects With Immune 
Thrombocytopenia (ITP), dated 15 August 2014, and agree to abide by all provisions 
set forth therein. 
I agree to comply with the International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines.  
I agree to ensure that Financial Disclosure Statements will be completed by: 
•
me (including, if applicable, my spouse [or legal partner] and dependent children)
•
my subinvestigators (including, if applicable, their spouses [or legal partners] and
dependent children)
at the start of the study and for up to 1 year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.  
Signature 
Name of Principal Investigator 
Date (DD Month YYYY) 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 3


Product:  Romiplostim 
Protocol Number:  20101221 
Date:  15 August 2014 
Page 3 of 69 
 
Protocol Synopsis 
Title:  A Single Arm, Open-label, Long-term Efficacy and Safety Study of Romiplostim in 
Thrombocytopenic Pediatric Subjects With Immune Thrombocytopenia (ITP) 
Study Phase:  3b 
Indication:  Pediatric ITP 
Primary Objective: 
• 
To describe the percentage of time that pediatric subjects with ITP have a platelet 
response in the first 6 months from the start of treatment with romiplostim 
Secondary Objectives:   
• 
To describe the percentage of time that pediatric subjects with ITP have a platelet 
response over the study duration 
• 
To describe the percentage of time that pediatric subjects with ITP have an increase in 
platelet count ≥  20 x 109/L above baseline over the study duration  
• 
To describe the use of rescue ITP medications 
• 
To describe the incidence of antibody formation 
• 
To describe the safety of romiplostim as a long-term treatment in pediatric 
thrombocytopenic subjects with ITP 
Exploratory Objectives: 
• 
To describe the incidence of sustained platelet response 
• 
To describe the incidence of splenectomy 
• 
To describe the subject incidence of romiplostim self-administration 
Hypotheses:  A formal hypothesis will not be tested in this study.  The percentage of time with a 
platelet count ≥ 50 x 109/L in the first 6 months of the study will be estimated.   
Primary Endpoint:   
• 
The percentage of time with a platelet count of ≥ 50 x 109/L starting from week 2 in the 
first 6 months of the treatment period without rescue medication use in the past 4 weeks  
Secondary Endpoints:   
• 
The percentage of time with a platelet count of ≥ 50 x 109/L starting from week 2 until the 
end of the treatment period without rescue medication use in the past 4 weeks 
• 
The percentage of time with an increase in platelet count ≥ 20 x 109/L above baseline 
starting from week 2 until the end of the treatment period without rescue medication use 
within the past 4 weeks. 
• 
Subject incidence of rescue ITP medications used  
• 
The incidence of anti-romiplostim neutralizing antibodies and cross-reactive antibodies to 
thrombopoietin (TPO) at any time during the study 
• 
The incidence of adverse events, including clinically significant changes in laboratory 
values  
Exploratory Endpoints 
• 
The subject incidence with a sustained platelet count of ≥ 50 x 109/L for 6 months or 
greater without the use of any ITP medications (concomitant, rescue, or romiplostim) 
• 
The incidence of splenectomy during the treatment period for subjects entering the study 
pre-splenectomy 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 4


Product:  Romiplostim 
Protocol Number:  20101221 
Date:  15 August 2014 
Page 4 of 69 
 
• 
The subject incidence of romiplostim self-administration 
Study Design:   
This is a phase 3b single arm, open label, multicenter study describing the percentage of time 
pediatric subjects with ITP have a platelet response while receiving romiplostim, defined as a 
platelet count ≥ 50 x 109/L and in the absence of ITP rescue medications in the past 4 weeks.  
This protocol will provide open label romiplostim to thrombocytopenic pediatric subjects with ITP 
diagnosed for at least 6 months and who have received at least 1 prior ITP therapy (excluding 
romiplostim) or are ineligible for ITP therapies.  
The study design consists of a 4-week screening period, up to a 3-year treatment period, an end 
of treatment (EOT) visit, and an end of study (EOS) visit. 
Sample Size:  Approximately 200 subjects 
Summary of Subject Eligibility Criteria:  
Eligible pediatric subjects diagnosed with ITP according to the American Society of Hematology 
(ASH) guidelines (Neunert et al, 2011) must have thrombocytopenia (defined as a platelet count 
≤ 30 x 109/L) or have bleeding that is uncontrolled with conventional therapy within 4 weeks of 
enrollment.   
For a full list of eligibility criteria, please refer to Section 4.1 and Section 4.2. 
Amgen Investigational Product Dosage and Administration:   
Investigational product will be administered as a subcutaneous injection.  The starting dose of 
romiplostim will be 1 µg/kg based on the subject’s recorded screening weight in the clinic by a 
qualified healthcare provider.  Throughout the treatment period, subjects will return to the clinic 
for platelet counts and undergo dose titrations under the supervision of the treating physician.  
Weekly dose increases will be made in increments of 1 µg/kg, up to a maximum dose of 
10 µg/kg, in an attempt to reach a target platelet count of ≥ 50 x 109/L.  Dose adjustments will be 
allowed to maintain a platelet count between ≥ 50 x 109/L and ≤ 200 x 109/L.  Subjects who 
receive their first 8 doses in clinic and achieve a platelet count ≥ 50 x 109/L without romiplostim 
dose adjustments for 4 consecutive weeks will be eligible to self-administer romiplostim or have 
the injection administered by a caregiver.   
For detailed instructions regarding investigational product presentation, dose, administration, and 
dose adjustments, please see Section 6. 
Control Group:  The study design does not include a control arm. 
Procedures:   
At specified time points, subjects will undergo the following assessments: informed consent (and 
assent, if applicable), confirmation of ITP diagnosis, ITP and medical history, physical exam 
including weight and vital signs.  Subjects will have complete blood counts with differentials, 
blood chemistry profiles, local platelet counts, and a blood or urine pregnancy test for females of 
child-bearing potential.  Research staff will document the use of concomitant and rescue 
medications and all adverse events reported for the subject.  Subjects will also provide blood 
samples for anti-TPO/romiplostim antibodies and peripheral blood smears.  
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and Table 2. 
Statistical Considerations:   
The primary analysis will be descriptive.  No formal hypothesis will be tested.  Summary statistics 
will be provided for the primary and secondary endpoints.  Categorical data will be presented in 
the form of number and percentage.  Continuous data will be provided with the descriptive 
statistics (n, mean, standard deviation, median, Q1 [25th percentile], Q3 [75th percentile], 
minimum, and maximum).  The analysis of efficacy and safety endpoints will be based on the set 
of subjects receiving at least one dose of romiplostim. 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
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Product:  Romiplostim 
Protocol Number:  20101221 
Date:  15 August 2014 
Page 5 of 69 
 
Interim analyses will be conducted to support regulatory filings, and accumulating data for this 
study will be summarized to provide ongoing assessments of the safety of romiplostim.  These 
interim analyses will occur at least annually until the end of the study. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor: Amgen Inc. 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
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Product:  Romiplostim 
Protocol Number:  20101221 
Date: 15 August 2014 
Page 6 of 69 
 
Study Design and Treatment Schema 
 
 
S 
C 
R 
E 
E 
N 
I 
N 
G 
 
P 
E 
R 
I 
O 
D 
TREATMENT PERIOD  
 
 
Number of Subjects = 200 
 
Starting dose of romiplostim will be 1µg/kg administered 
one time weekly in an attempt to reach a target platelet 
count ≥ 50 x 109/L   
 
Dose adjustments will be allowed during the treatment 
period to maintain a platelet count between ≥ 50 x 109/L 
and ≤ 200 x 109/L  
 
Reduction in concurrent ITP therapies may occur when 
there is a platelet count of ≥ 50 x 109/L 
 
E 
N 
D  
  
O 
F 
 
T 
R 
E 
A 
T 
M
E 
N 
T 
 
V 
I 
S 
I  
T 
E 
N 
D 
 
O 
F 
 
S 
T 
U 
D 
Y 
 
V 
I 
S 
I 
T 
 
4 weeks 
Up to 36 months in duration 
2 weeks 
2 weeks 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 7


Product:  Romiplostim 
Protocol Number:  20101221 
Date: 15 August 2014 
Page 7 of 69 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ASH 
American Society of Hematology 
ALT 
alanine aminotransferase  
AST 
aspartate aminotransferase  
BCSH 
British Committee for Standards in Hematology 
CBC 
complete blood counts 
CTCAE 
Common Terminology Criteria for Adverse Events 
eCRF 
electronic case report form 
end of study for individual 
subject (EOS) 
defined as the last day that protocol-specified procedures are 
conducted for subjects who do not complete the 36 month treatment 
period.  
end of treatment (EOT) 
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 
end of study (primary 
completion) 
defined as the time when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary 
outcome  
eTPO 
endogenous thrombopoietin 
INR 
international normalized ratio 
IP 
investigational product 
IRB/IEC 
institutional review board/independent ethics committee 
ITP 
immune thrombocytopenia 
IVIG 
intravenous Immunoglobulin 
IVRS  
interactive voice response system: telecommunication technology 
that is linked to a central computer in real time as an interface to 
collect and process information.  
source data 
information from an original record or a certified copy of the original 
record containing patient information for use in clinical research.  
The information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained 
in source documents (original records or certified copies, ICH 
Guideline E6).  Examples of source data include subject ID, 
randomization ID, and stratification value. 
study day 1 
defined as the first day that romiplostim is administered to the 
subject 
TB 
total bilirubin 
TPO 
thrombopoietin 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 8


Product:  Romiplostim 
Protocol Number:  20101221 
Date: 15 August 2014 
Page 8 of 69 
 
TABLE OF CONTENTS 
 
Page 
Protocol Synopsis ............................................................................................................ 3 
Study Design and Treatment Schema ............................................................................. 6 
Study Glossary ................................................................................................................ 7 
1. 
OBJECTIVES ....................................................................................................... 12 
1.1 
Primary ..................................................................................................... 12 
1.2 
Secondary ................................................................................................. 12 
1.3 
Exploratory ................................................................................................ 12 
2. 
BACKGROUND AND RATIONALE ...................................................................... 12 
2.1 
Disease ..................................................................................................... 12 
2.2 
Treatments for ITP in Pediatric Patients .................................................... 14 
2.3 
Romiplostim Background .......................................................................... 16 
2.4 
Pediatric Clinical Data ............................................................................... 16 
2.5 
Bone Marrow Reticulin Evaluation in ITP .................................................. 18 
2.6 
Anti-romiplostim Antibody Results ............................................................. 19 
2.7 
Pediatric Risk Assessment ........................................................................ 19 
2.8 
Rationale ................................................................................................... 19 
2.9 
Clinical Hypotheses ................................................................................... 20 
3. 
EXPERIMENTAL PLAN ........................................................................................ 20 
3.1 
Study Design ............................................................................................. 20 
3.1.1 
Subjects With an Onset of Sustained Platelet 
Response .................................................................................. 21 
3.1.2 
Non-responding Subjects .......................................................... 21 
3.2 
Number of Centers .................................................................................... 21 
3.3 
Number of Subjects ................................................................................... 22 
3.4 
Replacement of Subjects .......................................................................... 22 
3.5 
Estimated Study Duration .......................................................................... 22 
3.5.1 
Study Duration for Participants .................................................. 22 
3.5.2 
End of Study .............................................................................. 22 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 22 
4.1 
Inclusion Criteria ....................................................................................... 23 
4.2 
Exclusion Criteria ...................................................................................... 23 
5. 
SUBJECT ENROLLMENT .................................................................................... 24 
6. 
TREATMENT PROCEDURES .............................................................................. 25 
6.1 
Classification of Product(s) and/or Medical Device(s) ................................ 25 
Product: 
Date: 
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Clinical Study Report:  20101221
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Product:  Romiplostim 
Protocol Number:  20101221 
Date: 15 August 2014 
Page 9 of 69 
 
6.2 
Romiplostim .............................................................................................. 25 
6.2.1 
Dosage, Administration, and Schedule ...................................... 25 
6.2.2 
Dosage Adjustments: Delays or Rules for Withholding 
Investigational Product .............................................................. 26 
6.2.3 
Non-responders to Romiplostim ................................................ 27 
6.3 
Self-administration of Romiplostim ............................................................ 28 
6.4 
Concomitant Therapy ................................................................................ 29 
6.5 
Product Complaints ................................................................................... 30 
6.6 
Excluded Treatments During Study Period ................................................ 30 
6.7 
Other Treatment Procedures ..................................................................... 31 
7. 
STUDY PROCEDURES ....................................................................................... 31 
7.1 
Schedule of Assessments ......................................................................... 32 
7.1.1 
Routine Blood Tests .................................................................. 33 
7.1.2 
Platelet Counts .......................................................................... 34 
7.1.3 
Antibody Testing Procedures ..................................................... 35 
7.2 
Sample Storage and Destruction ............................................................... 35 
7.3 
Medical History ......................................................................................... 37 
7.4 
Concomitant Medications .......................................................................... 37 
7.5 
Screening .................................................................................................. 37 
7.6 
Romiplostim Treatment Period (Up to a 36 Months Duration) .................... 38 
7.7 
End of Treatment Visit (EOT) .................................................................... 39 
7.8 
End of Study Visit (EOS) ........................................................................... 39 
8. 
WITHDRAWAL AND REPLACEMENT OF SUBJECTS ........................................ 40 
8.1 
Subjects’ Decision to Withdraw ................................................................. 40 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 40 
8.2.1 
Reasons for Removal From Treatment ...................................... 41 
8.2.2 
Reasons for Removal From Study ............................................. 41 
8.3 
Replacement of Subjects .......................................................................... 41 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 41 
9.1 
Adverse Events ......................................................................................... 41 
9.1.1 
Definition of Adverse Events ...................................................... 41 
9.1.2 
Definition of Serious Adverse Events ......................................... 42 
9.2 
Reporting of Adverse Events ..................................................................... 42 
9.2.1 
Reporting Procedures for Adverse Events That do not 
Meet Serious Criteria ................................................................. 42 
9.2.2 
Reporting Procedures for Serious Adverse Events .................... 43 
9.3 
Pregnancy and Lactation Reporting .......................................................... 45 
10. 
STATISTICAL CONSIDERATIONS ...................................................................... 45 
10.1 
Study Endpoints, Subsets, and Covariates ................................................ 46 
10.1.1 
Study Endpoints ........................................................................ 46 
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Date: 
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Product:  Romiplostim 
Protocol Number:  20101221 
Date: 15 August 2014 
Page 10 of 69 
 
10.1.2 
Analysis Sets ............................................................................. 46 
10.1.2.1 
Full Analysis Set ...................................................... 46 
10.1.2.2 
Safety Analysis Set ................................................. 46 
10.1.2.3 
Efficacy Analysis Set ............................................... 46 
10.1.2.4 
Per Protocol Analysis Set ........................................ 47 
10.2 
Sample Size Considerations ..................................................................... 47 
10.3 
Planned Analyses ..................................................................................... 47 
10.3.1 
Interim Analyses ........................................................................ 47 
10.3.2 
Analysis of Key Study Endpoints ............................................... 47 
10.3.2.1 
Efficacy Endpoints ................................................... 47 
10.3.2.2 
Safety Endpoints ..................................................... 48 
10.3.3 
Primary Analysis ........................................................................ 48 
10.3.4 
Additional Analyses ................................................................... 49 
10.3.4.1 
Subject Accountability ............................................. 49 
10.3.4.2 
Demographic and Baseline Characteristics ............. 49 
10.3.4.3 
Investigational Product Administration ..................... 49 
11. 
REGULATORY OBLIGATIONS ............................................................................ 49 
11.1 
Informed Consent ...................................................................................... 49 
11.2 
Independent Ethics Committee/Institutional Review Board ........................ 50 
11.3 
Subject Confidentiality ............................................................................... 51 
11.4 
Investigator Signatory Obligations ............................................................. 52 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 52 
12.1 
Protocol Amendments and Study Termination .......................................... 52 
12.2 
Study Documentation and Archive ............................................................ 52 
12.3 
Study Monitoring and Data Collection ....................................................... 53 
12.4 
Investigator Responsibilities for Data Collection ........................................ 54 
12.5 
Language .................................................................................................. 55 
12.6 
Publication Policy ...................................................................................... 55 
12.7 
Compensation ........................................................................................... 56 
13. 
REFERENCES ..................................................................................................... 57 
14. 
APPENDICES ...................................................................................................... 60 
 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
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Product:  Romiplostim 
Protocol Number:  20101221 
Date: 15 August 2014 
Page 11 of 69 
 
List of Tables 
Table 1.  Dose Adjustment Rules
 
 .................................................................................. 27
Table 2.  Schedule of Assessments
 
 ............................................................................... 32
Table 3.  List of Analytes in Laboratory Specimens
 
 ....................................................... 34
 
List of Appendices 
Appendix A.  Additional Safety Assessment Information
 
 ................................................ 61
Appendix B.  Modified Bauermeister Scale
 
 .................................................................... 67
Appendix C.  Pregnancy Notification Worksheet
 
 ............................................................ 68
Appendix D.  Lactation Notification Worksheet
 
 .............................................................. 69
 
Product: 
Date: 
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Clinical Study Report:  20101221
09 September 2016
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Product:  Romiplostim 
Protocol Number:  20101221 
Date: 15 August 2014 
Page 12 of 69 
 
1. 
OBJECTIVES 
1.1 
Primary 
The primary objective is to describe the percentage of time that pediatric subjects with 
immune thrombocytopenia (ITP) have a platelet response in the first 6 months from the 
start of treatment with romiplostim. 
1.2 
Secondary 
The secondary objectives of the study are: 
• 
To describe the percentage of time that pediatric subjects with ITP have a platelet 
response over the study duration  
• 
To describe the  percentage of time that pediatric subjects with ITP have an increase 
in platelet count ≥ 20 x 109/L above baseline over the study duration  
• 
To describe the use of rescue ITP medications 
• 
To describe the incidence of antibody formation 
• 
To describe the safety of romiplostim as a long-term treatment in pediatric 
thrombocytopenic subjects with ITP 
1.3 
Exploratory 
• 
To describe the incidence of sustained platelet responses 
• 
To describe the incidence of splenectomy  
• 
To describe the subject incidence of romiplostim self-administration 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease  
Immune thrombocytopenia is an autoimmune disorder characterized by a low circulating 
platelet count (thrombocytopenia) and decreased platelet production.  Historically, the 
low circulating platelet counts were attributed to antibodies binding to platelet antigens, 
resulting in destruction of platelets in the reticuloendothelial system, primarily the spleen 
(Bottiger and Westerholm, 1972; McMillan, 1981; Kelton and Gibbons, 1982; 
George et al, 1995).  However, a recent international consensus report suggests that a 
more complex disease process is present in which impaired platelet production may play 
an important role in the disease (Provan et al, 2010).  Thrombocytopenia, as a result of 
ITP, places patients at risks for bruising, mucocutaneous bleeding, and, more seriously, 
intracranial hemorrhage.   
The annual incidence of ITP among children in the United States and Europe is 
estimated between 19 and 64 cases/million population, with a peak incidence between 
Product: 
Date: 
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Clinical Study Report:  20101221
09 September 2016
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Product:  Romiplostim 
Protocol Number:  20101221 
Date: 15 August 2014 
Page 13 of 69 
 
ages 2 and 10 and affecting boys and girls equally (Terrell et al, 2010; Glanz et al, 2008; 
Tarantino, 2006; Zeller et al, 2000; Lilleyman, 1999).  
Treatment guidelines for ITP have been published by the American Society of 
Hematology (ASH) ITP study group, (Neunert et al, 2011), the British Committee for 
Standards in Hematology and General Hematology Task Force (BCSH, 2003) and an 
International ITP consensus group (Provan et al, 2010).  Guidelines from these groups 
review and provide recommendations on the diagnosis, management and treatment 
options for ITP subjects.  
Unlike adult ITP in which the majority of cases are chronic in duration, pediatric ITP most 
commonly occurs in the acute form (platelet count < 150 x 109/L for < 6 months from 
diagnosis), accounting for 70% to 80% of ITP cases in children (Glanz et al, 2008).  
Many children with acute ITP require no treatment, and in approximately 60% to 75% of 
cases, the thrombocytopenia resolves within 2 to 4 months regardless of therapy 
(Nugent, 2006).  In pediatric ITP cases, 20% to 30% are considered chronic (platelet 
count < 150 x 109/L for > 6 months from diagnosis) and may become refractory to 
standard treatments (Glanz et al, 2008).  Chronic ITP in childhood has an estimated 
incidence of 0.46 per 100,000 children per year (Lilleyman, 1999; Zeller et al, 2000).  
Predictors for chronic ITP in children include older age (> 10 years) and an insidious 
presentation (Robb and Tiedeman, 1990).  In addition, chronic ITP in children is 
associated with higher presenting platelet count (> 20 x 109/L), lack of mucosal bleeding 
at presentation, and lack of a previous acute illness (Glanz et al, 2008). 
The traditional classification of chronic and acute ITP in the literature is based solely 
on persistence of thrombocytopenia from time of diagnosis, whereas previously 
mentioned, acute ITP is < 6 months and chronic ITP is > 6 months (Kuhne, 2003).  
However, this definition is commonly considered arbitrary (Bolton-Maggs, 2007; 
Buchanan and Adix, 2006; Glanz et al, 2008; Kuhne, 2006).  As a result, an international 
working group of ITP experts recently convened and re-defined the classification.  The 
working group now defines “newly diagnosed ITP” as 0 to 3 months from diagnosis, 
“persistent ITP” as lasting between 3 and 12 months from diagnosis, and “chronic ITP” 
as a disease duration ≥ 12 months.  This classification includes patients not reaching 
spontaneous remission or not maintaining complete response off therapy 
(Rodeghiero et al, 2009).  Based on these recent definitions, important determinants of 
disease severity and need for treatment include time since diagnosis, failure of prior ITP 
therapy, and bleeding symptoms. 
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2.2 
Treatments for ITP in Pediatric Patients   
The treatment of ITP in pediatric patients is warranted to prevent clinically significant 
bleeding events, especially intracerebral hemorrhage.  Although fatal bleeding events 
among children with ITP are rare and the overall incidence of intracerebral hemorrhage 
is between 0.2% and 1% (Cines and Blanchette, 2002), one review of 332 medical 
records revealed that 17% of children had major hemorrhage defined as intracranial 
bleeding, epistaxis requiring cautery or nasal packing, gross hematuria, or other 
bleeding causing a decline in hemoglobin concentration.  Approximately 75% of bleeding 
episodes in this review occurred in children with platelet counts < 10 x 109 /L 
(Tarantino, 2006). 
The principal aim of treating children with chronic ITP is to maintain a hemostatically 
safe platelet count and improve quality of life, instead of trying to achieve a cure 
(Kalpatthi and Bussel, 2008).  Clinical management of chronic ITP in children varies and 
does not always adhere to recommendations set forth by the ASH and the BCSH and 
General Hematology Task Force (Neunert et al, 2011; BCSH, 2003).  The ASH 
guidelines incorporate both clinical and platelet count data to arrive at specific treatment 
recommendations; drug therapy with either intravenous immunoglobulin (IVIG) or 
corticosteroids is recommended for children with a platelet count (< 20 x 109/L) and 
minor purpura, and for children with severe life-threatening bleeding 
(George et al, 1996).  The BCSH guidelines suggest that pronounced skin purpura and 
bruising may not reflect a serious risk of bleeding and recommend that only patients who 
experience significant mucous membrane bleeding receive treatment 
(Tarantino and Bolton-Maggs, 2007; Tarantino, 2006).  Furthermore, the BCSH 
recommends that IVIG be used only for emergency treatment or for those who do not 
respond to corticosteroids.   
In 2010, an international consensus report was published to address the investigation, 
diagnosis, and management of childhood ITP (Provan et al, 2010).  The consensus 
report guidance for the diagnosis and management of ITP remains largely unchanged 
from the previously published BCSH and ASH guidance.  Central to the committee’s 
recommendations is the adoption of an ITP classification by duration, which is separated 
into 3 distinct periods: newly diagnosed ITP (0 to 3 months from diagnosis), persistent 
ITP (3 to 12 months from diagnosis), and chronic ITP (12 months or more from 
diagnosis).  Once an ITP diagnosis and classification are confirmed, individual subject 
disease characteristics (eg, bleeding symptoms, platelet counts), psychosocial issues, 
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level of activity, and lifestyles should be considered when selecting the appropriate 
management and treatment of the disease. 
Regardless of which guidelines are being followed, medical management is generally 
preferred over splenectomy for children who have ITP between 6 and 12 months.  
Traditional pre-splenectomy treatment options include oral corticosteroids (including 
pulse oral dexamethasone), IVIG, and for children who are Rhesus-positive, intravenous 
(IV) anti-D (Blanchette and Price, 2003).  Less commonly, immunosuppressive 
strategies have been used to treat chronic ITP which include cyclophosphamide, 
azathioprine, cyclosporine, mycophenolate mofetil, and autologous stem cell 
transplantation (Buchanan and Adix, 2006).  While each of these therapies has been 
shown to result in increased platelet counts, the potential toxicity of these approaches 
compels physicians to weigh the likelihood of clinical efficacy against the likelihood of the 
occurrence of clinically relevant adverse events (Tarantino, 2006). 
Recently rituximab has also been used to treat pediatric ITP.  A prospective study of the 
use of rituximab among children with chronic refractory ITP demonstrated a 31% 
response rate with response defined as maintenance of a platelet count > 50 x 109/L for 
4 consecutive weeks (Bennett et al, 2006).  However, rituximab carries a significant 
warning regarding infusion reactions, tumor lysis syndrome, severe mucocutaneous 
reactions, and progressive multifocal leukoencephalopathy 
(Rituxan® [rituximab] Prescribing Information, 2012).  Long-term suppression of B cells 
by rituximab is generally not associated with decreased immunoglobulin levels (except 
possibly in very young children) or serious infections (Parodi et al, 2006).  Although the 
need for prophylactic IVIG has not been demonstrated, patients must be closely 
monitored.  Hepatitis B virus reactivation with fulminant hepatitis, hepatic failure, and 
death can occur in patients with hematologic malignancies treated with rituximab 
(Kalpatthi and Bussel, 2008; Rituxan® [rituximab] Prescribing Information, 2012). 
Splenectomy is considered only for those children who have severe ITP.  The fact that 
36% of chronic pediatric ITP patients are reported to experience spontaneous remission 
(Reid, 1995) suggests that there could be a role for therapeutic agents that have the 
ability to delay splenectomy.  Splenectomy is recommended in both ASH and BCSH 
guidelines for children with ITP lasting > 1 year with both low platelet count and 
bleeding symptoms, although the BCSH guidelines stress that splenectomy is warranted 
only with demonstrable impairment on quality of life (Kalphatthi and Bussel, 2008; 
Tarantino and Bolton-Maggs, 2007).  In the recently published international consensus 
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report, splenectomy is also cited as a surgical treatment option, but is generally deferred 
for as long as possible (Provan et al, 2010). 
Splenectomy is successful in resolution of life threatening thrombocytopenia in 
75% to 85% of pediatric patients but is associated with an increased risk of sepsis 
(Nugent, 2006).  A recent survey revealed that only approximately one-third of 
respondents would recommend splenectomy as first-line therapy for a child with severe 
chronic refractory ITP, a decision influenced mostly by factors affecting long-term 
outcome, such as risk of sepsis, thromboembolic events,  possible relapse, likelihood of 
spontaneous remission without splenectomy, and the irreversible nature of splenectomy 
(Neunert et al, 2008).  Moreover, splenectomy may not be warranted in younger patients 
who are at relatively high risk for infection with encapsulated organisms 
(Kuhne et al, 2007; Bennett et al, 2006).  
2.3 
Romiplostim Background  
Romiplostim is a recombinant non-glycosylated 59 kDa thrombopoietic protein produced 
in Escherichia coli.  It is a fusion protein (peptibody), composed of a human 
immunoglobulin IgG1 Fc domain with each single chain subunit covalently linked at the 
C-terminus to a peptide chain containing 2 thrombopoietin (TPO) receptor binding 
domains.  Romiplostim stimulates platelet production by a mechanism similar to that of 
endogenous thrombopoietin (eTPO); however, there is no amino acid sequence 
homology between romiplostim and eTPO.  The lack of sequence homology with eTPO 
reduces the probability that if antibodies to romiplostim are produced they will cross 
react with eTPO and cause thrombocytopenia.  
Romiplostim is approved for use in the adult chronic ITP setting in various regions of the 
world under the trade name of Nplate® (romiplostim); the specific clinical indication 
varies by region.  The most common side effects reported include headache, aching 
joints, dizziness, difficulty sleeping, muscle aches, pain in extremities and abdominal 
pain.   
For additional information on romiplostim, please refer to the most current version of the 
Romiplostim Investigator’s Brochure. 
2.4 
Pediatric Clinical Data 
Proof of concept for the treatment of ITP in the pediatric population has been established 
in Study 20060195.  Protocol 20060195 was a Phase 2 randomized, double-blind, 
placebo-controlled, 12-week study designed to assess the safety, tolerability, and 
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efficacy of romiplostim for the treatment of pediatric thrombocytopenic subjects with ITP.  
A total of 22 subjects (17 romiplostim; 5 placebo) between 12 months and 17 years of 
age were randomized in a 3:1 ratio to receive romiplostim or volume-matched placebo at 
a starting dose of 1 µg/kg administered weekly by subcutaneous injection.  Subjects 
returned to the clinic weekly for platelet counts and undergo dose titrations under the 
supervision of the treating physician.  
All 22 subjects received blinded investigational product (IP) and were evaluated for 
efficacy.  Of the 17 subjects who received romiplostim, 15 (88%) achieved a platelet 
response ≥ 50 x 109/L for 2 consecutive weeks during the 12-week treatment period 
(after excluding platelet counts within 4 weeks after rescue medication use).  The same 
15 subjects also achieved an increase in platelet count ≥ 20 x 109/L above baseline for 
2 consecutive weeks (after excluding platelet counts within 4 weeks of rescue 
medication use).  None of the placebo-treated subjects achieved either endpoint. 
With regards to rescue medication use, 2 of 17 subjects (11.8%) in the romiplostim 
group, and 2 of the 5 subjects (40.0%) in the placebo group received rescue medication 
support during the treatment period. 
During the treatment period, adverse events were reported for the majority of subjects in 
each treatment group (16 of 17 subjects [94.1%] in the romiplostim group and 
4 of 5 subjects [80%] in the placebo group), with most adverse events reported as mild 
to moderate in severity.  The most frequently reported adverse events (subject incidence 
> 25% in either treatment group) were (romiplostim, placebo) headache (6 subjects, 
35.3%; 2 subjects, 40.0%), epistaxis (6 subjects, 35.3%; 1 subject, 20.0%), cough 
(2 subjects, 11.8%; 2 subjects, 40.0%), vomiting (2 subjects, 11.8%; 2 subjects, 40.0%), 
and nasal congestion (0 subjects, 0.0%; 2 subjects, 40.0%). 
Bleeding was the only event of interest observed on study.  When adjusted for exposure 
duration, the rate of bleeding was 7.3 events per 100 subjects-weeks in the romiplostim 
arm and 11.9 events per 100 subject-weeks in the placebo arm.  Bleeding events were 
mostly mild and occurred early in the treatment period when platelet counts were 
< 50 x 109/L.  No bleeding adverse events were considered to be serious or treatment 
related. 
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2.5 
Bone Marrow Reticulin Evaluation in ITP 
Reticulin is a normal component of the bone marrow that can be detected with reticulin 
(silver) stain (Thiele et al, 2005; Kuter et al, 2007).  Increased reticulin (reticulin fibrosis) 
is associated with many benign conditions, while increased collagen fibrosis (detected 
by trichrome staining) is characteristic of myeloproliferative disease (Kuter et al, 2007). 
In a retrospective analysis of bone marrow biopsies from 40 patients with ITP, reticulin 
was present in approximately two-thirds of romiplostim-naïve patients (Mufti et al, 2006). 
Increased reticulin above normal levels may be observed with or without concomitantly 
increased collagen in several conditions. Increased reticulin without collagen fibrosis is 
associated with conditions such as hairy cell leukemia, human immunodeficiency virus 
infection, pulmonary arterial hypertension, and treatment with hematopoietic growth 
factors (Kuter et al, 2007). 
Increased reticulin has been observed following treatment with recombinant human 
thrombopoietin (rHuTPO), interleukin-3, and interleukin-11 (Kuter, 2007; 
Kuter et al, 2007), and is likely a response to stimulation of megakaryocytes by 
thrombopoietin (TPO) (Douglas et al, 2002), or related to cytokines or other factors that 
are elaborated by the megakaryocytes (Castro-Malaspina et al, 1981; 
Yanagida et al, 1997; Schmitt et al, 2000).  Bone marrow reticulin (or the presence of 
reticulin on study) was observed in 3.7% (10 of 271) of subjects evaluated who had 
received romiplostim for ITP [data on file].  Increased reticulin formation may be due to 
the increased number of megakaryocytes in the bone marrow as a result of romiplostim 
treatment, consistent with findings associated with other thrombopoietins (Kuter, 2007). 
Recent evidence has shown that the amount of bone marrow reticulin detected by silver 
staining often exhibits no correlation to disease severity, while the presence of type 1 
collagen, as detected by trichrome staining, is often associated with more severe 
disease, a poorer prognosis (Kuter et al, 2007), and may be associated with malignant 
conditions such as chronic idiopathic myelofibrosis (Tefferi, 2005). 
To prospectively evaluate the incidence of both reticulin and collagen formation in the 
bone marrow during treatment with romiplostim, a trial in adults with ITP receiving open 
label romiplostim for up to 3 years is in progress (Amgen study 20080009).  Three 
cohorts of subjects will undergo repeat bone marrow evaluation after 1, 2, or 3 years to 
evaluate the incidence and potential sequelae of reticulin and collagen formation in the 
bone marrow.  To date, no development of collagen has been seen in cohorts 1 (1 year) 
and 2 (2 years). Increase by 2 grades in reticulin has been observed in no subjects in 
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cohort 1 and 2 subjects in cohort 2.  Cohort 3 evaluations are in progress.  Bone marrow 
studies of children with ITP to evaluate reticulin and collagen formation have not 
previously been conducted. 
2.6 
Anti-romiplostim Antibody Results 
To date, anti-romiplostim neutralizing antibodies have been detected in samples from 
2 adult subjects with ITP.  One of the subjects presented with anti-romiplostim 
neutralizing antibodies at the end of study (EOS) time point but tested negative for 
neutralizing antibodies to romiplostim on follow-up 4 months later (after discontinuation 
of romiplostim).  The second subject had neutralizing antibodies to romiplostim at an 
unscheduled time point after dosing with romiplostim but tested negative for neutralizing 
antibodies to romiplostim at 2 follow-up time points (week 132 and EOS) after 
discontinuation of romiplostim.  No cross-reactive binding antibodies to TPO were 
observed. 
For a complete summary of all safety and efficacy data collected in both the adult and 
pediatric ITP indications for the romiplostim clinical development program, please refer 
to the most recent version of the Romiplostim Investigator’s Brochure. 
2.7 
Pediatric Risk Assessment 
Previously reported safety results of the earlier phase 2 study (20060195), the currently 
enrolling phase 3 study (20080279), and open-label long-term follow-up study 
(20090340) support a favorable benefit risk profile with the use of romiplostim in 
thrombocytopenic pediatric subjects.  This study represents the fourth investigation of 
romiplostim in thrombocytopenic pediatric subjects with ITP. 
2.8 
Rationale  
The treatment of ITP in pediatric patients is warranted to prevent clinically significant 
bleeding events, especially intracerebral hemorrhage.  The management of children with 
ITP who either fail to respond to treatment or relapse following splenectomy is often 
challenging.  It is recognized that multiple therapeutic options are available and can be 
used as a single agent or in combination.  However, the sustained remission rate with 
monotherapy has proved disappointing, and controlled studies have not been performed.  
Furthermore, small studies have demonstrated the potential for improved outcomes with 
combination therapy, but there is no accepted standard of care 
(Robb and Tiedeman, 1990).  Appreciating the toxicities associated with many of the 
available treatments and knowing the limitations of current therapies, including failure 
after splenectomy, the management of pediatric ITP remains medically challenging.  
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Treatment with a thrombomimetic therefore represents a unique opportunity to treat this 
challenging disease with a novel therapy.  The route of administration, schedule, starting 
dose, and subsequent dose adjustments of romiplostim have been well established in 
previous pediatric and adult ITP studies and will be used for dosing and administration in 
this protocol.  Romiplostim will be administered initially in the clinic by a qualified health 
care provider as a subcutaneous injection.  The starting dose of romiplostim will be 
1 µg/kg/week based on the subject’s recorded screening weight.  Throughout the 
treatment period, subjects will return to the clinic to provide platelet counts and undergo 
dose titrations under the supervision of the treating physician.  Weekly dose increases 
will continue in increments of 1 µg/kg up to a maximum dose of 10 µg/kg in an attempt to 
reach a target platelet count of ≥ 50 x 109/L.  Dose adjustments will be allowed to 
maintain a platelet count between ≥ 50 x 109/L and ≤ 200 x 109/L. 
2.9 
Clinical Hypotheses 
No formal hypothesis will be tested in this study.  The percentage of time with a platelet 
count ≥ 50 x 109/L in the first 6 months of the study will be estimated. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a phase 3b single arm, open-label, multicenter study evaluating the percentage of 
time pediatric subjects with ITP have a response while receiving romiplostim, defined as 
a platelet count ≥ 50 x 109/L and in the absence of  ITP rescue medications in the past 
4 weeks.  This protocol will provide open-label romiplostim to thrombocytopenic pediatric 
subjects with ITP diagnosed for at least 6 months and who have received at least 1 prior 
ITP therapy (excluding romiplostim) or are ineligible for other ITP therapies.  
The study design consists of a 4-week screening period, up to a 3-year treatment period, 
an end of treatment (EOT) visit, and an end of study (EOS) visit.  
Subjects entering the study on medications to raise platelet counts may remain on these 
concomitant medications, as needed, along with romiplostim.  After the initiation of 
romiplostim, if subjects require additional medications to raise platelet counts, or an 
increase in dose of existing medications, rescue ITP therapies may be initiated (see 
Section 6.4).  If the subject’s platelet count is ≥ 50 x 109/L, concomitant or rescue ITP 
therapies can be reduced or discontinued. 
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Approximately 200 subjects with ITP will be enrolled and will receive weekly romiplostim 
until they complete the study, discontinue participation in the study for any reason, or the 
study ends. 
The overall study design is described by a study schema at the end of the 
protocol synopsis section. 
The study endpoints are defined in Section 10.1. 
3.1.1 
Subjects With an Onset of Sustained Platelet Response  
During the treatment period, romiplostim doses will be adjusted as outlined in Table 1.  
Subjects who dose reduce romiplostim such that they no longer require treatment with 
romiplostim, no longer require ITP medications (concomitant or rescue), and have an 
onset of a sustained platelet response (defined as a consecutive platelet counts 
≥ 50 x 109/L) will be monitored for at least 6 months beginning with the first platelet count 
≥ 50 x 109/L.  Subjects whose platelet count remains ≥ 50 x 109/L in the absence of any 
medications for ITP for at least 6 months will then be followed every 12 weeks for the 
duration of the 36-month treatment period.   
If during the 36-month treatment period the platelet count subsequently falls below 
< 50 x 109/L, treatment with romiplostim at the initial starting dose may be resumed. 
Subsequent doses will be adjusted as shown in Table 1.  Clinic visits will be resumed 
per the Schedule of Assessments (Table 2). 
3.1.2 
Non-responding Subjects 
Subjects who have a platelet count ≤ 20 x 109/L for 4 consecutive weeks at the 
maximum romiplostim dose of 10 µg/kg should be discontinued from romiplostim and will 
be considered non-responders. If the subject is a non-responder but the investigator 
believes the subject has obtained clinical benefit, the investigator must contact the 
Amgen medical monitor for the subject to continue participation in the study. 
3.2 
Number of Centers 
There will be approximately 50 centers located in (but not limited to) Australia, Canada, 
Europe, Israel, South Africa, South America, and the United States.  
Sites that do not enroll any subjects within 6 months of site initiation may be closed. 
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3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects.”  It is 
anticipated that approximately 200 subjects will be enrolled into this study. 
Please refer to Section 10.2 for sample size considerations 
3.4 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Participants 
For an individual subject, the length of participation includes a 4-week screening period, 
up to a 36-month treatment period, an EOT visit, and an EOS visit.  The maximum 
duration for a subject completing the study will be approximately 3 years and 2 months.  
3.5.2 
End of Study 
Primary Completion
4. 
SUBJECT ELIGIBILITY 
:  the time when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary analysis.  This will 
occur once the last subject participating has completed the EOS visit. 
Before any study-specific procedure is performed, the appropriate written informed 
consent must be obtained (see Section 11.1).  In addition to written informed consent, 
the assent of the child also must be obtained if requested by the investigative site’s 
respective institutional review board/independent ethics committee (IRB/IEC). 
Once informed consent (and assent, if applicable) has been obtained, the site will 
register the subject in the interactive voice response system (IVRS) and enter limited 
information about screening of potential candidate (sex, age, and race), date, and 
outcome of the screening process (eg, enrolled into study, reason for ineligibility, or 
refused to participate). 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening). 
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4.1 
Inclusion Criteria 
4.1.1 
Diagnosis of primary ITP according to The American Society of 
Hematology (ASH) Guidelines (Neunert et al, 2011) at least 6 months 
before screening, regardless of splenectomy status 
4.1.2 
Age ≥ 1 year and < 18 years at the time of providing informed consent 
4.1.3 
Subject must be refractory to a prior ITP therapy, having relapsed after at 
least 1 prior ITP therapy, or be ineligible for other ITP therapies 
Examples of prior therapy include but are not limited to: corticosteroids, 
IVIG, anti-D immunoglobulin, and platelet transfusions.  Subjects who 
have failed a splenectomy are eligible for study participation 
4.1.4 
Subject has a documented platelet count ≤ 30 x109/L or is experiencing 
bleeding that is uncontrolled with conventional therapies  
4.1.5 
Subject’s legally acceptable representative (or subject, if applicable) has 
provided informed consent before any study-specific procedure; and 
subject has provided assent, where required by the IRB/IEC 
4.1.6 
Adequate hematologic, renal, and liver function during the screening 
period:   
• 
Hemoglobin > 10.0 g/dL 
• 
Serum creatinine ≤ 1.5 times the upper limit of normal  
• 
Total serum bilirubin ≤ 1.5 times the upper limit of normal  
• 
AST and ALT ≤ 3.0 times the upper limit of normal  
4.2 
Exclusion Criteria 
4.2.1 
Known history of a bone marrow stem cell disorder (Any abnormal bone 
marrow findings other than those typical of ITP must be approved by 
Amgen before a subject may be enrolled in the study) 
4.2.2 
Prior bone marrow transplant or peripheral blood progenitor cell 
transplant  
4.2.3 
Known active or prior malignancy except non-melanoma skin cancers 
within the last 5 years 
4.2.4 
Known history of myelodysplastic syndrome 
4.2.5 
Known history of bleeding diathesis 
4.2.6 
Known history of congenital thrombocytopenia 
4.2.7 
Known history of hepatitis B, hepatitis C or human immunodeficiency 
virus  
4.2.8 
Known history of systemic lupus erythematosus, Evans syndrome, or 
autoimmune neutropenia 
4.2.9 
Known history of antiphospholipid antibody syndrome or known positive 
for lupus anticoagulant 
4.2.10 
Known history of disseminated intravascular coagulation, hemolytic 
uremic syndrome, or thrombotic thrombocytopenic purpura 
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4.2.11 
History of venous thromboembolism or thrombotic events  
4.2.12 
Previous use of romiplostim. Previous use of eltrombopag within 4 
weeks of enrollment.  
4.2.13 
Previous use of PEG-rHuMGDF, recombinant human thrombopoietin 
(rHuTPO) or any other platelet producing agent 
4.2.14 
Rituximab (for any indication) or 6-mercaptopurine within 8 weeks of 
enrollment, or anticipated use at any time during the study 
4.2.15 
Splenectomy within 4 weeks of the screening visit 
4.2.16 
Alkylating agents within 8 weeks before the screening visit or anticipated 
use during the time of the proposed study 
4.2.17 
Vaccinations known to decrease platelet counts within 8 weeks before the 
screening visit 
4.2.18 
Currently enrolled in another investigational device or drug study, or less 
than 30 days since ending another investigational device or drug study(s), 
or receiving other investigational agent(s) 
4.2.19 
Subject will have investigational procedures performed while enrolled in 
this clinical study 
4.2.20 
Female subject of child bearing potential (defined as having first menses) 
is not willing to use, in combination with her partner highly effective 
methods of birth control during treatment and for 1 month after the end of 
treatment 
4.2.21 
Subject is pregnant or breast feeding, or might become pregnant within 
1 month after the end of treatment 
4.2.22 
Subject has known hypersensitivity to any recombinant Escherichia coli 
derived product (eg, Infergen, Neupogen, somatropin, and 
Actimmune®) 
4.2.23 
Subject has previously enrolled into this study 
4.2.24 
Subject will not be available for protocol-required study visits or 
procedures, to the best of the subject’s and investigator’s knowledge 
4.2.25 
Subject has any kind of disorder that, in the opinion of the investigator, 
may compromise the ability of the subject to give written informed 
consent and/or to comply with all required study procedures 
5. 
SUBJECT ENROLLMENT 
Before subjects may be entered into the study, Amgen requires a copy of the site’s 
written institutional review board/independent ethics committee (IRB/IEC) approval of the 
protocol, informed consent form and assent form if applicable.  All subjects or legally 
acceptable representatives must personally sign and date the consent and assent form 
(if applicable) before study-specific procedures are performed.  Adverse events are only 
reported for subjects enrolled in the study.  Subjects are considered enrolled once they 
have been entered through the IVRS and have received their first dose of IP. 
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All subjects who enter into the screening period for the study (entry is defined as the 
point at which informed consent is signed) will receive a unique subject identification 
number before any study procedures are performed.  This number will be used to 
identify the subject throughout the clinical study and must be used on all study 
documentation related to that subject. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed at the time of rescreening or enrollment. 
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product(s) and/or Medical Device(s) 
The Amgen Investigational Product used in this study: romiplostim. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, and 
administration of romiplostim. 
6.2 
Romiplostim  
Romiplostim will be manufactured and packaged by Amgen Inc. and distributed using 
Amgen’s clinical study IP distribution procedures.  Romiplostim is supplied in a 5 mL 
single-use vial as a sterile, white, preservative-free, lyophilized powder containing a 
protein concentration of 0.5 mg/mL of 10 mM histidine, 4.0% mannitol, 2.0% sucrose, 
0.004% polysorbate 20, and a pH 5.0 when reconstituted with 1.2 mL of sterile water for 
injection. 
6.2.1 
Dosage, Administration, and Schedule 
IP will be administered as a subcutaneous injection.  The starting dose of romiplostim 
will be 1 µg/kg based on the subject’s recorded screening weight.  Initially, IP will be 
administered in the clinic by a qualified health care provider and subjects will return to 
the clinic weekly to provide blood samples for platelet counts and undergo any dose 
titrations under the supervision of the treating physician.  Subjects who receive their first 
8 doses in the clinic and achieve a stable dose of romiplostim for at least 4 weeks may 
be allowed to self-inject romiplostim or have the injection administered by a caregiver.  
Weekly dose increases will continue in increments of 1 µg/kg up to a maximum dose of 
10 µg/kg in an attempt to reach a target platelet count of ≥ 50 x 109/L.  Dose adjustments 
will be allowed to maintain a platelet count between ≥ 50 x 109/L and ≤ 200 x 109/L.  
Dose adjustments will be evaluated every 12 weeks due to potential body weight 
changes. 
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If a dose of < 0.05 mL is required, dilution of romiplostim in a 1:2 ratio (a protein 
concentration of 0.25 mg/mL) or a 1:4 ratio (a protein concentration of 0.125 mg/mL) 
may be made with 0.9% saline to ensure an appropriate dispensable volume is 
delivered. 
Subjects will be monitored for the onset of a sustained platelet response (see 
Section 3.1.1) and, if achieved, may dose-reduce romiplostim.  If a subject no longer 
requires treatment with romiplostim but there is subsequently a fall in platelet counts of 
< 50 x 109/L during the 36-month treatment period, treatment with romiplostim should 
resume at the initial weekly dose of 1 μg/kg. 
The effects of overdose of romiplostim are not known.  In high-dose preclinical studies, 
the noted effects were related to the pharmacological action of romiplostim.  In the event 
of an overdose, platelet counts should be monitored frequently.  Please refer to 
Section 6.2.2 for dosage adjustments. 
Specific romiplostim details, including labeling, storage, preparation, dilution, 
administration, etc., are provided in a separate Investigational Product Instruction 
Manual.  Each romiplostim box number is to be recorded on each subject’s 
Investigational Product Administration electronic case report form (eCRF). 
6.2.2 
Dosage Adjustments: Delays or Rules for Withholding 
Investigational Product 
Each subject’s dose will be adjusted based on platelet counts.  The rules outlined in 
Table 1 describe how the adjustments are to be made during the study. 
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Table 1.  Dose Adjustment Rules 
Platelet count (x 109/L) 
Investigational Product Dose Adjustment Rulea 
< 50b 
Increase dose by 1 µg/kg each week (to a maximum of 10 µg/kg) 
50 to 200b 
Dose remains constant 
> 200 to < 400 b,c 
After the platelet count remains in this range for 2 consecutive 
weeks, dose reduce by 1 µg/kg  
> 400 b,c,d 
Withhold the dose and dose reduce by 1 µg/kg on the next 
scheduled day of dosing when platelet count falls < 200 x 109/L  
a If the platelet count is elevated in response to the initiation or increase in dose of another ITP medication, 
then the same dose of IP should be administered when the platelet count is ≤  200 x 109/L. 
b Romiplostim may be used with other therapies for ITP (refer to Section 6.4).  If the subject’s platelet count 
is ≥ 50 x 109/L, other ITP therapies may be reduced or discontinued. 
c If the current dose is 1 μg/kg and a dose reduction is required, the dose will be withheld until the platelet 
count falls to < 50 x 109/L.  Once the platelet count is < 50 x 109/L, dosing will resume at a dose of 1 μg/kg 
using the dose adjustment rules above. 
d If platelet count ≥ 400 x 109/L is due to rescue medications, it is at the discretion of the investigator to 
reduce the dose by 1 µg/kg. 
In situations in which withholding a romiplostim dose results in a rapid drop in platelet 
count, an alternate dosing schedule may be authorized on a case-by-case basis with the 
approval of an Amgen medical monitor. 
The subject’s body weight will be reassessed every 12 weeks.  Subsequent doses of 
romiplostim will be re-calculated using the new weight.  If the volume (mL or μL) of IP will 
be increasing due to an increase in body weight > 2.5 kg, the unit dose (μg/kg) of IP 
should not be increased until a platelet count has decreased to < 50 x 109/L requiring an 
increase in dose. 
All doses of romiplostim will be administered on a weekly basis.  Should a subject miss a 
dose of romiplostim, the dose can be taken within 1 day of the scheduled date of 
administration.  Should the subject miss a dose outside of the 1 day window, the subject 
will continue with the subsequent dose at the next scheduled weekly date. 
Dosing will be stopped at any time during the study if neutralizing antibodies to 
romiplostim or to eTPO are detected.  
6.2.3 
Non-responders to Romiplostim  
Subjects with a platelet count of < 20 x 109/L for 4 consecutive weeks at the maximum 
romiplostim dose of 10 µg/kg should be discontinued from romiplostim and will be 
considered non-responders.  Non-responders will be discontinued from the study and 
undergo all EOT and EOS procedures. 
If the subject is a non-responder but the investigator believes the subject has obtained 
clinical benefit, the investigator must contact the Amgen medical monitor for 
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consideration of continued participation in the study.  If subject is allowed to remain on 
study and receive a stable romiplostim dose for at least 4 weeks, the subject will be 
eligible for self- administration. 
6.3 
Self-administration of Romiplostim 
Romiplostim will initially be administered by the investigator or qualified health care 
professional at clinic visits.  At the investigator’s discretion, subjects who have been 
dosed in the clinic and achieve a platelet count ≥ 50 x 109/L without romiplostim dose 
adjustments for 4 consecutive weeks will be eligible to self-administer romiplostim or 
have the injection administered by a caregiver. 
Those subjects who self-administer their medication, as well as those who are eligible to 
self-administer but choose not to, will only be required to return to the site for ongoing 
evaluations (including platelet counts) at designated study visits (performed every 
4 weeks), as long as their dose of romiplostim remains stable. 
In the event of a change in dose of romiplostim (per the dose adjustment rules in  
Table 1), subjects will be required to return to the clinic for 2 consecutive weeks to 
confirm that the dose adjustment was appropriate.  Subjects will need to be on a stable 
dose and have a platelet count ≥ 50 x 109/L for 2 consecutive weeks without romiplostim 
dose adjustments before resuming self-administration.  
Before subjects begin romiplostim self-administration, it is the responsibility of the 
investigator to ensure that subjects or their caregivers are trained to prepare and 
administer the injection.  Subjects and/or subject’s caregivers will receive training and 
study tools designed to educate the subject on the proper storage, reconstitution, and 
self-administration of romiplostim.  Once subjects or their caregivers have adequately 
demonstrated their ability to reliably administer the medication, subjects may be allowed 
to self-inject (or have the injection given by their caregiver) away from the investigational 
site.  The completion of training on self- injection (or training to a caregiver) will be 
recorded in the subject’s source documentation.  All training will be monitored. 
The site will be required to ensure that subjects are supplied with necessary materials 
required for self-injecting, including dispensing of the IP.  All used vials of romiplostim 
must be returned to the clinic for drug accountability.  Subject diary cards to record the 
dose, dosing date, and any dosing or storage errors will be provided to subjects. 
While subjects are self-injecting, the IP must be provided to subjects every 4 weeks, 
during the regular clinic visits.  Shipping of romiplostim to subjects is prohibited.  
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Subjects are expected to store romiplostim in a refrigerator and to notify the site 
personnel if an error in storage or dosing was made. 
6.4 
Concomitant Therapy  
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care, except for those 
listed in Section 6.6. 
All prescription and non-prescription concomitant medications, used to treat conditions 
other than ITP, administered at the time of enrollment, ongoing after enrollment,  as well 
as changes in such concomitant medications and any new concomitant medications 
taken while the subject is on study, will be recorded on the appropriate eCRF through 
the EOT or the EOS visit, whichever is later. 
Concomitant medications are allowed for subjects enrolled into the study in any situation 
deemed medically necessary to increase platelet counts.  Medications to increase 
platelet counts starting before enrollment and continuing unchanged (dose and 
schedule) while on treatment with romiplostim will be defined as concomitant 
medications for ITP.  Rescue medication is defined as any medication or transfusion, 
other than romiplostim and excluded medications, that is administered after enrollment 
to the subject with the intent of raising platelet counts or to prevent bleeding and 
includes concomitant medications for ITP in which the dose and/or schedule is 
increased.  For the purposes of this study, the permitted rescue medications include the 
following: 
Concomitant and Rescue Therapy for ITP 
• 
corticosteroids 
• 
platelet transfusions 
• 
IVIG 
• 
azathioprine 
• 
anti-D immunoglobulin 
• 
danazol 
Antifibrinolytics can be used at any time during the study and will not be considered 
rescue medication(s). 
Inhaled and/or topical corticosteroids intended to treat non ITP conditions (eg, inhaled 
steroids for asthma) will not be considered concomitant medications for ITP or rescue 
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medications and continuing on such medication(s) will not affect the definition of platelet 
response. 
Rescue medication is allowed throughout the duration of the study when platelet counts 
are < 20 x 109/L and/or when a subject has bleeding or wet purpura.  Rescue medication 
is also allowed in any situation deemed medically necessary by the treating physician to 
increase platelet counts to treat or prevent bleeding. 
Reduction or discontinuation of concomitant or rescue medications for ITP is 
recommended based on investigator judgment when platelet counts are ≥ 50 x 109/L. 
Rescue medications are not provided by Amgen. 
6.5 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of any investigational or non-investigational product(s) or device(s). 
Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) or device(s) supplied by Amgen are to be reported 
according to the instructions provided in the IPIM. 
6.6 
Excluded Treatments During Study Period  
The following medications are not permitted during this study: 
• 
commercially available romiplostim (Nplate®) 
• 
other thrombopoietic receptor agonists (eg, eltrombopag, also known as Promacta® 
or Revolade®) 
• 
any cytotoxic agents or alkylating agents 
• 
Mycophenolate Mofetil 
• 
Rituximab 
• 
rHuTPO 
• 
interferon 
• 
treatments for ITP other than allowed rescue medications  
• 
any other investigational agents that are not approved for commercial use 
If a subject requires administration of any of the medications listed above, Amgen should 
be consulted before administration of the medication when possible.  In all cases, 
Amgen must be informed within 24 hours.  Amgen may decide that the subject will be 
ineligible to receive additional administrations of IP, in which case, the subject should 
complete the EOT and EOS visits. 
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6.7 
Other Treatment Procedures  
If treatment with romiplostim is deemed to be ineffective or intolerable, the investigator 
may decide to perform a splenectomy.  If a splenectomy is performed, the subject will 
discontinue treatment with romiplostim and follow the procedures for the EOT and EOS 
visits. 
7. 
STUDY PROCEDURES 
All subjects and/or their legally acceptable representatives (eg, parents, legal guardian) 
will sign and date the informed consent form before subjects can undergo any 
study-specific procedures.  If required by the IRB/IEC, the assent of the child also must 
be obtained in addition to written informed consent.  Refer to the Schedule of 
Assessments (Table 2) for an outline of the procedures required at each visit.  The visit 
schedule is calculated from day 1 (first administration of romiplostim).  All study 
procedures have a window of ± 1 day. Procedures that are part of routine care and not 
considered study specific procedures may be used as screening procedures to 
determine eligibility. 
Missed visits or procedures that are not completed must be reported as such in the 
subject’s source documentation, with an explanation of why the procedures were not 
completed. 
Any blood sample collected according to the Schedule of Assessments (Table 2) can be 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 
ensure minimized risks to study subjects.  This includes testing to ensure analytical 
methods produce reliable and valid data throughout the course of the study.  This can 
also include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability. 
If informed consent is provided by the subject, or the subject’s legally authorized 
representative, Amgen may do additional testing on remaining samples (ie, residual and 
back-up) to investigate and better understand ITP, the dose response and/or prediction 
of response to romiplostim, characterize antibody response, or characterize aspects of 
the molecule (eg, metabolites).  Results from this analysis will be documented and 
maintained, but may not be reported as part of this study. 
All subjects enrolled will have samples assayed for binding and if positive, neutralizing 
antibodies. 
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7.1 
Schedule of Assessments  
The Schedule of Assessments is found in Table 2 below. 
Table 2.  Schedule of Assessments 
 
 
Procedures 
 
 
Screening 
In Clinic 
Dosing  
Perioda 
Romiplostim Treatment 
Period (up to 36-months)b 
 
 
- 4 Weeks 
 
Week 1 
to  
Week  8 
Weekly 
Every 
4 
Weeks 
Every 
12 
Weeks 
End Of 
Treatment 
Visit 
End of 
Study  
Visit 
Informed consent 
X 
 
 
 
 
 
 
Confirmation of 
primary ITP diagnosis  
X 
 
 
 
 
 
 
ITP/medical history 
X 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
X 
X 
 
Vital signs 
X 
 
 
 
X 
X 
 
Weight   
X 
 
 
 
X 
 
 
Central lab CBC with 
differential  
X 
Xc 
 
Xb 
 
X 
 
Central lab blood 
(serum) chemistry 
X 
 
 
 
X 
X 
 
Local lab platelet 
counts 
X 
X 
Xb,d 
 
 
X 
X  
Local lab peripheral 
blood smear 
 
Xc  
 
Xb 
 
X  
 
Pregnancy test 
X 
 
 
 
Xf 
Xf 
 
Concomitant /rescue 
medications 
X 
X 
X 
X 
X 
X 
X 
Adverse event 
reporting 
 
X 
X 
X 
X 
X 
 
Serious adverse 
events 
X 
X 
X 
X 
X 
X 
X 
Antibody samplee 
 
Day 1 
(before 
first 
dose) 
 
 
W12, W52 
and every 
24 weeks 
thereafter 
X 
 
Romiplostim dosing  
 
X 
X 
 
 
 
 
ITP = immune thrombocytopenia; CBC = complete blood counts 
a  Week 1 to Week 8. All subjects will return to the clinic for weekly dosing of romiplostim, platelet counts by 
a local laboratory, recording of concomitant/rescue medications, and adverse event reporting.   
b   Subjects who complete 6 months of sustained platelet response (platelet count ≥ 50 x109/L in the absence 
of romiplostim or any ITP medications) will have assessments every 12 weeks for the duration of the  
36-month treatment period.  
c Central CBC with differential and local lab peripheral blood smears are to be performed every 4 weeks, 
including pre-dose at week 1.  Screening laboratory studies may be used in lieu of the pre-treatment day 1 
week 1 laboratory tests if performed within 10 days prior to the first dose. Bone marrow biopsy suggested 
if abnormalities detected.  
d  For subjects who establish a stable dose of romiplostim and are self-administering, have the injection 
administered by a caregiver, or meet this criterion but still prefer to come to the clinic for romiplostim 
administration, platelet counts will be monitored every 4 weeks. 
e  For subjects who test positive for antibodies, see Section 7.1.3. Antibody sampling during romiplostim 
treatment is only conducted if subject is receiving study drug. 
f  Local lab urine or serum pregnancy test for female subjects of child-bearing potential (defined as having 
first menses) 
 
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7.1.1 
Routine Blood Tests 
Screening and baseline blood tests for central laboratory testing must be obtained after 
written informed consent and assent (if applicable).  Screening laboratory studies may 
be used in lieu of any required pre-treatment day 1 week 1 laboratory tests if performed 
within 10 days prior to the first dose.  
Refer to the central laboratory manual for instructions on collection, preparation, storage, 
and shipment of blood samples.  Complete blood counts (CBC) with differential and 
blood chemistries will be evaluated at a central laboratory and as outlined in Table 3 
(List of Analytes in Laboratory Specimens). 
The investigator should review locally assessed peripheral blood smears before the first 
dose of romiplostim and every 4-12 weeks thereafter.  Additional locally-assessed blood 
smears may be collected more frequently as clinically indicated or at the request of 
Amgen.  Abnormalities such as nucleated red blood cells, teardrop cells (dacrocytes), 
and blasts should be recorded in the eCRFs.  
Should an abnormality be identified in a CBC or a peripheral blood smear at any time 
during the study, it is recommended that a bone marrow biopsy be performed and 
submitted to a central laboratory for further assessment.  In addition to routine analysis, 
silver and trichrome stains for the assessment of reticulin and collagen, as assessed by 
the modified Bauermeister scale (Appendix B), will be conducted by the central 
laboratory.  All data collected from the bone marrow biopsy will be reported to Amgen as 
part of the study.  
Urine or blood pregnancy testing, for female subjects of child bearing potential (defined 
as having first menses), will be reported by the local laboratory before the first dose of 
romiplostim, every 12 weeks thereafter, and at the end of treatment visit.  Pregnancy 
testing will not be analyzed or reported by the central laboratory. 
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Table 3.  List of Analytes in Laboratory Specimens 
Blood Chemistry 
Hematology 
Other Labs 
Blood urea nitrogen 
RBC 
Antibodiesa 
Creatinine 
Hemoglobin 
• to romiplostim 
Total bilirubin (TB) 
Hematocrit 
• to the peptide portion of romiplostim 
Alkaline phosphatase (ALP) 
MCV 
• cross-reacting to eTPO 
Lactate dehydrogenase  
MCH 
Local lab blood smearsb 
AST 
MCHC 
Local lab urine or blood pregnancy test  
ALT 
RDW 
(if applicable) 
 
 
Central lab optional bone marrow  
 
Plateletsc 
biopsy if abnormality is identified (see  
 
WBC 
Section 7.1.1) to include silver and  
 
Differential 
trichrome stain 
 
• Seg Neuts 
 
 
• Bands/stabs 
 
 
• Eosinophils 
 
 
• Basophils 
 
 
• Lymphocytes 
 
 
• Monocytes 
 
 
• Myeloblasts 
 
 
• Promyelocytes 
 
 
• Myelocytes 
 
 
• Metamyelocytes 
 
 
• Atypical lymphocytes  
 
Calculated ANC 
Nucleated RBC 
 
a Additional samples for antibody status may be obtained as requested by the investigator or Amgen. 
b Locally-assessed blood smears will be performed throughout the study and as requested by the 
investigator or Amgen. 
c Platelet counts are performed by local laboratory only. 
7.1.2 
Platelet Counts 
Platelet counts will be evaluated by the investigative site’s local laboratory and used to 
assess the need for romiplostim dose adjustments and to evaluate platelet response to 
therapy.  Platelet counts will not be analyzed or reported by the central laboratory.  The 
investigational site’s laboratory should be used whenever possible for the assessment of 
platelet counts; however, in certain circumstances platelet count may be assessed at a 
laboratory local to the subject’s residence.  Throughout this study, the laboratory 
analyzing a subject’s platelet count should be consistent. 
All platelet counts required for dosing decisions will be collected and recorded on the 
eCRFs. 
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7.1.3 
Antibody Testing Procedures 
Refer to the central laboratory manual for instructions on collection, preparation, storage, 
and shipment of antibody samples.  Baseline antibody samples must be obtained on 
day 1 before the first administration of romiplostim. 
Blood samples will be collected from all subjects for the measurement of 
anti-romiplostim binding antibodies.  Binding antibodies will be assessed for their ability 
to bind to romiplostim or the peptide portion of romiplostim, and their potential (if any) to 
cross-react with eTPO.  Samples testing positive for binding antibodies will also be 
tested for neutralizing antibodies by assessing their ability to neutralize romiplostim 
and/or eTPO in a cell-based bioassay.  Binding antibodies may be further characterized 
for quantity/titer, isotype, affinity and presence of immune complexes.  While the subject 
is receiving IP, blood samples will be collected for anti-romiplostim antibodies at 
week 12, week 52, every 24 weeks thereafter, and at the EOT visit.  Only positive results 
for neutralizing antibodies will be provided to investigational sites; if no results are 
provided, sites may assume that no neutralizing antibodies to romiplostim were 
identified. 
Subjects who test positive for neutralizing antibodies to romiplostim or to eTPO during 
the course of the study (or at the EOT visit) will be removed from treatment and will be 
asked to return for additional follow-up testing.  This testing should occur every 3 months 
starting from when the site has been notified of the positive result, until: (1) neutralizing 
antibodies are no longer detectable or (2) the subject has been followed for a period of 
at least 1 year (± 4 weeks).  More frequent testing (eg, every month) or testing for a 
longer period of time may be requested in the event of safety-related concerns.  
Subjects who test positive for binding, non-neutralizing antibodies and have clinical 
sequelae that are considered potentially related to an anti-romiplostim antibody 
response, may also be asked to return for additional follow-up testing. 
Should a subject fail to respond or fail to maintain a response to romiplostim, an 
unscheduled serum sample will be required to rule out anti-romiplostim antibodies.  
7.2 
Sample Storage and Destruction  
Any blood sample collected according to the Schedule of Assessments (Table 2) can be 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 
minimize risks to study subjects.  This includes testing to ensure analytical methods 
produce reliable and valid data throughout the course of the study.  This can also 
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include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability. 
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality. 
If informed consent is provided by or for the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand ITP 
and characterize aspects of the molecule (eg, mechanism of action/target, metabolites).  
Results from this analysis are to be documented and maintained, but are not necessarily 
reported as part of this study.  Samples can be retained for up to 20 years. 
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of exploratory studies are not placed in the subject’s 
medical record and are not to be made available to the subject, members of the family, 
the personal physician, or other third parties, except as specified in the informed 
consent. 
The subject and/or the subject’s legally authorized representative retain the right to 
request that the sample material be destroyed by contacting the investigator.  Following 
the request from the subject (or their legally authorized representative), the investigator 
is to provide the sponsor with the required study and subject number so that any 
remaining (eg, blood) samples and any other components from the cells can be located 
and destroyed.  Samples will be destroyed once all protocol-defined procedures are 
completed.  However, information collected from samples prior to the request for 
destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  
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7.3 
Medical History 
A complete medical history is required.  The complete medical history related to ITP 
including prior therapies, bleeding history, and any bone marrow biopsy data will be 
collected at screening.  For subjects referred to the research center, copies of the 
subject records from the referring physician should be obtained.  
7.4 
Concomitant Medications 
In addition to routine concomitant medications for conditions other than ITP, during the 
course of the study, all concomitant and rescue medications administered for ITP will be 
recorded in the eCRF from screening until the end of treatment or end of study visit.  
7.5 
Screening 
The screening period begins on the date that the subject (and/or the subject’s legally 
authorized representative) signs the IRB/IEC-approved informed consent form and 
continues until the date of enrollment.  Procedures that are part of routine care are not 
considered study-specific procedures.  All subjects will be screened for eligibility before 
enrollment. 
The following screening procedures must be completed within 4 weeks before the day of 
first dose of romiplostim:  
• 
informed consent (and assent if required by IRB/IEC) 
• 
confirmation of ITP diagnosis 
• 
ITP and medical history  
• 
physical exam as per standard of care including weight and vital signs.  Physical 
examination findings should be recorded on the medical history or adverse event 
eCRF 
• 
concomitant medications 
• 
central lab CBC with differential and blood chemistry 
• 
confirmation of one local lab platelet count ≤ 30 x 109/L and/or documentation of 
bleeding that was uncontrolled with conventional therapies for ITP 
• 
local lab urine or serum pregnancy test for female subjects of child-bearing potential 
(defined as having first menses) 
• 
serious adverse events that occurred after the signing of informed consent  
If subjects do not successfully complete screening within 4 weeks after initial informed 
consent, their screen failure will be registered in the IVRS.  Subjects who fail screening 
will be allowed to re-screen.  Subjects who rescreen must repeat relevant screening 
procedures within the new 4-week screening window.  If the subject’s screening platelet 
count is > 30 x 109/L without evidence of uncontrolled bleeding with conventional 
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therapies upon initial assessment the site may reassess the platelet count during the 
4-week screening period without registration of screen-failure or re-consenting the 
subject. 
7.6 
Romiplostim Treatment Period (Up to a 36 Months Duration) 
Subjects that meet all study entrance criteria will be enrolled using IVRS to receive 
romiplostim. 
The following procedures will be completed during the romiplostim treatment period at 
the times designated in the Schedule of Assessments (Table 2): 
• 
documentation of concomitant and rescue medications  
• 
adverse event reporting 
• 
central lab CBC with differential (every 4 weeks) 
• 
central lab blood chemistry (every 12 weeks) 
• 
local lab platelet counts. 
• 
collection of blood samples for anti-romiplostim antibodies (first sample is collected 
before first dose of romiplostim, then at week 12, week 52, and every 24 weeks 
thereafter) 
• 
local lab peripheral blood smear (every 4 weeks) 
• 
physical exam with vital signs and weight (every 12 weeks) 
• 
local lab urine or serum pregnancy test for female subjects of child-bearing potential 
(defined as having first menses) every 12 weeks 
• 
romiplostim administration 
Note: Administration of romiplostim should be the last procedure completed during each 
visit that it is required. 
For the first 8 weeks of treatment, all subjects will return to the clinic for weekly 
administration of romiplostim.  Subjects who have received their first 8 doses in the clinic 
and achieve a stable dose of romiplostim for at least 4 weeks may be allowed to 
self-inject romiplostim or have the injection administered by a caregiver.  For subjects 
who established a stable dose of romiplostim and are self-administering, platelet counts 
will be monitored every 4 weeks.  For complete details on self-administration, refer to 
Section 6.3.  Subjects who stop romiplostim and all other medications for ITP 
(concomitant or rescue) due to the onset of a sustained platelet response will continue to 
be monitored per the schedule of assessments for at least 6 months from the first 
platelet count ≥ 50 x 109/L. 
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If the subject has maintained a sustained platelet response, subsequent visits and 
procedures including the platelet counts, CBC, and peripheral blood smears will be 
performed every 12 weeks for the duration of the 36-month treatment period.  If the 
subject’s platelet counts fall to < 50 x 109/L and treatment with romiplostim is resumed, 
the visit schedule will revert to weekly platelet counts, and CBC with peripheral blood 
smear evaluations every 4 weeks.  The visit assessment weeks and procedures resume 
counting from first dose of romiplostim after enrollment. 
7.7 
End of Treatment Visit (EOT) 
All subjects will complete an EOT visit.  For subjects who complete the 36-month 
treatment period and who have been off romiplostim and other medications for ITP 
(concomitant or rescue) for 4 weeks or more, the EOT visit will be the final study visit 
and will occur after the completion of the 36-month treatment period.  For subjects 
ending the 36-month treatment period for non-response or other reasons while still 
receiving romiplostim, this visit will be 1 week after the last administration of romiplostim.   
The following assessments will be completed at the EOT visit: 
• 
physical exam, including vital signs 
• 
documentation of concomitant and rescue medications   
• 
adverse event reporting 
• 
central lab CBC with differential and blood chemistry 
• 
local lab platelet counts 
• 
collection of blood samples for anti-romiplostim antibodies  
• 
local lab peripheral blood smear 
• 
local lab urine or serum pregnancy test for female subjects of child-bearing potential 
(defined as having first menses) 
7.8 
End of Study Visit (EOS) 
Four weeks after the last dose of romiplostim for subjects who end the 36-month 
treatment period for non-response or other reasons while still receiving romiplostim will 
have an EOS visit. 
The following assessments will be completed at the EOS visit:  
• 
local lab platelet count 
• 
serious adverse event reporting  
• 
documentation of concomitant and rescue medications  
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8. 
WITHDRAWAL AND REPLACEMENT OF SUBJECTS 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to his or her future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to continue receiving IP or 
procedures at any time during the study but continue participation in the study.  If this 
occurs, the investigator is to discuss with the subject the appropriate processes for 
discontinuation from IP and must discuss with the subject the options for continuation of 
the Schedule of Assessments (Table 2) and collection of data, including endpoints and 
adverse events.  The investigator must document the change to the Schedule of 
Assessments (Table 2) and the level of follow-up that is agreed to by the subject (eg, 
follow-up in person, by telephone/mail, through family/friends, in 
correspondence/communication with other physicians, from review of the medical 
records). 
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.  Subjects who withdraw 
early should complete an EOT and EOS visit.  The data generated may potentially not 
be included in the subject’s study data, except in the case of a possibly related serious 
adverse event, where data will be collected. 
8.2 
 Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product and/or other protocol-required therapies, protocol procedures, or the study as a 
whole at any time prior to study completion. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1. 
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8.2.1 
Reasons for Removal From Treatment 
Reasons for removal from romiplostim or observation might include the following: 
• 
protocol specified criteria 
• 
subject request (or the subject’s legally authorized representative)  
• 
safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, requirement for alternative therapy, pregnancy)  
• 
death 
• 
lost to follow-up 
• 
decision by Sponsor (other than subject request, safety concern, lost to follow-up) 
8.2.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are as follows: 
• 
protocol specified criteria 
• 
decision by sponsor  
• 
withdrawal of consent from study 
• 
death 
• 
lost to follow-up 
8.3 
Replacement of Subjects 
Subjects who withdraw from the study early will not be replaced. 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Adverse Events 
9.1.1 
Definition of Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record. 
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates the pre-existing medical condition (eg, diabetes, migraine 
headaches, gout) has increased in severity, frequency, and/or duration, and/or has an 
association with a significantly worse outcome.  A pre-existing condition that has not 
worsened during the study, and involves an intervention such as elective cosmetic 
surgery or a medical procedure while on study is not considered an adverse event. 
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
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legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study. 
9.1.2 
Definition of Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria: 
• 
fatal 
• 
life threatening (places the subject at immediate risk of death) 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
congenital anomaly/birth defect 
• 
other medically important serious event 
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay). 
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, or events that necessitate 
an emergency room visit, outpatient surgery, or urgent intervention. 
9.2 
Reporting of Adverse Events 
9.2.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of investigational 
product through the end of treatment period are reported using the applicable eCRF (eg, 
Adverse Event Summary CRF). 
Because all subjects who enter the study will be diagnosed with ITP according to the 
ASH guidelines, ITP should not be reported as an adverse event during the conduct of 
the study. 
The investigator must assign the following adverse event attributes: 
• 
adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms) 
• 
dates of onset and resolution (if resolved) 
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• 
severity  
• 
assessment of relatedness to romiplostim  
• 
action taken 
The adverse event severity grading scale used will be the Common Terminology Criteria 
for Adverse Events (CTCAE) version 3.0 grading scale.  The severity grading scale used 
in this study is described in Appendix A. 
The investigator must assess whether the adverse event is possibly related to the 
romiplostim.  This relationship is indicated by a “yes” or “no” response to the question:  Is 
there a reasonable possibility that the event may have been caused by the romiplostim?   
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity (eg, administration of investigational product, protocol-required 
therapies, device(s) and/or procedure (including any screening procedure(s)).  This 
relationship is indicated by a “yes” or “no” response to the question:  “Is there a 
reasonable possibility that the event may have been caused by a study activity (eg, 
administration of investigational product, protocol-required therapies, device(s)), and/or 
procedure?”  
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the investigator's judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
The Investigator is expected to follow reported adverse events until stabilization or 
reversibility. 
9.2.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through 30 days after last dose of IP (for subjects who have sustained platelet 
responses and never resume IP after sustained response during the trial); or the later of 
the EOT and EOS visits, are recorded in the subject’s medical record and are submitted 
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to Amgen.  All serious adverse events must be submitted to Amgen within 24 hours 
following the investigator’s knowledge of the event via the applicable CRF. 
After the protocol-required reporting period defined above, the investigator does not 
need to actively monitor subjects for serious adverse events.  However, if the 
investigator becomes aware of a serious adverse event after this protocol-required 
reporting period, the investigator will report the event to Amgen within 24 hours following 
the investigator’s knowledge of the event.  Serious adverse events reported outside of 
the protocol-required reporting period will be captured within the safety database as 
clinical trial cases for the purposes of expedited reporting.  
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
Serious Adverse Event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event (eSAE) Contingency Report Form within 24 hours of the 
Investigator’s knowledge of the event.  See Appendix A for a sample of the Serious 
Adverse Event Worksheet/electronic Serious Adverse Event Contingency Report Form.  
For EDC studies where the first notification of a Serious Adverse Event is reported to 
Amgen via the eSerious Adverse Event Contingency Report Form, the data must be 
entered into the EDC system when the system is again available 
The investigator must assess whether the serious adverse event is possibly related to 
any study-mandated activity or procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure”? 
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility. 
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  The investigator 
may be asked to provide additional follow-up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the applicable CRF (eg, Adverse 
Event Summary CRF). 
If a subject is permanently withdrawn from the study because of a serious adverse 
event, this information must be submitted to Amgen. 
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Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and good 
clinical practice. 
The investigator should notify the appropriate IRB/IEC of serious adverse events 
occurring at the site and other adverse event reports received from Amgen, in 
accordance with local procedures and statutes. 
9.3 
Pregnancy and Lactation Reporting 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking protocol-required therapies report the pregnancy to Amgen as specified 
below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur after the last dose of protocol-required therapies 
through 1 month after the last dose of romiplostim.  
The pregnancy should be reported to Amgen’s global Pregnancy Surveillance Program 
within 24 hours of the investigator’s knowledge of the event of a pregnancy.  Report a 
pregnancy on the Pregnancy Notification Worksheet (Appendix C).  The Pregnancy 
Surveillance Program (PSP) will seek to follow the pregnant woman throughout her 
pregnancy and her baby up to 12 months after birth. 
If a lactation case occurs while the female subject is taking protocol-required therapies 
report the lactation case to Amgen as specified below.  
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur after the last dose of protocol-required therapies through  
1 month after the end of the dose of romiplostim.  
Any lactation case should be reported to Amgen’s global Lactation Surveillance Program 
(LSP) within 24 hours of the investigator’s knowledge of event.  Report a lactation case 
on the Lactation Notification Worksheet (Appendix D). 
10. 
STATISTICAL CONSIDERATIONS 
The statistical analysis of this open-label study will be descriptive in nature only.  No 
hypothesis testing is planned.  Categorical data will be presented in the form of number 
and percentage.  Continuous data will be provided with the descriptive statistics 
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(n, mean, standard deviation, median, Q1 [25th percentile], Q3 [75th percentile], 
minimum, and maximum).  
10.1 
Study Endpoints, Subsets, and Covariates 
10.1.1 
Study Endpoints 
Primary Endpoint:   
• 
The percentage of time with a platelet count of ≥ 50 x 109/L starting from week 2 in 
the first 6 months of the treatment period without rescue medication use within the 
past 4 weeks  
Secondary Endpoints:   
• 
The percentage of time with a platelet count of ≥ 50 x 109/L starting from week 2 until 
the end of the treatment period without rescue medication use within the past 
4 weeks  
• 
The percentage of time with an increase in platelet count ≥ 20 x 109/L above 
baseline starting from week 2 until the end of the treatment period without rescue 
medication use in the past 4 weeks. 
• 
Subject incidence of rescue ITP medications used  
• 
The incidence of anti-romiplostim neutralizing antibodies and cross reactive 
antibodies to TPO at any time during the study 
• 
The incidence of adverse events, including clinically significant changes in laboratory 
values  
Exploratory Endpoints: 
• 
The subject incidence with a sustained platelet count of ≥ 50 x 109/L for 6 months or 
greater without the use of any ITP medications (concomitant, rescue, or romiplostim)  
• 
The incidence of splenectomy during the treatment period for subjects entering the 
study pre-splenectomy 
• 
The subject incidence of romiplostim self-administration 
10.1.2 
Analysis Sets  
10.1.2.1 
Full Analysis Set 
The full analysis set will consist of all enrolled subjects.  Analyses for demographics and 
baseline characteristics will use this analysis set. 
10.1.2.2 
Safety Analysis Set 
The safety analysis set will consist of all subjects who receive at least 1 dose of 
romiplostim.  The analyses of all safety endpoints will be based on the safety analysis 
set. 
10.1.2.3 
Efficacy Analysis Set 
The efficacy analysis set will consist of all subjects who received at least 1 dose of 
romiplostim.  The analyses of all efficacy endpoints will be based on the efficacy analysis 
set.  
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10.1.2.4 
Per Protocol Analysis Set 
The per protocol analysis set will consist of all subjects who received at least 1 dose of 
IP and met all eligibility criteria.  A sensitivity analysis using the per protocol set will be 
conducted for the primary efficacy endpoint. 
10.2 
Sample Size Considerations 
The sample size for this study is governed by the number of pediatric ITP subjects who 
meet the eligibility requirements during enrollment period.  It is estimated that 
approximately 200 subjects will enroll into this study.  The percentage of time achieving 
platelet response in the first 6 months of treatment period for ITP subjects with 
romiplostim (both adults and pediatric) is estimated at 74%.  The standard deviation of 
percentage of time is estimated between 30% and 36% based on previous Nplate data. 
Given the sample size of 200 subjects, the half width of the 95% confidence interval (CI) 
for the percentage of time achieving platelet response is estimated to be between 4% 
and 5%. 
10.3 
Planned Analyses 
The analysis will be descriptive in nature.  No formal hypothesis is to be tested. 
10.3.1 
Interim Analyses 
Interim analyses will be conducted to support regulatory filings, and accumulated data 
for this study will be summarized to provide ongoing assessments of the safety of 
romiplostim.  These interim analyses will occur at least annually until the end of the 
study. 
10.3.2 
Analysis of Key Study Endpoints 
10.3.2.1 
Efficacy Endpoints 
The primary endpoint for this study is the percentage of time with platelet response 
starting from week 2 in the first 6 months of the treatment period.  Platelet response is 
defined as platelet count ≥ 50 x109/L at a scheduled protocol visit.  Platelet counts within 
4 weeks of a rescue ITP medication will not be deemed as platelet response. The 95% 
CI will be calculated for the estimated percentage of time. 
Summary statistics of platelet counts and responses will be provided at weeks 1 to 8 and 
then every 4 weeks. 
The percentage of time with platelet response starting from week 2 until the EOT period 
will be summarized with 95% CI. 
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Missing platelet counts at weeks 12 and 16, and every 4 weeks thereafter will be 
imputed by using the mean of the 2 closest non-missing platelet counts within ±1 week 
before study discontinuation.  If still missing after imputation, platelet counts will be 
considered as non-response. 
The proportion of subjects with splenectomy during the study will be summarized for the 
subjects who entered this study without splenectomy. 
10.3.2.2 
Safety Endpoints 
The exposure-adjusted incidence rates as well as subject incidence rates of adverse 
events will be summarized by system organ class and by preferred term according to the 
MedDRA dictionary.  Exposure-adjusted rate is defined as total number of events 
divided by time of duration when subjects were under observation.  The summary 
includes all treatment-emergent adverse events recorded from the start of IP on this 
study, or any worsening of conditions present at baseline before dosing in this study.  
This summary for adverse events will be performed for the following categories 
• 
all adverse events 
• 
romiplostim-related adverse events 
• 
serious adverse events 
• 
adverse events leading to withdrawal from the study 
• 
adverse events of interest (hemorrhage events, etc.) 
In addition, incidence and exposure-adjusted rates of adverse events by period may also 
be explored. 
Subject listings for all adverse events, serious adverse events, and adverse events 
leading to withdrawal from the study will be provided. 
The incidence and percentage of subjects who develop anti-romiplostim antibodies 
(binding and if positive, neutralizing) at any time will be tabulated. 
Summary statistics will be provided for blood chemistry and CBC at each time point.  
Shift tables between the worst post-baseline and baseline values will be provided (based 
on the National Cancer Institute CTCAE, version 3.0). 
10.3.3 
Primary Analysis 
The objective for the primary analysis will be to summarize the data with the respect to 
the primary and secondary endpoints for the trial. The primary analysis will occur after 
the last subject has completed all investigational treatment and observations on this 
protocol.  The primary analysis will serve as the final analysis for the trial. 
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10.3.4 
Additional Analyses 
10.3.4.1 
Subject Accountability 
The number of subjects who enrolled into the study, received at least 1 dose of IP, 
completed the IP, completed the study and prematurely withdrew, and the reason for 
premature withdrawal, will be summarized. 
10.3.4.2 
Demographic and Baseline Characteristics 
Demographics and selected current study baseline characteristics will be summarized 
using descriptive statistics and listed for the following: 
• 
age, sex, and race 
• 
height, weight 
• 
medical history 
• 
ITP history 
• 
baseline hematology 
• 
baseline physical examination 
• 
baseline vital signs 
10.3.4.3 
Investigational Product Administration 
Summary statistics will be provided for cumulative dose (by µg and µg/kg) and average 
weekly dose (by µg/week and µg/kg/week).  Exposure summary by baseline 
splenectomy status (yes/no) and concurrent ITP therapy status will also be provided.  
Weekly summary for weight-based dose will also be provided. 
A listing of IP administration, including weight-based dose and reason for ending IP will 
be provided. 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template will be 
communicated by letter from the Amgen Clinical Study Manager to the investigator.  The 
written informed consent documents should be prepared in the language(s) of the 
potential subject population. 
If the subject is ≥ age 7 but has not attained the legal age for consent for treatments or 
procedures involved in clinical investigations, under the applicable law of the jurisdiction 
in which the clinical investigation will take place, the investigator is responsible for 
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obtaining written assent from the subject.  For specific local information, consult the 
country-specific requirements of the applicable countries. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent and assent (if applicable) from the subject and/or 
legally acceptable representative after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study and before any protocol-specific 
screening procedures or any IP is administered.  A legally acceptable representative is 
an individual or other body authorized under applicable law to consent, on behalf of a 
prospective subject, to the subject’s participation in the clinical study. 
The investigator is also responsible for asking the subject or his/her legally acceptable 
representative if the subject has a primary care physician and if the subject agrees to 
have his/her primary care physician informed of the subject’s participation in the clinical 
study.  If the subject or his/her legally acceptable representative agrees to such 
notification, the investigator shall inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator should 
document such in the subject’s medical record. 
The acquisition of informed consent and, if applicable, assent and the subject’s 
agreement or refusal of his/her notification of the primary care physician is to be 
documented in the subject’s medical records, and the informed consent/assent form 
should be signed and personally dated by the subject or a legally acceptable 
representative and by the person who conducted the informed consent discussion.  The 
original signed informed consent form and assent form, if applicable, should be retained 
in accordance with institutional policy, and a copy of the signed consent form/assent 
form should be provided to the subject or legally acceptable representative. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form/assent form to the subject and must allow for questions.  
Thereafter, both the subject and the witness must sign the informed consent form/assent 
form to attest that informed consent was freely given and understood.   
11.2 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB/IEC for 
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written approval.  A copy of the written approval of the protocol and informed consent 
and if applicable the assent form must be received by Amgen before recruitment of 
subjects into the study and shipment of Amgen investigational product. 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
The investigator will be responsible for obtaining annual IRB/IEC/head of medical 
institution approval and renewal throughout the duration of the study.  Copies of the 
investigator’s reports and the IRB/IEC/head of the medical institution’s continuance of 
approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen: 
• 
Subjects are to be identified by a unique subject identification number. 
• 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations. 
• 
On the CRFs or other documents submitted to Amgen, subjects should be identified 
by a subject identification number only, with a complete and accurate date of birth on 
the demographics CRF. 
• 
For Serious Adverse Events reported to Amgen, subjects should be identified by 
their initials, date of birth, and a subject identification number, initials for faxed 
reports, in accordance with local laws and regulations), and date of birth (in 
accordance with local laws and regulations). 
• 
Documents that are not for submission to Amgen (eg, signed informed consent 
forms) should be kept in strict confidence by the investigator. 
In compliance with Federal regulations/ICH GCP Guidelines it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.  The investigator is obligated to inform and 
obtain the consent of the subject to permit named representatives to have access to 
his/her study-related records, including personal information, without violating the 
confidentiality of the subject. 
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11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 
The Coordinating investigator, identified by Amgen, will be one or more of the following: 
• 
a recognized expert in the therapeutic area 
• 
an investigator who provided significant contributions to either the design or 
interpretation of the study 
• 
an Investigator contributing a high number of eligible subjects 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
If Amgen amends the protocol, agreement from the investigator must be obtained.  The 
IRB/IEC/head of the medical institution must be informed of all amendments and give 
approval.  The investigator must send a copy of the approval letter from the IRB/IEC/ 
head of the medical institution to Amgen. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
Investigator reserve the right to terminate the Investigator’s participation in the study 
according to the study contract.  The investigator should notify the IRB/IEC head of the 
medical institution in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product as 
provided for by the local country’s regulatory mechanism.  However, Amgen reserves 
the unilateral right, at its sole discretion, to determine whether to supply Amgen 
investigational product, and by what mechanism, after termination of the study and 
before it is available commercially. 
12.2 
Study Documentation and Archive 
The investigator should maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on eCRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
eCRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
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In this study, the IVRS captures the following data points and these are considered 
source data:  subject identification number, the date of the screening, the date of 
enrollment, date of first dose and the date and reason for early withdraw or study 
completion.  
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.  Elements should include: 
• 
subject files containing completed CRF, informed consent forms, and subject 
identification list 
• 
study files containing the protocol with all amendments, investigator’s brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
• 
proof of receipt/delivery sheet, Investigational Product Accountability Record, Return 
of Investigational Product for Destruction, Final Investigational Product Reconciliation 
Statement (if applicable), and all drug-related correspondence 
In addition, all original source documents supporting entries in the eCRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Amgen Clinical Monitor is responsible for verifying the CRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 
research.  The Clinical Monitor is to have access to subject medical records and other 
study-related records needed to verify the entries on the CRFs. 
The investigator agrees to cooperate with the monitor to ensure that any problems 
detected in the course of these monitoring visits, including delays in completing CRFs, 
are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function (or 
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designees).  Inspection of site facilities (eg, pharmacy, drug storage areas, laboratories) 
and review of study-related records will occur to evaluate the study conduct and 
compliance with the protocol, ICH GCP, and applicable regulatory requirements. 
Data capture for this study is planned to be electronic: 
• 
All source documentation supporting entries into the electronic CRFs must be 
maintained and readily available. 
• 
Updates to electronic CRFs will be automatically documented through the software’s 
“audit trail.” 
• 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review will be performed on subject data received at Amgen.  During 
this review, subject data will be checked for consistency, omissions, and any 
apparent discrepancies.  In addition, the data will be reviewed for adherence to the 
protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or site notifications will be created in 
the EDC system database for site resolution and closed by Amgen reviewer. 
• 
The principal investigator signs only the Investigator Verification Form for this 
electronic data capture study.  This signature will indicate that the principal 
investigator inspected or reviewed the data on the CRF, the data queries, and the 
site notifications, and agrees with the content. 
Amgen (or designee) will perform self-evident corrections to obvious data errors in the 
clinical trial database, as documented in the Study-specific Self-evident Corrections 
Plan.  Examples of obvious data errors that may be corrected by Amgen (or designee) 
include deletion of obvious duplicate data (eg, same results sent twice with the same 
date with different visit—week 4 and early termination) and clarifying “other, specify” if 
data are provided (eg, race, physical examination).  Each investigative site will be 
provided a list of the types of corrections applied to study data at the initiation of the 
study and at study closeout. 
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 2), the investigator can search publically available 
records [where permitted]) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible. 
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12.5 
Language 
eCRFs must be completed in English.  TRADENAMES® (if used) for concomitant 
medications may be entered in the local language. Consult the country-specific 
requirements for language requirements. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.   
12.6 
Publication Policy 
To coordinate dissemination of data from this study, Amgen encourages the formation of 
a publication committee consisting of several principal investigators and appropriate 
Amgen staff, the governance and responsibilities of which are set forth in a Publication 
Charter.  The committee is expected to solicit input and assistance from other 
investigators and to collaborate with authors and Amgen staff as appropriate as defined 
in the Publication Charter.  Membership on the committee (both for investigators and 
Amgen staff) does not guarantee authorship—the criteria described below should be met 
for every publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors), which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, 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 should meet conditions 1, 2, and 3. 
• 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
• 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
• 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
• 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for corporate review.  The Clinical 
Study Agreement among the institution, principal investigator, and Amgen will detail the 
procedures for, and timing of, Amgen’s review of publications. 
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12.7 
Compensation  
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document.  Depending on the study agreement and consent 
form, subjects may be compensated for reasonable expenses not associated with study 
related injuries (eg, travel costs). 
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13. 
REFERENCES  
Amgen Romiplostim Investigator’s Brochure, version 11.0, 2012.  
BCSH Guidelines; Management of ITP in Adults, children and in pregnancy.  
Br J Haematol. 2003;120:574-596.  
Bain BJ, Clark DM, Lampert IA, Wilkins BS.  Bone Marrow Pathology.  2nd Edition.  
London:  Blackwell Science Ltd:  2001. 
Bauermeister DE.  Quantitation of bone marrow reticulin – a normal range.  Am J Clin 
Pathol.  1971;56:24-31. 
Bennett CM, Rogers ZR, Kinnamon DD, et al.  Prospective phase 1/2 study of rituximab 
in childhood and adolescent chronic immune thrombocytopenic purpura.  Blood.  
2006;107(7):2639-2642.  
Blanchette VS, Price V.  Childhood chronic immune thrombocytopenic purpura: 
unresolved issues.  J Pediatr Hematol Oncol.  2003;25(suppl 1):S28-S33.  
Bolton-Maggs, PHB. Management of immune thrombocytopenic purpura.  Pediatr Child 
Health.  2007;17:305-310.   
Bottiger LE, Westerholm B.  Thrombocytopenia. 1. Incidence and aetiology.  Acta Med 
Scand.  1972;191:535-540.  
Buchanan GR, Adix L.  Current challenges in the management of children with idiopathic 
thrombocytopenic purpura.  Pediatr Blood Cancer.  2006;47(5 Suppl):681-684.  
Castro-Malaspina H, Rabellino EM, Yen A, Nachman RL, Moore MAS. Human 
megakaryocyte stimulation of proliferation of bone marrow fibroblasts. Blood. 
1981;57:781-787. 
Cines DB, Blanchette VS.  Immune thrombocytopenic purpura. N Engl J Med. 
2002;346(13):995-1008.  
Douglas VK, Tallman MS, Cripe LD, Peterson LC. Thrombopoietin administered during 
induction chemotherapy to patients with acute myeloid leukemia induces transient 
morphologic changes that may resemble chronic myeloproliferative disorders. Am J Clin 
Pathol. 2002;117:844-850. 
George JN, Woolf SH, Raskob GE, et al.  Idiopathic thrombocytopenic purpura: a 
practice guideline developed by explicit methods for the American Society of 
Hematology.  Blood.  1996;88:3-40.  
George JN, El Harake MA, Aster RH.  Thrombocytopenia due to enhanced platelet 
destruction by immunologic mechanisms. In: Beutler E, et al, eds. Williams Hematology. 
New York: McGraw-Hill; 1995;1315-1355.  
Glanz J, France E, Xu S, Hayes T, Hambidge S.  A population-based, multisite cohort 
study of the predictors of chronic idiopathic thrombocytopenic purpura in children. 
Pediatrics.  2008;121(3):e506-e512.  
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals:  Writing and Editing for Biomedical 
Publication.  2006. http://www.icmje.org/ 
Kalpatthi R, Bussel J.  Diagnosis, pathophysiology and management of children with 
refractory immune thrombocytopenic purpura.  Curr Opin Pediatr.  2008;20:8-16.  
Kelton JG, Gibbons S.  Autoimmune platelet destruction: idiopathic thrombocytopenic 
purpura.  Semin Thromb Hemost.  1982;8:83-104.  
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Kuhne T, Blanchette VS, Buchanan GR, et al.  Splenectomy in children with idiopathic 
thrombocytopenic purpura: A prospective study of 134 children from the Intercontinental 
Childhood ITP Study Group.  Pediatr Blood Cancer.  2007;49:829-834  
Kuhne T.  Idiopathic thrombocytopenic purpura in childhood: controversies and 
solutions.  Pediatr Blood Cancer.  2006;47:650-652.  
Kuhne, T.  Investigation and management of newly diagnosed childhood idiopathic 
thrombocytopenic purpura: problems and proposed solutions.  Pediatric Hematol Oncol.  
2003;25(suppl 1):S24-S27.  
Kuter DJ. New thrombopoietic growth factors. Blood. 2007; pre-published online 
February 8, 2007; DOI 10.1182/Blood-2006-10-019315. 
Kuter DJ, et al. Bone marrow fibrosis: pathophysiology and clinical significance of 
increased bone marrow stromal fibers. Brit J Haematol. 2007:139:351-362. 
Lilleyman JS.  Management of childhood idiopathic thrombocytopenia.  Br J Hematol.  
1999;105:871-875.  
McMillan R.  Chronic idiopathic thrombocytopenic purpura.  N Engl J Med.  
1981;304:1135-1147.  
Mufti G, Bagg A, Hasserjian R, et al. Bone marrow reticulin in patients with immune 
thrombocytopenic purpura. Blood. 2006; 108 (11): 73b. Abstract 3982. 
Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr, Crowther MA.  The American 
Society 2011 evidence-based practice guideline for immune thrombocytopenia.  Blood.  
2011;117(16):4190-4207. 
Neunert CE, Bright BC, Buchanan GR.  Severe chronic refractory immune 
thrombocytopenic purpura during childhood: a survey of physician management.  
Pediatr Blood Cancer.  2008;51(4):513-515.  
Nugent D.  Immune thrombocytopenic purpura of childhood.  Hematol.  2006;97-103.  
Parodi E, Nobili B, Perrotta S.  Rituximab (Anti-CD20 monoclonal antibody) in children 
with chronic refractory symptomatic immune thrombocytopenic purpura: Efficacy and 
safety of treatment.  Int J Hematol.  2006:84:48-53. doi:10.1532/IJH97.E0518.  
Provan  D, Stasi R, Newland AC, et al.  International consensus report on the 
investigation and management of primary immune thrombocytopenia.  Blood.  
2010;115(2) 168-186.  
Reid MM.  Chronic idiopathic thrombocytopenic purpura: incidence, treatment, and 
outcome.  Arch Dis Child.  1995;72:125-128.  
Rituxan Prescribing Information located at: http://www.rituxan.com/updated October, 
2012. Last accessed March 2012.  
Robb LG, Tiedeman K.  Idiopathic thrombocytopenic purpura: predictors of chronic 
disease.  Arch Dis Child.  1990;65:502-506.  
Rodeghiero F, Stasi R, Gernsheimer T, et al.  Standardization of terminology, definitions 
and outcome criteria in immune thrombocytopenic purpura of adults and children: report 
from an international working group.  Blood.  2009;113(11):2386-2393.  
Schmitt A, Jouault H, Guichard J, Wendling F, Drouin A, Cramer EM. Pathologic 
interaction between megakaryocytes and polymorphonuclear leukocytes in 
myelofibrosis. Blood. 2000;96:1342-1347. 
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Tarantino MD, Bolton-Maggs PHB.  Update on the management of immune 
thrombocytopenic purpura in children.  Curr Opin Hematol.  2007;14:526-534.  
Tarantino M.  Recent advances in the treatment of childhood immune thrombocytopenic 
purpura.  Semin Hematol.  2006;43(3 Suppl 5):S11-S77; discussion S18-S19. Review.  
Tefferi A. Pathogenesis of myelofibrosis with myeloid metaplasia. J Clin Onc. 
2005:23:8520-8530. 
Terrell DR, Beebe LA, Vesely SK, Neas BR, Segal JB, George JN.  The incidence of 
immune thrombocytopenic purpura in children and adults: A critical review of published 
reports.  Am J Hematol.  2010;85:174-180. 
Thiele J, Kvasnicka, HM, Facchetti F, et al. European consensus on grading bone 
marrow fibrosis and assessment of cellularity. Haematologica. 2005:90:1128-1132.  
Yanagida M, Ide Y, Imai A, et al. The role of transforming growth factor- in 
PEGrHuMGDF- induced reversible myelofibrosis in rats. Br J Haematol. 
1997;99:739-745. 
Zeller B, Helgestad J, Hellebostad M, et al.  Immune thrombocytopenic purpura in 
childhood in Norway: a prospective, population-based registration.  Pediatric Hematol 
Oncol.  2000;17:551-558. 
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14. 
APPENDICES  
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Appendix A.  Additional Safety Assessment Information 
The National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE), version 3.0 is available at the following link:  
Adverse Event Toxicity Grading Scale 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
Serious Adverse Event Completion Instructions 
Completion Instructions - Electronic Adverse Event Contingency Report Form 
NOTE:  This form is to be used under restricted conditions outlined on page 1 below.  If you must fax 
an event report to Amgen, you must also enter that event into the EDC system (eg, Rave) when it 
becomes available.    
(for use for Studies using Electronic Data Capture [EDC]) 
The protocol will provide instruction on what types of events to report for the study. This form is to 
be used ONLY to report events that must be captured in the Amgen safety database. *Indicates a 
mandatory field. 
General Instructions 
Definitions:  
• 
Adverse Event - Any untoward medical occurrence in a clinical trial subject. The event does 
not necessarily have a causal relationship with study treatment. 
• 
Serious Adverse Event – An adverse event that meets serious criteria 
• 
Suspected Adverse Reaction (SAR) – An adverse event that is suspected to be related to an 
Amgen product in an observational study.  
• 
Serious Suspected Adverse Reaction – An SAR that meets serious criteria 
What types of events to report on this form: 
Type of Event 
Clinical Trials 
Adverse Event that is not serious 
No 
Serious Adverse Event (regardless of 
relationship) 
Yes 
  
Type of Event 
Observational Studies 
Suspected Adverse Reaction (SAR) 
Yes 
Serious Suspected Adverse Reaction 
Yes 
Serious Adverse Events that are not suspected 
to be related 
ONLY if instructed by protocol or by local 
Amgen office or CRA 
  
1. Site Information  
Site Number* – Enter your assigned site number for this study  
Investigator*, Country*, Reporter*, Phone No., and Fax No. – Enter information requested   
2. Subject Information  
Subject ID Number* – Enter the entire number assigned to the subject  
Age at event onset, Sex, and Race – Enter the subject’s demographic information  
End of Study date – If the subject has already completed the study or terminated the study early, enter 
the End of Study date  
If you are submitting follow-up information to a previous report, provide the adverse event term for 
the previous report as well as the start date for the initial event.   
3. Adverse Event 
Provide the date the Investigator became aware of this Information 
Adverse Event Diagnosis or Syndrome* –   
 If the diagnosis is known, it should be entered. Do not list all signs/symptoms if they are 
included in the diagnosis.  
 If a diagnosis is not known, the relevant signs/symptoms should be entered.  
 If the event is fatal, the cause of death should be entered and autopsy results should be 
submitted, when available.   
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Date Started* – Enter date the adverse event first started rather than the date of diagnosis or 
hospitalization. For serious events, the start date is the date the event started, not the date on which the 
event met serious criteria. This is a mandatory field. 
Date Ended – Enter date the adverse event ended. For serious events, this is not the date when the 
event no longer met serious criteria.  If the event has not ended at the time of the initial report, a follow-
up report should be completed when the end date is known.  If the event is fatal, enter the date of death 
as the end date. 
If event occurred before the first dose of Investigational Product (IP)/drug under study, add a 
check mark in the corresponding box. 
Is event serious?* – Indicate Yes or No. This is a mandatory field. 
Serious Criteria Code* – This is a mandatory field for serious events. Enter all reasons why the 
reported event has met serious criteria: 
 Immediately life-threatening – Use only if the subject was at immediate risk of death from the 
event as it occurred.  Emergency treatment is often required to sustain life in this situation. 
 If the investigator decides an event should be reported in an expedited manner, but it does not 
meet other serious criteria, “Other Medically Important Serious Event” may be the appropriate 
serious criterion. 
Relationship to IP/drug under study* – The Investigator must determine and enter the relationship of 
the event to the IP/drug under study at the time the event is initially reported. For observational 
studies, remember that SARs are, by definition, related to the drug under study. This is a 
mandatory field. 
Relationship to Amgen device* – The Investigator must determine and enter the relationship of the 
event to the Amgen device (e.g. prefilled syringe, auto-injector) at the time the event is initially reported. 
If the study involves an Amgen device, this is a mandatory field. This question does not apply to 
non-Amgen devices used in the study (e.g. heating pads, infusion pumps) 
Outcome of Event* – Enter the code for the outcome of the event at the time the form is completed. 
This is a mandatory field for serious events.  
 Resolved – End date is known 
 Not resolved / Unknown – End date is unknown 
 Fatal – Event led to death 
If event is related to a study procedure, such as a biopsy, radiotherapy or withdrawal of a current drug 
treatment during a wash-out period, add a check mark to the corresponding box. This does not include 
relationship to IP/drug under study or concomitant medication – only diagnostic tests or activities 
mandated by the protocol. 
4. Hospitalization 
If the subject was hospitalized, enter admission and discharge dates.  Hospitalization is any in-patient 
hospital admission for medical reasons, including an overnight stay in a healthcare facility, regardless of 
duration.  A pre-existing condition that did not worsen while on study which involved a hospitalization for 
an elective treatment, is not considered an adverse event.  Protocol specified hospitalizations are 
exempt.   
5. IP/Drug Under Study Administration including Lot # and Serial # when known / available. 
At the top of Page 2, provide your Site Number and the Subject ID Number in the designated section. 
Blinded or open-label – If applicable, indicate whether the investigational product is blinded or 
open-label 
Initial Start Date – Enter date the product was first administered, regardless of dose.  
Date of Dose Prior to or at the time of the Event – Enter date the product was last administered prior 
to, or at the time of, the onset of the event.  
Dose, Route, and Frequency at or prior to the event – Enter the appropriate information for the dose, 
route and frequency at, or prior to, the onset of the event.  
Action Taken with Product – Enter the status of the product administration.   
6. Concomitant Medications  
Indicate if there are any medications.  
Medication Name, Start Date, Stop Date, Dose, Route, and Frequency – Enter information for any 
other medications the subject is taking.  Include any study drugs not included in section 5 (Product 
Administration) such as chemotherapy, which may be considered co-suspect.  
Co-suspect – Indicate if the medication is co-suspect in the event  
Continuing – Indicate if the subject is still taking the medication  
Event Treatment – Indicate if the medication was used to treat the event    
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7. Relevant Medical History  
Enter medical history that is relevant to the reported event, not the event description. This may include 
pre-existing conditions that contributed to the event allergies and any relevant prior therapy, such as 
radiation.  Include dates if available.   
8. Relevant Laboratory Tests   
Indicate if there are any relevant laboratory values.  
For each test type, enter the test name, units, date the test was run and the results.  
9. Other Relevant Tests  
Indicate if there are any tests, including any diagnostics or procedures.  
For each test type, enter the date, name, results and units (if applicable).   
At the top of Page 3, provide your Site Number and the Subject ID Number in the designated section.
10. Case Description  
  
Describe Event – Enter summary of the event.  Provide narrative details of the events listed in section 3.  
Include any therapy administered, such as radiotherapy; (excluding medications, which will be captured 
in section 6). If necessary, provide additional pages to Amgen.  
Complete the signature section at the bottom of page 3 and fax the form to Amgen.  If the reporter is 
not the investigator, designee must be identified on the Delegation of Authority form.  
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Appendix B.  Modified Bauermeister Scale 
Grade Quantification of bone marrow reticulin and collagen 
0 
No reticulin fibres demonstrable 
1 
Occasional fine individual fibres and foci of a fine fibre network 
2 
Fine fibre network throughout most of the section; no coarse fibres 
3 
Diffuse fibre network with scattered thick coarse fibres but no mature collagen 
(negative to trichrome staining) 
4 
Diffuse, often course fibre network with areas of collagenization (positive 
trichrome staining) 
(Bauermeister, 1971; Bain et al, 2001) 
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Appendix C.  Pregnancy Notification Worksheet 
 
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Appendix D.  Lactation Notification Worksheet 
 
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Amendment # 1 
Protocol Title:  A Single Arm, Open-label, Long-term Efficacy and Safety Study of 
Romiplostim in Thrombocytopenic Pediatric Subjects With Immune 
Thrombocytopenia (ITP) 
Amgen Protocol Number 20101221 
EudraCT number 2011-005019-96 
 
Amendment Date: 
15 July 2014 
 
 
 
Rationale: 
As a result of regulatory reviews, additional routine monitoring has been added to the 
protocol. This amendment includes the following changes: 
• 
To update the inclusion criteria to include hematologic, renal, and liver criteria  
• 
To add pregnancy monitoring as applicable every 12 weeks and at the end of 
treatment visit  
 
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Description of Changes: 
 
Section: Header of the Document and Investigator’s Agreement 
Replace:  15 January 2014 
With:   15 July 2014 
 
Section: Title Page, 
Add:  Amendment 1:  15 July 2014 
 
 
Section 4.1.6: Inclusion Criteria  
Add:  
Adequate hematologic, renal, and liver function during the screening period:   
• 
Hemoglobin > 10.0 g/dL 
• 
Serum creatinine ≤ 1.5 times the upper limit of normal  
• 
Total serum bilirubin ≤ 1.5 times the upper limit of normal  
• 
AST and ALT ≤ 3.0 times the upper limit of normal  
 
Section 7.1, Table 2 Schedule of Assessments 
Add: 
Xf under Pregnancy test after Every 12 weeks and End of Treatment Visit 
Add footnote f: 
f   local lab urine or serum pregnancy test for female subjects of child-bearing 
potential (defined as having first menses) 
 
Section 7.1.1 Routine Blood Tests, Paragraph 5 
Add:  
Urine or blood pregnancy testing, for female subjects of child bearing potential (defined 
as having first menses), will be reported by the local laboratory before the first dose of 
romiplostim, every 12 weeks thereafter, and at the end of treatment visit.  Pregnancy 
testing will not be analyzed or reported by the central laboratory. 
 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 72


 
 
 
Product:  Romiplostim 
Protocol Number:  20101221 
Date: 15 July 2014 
Page 3 of 3 
 
 
Section 7.6 Romiplostim Treatment Period (Up to a 36 Months Duration) 
Add: 
• 
local lab urine or serum pregnancy test for female subjects of child-bearing 
potential (defined as having first menses) every 12 weeks 
 
Section 7.7 End of Treatment Visit (EOT) 
Add: 
• 
local lab urine or serum pregnancy test for female subjects of child-bearing 
potential (defined as having first menses) every 12 weeks 
 
 
 
 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 73


 
 
 
Product:  Romiplostim 
Protocol Number:  20101221 
Date:  15 August 2014 
 
Page 1 of 16 
 
 
 
Amendment # 2 
Protocol Title:  A Single Arm, Open-label, Long-term Efficacy and Safety Study of 
Romiplostim in Thrombocytopenic Pediatric Subjects With Immune 
Thrombocytopenia (ITP) 
Amgen Protocol Number 20101221 
EudraCT number 2011-005019-96 
 
Amendment Date: 
15 August 2014 
 
 
 
Rationale: 
As a result of regulatory reviews and study template updates, this amendment includes 
the following changes: 
• 
Modification of the exclusion criteria to allow prior use of eltrombopag  
• 
Correction in the dosing modification Table 1 Dose Adjustment rules 
• 
Removal of reticulocytes from the laboratory specimens 
• 
Addition of “protocol specified criteria” to  Sections 8.2.1, Reasons for Removal 
from Treatment and 8.2.2, Reasons for Removal from Study  
• 
Update of the Appendix A, SAE Completion Instructions for faxed forms 
 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 74


 
 
 
Product:  Romiplostim 
Protocol Number:  20101221 
Date:  15 August 2014 
 
Page 2 of 16 
 
 
 
Description of Changes: 
 
Section: Header of the Document and Investigator’s Agreement 
Replace:  15 July 2014 
With:   15 August 2014 
 
Section: Title Page, 
Add:  Amendment 2:  15 August 2014 
 
 
Section 4.2.12: Exclusion Criteria  
Replace: 
Previous use of romiplostim or eltrombopag  
With:  
Previous use of romiplostim. Previous use of eltrombopag within 4 weeks of 
enrollment.  
 
Section 6.2.2: Table 1 Dose Adjustment Rules  
Replace: 
Table 1.  Dose Adjustment Rules 
Platelet count (x 109/L) 
Investigational Product Dose Adjustment Rulea 
< 50b 
Increase dose by 1 µg/kg each week (to a maximum of 10 µg/kg) 
50 to 200b 
Dose remains constant 
> 200 to < 400 b,c 
After the platelet count remains in this range for 2 consecutive 
weeks, dose reduce by 1 µg/kg on the next scheduled dosing day 
> 400 b,c,d 
Withhold the dose and dose reduce by 1 µg/kg on the next 
scheduled day of dosing when platelet count falls < 200 x 109/L  
a If the platelet count is elevated in response to the initiation or increase in dose of another ITP medication, 
then the same dose of IP should be administered when the platelet count is ≤  200 x 109/L. 
b Romiplostim may be used with other therapies for ITP (refer to Section 6.4).  If the subject’s platelet count 
is ≥ 50 x 109/L, other ITP therapies may be reduced or discontinued. 
c If the current dose is 1 μg/kg and a dose reduction is required, the dose will be withheld until the platelet 
count falls to < 50 x 109/L.  Once the platelet count is < 50 x 109/L, dosing will resume at a dose of 1 μg/kg 
using the dose adjustment rules above. 
d If platelet count ≥ 400 x 109/L is due to rescue medications, it is at the discretion of the investigator to 
reduce the dose by 1 µg/kg. 
 
 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 75


 
 
 
Product:  Romiplostim 
Protocol Number:  20101221 
Date:  15 August 2014 
 
Page 3 of 16 
 
 
 
With : 
Table 1.  Dose Adjustment Rules 
Platelet count (x 109/L) 
Investigational Product Dose Adjustment Rulea 
< 50b 
Increase dose by 1 µg/kg each week (to a maximum of 10 µg/kg) 
50 to 200b 
Dose remains constant 
> 200 to < 400 b,c 
After the platelet count remains in this range for 2 consecutive 
weeks, dose reduce by 1 µg/kg  
> 400 b,c,d 
Withhold the dose and dose reduce by 1 µg/kg on the next 
scheduled day of dosing when platelet count falls < 200 x 109/L  
a If the platelet count is elevated in response to the initiation or increase in dose of another ITP medication, 
then the same dose of IP should be administered when the platelet count is ≤  200 x 109/L. 
b Romiplostim may be used with other therapies for ITP (refer to Section 6.4).  If the subject’s platelet count 
is ≥ 50 x 109/L, other ITP therapies may be reduced or discontinued. 
c If the current dose is 1 μg/kg and a dose reduction is required, the dose will be withheld until the platelet 
count falls to < 50 x 109/L.  Once the platelet count is < 50 x 109/L, dosing will resume at a dose of 1 μg/kg 
using the dose adjustment rules above. 
d If platelet count ≥ 400 x 109/L is due to rescue medications, it is at the discretion of the investigator to 
reduce the dose by 1 µg/kg. 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 76


 
 
 
Product:  Romiplostim 
Protocol Number:  20101221 
Date:  15 August 2014 
 
Page 4 of 16 
 
 
 
Section 7.1.1: Table 3 List of Analytes in Laboratory Specimens  
Remove Reticulocytes from Hematology  
Replace: 
Table 3.  List of Analytes in Laboratory Specimens 
Blood Chemistry 
Hematology 
Other Labs 
Blood urea nitrogen 
RBC 
Antibodiesa 
Creatinine 
Hemoglobin 
• to romiplostim 
Total bilirubin (TB) 
Hematocrit 
• to the peptide portion of romiplostim 
Alkaline phosphatase (ALP) 
MCV 
• cross-reacting to eTPO 
Lactate dehydrogenase  
MCH 
Local lab blood smearsb 
AST 
MCHC 
Local lab urine or blood pregnancy test  
ALT 
RDW 
(if applicable) 
 
Reticulocytes 
Central lab optional bone marrow  
 
Plateletsc 
biopsy if abnormality is identified (see  
 
WBC 
Section 7.1.1) to include silver and  
 
Differential 
trichrome stain 
 
• Seg Neuts 
 
 
• Bands/stabs 
 
 
• Eosinophils 
 
 
• Basophils 
 
 
• Lymphocytes 
 
 
• Monocytes 
 
 
• Myeloblasts 
 
 
• Promyelocytes 
 
 
• Myelocytes 
 
 
• Metamyelocytes 
 
 
• Atypical lymphocytes  
 
Calculated ANC 
Nucleated RBC 
 
a Additional samples for antibody status may be obtained as requested by the investigator or Amgen. 
b Locally-assessed blood smears will be performed throughout the study and as requested by the 
investigator or Amgen. 
c Platelet counts are performed by local laboratory only. 
 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 77


 
 
 
Product:  Romiplostim 
Protocol Number:  20101221 
Date:  15 August 2014 
 
Page 5 of 16 
 
 
 
With: 
Table 3.  List of Analytes in Laboratory Specimens 
Blood Chemistry 
Hematology 
Other Labs 
Blood urea nitrogen 
RBC 
Antibodiesa 
Creatinine 
Hemoglobin 
• to romiplostim 
Total bilirubin (TB) 
Hematocrit 
• to the peptide portion of romiplostim 
Alkaline phosphatase (ALP) 
MCV 
• cross-reacting to eTPO 
Lactate dehydrogenase  
MCH 
Local lab blood smearsb 
AST 
MCHC 
Local lab urine or blood pregnancy test  
ALT 
RDW 
(if applicable) 
 
Plateletsc 
Central lab optional bone marrow  
 
WBC 
biopsy if abnormality is identified (see  
 
Differential 
Section 7.1.1 ) to include silver and  
 
Seg Neuts 
trichrome stain 
 
• Bands/stabs 
 
 
• Eosinophils 
 
 
• Basophils 
 
 
• Lymphocytes 
 
 
• Monocytes 
 
 
• Myeloblasts 
 
 
• Promyelocytes 
 
 
• Myelocytes 
 
 
• Metamyelocytes 
 
 
• Atypical lymphocytes  
 
• Calculated ANC 
Nucleated RBC 
 
 
 
 
a Additional samples for antibody status may be obtained as requested by the investigator or Amgen. 
b Locally-assessed blood smears will be performed throughout the study and as requested by the 
investigator or Amgen. 
c Platelet counts are performed by local laboratory only. 
 
Section 8.2.1: Reasons for Removal from Treatment 
Add: 
Reasons for removal from romiplostim or observation might include the following: 
• 
protocol specified criteria 
• 
subject request (or the subject’s legally authorized representative)  
• 
safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, requirement for alternative therapy, pregnancy)  
• 
death 
• 
lost to follow-up 
 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 78


 
 
 
Product:  Romiplostim 
Protocol Number:  20101221 
Date:  15 August 2014 
 
Page 6 of 16 
 
 
 
Section 8.2.2: Reasons for Removal from Study 
Add: 
Reasons for removal of a subject from the study are as follows: 
• 
protocol specified criteria 
• 
decision by sponsor  
• 
withdrawal of consent from study 
• 
death 
• 
lost to follow-up 
 
Appendix A: Additional Safety Assessment Information 
Replace: 
Serious Adverse Event Completion Instructions 
Completion Instructions - Electronic Adverse Event Contingency Report Form 
(for use for Studies using Electronic Data Capture [EDC]) 
 
The following minimum fields must be completed prior to faxing the form:  
1) Site Number; 2 ) Subject ID Number; Initials; 3) Serious Adverse Event Diagnosis; Serious Criteria Code; 
Start Date of Event; 10) Signature  
Ensure both pages are faxed with each submission    
  
Note:  Only events that meet serious criteria should be reported on this form.   
  
Submit a Serious Adverse Event Report (SAER) form within 24 hours of the Investigator’s knowledge 
of the event.  
  
Data on the AE Summary CRF must agree with data submitted on the SAER form in the following 
areas:  adverse event term(s), serious criteria and relationship of product to event.  
  
Only include information that is relevant (pertinent) to the event(s) included on this SAER (eg, 
concomitant medications, medical history, laboratory and diagnostic tests)  
 
Header Information  
New / Follow-up – Indicate if this is a new adverse event, or a follow-up of a pre-reported event.  
Follow-up – Send a Follow-up report if additional data adds to or changes the clinical interpretation of the 
event.  Some examples are:  
 
The initial reported event has changed and additional serious criteria have been met (such as if 
event outcome is now fatal).  
 
Signs and symptoms were reported at the time of the initial report and a final diagnosis has now 
been made.  
 
A change in relationship of a study procedure or activity has occurred from the initial report.  
 
A significant change has occurred in the start date of the event or start date of a suspect 
concomitant medication.  
 
Additional concomitant medications and/or diagnostics have been identified that may contribute to 
or explain the event.  
When sending a follow-up report, either:  
 
On a photocopy of the prior report, add the additional information, re-sign and date, then fax in the 
follow-up form – or –  
 
Complete a new form with the new information.  If the serious adverse event terms have not 
changed, please write, in section 3 the following:  “No changes in serious adverse event terms from previous 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 79


 
 
 
Product:  Romiplostim 
Protocol Number:  20101221 
Date:  15 August 2014 
 
Page 7 of 16 
 
 
 
SAER form”, then fax in the follow-up form.  
 
If a new serious adverse event term is to be added to the terms previously reported, add this new 
term to a photocopy of the initial form.    
 
If an earlier reported adverse event is being replaced by a new diagnosis or event term, on a 
photocopy of the initial report, strike through the term to be deleted, sign and date the deletion and add the 
updated event term.  
1. Site Information  
Site Number – Enter your assigned site number for this study  
Investigator, Country, Reporter, Phone No., and Fax No. – Enter information requested  
2. Subject Information  
Subject ID Number – Enter the entire number assigned to the subject  
 Initials – Enter the subject’s initials in accordance with local laws.  If middle initial is unknown or does not 
exist, please enter a “hyphen“ (eg, ESB, E-B)  
 Date of Birth, Sex, and Race – Enter the subject’s demographic information   
3. Serious Adverse Event  
Provide the date the Investigator became aware of this Serious Adverse Event Information 
Serious Adverse Event Diagnosis or Syndrome –   
 
If the diagnosis is known, it should be entered.  Do not list all signs/symptoms if they are included in 
the diagnosis.  
 
If a diagnosis is not known, the relevant signs/symptoms meeting serious criteria should be 
entered.  
 
If the event is fatal, the cause of death should be entered and autopsy results should be submitted, 
when available.  Do not enter “Death”, as this is an outcome, not an event.  
Date Started – Enter date the adverse event first started; not when the event met serious criteria, when a 
diagnosis was made or when the subject was hospitalized.  
Date Ended – Enter date the adverse event ended, not the date when the event no longer met serious 
criteria.  If the event has not ended at the time of the initial report, a follow-up report should be completed 
when the end date is known.  If the event is fatal, enter the date of death as the end date.  
Serious Criteria Code – Enter reason why the reported event has met serious criteria:  
 
Immediately life-threatening – Use only if the subject was at immediate risk of death from the event 
as it occurred.  Emergency treatment is often required to sustain life in this situation.  
 
If the investigator decides an event should be reported in an expedited manner, but it does not 
meet other serious criteria, “Other significant medical hazard” may be the appropriate serious criteria.  
Relationship to IP* – The Investigator must determine and enter the relationship of the event to the IP at 
the time the event is initially reported. This is a mandatory field. 
Relationship to Amgen device – The Investigator must determine and enter the relationship of the event to 
the Amgen device at the time the event is initially reported. If the study involves an Amgen device, this is 
a mandatory field. 
Outcome of Event – Enter the code for the outcome of the event at the time the form is completed.  
 
 Resolved – End date is known  
 
 Resolving / Not resolved – End date is unknown  
 
 Fatal – Event led to death  
 If event is related to a study procedure, such as a biopsy, radiotherapy or withdrawal of a current drug 
treatment during a wash-out period, add a check mark to the corresponding box. This does not include 
relationship to concomitant administration – only diagnostic tests or activities mandated by the protocol.   
4. Hospitalization  
If the subject was hospitalized, enter admission and discharge dates.  Hospitalization is any in-patient 
hospital admission for medical reasons, including an overnight stay in a healthcare facility, regardless of 
duration.  A pre-existing condition that did not worsen while on study, which involved a hospitalization for an 
elective treatment, is not considered an adverse event.  Protocol specified hospitalizations are exempt. 
However, if the subject is retained in the study unit and becomes an in-patient due to an AE, the event would 
be reportable as an SAE.  
5. Investigational Product 
Investigational Product – If applicable, indicate whether the Investigational Product is blinded or 
open-label 
Initial Start Date – Enter date the product was first administered, regardless of dose. 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 80


 
 
 
Product:  Romiplostim 
Protocol Number:  20101221 
Date:  15 August 2014 
 
Page 8 of 16 
 
 
 
Date of Dose Prior to or at the time of the Event – Enter date the product was last administered prior to, 
or at the time of, the onset of the event. 
Action Taken with Product – Enter the status of the product administration. 
Dose, Route, and Frequency at or prior to the event – Enter the appropriate information for the dose, 
route and frequency at, or prior to, the onset of the event  
6. Relevant Concomitant Medications  
Indicate if there are any relevant medications, including protocol-specified diluents and challenge 
agents.  
Medication Name, Start Date, Stop Date, Dose, Route, and Frequency – Enter information for any other 
relevant medications the subject is taking.  Include any study drugs not included in section 5 (Product 
Administration) such as chemotherapy, which may be considered co-suspect.  
Co-suspect – Indicate if the medication is suspect for the event  
Continuing – Indicate if the subject is still taking the medication  
Event Treatment – Indicate if the medication was used to treat the event   
7. Relevant Medical History  
Enter medical history that is relevant to the reported event, not the event description. This may include pre-
existing conditions that contributed to the event allergies and any relevant prior therapy, such as radiation.  
Include dates if available.  
8. Relevant Laboratory Tests   
Indicate if there are any relevant laboratory values.  
For each test type, enter the test name, units, date the test was run and the results.   
9. Other Relevant Tests  
Indicate if there are any tests, including any diagnostics or procedures. 
For each test type, enter the date, name, results and units (if applicable). 
10. Case Description  
Describe Event – Enter summary of the event.  Provide narrative details of the events listed in section 3.  
Include any therapy administered, such as radiotherapy; (excluding medications, which will be captured in 
section 6). 
Footer  
Signature, Title and Date – The Investigator or designee must sign the form and provide their title and 
date.  Designee must be identified on the Delegation of Authority form. 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 81


 
 
 
Product:  Romiplostim 
Protocol Number:  20101221 
Date:  15 August 2014 
 
Page 9 of 16 
 
 
 
 
 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 82


 
 
 
Product:  Romiplostim 
Protocol Number:  20101221 
Date:  15 August 2014 
 
Page 10 of 16 
 
 
 
 
 
 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 83


 
 
 
Product:  Romiplostim 
Protocol Number:  20101221 
Date:  15 August 2014 
 
Page 11 of 16 
 
 
 
With: 
Serious Adverse Event Completion Instructions 
Completion Instructions - Electronic Adverse Event Contingency Report Form 
(for use for Studies using Electronic Data Capture [EDC]) 
NOTE:  This form is to be used under restricted conditions outlined on page 1 below.  If you must fax 
an event report to Amgen, you must also enter that event into the EDC system (eg, Rave) when it 
becomes available.    
General Instructions 
The protocol will provide instruction on what types of events to report for the study. This form is to 
be used ONLY to report events that must be captured in the Amgen safety database. *Indicates a 
mandatory field. 
Definitions:  
• 
Adverse Event - Any untoward medical occurrence in a clinical trial subject. The event does 
not necessarily have a causal relationship with study treatment. 
• 
Serious Adverse Event – An adverse event that meets serious criteria 
• 
Suspected Adverse Reaction (SAR) – An adverse event that is suspected to be related to an 
Amgen product in an observational study.  
• 
Serious Suspected Adverse Reaction – An SAR that meets serious criteria 
What types of events to report on this form: 
Type of Event 
Clinical Trials 
Adverse Event that is not serious 
No 
Serious Adverse Event (regardless of 
relationship) 
Yes 
  
Type of Event 
Observational Studies 
Suspected Adverse Reaction (SAR) 
Yes 
Serious Suspected Adverse Reaction 
Yes 
Serious Adverse Events that are not suspected 
to be related 
ONLY if instructed by protocol or by local 
Amgen office or CRA 
  
1. Site Information  
Site Number* – Enter your assigned site number for this study  
Investigator*, Country*, Reporter*, Phone No., and Fax No. – Enter information requested   
2. Subject Information  
Subject ID Number* – Enter the entire number assigned to the subject  
Age at event onset, Sex, and Race – Enter the subject’s demographic information  
End of Study date – If the subject has already completed the study or terminated the study early, enter 
the End of Study date  
If you are submitting follow-up information to a previous report, provide the adverse event term for 
the previous report as well as the start date for the initial event.   
3. Adverse Event 
Provide the date the Investigator became aware of this Information 
Adverse Event Diagnosis or Syndrome* –   
 
If the diagnosis is known, it should be entered. Do not list all signs/symptoms if they are included in 
the diagnosis.  
 
If a diagnosis is not known, the relevant signs/symptoms should be entered.  
 
If the event is fatal, the cause of death should be entered and autopsy results should be submitted, 
when available.   
Date Started* – Enter date the adverse event first started rather than the date of diagnosis or 
hospitalization. For serious events, the start date is the date the event started, not the date on which the 
event met serious criteria. This is a mandatory field. 
Date Ended – Enter date the adverse event ended. For serious events, this is not the date when the 
event no longer met serious criteria.  If the event has not ended at the time of the initial report, a follow-
up report should be completed when the end date is known.  If the event is fatal, enter the date of death 
as the end date. 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 84


 
 
 
Product:  Romiplostim 
Protocol Number:  20101221 
Date:  15 August 2014 
 
Page 12 of 16 
 
 
 
If event occurred before the first dose of Investigational Product (IP)/drug under study, add a 
check mark in the corresponding box. 
Is event serious?* – Indicate Yes or No. This is a mandatory field. 
Serious Criteria Code* – This is a mandatory field for serious events. Enter all reasons why the 
reported event has met serious criteria: 
 
Immediately life-threatening – Use only if the subject was at immediate risk of death from the event 
as it occurred.  Emergency treatment is often required to sustain life in this situation. 
 
If the investigator decides an event should be reported in an expedited manner, but it does not 
meet other serious criteria, “Other Medically Important Serious Event” may be the appropriate serious 
criterion. 
Relationship to IP/drug under study* – The Investigator must determine and enter the relationship of 
the event to the IP/drug under study at the time the event is initially reported. For observational 
studies, remember that SARs are, by definition, related to the drug under study. This is a 
mandatory field. 
Relationship to Amgen device* – The Investigator must determine and enter the relationship of the 
event to the Amgen device (e.g. prefilled syringe, auto-injector) at the time the event is initially reported. 
If the study involves an Amgen device, this is a mandatory field. This question does not apply to 
non-Amgen devices used in the study (e.g. heating pads, infusion pumps) 
Outcome of Event* – Enter the code for the outcome of the event at the time the form is completed. 
This is a mandatory field for serious events.  
 
Resolved – End date is known 
 
Not resolved / Unknown – End date is unknown 
 
Fatal – Event led to death 
If event is related to a study procedure, such as a biopsy, radiotherapy or withdrawal of a current drug 
treatment during a wash-out period, add a check mark to the corresponding box. This does not include 
relationship to IP/drug under study or concomitant medication – only diagnostic tests or activities 
mandated by the protocol. 
4. Hospitalization 
If the subject was hospitalized, enter admission and discharge dates.  Hospitalization is any in-patient 
hospital admission for medical reasons, including an overnight stay in a healthcare facility, regardless of 
duration.  A pre-existing condition that did not worsen while on study which involved a hospitalization for 
an elective treatment, is not considered an adverse event.  Protocol specified hospitalizations are 
exempt.   
At the top of Page 2, provide your Site Number and the Subject ID Number in the designated section. 
5. IP/Drug Under Study Administration including Lot # and Serial # when known / available. 
Blinded or open-label – If applicable, indicate whether the investigational product is blinded or open-
label 
Initial Start Date – Enter date the product was first administered, regardless of dose.  
Date of Dose Prior to or at the time of the Event – Enter date the product was last administered prior 
to, or at the time of, the onset of the event.  
Dose, Route, and Frequency at or prior to the event – Enter the appropriate information for the dose, 
route and frequency at, or prior to, the onset of the event.  
Action Taken with Product – Enter the status of the product administration.   
6. Concomitant Medications  
Indicate if there are any medications.  
Medication Name, Start Date, Stop Date, Dose, Route, and Frequency – Enter information for any 
other medications the subject is taking.  Include any study drugs not included in section 5 (Product 
Administration) such as chemotherapy, which may be considered co-suspect.  
Co-suspect – Indicate if the medication is co-suspect in the event  
Continuing – Indicate if the subject is still taking the medication  
Event Treatment – Indicate if the medication was used to treat the event    
7. Relevant Medical History  
Enter medical history that is relevant to the reported event, not the event description. This may include 
pre-existing conditions that contributed to the event allergies and any relevant prior therapy, such as 
radiation.  Include dates if available.   
8. Relevant Laboratory Tests   
Indicate if there are any relevant laboratory values.  
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 85


 
 
 
Product:  Romiplostim 
Protocol Number:  20101221 
Date:  15 August 2014 
 
Page 13 of 16 
 
 
 
For each test type, enter the test name, units, date the test was run and the results.  
9. Other Relevant Tests  
Indicate if there are any tests, including any diagnostics or procedures.  
For each test type, enter the date, name, results and units (if applicable).   
At the top of Page 3, provide your Site Number and the Subject ID Number in the designated section.  
10. Case Description  
Describe Event – Enter summary of the event.  Provide narrative details of the events listed in section 3.  
Include any therapy administered, such as radiotherapy; (excluding medications, which will be captured 
in section 6). If necessary, provide additional pages to Amgen.  
Complete the signature section at the bottom of page 3 and fax the form to Amgen.  If the reporter is 
not the investigator, designee must be identified on the Delegation of Authority form.  
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 86


 
 
 
Product:  Romiplostim 
Protocol Number:  20101221 
Date:  15 August 2014 
 
Page 14 of 16 
 
 
 
 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 87


 
 
 
Product:  Romiplostim 
Protocol Number:  20101221 
Date:  15 August 2014 
 
Page 15 of 16 
 
 
 
 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 88


 
 
 
Product:  Romiplostim 
Protocol Number:  20101221 
Date:  15 August 2014 
 
Page 16 of 16 
 
 
 
 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 89


Product:  Romiplostim 
Protocol Number:  20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 1 of 25 
 
 
Protocol Supplement for the European Union (EU), Switzerland, and Turkey 
Title:  A Single Arm, Open-label, Long-term Efficacy and Safety Study of 
Romiplostim in Thrombocytopenic Pediatric Subjects With Immune 
Thrombocytopenia (ITP) 
 
Amgen Protocol Number (Romiplostim) 20101221 
 
 
Supplement version # 1: 
 
Supplement version #2: 
15 April 2014 
 
15 July 2014 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 90


Product:  Romiplostim 
Protocol Number:  20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 2 of 25 
 
1. 
Explanation of Country-specific Changes to the Protocol 
This supplement to the protocol provides language for European Union (EU)-specific 
regulatory requirements and other procedures to follow in the execution of the global 
study in the EU, Switzerland, and Turkey.  These changes are being made to fulfill the 
binding elements of the Pediatric Investigation Plan and include the addition of 
mandatory bone marrow biopsies and aspirates for evaluation of collagen, reticulin and 
cytogenetics at baseline and after Year 1 and Year 2 (in separate cohorts) to assess the 
long term safety of romiplostim in pediatric patients with immune thrombocytopenia 
purpura (ITP).  
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Product:  Romiplostim 
Protocol Number: 20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 3 of 25 
 
Summary of Text Changes to Protocol for the EU, Switzerland, and Turkey 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Protocol Synopsis 
Primary Objective  
• 
To describe the 
percentage of time that 
pediatric subjects with 
ITP have a platelet 
response in the first 
6 months from the start 
of treatment with 
romiplostim 
• 
To describe the percentage of time that pediatric subjects with ITP have a platelet response 
in the first 6 months from the start of treatment with romiplostim  
• 
To evaluate incidence of changes in bone marrow findings at Year 1 and Year 2 after 
initial exposure to romiplostim  
 
Page 1 of 23 
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Product:  Romiplostim 
Protocol Number: 20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 4 of 25 
 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Protocol Synopsis 
Secondary 
Objectives 
• 
To describe the 
percentage of time that 
pediatric subjects with 
ITP have a platelet 
response over the study 
duration 
• 
To describe the 
percentage of time that 
pediatric subjects with 
ITP have an increase in 
platelet count ≥ 20 x 
109/L above baseline 
over the study duration 
• 
To describe the use of 
rescue ITP medications 
• 
To describe the 
incidence of antibody 
formation 
• 
To describe the safety of 
romiplostim as a 
long-term treatment in 
pediatric 
thrombocytopenic 
subjects with ITP 
• 
To describe the percentage of time that pediatric subjects with ITP have a platelet response 
over the study duration 
• 
To describe the percentage of time that pediatric subjects with ITP have an increase in 
platelet count ≥ 20 x 109/L above baseline over the study duration 
• 
To describe the use of rescue ITP medications 
• 
To describe the incidence of antibody formation 
• 
To describe the safety of romiplostim as a long-term treatment in pediatric 
thrombocytopenic subjects with ITP 
• 
To evaluate the incidence of increased reticulin as evidenced by silver staining at 
Year 1 or Year 2, after exposure to romiplostim 
Page 2 of 23 
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Product:  Romiplostim 
Protocol Number: 20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 5 of 25 
 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Protocol Synopsis 
Primary Endpoint 
• 
The percentage of time 
with a platelet count of 
≥ 50 x 109/L starting 
from week 2 in the first 
6 months of the 
treatment period without 
rescue medication use in 
the past 4 weeks  
 
• 
The percentage of time with a platelet count of ≥ 50 x 109/L starting from week 2 in the first 
6 months of the treatment period without rescue medication use in the past 4 weeks  
• 
Evaluation of bone marrow changes after Year 1 and Year 2 for the following: 
- Incidence of collagen as evidenced by trichrome staining (using the modified 
Bauermeister grading scale) after romiplostim exposure  
- Incidence of bone marrow reticulin increases in severity ≥ 2 grades (ie, grade 0 to 
2-4, 1 to 3-4, 2 to 4), compared to baseline, or an increase to grade 3 or grade 4 as 
evidenced by reticulin silver staining using the modified Bauermeister grading 
scale after romiplostim exposure  
- Incidence of bone marrow abnormalities (eg, myelodysplastic syndrome, 
monosomy 7) as evidenced by cytogenetics and fluorescence in situ hybridization 
Page 3 of 23 
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Product:  Romiplostim 
Protocol Number: 20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 6 of 25 
 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Protocol Synopsis 
Secondary 
Endpoints 
• 
The percentage of time 
with a platelet count of 
≥ 50 x 109/L starting 
from week 2 until the 
end of the treatment 
period without rescue 
medication use within 
the past 4 weeks  
• 
The percentage of time 
with an increase in 
platelet count ≥ 20 x 
109/L above baseline 
starting from week 2 
until the end of the 
treatment period without 
rescue medication use in 
the past 4 weeks. 
• 
Subject incidence of 
rescue ITP medications 
used  
• 
The incidence of 
anti-romiplostim 
neutralizing antibodies 
and cross-reactive 
antibodies to 
thrombopoietin (TPO) at 
any time during the 
study 
• 
The incidence of 
adverse events, 
including clinically 
significant changes in 
laboratory values  
• 
The percentage of time with a platelet count of ≥ 50 x 109/L starting from week 2 until the 
end of the treatment period without rescue medication use within the past 4 weeks  
• 
The percentage of time with an increase in platelet count ≥ 20 x 10 9/L above baseline 
starting from week 2 until the end of the treatment period without rescue medication use in 
the past 4 weeks. 
• 
Subject incidence of rescue ITP medications used  
• 
The incidence of anti-romiplostim neutralizing antibodies and cross-reactive antibodies to 
TPO at any time during the study 
• 
The incidence of adverse events, including clinically significant changes in laboratory 
values  
• 
The incidence of increased reticulin as evidenced by silver staining at Year 1 or  
Year 2, after exposure to romiplostim 
Page 4 of 23 
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Product:  Romiplostim 
Protocol Number: 20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 7 of 25 
 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Protocol Synopsis 
Sample Size  
Approximately 200 subjects 
Approximately 200 subjects for the study overall; at least 60 of the 200 will be enrolled on 
this protocol supplement  
Protocol Synopsis 
Procedures  
At specified time points, 
subjects will undergo the 
following assessments: 
collection of informed 
consent (and assent, if 
applicable), confirmation of 
primary ITP diagnosis, ITP 
and medical history, and 
physical exam including 
weight and vital signs.  
Subjects will have complete 
blood counts with 
differentials, blood chemistry 
profiles, local platelet counts, 
and a blood or urine 
pregnancy test for females of 
child-bearing potential.  
Research staff will document 
the use of concomitant and 
rescue medications and all 
adverse events reported for 
the subject.  Subjects will 
also provide blood samples 
for anti-TPO/romiplostim 
antibodies and peripheral 
blood smears.  
 
At specified time points, subjects will undergo the following assessments: collection of informed 
consent (and assent, if applicable), confirmation of primary ITP diagnosis, ITP and medical 
history, physical exam including weight and vital signs, and baseline bone marrow biopsy 
and aspirate.  Subjects will have complete blood counts with differentials, blood chemistry 
profiles, local platelet counts, and a blood or urine pregnancy test for females of child-bearing 
potential.  Research staff will document the use of concomitant and rescue medications and all 
adverse events reported for the subject.  A repeat bone marrow biopsy and aspirate will be 
performed after Year 1 or Year 2, based on the cohort assignment.   Subjects will also 
provide blood samples for anti-TPO/romiplostim antibodies and peripheral blood smears.  
 
Page 5 of 23 
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Product:  Romiplostim 
Protocol Number: 20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 8 of 25 
 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Protocol Synopsis 
Add after second 
paragraph of 
Statistical 
Considerations 
Not applicable 
The analyses of bone marrow collagen as evidenced by trichrome staining, bone marrow 
reticulin increases using the modified Bauermeister grading scale, and cytogenetic 
abnormalities in the bone marrow after Year 1 and Year 2 will be descriptive. The 
proportion of subjects developing collagen, increase in reticulin, and any cytogenetic 
abnormalities in the bone marrow and the corresponding 95% exact confidence interval 
will be provided by treatment cohort. Logistical regression may be used to investigate 
the association of bone marrow abnormality and potential predictive factors.  
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Product:  Romiplostim 
Protocol Number: 20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 9 of 25 
 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Study Design and 
Treatment 
Schema 
Add to Treatment 
Period Box 
Treatment Period 
Number of Subjects = 200 
 
Starting dose of romiplostim 
will be 1µg/kg administered 
one time weekly in an 
attempt to reach a target 
platelet count ≥ 50 x 109/L   
 
Dose adjustments will be 
allowed during the treatment 
period to maintain a platelet 
count between ≥ 50 x 109/L 
and ≤ 200 x 109/L  
 
Reduction in concurrent ITP 
therapies may occur when 
there is a platelet count of 
≥ 50 x 109/L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 7 of 23 
Bone Marrow 
Biopsy 
Bone Marrow 
Biopsy 
Year 1 Cohort 
N=30 
Year 2 Cohort 
N=30 
Day 1 
12 Months 
24 Months 
Screening/ 
Enrollment  
 
For the subjects in 
the bone marrow 
subset only, a bone 
marrow biopsy within 
1 year prior to 
planned first dose of 
romiplostim or 
consent to a pre-
treatment bone 
marrow biopsy and 
aspirate within 
3 weeks prior to 
planned first dose of 
romiplostim. 
Sequential enrollment 
to Year 1 or Year 2 
bone biopsy cohort. 
Treatment Period 
Number of Subjects = 200 
 
Starting dose of romiplostim will be 1µg/kg administered 
one time weekly in an attempt to reach a target platelet 
count ≥ 50 x 109/L   
Dose adjustments will be allowed during the treatment 
period to maintain a platelet count between ≥ 50 x 109/L 
and ≤ 200 x 109/L  
Reduction in concurrent ITP therapies may occur when 
there is a platelet count of ≥ 50 x 109/L 
Mandatory bone marrow biopsy and aspirates will be 
performed in at least 60 subjects at screening and 
after Year 1 or Year 2 in separate cohorts as follows: 
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Product:  Romiplostim 
Protocol Number: 20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 10 of 25 
 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Section 1.1  
Primary 
Objectives  
The primary objective is to 
describe the percentage of 
time that pediatric subjects 
with immune 
thrombocytopenia (ITP) have 
a platelet response in the 
first 6 months from the start 
of treatment with 
romiplostim. 
 
The primary objective(s) are as follows: 
• 
to describe the percentage of time that pediatric subjects with immune thrombocytopenia 
(ITP) have a platelet response in the first 6 months from the start of treatment with 
romiplostim 
• 
to evaluate incidence of changes in bone marrow findings at Year 1 and Year 2 after 
initial exposure to romiplostim  
Page 8 of 23 
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Protocol Number: 20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 11 of 25 
 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Section 1.2  
Secondary 
Objectives 
The secondary objectives of 
the study are:  
• 
To describe the 
percentage of time that 
pediatric subjects with 
ITP have a platelet 
response over the study 
duration 
• 
To describe the 
percentage of time that 
pediatric subjects with 
ITP have an increase in 
platelet count ≥ 20 x 
109/L above baseline 
over the study duration 
• 
To describe the use of 
rescue ITP medications 
• 
To describe the 
incidence of antibody 
formation 
• 
To describe the safety of 
romiplostim as a 
long-term treatment in 
pediatric 
thrombocytopenic 
subjects with ITP 
The secondary objectives of the study are:  
• 
The percentage of time with a platelet count of ≥ 50 x 109/L starting from week 2 until the 
end of the treatment period without rescue medication use within the past 4 weeks  
• 
The percentage of time with an increase in platelet count ≥ 20 x 10 9/L above baseline 
starting from week 2 until the end of the treatment period without rescue medication use in 
the past 4 weeks. 
• 
Subject incidence of rescue ITP medications used  
• 
The incidence of anti-romiplostim neutralizing antibodies and cross-reactive antibodies to 
TPO at any time during the study 
• 
The incidence of adverse events, including clinically significant changes in laboratory 
values  
• 
The incidence of increased reticulin as evidenced by silver staining at Year 1 or 
Year 2, after exposure to romiplostim 
 
Page 9 of 23 
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Product:  Romiplostim 
Protocol Number: 20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 12 of 25 
 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Section 3.1 
Study Design 
Add new 
paragraph 2 
This is a phase 3b single 
arm, open-label, multicenter 
study evaluating the 
percentage of time pediatric 
subjects with ITP have a 
response while receiving 
romiplostim, defined as a 
platelet count ≥ 50 x 109/L 
and in the absence of  ITP 
rescue medications in the 
past 4 weeks.  This protocol 
will provide open-label 
romiplostim to 
thrombocytopenic pediatric 
subjects with ITP diagnosed 
for at least 6 months and 
who have received at least 1 
prior ITP therapy (excluding 
romiplostim) or are ineligible 
for other ITP therapies.  
 
This is a phase 3b single arm, open-label, multicenter study evaluating the percentage of time 
pediatric subjects with ITP have a response while receiving romiplostim, defined as a platelet 
count ≥ 50 x 109/L and in the absence of  ITP rescue medications in the past 4 weeks.  This 
protocol will provide open-label romiplostim to thrombocytopenic pediatric subjects with ITP 
diagnosed for at least 6 months and who have received at least 1 prior ITP therapy (excluding 
romiplostim) or are ineligible for other ITP therapies.  
The study design consists of a 4-week screening period, up to a 3-year treatment period, an 
end of treatment (EOT) visit, and an end of study (EOS) visit.  
A subset of at least 60 subjects will be enrolled sequentially into the following cohorts: 
• 
Bone marrow biopsy and aspirate at baseline and Year 1 
• 
Bone marrow biopsy and aspirate at baseline and Year 2 
All subjects in these 2 cohorts will receive romiplostim for 3 years, unless withdrawn 
from the study early. They will complete an End of Treatment (EOT) visit at the 
conclusion of their treatment period and will then return an End of Study (EOS) visit. 
 
Section 3.2  
Number of 
Centers 
There will be approximately 
50 centers located in (but not 
limited to) Australia, Canada, 
Europe, Israel, South Africa, 
South America, and the 
United States.  
There will be approximately 50 centers located in (but not limited to) Australia, Canada, Europe, 
Israel, South Africa, South America, and the United States.  Approximately 35 centers from 
the EU, Switzerland, and Turkey will participate in this supplement.  
 
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Product:  Romiplostim 
Protocol Number: 20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 13 of 25 
 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Section 3.3 
Number of 
Subjects 
Participants in this clinical 
investigation shall be 
referred to as “subjects.”  It 
is anticipated that 
approximately 200 subjects 
will be enrolled into this 
study. 
 
Participants in this clinical investigation shall be referred to as “subjects.”  It is anticipated that 
approximately 200 subjects will be enrolled into this study. Of the 200 subjects, at least 
30 subjects will be enrolled into each of 2 cohorts, which are identified by bone marrow 
biopsy time points (Year 1 or Year 2).   
Section 4.1 
Inclusion Criteria 
Not applicable 
Inclusion criteria 4.1.7 
• 
Subject must agree to a scheduled bone marrow biopsy and aspirate at Year 1 or 
Year 2 following romiplostim treatment and any unscheduled biopsies if clinically 
indicated 
 
Section 4.1 
Inclusion Criteria 
Not applicable 
Inclusion criteria 4.1.8 
• 
A reticulin grade of 0, 1, 2, or 3 according to the modified Bauermeister grading 
scale,  as assessed by central laboratory from a bone marrow biopsy performed  
within 1 year prior to planned first dose of romiplostim or consent to a pre-treatment 
bone marrow biopsy and aspirate prior to planned first dose of romiplostim  
Section 5  
Subject 
Enrollment 
Add Cohorts 
subsection 
Not applicable 
This protocol supplement will recruit 2 cohorts based on subject allocation for their 
on-study bone marrow biopsy at Year 1 or Year 2.   
Cohorts 
Cohorts will be confirmed through the IVRS after the subject meets all eligibility criteria 
(including central laboratory bone marrow biopsy and aspirate review).  Once the first 
cohort has completed enrollment, the second cohort will begin enrolling.  At least 
30 subjects will be sequentially enrolled into the two cohorts.   
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Protocol Number: 20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 14 of 25 
 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Section 7.1,  
Add new Table 2b  
Not applicable 
Renumber Table 2, as 
Table 2a 
Table 2b.  Bone Marrow Assessments 
 
 
Procedures 
 
 
Screening 
Treatment Phase 
(up to 36 months) 
End of 
Treatment 
 
Year 1 
Year 2 
End of 
Study  
Visit 
Bone Marrow 
Biopsy, 
Cohort 1a 
X 
X 
 
Xb 
Xc 
Bone Marrow 
Biopsy, 
Cohort 2a 
X 
 
X 
Xb 
Xc 
 
a  Bone Marrow Biopsy:  A baseline bone marrow biopsy and aspirate is required to 
determine eligibility; this can be either a bone marrow biopsy within 1 year prior to 
planned first dose of romiplostim (with available bone marrow tissue block or a 
minimum of 5 unstained, evaluable histological slides to send to a central laboratory) 
or a pre-treatment bone marrow biopsy and aspirate within 3 weeks prior to planned 
first dose of romiplostim.  Central laboratory evaluation is required prior to the first 
dose of romiplostim.  A further bone marrow biopsy and aspirate  is required at Year 
1 or Year 2, depending on the cohort in which the subject is enrolled (as designated 
by IVRS).  Additional bone marrow biopsies and aspirates may be performed if 
clinically indicated at the discretion of the investigator and/or Amgen. 
b  End of Treatment (EOT):  Subjects who are non-responders and withdraw from the 
study will require a bone marrow biopsy and aspirate at the EOT visit.  A bone 
marrow biopsy and aspirate should be obtained for discontinued subjects who have 
not yet had a cohort-defined bone marrow biopsy performed. 
c   End of Study (EOS):  EOS will be delayed for subjects who are withdrawn from the 
study due to the presence of collagen, or subjects who have a change to grade 3 
reticulin, per central laboratory evaluation of a bone marrow biopsy.  These subjects 
will complete an EOS visit 12 weeks after discontinuation of romiplostim and will 
require a repeat bone marrow biopsy. 
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Product:  Romiplostim 
Protocol Number: 20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 15 of 25 
 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Add new section 
7.1.4 Bone 
Marrow Biopsy 
 
Not applicable 
Bone Marrow Biopsy 
For the protocol supplement, a baseline bone marrow biopsy and aspirate is required to 
determine eligibility; central laboratory evaluation is required prior to first dose of 
romiplostim.  A baseline bone marrow biopsy can be either a bone marrow biopsy within 
1 year prior to the planned first dose of romiplostim (with available bone marrow tissue 
block or a minimum of 5 unstained, evaluable histological slides to send to a central 
laboratory) or a pre-treatment bone marrow biopsy and aspirate within 3 weeks prior to 
planned first dose of romiplostim.  
A repeat bone marrow biopsy and aspirate is required at Year 1 or Year 2 ( ± 4 week 
window) depending on the cohort assignment. A bone marrow biopsy and aspirate 
should be obtained for discontinued subjects who have not yet had a cohort-defined 
bone marrow biopsy performed. 
Should collagen be detected in any subjects during the course of the study, study drug 
will be discontinued and the subject will undergo an EOT visit.  A repeat bone marrow 
biopsy will be required 12 weeks later at the EOS visit (+ 2 week window) for subjects 
who are withdrawn from the study due to the presence of collagen. 
Subjects who have a change to grade 3 reticulin, per central laboratory evaluation of a 
bone marrow biopsy, will undergo a repeat bone marrow biopsy 12 weeks after their last 
dose of romiplostim at the EOS visit (+ 2 week window).   
Subjects who are considered non-responders and will be discontinued from the study 
will require a bone marrow biopsy and aspirate sample to be taken at the EOT visit 
(+ 2 week window).  A repeat bone marrow biopsy will also be required 12 weeks later at 
EOS visit (+ 2 week window) for non-responders who have a change to grade 3 reticulin 
or collagen, per central laboratory evaluation of a bone marrow biopsy. 
Bone marrow biopsies and aspirates where applicable, will be sent to a central 
laboratory for reticulin and collagen staining and analysis.  Refer to Central Laboratory 
Manual for instructions on collection, preparation, storage, and shipment of samples. 
The modified Bauermeister Scale (Bauermeister, 1971) will be used for this study.  
Subjects with a reticulin grade of 0, 1, 2, or 3 will be eligible for this study.   
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Protocol Number: 20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 16 of 25 
 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Add new section 
7.1.4 Bone 
Marrow Biopsy 
(continued) 
 
Not applicable 
Additional bone marrow biopsies and aspirates may be performed, if clinically indicated, 
at the discretion of the investigator and/or Amgen.  At any time an unscheduled bone 
marrow biopsy and aspirate are performed on study, available bone marrow tissue block 
(paraffin embedded) or unstained histological slides will be submitted to the central 
laboratory for evaluation.  Some examples of when a clinically indicated bone marrow 
biopsy and aspirate might be performed include abnormalities seen on a peripheral 
blood smear (eg, evidence of blast cells) or a CTCAE grade ≥ 2 shift in either anemia or 
neutropenia. 
Section 7.1.1 
Routine Blood 
Tests, Table 3, 
List of Analytes in 
Laboratory 
Specimens, under 
Other Labs 
Central lab optional bone 
marrow biopsy if abnormality 
is identified (see Section 
7.1.1) to include silver and 
trichrome stain 
Bone marrow biopsy and aspirate 
• 
Megakaryocyte count 
• 
Reticulin/collagen grade (Bauermeister score) 
• 
Trichrome staining 
• 
Silver staining 
• 
Cytogenetics and fluorescence in situ hybridization(FISH)  
Section 7.5 
Screening 
Not applicable 
Add  
• 
bone marrow biopsy and aspirate (central laboratory evaluation is required prior to 
first administration of romiplostim)   
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Date:  15 July 2014 
Page 17 of 25 
 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Section 7.6 
Add subsection 
under Romiplostim 
Treatment Period 
(Up to a 36 Months 
Duration)  
The following procedures will 
be completed during the 
romiplostim treatment period 
at the times designated in the 
Schedule of Assessments 
(Table 2): 
• 
documentation of 
concomitant and rescue 
medications  
• 
adverse event reporting 
• 
central lab CBC with 
differential (every 
4 weeks) 
• 
central lab blood 
chemistry (every 
12 weeks) 
• 
local lab platelet counts.  
• 
collection of blood 
samples for anti-
romiplostim antibodies 
(first sample is collected 
before first dose of 
romiplostim, then at week 
12, week 52, and every 
24 weeks thereafter) 
• 
local lab peripheral blood 
smear (every 4 weeks) 
• 
physical exam with vital 
signs and weight (every 
12 weeks) 
• 
romiplostim administration 
The following procedures will be completed during the romiplostim treatment period at the times 
designated in the Schedule of Assessments (Table 2): 
• 
documentation of concomitant and rescue medications  
• 
adverse event reporting 
• 
central lab CBC with differential (every 4 weeks) 
• 
central lab blood chemistry (every 12 weeks) 
• 
local lab platelet counts 
• 
collection of blood samples for anti-romiplostim antibodies (first sample is collected before first 
dose of romiplostim, then at week 12, week 52, and every 24 weeks thereafter) 
• 
local lab peripheral blood smear (every 4 weeks) 
• 
physical exam with vital signs and weight (every 12 weeks) 
• 
local lab urine or serum pregnancy test for female subjects of child-bearing potential 
(defined as having first menses) every 12 weeks 
• 
romiplostim administration 
Additional Procedures Required for Cohort 1 or Cohort 2 
• 
Bone marrow biopsy and aspirate (one scheduled biopsy, dependent on cohort) 
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Protocol Number: 20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 18 of 25 
 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Section 7.7  
End of Treatment 
Visit (EOT)  
All subjects will complete an 
EOT visit.  For subjects who 
complete the 36-month 
treatment period and who 
have been off romiplostim 
and other medications for 
ITP (concomitant or rescue) 
for 4 weeks or more, the 
EOT visit will be the final 
study visit and will occur 
after the completion of the 
36-month treatment period.  
For subjects ending the 36-
month treatment period for 
non-response or other 
reasons while still receiving 
romiplostim, this visit will be 
1 week after the last 
administration of 
romiplostim.   
All subjects will complete an EOT visit.  For subjects who complete the 36-month treatment 
period and who have been off romiplostim and other medications for ITP (concomitant or 
rescue) for 4 weeks or more, the EOT visit will be the final study visit and will occur after the 
completion of the 36-month treatment period.  For subjects ending the 36-month treatment 
period for non-response or other reasons while still receiving romiplostim, this visit will be 
1 week after the last administration of romiplostim.   
In addition, a bone marrow biopsy and aspirate should be obtained for discontinued 
subjects who have not yet had a cohort-defined bone marrow biopsy performed. 
 
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Protocol Number: 20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 19 of 25 
 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Section 7.8  
End of Study Visit  
Four weeks after the last 
dose of romiplostim for 
subjects who end the 
36-month treatment period 
for non-response or other 
reasons while still receiving 
romiplostim will have an 
EOS visit.  
The following assessments 
will be completed at the EOS 
visit:  
• 
local lab platelet count 
• 
serious adverse event 
reporting  
• 
documentation of 
concomitant and rescue 
medications  
Four weeks after the last dose of romiplostim for subjects who end the 36-month treatment 
period for non-response or other reasons while still receiving romiplostim will have an EOS visit.  
The following assessments will be completed at the EOS visit:  
• 
local lab platelet count 
• 
serious adverse event reporting  
• 
documentation of concomitant and rescue medications  
• 
Bone marrow biopsy and aspirate (only for subjects with collagen or a change to 
grade 3 or 4 reticulin) 
Page 17 of 23 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 108


Product:  Romiplostim 
Protocol Number: 20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 20 of 25 
 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Section 10.1.1 
Study Endpoints 
Primary Endpoint 
• 
The percentage of time 
with a platelet count of 
≥ 50 x 109/L starting 
from week 2 in the first 
6 months of the 
treatment period without 
rescue medication use 
within the past 4 weeks  
 
• 
The percentage of time with a platelet count of ≥ 50 x 109/L starting from week 2 in the first 
6 months of the treatment period without rescue medication use within the past 4 weeks  
• 
Evaluation of bone marrow changes after Year 1 or Year 2  for the following: 
- Incidence of collagen as evidenced by trichrome staining (using the modified 
Bauermeister grading scale) after romiplostim exposure  
- Incidence of bone marrow reticulin increases in severity ≥ 2 grades (ie, grade 0 to 
2-4, 1 to 3-4, 2 to 4), compared to baseline, or an increase to grade 3 or grade 4 as 
evidenced by reticulin silver staining using the modified Bauermeister grading 
scale after romiplostim exposure  
- Incidence of bone marrow abnormalities (eg, myelodysplastic syndrome, 
monosomy 7) as evidenced by cytogenetics and fluorescence in situ hybridization  
 
Page 18 of 23 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 109


Product:  Romiplostim 
Protocol Number: 20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 21 of 25 
 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Section 10.1.1 
Study Endpoints 
Secondary 
Endpoint 
• 
The percentage of time 
with a platelet count of 
≥ 50 x 109/L starting 
from week 2 until the 
end of the treatment 
period without rescue 
medication use within 
the past 4 weeks  
• 
The percentage of time 
with an increase in 
platelet count ≥ 20 x 
109/L above baseline 
starting from week 2 
until the end of the 
treatment period without 
rescue medication use in 
the past 4 weeks 
• 
Subject incidence of 
rescue ITP medications 
used  
• 
The incidence of anti-
romiplostim neutralizing 
antibodies and cross 
reactive antibodies to 
TPO at any time during 
the study 
• 
The incidence of 
adverse events, 
including clinically 
significant changes in 
laboratory values  
 
• 
The percentage of time with a platelet count of ≥ 50 x 109/L starting from week 2 until the 
end of the treatment period without rescue medication use within the past 4 weeks  
• 
The percentage of time with an increase in platelet count ≥ 20 x 10 9/L above baseline 
starting from week 2 until the end of the treatment period without rescue medication use in 
the past 4 weeks. 
• 
Subject incidence of rescue ITP medications used  
• 
The incidence of anti-romiplostim neutralizing antibodies and cross reactive antibodies to 
TPO at any time during the study 
• 
The incidence of adverse events, including clinically significant changes in laboratory 
values  
• 
The incidence of increased reticulin as evidenced by silver staining at Year 1 or 
Year 2, after exposure to romiplostim 
Page 19 of 23 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 110


Product:  Romiplostim 
Protocol Number: 20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 22 of 25 
 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Section 10.2 
Sample Size 
Considerations 
Not applicable 
A sample size of at least 60 subjects was selected for subjects undergoing bone marrow 
evaluations.  The sample size was chosen to provide an assessment/estimation of the 
development of bone marrow abnormalities (eg, collagen as evidenced by trichrome 
staining) at Year 1 or Year 2 after romiplostim exposure using the modified Bauermeister 
grading scale. 
With 30 subjects in each cohort, the number of evaluable bone marrow results in each 
cohort is expected to be between 20 and 25.   The assumption of 20 to 25 evaluable 
subjects is based on the approximate 30% rate of repeat inevaluable or missing bone 
marrow samples observed in the current Amgen adult ITP bone marrow study with 
romiplostim (Study 20080009).  The 95% exact confidence intervals for outcomes of 
bone marrow abnormalities when there are 20 and 25 evaluable bone marrow results are 
described in Table 4.   
No historical data are available regarding the change in bone marrow morphology in this 
patient population.  Clinical data from adult ITP subjects receiving romiplostim 
demonstrated that increases in bone marrow reticulin (or the presence of reticulin on 
study) were observed in 3.7% (10 of 271 of subjects: romiplostim 120-day safety update 
dataset used).  However the potential incidence rate could be higher or lower given that 
bone marrow assessments were not systematically performed on all subjects during 
clinical studies.   
Page 20 of 23 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 111


Product:  Romiplostim 
Protocol Number: 20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 23 of 25 
 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Section 10.2 
Sample Size 
Considerations 
(continued) 
 
 
Table 4.  95% Exact Confidence Intervals for the Incidence Rate of a Bone Marrow 
Abnormality 
Number of Subjects with Evaluable Bone Marrow = 20 
 
Number of 
Subjects With a 
Bone Marrow 
Abnormality 
Incidence  
Rate 
95% CI Lower 
Bound 
95% CI Upper 
Bound 
0 
0.0% 
0.0% 
16.8% 
1 
5.0% 
0.1% 
24.9% 
2 
10.0% 
1.2% 
31.7% 
3 
15.0% 
3.2% 
37.9% 
4 
20.0% 
5.7% 
43.7% 
5 
25.0% 
8.7% 
49.1% 
 
Number of Subjects with Evaluable Bone Marrow = 25 
 
Number of 
Subjects With a 
Bone Marrow 
Abnormality 
Incidence  
Rate 
95% CI Lower 
Bound 
95% CI Upper 
Bound 
0 
0.0% 
0.0% 
13.7% 
1 
4.0% 
0.1% 
20.4% 
2 
8.0% 
1.0% 
26.0% 
3 
12.0% 
2.5% 
31.2% 
4 
16.0% 
4.5% 
36.1% 
5 
20.0% 
6.8% 
40.7% 
 
Page 21 of 23 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 112


Product:  Romiplostim 
Protocol Number: 20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 24 of 25 
 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Section 10.3.1 
Interim Analyses 
Interim analyses will be 
conducted to support 
regulatory filings, and 
accumulated data for this 
study will be summarized to 
provide ongoing 
assessments of the safety of 
romiplostim.  These interim 
analyses will occur at least 
annually until the end of the 
study.  
 
Interim analyses will be conducted to support regulatory filings, and accumulated data for this 
study will be summarized to provide ongoing assessments of the safety of romiplostim.  These 
interim analyses will occur at least annually until the end of the study. 
A Bone Marrow Panel comprised of experts in the treatment of ITP and interpreting bone 
marrow pathology will convene approximately one time per cohort when all bone 
marrow biopsy samples have been evaluated for each respective cohort.  The Bone 
Marrow Panel will independently review the central lab bone marrow results and report 
those results to Amgen once each respective cohort has completed.  The bone marrow 
panel is not chartered to make recommendations to study conduct. 
A report will be generated including details of study compliance, the number of samples 
submitted and bone marrow biopsy results.  Additional data may be summarized at 
intervals throughout the duration of the study.  These data may be provided for 
regulatory or publication activities. 
Page 22 of 23 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 113


Product:  Romiplostim 
Protocol Number: 20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 25 of 25 
 
Table 1.  Summary of Changes 
Protocol Section 
Text in Protocol 
Text For the EU, Switzerland, and Turkey 
Section 10.3.4 
Additional 
Analysis, 
Add section 
10.3.4.4 Bone 
Marrow Analysis 
Not applicable 
Section 10.3.4.4 Bone Marrow Analysis 
The number and percentage of subjects who develop collagen as evidenced by 
trichrome staining at Year 1 or Year 2, will be summarized by study cohort, splenectomy 
status at baseline, years since diagnosis (≤ 3 vs > 3 years), age at enrollment (≥ 1 year to 
< 6 years; 6 years to <12 years; 12 years to < 18 years) and maximum doses and drug 
exposures if appropriate.  In addition, logistic regression may be used to investigate the 
association of bone marrow abnormality and potential predictive factors. 
The number and percentage of subjects with collagen as evidenced by trichrome 
staining 12 weeks after romiplostim discontinuation among subjects who developed 
collagen will be summarized. 
The number and percentage of subjects with bone marrow reticulin increases by ≥ 2 
severity grades or any increase to grade 4 (ie, grade 0 to 2-4, 1 to 3-4, 2 to 4), or change 
to grade 3 to 4 over baseline as evidenced by reticulin silver staining at Year 1 or Year 2, 
post romiplostim exposure using the modified Bauermeister grading scale will be 
summarized.  
The number and percentage of subjects with improvement of reticulin to a grade of ≤ 2 
for subjects who developed grade 3 reticulin after initial exposure to romiplostim as 
measured by the modified Bauermeister grading scale will be summarized. 
Page 23 of 23 
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 114


Product:  Romiplostim 
Protocol Number:  20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 1 of 2 
 
 
Supplement Version #2  
Protocol Supplement for the European Union (EU), Switzerland, and Turkey 
Protocol Title:  A Single Arm, Open-label, Long-term Efficacy and Safety Study of 
Romiplostim in Thrombocytopenic Pediatric Subjects With Immune 
Thrombocytopenia (ITP) 
Amgen Protocol Number 20101221 
EudraCT number 2011-005019-96 
 
Amendment Date: 
15 July 2014 
 
Rationale: 
As a result of regulatory reviews, modifications have been made to the numbering and 
content of the supplement inclusion criteria  
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 115


Product:  Romiplostim 
Protocol Number:  20101221 (Supplement Version 2) 
Date:  15 July 2014 
Page 2 of 2 
 
 
Description of Changes: 
Section: Header of the Document  
Replace:  15 April 2014 
With:   15 July 2014 
Section: Title Page, 
Add:  Supplement Version #2:  15 July 2014 
Page 13, Section 4.1:  Inclusion Criteria  
Renumber inclusion criteria 4.1.6 with 4.1.7 
Page 13, Section 4.1:  Inclusion Criteria  
Renumber inclusion criteria 4.1.7 with 4.1.8 
Replace: 
Baseline bone marrow reticulin grade of 0, 1, 2, or 3 according to the modified 
Bauermeister grading scale, as assessed by central laboratory 
With: 
A reticulin grade of 0, 1, 2, or 3 according to the modified Bauermeister grading 
scale,  as assessed by central laboratory from a bone marrow biopsy performed  
within 1 year prior to planned first dose of romiplostim or consent to a 
pre-treatment bone marrow biopsy and aspirate prior to planned first dose of 
romiplostim  
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 116

SAP_001.pdf: 
16.1.9
Documentation of Statistical Methods
Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 1


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Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 2
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Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 3


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Clinical Study Report:  20101221
09 September 2016
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Romiplostim
Clinical Study Report:  20101221
09 September 2016
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Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 6


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Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 7


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Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 8


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Clinical Study Report:  20101221
09 September 2016
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Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 10


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Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 11


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Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 12


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Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 13


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Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 14


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Product: 
Date: 
Romiplostim
Clinical Study Report:  20101221
09 September 2016
Page 15