Conditions: Cytomegalovirus (CMV)-Positive Recipients Allogeneic, Hematopoietic Cell Transplant (HCT)
Keywords: ASP0113 Cytomegalovirus (CMV) Hematopoietic Cell Transplant (HCT)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 514
Healthy volunteers: no

Brief summary:
The purpose of the study was to evaluate the efficacy of ASP0113 compared with placebo as measured by a primary composite endpoint of overall mortality and CMV end organ disease (EOD) through 1 year post-transplant. Safety of ASP0113 in participants undergoing allogeneic HCT will also be evaluated.

Detailed description:
Participants will be followed for 5.5 years post-transplant for long-term safety via an annual telephone contact.

Arms:
arm 1: Participants received 1 mL of 5 mg/mL of ASP0113 via intramuscular injection in the deltoid muscle alternating sides with each dose on days -14 to -3 pretransplant, 14 to 40, 60, 90 and 180 in relation to the day of transplant (Day 0). arm 2: Participants received 1 mL of 5 mg/mL of matching placebo via intramuscular injection in the deltoid muscle alternating sides with each dose on days -14 to -3 pretransplant, 14 to 40, 60, 90 and 180 in relation to the day of transplant (Day 0).

Interventions: intervention 1: ASP0113 intervention 2: Placebo
Intervention descriptions: intervention 1: Intramuscular injection intervention 2: Intramuscular injection

Protocol document:
Prot_000.pdf: 
A Randomized, Double-Blind, Placebo-Controlled, Phase 
3 Trial to Evaluate the Protective Efficacy and Safety of a 
Therapeutic Vaccine, ASP0113, in Cytomegalovirus 
(CMV)-Seropositive Recipients Undergoing Allogeneic, 
Hematopoietic Cell Transplant (HCT)
ISN/Protocol 0113-CL-1004
ClinicalTrials.gov Identifier: NCT01877655
Date of Protocol: Final Version 6.1, dated 28 Oct 2016
Sponsor: Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062


Sponsor: APGD
ISN/Protocol 0113-CL-1004
EudraCT number 2013-000903-18
- CONFIDENTIAL -
28 Oct 2016
Astellas
Page 1 of 136
Version 6.1 Incorporating Non-Substantial Amendment 1
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial 
to Evaluate the Protective Efficacy and Safety of a Therapeutic 
Vaccine, ASP0113, in Cytomegalovirus (CMV)-Seropositive Recipients 
Undergoing Allogeneic, Hematopoietic Cell Transplant (HCT)
Protocol for Phase 3 Study of ASP0113
ISN/Protocol 0113-CL-1004
Version 6.1
Incorporating Non-Substantial Amendment 1 [See Attachment 1]
28 October 2016
IND 11,381
EudraCT 2013-000903-18
Sponsor:
Astellas Pharma Global Development, Inc. (APGD)
Research & Development 
1 Astellas Way
Northbrook, IL 60062
Protocol History:
Version 1.0 Original [27Mar2013]
Version 2.0 [JP] Incorporating Country-Specific Substantial Amendment 1 [01Oct2013]
Version 3.0 (Global) Incorporating Substantial Amendment 2 [28Mar2014]
Version 4.0 [JP] Incorporating Country-Specific Substantial Amendment 3 [20May2014]
Version 5.0 (Global) Incorporating Substantial Amendment 4 [04Dec2015]
Version 6.0 (Global) Incorporating Substantial Amendment 5 [04Aug2016]
This confidential document is the property of the Sponsor. No unpublished information 
contained in this document may be disclosed without prior written approval of the Sponsor.


Sponsor: APGD
ISN/Protocol 0113-CL-1004
EudraCT number 2013-000903-18
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Table of Contents 
I.
SIGNATURES ······················································································ 8
II.
CONTACT DETAILS OF KEY SPONSOR PERSONNEL ······························11
III.
LIST OF ABBREVIATIONS AND KEY TERMS··········································13
IV.
SYNOPSIS··························································································17
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································27
1
INTRODUCTION·················································································34
1.1
Background ····················································································34
1.2
Product Composition ·········································································35
1.3
Nonclinical and Clinical Data ·······························································35
1.3.1
Nonclinical Data·········································································35
1.3.2
Clinical Data ·············································································36
1.3.2.1
Phase 1 (VCL-CB01-101) Results···············································36
1.3.2.2
Phase 2 (CB01-202) Results······················································37
1.4
Summary of Key Safety Information for Study Drugs ···································39
1.5
Risk-Benefit Assessment·····································································39
2
STUDY OBJECTIVES, DESIGN AND VARIABLES·····································40
2.1
Study Objectives ··············································································40
2.2
Study Design and Dose Rationale···························································40
2.2.1
Study Design·············································································40
2.2.2
Dose Rationale···········································································43
2.3
Variables ·······················································································44
2.3.1
Primary Variable ········································································44
2.3.2
Secondary Variables ····································································44
2.3.3
Exploratory Variables···································································44
2.3.4
Safety Assessments ·····································································45
2.3.5
Pharmacogenomics (PGx) Assessment (Optional)··································45
3
STUDY POPULATION··········································································45
3.1
Selection of Study Population ·······························································45
3.2
Inclusion Criteria··············································································45
3.3
Exclusion Criteria·············································································48
3.4
Contraception and Pregnancy Avoidance ··················································49


Sponsor: APGD
ISN/Protocol 0113-CL-1004
EudraCT number 2013-000903-18
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3.5
Discontinuation Criteria for Individual Subjects ··········································49
4
STUDY PRODUCTS ·············································································51
4.1
Description of Study Products·······························································51
4.1.1
Test Product··············································································51
4.1.2
Comparative Product····································································51
4.2
Packaging and Labeling······································································51
4.3
Study Drug Handling ·········································································51
4.4
Blinding ························································································53
4.4.1
Blinding Method·········································································53
4.4.2
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking ··················································································53
4.4.3
Breaking the Treatment Code for Emergency ·······································54
4.4.4
Breaking the Treatment Code by the Sponsor ·······································54
4.5
Assignment and Allocation ··································································54
5
TREATMENTS AND EVALUATION························································55
5.1
Dosing and Administration of Study Drugs and Other Medications····················55
5.1.1
Dose/Dose Regimen and Administration Period ····································55
5.1.2
Increase or Reduction in Dose of the Study Drugs··································55
5.1.3
Treatment Compliance··································································56
5.1.4
Emergency Procedures and Management of Overdose ·····························56
5.1.5
Previous, Concomitant and Prohibited Medication (Drugs and Therapies) ······56
5.1.5.1
Previous Medication (Drugs and Therapies) ···································56
5.1.5.2
Concomitant Medication (Drugs and Therapies) ······························56
5.1.5.3
Prohibited Concomitant Medications (Drugs and Therapies) ················57
5.2
Demographics and Baseline Characteristics ···············································57
5.2.1
Demographics············································································57
5.2.2
Medical History··········································································57
5.2.3
Transplant Information ·································································58
5.2.4
Modified HCT-CI Score································································58
5.3
Efficacy and Immunogenicity Assessments ···············································58
5.3.1
CMV Plasma Viral Load Assessment ················································58
5.3.2
Graft-Versus-Host Disease·····························································59
5.3.3
CMV EOD ···············································································60
5.3.4
Infection ··················································································60


Sponsor: APGD
ISN/Protocol 0113-CL-1004
EudraCT number 2013-000903-18
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5.3.5
Cause of Death···········································································60
5.3.6
Engraftment ··············································································60
5.3.6.1
Failure to Engraft ··································································60
5.3.6.2
Rejection/poor Graft Function ···················································60
5.3.6.3
Graft Failure········································································60
5.3.6.4
Platelet Recovery ··································································60
5.3.6.5
Incidence of Relapse of Primary Disease Requiring Therapy················60
5.3.7
Immunogenicity ·········································································61
5.3.8
Resource Utilization and Patient Reported Outcomes ······························61
5.3.8.1
EQ-5D···············································································62
5.3.8.2
FACT-BMT ········································································62
5.3.8.3
Work Productivity and Activity Impairment: General Health 
Questionnaire·······································································62
5.3.8.4
Health Economic Assessment····················································62
5.3.9
Optional Donor Sub-Study (Not Applicable to Sites in Japan) ····················62
5.4
Safety Assessment ············································································63
5.4.1
Vital Signs················································································63
5.4.2
Adverse Events ··········································································63
5.4.2.1
Local Reactogenicity Assessments ··············································63
5.4.3
Laboratory Assessments································································64
5.4.3.1
Abnormal LFTs ····································································65
5.4.3.2
Bronchoalveolar Lavage Fluid···················································65
5.4.4
Physical Examination···································································65
5.4.5
Long-Term Follow-up ··································································65
5.5
Adverse Events and Other Safety Aspects ·················································66
5.5.1
Definition of Adverse Events ··························································66
5.5.2
Adverse Events of Special Interest····················································66
5.5.2.1
Malignancy ·········································································66
5.5.2.2
Sinusoidal Obstruction Syndrome (SOS) [Hepatic Veno-occlusive 
Disease (VOD)]····································································66
5.5.2.3
Adverse Events Commonly Associated with Vaccines ·······················67
5.5.3
Definition of SAEs ······································································67
5.5.4
Criteria for Causal Relationship to the Study Drug ·································68
5.5.5
Criteria for Defining the Severity of an Adverse Event ····························68
5.5.6
Reporting of SAEs ······································································69
5.5.7
Follow-up to Adverse Events ··························································70


Sponsor: APGD
ISN/Protocol 0113-CL-1004
EudraCT number 2013-000903-18
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5.5.8
Monitoring of Common Serious Adverse Events and Endpoint Events ··········70
5.5.9
Procedure in Case of Pregnancy·······················································71
5.5.10
Supply of New Information Affecting the Conduct of the Study··················72
5.5.11
Deviations from the Protocol and Other Actions Taken to Avoid Life-
Threatening Risks to Subjects (FOR SITES IN JAPAN ONLY)··················72
5.6
Test Drug Concentration ·····································································72
5.7
Other Measurements, Assessments, or Methods ··········································73
5.7.1
Pharmacogenomics (PGx)······························································73
5.8
Total Amount of Blood·······································································73
6
DISCONTINUATION············································································73
6.1
Discontinuation of Individual Subject(s)···················································73
6.2
Discontinuation of the Study ································································73
7
STATISTICAL METHODOLOGY ···························································74
7.1
Sample Size····················································································75
7.2
Analysis Set····················································································75
7.2.1
Safety Analysis Set······································································75
7.2.2
Full Analysis Set ········································································75
7.2.3
Per Protocol Set··········································································75
7.2.4
Pharmacokinetic Analysis Set ·························································76
7.2.5
Immunogenicity Analysis Set··························································76
7.3
Demographics and Other Baseline Characteristics········································76
7.4
Analysis of Efficacy ··········································································76
7.4.1
Analysis of Primary Variable ··························································76
7.4.1.1
Primary Analysis···································································76
7.4.1.2
Secondary Analysis for the Primary Endpoint ·································77
7.4.1.3
Subgroup Analysis·································································77
7.4.2
Analysis of Secondary Variables ······················································77
7.4.2.1
Key Secondary Variables·························································77
7.4.2.2
Other Secondary Variable ························································78
7.4.3
Analysis of Other Variables····························································78
7.5
Analysis of Safety·············································································79
7.6
Analysis of Pharmacokinetics ·······························································81
7.7
Analysis of Pharmacogenomics ·····························································81


Sponsor: APGD
ISN/Protocol 0113-CL-1004
EudraCT number 2013-000903-18
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7.8
Protocol Deviations and Other Analysis ···················································81
7.9
Interim Analyses and Early Discontinuation of the Clinical Study ·····················81
7.9.1
DMC ······················································································81
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········82
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················82
8.1
Procedure for Clinical Study Quality Control ·············································82
8.1.1
Data Collection ··········································································82
8.1.2
Specification of Source Documents···················································82
8.1.3
Clinical Study Monitoring······························································83
8.1.4
Direct Access to Source Data/Documents············································83
8.1.5
Data Management ·······································································83
8.1.6
Protocol Deviations ·····································································83
8.1.7
End of Trial in All Participating Countries···········································84
8.2
Ethics and Protection of Subject Confidentiality··········································84
8.2.1
IRB / IEC / CA ··········································································84
8.2.2
Ethical Conduct of the Study···························································85
8.2.3
Informed Consent of Subjects ·························································85
8.2.3.1
Subject Information and Consent················································85
8.2.3.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information·····························85
8.2.4
Subject Confidentiality ·································································86
8.3
Administrative Matters ·······································································87
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ·····87
8.3.2
Documents and Records Related to the Clinical Study·····························87
8.3.3
Protocol Amendment and/or Revision················································89
8.3.4
Insurance of Subjects and Others (FOR JAPAN SITES ONLY)··················89
8.3.5
Signatory Investigator for Clinical Study Report····································90
9
QUALITY ASSURANCE········································································90
10
STUDY ORGANIZATION······································································90
10.1
Data Monitoring Committee (DMC) ·······················································90
10.2
Adjudication Committee ·····································································90
10.3
Other Study Organization ····································································90
10.3.1
Home Healthcare ········································································90
11
REFERENCES ····················································································91


Sponsor: APGD
ISN/Protocol 0113-CL-1004
EudraCT number 2013-000903-18
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12
APPENDICES ·····················································································94
12.1
Appendix 1:  Laboratory Tests ······························································94
12.2
Appendix 2:  Definition of CMV Disease··················································96
12.3
Appendix 3: Common Serious Adverse Events and Endpoint Events··················97
12.4
Appendix 4: Protocol Defined Definitions of Comorbidities for the HCT-
Comorbidity Index ············································································98
12.5
Appendix 5: Dynamic International Prognostic Scoring System for Survival in 
Primary Myelofibrosis······································································ 101
12.6
Appendix 6:  Definition of Morphologic Complete Remission ······················· 102
12.7
Appendix 7:  Grading of Reactogenicity ················································· 103
12.8
Appendix 8:  Severity Grading Table and Recurrence Interval Definitions for 
Infections····················································································· 104
12.9
Appendix 9:  Staging and Grading of Acute Graft versus Host Disease ············· 108
12.10
Appendix 10:  Rule of Nines Burn Chart················································· 110
12.11
Appendix 11:  Criteria for the Diagnosis of Chronic Graft Versus Host Disease ··· 111
12.12
Appendix 12:  Grading of Chronic Graft versus Host Disease ························ 115
12.13
Appendix 13:  Organ Scoring and Global Scoring of Chronic Graft versus Host 
Disease ······················································································· 116
12.14
Appendix 14:  EQ-5D Questionnaire ····················································· 119
12.15
Appendix 15:  FACT-BMT (Version 4)·················································· 121
12.16
Appendix 16:  Work Productivity and Activity Impairment Questionnaire:  
General Health Version 2.0 ································································ 124
12.17
Appendix 17:  Definitions of Conditioning Regimens ································· 126
12.18
Appendix 18:  Liver Safety Monitoring and Assessment ······························ 127
12.19
Appendix 19:  Pharmacogenomics (PGx) Sub-Study··································· 129
12.20
Appendix 20:  Long-term Follow-up Questionnaire···································· 131
12.21
Appendix 21:  Health Economic Assessment (Inpatient and Outpatient 
Utilization)··················································································· 132
12.22
Appendix 22:  Karnofsky Performance Scale ··········································· 133
13
ATTACHMENT 1:  NON-SUBSTANTIAL AMENDMENT 1························· 134
14
SPONSOR’S SIGNATURES·································································· 136


Sponsor: APGD
ISN/Protocol 0113-CL-1004
EudraCT number 2013-000903-18
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I. SIGNATURES
1a. SPONSOR’S SIGNATURE
Required signatures (e.g., Protocol authors, Sponsor’s reviewers and contributors, etc.) are 
located in Section 14 Sponsor’s Signatures; e-signatures (when applicable) are located at the 
end of this document.
1b. AGREEMENT BETWEEN THE SPONSOR’S RESPONSIBLE PERSON AND 
THE INVESTIGATOR (for sites in Japan)
This clinical study will be conducted in adherence to GCP, ICH Guidelines and applicable 
laws and regulatory requirements, as well as this study protocol. As the evidence of the 
agreement, the Investigator (
) and responsible person of the 
Sponsor (
) inscribe in the bipartite agreement.


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2.  COORDINATING INVESTIGATOR’S SIGNATURE
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Evaluate 
the Protective Efficacy and Safety of a Therapeutic Vaccine, ASP0113, in 
Cytomegalovirus (CMV)-Seropositive Recipients Undergoing Allogeneic, 
Hematopoietic Cell Transplant (HCT) 
ISN/Protocol 0113-CL-1004 
Version 6.1 / Incorporating Non-Substantial Amendment 1
28 October 2016
I have read all pages of this clinical study protocol for which Astellas is the Sponsor. I agree that it 
contains all the information required to conduct this study.
Coordinating Investigator:
Signature:
Date 
Printed Name:
Address:


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3. INVESTIGATOR’S SIGNATURE
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Evaluate 
the Protective Efficacy and Safety of a Therapeutic Vaccine, ASP0113, in 
Cytomegalovirus (CMV)-Seropositive Recipients Undergoing Allogeneic, 
Hematopoietic Cell Transplant (HCT) 
ISN/Protocol 0113-CL-1004 
Version 6.1 / Incorporating Non-Substantial Amendment 1
28 October 2016
I have read all pages of this clinical study protocol for which Astellas is the Sponsor. I agree to 
conduct the study as outlined in the protocol and to comply with all the terms and conditions set out 
therein. I confirm that I will conduct the study in accordance with ICH GCP guidelines and applicable 
local regulations. I will also ensure that sub-Investigator(s) and other relevant members of my staff 
have access to copies of this protocol and the ICH GCP guidelines to enable them to work in 
accordance with the provisions of these documents.
Principal Investigator:
Signature:
Printed Name:
Date
Address:






Sponsor: APGD
ISN/Protocol 0113-CL-1004
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III.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of Abbreviations
AC
Adjudication Committee
ADL
Activities of Daily Living
ADR
Adverse Drug Reactions
AE
Adverse Event
aGVHD
Acute Graft-versus-host Disease
ALC
Absolute Lymphocyte Count
ALL
Acute Lymphocytic Leukemia
ALT
Alanine Aminotransferase (GPT)
AML
Acute Myelogenous Leukemia
ANC
Absolute Neutrophil Count
AST
Aspartate Aminotransferase (GOT)
ASP0113
DNA vaccine being tested in this study
AUL
Acute Undifferentiated Leukemia
AUST
Astellas US Technologies, Inc.
AVT
Antiviral Therapy
BAK
Benzalkonium Chloride
BAL
Bronchoalveolar Lavage
BMT
Bone Marrow Transplant
BMTS
Bone Marrow Transplantation Subscale
CA
Competent Authorities
cGVHD
Chronic Graft-versus-host Disease
CIOMS
Council for International Organizations of Medical Sciences
CMH
Cochran-Mantel-Haenszel
CMV
Cytomegalovirus
CPK
Creatine Phosphokinase
CR
Complete Remission
CRO
Contract Research Organization
DLCO
Diffusing Lung Capacity of Carbon  Monoxide
DMC
Data Monitoring Committee
EBV
Epstein-Barr Virus
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EOD
End Organ Disease
EQ-5D
EuroQol-5D
ER
Emergency Room
FACT-BMT
Functional Assessment of Cancer Therapy – Bone Marrow Transplant
FAS
Full Analysis Set
FEV1
Forced Expiratory Volume
gB
Glycoprotein B
G-CSF
Granulocyte colony stimulating factor
GCP
Good Clinical Practice
GVHD
Graft-versus-host Disease
H0
Null Hypothesis
H1
Alternative Hypothesis
HCT
Hematopoietic Cell Transplant


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Abbreviations
Description of Abbreviations
HCT-CI
Hematopoietic Cell Transplant Comorbidity Index
HEA
Health Economics Assessment
HHC
Home Healthcare
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HLA
Human Leukocyte Antigen
IAS
Immunogenicity Analysis Set
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICS
Intracellular Cytokine Staining
IEC
Independent Ethics Committee
IFN-
Interferon γ
IgG
Immunoglobulin G
IND
Investigational New Drug
IRB
Institutional Review Board
ISN
International Study Number
ITT
Intent-to-treat
IU
International Unit
KPS
Karnofsky Performance Scale
LFT
Liver Function Tests
MDS
Myelodysplastic Syndrome
MHC
Major Histocompatibility Complex
MUGA
Multi gated Acquisition Scan
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
PB
Privacy Board
PBS
Phosphate-buffered Saline
PCR
Polymerase Chain Reaction
pDNA
Plasmid DNA
PE
Physical Examination
PFT
Pulmonary Function Test
PGx
Pharmacogenomics
PHI
Protected Health Information
PP
Per Protocol
pp65
Phosphoprotein 65
PPS
Per Protocol Set
QOL
Quality of Life
RBC
Red Blood Cell
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
TEAE
Treatment-emergent Adverse Event
ULN
Upper Limit of Normal
VE
Vaccine Efficacy 
WPAI:GH
Work Productivity and Activity Impairment Questionnaire: General Health


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Version 6.1 Incorporating Non-Substantial Amendment 1
List of Key Study Terms
Terms
Definition of terms
Adverse event
An adverse event is any untoward medical occurrence in a subject 
administered a study drug or has undergone study procedures and which does 
not necessarily have a causal relationship with the treatment.
Adverse reaction
An adverse reaction means any adverse event caused by a drug.
Baseline
Baseline is the time point prior to the first dose of randomized study drug. Visit 
2 is considered the baseline visit in this study. The last measurement / 
evaluation prior to the first dose of randomized therapy are considered the 
baseline measure/evaluation.
CMV infection
Replication of CMV (isolation of the virus or detection of viral protein or
nucleic acid in any body fluid or tissue)
CMV end organ 
disease (EOD)
As defined in [Appendix 2]
CMV viremia
Presence of CMV in the blood
End of study
The point in time when the last protocol-defined assessment has been 
completed (end of the long-term follow-up period)
End of treatment
The point in time when the subject receives the last dose of study drug
Enrollment
The point in time when the subject signs the informed consent
Evaluable subject
A subject who meets all inclusion criteria and does not meet any exclusion 
criteria and who has received at least 1 injection of study drug
Long-term Follow-
up Period
The period of time from the day 365 visit (V14) through the completion of the 
4½ year additional safety follow-up
Long-term follow-
up withdrawal
A subject who completes the primary study period but does not complete the 
long-term follow-up period for any reason
Preemptive therapy
A therapeutic treatment regimen where treatment for an infection/disease is 
initiated only after it is detected/confirmed
Primary follow-up
period
The period of time from the end of the study drug treatment through the day 
365 visit (V14)
Primary study 
period
The period of time from enrollment (signing of informed consent) through the 
day 365 visit (V14)
Primary study 
withdrawal
A subject who is randomized but does not complete the primary study period 
for any reason
Principal 
investigator
A physician responsible for the conduct of the clinical trial at a trial site. If a 
trial is conducted by a team of individuals at a trial site, the Principal 
Investigator is the responsible leader of the team.
Prophylactic 
therapy
A treatment regimen where treatment is administered prior to the detectable 
presence of infection or disease as a preventative measure


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Terms
Definition of terms
Randomization
The action to allocate a subject to a treatment group. In this study, 
randomization occurs after the subject has met all inclusion and exclusion 
criteria between days -3 to -14 prior to the transplant date.
Screening
The process for identifying a candidate for the study and evaluating their
eligibility to participate
Screen failure
A subject who signs the informed consent and undergoes the protocol-specific 
screening procedures, but does not fulfill the protocol inclusion and/or 
exclusion criteria. This subject is not to be randomized.
Serious adverse 
event
An adverse event is considered “serious” if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: results in 
death, is life threatening, results in persistent or significant disability / 
incapacity or substantial disruption of the ability to conduct normal life 
functions, results in congenital anomaly or birth defect, requires inpatient 
hospitalization or leads to prolongation of hospitalization, or is a medically 
important event.
Source data
All information in original records and certified copies of original records of 
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.
Source documents
Original documents, data and records including source data
Subject
An individual who participates in a clinical trial
Treatment period
The period of time from the first dose of study drug through the last dose of 
study drug


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ISN/Protocol 0113-CL-1004
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IV.
SYNOPSIS
Title of Study
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Evaluate 
the Protective Efficacy and Safety of a Therapeutic Vaccine, ASP0113, in 
Cytomegalovirus (CMV)-Seropositive Recipients Undergoing Allogeneic, 
Hematopoietic Cell Transplant (HCT)
Planned Study 
Period: 
Primary Study Period: From 3Q2013 to 3Q2017
Long-Term Follow-up Period: until 1Q2022
Study Objectives 

To evaluate the efficacy of ASP0113 compared with placebo as measured 
by a primary composite endpoint of overall mortality and CMV end organ 
disease (EOD) through 1 year post-transplant.

To evaluate the safety of ASP0113 in subjects undergoing allogeneic HCT. 
Planned Total 
Number of Study 
Centers and 
Location
Approximately 90 sites globally 
Countries may include, but are not limited to, Australia, Belgium, Canada, 
France, Germany, Japan, South Korea, Spain, Sweden, Taiwan and United 
States
Design and 
Methodology
This is a randomized, double-blind, placebo-controlled trial of approximately 
500 cytomegalovirus (CMV)-seropositive recipients undergoing allogeneic, 
hematopoietic cell transplant (HCT). Subjects will be randomized in a 1:1 ratio, 
ASP0113 or placebo, and stratified by donor-recipient relatedness and donor 
CMV serostatus. At least 30% of subjects enrolled will be donor
CMV-seronegative.
The test compound will be a vaccine (ASP0113) which contains 2 plasmids 
encoding glycoprotein B (gB) and phosphoprotein 65 (pp65), each at 
2.5 mg/mL, formulated with CRL1005 poloxamer and benzalkonium chloride 
(BAK).  The placebo control will be phosphate-buffered saline (PBS). 
Subjects will receive either 5 doses of ASP0113 or placebo on days -14 to -3, 
14-40, 60 ±5, 90 ±10 and 180 ±10 in relation to the day of transplant (donor cell 
infusion). 
The first injection must be given within 72 hours prior to the start of chemo-
therapy and radiation therapy for conditioning and the second injection is to be 
given as close as possible to, but not prior to, day 14.
The platelet count must be ≥ 50000 mm3 (spontaneously or after platelet 
transfusion) performed by the local laboratory within 3 days prior to all study 
drug injections. Prior to all study drug injections, confirmation must be made 
that there is no medical contraindication to an IM injection. Results received in 
an equivalent local unit of measure must be converted to SI units.  Syringes will 
be masked prior to dosing to blind the subjects and all other personnel who need 
to remain blinded to the treatment assignment (i.e., site staff other than 
pharmacy personnel and staff designated to administer study drug injections). 
CMV plasma viral load will be monitored per the following schedule during the 
primary study period (through day 365/V14): weekly (±2 days) during days 
0-100, every other week (± 5 days) during days 101-180, every 30 days
(±5 days) during days 181-365. The CMV plasma viral loads will be performed 
by the central laboratory. CMV plasma viral load will also be performed by the 
central laboratory at the initiation of CMV-specific antiviral therapy (AVT). 


Sponsor: APGD
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Version 6.1 Incorporating Non-Substantial Amendment 1
Design and 
Methodology
continued
Upon initiation of CMV-specific AVT, plasma viral load testing will be 
performed at least weekly until the CMV-specific AVT is discontinued, at
which point, the regularly scheduled viral load assessments will resume. 
Note: CMV plasma viral loads may be performed at a local laboratory approved 
by the Sponsor and at the discretion of the Investigator. However, every time a 
viral load sample is sent to the local laboratory a sample will also be sent to the 
central laboratory for confirmatory testing. Pre-emptive therapy may be started 
based on the central or local laboratory assessment and the subject’s clinical 
condition.
Adjudicated CMV-specific AVT will be assessed for subjects up to1 year 
following transplant through the primary study period (through day 365/V14).
Immunologic response will be assessed in all subjects at V2, V5, V8, V9, V11 
and V14. If the visit coincides with a study drug administration, the sample will 
be drawn prior to injection. 
In addition, if a CMV seropositive donor has consented and is participating in 
the optional donor cell sub-study, a 20 mL peripheral blood sample from the 
donor will be obtained prior to the stem cell donation for recipients participating 
in the main trial to test for CMV-specific T-cells.  For those donating peripheral 
stem cells, the donor blood sample is to be collected prior to the initiation of 
mobilization therapy (e.g., G-CSF).  This process is not applicable to sites in 
Japan.
Subjects will be evaluated for local reactogenicity and systemic signs 
for 60 minutes after each injection. Subjects will be directly observed for 
15 minutes following the injection for any injection-related side effects, then 
remain in a designated area at the study site for 45 minutes so that side effects 
can be noted and treated, if necessary. Local reactogenicity will also be 
evaluated for each of the 7 consecutive days following each injection beginning 
approximately 24 hours after the dose (day 1-7 post dose). The assessments for 
each of the 7 consecutive days following an injection will be done by the subject 
and reported to the site via diary. When reactogenicity is reported as an AE, it 
must be followed until resolution or medically stable. All local reactions 
≥grade 3 [Appendix 7] require confirmation by a health care professional.
Subjects will be contacted after the last injection of vaccine through 5.5 years 
post-transplant for long-term safety related to the DNA vaccine.  Items to be 
assessed include mortality, development of any new/ recurrent cancer, 
development of infection requiring hospitalization or resulting in death and 
erythema and/or induration at the injection sites [Appendix 20].  
All AEs and SAEs will be collected from signing of the informed consent 
through 30 days post last dose of study drug. All events requiring adjudication, 
grade 3 and higher grade AEs as well as SAEs will be collected from 31 days 
post last dose of study drug through 1 year post-transplant. A change in medical 
status or medical history from time of signing of informed consent through first 
dose of study drug is to be reported as an AE or SAE, as appropriate. 
An independent Data Monitoring Committee (DMC) will be chartered to 
oversee safety issues and futility analysis.


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Design and 
Methodology
continued
Futility analysis will be performed when the first 100 subjects have been 
randomized, and every 3 months thereafter until the total enrollment reaches 
400 subjects. Futility analyses are based on the rate of CMV viremia defined as 
CMV plasma load ≥1000 IU/mL as assessed by the central laboratory. At each 
futility analysis, a Bayesian posterior probability that the hazard ratio for 
viremia of the ASP0113 treatment group to the placebo treatment group will be 
less than 0.75 will be calculated. The study may stop for futility if this posterior 
probability is less than 0.15.
An Adjudication Committee (AC) will be chartered to adjudicate all cases of 
CMV EOD, initiation of CMV-specific AVT, and cause of death.
Number of 
Subjects Planned
Approximately 500 subjects will be enrolled and receive study drug in the study. 
Selection Criteria
Inclusion Criteria: 
A subject is eligible for the study if all of the following apply:
1.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-
approved written informed consent and privacy language as per national 
regulations (e.g., Health Insurance Portability and Accountability Act
(HIPAA) Authorization for U.S. sites) must be obtained from the subject or 
legally authorized representative prior to any study-specific related 
procedures (including withdrawal of prohibited medication, if applicable).
2.
Subject is a male or female subject who is at least 18 years old or the legal 
age of consent (whichever is greater). 
3.
Subject is a CMV-seropositive HCT recipient as confirmed by local 
laboratory at screening.
4.
Subject is planned to undergo either of the following:
a. Sibling Donor Transplant – 7/8 Human Leukocyte Antigen (HLA)-A, -
B, -C, -DRß1 match utilizing high resolution typing or 8/8 (HLA)-A, -B, 
-C, -DRß1 match utilizing low or high resolution typing.*
b. Unrelated Donor Transplant - 7/8 or 8/8 HLA-A, -B, -C, -DRß1 match 
utilizing high resolution typing.*
* A minimum of 8 allele matching is required. Subjects with matches 
performed at more than 8 alleles are included if they have 7/8 or 8/8 
match at the HLA-A, -B, -C, –DRß1 alleles.
5.
Subject is scheduled to receive an allogeneic peripheral blood stem cell or 
bone marrow transplant (BMT) for the treatment of hematologic disorders 
as indicated in Inclusion Criterion 6.
6.
Subject has 1 of the following underlying diseases:
a. Acute myeloid leukemia (AML), with or without a history of 
myelodysplastic syndrome (MDS), in first or second complete remission 
[Appendix 6] or in early relapse (< 20% blasts in bone marrow with no 
circulating blasts in peripheral blood and no extramedullary leukemia).
b. Acute lymphoblastic leukemia (ALL), in first or second complete 
remission [Appendix 6]
c. Acute undifferentiated leukemia (AUL) in first or second complete 
remission [Appendix 6]


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Version 6.1 Incorporating Non-Substantial Amendment 1
Selection Criteria
continued
Inclusion Criteria continued: 
d. Acute biphenotypic leukemia in first or second complete remission 
[Appendix 6]
e. Chronic myelogenous leukemia (CML) in either chronic or accelerated 
phase
f. Chronic lymphocytic leukemia.
g. One of the following MDS defined by the following:
i.
Refractory anemia with evidence of dysplasia
ii.
Refractory anemia with ringed sideroblasts
iii.
Refractory cytopenia with multilineage dysplasia
iv.
Refractory cytopenia with multilineage dysplasia and ringed sidero-
blasts
v.
Refractory anemia with excess blasts-1 (5%-10% blasts)
vi.
Refractory anemia with excess blasts-2 (10%-20% blasts)
vii.
MDS, unclassified
viii.
MDS associated with isolated deletion (5q)
ix.
Chronic myelomonocytic leukemia 
h. Primary or secondary myelofibrosis without leukemic transformation 
except if Dynamic International Prognostic Scoring System category of 
high or intermediate -2 [Appendix 5]
i. Lymphoma (including Hodgkin’s) with chemosensitive disease (≥50% 
response to chemotherapy)
7.
Female subject must be either:
Of non-childbearing potential:
o
Postmenopausal (defined as at least 1 year without any menses) 
prior to screening, and if < 50 years of age and  not documented to 
be surgically sterile must have a negative urine or serum 
pregnancy test at screening, or 
o
Documented surgically sterile or status post-hysterectomy (at least 
1 month prior to screening)  
Or, if of childbearing potential:
o
Must have a negative urine or serum pregnancy test at screening, 
and 
If heterosexually active, must use at least 1 form of birth control* 
(which must be a barrier method) starting at screening and 
through the primary study period.
8.
Female subject must not be breastfeeding at screening, through the treatment 
period and through the primary study period.
9.
Female subject must not donate ova starting at screening, through the 
treatment period and through the primary study.
10. Male subject and their female spouse/partners who are of childbearing 
potential must be using highly effective contraception consisting of 2 forms 
of birth control* (1 of which must be a barrier method) starting at screening, 
through the treatment period and through the primary study period.


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Selection Criteria
continued
Inclusion Criteria continued: 
* Acceptable forms include: 
Consistent and correct usage of established oral contraception.
Established intrauterine device or intrauterine system.
Barrier methods of contraception: condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository <Not applicable for sites in Japan: 
with spermicidal foam/gel/film/cream/suppository>
For sites in Japan: calendar-based contraceptive methods (Knaus-
Ogino or rhythm method)
11. Male subject must not donate sperm starting at screening, through the 
treatment period and through the primary study period.
12. Subject is willing to comply with the protocol.
13. Subject agrees not to participate in another interventional study while on 
treatment. New regimens of approved chemotherapeutic drugs or antibodies, 
conditioning drugs, irradiation and T-cell depleting antibodies, except 
alemtuzumab, are allowed. 
Waivers to the inclusion criteria will NOT be allowed.
Exclusion Criteria:
A subject will be excluded from participation if any of the following apply:
1.
Subject has active CMV disease or infection or has received treatment for 
active CMV disease or infection within 3 months (90 days) prior to 
transplant. 
2.
Subject has planned CMV prophylactic therapy with antiviral drugs or 
CMV-specific immunoglobulins from randomization through the primary 
study period completion/day 365 visit (V14). 
3.
Subject has a modified hematopoietic cell transplant comorbidity index 
(HCT-CI) score ≥4 [Appendix 4].
4.
Subject is known to be positive for human immunodeficiency virus (HIV), 
hepatitis B surface antigen or hepatitis C ribonucleic acid (RNA)
polymerase chain reaction (PCR).
5.
Donor CMV serostatus is unknown.
6.
Subject has received any of the following substances or treatments: 

Alemtuzumab within 60 days prior to transplant, including 
conditioning regimen. Subjects for whom treatment with alemtuzumab 
is planned at any time from 60 days prior to through 1 year post-
transplant must not be enrolled in the trial.

T cell depletion of donor cell product.

Administration of a CMV vaccine, including any prior exposure to 
ASP0113.
7.
Subject has received an allogeneic stem cell transplant within 1 year prior to 
transplant (subjects who have received a prior autologous transplant are 
allowed).


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Selection Criteria
continued
8.
Subject has a current malignancy in addition to the malignancy being treated 
for the study or the subject has a history of any other malignancy (within the 
past 5 years prior to screening) except non-metastatic basal or squamous cell 
carcinoma of the skin that has been treated successfully or cancer in situ of 
the cervix uteri that has been handled by local surgery.
9.
Subject has an unstable medical or psychiatric condition, including a history 
of illicit drug(s) or alcohol abuse that the Investigator believes will interfere 
with protocol requirements.
10. Subject has had an allergic reaction to any component of the vaccine.  
Subject has had an allergic reaction to aminoglycosides as kanamycin is 
used in the manufacturing process of the vaccine.
11. Subject has participated in any interventional clinical study or has been 
treated with any investigational research products within 30 days or 5 half-
lives, whichever is longer, prior to the initiation of screening. 
(Investigational research products are considered those products that have 
not been approved for any indication in the country where the subject is 
enrolled. New regimens of approved chemotherapeutic drugs or antibodies, 
conditioning drugs, irradiation and T-cell depleting antibodies, except 
alemtuzumab, are allowed.)
12. Subject has received a prior HCT and has residual cGVHD.
13. Subject who is scheduled to have a cord blood transplant or a haploidentical 
transplant.
14. Subject has a platelet count of less than 50000 mm3 within 3 days prior to
randomization (platelet transfusions are allowed). Results received in an 
equivalent local unit of measure must be converted to SI units.
15. Subject has aplastic anemia or multiple myeloma.
16. For sites in Japan only: Other subjects considered ineligible by the 
Investigator/sub-Investigator.
Waivers to the exclusion criteria will NOT be allowed.
Primary Study 
Period 
Discontinuation 
Criteria 
Study Discontinuation
Subjects will be withdrawn from study and will receive no further follow-up 
except for mortality (at day 365 post-transplant) through public record /sources
if the following occurs:

Withdrawal of consent by subject 
Subjects will be withdrawn from the study and will receive no further follow-up 
if the following occurs:

Subject did not receive first dose of study drug
Treatment Only Discontinuation
Subjects will be withdrawn from study drug treatment if any of the following 
occur; however, they are to continue to be followed according to the protocol 
Schedule of Assessments [Table 1] with exception of the dose follow-up 
visits (i.e., V3, V6, V8, V10, and V12). 

Investigator’s decision that further treatment is not in the best interest of the 
subject.

Pregnancy (female subjects only).

Failure to engraft.


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
Local reactogenicity with a grade ≥3 based on the criteria defined in 
[Appendix 7] and confirmed by a health care professional.

Anaphylaxis with a grade ≥ 3 based on National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03.

Seizure considered possibly or probably related to study drug treatment.  

Participation in another interventional trial with an investigational research 
product (investigational research products are considered those products 
that have not been approved for any indication in the country where the 
subject is enrolled).
If a subject is withdrawn from study drug treatment and is unable to comply with 
study procedures as defined in the Schedule of Assessments, the subject must be 
asked if they are willing to be followed for SAEs through 30 days of last dose of 
study drug treatment, to attend the scheduled final study visit (V14), to be 
assessed for CMV EOD, and/or to be followed for mortality.  They must also be 
asked if they are willing to be followed through the long term follow-up period.
Subjects who discontinue from the study after one or more doses of study drug 
will not be replaced. Subjects who are randomized but never receive study drug 
will be replaced, to a total of approximately 500 dosed subjects.
Test Drug Dose 
Mode of 
Administration 
Duration of 
Treatment
ASP0113 will be dosed as 1 mL administered IM in the deltoid muscle with a 
needle and syringe, alternating sides with each dose, if possible.
Subjects will receive 5 injections of ASP0113 over an approximate 6 month 
period.
Reference Drug
Dose 
Mode of 
Administration 
Duration of 
Treatment
Placebo is PBS and will be dosed as 1 mL administered intramuscularly in the 
deltoid muscle with a needle and syringe, alternating sides with each dose, if 
possible.
Subjects will receive 5 injections of placebo over an approximate 6 month 
period.
Concomitant 
& Prohibited 
Medications & 
Therapies
Concomitant Medications & Therapies
Conditioning Regimens
Subjects are to undergo a conditioning regimen that is standard of care for the 
institution at which they are enrolled. Both myeloablative and 
non-myeloablative (reduced intensity) conditioning regimens are allowed. Note 
that alemtuzumab is not allowed within 60 days prior to transplant.
Viral Prophylaxis
Viral prophylaxis for infection other than CMV is to be administered according 
to standard institutional protocols. Prophylactic use of aciclovir (acyclovir), 
valaciclovir (valacyclovir), or famciclovir must not exceed the following doses 
following transplant (day 0) through 1 year post-transplant (day 365/V14) 
[Kumar, 2011; Tomblyn, 2009].
Aciclovir: 
1600 mg orally (total daily dose), or 500 mg/m2/day IV* (total daily dose).
*If dose is IV it may be rounded up to the nearest 100 mg.
Valaciclovir: 1000 mg po (total daily dose).
Famciclovir: 500 mg po (total daily dose). 
These doses may NOT be exceeded for prophylaxis but may be exceeded if 
necessary to treat active infections post-transplant.


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Prohibited Concomitant Medications (Drugs and Therapies)
The following medications and therapies are prohibited throughout the study 
[through the primary study period completion/day 365 visit (V14)]:
●
Investigational research products that have not been approved for any 
indication in the country where the subject is enrolled. 
o
New regimens of approved chemotherapeutic drugs or antibodies, 
conditioning drugs, irradiation and T-cell depleting antibodies, except 
alemtuzumab, are allowed.
●
Prophylactic use of antiviral drugs for CMV viremia from time of 
Randomization through completion of the primary study period 
completion/ day 365 visit (V14). 
●
Prophylactic use of CMV specific immunoglobulin. 
●
Alemtuzumab within 60 days prior to transplant (including conditioning 
regimen) through completion of the primary study period completion/day 
365 visit (V14) unless required for disease relapse post-transplant.
Primary 
Variables
The primary endpoint of the study is the composite of overall mortality and 
CMV EOD through one year post-transplant.
Secondary 
Variables
Key secondary endpoints:  
●
Time to first protocol-defined CMV viremia [CMV plasma viral load 
≥1000 IU/mL as assessed by the central laboratory] through 1 year 
post-transplant.
●
Time to first adjudicated CMV-specific AVT through 1 year post-
transplant.
Additional secondary endpoint:
●
Time to first CMV-specific AVT for protocol-defined CMV viremia[CMV 
plasma viral load ≥ 1000 IU/mL as assessed by the central laboratory] or 
CMV EOD through one year post-transplant.
Exploratory 
Variables
●
Clinical outcomes:
Overall mortality
Incidence of CMV EOD
Incidence of grade 3-4 aGVHD
Incidence of severe cGVHD
Incidence of grade 3 treatment-emergent infections other than CMV
Maximum grade of aGVHD
Maximum cGVHD score
Relapse mortality (death due to relapse of the subject’s primary 
disease)
Non-relapse mortality (death due to causes unrelated to the subject’s 
primary disease)
Incidence of graft rejection
Incidence of failure to engraft
Time to engraftment
Time to platelet recovery 
Incidence of relapse of primary disease requiring therapy
Number of episodes of protocol-defined CMV viremia [CMV plasma 
viral load ≥ 1000 IU/mL as assessed by the central laboratory]


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Time to grade 3 treatment-emergent viral, bacterial, or fungal 
infections other than CMV 

Duration of hospitalization(s)

Health economic/resource utilization

Subjects’ quality of life (EQ-5D, FACT-BMT, and Work Productivity and 
Activity Impairment Questionnaire: General Health [WPAI: GH])

Immunogenicity Variables
T-cell responses to pp65 
gB-specific antibody levels
Safety 
Assessments
●
Vital signs
●
Adverse events 
●
Local reactogenicity signs and symptoms using both the NCI-CTCAE 
Version 4.03 grading scale and the protocol-specified reactogenicity scale 
[Appendix 7]
●
Clinical laboratory assessments as defined in [Appendix 1]
●
Physical examination (PE)
Statistical 
Methods
This is a randomized, double-blind, placebo-controlled trial of approximately 
500 subjects. In the primary analysis set of a phase 2 study of the efficacy of 
ASP0113 in HCT, 7 subjects died and 2 additional subjects experienced CMV 
EOD out of 40 treated with ASP0113, for an overall failure rate of 22.5%, 
while among the placebo subjects 11 subjects died and 1 additional subject
experienced CMV EOD out of 34, for an overall failure rate of 35.3%. 
To detect the estimated difference in mortality and CMV EOD from the phase 2 
study (35.3% vs. 22.5%), the study needs a sample size of at least 424 (212 per 
arm) to have 80% power at the 2-sided significance level of 0.050. A trial of 
size 500 (250 per arm) is expected to have 86% power for the composite 
endpoint.
The full analysis set (FAS) consists of all randomized subjects who receive at 
least 1 dose of randomized study drug.
Efficacy analyses will be limited to the data obtained from time first of dose of 
study drug through the 1 year post-transplant follow-up period. Data collected 
after the 1 year post-transplant follow-up period for the long-term follow-up 
will not be included for the primary analysis of efficacy variables. 
Comparison between ASP0113 and placebo with respect to the primary 
endpoint will be performed using the Cochran-Mantel-Haenszel test stratified 
by factors for randomization (donor-recipient relatedness and donor CMV 
serostatus). 
In a supportive analysis, time to first occurrence of a primary endpoint event 
will be analyzed in a Cox proportional hazards model where the time-to-event 
will be calculated in days from transplant to the earliest of death or CMV EOD. 
Subjects not experiencing the primary endpoint event will be censored at the 
time of their last follow-up visit. The Cox model will include treatment and the 
stratification factors for randomization.
Key secondary endpoints of time to first protocol defined CMV viremia 
through 1 year post-transplant and time to first adjudicated CMV-specific AVT 
through 1 year will each be compared between treatments using a Cox 
proportional hazards model with factors for treatment, donor-recipient 
relatedness, and donor CMV serostatus.


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The endpoint of time to first CMV-specific AVT for protocol-defined CMV 
viremia or CMV EOD through 1 year post-transplant will be analyzed using a
Cox proportional hazards model as described above.
Incidence of overall mortality, CMV EOD, grade 3-4 aGVHD, severe cGVHD, 
grade 3 infections other than CMV, relapse mortality, non-relapse mortality, 
graft rejection, failure to engraft, and relapse of primary disease requiring 
therapy will each be tested using a stratified analysis of the binary response 
using a CMH test to account for the stratification variables used as part of the 
randomization. 
Number of episodes of protocol-defined CMV viremia will be compared 
between treatments using a stratum-adjusted Kruskal-Wallis test, adjusting for 
donor-recipient relatedness and donor CMV status.
To estimate the association between CMV viremia and mortality, a 
multivariable Cox proportional hazards model will be constructed in a time-
dependent manner. The model will be adjusted for the factors used to stratify 
the randomization. CMV viremia will be treated as a time-dependent variable, 
starting at the time of the first occurrence of protocol-defined CMV viremia.
The maximum grade of aGVHD, maximum cGVHD global score, and duration 
of hospitalizations will each be tested using a stratum-adjusted Kruskal-Wallis 
test. 
The treatment effect on time to engraftment and time to platelet recovery will 
each be analyzed in a Cox proportional hazards model including the factors 
used to stratify the randomization. 
Treatments will be compared with respect to each domain of the EQ-5D, the 
FACT-BMT, and productivity outcomes from the WPAI:GH using analysis of 
covariance (ANCOVA) of change from baseline to final visit with treatment, 
donor-recipient relatedness, and donor CMV serostatus as factors and baseline 
value as covariate.
Safety Analysis
The SAF will consist of all randomized subjects who have received at least 
1 study drug injection. This analysis set will be used for all summaries of AEs, 
reactogenicity, clinical lab data, physical exams, vital signs and subject survival 
through 1 year post first study drug injection. All recorded AEs will be listed, 
including duration, outcome, toxicity grade, and association with use of study 
drug.
Pharmaco-
genomics (PGx) 
Subjects who consent to participate in the optional pharmacogenomics (PGx) 
sub-study will have a saliva sample collected during the baseline visit (V2), 
after randomization, but prior to the first dose of study drug. These samples will 
be stored for exploratory retrospective PGx analyses.


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V. FLOW CHART AND SCHEDULE OF ASSESSMENTS
Flow Chart
Primary Study Period: Screening/ICF through 12-months post-transplant (Day 365/Visit 14)
1.
Screening visit and V2 (first dose) may occur either separately or on the same day. Eligibility will be 
determined using local laboratory results collected at the screening visit.  The first dose of study drug 
must be administered prior to conditioning therapy.  The dosing interval in relation to 
transplant/conditioning must be maintained.
2.
Local laboratory assessments may be repeated 1 time if abnormal within the 25 day screening period.
3.
The subject may be rescreened 1 time if the transplant is delayed and it will be outside the 25 day 
screening window.  If outside the 25 day screening period, all screening procedures must be repeated.
4.
Baseline is date of first dose (V2). The day of transplant (donor cell infusion) is day 0 and all visit days 
are relative to day 0.
5.
Note that the day 365 visit must occur on day 365 +14 days (between day 365 to 379); it cannot occur 
prior to day 365.
Long-term Follow-up Period: Primary Study Period Completion through Long-term 
Follow-up Completion (Day 365/Visit 14 through 5.5 years Post-Transplant)
* Subjects will be contacted after the last injection of vaccine through 5.5 years post-transplant for long-term 
safety related to the DNA vaccine. Items to be assessed by telephone interview, and available patient records
include; mortality, development of any new/recurrent cancer, development of infection requiring 
hospitalization or resulting in death, and erythema and induration at the injection site [Appendix 20].








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7.
Safety Laboratory will be drawn at the screening visit using the local laboratory. Safety laboratory will be done by a central laboratory at baseline, before doses 2-5, and at each follow-up 
time point for doses 2-5, and will include hematology and biochemistry, including a hepatic profile. Please refer to [Protocol Appendix 1] for a full list of routine safety parameters that will be 
tested, and to [Section 5.4.3] and the Laboratory Manual for further instruction on laboratory collection and processing.
8.
Screening for cytomegalovirus (CMV) immunoglobulin G (IgG) seropositivity by the local laboratory may be performed up to 30 days prior to transplant and before randomization.
9.
The modified hematopoietic cell transplant-comorbidity index (HCT-CI) score are to be completed during screening with history and laboratory from the screening visit. Local laboratory 
results are to be used in the assessment. Local laboratories may be repeated once to score the HCT-CI. Pulmonary function tests (PFTs) including forced expiratory volume (FEV1) and 
diffusing lung capacity of carbon monoxide (DLco), multi gated acquisition scan (MUGA), and/or echocardiograms performed within 6 months (180 days) prior to screening are to be used 
for scoring pulmonary and cardiac comorbidities. PFTs (FEV1 and DLco), MUGAs /or echocardiograms not performed within 6 months of screening will have to be repeated for scoring 
purposes. 
10.
For all females of childbearing potential and all females who are of non-childbearing potential but are < 50 years of age and not documented to be surgically sterile, a urine or serum 
pregnancy test will be performed at screening, on the same day and prior to each dose, at visit 13, and at the primary study period completion/day 365 visit (V14). All pregnancy tests will be 
done locally. For subjects who receive mycophenolate mofetil, additional pregnancy testing should be done in accordance with local regulatory requirements.
11.
All AEs and SAEs will be collected from signing of the informed consent through 30 days post last dose of study drug. All events requiring adjudication (CMV end organ disease [EOD], 
initiation of CMV-specific antiviral therapy [AVT], and cause of death), grade 3 and higher grade AEs as well as all SAEs will be collected from 31 days post last dose of drug through 1 year 
post-transplant. A change in medical status or medical history from time of signing of informed consent through first dose of study drug is to be reported as an AE or SAE as applicable. In 
this study, the day 0 HCT is not considered an AE.  
12.
The EuroQol – 5D (EQ-5D), Functional Assessment of Cancer Therapy – Bone Marrow Transplant (FACT-BMT), and Work Productivity and Activity Impairment Questionnaire (WPAI) are 
to be completed by the subject prior to any other study assessments or visit procedures. Subjects are to complete these assessments in the following order: EQ-5D first, FACT-BMT second, 
WPAI:GH last. For all 3 patient-reported outcome measures, i.e. EQ-5D, FACT-BMT, WPAI, the answers must come from the subject. If the subject is unable to fill out the questionnaire, the 
assessment should not be performed. If the subject is unable to answer a question, the rest of the questionnaire still needs to be completed.
13.
Immunogenicity laboratories include collection of blood for the glycoprotein B (gB) antibody and phosphoprotein 65 (pp65) T-cell assays. Samples are to be drawn on visits V2, V5, V8, V9, 
V11 and V14. Samples for T-cell assays will not be collected if the absolute lymphocyte count is known to be < 500 mm3 by local or central laboratory measurement. If the visit coincides 
with a study drug administration, the sample will be drawn prior to injection.
14.
The platelet count must be at least ≥ 50000 mm3 (spontaneously or after platelet transfusion) performed by the local laboratory within 3 days prior to all study drug injections. Prior to all 
study drug injections, confirmation must be made that there is no medical contraindication to an IM injection. Results received in an equivalent local unit of measure must be converted to SI 
units.  If the subject’s platelet count does not meet this threshold at the time of the visit, the subject may return for the study drug injection and local reactogenicity assessment at a later time 
within the allowable window for the visit. If the subject’s platelet count does not meet this threshold during the visit window, the dose must be skipped and the corresponding follow-up safety 
laboratory and reactogenicity assessment should not be done. The second injection should be given as close to, but not prior to, day 14 as possible.
15.
Subjects who consent to participate in the pharmacogenomics (PGx) substudy will have a saliva sample collected during the baseline visit (V2), after randomization but prior to the first dose 
of study drug.
16.
Plasma viral load by the central laboratory will be monitored weekly (± 2 days) during days 0-100, every other week (±5 days) during days 101-180, every 30 days (±5 days) during days 
181-365, at the initiation of CMV-specific AVT, when clinically indicated, and every time a viral load sample is sent to the local laboratory. When CMV-specific AVT is initiated, a central 
CMV viral load will be obtained a minimum of weekly until CMV-specific AVT is discontinued. Thereafter, the regularly scheduled viral load assessments will resume according to the 
scheduled protocol assessments.
Footnotes continued on next page


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17.
The first dose is to be given at day -14 to -3 prior to transplant and within 72 hours prior to the start of chemotherapy and radiation therapy for conditioning. 
18.
The subject must be monitored directly for the first 15 minutes of the injection. The subject must be in the clinic, but does not require direct monitoring, from 15 minutes through 1 hour 
after the injection.
19.
Local reactogenicity will be evaluated 1 hour (± 10 minutes) after each injection and for each of the 7 consecutive days following each injection beginning approximately 24 hours following 
each dose (day 1-7 postdose). The assessments for each of the 7 consecutive days following an injection will be done by the subject and reported to the site via diary. When reactogenicity is 
reported as an AE, it is to be followed until resolution or medically stable. All local reactions 
≥grade 3 (Appendix 7) require confirmation by a health care professional.
20.
The date of transplant (donor cell infusion) defines day 0 and all visit days are relative to day 0. Based on this schedule, V3 may occur prior to or after the day of transplant, day 0.  
21.
Transplant information includes recipient transplant volume infused, HLA typing of the donor and recipient, HLA cross match at time of transplant (as determined by the site’s standard 
method of determination and, if available), type of transplant, the number of CD34+ stem cells/kg infused if available, donor and recipient CMV serostatus, if available the hepatitis B virus 
(HBV) serostatus, hepatitis C virus (HCV) serostatus, and Epstein Barr Virus (EBV) serostatus of the donor and recipient; blood type of the donor and recipients. ABO cross match (if 
available), donor-recipient relatedness, donor gender, age, race (if available) and ethnicity (for the USA only and if available); donor product plasma, volume and RBC depletion status; and if 
available donor cell product CD3+, CD4+, CD8+ and CD56+ cell counts. For bone marrow recipients, the number of mononuclear cells transfused must also be included, if possible.
22.
Optional: A 20 mL peripheral blood sample from the CMV seropositive donors will be obtained prior to the stem cell donation for recipients participating in the main trial to test for CMV-
specific T-cells (requires donors’ consent). For those donating peripheral stem cells, the donor blood sample is to be collected prior to the initiation of mobilization therapy (e.g., G-CSF). 
Not applicable to sites in Japan.
23.
Acute and chronic GVHD is to be assessed and graded/globally scored and the KPS will be used to assess performance status at baseline and V5, V7, V9, V11, and V13 following transplant 
(day 0) through the primary study period completion/day 365 visit (V14) except when the visit is conducted by HHC. In addition, aGVHD needs to be assessed weekly through day 100. 
When a diagnosis of aGVHD is made for a subject, assessments are to continue weekly until resolution for maximal grade and stage by key organs. Local laboratories may be used for 
staging. When a diagnosis of cGVHD or aGVHD is made by a health care professional for a subject, the subject should return to the study center for evaluation and data collection, and 
assessments are to be done at each regularly scheduled protocol visit until resolution; the maximum score during the interval from the last assessment to the current assessment is to be 
recorded for assessments performed at the study site. 
24.
If the subject does not meet the criteria for dosing by day 40, V5 procedures (except study drug injection and local reactogenicity assessment) need to be completed within 5 days of day 40 
(day 40 to 45) and V6 should be skipped.   
25.
The day 365 visit must occur on day 365 +14 days (between day 365 to 379); it cannot occur prior to day 365 for subjects who do not prematurely withdraw from both treatment and
continued follow-up. For a subject who prematurely withdraws from the study (discontinues treatment with no continued follow-up), the study completion visit is to be completed within 
14 days of study withdrawal. 


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Table 2
Schedule of Assessments – Long-term Follow-up Period
Month (post-transplant)
18
24
36
48
60
66
Year (relative to transplant/Day 0)
1.5
2
3
4
5
5.5
Window
(months)
± 1
± 1.5
± 1.5
± 1.5
± 1.5
±1.5
Mortality, including primary cause of death and date
X
X
X
X
X
X
Development of any new/recurrent cancer
X
X
X
X
X
X
Development of infection requiring hospitalization or resulting in death
X
X
X
X
X
X
Erythema or induration at sites of study drug injections
X
X
X
X
X
X
Subjects will be contacted after the primary study period (day 365) through 5.5 years post-transplant for long-term safety related to the DNA vaccine. 
Items to be assessed by telephone interview, and available patient records include; mortality, development of any new/recurrent cancer, development of 
infection requiring hospitalization or resulting in death, and erythema or induration at sites of study drug injection (see [Appendix 20]).  During the 
long-term follow-up period, if an SAE is identified and deemed possibly or probably related to the study medication, an SAE report on the SAE 
worksheet must be sent to the Sponsor per [Section 5.5.6], for all sites except those in Japan.  For sites in Japan only: an SAE report on the JUTOKUNA 
YUUGAIJISHOU HOUKOKUSHO must be sent to the delegated CRO per [Section 5.5.6].


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1
INTRODUCTION
Cytomegalovirus (CMV) is a member of the Herpesviridae family that establishes latency in host 
cells after acute infection. Immunocompromised patients, including patients undergoing 
hematopoietic cell transplant (HCT), are particularly vulnerable to CMV infection and 
reactivation. CMV infection is a risk factor for CMV end organ disease (EOD), as well as a risk 
factor for acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), 
bacterial and fungal infections, and increased mortality. ASP0113 is a DNA vaccine designed to 
prevent CMV infection in immunocompromised hosts. It contains 2 plasmids which encode the 
antigens gB and pp65 to induce humoral and cellular immunity to the virus. A phase 1 and phase
2 study suggest that the vaccine is safe, immunogenic and effective in preventing CMV viremia 
in CMV seropositive subjects undergoing hematopoietic transplant. This phase 3 pivotal, 
randomized, double-blind, placebo-controlled trial is designed to assess the incidence of 
mortality through 1 year post-transplant in the ASP0113 group as compared to the placebo group.
1.1
Background
Members of the Herpesviridae family are a group of viruses that includes the CMV, 
Epstein-Barr virus (EBV), herpes simplex viruses and varicella zoster virus. Herpesviridae 
viruses are double-stranded DNA viruses that become latent in host cells after acute infection. 
CMV infection is ubiquitous and evidence of seroconversion has been found in all populations. 
CMV infection is usually harmless, except in the fetus and immunocompromised hosts. In the 
immunocompromised host, primary infection, re-infection, and reactivation can cause 
significant morbidity and mortality.
Persons undergoing HCT are particularly susceptible to both primary infection and 
reactivation of CMV as a result of the interventions and drugs that ablate and suppress their 
immune systems. Patients with viremia that results from primary infection or reactivation of 
CMV are at greatly increased risk of CMV tissue-invasive disease and may also be at risk for 
mortality not resulting from direct tissue invasion of CMV, aGVHD, cGVHD and non-CMV 
infections due to the immunomodulatory effects of CMV [Cantoni et al, 2010; Boeckh & 
Ljungman, 2009].
CMV tissue-invasive disease was the leading cause of death due to infectious disease among 
CMV-seropositive recipients of HCT prior to the introduction of effective antiviral therapy 
(AVT) in the 1990s.  Since the introduction of effective AVT, the mortality from CMV 
disease during the first 3 months after HCT has been reduced from 20-30% to less than 5% in 
most studies [Boeckh and Nichols, 2004].  However, despite the significant decrease in CMV 
tissue-invasive disease related mortality, many studies indicate that survival continues to be 
decreased in CMV-seropositive patients, suggesting an indirect effect of subclinical CMV 
infection on mortality [Craddock et al, 2011; Yakoub-Agha et al, 2006; Boeckh & Nichols, 
2004]. Mortality related to CMV seropositivity may partially result from an increase in 
aGVHD, cGVHD and infections other than CMV as these outcomes result in decreased 
survival and are associated with CMV infection and CMV seropositivity in the recipient or 
donor [Srinivasin et al, 2012; Cantoni et al, 2010; Larsson et al, 2004; Nichols et al, 2002]. 


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Two strategies currently exist to prevent CMV disease in transplant recipients. In the 
preemptive approach, viremia is monitored on a regular schedule and when a certain threshold 
of viremia is detected, AVT is initiated. Alternatively, in the prophylactic approach, AVT is 
administered for an arbitrary period of time to prevent reactivation. In HCT, preemptive 
therapy is used more commonly than prophylaxis because of the toxicities associated with 
CMV-specific AVT, including myelosuppression. 
Given the side effect profile of current AVT used to prevent CMV disease, and the inability 
of current strategies to prevent CMV infection, alternate strategies to prevent CMV disease 
and infection are needed. ASP0113 is a first-in-class therapeutic vaccine that is designed for 
the prevention of CMV infection in HCT recipients through the stimulation of both humoral 
and cell-mediated immune responses. It contains 2 plasmids which encode CMV 
glycoprotein B (gB) and tegument phosphoprotein 65 (pp65). gB is the major neutralizing 
target for antibodies stimulated by CMV in healthy humans [Britt et al, 1990]; pp65 is 1 of 
the proteins most frequently recognized by CD8+ and CD4+ cells in healthy humans [Kern et 
al, 2002; Gyulai et al, 2000; Wills et al, 1996]. ASP0113 appears to be both effective and 
safe and therefore warrants further study.
1.2
Product Composition
Plasmid DNA (pDNA) is covalently closed, circular, double-stranded DNA molecules that 
are engineered to encode protective antigens from infectious disease pathogens. This 
platform technology provides an ideal approach for treating immunocompromised subjects 
because it eliminates the safety concerns engendered by the use of live viral vectors yet 
preserves the ability to induce both cellular and humoral responses. In addition, a pDNA 
vaccine is delivered without other viral genes that may be involved in evasion of the immune 
system; ASP0113 does not include CMV-encoded genes involved in the downregulation of 
major histo-compatibility complex (MHC) molecules, production of chemokine receptors, or 
mimics of cytokines [Mocarski, 2002].
ASP0113 is a bivalent product that consists of 2 separate pDNAs each containing a 
codon-optimized CMV gene. Phosphoprotein 65 (pp65) is included to induce CD4+ and 
CD8+ T-cell responses; gB is included to induce antibodies. The plasmids are formulated 
with CRL1005 poloxamer and BAK, a cationic surfactant, in PBS. The combination of 
CRL1005 and BAK produces a thermodynamically stable self-assembled particulate system 
at room temperature and is used as a gene delivery system. The addition of CRL1005 and 
BAK has been shown to enhance immunogenicity in mice vaccinated with ASP0113.
1.3
Nonclinical and Clinical Data
1.3.1
Nonclinical Data
Vaccination of mice with ASP0113 led to production of antibodies against gB and, to a lesser 
extent, against pp65. Vaccination of mice with A0113 did result in a robust T-cell response 
to pp65. Plasmid copy number of ASP0113 was not detectable or quantifiable in the gonads, 
spleen, liver, heart, lymph node, kidney, brain or blood 15 days post injection. On day 
62 post injection, plasmid was present at the bone marrow and the injection site, however, 


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their copy numbers were reduced by approximately 596-fold and 76-fold, respectively, 
compared to day 3. No genomic integration of the pDNA was observed 2 months after 
vaccination.  
Administration of ASP0113 as a single dose is well-tolerated and results in no demonstrable 
clinical signs of toxicity due to injection of vaccine. Repeat dose administration of ASP0113 in 
rabbits is well-tolerated, with no drug-related changes in clinical signs. However, vaccination 
with ASP0113 did lead to a significant, but reversible, increase in creatine phosphokinase 
(CPK) and minimal to moderate inflammation of the muscle, skin and subcutis, that persisted 
to a slight degree in the recovery period. Based on these nonclinical animal studies, ASP0113 
is considered safe and well-tolerated, is not anticipated to present a toxicity risk in humans 
when delivered by IM injection, and immunogenicity data suggest that vaccination can induce 
immune responses to human CMV. For a detailed summary of the nonclinical studies please 
refer to the Investigator’s Brochure (IB).
1.3.2
Clinical Data
To date, ASP0113 has been evaluated in a phase 1 study in healthy volunteers and a phase 2 
study of matched related donor/recipient pairs and related or unrelated recipients undergoing 
allogeneic HCT for hematologic disorders.  
1.3.2.1 Phase 1 (VCL-CB01-101) Results
The first clinical study of ASP0113 was a multicenter, randomized, open-label phase 1 clinical 
study (VCL-CB01-101) designed to evaluate the safety and immunogenicity of ASP0113 in 44
healthy adult CMV-seropositive and CMV-seronegative volunteers at doses of either 1 mg or 
5 mg IM administered on weeks 0, 2, and 8 in a dose escalation format and at a dose of 5 mg 
IM administered on days 0, 3, 7 and 28 (accelerated schedule)[Wloch et al, 2008].
Overall ASP0113 was safe and well-tolerated. Volunteers receiving the higher dose or 
accelerated vaccine schedule tended to experience more local reactogenicity, but the severity 
of the treatment-emergent adverse events (TEAEs) did not increase with increasing dose and 
a more compressed schedule. The incidence of local reactogenicity, predominantly injection 
site pain, was 62.5% for the lowest weekly dose group, 87.5% for the highest weekly dose 
group, and 100% for the accelerated schedule group. Several cutaneous TEAEs were 
considered related to ASP0113 by the Investigator and included erythema, rash and pruritus. 
One volunteer did experience a transient increase in CPK value greater than 5 x the upper 
limit of normal (ULN), but less than 10 x normal. 
Immune responses to the 2 immunogens encoded in the vaccine, gB and pp65, were assessed 
by the use of an indirect gB binding enzyme-linked immunosorbent assay for antibody 
responses to gB and a pp65 direct ex-vivo interferon γ (IFN-γ) enzyme-linked 
immunosorbent spot assay for T-cell responses to pp65. At 16 weeks, antibody and/or cell 
responses were elicited in 38% and 50% of the CMV-seronegative volunteers administered 
1 mg and 5 mg ASP0113, respectively. CMV-seropositive volunteers had increases in pp65 
T-cell responses of 12.5% and 37.5% across all groups, but no increase in gB antibody levels 
were detected for CMV-seropositive volunteers.


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1.3.2.2 Phase 2 (CB01-202) Results
The second clinical study of ASP0113 was a multicenter, randomized, double-blind phase 2 
clinical study designed to evaluate the efficacy, immunogenicity and safety of ASP0113 in 
donors and CMV-seropositive recipients undergoing 5 of 6 or 6 of 6 HLA-allele-matched 
allogeneic HCT for the treatment of hematologic disorders [Kharfan-Dabaja, 2012]. A total 
of 108 subjects were enrolled in the study, including 14 donor/recipient pairs, and received at 
least 1 dose of study drug [5 mg/mL (1 mL dose)] or placebo. Recruitment of donor/
recipient pairs was found to be impractical early in the study so that arm was discontinued; 
the results are not discussed here. The intent-to-treat (ITT) and per protocol (PP) populations 
comprise 80 and 74 transplant recipients, respectively. Recipients received injections at 
approximately days -5 to -3, 21 to 42 (1 injection in this window, health permitting), on day 
84, and on day 196 relative to transplantation. Results shown below are for the PP population.
The primary efficacy endpoint of the study was the occurrence of clinically significant CMV 
viremia, defined as detection of CMV viremia that resulted in the initiation of CMV-specific
antiviral therapy during the first year of transplant. The clinical decision to treat at the sites 
was based on the most current local or central CMV assay results. CMV-specific antiviral 
therapy was initiated for a lower percentage of recipient subjects in the ASP0113 group 
(47%) than in the placebo group (61.8%), but the difference was not statistically significant 
(P = 0.145, Cochran-Mantel-Haenszel [CMH] test stratified by site). The PP population was 
modified for this analysis to exclude 2 subjects who received CMV-specific AVT because of 
false positive results from the local viral load assay).  
When the occurrence of CMV viremia, as defined as ≥500 copies/mL by a laboratory 
developed test (LDT) based upon the LightCycler® polymerase chain reaction (PCR), was 
evaluated in a central laboratory, the rate was lower in the ASP0113 group (33%) than in the 
placebo group (62%) and was statistically significant (P = 0.008, CMH test stratified by site). 
Post-hoc analyses of the phase 2 data also suggest that the clinical endpoints which have been 
reported to be associated with CMV infection may be reduced as a result of vaccination with 
ASP0113, including mortality, aGVHD and cGVHD. For the clinical endpoints of aGVHD, 
cGVHD, and mortality and a composite of CMV EOD, aGVHD, cGVHD and mortality, the 
observed rate for ASP0113 was lower than the corresponding observed rate for placebo, 
although the differences were not statistically significant [Table 3].


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Table 3
Incidence of CMV EOD, Death, aGVHD (Grade 3-4), cGVHD (High 
Risk) and a Composite of All Variables
ASP0113 (n=40)
Placebo (n=34)
P value
CMV EOD
3 (7.5%)
3 (8.8%)
1.000§
Mortality 
7 (17.5%)
11 (32.4%)
0.1775§
aGVHD (grade 3-4) †
2 (5.0%)
5 (14.7%)
0.2364§
cGVHD (high risk) ‡
4 (10.0%)
7 (20.6%)
0.3259§
Composite
13 (32.5%)
18(52.9%)
0.0995§
aGVHD: acute graft-versus-host disease; cGVHD: chronic GVHD; CMV: cytomegalovirus; EOD: end-organ 
disease
Per-protocol population: all unpaired recipients who met the inclusion/exclusion criteria and received at least 
1 injection and had at least 1 post-transplant assessment relevant to an efficacy endpoint.
†Glucksberg et al, Transplantation 1974
‡Akpek et al, Blood 2003
§ Fisher’s Exact Test
Further investigation of the phase 2 study results of the relationship between CMV viremia and 
potential phase 3 endpoints was investigated by Cox proportional hazards models using past or 
current viremia as a time-dependent covariate.  Results of these analyses are summarized in 
[Table 4].  Although incidence of each of these events is numerically greater among subjects 
who have had CMV viremia, the effect of CMV viremia is not statistically significant. 
Table 4
Results of Cox Proportional Hazards Models on the Effect of Past or Current 
CMV Viremia (defined as viral load > 1000 by central lab assay) on Endpoint 
Events
Component
Events
Hazard Ratio
95% CI
P value
aGVHD (Grade 3-4)
7
1.13
0.20, 6.51
0.88
cGVHD (Severe)
11
1.27
0.39, 4.16
0.69
Severe Infection (CTCAE Grade 3-5)
48
1.72
0.84, 3.49
0.14
aGVHD: acute graft versus host disease; cGVHD: chronic graft versus host disease; CTCAE: common 
terminology criteria for adverse events; CMV: cytomegalovirus
Immune responses to the 2 immunogens, gB and pp65, encoded in the vaccine were assessed 
by 2 immunoassays: 1) a gB-specific IgG-binding ELISA; and 2) an ex vivo pp65-specific 
IFN-γ ELISPOT [Kharfan-Dabaja, 2012]. T-cell responses to CMV pp65 and gB as well as 
gB-specific serum antibody levels were similar in the ASP0113 and placebo recipients prior 
to conditioning therapy and transplant. The CMV pp65 T-cell responses were numerically 
enhanced in the ASP0113 group relative to the placebo group at all post-transplant times 
evaluated;  the differences in the responses were statistically significant by the Wilcoxon 
rank sum test at day 84 (P = 0.036). Please refer to the IB regarding other post-hoc analyses 
of the immunogenicity data.
The geometric mean gB-antibody levels in recipients in the ASP0113 group compared with 
recipients in the placebo group showed a trend towards significance at the fourth injection 
(P = 0.064, Wilcoxon rank sum test) and reached significance by day 365 (P = 0.009, 
Wilcoxon rank sum test). Although the geometric mean gB antibody levels were higher for 
the ASP0113 recipients at all time points evaluated, the repeated measurement ANOVA 


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using log10 transformed data from days 56 to 365 did not show a significant difference 
between the longitudinal gB antibody responses (P = 0.749).
Overall the vaccine appears to be safe and well-tolerated. The incidence of local reactogenicity 
was higher in the ASP0113 group than in the placebo group (22.9% and 10.9%, respectively), 
primarily due to injection site pain. Fatalities were reported for 20.8% recipients in the 
ASP0113 group and 32.6% recipients in the placebo group during the 1-year study follow-up.  
No recipient died due to study drug-related AEs. No subject experienced CPK elevation in this 
study. One subject in the ASP0113 arm discontinued the study due to a serious allergic 
reaction that was considered by the Investigator to be possibly related to ASP0113. The subject 
developed 
 
.
1.4
Summary of Key Safety Information for Study Drugs
ASP0113 in nonclinical studies was in general well-tolerated. Nonclinical studies 
demonstrated that the risk of integration of injected DNA into the host’s genome is negligible 
per FDA regulatory guidance and induction of autoimmunity is unlikely. No systemic organ 
toxicity was noted. There was no local reactogenicity reported, but in the highest dose groups 
in a repeated-dose toxicity study in rabbits, there was histologic evidence of inflammation in 
the muscles injected with vaccine and concurrent elevations in CPK.  
In the phase 1 and phase 2 clinical studies the vaccine was safe and well-tolerated. One healthy 
volunteer had a transient elevation in CPK (> 5x normal but < 10x normal). Local (injection 
site) reactions including pain, induration, erythema, pruritus, discomfort and swelling were 
reported more frequently in the higher dosing group and more accelerated schedule with 
ASP0113 in healthy volunteers and in the ASP0113 treated group when compared to the 
placebo group. The only discontinuation due to an SAE that was possibly related to ASP0113 
was the transplant recipient who was previously discussed in [Section 1.3.2.2].
1.5
Risk-Benefit Assessment
Despite currently licensed CMV-specific antiviral therapies, CMV disease continues to cause 
significant morbidity and mortality in transplant recipients and CMV infection may be 
associated with multiple other clinical outcomes including infections other than CMV 
aGVHD, cGVHD and mortality. In addition, the treatments and associated toxicities can 
incur significant healthcare costs. 
ASP0113 appeared to show efficacy in a single phase 2 trial over multiple secondary end-
points. The incidence of local reactogenicity may be greater with ASP0113 than placebo. In 
addition, while there were CPK elevations at the highest dose level in toxicity studies in 
rabbits, significant damage to the muscle, as determined by CPK elevations greater than 
10 times the ULN, has not been observed in humans. One SAE (hypersensitivity/allergic 
reaction) leading to discontinuation responded well to medical treatment and was deemed not 
life-threatening. False positive results in the assessment of CMV viral load can occur in 
subjects receiving ASP0113 with the use of PCR assays that utilize primers targeted at gB 


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and pp65. Such false positive results, if unrecognized, can lead to misdiagnosis and 
unnecessary initiation of AVT. 
Given the continued morbidity and mortality associated with CMV infection and treatment, the 
evidence of efficacy in the phase 2 trial in HCT recipients and the safety profile of ASP0113, 
continued investigation is warranted.  
2
STUDY OBJECTIVES, DESIGN AND VARIABLES
2.1
Study Objectives
●
To evaluate the efficacy of ASP0113 compared with placebo as measured by a primary 
composite endpoint of overall mortality and CMV EOD through 1 year post-transplant.
●
To evaluate the safety of ASP0113 in subjects undergoing allogeneic HCT.
2.2
Study Design and Dose Rationale
2.2.1
Study Design
This is a randomized, double-blind, placebo-controlled trial of approximately 500 subjects 
being conducted in North America, Europe, Asia, and Australia. Subjects will be randomized 
in a 1:1 ratio, ASP0113 or placebo, and stratified by donor-recipient relatedness and donor 
CMV serostatus. At least 30% of subjects enrolled will be donor-seronegative. The test
compound will be a vaccine (ASP0113) which contains 2 plasmids encoding gB and pp65, 
each at 2.5 mg/mL, formulated with CRL1005 poloxamer and benzalkonium chloride (BAK). 
The placebo control will be phosphate-buffered saline (PBS). Subjects will receive either 
5 doses of ASP0113 or placebo on days -14 to -3, 14-40, 60 ±5, 90 ±10 and 180 ±10 in 
relation to the day of transplant (donor cell infusion). The first injection must be given within 
72 hours prior to the start of chemotherapy and radiation therapy for conditioning and the
second injection should be given as close as possible to, but not prior to, day 14. The platelet 
count must be at least ≥ 50000/mm3 (spontaneously or after platelet transfusion) performed 
by the local laboratory within 3 days prior to all study drug injections. Prior to all study drug 
injections, confirmation must be made that there is no medical contraindication to an IM 
injection. Results received in an equivalent local unit of measure must be converted to SI 
units. Syringes will be masked prior to dosing to blind the subjects and all other personnel 
who need to remain blinded to the treatment assignment (i.e., site staff other than pharmacy 
personnel and staff designated to administer study drug injections).
The pre-specified primary endpoint is the composite of overall mortality and CMV EOD, 
through 1 year post-transplant. Despite the significant decrease in CMV tissue-invasive 
disease related mortality, many studies indicate that survival continues to be decreased in 
CMV-seropositive patients, suggesting an indirect effect of subclinical CMV infection on 
mortality (see [Table 5]) [Craddock et al, 2011 Yakoub-Agha et al, 2006; Boeckh & Nichols, 
2004]. 


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Table 5
Association of CMV with Patient Survival
Source
Number of 
Patients
Underlying Disease
CMV-seropositive Recipients 
Compared with CMV-seronegative 
Recipients with a Seronegative Donor
Broers et al, 2000
115
Mixed
24% absolute decline in OS (P = 0.01)
McGlave et al, 
2000
1423
CML
20% relative decline in DFS
(P = 0.002)
Cornelissen et al, 
2001
127
ALL
38% relative decline in DFS (P = 0.05)
Craddock et al, 
2001
106
CML
22% absolute decline in OS
(P = 0.006)
Kroger et al, 2001
125
Mixed
41% absolute decline in OS 
(P < 0.001)
Castro-Malaspina
et al, 2002
510
MDS
46% relative decline in DFS 
(P = 0.001)
Doney, 2003
182
ALL
99% relative rise in TRM (P =.01)
Yakoub-Agha et 
al, 2006
236
Mixed
16.4% absolute decline in OS 
(P = 0.01)
Craddock et al, 
2011
168
Primary refractory 
AML
13% absolute decline in OS (P = 0.09)
Table modified from Boeckh & Nichols, 2004.  
AML: acute myelogenous leukemia; CML: chronic myelogenous leukemia; CMV: cytomegalovirus; DFS: 
disease free survival; MDS: myelodyplastic syndrome; OS: overall survival; TRM: transplant-related mortality
Some publications have suggested that mortality related to CMV seropositivity may partially 
result from an increase in aGVHD, cGVHD and infections other than CMV as these outcomes 
result in decreased survival and are associated with CMV infection and CMV seropositivity in 
the recipient or donor [Srinivasin et al, 2012; Cantoni et al, 2010; Larsson et al, 2004; Nichols 
et al, 2002].
A key secondary endpoint is CMV viremia. CMV viremia will be protocol-defined as CMV 
plasma viral load of ≥ 1000 IU/mL as assessed by the central laboratory through 1 year 
post-transplant. Another key secondary endpoint is adjudicated CMV-specific AVT through 
1 year post-transplant.
CMV plasma viral load will be monitored per the following schedule during the primary 
study period (through day 365/V14): weekly (± 2 days) during days 0-100, every other week
(± 5 days) during days 101-180, every 30 days (± 5 days) during days 181-365.  The CMV 
plasma viral loads will be performed by the central laboratory. CMV plasma viral load will 
also be performed by the central laboratory at the initiation of CMV-specific AVT. Upon 
initiation of CMV-specific AVT, plasma viral load testing will be performed at least weekly
until the CMV-specific AVT is discontinued, at which point, the regularly scheduled plasma 
viral load assessments will resume.
Note: CMV plasma viral loads may be performed at a local laboratory approved by the 
Sponsor and at the discretion of the Investigator. However, every time a viral load sample is 
sent to the local laboratory a sample will also be sent to the central laboratory for 


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confirmatory testing. Pre-emptive therapy may be started based on the central or local 
laboratory assessment and the subject’s clinical condition.
As 1 of the plasmids of the ASP0113 vaccine codes for the pp65 antigen, the theoretical 
possibility of interference with the pp65 antigenemia assay has been raised. At present, there 
are no data to suggest that such interference occurs. However, to ensure patient safety and 
study integrity, sites that use pp65 antigen as their local methodology for the detection of 
CMV infection must adhere to the procedures defined below as a condition of participation in 
the trial.
●
The local pp65 antigenemia results must be entered into the eCRF database within 
72 hours (or next business day) of receipt to facilitate in-time monitoring of results.
●
The Medical Monitor must be called within 48 hours (or next business day) if the pp65 
antigenemia test is positive and the central laboratory PCR viral load result is negative.
●
Both the pp65 antigenemia and the central laboratory test must be repeated within 
48 hours if the local pp65 antigenemia result is positive, the central laboratory PCR viral 
load result is negative and the subject is treated with CMV-specific AVT.
The plasmids in the study vaccine may interfere with certain PCR assays. If a PCR assay is 
used that amplifies the genes UL55/gB or UL83/pp65, this could result in either a false 
positive viral load or unblinding of the study subject.
Sites that are determined to have unacceptable PCR assay in their local laboratory but were 
able to determine a Sponsor deemed acceptable work practice flow for utilizing another 
acceptable local assay or methodology will be allowed to participate in the trial.
Note:  Local CMV plasma viral load testing may be performed only at a local laboratory 
approved by the Sponsor.
Adjudicated CMV-specific AVT will be assessed for subjects up to 1 year following transplant 
through the primary study period (through day 365/V14).
Immunologic response will be assessed in all subjects at V2, V5, V8, V9, V11 and V14. If the 
visit coincides with a study drug administration, the sample will be drawn prior to injection. 
In addition, if a CMV seropositive donor has consented and is participating in the optional 
donor cell sub-study, a 20 mL peripheral blood sample from the donor will be obtained prior 
to the stem cell donation for recipients participating in the main trial to test for CMV-specific 
T-cells. For those donating peripheral stem cells, the donor blood sample is to be collected 
prior to the initiation of mobilization therapy (e.g., granulocyte colony stimulating factor 
[G-CSF]).
Subjects will be evaluated for local reactogenicity and systemic signs and symptoms for 
60 minutes (±10 minutes) after each injection. Subjects will be directly observed for 
15 minutes following the injection for any injection-related side effects, then remain in a 
designated area at the study site for 45 minutes so that side effects can be noted and treated, if 
necessary. Local reactogenicity will also be evaluated for each of the 7 consecutive days 
following each injection beginning approximately 24 hours after the dose (day 1-7 post dose). 


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The assessments for each of the 7 consecutive days following an injection will be done by the 
subject and reported to the site via diary. When reactogenicity is reported as an AE, it must be 
followed until resolution or medically stable. All local reactions ≥ Grade 3 [Appendix 7] 
require confirmation by a health care professional.
Subjects will be contacted after the last injection of vaccine through 5.5 years post-transplant 
for long-term safety related to the DNA vaccine.  Items to be assessed by telephone interview 
and available patient records include mortality, development of any new/recurrent cancer, 
development of infection requiring hospitalization or resulting in death, and erythema and/or 
induration at the injection sites [Appendix 20].  
All AEs and SAEs will be collected from signing of the informed consent through 30 days post 
last dose of study drug. All events requiring adjudication, Grade 3 and higher AEs as well as 
SAEs will be collected from 31 days post last dose of study drug through 1 year post-transplant.
A change in medical status or medical history from time of signing of informed consent 
through first dose of study drug is to be reported as an AE or SAE as appropriate. 
An independent Data Monitoring Committee (DMC) will be chartered to oversee safety 
issues and futility analysis. 
An Adjudication Committee (AC) will be chartered to adjudicate all cases of CMV EOD, 
initiation of CMV-specific AVT, and cause of death.
2.2.2
Dose Rationale
Efficacy and safety data was collected from normal healthy subjects in a phase 1 trial as well 
as HCT recipients in a phase 2 clinical trial (VCL-CB01-101 and CB01-202, respectively). The 
dose used in the phase 2 study was 1 mL of 5 mg/mL and 4 doses were given over 
approximately a 6 month time period. The dose and dose schedule appeared to be well
tolerated.
The first dose of vaccine is scheduled to be administered at -14 to -3 days prior to transplant, 
and within 72 hours prior to the start of conditioning therapy. The first dose is scheduled 
during this time frame to ensure protein expression at the time of infusion of the donor stem 
cells as animal models demonstrate that the peak protein expression after injection of a DNA 
plasmid is between 3 and14 days. This dose is given prior to the start of conditioning therapy 
as protein expression may be decreased because of a catabolic state in the patient after the start 
of conditioning therapy. The second dose of vaccine is scheduled as close to Day 14 after 
transplant as possible to ensure protein expression and development of a protective immune 
response at the expected time of the first viremic episodes, which is approximately 30 days 
after transplant. Finally, doses are scheduled for 60, 90 and 180 days after transplant to help 
protect against late-onset viremia.


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2.3
Variables
2.3.1
Primary Variable
The primary endpoint of the study is the composite of overall mortality and CMV EOD 
through 1 year post-transplant. 
2.3.2
Secondary Variables
The 2 key secondary endpoints are: 
●
Time to first protocol-defined CMV viremia [CMV plasma viral ≥1000 IU/mL as 
assessed by the central laboratory] through 1 year post-transplant.
●
Time to first adjudicated CMV-specific AVT through 1 year post-transplant.
Additional secondary endpoints are:
●
Time to first CMV-specific AVT for protocol-defined CMV viremia[CMV plasma viral 
load ≥ 1000 IU/mL as assessed by the central laboratory] or CMV EOD through one 
year post-transplant.
2.3.3
Exploratory Variables
●
Clinical outcomes: 
Overall mortality
Incidence of CMV EOD
Incidence of Grade 3-4 aGVHD
Incidence of severe cGVHD
Incidence of grade 3 treatment-emergent viral, bacterial, or fungal infections other 
than CMV 
Maximum grade of aGVHD
Maximum cGVHD score
Relapse mortality (death due to relapse of the subject’s primary disease)
Non-relapse mortality (death due to causes unrelated to the subject’s primary 
disease)
Incidence of graft rejection
Incidence of failure to engraft
Time to engraftment
Time to platelet recovery
Incidence of relapse of primary disease requiring therapy.
Number of episodes of protocol-defined CMV viremia [CMV plasma viral load 
≥ 1000 IU/mL by the Abbott RealTime CMV assay as assessed by the central 
laboratory]
Time to Grade 3 treatment-emergent viral, bacterial, or fungal infections other than 
CMV 
●
Duration of hospitalization(s)
●
Health economic/resource utilization


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●
Subjects’ quality of life (QOL) variables (EQ-5D, Functional Assessment of Cancer 
Therapy – Bone Marrow Transplant [FACT-BMT], and Work Productivity and Activity 
Impairment Questionnaire: General Health [WPAI: GH])
●
Immunogenicity variables
T-cell responses to pp65
gB-specific antibody levels
2.3.4
Safety Assessments
●
Vital signs
●
Adverse events (AEs)
●
Local reactogenicity signs and symptoms using both the NCI-CTCAE Version 4.03 
grading scale and the protocol-specified reactogenicity scale [Appendix 7]
●
Clinical laboratory assessments as defined in [Appendix 1]
●
Physical examination (PE)
2.3.5
Pharmacogenomics (PGx) Assessment (Optional)
An optional PGx saliva sample will be collected during the baseline visit (V2) after 
randomization but prior to the first dose of study drug. These may be assessed retrospectively
to include:
●
Exploratory analysis of the relationship between genes potentially involved in 
immunogenicity and response to ASP0113 in terms of efficacy and/or safety.
●
Exploratory analysis of the relationship between genes of relevance to toxicity and/or
safety issues and response to ASP0113 with respect to safety.
Please refer to [Appendix 19] (PGx Sub-Study) for additional information on the retrospective 
PGx sub-study associated with this study.
3
STUDY POPULATION
3.1
Selection of Study Population
This study will randomize HCT recipients who are at least 18 years of age or of legal age of 
consent and are CMV-seropositive.  
Subjects will be enrolled in the trial based on positive CMV serostatus, which will be CMV 
IgG antibody detection by the local laboratory. Testing will be performed prior to 
randomization. Presence of anti-CMV IgG antibodies will indicate a positive CMV status. 
3.2
Inclusion Criteria 
A subject is eligible for the study if all of the following apply: 
1.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved written 
informed consent and privacy language as per national regulations (e.g., Health Insurance 
Portability and Accountability Act [HIPAA] Authorization for U.S. sites) must be 


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obtained from the subject or legally authorized representative prior to any study-specific 
related procedures (including withdrawal of prohibited medication, if applicable).
2.
Subject is a male or female subject who is at least 18 years old or the legal age of consent 
(whichever is greater). 
3.
Subject is a CMV-seropositive HCT recipient as confirmed by local laboratory at screening.
4.
Subject is planned to undergo either of the following:  
a. Sibling Donor Transplant - 7/8 HLA-A, -B, -C, -DRß1 match utilizing high 
resolution typing or 8/8 HLA-A, -B, -C, -DRß1 match utilizing low or high
resolution typing.*
b. Unrelated Donor Transplant - 7/8 or 8/8 HLA-A, -B, -C, -DRß1 match utilizing 
high resolution typing.*
* A minimum of 8 allele matching is required.  Subjects with matches performed at 
more than 8 alleles are included if they have 7/8 or 8/8 match at the HLA-A, -B, -
C, -DRß1 alleles.
5.
Subject is scheduled to receive an allogeneic peripheral blood stem cell or bone marrow
transplant (BMT) for the treatment of hematologic disorders as indicated in Inclusion 
Criterion 6.
6.
Subject has 1 of the following underlying diseases:
a.
Acute myeloid leukemia (AML), with or without a history of myelodysplastic 
syndrome (MDS), in first or second complete remission (CR) [Appendix 6] or in 
early relapse (< 20% blasts in bone marrow with no circulating blasts in 
peripheral blood and no extramedullary leukemia).
b. Acute lymphoblastic leukemia (ALL), in first or second CR [Appendix 6].
c.
Acute undifferentiated leukemia (AUL) in first or second CR [Appendix 6].
d. Acute biphenotypic leukemia in first or second CR [Appendix 6].
e.
Chronic myelogenous leukemia (CML) in either chronic or accelerated phase.
f.
Chronic lymphocytic leukemia.
g. One of the following MDS defined by the following:
i. Refractory anemia with evidence of dysplasia.
ii. Refractory anemia with ringed sideroblasts.
iii. Refractory cytopenia with multilineage dysplasia.
iv. Refractory cytopenia with multilineage dysplasia and ringed sideroblasts. 
v. Refractory anemia with excess blasts-1 (5%-10% blasts).
vi. Refractory anemia with excess blasts-2 (10%-20% blasts).
vii. MDS, unclassified.
viii. MDS associated with isolated deletion (5q).
ix. Chronic myelomonocytic leukemia.
h. Primary or secondary myelofibrosis without leukemic transformation except if 
Dynamic International Prognostic Scoring System category of high or 
intermediate-2 [Appendix 5].


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i.
Lymphoma (including Hodgkin’s) with chemosensitive disease (≥50% response 
to chemotherapy).
7.
Female subject must be either:
●
Of non-childbearing potential
o
Postmenopausal (defined as at least 1 year without any menses) prior to 
screening, and if < 50 years of age and not documented to be surgically sterile
must have a negative urine or serum pregnancy test at screening, or 
o
Documented surgically sterile or status post-hysterectomy (at least 1 month 
prior to screening), or 
●
Or, if of childbearing potential 
o
Must have a negative urine or serum pregnancy test at screening, and 
o
If heterosexually active, must use at least 1 form of birth control* (which must 
be a barrier method) starting at screening and through the primary study 
period.
8.
Female subject must not be breastfeeding at screening, through the treatment period and 
through the primary study period.
9.
Female subject must not donate ova starting at screening, through the treatment period 
and through the primary study period.
10. Male subject and their female spouse/partners who are of childbearing potential must be 
using highly effective contraception consisting of 2 forms of birth control* (1 of which 
must be a barrier method) starting at screening, through the treatment period and through
the primary study period.
* Acceptable forms include: 
Consistent and correct usage of established oral contraception.
Established intrauterine device (IUD) or intrauterine system (IUS).
Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository <Not 
applicable to sites in Japan: with spermicidal foam/gel/film/cream/suppository>
For sites in Japan: calendar-based contraceptive methods (Knaus-Ogino or rhythm 
method)
11. Male subject must not donate sperm starting at screening, through the treatment period 
and through the primary study period.  
12. Subject is willing to comply with the protocol.
13. Subject agrees not to participate in another interventional study while on treatment. New 
regimens of approved chemotherapeutic drugs or antibodies, conditioning drugs, 
irradiation and T-cell depleting antibodies, except alemtuzumab, are allowed.
Waivers to the inclusion criteria will NOT be allowed.


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3.3
Exclusion Criteria 
A subject will be excluded from participation if any of the following apply:
1.
Subject has active CMV disease or infection or has received treatment for active CMV 
disease or infection within 3 months (90 days) prior to transplant.
2.
Subject has planned CMV prophylactic therapy with antiviral drugs or CMV-specific 
immunoglobulins from randomization through the primary study period completion/day 
365 visit (V14). 
3.
Subject has a modified hematopoietic cell transplant comorbidity index (HCT-CI) 
score ≥4 [Appendix 4].
4.
Subject is known to be positive for human immunodeficiency virus (HIV), hepatitis B 
surface antigen or hepatitis C RNA PCR.
5.
Donor CMV serostatus is unknown.
6.
Subject has received any of the following substances or treatments:
a. Alemtuzumab within 60 days prior to transplant, including conditioning regimen. 
Subjects for whom treatment with alemtuzumab is planned at any time from 60 days 
prior to through 1 year post-transplant must not be enrolled in the trial.
b. T-cell depletion of donor cell product.
c. Administration of a CMV vaccine, including any prior exposure to ASP0113.
7.
Subject has received an allogeneic stem cell transplant within 1 year prior to transplant 
(subjects who have received a prior autologous transplant are allowed).
8.
Subject has a current malignancy in addition to the malignancy being treated for the 
study or the subject has a history of any other malignancy (within the past 5 years prior 
to screening) except non-metastatic basal or squamous cell carcinoma of the skin that has 
been treated successfully or cancer in situ of the cervix uteri that has been handled by 
local surgery.
9.
Subject has an unstable medical or psychiatric condition, including a history of illicit 
drug(s) or alcohol abuse that the Investigator believes will interfere with protocol 
requirements.
10. Subject has had an allergic reaction to any component of the vaccine. Subject has had an 
allergic reaction to aminoglycosides as kanamycin is used in the manufacturing process 
of the vaccine.
11. Subject has participated in any interventional clinical study or has been treated with any 
investigational research products within 30 days or 5 half-lives, whichever is longer, prior 
to the initiation of screening. (Investigational research products are considered those 
products that have not been approved for any indication in the country where the subject is 
enrolled. New regimens of approved chemotherapeutic drugs or antibodies, conditioning 
drugs, irradiation and T-cell depleting antibodies, except alemtuzumab, are allowed.) 


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12. Subject who has received a prior HCT and has residual cGVHD.
13. Subject who is scheduled to have a cord blood transplant or a haploidentical transplant.
14. Subject has a platelet count of less than 50000 mm3 within 3 days prior to randomization
(platelet transfusions are allowed). Results received in an equivalent local unit of 
measure must be converted to SI units.
15. Subject has aplastic anemia or multiple myeloma.
16. For sites in Japan only: Other subjects considered ineligible by the Investigator/sub-
Investigator.
Waivers to the exclusion criteria will NOT be allowed. 
3.4
Contraception and Pregnancy Avoidance 
During the screening period of the study and at the time of randomization, a urine or serum 
pregnancy test will be performed on all women of childbearing potential and all women who 
are of non-childbearing potential but are < 50 years of age and not documented to be 
surgically sterile. Subsequently, urine or serum pregnancy tests will be performed on the 
same day and prior to each dose, at visit 13 and at the primary study period completion/ day 
365 visit (V14). All pregnancy tests will be done locally. For subjects who receive 
mycophenolate mofetil, additional pregnancy testing must be done in accordance with local 
regulatory requirements.
Subjects who become pregnant or have a positive pregnancy test during the treatment period 
will be withdrawn from further study treatment [Section 3.5].
Female subjects or partners of male subjects who become pregnant during the study will be 
followed through delivery. Pregnancy of female subjects or female partners of male subjects 
from first dose through 1 year post-transplant will be reported as an SAE [Section 5.5.9]. 
3.5
Discontinuation Criteria for Individual Subjects
A subject discontinued from study drug treatment is a subject who enrolled in the study and 
for whom study drug treatment is terminated prematurely for any reason.  
A subject is free to withdraw from the study drug treatment and/or study follow-up for any 
reason and at any time without giving reason for doing so and without penalty or prejudice. 
This is referred to as withdrawal of consent if the subject does not allow efforts to be made 
even to assess survival status. Withdrawal of consent can only occur if it is subject-initiated.
The Investigator is also free to terminate a subject's study drug treatment at any time if the 
subject's clinical condition warrants it and the Investigator deems that further treatment is not 
in the best interest of the subject.
Study drug administration and participation in the study will continue for subjects when a 
non-fatal endpoint is met. 


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If a subject fails to receive 1 or more doses of study drug after the first injection, but is able 
to continue in the trial, the subject’s participation in the trial should not be terminated.  
Study Discontinuation
Subjects will be withdrawn from study and will receive no further follow-up except for 
mortality (at day 365 post-transplant) through public records/sources if the following occurs:
●
Withdrawal of consent by subject
Subjects will be withdrawn from study and will receive no further follow-up if the following 
occurs:
●
Subject did not receive first dose of study drug 
For a subject who prematurely withdraws from the study (discontinues treatment with no 
continued follow-up) the study completion visit must be completed within 14 days of study 
withdrawal.
Treatment Only Discontinuation
Subjects will be withdrawn from study drug treatment if any of the following occur. However, 
they are to continue to be followed according to the protocol Schedule of Assessments [Table 1] 
with exception of the dose follow-up visits (i.e. V3, V6, V8, V10, and V12). 
●
Investigator’s decision that further treatment is not in the best interest of the subject.
●
Pregnancy (female subjects only).
●
Failure to engraft.
●
Local reactogenicity with a Grade ≥3 based on the criteria defined in [Appendix 7] and 
confirmed by a health care professional. 
●
Anaphylaxis with a Grade ≥ 3 based on NCI-CTCAE Version 4.03.
●
Seizure considered possibly or probably related to study drug treatment.
●
Participation in another interventional trial for an investigational research product 
(investigational research products are considered those products that have not been 
approved for any indication in the country where the subject is enrolled).
If a subject is withdrawn from study drug treatment and is unable to comply with study 
procedures as defined in the Schedule of Assessments, the subject must be asked if they are 
willing to be followed for SAEs through 30 days of last dose of study drug treatment, to 
attend the scheduled final study visit (V14), to be assessed for CMV EOD, and/or to be
followed for mortality. They must also be asked if they are willing to be followed through the 
long term follow-up period.
Subjects who discontinue from the study after one or more doses of study drug will not be 
replaced. Subjects who are randomized but never receive study drug will be replaced, to a 
total of approximately 500 dosed subjects. 


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4
STUDY PRODUCTS
4.1
Description of Study Products
4.1.1
Test Product
ASP0113 contains 2 closed circular plasmid macromolecules. The plasmids are purified from 
cellular components and formulated with CRL1005 poloxamer and BAK, a cationic surfactant, 
in PBS. The combination of CRL1005 and BAK produces a thermodynamically stable 
self-assembled particulate system with a defined particle size, surface charge and stability 
profile at room temperature. BAK is used to control and maintain the particle size distribution 
of the formulation.  
ASP0113 will be supplied by the Sponsor as a frozen solution in single dose 2-mL vials 
containing 1.3 mL of 5 mg/mL ASP0113. ASP0113 is packaged in a cardboard secondary 
container.
ASP0113 is a milky white suspension at room temperature, and clear at temperatures below 
the cloud point of CRL1005 (4°C -7°C). ASP0113 is to be stored frozen at -25oC ± 10oC. 
Detailed instructions for the preparation and administration of ASP0113 will be provided in 
the Pharmacy Manual.
4.1.2
Comparative Product
Placebo will be supplied by the Sponsor in 2-mL vials containing PBS. It is a clear colorless 
liquid. Placebo is to be stored frozen at -25°C ± 10°C. 
Detailed instructions for the preparation and administration of placebo will be provided in the 
Pharmacy Manual.
4.2
Packaging and Labeling
All medication used in this study will be prepared, packaged, and labeled under the 
responsibility of a qualified person at Astellas US Technologies, Inc. (AUST) or designee in 
accordance with AUST Standard Operating Procedures (SOPs), Good Manufacturing Practice  
guidelines, ICH Good Clinical Practice (GCP) guidelines, and applicable local 
laws/regulations.
4.3
Study Drug Handling
Current International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use GCP Guidelines require the Investigator to 
ensure that study drug deliveries from the Sponsor are received by a responsible person (e.g.,
pharmacist), and
●
That such deliveries are recorded.
●
That study drug is handled and stored according to labeled storage conditions,
●
That only study drug with appropriate expiry/retest  is dispensed to study subjects in 
accordance with the protocol, and


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●
That any unused study drug is returned to the Sponsor or standard procedures for the 
alternative disposition of unused study drug are followed with prior Sponsor approval.
Drug inventory and accountability records for the study drugs will be kept by the Investigator/ 
pharmacist. Study drug accountability throughout the study must be documented. The 
following guidelines are therefore pertinent:
●
The Investigator agrees to not supply study drugs to any persons except the subjects in 
this study.
●
The Investigator/pharmacist will keep the study drugs in a pharmacy or other locked and 
secure storage facility under controlled storage conditions, accessible only to those 
authorized by the Investigator to dispense these test drugs.
●
A study drug inventory will be maintained by the Investigator/pharmacist. The inventory 
will include details of material received and a clear record of when they were dispensed 
and to which subject.
●
At the conclusion or termination of this study, the Investigator/pharmacist agrees to 
conduct a final drug supply inventory and to record the results of this inventory on the 
Drug Accountability Record. It must be possible to reconcile delivery records with those 
of used and returned medication. Any discrepancies must be accounted for. Appropriate 
forms of deliveries and returns must be signed by the person responsible.
●
Used or unused study drug must be returned to the depot for destruction unless 
prohibited by local policy. In this instance, study drug may be destroyed at the study 
center according to standard institutional procedures and preferably after drug 
accountability has been conducted by the Sponsor or representative. Should this occur, a 
copy of the standard institutional procedure for destroying investigational drugs will be 
provided to the Sponsor. Upon destruction, a copy of the certificate of destruction must 
be provided for the Sponsor files and site drug accountability records.
For sites in Japan:
The head of the study center or the study drug storage manager should take accountability of 
the study drugs as following issues.
●
The study drug storage manager should store and take accountability of the study drugs 
in conforming to the procedures for handling the study drugs written by the Sponsor.
●
The study drug storage manager should prepare and retain records of the study drug's 
receipt, the inventory at the study center, the use by each subject, and the return to the 
Sponsor or alternative disposal of unused study drugs. These records should include 
dates, quantities, batch/serial numbers, expiration dates (if applicable), and the subject 
identification codes.
The study drug storage manager should prepare and retain records that document adequately 
that the subjects were provided the doses specified in the protocol, and reconcile all the study 
drugs supplied from the Sponsor.


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4.4
Blinding
4.4.1
Blinding Method 
Subjects will be assigned to a double-blind treatment arm in the order in which they are 
entered into the interactive response technology randomization system. Subjects will receive 
their allocated treatment assignment according to a computer-generated randomization 
schedule prepared by the Sponsor or designee prior to the start of the study. (Refer to 
[Section 4.5]).
Only the pharmacist and designated staff, including the person(s) injecting the vaccine will 
be unblinded to treatment. All other study site staff will remain blinded to subjects’ treatment 
assignment. The syringes will be masked prior to dosing to maintain the blind for subjects 
and all other personnel. Details regarding study blinding will be described in the Pharmacy 
Manual for the study.  
4.4.2
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking 
The randomization list and study medication blind will be maintained by the IRT system 
vendor.
The DMC will be provided with access to the dosing assignment for periodic review of the 
unblinded data as documented in the DMC Charter.
Study drug treatment may be revealed only for reasons relating to the subject’s safety and 
when critical therapeutic decisions are contingent on knowing the assigned study drug (refer 
to [Section 4.4.3]). 
Withdrawal of a subject from the study [Section 3.5] is not a sufficient reason to break the 
study blind. The only reason to break the blind is whether the information gained materially 
alters the subsequent care of the subject. The reason to break the blind must be discussed 
with the Medical Monitor prior to breaking the blind. After receiving authorization for 
unblinding from the Sponsor, the Investigator will utilize the IRT to unblind the subject’s 
treatment assignment.  Unblinding through the interactive system may only be done by 
designated individuals at the site (typically the Investigator or any others specified by the 
Sponsor). As treatment assignment information for each subject will be kept in the site’s 
pharmacy records, if for some reason access to the IRT is not available the Investigator may 
obtain this information from the Pharmacist or designee. If the clinician breaking the blind is 
unable to reach the Medical Monitor and an urgent safety issue with direct impact on patient 
care decisions warrants this action, the blind may be broken, but the Medical Monitor must 
be informed as soon as possible after the blind is broken.
If the blind is broken for a subject, the reason is to be documented as a written entry in the 
source document. Key information will be recorded at the time the blind is broken and 
entered in the subject’s electronic case report form (eCRF). This includes the subject number, 
date the blind was broken, the reason, the person who requested the breaking of the blind, the 


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name of the person who broke the blind, and the name of the APGD-US representative 
contacted.
4.4.3
Breaking the Treatment Code for Emergency 
Breaking the treatment code, or unblinding of an individual subject’s treatment assignment, 
may be done only for reasons relating to subject safety or when critical therapeutic decisions 
are contingent upon knowing the blinded study drug assignment. As noted in [Section 4.4.2],
the only reason to break the blind is whether the information gained materially alters the 
subsequent care of the subject. The reason to break the blind must be discussed with the 
Medical Monitor prior to breaking the blind. If the clinician breaking the blind is unable to 
reach the Medical Monitor and an urgent safety issue with direct impact on patient care 
decisions warrants this action, the blind may be broken, but the Medical Monitor must be 
informed as soon as possible after the blind is broken.   
If it becomes necessary to break the code during the study, the date, time and reason will be 
collected in the subject’s eCRF and the appropriate source documents at the site.
4.4.4
Breaking the Treatment Code by the Sponsor
The Sponsor may break the treatment code for subjects who experience a Suspected 
Unexpected Serious Adverse Reaction (SUSAR) in order to determine if the individual case 
or a group of cases requires expedited regulatory reporting. A code breaking process will be 
provided to the limited staff who are empowered to break the codes for all SUSAR cases for
regulatory reporting purposes.
4.5
Assignment and Allocation
At the screening visit, after the Informed Consent Form (ICF) has been signed, the subject 
will receive a subject number assignment through the IRT for use throughout the study. 
Subjects who subsequently meet all inclusion and none of the exclusion criteria will be 
randomly assigned to receive either ASP0113 or placebo. The randomization to treatment
will be equally allocated (i.e., 1:1) and stratified by donor-recipient relatedness and donor 
CMV serostatus. At least 30% of subjects enrolled will be donor-seronegative.
The IRT vendor will generate the randomization schedule. To obtain the randomized 
treatment assignment for a subject, the pharmacist or designee will utilize an IRT, which is 
available 7 days a week, 24 hours a day.
Randomization is to be done after the completion of the screening period, and at 
least -14 to -3 days prior to the anticipated transplant day (day 0). The first injection must be 
given within 72 hours prior to the start of conditioning therapy after randomization.  After 
submitting required information about the eligible subject, the drug kit number assignment 
will be provided.
Study drug assignment will remain blinded to all site staff except the pharmacist and 
designated staff.  


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If a subject is randomized but does not receive study drug, the subject number will not be 
used again. In this instance, the treatment assignment should only be known by the 
pharmacist and designated staff (i.e., the blind must be maintained as it is with all other 
subjects).
5
TREATMENTS AND EVALUATION
5.1
Dosing and Administration of Study Drugs and Other Medications
5.1.1
Dose/Dose Regimen and Administration Period
One (1) mL of 5 mg/mL ASP0113 or placebo will be administered to the subjects at the 
clinical site when there is no medical contraindication to an IM injection, in the deltoid muscle, 
alternating sides with each dose if possible. Preparation of study drug will be described in the 
Pharmacy Manual for the study. The syringes will be masked to maintain the study blind.  
The platelet count must be ≥ 50000/ mm3 (spontaneously or after platelet transfusion) 
performed by the local laboratory within 3 days prior to all study drug injections. Prior to all 
study drug injections, confirmation must be made that there is no medical contra-indication to 
an IM injection. Results received in an equivalent local unit of measure must be converted to 
SI units. If the subject’s platelet count does not meet this threshold at the time of the visit, the 
subject may return for the study drug injection and local reactogenicity assessment at a later 
time within the allowable window for the visit. If the subject’s platelet count does not meet 
this threshold during the visit window, the dose must be skipped, and the reactogenicity 
assessment and dose follow-up visit(s) should not be done.
Doses will be given at the following time points:
●
Dose 1 at day -14 to -3 pretransplant, within 72 hours prior to the start of chemotherapy 
and radiation therapy for conditioning.
●
Dose 2 at day 14-40 (but not prior to day 14).
o
Dose 2 is to be administered as close to day 14 as possible. If the subject cannot be 
dosed by day 40 based on these criteria, V5 procedures (except study drug injection 
and local reactogenicity assessment) is to be completed within 5 days of day 40
(day 40 to 45) and V6 should be skipped.
●
Dose 3 at day 60 (± 5 days)
●
Dose 4 at day 90 (± 10 days)
●
Dose 5 at day 180 (± 10 days)
5.1.2
Increase or Reduction in Dose of the Study Drugs
Dose increases or decreases are not allowed.


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5.1.3
Treatment Compliance
The number of study drug doses administered will be collected in the eCRF. If a subject fails 
to receive 1 or more doses of study drug after the first injection, but is able to continue in the 
trial, the subject’s participation in the trial should not be terminated.  
5.1.4
Emergency Procedures and Management of Overdose
No maximum tolerated dose for ASP0113 has been identified. In the event of an adverse 
clinical response to ASP0113 injection, interventions should be guided by the subject’s 
symptoms and condition. 
5.1.5
Previous, Concomitant and Prohibited Medication (Drugs and Therapies)
5.1.5.1 Previous Medication (Drugs and Therapies) 
Subjects who have received any of the following substances or treatments are not eligible for 
the study:
●
Investigational research products within 30 days or 5 half-lives, whichever is longer, 
prior to the initiation of screening. (Investigational research products are considered 
those products that have not been approved for any indication in the country where the 
subject is enrolled. New regimens of approved chemotherapeutic drugs or antibodies and 
conditioning drugs, irradiation and T-cell depleting antibodies, except alemtuzumab, are 
allowed).
●
Alemtuzumab within 60 days prior to transplant, including conditioning regimen.
●
T-cell depletion of donor product.
●
Administration of a CMV vaccine, including any prior exposure to ASP0113.
5.1.5.2 Concomitant Medication (Drugs and Therapies)
All concomitant medications and therapies administered from 30 days prior to transplant 
through 30 days post last dose of study drug will be collected on the eCRF; Concomitant 
medications and therapies associated with all events requiring adjudication, Grade 3 and 
higher AEs as well as all SAEs will be collected from 31 days post last dose of drug through 
1 year post-transplant. Over-the-counter medications, and herbal remedies do not need to be 
captured beginning 30 days after the last dose of study drug.
5.1.5.2.1
Conditioning Regimens
Subjects are to undergo a conditioning regimen per local care for the institution at which they 
are enrolled. Both myeloablative and non-myeloablative (reduced intensity) conditioning 
regimens are allowed (see [Appendix 17]). 
Note: alemtuzumab is not allowed within 60 days prior to transplant.
5.1.5.2.2
Viral Prophylaxis 
Viral prophylaxis for infection other than CMV is to be administered according to standard 
institutional protocols. Prophylactic use of aciclovir (acyclovir), valaciclovir (valacyclovir), 


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or famciclovir must not exceed the following doses following transplant (day 0) through 
1 year post-transplant (day 365/V14) [Kumar, 2011; Tomblyn, 2009].
Aciclovir: 
●
1600 mg orally (total daily dose), or
●
500 mg/m2/day iv (total daily dose) – The dose may be rounded up to nearest 100 mg.
Valaciclovir: 1000 mg po (total daily dose)
Famciclovir: 500 mg po (total daily dose)
These doses may NOT be exceeded for prophylaxis but may be exceeded if necessary to treat 
active infections post-transplant.  
5.1.5.3 Prohibited Concomitant Medications (Drugs and Therapies) 
The following medications and therapies are prohibited throughout the study (through the 
primary study period completion/day 365 visit [V14]):
●
Investigational research products that have not been approved for any indication in the 
country where the subject is enrolled. 
o
New regimens of approved chemotherapeutic drugs or antibodies; conditioning 
drugs, irradiation and T-cell depleting antibodies, except alemtuzumab, are allowed.
●
Prophylactic use of antiviral drugs for CMV viremia from time of randomization through 
completion of the primary study period completion/day 365 visit (V14).
●
Prophylactic use of CMV-specific immunoglobulin.
●
Alemtuzumab within 60 days prior to transplant (including conditioning regimen) 
through completion of the primary study period completion/day 365 visit (V14) unless 
required for disease relapse post-transplant.
5.2
Demographics and Baseline Characteristics 
5.2.1
Demographics
The subject’s date of birth, sex, race, and ethnicity (USA only) will be recorded at the 
screening visit. 
5.2.2
Medical History
A detailed medical history for each subject, including history of prior CMV, will be obtained 
at the screening visit. All relevant past and present conditions will be recorded for the main 
body systems, as well as prior surgical procedures.
A detailed description of the subject’s current disease status and conditioning regimen 
(including doses) will be recorded at the baseline visit (V2). A determination of myeloablative 
vs. non-myeloablative regimens will be made by the Investigator based on the definitions 
included in [Appendix 17].
Any untoward medical events that occur from the time of consent and during the screening 
period (prior to study drug administration) will be captured as AEs in the eCRF. A change in 


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medical status or medical history from time of signing of informed consent through first dose 
of study drug is to be reported as an AE or SAE as appropriate.
5.2.3
Transplant Information
The following transplant information will be collected for each subject:
●
Volume infused (in mL)
●
Human leukocyte antigen (HLA) typing of the donor and recipient
●
HLA cross match at time of transplant (as determined by the site’s standard method of 
determination and if available)
●
Type of transplant
●
Number of CD34+ stem cells/kg infused, if available
●
CMV-serostatus of the donor and recipient
●
Hepatitis B virus, HCV, and EBV serostatus of the donor and recipient, if available
●
Donor CD3+, CD4+, CD8+ and CD56+ cell counts from donor cell product, if available
●
Blood type of the donor and recipient
●
ABO cross match, if available
●
Donor-recipient relatedness
●
Donor gender
●
Donor age
●
Donor race, if available
●
Donor ethnicity, if available (USA only)
●
Donor product plasma volume and red blood cell (RBC) depletion status
●
Donor CMV-specific T-cells quantity (optional and requires informed consent from donor)
●
Number of mononuclear cells transfused, if available (for bone marrow recipients only).
5.2.4
Modified HCT-CI Score
The subject’s Modified HCT-CI score must be determined during the screening period using 
the history and laboratory results obtained on the day of screening. Pulmonary function tests 
(PFTs) including forced expiratory volume and diffusing lung capacity of carbon monoxide,
multi gated acquisition scans, and/or echocardiograms performed within 6 months (180 days) 
prior to screening are to be used for scoring pulmonary and cardiac comorbidities.
Modified HCT-CI definitions and scores are located in [Appendix 4].
5.3
Efficacy and Immunogenicity Assessments 
5.3.1
CMV Plasma Viral Load Assessment
CMV plasma viral load will be assessed by Abbott’s RealTime CMV assay using a fully 
automated system entailing extraction of CMV DNA and amplification of viral DNA with 
virus specific primers and probes.
 


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A subject’s viremia status will be monitored by the site on a regular schedule, as outlined in 
Table 1a, and at any time it is clinically indicated. Central laboratory measurements for 
routine surveillance of viremia will be performed at the following time points:
●
Every 7 days (weekly ± 2 days) from days 0 to 100.
●
Every 14 days (every other week ± 5 days) from days 101 to 180,
●
Every 30 days (every 30 days ± 5 days) from days 181 to 365.
A central laboratory measurement will also be performed at the initiation of CMV-specific
AVT, when clinically indicated and/or each time a local laboratory is used to assess the viral 
load. Upon initiation of CMV-specific AVT, plasma viral load testing will be performed at 
least weekly until the CMV-specific AVT is discontinued, at which point, the regularly 
scheduled plasma viral load assessments will resume. Please refer to the Laboratory Manual 
for more exact instructions. 
5.3.2
Graft-Versus-Host Disease 
Acute and chronic GVHD must be assessed and graded/globally scored and the Karnofsky 
Performance Scale (KPS) will be used to assess performance status at baseline and visits V5, 
V7, V9, V11, and V13 following transplant (day 0) through the primary study period 
completion/day 365 visit (V14). In addition, aGVHD is to be assessed weekly through day 
100. Local laboratory values may be used for grading.  
When a diagnosis of aGVHD is made for a subject, assessments must continue weekly (local 
laboratory values may be used for grading), until resolution for maximal grade and stage by 
key organ. When a diagnosis of cGVHD is made for a subject, the subject must return to the 
study center for evaluation and data collection, and assessments must be done at each 
regularly scheduled protocol visits, except those visits conducted by HHC, until resolution 
the maximum score by any assessment at the study site will also be recorded. Refer to 
[Appendix 11] for the criteria for the diagnosis of cGVHD.
All results of biopsies obtained for confirming the diagnosis of aGVHD and cGVHD will 
also be recorded.
Local laboratory values used for grading of GVHD must be entered into the eCRF.
The following grading/global scoring scales for acute and chronic GVHD will be utilized for 
the study:
●
aGVHD: Occurrence, stage, and overall grade of aGVHD will be based on the aGVHD 
tables presented in [Appendix 9].
●
cGVHD:  Grading as limited or extensive as assessed based on definitions in 
[Appendix 12].
●
cGVHD: Occurrence, organ scoring and global scoring of cGVHD will be based on the 
information presented in [Appendix 12 and Appendix 13].
●
KPS: Performance status as recorded in percentages will be based on the table presented 
in [Appendix 22].


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5.3.3
CMV EOD 
CMV EOD is defined as presented in [Appendix 2]: Definition of CMV Disease.
5.3.4
Infection
Except for CMV, infection is defined as presented in [Appendix 8], Severity Grading Table 
and Recurrence Interval Definitions for Infections. Infection grading using both of these 
appendix definitions as well as the NCI-CTCAE Version 4.03 grading scale is required.  
5.3.5
Cause of Death 
All diagnoses at the time of death will be captured in the eCRF. Additionally, the cause of 
death on the subject’s death certificate, if available, must be reported. The cause of death will 
be adjudicated by the AC.
5.3.6
Engraftment
The date of engraftment is defined as the first of 3 consecutive measurements post nadir 
where the peripheral blood absolute neutrophil count (ANC) is > 500/mm3 (0.5x109/L). If the 
subject’s blood neutrophil count does not nadir below 500/mm3 (0.5x109/L), the day of 
engraftment should be recorded as day 0. Results received in an equivalent local unit of 
measure must be converted to SI units.
5.3.6.1 Failure to Engraft
The subject has never engrafted and has an ANC < 500/mm3 (0.5x109/L). 
5.3.6.2 Rejection/poor Graft Function
ANC sustained > 0.5 x 109/L for 3 or more consecutive days with subsequent decrease to 
< 0.5x 109/L and bone marrow examination with < 5% cellularity.
5.3.6.3 Graft Failure
Graft failure includes persistent neutropenia, < 5% donor chimerism, and ANC < 0.5x109/L 
for 3 or more consecutive laboratory values [CIBMTR Forms manual, 2007].
5.3.6.4 Platelet Recovery
The first date of 3 consecutive laboratory values obtained on different days where the platelet 
count was > 20 x 109/L.  All dates must reflect no platelet transfusions in the previous 7 days.  
If the subject’s platelet count does not nadir below 20 x 109/L, the day of platelet recovery 
should be recorded as day 0.
5.3.6.5 Incidence of Relapse of Primary Disease Requiring Therapy
Diagnoses and type of recurrence of the primary disease requiring therapy must be captured in 
the eCRFs. Therapies to include are chemotherapeutic drugs or antibodies, irradiation, or a 
second HCT.


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5.3.7
Immunogenicity
Because subject inclusion is dependent on serological evidence of previous CMV infection, 
IgG antibodies to gB will be present prior to transplantation.
An indicator of immunogenicity elicited by the vaccine is predicted to be an increase in 
gB-specific antibody levels and the T-cell response to pp65 protein over time compared with the 
placebo group.  
Two immunogenicity assessments will be performed:
1. T-cell response to viral protein pp65 using either ELISPOT assay and/or intracellular 
cytokine staining (ICS).
2. Antibody response to gB antigen using an ELISA-based platform.
Assessments will be done from peripheral blood mononuclear cells (T-cells) or serum samples 
(antibody) isolated over the course of the trial. Time points of the assessments are as follows:
●
On V2, V5, V8, V9, V11 and V14.
o
Samples for T-cell assays will not be collected if the ALC is known to be 
≤500 mm3 by local or central laboratory measurement. 
o
If the visit coincides with a study drug administration, the sample will be drawn 
prior to injection.
Further details will be available in the Laboratory Manual.
5.3.8
Resource Utilization and Patient Reported Outcomes 
Additional assessments include the following resource utilization and patient reported outcome 
measures:
●
EuroQol (EQ-5D)
●
FACT-BMT
●
WPAI:GH
●
Health Economic Assessment (HEA)
The EQ-5D, FACT-BMT, and WPAI:GH will be assessed at each dosing visit, at V13, and at 
the primary study period completion/day 365 visit (V14). These questionnaires are to be 
completed by the subject prior to any other study assessments or visit procedures. Subjects are 
to complete these assessments in the following order: EQ-5D first, FACT-BMT second, WPAI 
last. For all 3 patient-reported outcome measures, i.e. EQ-5D, FACT-BMT, WPAI, the 
answers must come from the subject. If a subject is unable to answer a question, the rest of the 
questionnaire is still to be completed. If a subject is not able to provide any answers to the 
questions, the assessment should be skipped.   
Health economic information will be collected for subjects through the primary study period 
completion/day 365 visit (V14) [Section 5.3.8.4].


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5.3.8.1 EQ-5D
The EQ-5D is an international standardized non-disease specific (i.e. generic) instrument for 
describing and valuing health status. It is a measure of health-related QOL, capable of being 
expressed as a single index value and specifically designed to complement other health status 
measures. The questionnaire will be provided in the local language of the subject. The EQ-5D 
has 5 domains: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and 
Anxiety/Depression. Each domain has 5 response levels (e.g., 1 = no problems, 2 = slight 
problems, 3 = moderate problems, 4 = severe problems, 5 = extreme problems). In addition, it 
has a visual analogue scale that elicits a self-rating by the respondent of his/her health status 
[Appendix 14].
5.3.8.2 FACT-BMT
The FACT-BMT is a self-administered instrument designed to assess multi-dimensional 
aspects of QOL in BMT patients. The questionnaire will be provided in the local language of 
the subject.  It consists of the 27-item FACT-General (FACT-G) and the 23-item Bone 
Marrow Transplantation Subscale (BMTS). The FACT-G assesses 4 primary dimensions of 
QOL, including physical well-being (7 items), social/family well-being (7 items), emotional 
well-being (6 items), and functional well-being (7 items). A 5 point response scale ranging 
from 0 to 4 is used (0 = 'not at all'; 1 = 'a little bit'; 2 = 'somewhat'; 3 = 'quite a bit'; and 
4 = 'very much') [Appendix 15].
5.3.8.3 Work Productivity and Activity Impairment: General Health Questionnaire 
The WPAI:GH is a 6-question instrument designed to assess the effect of health problems 
(physical or emotional problem or symptom) on an individual’s ability to work and perform 
regular activities [Appendix 16]. The questionnaire will be provided in the local language of 
the subject.
5.3.8.4 Health Economic Assessment 
Health Economic Assessments (see [Appendix 21]) will include the following: 
hospitalizations recorded as number of days in the Intensive Care Unit, Step-down Unit, and 
general medical ward, (including bone marrow transplant [BMT] unit), (including emergency 
room [ER] visits greater than 24 hours) also non-protocol-related physician (MD/DO) visits 
and ER visits less than or equal to 24 hours. The information will be collected by the site via 
a retrospective review of the subject’s medical record. HEA data will include both data being 
routinely captured for the subject (e.g., concomitant medications) as well as data that will be 
used specifically for these analyses (e.g., information on hospitalizations).
5.3.9
Optional Donor Sub-Study (Not Applicable to Sites in Japan)
For CMV seropositive donors, there is an optional sub-study for the testing of CMV-specific 
T-cells. A 20 mL peripheral blood sample from the donor will be obtained prior to the stem 
cell donation for recipients participating in the main trial. For those donating peripheral stem 
cells, the donor blood sample is to be collected prior to the initiation of mobilization therapy 
(e.g., G-CSF). Whether donors donating at institutions other than the site where the HCT will 


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occur will be able to participate is dependent on the capabilities of each country and 
subsequent institution to arrange the logistics. If the donor does not consent to participate in 
the sub-study, the recipient will not be impacted and will still receive the HCT and be allowed 
to continue in the main trial.
5.4
Safety Assessment
Safety assessments include the following:
●
Vital signs
●
AEs
●
Local reactogenicity
●
Laboratory assessments
●
PE
5.4.1
Vital Signs
Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature and 
weight) will be collected at all dosing visits, and at screening (V1), V13 and V14.  Height will 
be collected at screening only.
Vital signs will be collected as follows:
●
Vital signs will be collected immediately prior to injection and 60 (±10) minutes post 
injection (except weight) at study visits accompanied by injection.
●
Vital signs will be collected once at screening (V1), and at V13 and V14.
5.4.2
Adverse Events
All AEs and serious adverse events (SAEs) will be collected from signing of the informed 
consent through 30 days following the last dose of study drug. All events requiring 
adjudication, Grade 3 and higher grade AEs as well as SAEs will be collected from 31 days post 
last dose of drug through 1 year post-transplant. A change in medical status or medical history 
from time of signing of the informed consent through first dose of study drug are to be reported 
as an AE, or SAE as appropriate. In this study, the day 0 HCT is not considered an AE.  
Data to be recorded includes the AE, date of onset, date of resolution, intensity, action taken 
with respect to study drug, treatment required, relationship to study drug and outcome of the 
event.  
Grade 3 or greater AEs ongoing at V14 will be followed up for as long as necessary to 
adequately evaluate the subject’s safety or until the event stabilizes. If the event resolves 
during the study, a resolution date will be documented on the case report form.
5.4.2.1 Local Reactogenicity Assessments
Subjects will be evaluated for local reactogenicity and systemic signs for 60 minutes
(± 10 minutes) after each injection. Subjects will be directly observed for 15 minutes 
following the injection for any injection-related side effects, then remain in a designated area 
at the study site for 45 minutes so that side effects can be noted and treated, if necessary. 


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Local reactogenicity will also be evaluated for each of the 7 consecutive days following each 
injection. The assessments for each of the 7 consecutive days following an injection will be 
done by the subject and reported to the site via diary. When reactogenicity is reported as an 
AE, it must be followed until resolution or medically stable. All local reactions ≥Grade 3 
[Appendix 7] require confirmation by a health care professional.
Grading of reactogenicity will be done using the protocol-specified reactogenicity scale 
[Appendix 7]. The daily maximum measurement of local reactogenicity signs will be recorded.
5.4.3
Laboratory Assessments 
Please refer to [Appendix 1] for a list of laboratory tests to be performed during the study.
Blood and urine samples will be collected for the following laboratory assessments:
●
Urine or serum pregnancy testing for all females of childbearing potential and all 
females who are of non-childbearing potential but are < 50 years of age and not 
documented to be surgically sterile will be performed at the screening visit. 
Subsequently, a urine or serum pregnancy test will be performed at V2, V5, V7, V9, 
V11, V13, and at the primary study period completion/day 365 visit (V14). All 
pregnancy tests will be done locally and performed on the same day and prior to study 
drug administration on visits that coincide.
●
CMV IgG antibody assay will be measured at screening by the local laboratory. CMV 
plasma viral load will be monitored as outlined in [Section 5.3.1].
o
Local laboratory values for CMV viral load must be collected in the eCRF.
●
Hematology (RBC, white blood cells [total leukocytes], hemoglobin, hematocrit, 
platelets [thrombocytes], neutrophils [ANC], eosinophils, basophils, lymphocytes, 
monocytes and blast cells) will be measured at V1, V2, and V5-V12. 
●
Platelet count must be performed locally and within 3 days prior to study drug dosing. 
For dose 1, it must be done within 3 days prior to randomization.
●
Biochemistry (sodium, potassium, calcium, chloride, glucose, creatinine, CPK/CK, total 
protein, albumin) will be measured at V1, V2, and V5-V12.
o
If local or central CPK/CK levels are 5x the ULN at any time during the primary 
study period, a repeat laboratory draw must be performed and sent to the central 
laboratory for testing. In addition, these local laboratory levels must be captured 
in the eCRF for the subject.
o
Local laboratory values used for grading of GVHD must also be captured in the 
eCRF for the subject.
●
Hepatic profile (total bilirubin, direct bilirubin, alkaline phosphatase, aspartate amino-
transferase [AST], alanine aminotransferase [ALT]) will be measured at V1, V2 and V5-
V12.  See [Appendix 18] for follow-up of liver function tests (LFTs) beyond the ULN
o
If local or central AST or ALT are > 20 x ULN, or bilirubin is found to be
≥10 x ULN at any time during the primary study period, a repeat laboratory draw 


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must be performed and sent to the central laboratory for testing. In addition, these 
local laboratory levels must be captured in the eCRF for the subject.
Clinically significant laboratory results must be followed until resolution or until they are no 
longer clinically significant or are medically stable.
●
Immunogenicity: gB-specific antibody levels and T-cell responses to pp65.
A saliva sample will be collected at V2 after randomization but prior to the first dose of study 
drug for subjects who agree to participate in the optional PGx substudy.
For CMV seropositive donors who consent to participate in the optional substudy, a 20 mL 
peripheral blood sample from the donor will be obtained prior to the stem cell donation for 
recipients participating in the main trial to test for CMV-specific T-cells. For those donating 
peripheral stem cells, the donor blood sample is to be collected prior to the initiation of 
mobilization therapy (e.g., G-CSF).
5.4.3.1 Abnormal LFTs
See [Appendix 18] (Liver Safety Monitoring and Assessment) for information on monitoring 
and assessment of abnormal LFTs.
5.4.3.2 Bronchoalveolar Lavage Fluid
In the event that a bronchoalveolar lavage (BAL) sample is obtained for CMV pneumonia 
evaluation some of this sample will be sent to the central laboratory for storage and possible 
central reading.
5.4.4
Physical Examination 
Complete PE will be performed at the screening and baseline visits (V1 and V2) and at the 
primary study period completion/day 365 visit (V14). The PE will include the following:  an 
examination of the skin, general appearance, neck (including thyroid), eyes, ears, nose, throat, 
lymph nodes, chest (lungs), heart, abdomen, musculoskeletal system, neurological system and 
any additional assessments needed to establish baseline status or evaluate symptoms or AEs. 
At all other visits where a PE is performed, symptom-directed PEs may be done. Performance 
status will be assessed using the KPS [Appendix 22] at baseline visit (V2).
The Investigator or qualified medical personnel who routinely perform these evaluations in 
this patient population will conduct the examination, determine findings, and assess any 
abnormalities as to clinical significance.
5.4.5
Long-Term Follow-up
Subjects will be contacted after the primary study period (day 365) through 5.5 years 
post-transplant for long-term safety related to the DNA vaccine. Items to be assessed by 
telephone interview and available patient records include mortality, development of any 
new/recurrent cancer, development of infection requiring hospitalization or resulting in 
death, and erythema and induration at the sites of study drug injections [Appendix 20].  


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During the long-term follow-up period, if an SAE is identified and deemed possibly or 
probably related to the study medication, an SAE report on the SAE worksheet must be sent 
to the Sponsor per [Section 5.5.6] for all sites except those in Japan.  For study sites in Japan, 
an SAE report on the JUTOKUNA YUUGAIJISHOU HOUKOKUSHO must be sent to 
delegated CRO per [Section 5.5.3].
5.5
Adverse Events and Other Safety Aspects
5.5.1
Definition of Adverse Events 
An AE is defined as any untoward medical occurrence in a subject administered a study drug 
or has undergone study procedures and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product.
Some countries may have additional local requirements for events that are required to be 
reported as AEs or in an expedited manner similar to an SAE.  In these cases, it is the 
investigator’s responsibility to ensure these and other reporting requirements are followed 
and that the information is appropriately recorded in the eCRF accordingly.  
In this study, the day 0 HCT is not considered an AE. All AEs will be collected from signing 
of the informed consent through 30 days after last dose of study drug.  Only events requiring 
adjudication, Grade 3 and higher AEs will be collected from 31 days after last dose of study 
drug through 1 year post-transplant. 
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, 
electrocardiogram [ECG] data, PE) should be defined as an AE only if the abnormality meets 
1 of the following criteria:
●
Induces clinical signs or symptoms.
●
Requires active intervention.
●
Requires interruption or discontinuation of study medication.
●
The abnormality or investigational value is clinically significant in the opinion of the 
Investigator.
5.5.2
Adverse Events of Special Interest
The following definitions must be used to properly record and report adverse events for the 
study.
5.5.2.1 Malignancy
All new malignancies or relapses of prior malignancies and relapses of primary malignancy 
requiring treatment will be recorded. 
5.5.2.2 Sinusoidal Obstruction Syndrome (SOS) [Hepatic Veno-occlusive Disease (VOD)]
In the absence of a histological diagnosis, recipients must fulfill the criteria below for a 
diagnosis of SOS.


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No other identifiable cause for liver disease with at least 2 or more of the following clinical 
signs and symptoms:
●
Jaundice (bilirubin >2 mg/dL or > 34 µmol/L).
●
Hepatomegaly with right upper quadrant pain.
●
Ascites and/or weight gain (> 5% over baseline).
5.5.2.3 Adverse Events Commonly Associated with Vaccines
The following AEs have been reported with other vaccines and will be subject to specific 
monitoring:
●
Acute local vaccines reactions: local pain, redness, swelling or induration (as defined in 
Section 5.4.2.1)
●
Allergic and demyelination reactions
5.5.3
Definition of SAEs
An AE is considered “serious” if, in the view of either the Investigator or Sponsor, it results 
in any of the following outcomes:
●
Results in death.
●
Is life threatening (an AE is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the subject at immediate risk of death. It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death).
●
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions. 
●
Results in congenital anomaly, or birth defect.
●
Requires inpatient hospitalization or leads to prolongation of hospitalization 
(hospitalization for treatment/observation/examination caused by AE is to be considered 
as serious).
●
Results in drug exposure during pregnancy. 
●
Other medically important events.
In this study, the day 0 HCT is not considered an SAE.
Medical and scientific judgment must be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent 1 of the other outcomes listed in the definition above. These 
events, including those that may result in disability/incapacity, are also usually considered 
serious. Examples of such events are intensive treatment in an ER or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse.
Safety events of interest on the medicinal products administered to the subject as part of the 
study (e.g., study drug, comparator, background therapy) that may require expedited 
reporting and/or safety evaluation include, but are not limited to:


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Overdose of a Sponsor medicinal product
●
Suspected abuse/misuse of a Sponsor medicinal product
●
Inadvertent or accidental exposure to a Sponsor medicinal product
●
Medication error involving a Sponsor product (with or without subject/patient exposure 
to the Sponsor medicinal product, e.g., name confusion)
All of the events of interest noted above must be recorded on the eCRF. Any situation 
involving these events of interest that also meets the criteria for an SAE must be recorded on 
the AE page of the eCRF and marked ‘serious’ and the SAE worksheet (for sites in Japan: 
JUTOKUNA YUUGAIJISHOU HOUKOKUSHO) completed.
The Sponsor has a list of events that they classify as “always serious” events.  If an AE is 
reported that is considered to be an event per their classification as “always serious”, 
additional information on the event may be requested.
SAEs as listed in [Appendix 3] (Common Serious Adverse Events and Endpoint Events) 
must be reported to Astellas within 24 hours, but a single occurrence of SAEs listed in 
[Appendix 3] may be excluded from expedited reporting from Astellas to the regulatory 
agencies or/and competent authorities (CAs) (See [Appendix 3] for more information).
If a subject becomes pregnant during treatment, this must be reported as if it were a SAE. 
Refer to [Section 5.5.9], Procedure in Case of Pregnancy.
5.5.4
Criteria for Causal Relationship to the Study Drug
AEs that fall under either "Possible" or "Probable" must be defined as "adverse events whose 
relationship to the study drugs could not be ruled out."
Causal Relationship
to the Study Drug
Criteria for Causal Relationship
Not Related
A clinical event, including laboratory test abnormality, with a temporal  
relationship to drug administration which makes a causal relationship 
improbable, and/or in  which other drugs, chemicals or underlying 
disease provide plausible explanations.
Possible
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, but which 
could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or unclear.
Probable
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely to be 
attributed to concurrent disease or  other drugs or chemicals, and 
which follows a clinically reasonable response on re-administration 
(rechallenge) or withdrawal (dechallenge).
5.5.5
Criteria for Defining the Severity of an Adverse Event
The NCI-CTCAE Version 4.03 (including laboratory abnormalities) will be used to measure 
the severity of AEs, except local reactogenicity which will use both the NCI-CTCAE Version 
4.03 and the protocol-specific reactogenicity scale [Appendix 7].


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5.5.6
Reporting of SAEs
For all countries, except Japan, in the case of an SAE, the Investigator must contact the 
Sponsor by telephone or fax immediately (within 24 hours of awareness). 
The Investigator must complete and submit an SAE Worksheet containing all information 
that is required by the Regulatory Authorities to the Sponsor by fax or email immediately 
(within 24 hours of awareness). If the faxing or emailing of an SAE Worksheet is not 
possible or is not possible within 24 hours, the local drug safety contact must be informed by 
phone.  
For sites in Japan only: In the case of an SAE, the Investigator/Sub- investigator must report 
the SAE to the head of the study center and also contact the delegated CRO by telephone or fax 
immediately (within 24 hours of awareness).
The Investigator must complete and submit JUTOKUNA YUUGAIJISHOU 
HOUKOKUSHO containing all information that is required by the regulatory authorities to 
the delegated CRO and head of the study center by fax immediately (within 24 hours of 
awareness). If faxing of JUTOKUNA YUUGAIJISHOU HOUKOKUSHO is not possible, or 
is not possible within 24 hours, the delegated CRO should be informed by phone.
For contact details for each country/region, see Section II Contact Details of Key Sponsor's 
Personnel. Please fax the SAE Worksheet (Specific to sites in Japan: JUTOKUNA 
YUUGAIJISHOU HOUKOKUSHO) to:
Fax:
Tel: 
For study sites outside of Japan, the Investigator must fax or email the SAE Worksheet to: 
Fax number:
International Fax: 
Email: 
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
Sponsor's Medical Monitor or his/her designee [Section II]. 
For study sites outside of Japan: Follow-up information for the event must be sent promptly 
(within 7 days of the initial notification).
Full details of the SAE should be recorded on the medical records and on the eCRF.
The following minimum information is required:
●
ISN/Study number, 
●
Subject number, sex and age,
●
The date of report,


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●
A description of the SAE (event, seriousness of the event), and
●
Causal relationship to the study drug.
The Sponsor or Sponsor's designee will submit expedited safety reports (i.e. IND Safety 
Reports) to the regulatory agencies (i.e. FDA) as necessary, and will inform the investigators 
of such regulatory reports. Investigators must submit safety reports as required by their 
IRB/IEC within timelines set by regional regulations (i.e. EU, (e)CTD, FDA). 
Documentation of the submission to and receipt by the IRB/IEC of expedited safety reports 
should be retained by the site.
The Sponsor/ delegated CRO will notify all investigators responsible for ongoing clinical 
studies with the study drug of all SAEs which require submission per local requirements 
IRB/IEC/the heads of the study sites.
The heads of the study sites/investigators should provide written documentation of IRB/IEC
notification for each report to the Sponsor per local requirements IRB/IEC.
The study site may contact the Sponsor's Medical Monitor/Expert for any other problem 
related to the safety, welfare, or rights of the subject.
UNIQUE to studies enrolling subjects in EU: For SUSARs from a blinded trial, unblinded 
CIOMS-I report will be submitted to the authorities and IRB/IEC where required.
All observed or spontaneously reported SAEs occurring up to 12 months after transplant 
must be captured on the eCRFs and reported to the Sponsor (for sites in Japan: the delegated 
CRO) in accordance with these guidelines. All SAEs will be recorded within the source 
documents, on the SAE worksheets (for sites in Japan: JUTOKUNA YUUGAIJISHOU 
HOUKOKUSHO) which will be faxed to the Sponsor (for sites in Japan: the delegated CRO), 
and collected in the eCRF. AEs leading to subject discontinuation from the study will be 
collected in the appropriate section of the eCRF.
For the purposes of expedited safety reporting to the regulatory agencies, SAEs describing an 
event listed in [Appendix 3] as common and disease related or a protocol-defined endpoint 
(e.g., CMV diseases) may not be reported by Astellas for a single occurrence for a given 
subject.  However, Astellas may report as appropriate aggregated cases of such events.
5.5.7
Follow-up to Adverse Events
All AEs reported during the study are to be followed up until resolved or judged to be no 
longer clinically significant, or until they become chronic to the extent that they can be fully 
characterized.
If during an AE follow-up, the AE progresses to an "SAE", or if a subject experiences a new 
SAE, the Investigator must immediately report the information to the Sponsor. 
5.5.8
Monitoring of Common Serious Adverse Events and Endpoint Events
Common serious AEs are SAEs commonly anticipated to occur in the study population 
independent of drug exposure. SAEs classified as “common” are provided in 
[Appendix 3] Common Serious Adverse Events and Endpoint Events for your reference. The 


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list does NOT change your reporting obligations or prevent the need to report an AE meeting 
the definition of an SAE as detailed above. The purpose of this list is to alert you that some 
events reported as SAEs may not require expedited reporting to the regulatory authorities 
based on the classification of “common serious adverse events” as specified in 
[Appendix 3] Common Serious Adverse Events and Endpoint Events. The Sponsor will 
monitor these events throughout the course of the study for any change in frequency. Any 
changes to this list will be communicated to the participating investigational sites. 
Investigators must report individual occurrences of these events as stated in [Section 5.5.6] 
Reporting of Serious Adverse Events. 
5.5.9
Procedure in Case of Pregnancy
If a female subject or partner of a male subject becomes pregnant from first dose through
1 year post-transplant, the Investigator must report the information to the Sponsor/delegated 
CRO as if it is an SAE. The expected date of delivery or expected date of the end of the
pregnancy, last menstruation, estimated fertility date, pregnancy result, neonatal data, and 
any other clinically relevant information must be included, if available and if the mother has 
granted release of medical information.
The Investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome to the Sponsor/delegated CRO.
When the outcome of the pregnancy falls under the criteria for SAEs (spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly [including anomaly in a 
miscarried fetus)], the Investigator must respond in accordance with the report procedure for 
SAEs.  Additional information regarding the outcome of a pregnancy (which is categorized 
as an SAE) is mentioned below.
●
“Spontaneous abortion” includes miscarriage, abortion and missed abortion.
●
Death of an infant within 1 month (30 days) after birth must be reported as an SAE
regardless of its relationship with the study drug. 
●
If an infant dies more than 1 month (30 days) after the birth, it must be reported if a 
relationship between the death and intrauterine exposure to the study drug is judged as 
“possible” by the Investigator.
●
In the case of a delivery of a living newborn, the “normality” of the infant is evaluated at 
the birth.
●
“Normality” of the miscarried fetus is evaluated by visual examination unless test results 
which indicate a congenital anomaly are obtained prior to miscarriage.
If during the conduct of a clinical trial, a male subject makes his partner pregnant through 
1 year post-transplant, the subject will be asked to report the pregnancy to the Investigator. 
The Investigator will report the pregnancy to the Sponsor via an SAE/delegated CRO
reporting form.


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5.5.10
Supply of New Information Affecting the Conduct of the Study
When new information becomes available necessary for conducting the clinical study 
properly, the Sponsor will inform all investigators involved in the clinical study as well as the 
regulatory authorities. Investigators should inform the IRB/IEC of such information when 
needed.
The following 2 paragraphs are specific to sites in Japan:
1.
When information is obtained regarding serious and unexpected adverse drug reactions
(ADRs) (or other) that are specified in Article 273 of the Act on Securing Quality, 
Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular 
Therapy Products, Gene Therapy Products, and Cosmetics, in compliance with Article 
80-2 Paragraph 6 of the Act described above, the Sponsor should inform all the 
investigators involved in the clinical study, the head of the study site, and the regulatory 
authorities of such information. The head of the study site who receives such information 
will decide whether the clinical study should be continued after hearing the opinions of 
the IRB.  The Investigator will supply the new information to the subjects, in compliance 
with [Section 8.2.3.2] Supply of New and Important Information Influencing the 
Subject’s Consent and Revision of the Written Information.
2.
In addition to the above item (1), when the head of the study site receives the revisions 
of the IB, protocol, or written information, information on the matters covering the 
quality of the study drug, efficacy and safety, information necessary for conducting the 
clinical study properly, or documents to be examined by the IRB should be sent to the 
IRB.
5.5.11
Deviations from the Protocol and Other Actions Taken to Avoid Life-
Threatening Risks to Subjects (FOR SITES IN JAPAN ONLY)
The following 2 paragraphs are specific to sites in Japan:
The Investigator must not deviate from or amend the protocol, excluding an emergency case 
for avoiding risks to the subjects. When the Investigator does not follow the protocol in order 
to avoid urgent risks for subjects, the Investigator should take the following actions. 
1.
Describe the contents of the deviation or amendment and the reasons for it in a written 
notice, and immediately send the document stating the deviation or amendment and the 
reasons to the Sponsor and the head of the study site. Keep a copy of the notice.
2.
Consult with the Sponsor at the earliest possibility for cases in which it is necessary to 
amend the protocol. Obtain approval for a draft of the amended protocol from the IRB 
and the head of the study site as well as written approval from the Sponsor.
5.6
Test Drug Concentration 
Not applicable.


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5.7
Other Measurements, Assessments, or Methods 
5.7.1
Pharmacogenomics (PGx)
During the baseline visit (V2), after randomization but prior to the first dose of study drug, 
subjects who consent to participate in the retrospective PGx assessment will have 2 mL of
saliva collected and sent to the central laboratory.
Please refer to [Appendix 19] for more information regarding pharmacogenomic sampling
and to the study Laboratory Manual for laboratory specimen handling instructions.
5.8
Total Amount of Blood
The total amount of blood to be collected for central laboratory assessments for the primary 
study period per subject should not exceed 63 mL at any study visit and is expected to be 
approximately 681 mL total for the study for all countries, except Japan. For sites in Japan: 
total blood volume for the study is approximately 550 mL. 
For CMV seropositive donors who consent to participate in the optional donor sub-study, a 
20 mL peripheral blood sample from the donor will be obtained prior to the stem cell 
donation for recipients participating in the main trial test for CMV-specific T-cells. For those 
donating peripheral stem cells, the donor blood sample is to be collected prior to the initiation 
of mobilization therapy (e.g., G-CSF).
Refer to the Laboratory Manual for more details regarding blood collection.
6
DISCONTINUATION
6.1
Discontinuation of Individual Subject(s) 
A discontinuation is a subject who enrolled in the study and for whom study treatment is 
permanently discontinued prematurely for any reason.  Only subjects who have received at 
least a single study dose and discontinued will be followed for safety.
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice. The 
Investigator is also free to terminate a subject’s drug treatment, if warranted by the subject’s 
medical condition. 
6.2
Discontinuation of the Study
When the Sponsor is aware of information on matters concerning the quality and safety of the 
study drugs, as well as other important information that may affect proper conduct of the 
clinical study, the Sponsor may discontinue the clinical study and send a written notice of the 
discontinuation along with the reasons to the Investigator (for sites in Japan: to the head of 
the study site), and regulatory authorities.
The DMC is responsible for periodically reviewing select accruing data for the purpose of 
ensuring subject safety. The DMC is an independent multidisciplinary group consisting of 


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clinicians and a biostatistician external to Astellas that, collectively, has experience in the 
management of patients undergoing HCT and other diseases, and in the conduct and 
monitoring of randomized clinical trials with interim analyses.
The DMC statistician will perform a futility analysis on efficacy data for presentation to the 
DMC at selected DMC meetings. The futility of ASP0113 will be monitored based on its 
effect on viremia (defined as a CMV plasma viral load ≥1000 IU/mL as assessed by the 
central laboratory). It is believed that viremia is a surrogate of treatment effect on clinical 
endpoints. Subjects receiving ASP0113 had a statistically significant reduction in viremia 
relative to placebo in the phase 2 trial of ASP0113. Although there are no explicit safety 
stopping rules, all safety issues will be thoroughly evaluated by the DMC with special 
attention paid to local reactogenicity and hypersensitivity cases.
Futility analysis will be performed when the first 100 subjects have been randomized, and 
every 3 months thereafter until the total enrollment reaches 400 subjects. Futility analysis are 
based on the rate of CMV viremia defined as CMV plasma load ≥1000 IU/mL as assessed by 
the central laboratory. Analysis will include all available viremia data obtained from the 
central laboratory up to the time of a cut-off point for each futility analysis. At each futility 
analysis, a Bayesian posterior probability that the hazard ratio for viremia of the ASP0113 
treatment group to the placebo treatment group will be less than 0.75 will be calculated.
The study may stop for futility if: Posterior Probability of (Virtrt/Vircon < 0.75) < 0.15 at any 
time point when futility analysis is performed, including when a planned interim data 
analysis is conducted, where Virtrt is the hazard of viremia in the ASP0113 group and Vircon
is the hazard of viremia in the placebo group.
The DMC will determine if the futility criterion for discontinuation of the study has been 
met. If the criterion has been met, sufficient information will be provided to Astellas 
representatives to enable them to evaluate and, if applicable, act on the recommendation of 
the DMC.
If an Investigator intends to discontinue participation in the study, the Investigator must 
immediately inform the Sponsor (UNIQUE to JP: and the head of the Study site) of the 
discontinuation and the reason for it.
7
STATISTICAL METHODOLOGY
This is a randomized, double-blind, placebo-controlled trial of approximately 500 subjects.
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
standard deviation, minimum, median and maximum) for continuous endpoints, and 
frequency and percentage for categorical endpoints. Statistical tests will be conducted using a 
significance level of 0.05. Confidence intervals will be 95%, except were otherwise indicated.


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7.1
Sample Size
In the primary analysis set of a phase 2 study of the efficacy of ASP0113 in HCT, 7 subjects
died and 2 additional subjects experienced CMV EOD out of 40 treated with ASP0113, for 
an overall failure rate of 22.5%. while among the placebo subjects 11 subjects died and 1 
additional subject experienced CMV EOD out of 34, for an overall failure rate of 35.3%. 
To detect the estimated difference in mortality and CMV EOD from the phase 2 study 
(35.3% vs. 22.5%), the study needs a sample size of at least 424 (212 per arm) to have 80% 
power at the 2-sided significance level of 0.050. A trial of size 500 (250 per arm) is expected 
to have 86% power for the composite endpoint.
All calculations are based on 1:1 randomization and used nQuery Advisor 7.0.
7.2
Analysis Set
Prior to database lock, a Final Review of Data and TLFs Meeting will be held to allow a 
review of the clinical trial data and to verify the data that will be used for analysis set 
classification. If required, consequences for the statistical analysis will be discussed and 
documented.  A meeting to determine analysis set classifications will also be held prior to 
database lock.
7.2.1
Safety Analysis Set 
The safety analysis set (SAF) consists of all randomized subjects who received at least 1 dose 
of randomized study drug. Subjects will be included in analyses using the SAF based on 
treatment actually received.
The SAF will be used for summaries of demographic and baseline characteristics and 
analysis for all safety and tolerability related variables.
7.2.2
Full Analysis Set 
The full analysis set (FAS) consists of all randomized subjects who receive at least 1 dose of 
randomized study drug. Subjects will be included in analyses using the FAS based on 
assigned treatment, even if 1 or more doses of the incorrect treatment were given. The FAS 
will be used for summaries of demographic and baseline characteristics and for primary 
analysis of the efficacy variables.
7.2.3
Per Protocol Set 
The per protocol set (PPS) includes all subjects of the FAS who have no major protocol 
violations. Criteria will be defined in the SAP.
Final judgments on exclusion of subjects from the PPS, based on protocol violations, are to 
be made at the Blind Data Review Meeting held prior to unblinding. 
The PPS will be used for secondary analyses of efficacy variables. Also, selected 
demographic and baseline characteristics will be summarized for the PPS.


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7.2.4
Pharmacokinetic Analysis Set 
Pharmacokinetic analysis will not be performed in this study.
7.2.5
Immunogenicity Analysis Set
The immunogenicity analysis set (IAS) includes subjects who received randomized study
drug for whom at least 1 post-transplant immunogenicity measurement is available.
The IAS will be used for analyses of the immunogenicity data.
7.3
Demographics and Other Baseline Characteristics
Demographics and baseline characteristics such as age, race, gender, height, weight, baseline 
disease status, baseline disease therapy, and donor-recipient relatedness will be summarized 
overall and by treatment group using each analysis set. For subjects with donors included in 
the optional donor substudy, numbers and percent of donors with T-cell immunity to pp65 
will be summarized by treatment group. 
Continuous variables will be summarized by descriptive statistics (e.g., n, mean, standard 
deviation, minimum, median, and maximum) and discrete variables will be summarized by 
the number and percentage of subjects in each category.
7.4
Analysis of Efficacy
7.4.1
Analysis of Primary Variable
7.4.1.1 Primary Analysis
In order to compare the effect on the primary composite endpoint between ASP0113 and 
placebo, the following null hypothesis will be constructed:
H0: Odds Ratio = 1.
The accompanying alternative hypothesis is:
H1: Odds Ratio ≠ 1.
The 2-sided P value for the above hypothesis tests will be calculated using the CMH test 
stratified by the 2 stratification factors for randomization (donor-recipient relatedness and 
donor CMV serostatus). The effect of ASP0113 will be considered statistically significant if 
the CMH rejects the null hypothesis at the significance level of 0.050.   
Every effort will be made to collect each subject’s status that will define the outcome of the 
primary endpoint. For the primary analysis, subjects with unknown survival status will be 
considered as having the primary endpoint event.  
In addition, the Breslow-Day test will be used to assess the consistency of the odds ratio 
across the strata. In the event that the Breslow-Day test is significant at the 0.10 level, 
tabulations of the treatment effect will be provided for each stratum to assess the strength of 
possible treatment-by-strata interactions.


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In a supportive analysis, time to first occurrence of a primary endpoint event will be analyzed 
in a Cox proportional hazards model where the time-to-event will be calculated in days from 
transplant to the earliest of death or CMV EOD. Subjects not experiencing the primary 
endpoint event will be censored at the time of their last follow-up visit. The Cox model will 
include treatment and the stratification factors for randomization. The effect of ASP0113 
compared with placebo will be estimated as 1- hazard ratio, which is estimated from the Cox 
model.  The corresponding 95% CI for the effect will be presented. 
Efficacy analyses will be limited to the data obtained from time of first dose of study drug 
through the 1 year post-transplant follow-up period.  Data collected after the 1 year 
post-transplant follow-up period for the long-term follow-up will not be included for the 
primary analysis of the primary endpoint.
7.4.1.2 Secondary Analysis for the Primary Endpoint
An analysis of the primary endpoint will be repeated on the PPS. The method used for this 
analysis will be identical to the primary analysis described in [Section 7.4.1.1]. Additional 
sensitivity analyses for the primary endpoint will be conducted using only the subjects having 
complete follow-up through 1 year post-transplant and using alternative imputations of 
outcomes.
7.4.1.3 Subgroup Analysis
The impact on treatment effect will be assessed by a Breslow-Day test for each of the 
following factors:  age (less than study median, greater than or equal to study median), race
(white, non-white), gender (male, female), subjects who had ATG as part of their 
conditioning regimen vs. those who did not, and myeloablative vs. non-myeloablative 
conditioning regimen. If the P value of Breslow-Day test is ≤ 0.10 the treatment effect will be 
estimated for each strata of the subgroup.  
If enough donors are enrolled in the optional donor substudy then subgroup analyses by 
donor T-cell mediated immunity will also be performed.
7.4.2
Analysis of Secondary Variables
7.4.2.1 Key Secondary Variables
A Cox proportional hazards model will be used to assess the effect on the time-to-first 
protocol-defined CMV viremia through 1 year post-transplant. Protocol-defined CMV 
viremia is defined as a CMV plasma load ≥1000 IU/mL as assessed by the central laboratory.  
The Cox model will contain the same terms as the 1 described above. Vaccine efficacy will 
be estimated as:
VE = 1 – hazard ratio, and 95 % CI will be provided.
To compare the treatment effect on protocol-defined CMV viremia between ASP0113 and 
placebo, the following null hypothesis will be constructed:
H0: VE ≤ 20%.


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The accompanying alternative hypothesis is:
H1: VE > 20%.
The P value for the above hypothesis tests will use a Wald statistic using the Cox model 
parameter estimate for the treatment effect, θt:
Z = (θt – ln(1-20%))/S.E.(θt)
The 95% CI for VE will be calculated by taking 1 minus the 95% CI for the hazard ratio. 
Alternative hypothesis will be accepted if the 95% CI for VE excludes 20%.
The hazard rate of first adjudicated CMV-specific AVT through 1 year post-transplant and 
for first CMV-specific AVT for protocol defined viremia will be analyzed similar to the 
analysis for CMV viremia. These analyses will test for simple superiority (0% efficacy 
margin) rather than use a 20% efficacy margin. 
7.4.2.2 Other Secondary Variable
The endpoint of time to first CMV-specific AVT for protocol-defined CMV viremia or CMV 
EOD through 1 year post-transplant will be analyzed using a Cox proportional hazards model 
which includes effects for treatment, donor CMV serostatus, and donor-recipient relatedness.
7.4.3
Analysis of Other Variables 
The maximum grade of aGVHD, maximum cGVHD global score, number of episodes of 
protocol-defined CMV viremia, and duration of hospitalizations will each be tested using a 
Kruskal-Wallis test. 
Incidence of overall mortality, CMV EOD, grade 3-4 aGVHD, severe cGVHD, grade 3 
infections other than CMV, relapse mortality, non-relapse mortality, graft rejection, failure to 
engraft, and incidence of relapse of primary disease requiring therapy will each be tested 
using a stratified analysis of the binary response using a CMH test to account for the 
stratification variables used as part of the randomization. Subjects who discontinue the study 
without experiencing the event considered in the analysis will be considered as having the 
event for the statistical analysis.
Number of episodes of protocol-defined CMV viremia [CMV plasma viral load 
≥1000 IU/mL by the Abbott RealTime CMV assay as assessed by the central laboratory] will 
be compared between treatments using the stratum-adjusted Kruskal-Wallis test, adjusting for 
donor-recipient relatedness and donor CMV status. To estimate the association between 
CMV viremia and mortality, a multivariable Cox proportional hazards model will be 
constructed in a time-dependent manner. The model will be adjusted for the factors used to 
stratify the randomization. CMV viremia will be treated as a time-dependent variable, 
starting at the time of the first occurrence of protocol-defined CMV viremia.
The maximum grade of aGVHD, maximum cGVHD global score, and duration of 
hospitalizations will each be tested using a stratum-adjusted Kruskal-Wallis test adjusting for 
donor-recipient relatedness and donor CMV serostatus. 


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The treatment effect on time to engraftment and time to platelet recovery will each be 
analyzed in a Cox proportional hazards model including the factors used to stratify the 
randomization.
Immunogenicity analysis will be conducted using the IAS. Descriptive statistics on the raw 
and log transformed results will be presented by treatment group and collection time point. 
The Wilcoxon rank sum test will be used to compare treatment groups at each of the time 
points for immunogenicity assessment for the following:
●
Antibody response to gB antigen 
●
T cell response to viral protein pp65
The EQ-5D response for each domain will be summarized by treatment arm at each visit. The 
total FACT-BMT and the corresponding change from baseline will be summarized by 
treatment arm at each visit and at final visit. The productivity outcomes from the WPAI will 
be summarized by treatment arm at each visit and at final visit. Treatments will be compared 
with respect to these scales using analysis of covariance of change from baseline to final visit 
with treatment, donor-recipient relatedness, and donor CMV serostatus as factors and 
baseline value as a covariate.
7.5
Analysis of Safety
The SAF will consist of all randomized subjects who have at least 1 study drug injection.
This analysis set will be used for all summaries and analysis of AEs, reactogenicity, clinical 
laboratory data, PEs, vital signs, and subject survival through 1 year post first study drug 
injection. All recorded AEs will be listed, including duration, outcome, toxicity grade, and 
association with use of study drug. In addition, the toxicity of antiviral therapy will be 
identified from its association with those products.
All AEs and SAEs will be collected from signing of the ICF through 30 days post last dose of 
study drug. All events requiring adjudication, Grade 3 and higher AEs and SAEs will be 
collected from 31 days post last dose of drug through 1 year post-transplant. AEs and SAEs 
are to be reported as a change in medical status or medical history from time of signing of 
informed consent through first dose of study drug. In this study, the day 0 HCT is not 
considered an AE.
TEAEs will be defined as those that occurred after the first dose of study drug and within 
30 days of the last dose of study drug.
The coding dictionary for this study will be MedDRA. It will be used to summarize AEs by 
system organ class and preferred term.
Tables will include the following details:
●
Number of TEAEs
●
Number and percentage of subjects with TEAEs
●
Number and percentage of subjects with drug related TEAEs
●
Number of serious TEAEs


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●
Number and percentage of subjects with serious TEAEs
●
Number and percentage of subjects with TEAEs by NCI-CTCAE Version 4.03 scale. 
AEs will be summarized by their worst CTCAE grade
●
TEAEs that are deemed by the Investigator as local reactogenicity will be graded and 
summarized by their worst grade. The grading will be done using both the NCI-CTCAE 
Version 4.03 grading scale and in accordance with the FDA’s Guidance for Industry: 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials [Appendix 7]
●
Number of deaths
The number and percentage of subjects with TEAEs, as classified by system organ class and 
patient, as well as the number and percentage of subjects with at least 1 TEAE, will be 
summarized for each treatment group. Similar summaries will also be provided for drug 
related TEAEs, serious TEAEs, and TEAEs that lead to study discontinuation. A drug-related 
TEAE is defined as any TEAE with at least possible relationship to study treatment as 
assessed by the Investigator or with missing assessment of the causal relationship.  
Additionally, the following tables will be presented for AEs occurring any time after first 
dose of study drug during the primary study period:
●
Number and percentage of subjects with drug related AEs
●
Number of serious AEs
●
Number and percentage of subjects with serious AEs
●
Number and percentage of subjects with AEs by CTCAE scale. AEs will be summarized 
by their worst CTCAE grade
●
AEs that are deemed by the Investigator as local reactogenicity summarized by their 
worst grade 
●
Number of deaths
Lastly, the following tables will be presented for the Long-term Follow-up Period overall and 
by target month:
●
Number of deaths
●
Number of new or recurrent cancers
●
Number and percentage of subjects with new or recurrent cancers
●
Number of infections requiring hospitalization or resulting in death
●
Number and percentage of subjects with infections requiring hospitalization or resulting 
in death
●
Number of subjects with local erythema or induration at site of injection of study drug
●
Number and percentage of subjects with local erythema or induration at site of injection 
of study drug
The number and percentage of subjects completing each long-term follow-up period 
assessment will be presented by target month and treatment arm.


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7.6
Analysis of Pharmacokinetics
Pharmacokinetics will not be analyzed in this study.
7.7
Analysis of Pharmacogenomics
Samples will be collected and stored as described in [Appendix 19], Pharmacogenomics
Sub-study, for potential retrospective analysis.
7.8
Protocol Deviations and Other Analysis
Protocol deviations as defined in [Section 8.1.6] will be summarized for all randomized 
subjects by treatment group and total as well as by site. A data listing will be provided by site 
and subject.
The protocol deviation criteria will be uniquely identified in the summary table and listing. 
The unique identifiers will be as follows:
PD1- Entered into the study even though they did not satisfy entry criteria,
PD2- Developed withdrawal criteria during the study and was not withdrawn,
PD3- Received wrong treatment or incorrect dose,
PD4- Received excluded concomitant treatment.
7.9
Interim Analyses and Early Discontinuation of the Clinical Study
Futility analysis will be conducted during this study. Futility will be monitored based on the 
effect of ASP0113 on viremia (defined as a CMV plasma viral load ≥1000 IU/mL as assessed 
by the central laboratory).  It is believed that viremia is a surrogate of treatment effect. 
Futility analysis will be performed when the first 100 subjects have been randomized, and 
every 3 months thereafter until the total enrollment reaches 400 subjects. At each futility 
analysis, a Bayesian posterior probability that the hazard ratio for viremia of the ASP0113 
treatment group to the placebo treatment group will be less than 0.75 will be calculated.  The 
study may stop for futility if this posterior probability is less than 0.15. 
Futility analysis will be carried out by an external data analysis group. Sponsor personnel 
will not have access to unblinded interim analysis data during the study unless the futility 
criterion is met and the Sponsor needs to make a decision on discontinuing the trial.
7.9.1
DMC
A DMC, independent of the Sponsor and investigators, will be established to review the 
safety data throughout the study. The independent DMC statistician will have access to the 
randomization schedule. Unblinded deliverables for use by the DMC will be created by an 
independent data analysis center. The Sponsor will not have access to the unblinded tables 
and listings created for the DMC. All subjects who have been enrolled will be included in the 
DMC reviews and all data submitted to the DMC will remain blinded to Astellas personnel 
involved in the study.


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Further details of the futility assessments and DMC safety review are available in the SAP, 
the Interim Statistical Analysis Plan (IAP) and DMC charter.
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
In the analysis of the primary endpoint, subjects with unknown survival status will be 
assumed to have had the primary endpoint. Sensitivity analysis excluding those subjects from 
the denominator will be conducted. Other imputations of missing data will be considered 
based on the nature and quantity of missing data with appropriate statistical methods which 
will be fully specified prior to unblinding. Assignments of observations to visits for analyses 
by scheduled visit will be based on dates relative to date of transplantation. The details will 
be described in the SAP.
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS
8.1
Procedure for Clinical Study Quality Control
8.1.1
Data Collection
The Investigator or site designee is responsible to ensure that all data in the eCRFs and 
queries are accurate and complete and that all entries are verifiable with source documents. 
These documents are to be appropriately maintained by the site.
The Investigator or designee will enter data collected using an Electronic Data Capture 
system or data will be electronically transferred by an external vendor to Astellas’ clinical 
database (e.g., central lab data).  Data will be collected for all subjects who sign an ICF and 
are screened for the study, whether or not they are subsequently randomized.  For screening 
failures, minimal demographic data and reason for screening failure will be collected.
The monitor should verify the data in the eCRFs with source documents and confirm that 
there are no inconsistencies between them. 
For screen failures the minimum demographic data (i.e., sex, age, informed consent date) and 
reason for screen failure will be collected in the eCRF and the screen failure log if applicable.
8.1.2
Specification of Source Documents
Source data must be available at the site to document the existence of the study subjects and 
substantiate the integrity of study data collected. Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject.
The following information should be included in the source medical records:
●
Demographic data (date of birth, sex, race, ethnicity (USA only), height and body 
weight)
●
Inclusion and exclusion criteria details
●
Participation in study and signed and dated ICFs


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●
Visit dates
●
Medical history and PE details
●
Key efficacy and safety data as specified in the protocol
●
AEs and concomitant medication
●
Results of relevant examinations (e.g., ECG tracings, X-ray films etc.)
●
Laboratory printouts (if applicable)
●
Kit number assignment and dispensing and return of study drug details
●
Reason for premature discontinuation (if applicable)
●
Subject number
8.1.3
Clinical Study Monitoring
The Sponsor or delegated contract research organization (CRO) is responsible for monitoring 
the clinical study to ensure that subject's human rights, safety, and well-being are protected, 
that the study is properly conducted in adherence to the current protocol and GCP, and study 
data reported by the Investigator/sub-Investigator are accurate and complete and that they are 
verifiable with study-related records such as source documents. The Sponsor is responsible 
for assigning study monitor(s) to this study for proper monitoring. They will monitor the 
study in accordance with planned monitoring procedures.
8.1.4
Direct Access to Source Data/Documents
The Investigator and the study site must accept monitoring and auditing by the Sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities. 
In these instances, they must provide all study-related records, such as source documents 
(refer to [Section 8.1.2]) when they are requested by the Sponsor monitors and auditors, the 
IRB/IEC, or regulatory authorities. The confidentiality of the subject's identities shall be well 
protected and maintained in compliance with local and national regulations when the source 
documents are subject to direct access.
8.1.5
Data Management
Data management will be coordinated by the Global Data Science Department of the Sponsor
or designee in accordance with the SOPs for data management.  All study specific processes 
and definitions will be documented by Data Management in the Data Management Plan for 
the study.  The eCRF completion and correction processes will be referenced in the eCRF 
instructions. Coding of AEs and medical terms will be performed using MedDRA and World 
Health Organization dictionaries.
8.1.6
Protocol Deviations
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The Investigator is responsible for ensuring 
the study is conducted in accordance with the procedures and evaluations described in this 
protocol and must protect the rights, safety, and welfare of subjects. The Investigator should 
not implement any deviation from, or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to trial subjects.  


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A protocol waiver is a documented prospective approval of a request from an Investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited within Astellas.
For the purposes of this protocol, deviations requiring notification to Sponsor are defined as 
any subject who: 
●
Entered into the study even though they did not satisfy entry criteria. 
●
Developed withdrawal criteria during the study and was not withdrawn. 
●
Received wrong treatment or incorrect dose. 
●
Received excluded concomitant treatment. 
When a deviation from the protocol is identified for an individual subject, the Investigator or 
designee must ensure the Sponsor is notified. The Sponsor will follow-up with the 
Investigator, as applicable, to assess the deviation and the possible impact to the safety and/or 
efficacy of the subject to determine subject continuation in the study. 
If a deviation impacts the safety of a subject, the Investigator must contact Sponsor
immediately.
The Investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities criteria are documented and communicated appropriately. All documentation and 
communications to the IRB/IEC and applicable regulatory authorities will be provided to 
Astellas and maintained within the Trial Master File.  
NOTE:  Other deviations outside of the categories defined above that are required to be 
reported by the IRB/IEC in accordance with local requirements will be reported, as 
applicable.
8.1.7
End of Trial in All Participating Countries
The end of trial in all participating countries is defined as the last subject’s last visit.
8.2
Ethics and Protection of Subject Confidentiality
8.2.1
IRB / IEC / CA
GCP requires that the clinical protocol, any protocol amendments, the IB, the informed 
consent and all other forms of subject information related to the study (e.g., advertisements 
used to recruit subjects) and any other necessary documents be reviewed by an IEC/IRB. 
The IEC/IRB will review the ethical, scientific and medical appropriateness of the study 
before it is conducted.  IEC/IRB approval of the protocol, informed consent and subject 
information and/or advertising, as relevant, will be obtained prior to the authorization of drug 
shipment to a study site.
Any substantial amendments to the protocol will require IEC/IRB approval prior to 
implementation of the changes made to the study design at the site.  The Investigator will be 
required to submit, maintain and archive study essential documents according to ICH GCP.
Any SAEs that meet reporting criteria, as dictated by local regulations, will be reported to 
both responsible Ethics Committees and Regulatory Agencies, as required. During the 


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conduct of the study, the Investigator should promptly provide written reports (e.g., ICH 
Expedited Reports, and any additional reports required by local regulations) to the IEC/IRB, 
providing notice of any changes that affect the conduct of the study and/or increase the risk 
to subjects. Written documentation of the submission to the IEC/IRB should also be provided 
to the Sponsor.
If required by local regulations, the Investigator shall make accurate and adequate written 
progress reports to the IEC/IRB at appropriate intervals, not exceeding 1 year. The 
Investigator shall make an accurate and adequate final report to the IRB/IEC within 90 days 
after the close-out visit for Astellas sponsored studies, within 1 year after last subject out or 
termination of the study.
8.2.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki. 
8.2.3
Informed Consent of Subjects
8.2.3.1 Subject Information and Consent
The Investigator or his/her representative will explain the nature of the study to the subject or 
his/her guardian or legal representative, and answer all questions regarding this study.  Prior 
to any study-related screening procedures being performed on the subject, the informed 
consent statement will be reviewed and signed (specific to sites in Japan place a personal 
seal) and dated by the subject or his/her guardian or  legal representative, the person who 
administered the informed consent and any other signatories according to local requirements. 
A copy of the signed (specific to sites in Japan or sealed) informed consent form will be 
given to the subject and the original will be placed in the subject’s medical record. An entry 
must also be made in the subject’s dated source documents to confirm that informed consent 
was obtained prior to any study-related procedures and that the subject received a signed 
copy.
The signed/sealed consent forms will be retained by the Investigator and made available (for 
review only) to the study monitor, auditor, regulatory authorities and other applicable 
individuals upon request.
8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information
1.
The Investigator/sub-Investigator will immediately inform the subject orally whenever 
new information becomes available that may be relevant to the subject's consent or may 
influence the subject's willingness to continue participation in the study (e.g., report of 
serious ADRs). The communication must be documented in the subject's medical records, 
and it should be confirmed whether the subject is willing to remain in the study or not. 
2.
The Investigator must update the ICF and the updated ICF is submitted for approval to 
the IRB/IEC. The Investigator or his/her representative must obtain written informed 


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consent from the subject on all updated ICFs throughout their participation in the study. 
The Investigator or his/her designee must reconsent subjects with the updated ICF even 
if relevant information was provided orally. The subject and the Investigator or his/her 
representative who obtained the written informed consent should sign and date the ICF
(specific to sites in Japan: place a personal seal). A copy of the signed (specific to sites 
in Japan: or sealed) ICF will be given to the subject and the original will be placed in the 
subject’s medical record. An entry must be made in the subject’s records documenting 
the reconsent process.
8.2.4
Subject Confidentiality
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Such medical information may be 
given only after approval of the subject to the subject's physician or to other appropriate 
medical personnel responsible for the subject's well-being.
The Sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons.
The Sponsor affirms the subject's right to protection against invasion of privacy. Only a 
subject identification number and/or initials (if not prohibited by local regulations) will 
identify subject data retrieved by the Sponsor. However, the Sponsor requires the 
Investigator to permit the Sponsor, Sponsor's representative(s), the IRB/IEC and when 
necessary, representatives of the regulatory health authorities to review and/or to copy any 
medical records relevant to the study.
The Sponsor will ensure that the use and disclosure of protected health information (PHI) 
obtained during a research study complies with the federal and/or regional legislation related 
to the privacy and protection of personal information (e.g., HIPAA for U.S. sites).
For US sites, the HIPAA Privacy Rule provides federal protection for the privacy of PHI by 
implementing standards to protect and guard against the misuse of individually identifiable 
health information of subjects participating in Sponsored clinical trials. "Authorization" is 
required from each research subject, i.e. specific permission granted by an individual to a 
covered entity for the use or disclosure of an individual's PHI. A valid authorization must 
meet the implementation specifications under the HIPAA Privacy Rule. Authorization may 
be combined into the Informed Consent document (approved by the IRB/IEC) or it may be a 
separate document [approved by the IRB/IEC or designated privacy board (PB)] or provided 
by the Investigator or Sponsor (without IRB/IEC or PB approval). It is the responsibility of 
the Investigator and institution to obtain such waiver/authorization in writing from the 
appropriate individual.
For sites in Japan:
All individuals and organizations involved in the study must pay very careful attention to 
protect subjects' privacy with appropriate measures, for example, by prohibiting the use of any 


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private information that may identify a subject (e.g., name or address). These details shall be 
processed in accordance with the applicable local and regional laws.
Even though any individuals involved in the study, including the Sponsor monitors and 
auditors, may get to know matters related to subjects' privacy due to direct access to source 
documents, or from other sources, they may not leak the content to third parties.
8.3
Administrative Matters
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the IB and other pertinent information is confidential and remains the property of the 
Sponsor. Details should be disclosed only to the persons involved in the approval or conduct 
of the study. The Investigator may use this information for the purpose of the study only. It is 
understood by the Investigator that the Sponsor will use the information obtained during the 
clinical study in connection with the development of the drug and therefore may disclose it as 
required to other clinical investigators or to regulatory agencies. In order to allow for the use 
of the information derived from this clinical study, the Investigator understands that he/she 
has an obligation to provide the Sponsor with all data obtained during the study.
The study will be considered for publication or presentation at (scientific) symposia and 
congresses. The Investigator will be entitled to publish or disclose the data generated at their 
respective study site only after submission to the Sponsor all transcripts, texts of 
presentations, and abstracts related to the study at least (for sites in Japan: 90 days prior to
the intended submission for publication or any other disclosure studies, or) 30 days prior to 
the intended submission for publication or any other disclosure studies for APGD-Sponsored 
studies. This is necessary to confirm whether any inventive knowledge should be protected 
by a patent or not and to prepare and file a patent application accordingly. In addition this is 
in no way intended to restrict publication of facts or opinions formulated by the Investigator. 
The Sponsor will inform the Investigator in writing of any objection or question arising 
within 30 days of receipt of the proposed publication material.
For sites in Japan: After agreement between investigator(s) and Sponsor, the manuscript is 
free for publication.
8.3.2
Documents and Records Related to the Clinical Study
The Sponsor will provide the Investigator and/or institution with the following:
●
Study protocol (and amendments, as applicable)
●
IB (and amendments, as applicable)
●
CRFs and SAE Report Worksheet 
●
Study drug with all necessary documentation
●
Study contract
●
For sites in Japan: JUTOKUNA YUUGAIJISHOU HOUKOKUSHO


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In order to start the study, the Investigator and/or study site is required to provide the 
following documentation to the Sponsor: 
●
Financial disclosure in compliance with US federal regulation 21CFR Part 54.
●
Signed Investigator's Statement in this protocol.
●
Executed Research Agreement.
●
Signed and dated FDA form 1572.
●
Copy of the approved ICF and separate authorization form, if appropriate.
●
IEC/IRB approval of the protocol, protocol amendments (if applicable) and ICF (and 
separate authorization form, if appropriate), stating clearly the Sponsor's name, study 
number and study drug, including a membership list with names and qualifications.
●
Current Curricula Vitae of all investigators (signed and dated).
●
Laboratory normal reference ranges (if applicable, signed and dated by the responsible 
laboratory employee).
●
Medical/Laboratory/Technical procedures/tests certifications or accreditations or 
established quality control or other validation, where required.
●
List of sub-Investigators and collaborators (Japan sites only)
●
Instruction and decision of the head of the study center (Japan sites only)
At the end of the study, the Sponsor is responsible for the following:
●
Collection of and/or destruction of unused CRFs and other study documentation.
●
Ensuring destruction of unused study drug
The Investigator will archive all study data (e.g., Subject Identification Code List, source 
data, CRFs, and Investigator's File) and relevant correspondence.  These documents are to be 
kept on file for the appropriate term determined by local regulation (for US sites, 2 years 
after approval of the NDA or discontinuation of the IND). 
For countries except Japan: The Sponsor will notify the site/Investigator if the 
NDA/MAA/J-NDA is approved or if the IND/IMPD/CHIKEN TODOKE is discontinued.  
The Investigator agrees to obtain the Sponsor's agreement prior to disposal, moving, or 
transferring of any study-related records. The Sponsor will archive and retain all documents 
pertaining to the study according to local regulations.
Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes. All data will be entered on eCRFs supplied for 
each subject.
For sites in Japan only:
The records to be retained at the study centers are the ones listed as essential documents in 
GCP. These records shall be retained by the head of the study center or the record keeper 
designated by the head until notice issued by the Sponsor on completion of the retention period 
is received. These documents are also subject to direct access and should be provided upon 
request from the Sponsor or regulatory authorities.


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The head of the study center will retain the essential documents that should be stored at the 
study center in an appropriate manner according to the rules of the study center concerned until 
the date defined in 1. or 2. below, whichever comes later.
1. Approval date of marketing of the test drug (if development of the drug is discontinued, until 
3 years after the decision to discontinue development is notified)
2. Until 3 years after discontinuation or termination of the study.
8.3.3
Protocol Amendment and/or Revision
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments: substantial amendments and/or non-substantial amendments. 
Depending on the nature of the amendment, either IRB/IEC Competent Authority approval or 
notification is required. The changes will become effective only after the approval of the 
Sponsor, the Investigator, the regulatory authority (except sites in Japan), and the IRB/IEC (if 
applicable). (Unique to sites in Japan: followed by the approval of the head of the study site).
Amendments to this protocol must be signed by the Sponsor and the Investigator. Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented 
which affects subject safety or the evaluation of safety, and/or efficacy. Modifications to the 
protocol that are administrative in nature do not require IRB/IEC approval, but will be 
submitted to the IRB/IEC for their information, if required by local regulations.
If there are changes to the ICF, written verification of IRB/IEC approval must be forwarded 
to the Sponsor. An approved copy of the new ICF must also be forwarded to the Sponsor.
8.3.4
Insurance of Subjects and Others (FOR JAPAN SITES ONLY)
If a subject suffers any study-related injury, the Sponsor will compensate appropriately 
according to the severity and duration of the damage. However, if it was caused intentionally 
or was due to gross negligence by the study center, the Sponsor will consult with the study 
center about handling the injury, based on the agreed study contract.
Compensation for study-related injury is provided by the following procedures:
1.
If a subject incurs an injury as a result of participation in the clinical study, the study 
center should provide medical treatment and other necessary measures. The Sponsor 
should be notified of the injury.
2.
When the subject claims compensation from the study center for the above study-related 
injury, or such compensation may be claimed, the study center should immediately 
communicate the fact to the Sponsor. Both parties should work together towards 
compensation settlement.
3.
The Sponsor shall pay compensation or indemnification and bear expenses necessary for 
the settlement as provided in the clinical contract.
4.
The Sponsor shall make an arranging for insurance and take measures necessary to 
ensure the compensation or indemnification mentioned above.


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8.3.5
Signatory Investigator for Clinical Study Report
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study report 
which forms part of a marketing authorization application be signed by the representative for 
the Coordinating Investigator(s) or the Principal Investigator(s). The representative for the 
Coordinating Investigator(s) or Principal Investigator(s) will have the responsibility to review 
the final study results to confirm to the best of his/her knowledge it accurately describes the 
conduct and results of the study. The representative for Coordinating Investigator(s) or 
Principal Investigator(s) will be selected from the participating Investigators by the Sponsor
prior to database lock.
9
QUALITY ASSURANCE
The Sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that trials are conducted and data are generated, documented 
(record), and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s).
The Sponsor or Sponsor's designee may arrange to inspect/audit the clinical study at any or 
all investigational sites. The auditor is independent from the clinical monitoring and project 
management team at the Sponsor. The audit may include on-site review of regulatory 
documents, case report forms, and source documents. Direct access to these documents will 
be required by the auditors.
10
STUDY ORGANIZATION
10.1
Data Monitoring Committee (DMC) 
A DMC external from the Sponsor will be chartered to oversee safety issues and to assess the 
quality of the trial conduct. The DMC will consist of independent reviewers who are not 
directly involved in the conduct of the study. For additional details of the DMC refer to 
[Section 7.9.1] and the study DMC Charter. 
10.2
Adjudication Committee
An AC external from the Sponsor will be charted to adjudicate all subjects for cases of CMV 
EOD, initiation of CMV-specific AVT, and cause of death. The AC will consist of a 
multidisciplinary group of independent clinician-scientists who are not directly involved in 
the conduct of the study. For details of the committee refer to the study AC Charter.
10.3
Other Study Organization
10.3.1
Home Healthcare 
For sites in applicable regions, laboratory draws for central laboratory testing and collection 
of subject local reactogenicity diaries may be performed by qualified staff from the 
designated home healthcare agencies for the study.  


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REFERENCES
Available upon request
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marrow transplantation for myelodysplastic syndromes: outcome analysis in 510 transplants 
facilitated by the National Marrow Donor Program. Blood. 2002;99:1943-51.
Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Revised 
recommendations of the international working group for diagnosis, standardization of response 
criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid 
leukemia. J Clin Oncol. 2003;21(24):4642-9.
Cornelissen JJ, Carston M, Kollman C, King R, Dekker AW, Löwenberg B, et al. Unrelated marrow 
transplantation for adult patients with poor-risk acute lymphoblastic leukemia: strong graft-
versus-leukemia effect and risk factors determining outcome. Blood. 2001;97:1572-7.
Craddock C, Szydlo RM, Dazzi F, Olavarria E, Cwynarski K, Young A et al. Cytomegalovirus 
seropositivity adversely influences outcome after T-depleted unrelated donor transplant in 
patients with chronic myeloid leukemia:  the case for tailored graft-versus-host disease 
prophylaxis. Br J Haematol. 2001;112:228-36.
Craddock C, Labopin M, Pillai S, Finke J, Bunjes D, Greinix H, et al. Factors predicting outcome 
after unrelated donor stem cell transplantation in primary refractory acute myeloid leukemia. 
Leukemia. 2011;25:808-13.
Doney K, Hagglund H, Leisenring W, Chauncey T, Appelbaum FR, and Storb R. Predictive factors 
for outcome of allogeneic hematopoietic cell transplantation for adult acute lymphoblastic 
leukemia. Biol. Blood Marrow Transp. 2003;9:472-81.


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Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National institutes of health 
consensus development project on criteria for clinical trials in chronic graft-versus-host disease:  
1. diagnosis and staging working group report. Biology of Blood and Marrow Transplantation 
2005;11:945-55.  
Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, et al. Clinical manifestations of 
graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. 
Transplantation. 1974;18:295-304.
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” issued by 
FDA on July 2009.
Guidance for Industry titled “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials” issued by FDA on September 2007.  
Gyulai Z, Endresz V, Burian K, Pincus S, Toldy J, Cox WI, et al. Cytotoxic T lymphocyte (CTL) 
responses to human cytomegalovirus pp65, IE1-Exon4, gB, pp150, and pp28 in healthy
individuals: reevaluation of prevalence of IE1-specific CTLs. J Infect Dis. 2000;181:1537-46.
Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer, in Macleod 
CM (ed): Evaluation of Chemotherapeutic Agents. New York, Columbia University Press, 
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Kern F, Bunde T, Faulhaber N, Kiecker F, Khatamzas E, Rudawski IM, et al. Cytomegalovirus (CMV) 
phosphoprotein 65 makes a large contribution to shaping the T cell repertoire in CMV-exposed
individuals. J Infect Dis. 2002;185:1709-16.
Kharfan-Dabaja MA, Boeckh M, Wilck MB, Langston AA, Chu AH, Wloch MK, et al. A novel 
cytomegalovirus DNA vaccine in allogeneic haemopoietic stem-cell transplantation: a 
randomized, double-blind, placebo-controlled phase 2 trial. The Lancet Infectious Diseases. 
2012;12:290-9. Corrections in 2013;13:12. 
Kroger N, Zabelina T, Kruger W, Renges H, Stute N, Schrum J et al. Patient cytomegalovirus 
seropositivity with or without reactivation is the most important prognostic factor for survival 
and treatment-related mortality in stem cell transplantation from unrelated donors using 
pretransplant in vivo T-cell depletion with anti-thmocyte globulin. Br J Haematol. 
2001;113:1060-71.
Kumar D, Humar A. The AST handbook of transplant infections. 2011.
Larsson K, Aschan J, Remberger M, Ringden O, Winiarski J, Ljungman P. Reduced risk for extensive 
chronic graft-versus-host disease in patients receiving transplants with human leukocyte 
antigen-identical sibling donors given polymerase chain reaction-based preemptive therapy 
against cytomegalovirus. Transplantation. 2004;77:526-31.
Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant 
recipients. Clinical Infectious Diseases. 2002;34:1094-7.
McGlave PB, Shu XO, Wen W, Anasetti C, Nademanee A, Champlin R, et al. Unrelated donor 
marrow transplantation for chronic myelogenous leukemia:  9 years’ experience of the national 
marrow donor program. Blood. 2000;95:2219-25.
Mocarski ES, Jr. Immunomodulation by cytomegaloviruses: manipulative strategies beyond evasion. 
Trends Microbiol. 2002;10:332-9.


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Nichols WG, Corey L, Gooley T, Davis C, Boeckh M. High risk of death due to bacterial and fungal 
infection among cytomegalovirus (CMV)-seronegative recipients of stem cell transplants from 
seropositive donors: evidence for indirect effects of primary CMV infection. J Infect Dis. 
2002;185:273-82.
Pasquini MC, Wang Z. Current uses and outcome of hematopoietic stem cell transplantation: CIBMTR 
Summary Slides, 2009.
Passamonti F, Cervantes F, Vannucchi AM, Morra E, Rumi E, Pereira A, et. al. A dynamic prognostic 
model to predict survival in primary myelofibrosis:  a study by the IWG-MRT (International 
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2010;115:1703-8.
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conference on acute GVHD grading. BMT. 1995;15:825-28.
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international prognostic scoring system for myelofibrosis predicts outcomes after hematopoietic 
cell transplantation. Blood. 2012;119:2657-64.
Sorror ML, Maris MB, Storb R, Baron F, Sandmaier MB, Maloney DG, et al. Hematopoietic cell 
transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before 
allogeneic HCT. Blood. 2005;106:2912-9.
Sorror, ML. How I assess comorbidities before hematopoietic cell transplantation. Blood. 
2013;121:2854-63.
Srinivasan A, Wang C, Srivastava DK, Burnette K, Shenep JL, Leung W, et al. Timeline, 
epidemiology and risk factors for bacterial, fungal and viral infections in children and 
adolescents after allogeneic hematopoietic stem cell transplant. Bio Blood Marrow Transplant. 
2012:1-8.
Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, et al. Guidelines for preventing 
infectious complications among hematopoietic cell transplantation recipients: A global 
perspective. Biol Blood Marrow Transplant. 2009;15:1143-238.
Wills MR, Carmichael AJ, Mynard K, Jin X, Weekes MP, Plachter B, et al. The human cytotoxic T-
lymphocyte (CTL) response to cytomegalovirus is dominated by structural protein pp65:  
frequency, specificity, and T-cell receptor usage of pp65-specific CTL. J Virol. 1996;70:7569-79.
Wingard JR, Carter SL, Walsh TJ, Kurtzberg J, Small TN, Baden LR, et al. Randomized double-blind 
trial of fluconazole versus voriconazole for prevention of invasive fungal infection after 
allogeneic hematopoietic cell transplantation. Blood. 2010;116:5111-8.
Wloch MK, Smith LR, Boutsaboualoy S, Reyes L, Han C, Kehler J, et al. Safety and Immunogenicity 
of a Bivalent Cytomegalovirus DNA Vaccine in Healthy Adult Subjects. JID. 2008;197:1634-42.  
Yakoub-Agha I, Mesnil F, Kuentz M, Boiron JM, Ifrah N, et al. Allogeneic marrow stem-cell 
transplantation from human leukocyte antigen-identical siblings versus human leukocyte 
antigen-allelic-matched unrelated donors (10/10) in patients with standard-risk hematologic 
malignancy:  A prospective study from the French Society of Bone Marrow Transplantation 
and Cell Therapy. J Clin Onc. 2006;24:5695-702.
Company Reports:
ASP0113 Investigator’s Brochure


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12
APPENDICES
12.1
Appendix 1:  Laboratory Tests
Central Laboratory Testing
Laboratory Test
Visit
Parameters to be Analyzed
CMV Plasma Viral Load
Weekly (days 0-100)
Every other week (days 
101-180)
Every 30 days (days 181-
365)
●
Cytomegalovirus (CMV) plasma viral load
Hematology
V2, V5-V12, including 
safety follow-up time 
points for doses 4 & 5
●
Red blood cells
●
White blood cells (total leukocytes)
●
Hemoglobin
●
Hematocrit
●
Platelets (thrombocytes)
●
Neutrophils (ANC)
●
Eosinophils
●
Basophils
●
Lymphocytes
●
Monocytes
●
Blast cells
Biochemistry
V2, V5-V12, including 
safety follow-up time 
points for doses 4 & 5
●
Sodium
●
Potassium
●
Calcium
●
Chloride
●
Glucose
●
Creatinine
●
Creatine phosphokinase (CPK)/Creatine kinase 
(CK)
●
Total protein
●
Albumin
Hepatic Profile
V2, V5-V12, including 
safety follow-up time 
points for doses 4 & 5
●
Total bilirubin
●
Direct bilirubin
●
Alkaline Phosphatase
●
Aspartate aminotransferase
●
Alanine aminotransferase (ALT)
Immunogenicity
V2, V5, V8, V9, V11 & 
V14
●
gB-specific antibody levels
●
T-cell responses to phosphoprotein 65
Pharmacogenomics (PGx) 
– optional – saliva
V2
●
Genomic analyses


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12.1
Appendix 1:  Laboratory Tests continued
Local Laboratory Testing
Laboratory Test
Visit
Parameters to be Analyzed
CMV Screening
Screening (V1)
●
CMV antibody assay
CMV Plasma Viral Load
As allowed per protocol
●
CMV plasma viral load
Urine or Serum Pregnancy 
Test (all females of 
childbearing potential and 
all females who are of 
non-childbearing potential 
but are < 50 years of age 
and not documented to be 
surgically sterile)
V1, V2, V5, V7, V9, 
V11, V13 & V14
●
Human Chorionic Gonadotropin (hCG)
Platelet Count
V2, V5, V7, V9 & V11
●
Platelet count
Hematology
Screening (V1)
●
Red blood cells
●
White blood cells (total leukocytes)
●
Hemoglobin
●
Hematocrit
●
Platelets (thrombocytes)
●
ANC 
●
Eosinophils
●
Basophils
●
Lymphocytes
●
Monocytes
●
Blast cells
Biochemistry
Screening (V1)
●
Sodium
●
Potassium
●
Calcium
●
Chloride
●
Glucose
●
Creatinine
●
CPK/CK
●
Total protein
●
Albumin
Hepatic Profile
Screening (V1)
●
Total bilirubin
●
Direct bilirubin
●
Alkaline Phosphatase
●
ALT
●
AST


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12.2
Appendix 2:  Definition of CMV Disease
Disease type
Definition
CMV pneumonia
Signs and/or symptoms of pulmonary disease combined with the detection of 
cytomegalovirus (in BAL fluid*) or lung tissue samples performed by virus 
isolation, histopathologic testing, immunohistochemical analysis, or in situ 
hybridization  
(The presence of fungal copathogens such as Aspergillus species, together with 
radiologic signs typical of Aspergillus pneumonia [e.g., a halo sign or a crescent 
sign] indicates fungal pneumonia rather than CMV pneumonia)
CMV gastrointestinal 
disease
Combination of clinical symptoms from the upper or lower gastrointestinal tract, 
findings of macroscopic mucosal lesions on endoscopy, and demonstration of
CMV infection (by culture, histopathologic testing, immunohistochemical 
analysis, or in situ hybridizations) in a gastrointestinal tract biopsy specimen. If 
CMV is detected in normal mucosa near a lesion consistent with those typical of 
CMV infection, this can be accepted as CMV gastrointestinal disease.
CMV hepatitis
Elevated bilirubin and/or enzyme levels during liver function testing, absence 
of other documented cause of hepatitis, and detection of CMV infection (by 
culture, histopathologic testing, immunohistochemical analysis, or in situ 
hybridization) in a liver biopsy specimen. Other pathogens, such as hepatitis C 
virus, may be present without excluding the diagnosis of CMV hepatitis.
CMV CNS disease
CNS symptoms together with the detection of CMV in cerebrospinal fluid 
samples, by culture or PCR, or in brain biopsy specimens, by culture, 
histopathologic testing, immunohistochemical analysis, or in situ hybridization.
CMV retinitis
Lesions typical of CMV retinitis must be confirmed by an ophthalmologist or as 
confirmed by detection of CMV in vitreous fluid by culture or PCR.
CMV nephritis
CMV infection (by culture, immunohistochemical analysis, or in situ 
hybridization) together with the identification of histologic features of CMV 
infection in a kidney biopsy specimen obtained from a patient with renal 
dysfunction.  Detection of CMV in the urine of a patient with kidney dysfunction 
does not fulfill the definition of CMV nephritis.
CMV cystitis
CMV infection (by culture, immunohistochemical analysis, or in situ 
hybridization) together with the identification of conventional histologic features 
of CMV infection in a bladder biopsy specimen obtained from a patient with 
cystitis. Detection of CMV in urine combined with identification of symptoms 
does not fulfill the definition of CMV cystitis.
CMV myocarditis
CMV infection (by culture, immunohistochemical analysis, or in situ 
hybridization) together with the identification of conventional histologic features 
of CMV infection in a heart biopsy specimen obtained from a patient with 
myocarditis.  
CMV pancreatitis
CMV infection (by culture, immunohistochemical analysis, or in situ 
hybridization) together with the identification of conventional histologic features 
of CMV infection in a pancreatic biopsy specimen obtained from a patient with 
pancreatitis.  
Other CMV disease 
categories
Definitions for additional disease categories include the presence of compatible 
symptoms and signs and documentation of CMV by biopsy with other relevant 
causes excluded.
BAL: bronchoalveolar lavage; CMV: cytomegalovirus; CNS: central nervous system; PCR: polymerase chain 
reaction
*Whenever a BAL is performed, fluid should be collected and a sample will be stored at the central laboratory. 
Reference:  
Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients.  
Clinical Infectious Diseases. 2002;34:1094-7.


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12.3
Appendix 3: Common Serious Adverse Events and Endpoint Events
The following is a list of serious adverse events (SAEs) that the Sponsor considers to be 
associated with the disease state being studied. The list does NOT change your reporting 
obligations or prevent the need to report an adverse event meeting the definition of an 
SAE as detailed in [Section 5.5.3] Definition of Serious Adverse Event (SAE). The purpose 
of this list is to alert you that some events reported as SAEs may not require expedited reporting 
to the regulatory authorities based on the classification of “common serious adverse 
events”. You are required to follow the requirements detailed in [Section 5.5.6] Reporting of 
Serious Adverse Events (SAE).
For an investigational new drug (IND) safety reporting, single occurrences of the following 
events may be excluded from expedited reporting to the regulatory agencies (e.g., the FDA). 
If aggregate analysis of these events indicates that they occur more frequently with study drug, 
an expedited IND safety report may be submitted to the regulatory agencies.  
●
Anemia
●
Leukopenia
●
Lymphopenia
●
Neutropenia and febrile neutropenia
●
Thrombocytopenia
●
Pancytopenia
●
Cholestatic liver disease
●
Sinusoidal obstruction syndrome (Hepatic veno-occlusive disease)
●
Abnormal LFTs
●
Relapse of primary malignancy or disease
●
The following protocol-defined clinical endpoint events as reported by the Investigator, 
including those with a fatal outcome:

CMV infection and CMV diseases including but may not be limited to those listed 
in [Appendix 2] 

GVHD (any grade), acute or chronic, including liver involvement


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12.4
Appendix 4: Protocol Defined Definitions of Comorbidities for the 
HCT-Comorbidity Index  
Comorbidity
Definition
Modified HCT-
CI Weighted 
Score
Arrhythmia
Atrial fibrillation or flutter, sick sinus syndrome, or ventricular 
arrhythmias
1
Cardiac*
Coronary artery disease,§ congestive heart failure, myocardial 
infarction, or ejection fraction (EF) < 50%
1
Inflammatory Bowel 
Disease
Crohn’s disease or ulcerative colitis
1
Diabetes
Requiring treatment with insulin or oral hypoglycemic but not 
diet alone
1
Cerebrovascular disease
Transient ischemic attack or cerebrovascular accident
1
Psychiatric disturbance
Unstable depression or anxiety condition that the Investigator 
believes will interfere with protocol requirements, including 
compliance with long-term follow-up.
1
Hepatic, mild
Chronic hepatitis, bilirubin > ULN to 1.5 X ULN, or 
AST/ALT > ULN to 2.5 X ULN
1
Obesity
Patients with a body mass index > 35 kg/m2
1
Infection
Requiring continuation of antimicrobial treatment after Day 0
1
Rheumatologic
Systemic lupus erythematosus (SLE), rheumatoid arthritis 
(RA), polymyositis, mixed connective tissue disease (CTD), or 
polymyalgia rheumatic
2
Peptic Ulcer
Requiring treatment
2
Moderate/severe renal**
Serum creatinine > 2 mg/dL, on dialysis, or prior renal 
transplantation
2
Moderate pulmonary*
Diffusion capacity of carbon monoxide (DLco) and/or FEV1
66%-80% or dyspnea on slight activity
2
Prior solid tumor
Treated at any time point in the patient’s past history, 
excluding nonmelanoma skin cancer
3
Heart valve disease
Except mitral valve prolapsed
3
Severe pulmonary*
DLco and/or FEV1 < 65% or dyspnea at rest or requiring 
oxygen
3
Moderate/severe hepatic
Liver cirrhosis, bilirubin > 1.5 X ULN, or AST/ALT > 2.5 X 
ULN
3
*Pulmonary function tests (PFTs), multi gated acquisition scans (MUGAs), and/or echocardiograms performed 
within 6 months (180 days) prior to Screening may be used for scoring pulmonary and cardiac comorbidities.
**When assessing Renal function, to convert creatinine from micromoles per liter (Umole/L) to milligrams per 
deciliter (mg/dL), divide micromoles per liter by 88.4 (Umole/L ÷ 88.4 = mg/dL).
The definitions for each comorbidity based on definitions published by Sorror in 2013 are provided below:


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Arrhythmia (score 1): Any type of arrhythmia that has necessitated the delivery of a specific anti-arrhythmia 
treatment at any time in the patient’s past medical history.  A score is assigned even if the patient was in normal 
sinus rhythm at the time of data acquisition or at the landmark date.  
No score is assigned to transient arrhythmias that never required treatment.
Cardiovascular Comorbidity (score 1):  Assigned for cardiovascular comorbidity in the presence of 1 or more 
of the following 3 presentations:
1.
Coronary artery disease:  This is based on the presence of a documented diagnosis of chronic exertional 
angina, unstable angina, or myocardial infarction at any point the patient’s past medical history.  
Information on prior placement of a coronary stent or undergoing a coronary artery bypass graft surgery 
should support coding this comorbidity.
2.
Congestive heart failure: At any time in the patient’s medical history, symptoms/signs of congestive heart 
failure (e.g., an exertional or paroxysmal nocturnal dyspnea) that later responded to diuretics, afterload-
reducing agents, B-blocker, and/or digitalis.
3.
Low Ejection Fraction (EF).  Patients with an EF of 50% or lower as determined by an echocardiogram or 
a multigated acquisition scan. 
This should be from the most recent measurements.
Inflammatory bowel disease (score 1): The presence of documented prior diagnosis (history of an endoscopic 
examination of the mucosa with or without confirmatory histology and radiologic findings) of Crohn’s disease 
or ulcerative colitis requiring treatment at any time in the patient’s past medical history.
Diabetes (score 1):  Diagnosis of diabetes or steroid-induced hyperglycemia requiring continuous treatment 
with insulin or oral hypoglycemic drugs within 4 weeks prior to screening.
Cerebrovascular disease (score 1): A prior diagnosis of transient ischemic attack, subarachnoid hemorrhage, 
or cerebral thrombosis, embolism, or hemorrhage at any time in the past medical history.
Psychiatric disorder (score 1): Unstable depression or anxiety condition that the Investigator believes will 
interfere with protocol requirements, including compliance with long-term follow-up*
Hepatic comorbidity (score 2 levels of severity):  The safety laboratories obtained at screening should be 
used to assess this score.  
1.
Mild hepatic comorbidity (score 1):  The presence of 1 or more of the following 3 clinical 
presentations: (1) elevated total bilirubin to a value higher than the upper limit of normal (ULN) and up to 
1.5 times the ULN. (2) elevated values of alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) to values higher than the ULN and up to 2.5 times the ULN; or (3) a prior diagnosis of an infection 
with hepatitis B or C at any time in the patient’s past medical history.
2.
Moderate to severe hepatic comorbidity (score 3): The presence of 1 or more of the following 3 
clinical presentations: (1) elevated values of total bilirubin to a level higher than 1.5 times the ULN; (2) 
elevated values of ALT or AST to levels higher than 2.5 times the ULN or (3) a documented diagnosis of 
liver cirrhosis at any time in the patient’s past medical history.
Obesity (score 1):  A body mass index higher than 35.00 kg/m2
Infection (score 1):  The presence of 1 or more of the following 4 clinical presentations at screening: (1) a 
documented infection (e.g., by culture or biopsy); (2) fever of unknown origin; (3) pulmonary nodules 
suspicious for fungal pneumonia; (4) a requirement for prophylaxis against tuberculosis.
Table continued on next page


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Rheumatologic comorbidity (score 2):  The presence of a documented prior diagnosis of an autoimmune 
rheumatologic disease that has required administration of a specific treatment at any time in the patient’s past 
medical history.  Diagnosis include systemic lupus erythematosus, rheumatoid arthritis, Sjogren’s syndrome, 
scleroderma, polymyositis, dermatomyositis, mixed connective tissue disease, polymylagia rheumatic, 
polychondritis, sarcoidosis and vasculitis syndromes.  It does not include degenerative joint disease 
(osteoarthritis) or other musculoskeletal injuries.
Peptic ulcer (score 2): The presence of a prior endoscopic or radiologic diagnosis of gastric or duodenal ulcer 
at any point in the patient’s past medical history.
Renal comorbidity (score 2): The creatinine from the safety laboratories obtained at screening should be used 
to assess this score. 
The presence of 1 or more of the following 3 presentations: (1) elevated values of serum creatinine to more than 
2 mg/dL or more than 176.8 umol/L; (2) chronic renal disease requiring weekly dialysis within 4 weeks of 
screening; (3) a documented prior history of renal transplantation at any point in the patient’s past medical 
history.
Pulmonary comorbidity (score 2 different levels of severity): The diffusing lung capacity of carbon 
monoxide (DLco) should be corrected for the concurrent hemoglobin.  The most recent set of pulmonary 
function test (PFTs) are to be used for criteria using DLco and forced expiratory volume (FEV1).
1.
Moderate pulmonary comorbidity (score 2):  The presence of 1 or more of the following 3 clinical 
presentations: (1) a corrected percentage of DLco in the range of 66% to 80%; (2) a percentage of FEV1 
in the range of 66% to 80%; (3) shortness of breath on slight activity that is attributed to a pulmonary 
disease and cannot be corrected by blood transfusion for a noticeable anemia within 2 weeks of screening.
2.
Severe pulmonary comorbidity (score 3):  The presence of 1 or more of the following 4 clinical 
presentations: (1) a corrected percentage of DLco of 65% or less; (2) a percentage of FEV1 of 65% or 
less; (3) shortness of breath at rest that is attributed to a pulmonary disease and cannot be corrected by 
blood transfusion for a noticeable anemia within 2 weeks prior to screening; (4) the need for intermittent 
or continuous oxygen supplementation within 4 weeks of screening.
Prior malignancy (score 3): The presence of a prior diagnosis of any malignancy that required receiving a 
specific treatment  at any point in the patient’s past medical history except for the malignancy for which the 
patient is receiving the hematopoietic cell transplant (HCT).  Patients with a prior malignancy from the same 
lineage of cells of the current malignancy should not be assigned a score for this comorbidity (e.g., if a subject 
had a diagnosis of non-Hodgkin lymphoma that was preceded by Hodgkin lymphoma or if a patient had a 
diagnosis of an acute myeloid leukemia that was preceded by myelodysplastic syndrome).  
Basal cell carcinomas and squamous cell carcinoma of the skin should not be assigned a score for this 
comorbidity.
Heart valve disease (score 3): The most recent echocardiogram, if performed, obtained should be used to 
score this comorbidity.
The presence of 1 or more of the following 3 clinical presentations: (1) at least a moderate or severe degree of 
valve stenosis or insufficiency, as determined by echocardiogram; (2) prosthetic mitral or aortic valve; (3) 
symptomatic mitral valve prolapse. 
Reference:  
Sorror ML, Maris MB, Storb R, Baron F, Sandmaier MB, Maloney DG, et al. Hematopoietic cell transplantation (HCT)-
specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood.. 2005;106:2912-19.
Sorror, ML. How I assess comorbidities before hematopoietic cell transplantation. Blood. 2013;121;2854-63.


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12.5
Appendix 5: Dynamic International Prognostic Scoring System for 
Survival in Primary Myelofibrosis
Value
Prognostic Variable
0
1
2
Age, y
≤65
> 65
White blood cell count , X109/L
≤25
> 25
Hemoglobin, g/dL
≥10
< 10
Peripheral blood blast, %
< 1
≥1
Constitutional symptoms, Y/N
N
Y
The risk category is obtained by adding up the values of each prognostic variable. Risk 
categories are defined as:
●
Low: 0
●
Intermediate-1: 1 or 2
●
Intermediate-2: 3 or 4
●
High: 5 or 6.
Reference: 
Passamonti F, Cervantes F, Vannucchi AM, Morra E, Rumi E, Pereira A, et al. A dynamic prognostic 
model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International 
Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood.
2010;115:1703-08.


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12.6
Appendix 6:  Definition of Morphologic Complete Remission
Complete remission will be defined as all of the following according to the revised 
recommendations of the international working group:
1.
A bone marrow aspirate containing spicules with < 5% blasts with a count of at least 
200 nucleated cells and no Auer rods seen. If spicules are absent in the aspirate, a bone 
marrow biopsy should confirm that < 5% blasts are present.
2.
No evidence of a persistently abnormal leukemic population by flow cytometry, if 
performed†.
3.
Absolute neutrophil count > 1000/µL and platelet count > 100000/µL.
4.
No extramedullary leukemia.
5.
No blasts in peripheral blood.
†: If a result of flow cytometry is available, complete remission needs to be confirmed based all criteria 
including No.2. Otherwise, complete remission will be evaluated per the above criteria except for No.2.
Reference:  
Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Revised 
recommendations of the international working group for diagnosis, standardization of response 
criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid 
leukemia. J Clin Oncol. 2003; 21(24): 4642-9.


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12.7
Appendix 7:  Grading of Reactogenicity
Local Reaction
To Injectable 
Product
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially
Life -Threatening
(Grade 4)
Pain 
Does not interfere 
with activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency room 
(ER) visit or 
hospitalization 
Tenderness 
Mild discomfort 
to touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
ER visit or 
hospitalization 
Erythema/Redness†
2.0 – 5 cm 
5.1 – 10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration 
/Swelling‡
2.0 – 5 cm and 
does not interfere 
with activity 
5.1 – 10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
Necrosis 
†
In addition to grading the measured local reaction at the greatest single diameter, the measurement should be 
recorded as a continuous variable. 
‡
Induration/Swelling is to be evaluated and graded using the functional scale as well as the actual 
measurement.
Reference:
Guidance for Industry titled “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials” issued by FDA on September 2007.  








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Reference:
Blood and Marrow Transplant Clinical Trials Network, Technical MOP, Version 3.0, 19 Mar 2013.  
Accessed from http://www.bmtctn.net. Accessed on 31 August 2015.


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12.9
Appendix 9:  Staging and Grading of Acute Graft versus Host 
Disease 
Staging of aGVHD
Skin†
0 = No rash
1 = Maculopapular rash < 25% of body surface
2 = Maculopapular rash 25%-50% of body surface
3 = Generalized erythroderma (maculopapular rash > 50%)
4 = Generalized erythroderma with bullous formation and desquamation
Lower Intestinal Tract‡
0 = Diarrhea < 500 mL/day or 280 mL/m2
1 = Diarrhea > 500 but ≤ 1000 mL/day or 280-555 mL/m2
2 = Diarrhea > 1000 but ≤ 1500 mL/day or 556-833 mL/m2
3 = Diarrhea > 1500 mL/day or > 833mL/m2
4 = Severe abdominal pain with or without ileus or stool with frank blood or melena
Upper Intestinal Tract§
0 = No protracted nausea and vomiting
1 = Persistent nausea, vomiting, or anorexia
Liver¶
0 = Bilirubin < 2.0 mg/dL
1 = Bilirubin 2.0 – 3.0 mg/dL
2 = Bilirubin 3.1 – 6.0 mg/dL
3 = Bilirubin 6.1 – 15.0 mg/dL
4 = Bilirubin > 15.0 mg/dL
Biopsy Result
PS = Positive
NG = Negative
EQ = Equivocal
ND = Not done
†Use 'Rule of Nines' or burn chart to determine extent of rash.
‡Downgrade 1 stage if an additional cause of diarrhea has been documented.
§Persistent nausea with histologic evidence of GVHD in the stomach or duodenum.
¶Range given as total bilirubin. Downgrade 1 stage if an additional cause of elevated bilirubin has been 
documented.
Overall Grade of aGVHD†
Grade 0:
●
No skin rash and
●
No protracted nausea and vomiting and
●
No diarrhea or diarrhea < 500 mL/day and 
●
Bilirubin < 2.0 mg/dL
Grade III:
●
Skin – no rash to rash > 50% of body surface 
with 
●
Diarrhea >1500 mL/day or severe abdominal 
pain or
●
Bilirubin 3.1 – 15.0 mg/dL
Grade I:
●
Skin Rash < 50% of body surface and
●
No diarrhea or diarrhea < 500 mL/day and 
●
Bilirubin < 2.0 mg/dL
Grade IV‡:
●
Skin – generalized erythroderma or 
●
Bilirubin > 15.0 mg/dL
Grade II:
●
Skin rash > 50% of body surface or
●
Diarrhea > 500 mL/day or 
●
Bilirubin 2.0 – 3.0 mg/dL or
●
Persistent nausea/vomiting
†Criteria for grading given as minimum degree of organ involvement required to confer that grade.
‡Grade IV may also include lesser organ involvement but with extreme decrease in performance status.


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References:
BMT CTN 0201 Data listing for data review committee (DRC). Updated 12 Mar 2010.
Przepiorka D, Weisdorf D, Martin P, Klingemann H-G, Beatty P, Hows J, and Thomas ED. Meeting 
report: Consensus conference on acute GVHD grading. BMT 1995; 15:825-8.


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12.10 Appendix 10:  Rule of Nines Burn Chart


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12.11 Appendix 11:  Criteria for the Diagnosis of Chronic Graft Versus 
Host Disease
The diagnosis of cGVHD requires the following 3 criteria:
1.
Distinction from acute GVHD, 
2.
Presence of at least 1 diagnostic clinical sign of chronic GVHD or presence of at least 
1 distinctive manifestation confirmed by pertinent biopsy or other relevant tests,
3.
Exclusion of other possible diagnosis.


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Organ or Site
Diagnostic (Sufficient to 
Establish the Diagnosis of 
cGVHD)
Distinctive (Seen in cGVHD, but Insufficient 
Alone to Establish a Diagnosis of cGVHD)
Other Features
Common (seen with Both 
Acute and Chronic 
GVHD)
Skin 
Poikiloderma 
Depigmentation 
Sweat impairment 
Erythema 
Lichen planus-like features 
Ichthyosis 
Maculopapular rash
Sclerotic features 
Keratosis pilaris 
Pruritus
Morphea-like features 
Hypopigmentation 
Lichen sclerosus-like features
Hyperpigmentation 
Nails
Dystrophy 
Longitudinal ridging, splitting, or brittle features
Onycholysis 
Pterygium unguis 
Nail loss (usually symmetric; affects most nails)†
Scalp and body 
hair
New onset of scarring or nonscarring
Thinning scalp 
Scalp alopecia (after recovery from chemoradiotherapy)
Hair, typically patchy, coarse, 
or dull (not explained by 
endocrine or other causes)
Scaling, papulosquamous lesions
Premature gray hair
Mouth 
Lichen-type features 
Xerostomia 
Gingivitis 
Hyperkeratotic plaques 
Mucocele 
Mucositis 
Restriction of mouth opening from 
sclerosis
Mucosal atrophy 
Erythema 
Pseudomembranes† 
Pain 
Ulcers† 
Eyes 
New onset dry, gritty, or painful eyes‡
Photophobia 
Cicatricial conjunctivitis 
Periorbital 
Keratoconjunctivitis sicca‡ 
Hyperpigmentation 
Conﬂuent areas of punctate 
Blepharitis (erythema of the 
eyelids with edema)
Keratopathy
Genitalia 
Lichen planus-like features 
Erosions† 
Vaginal scarring or stenosis 
Fissures† 
Ulcers† 
Table continued on next page


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Organ or Site
Diagnostic (Sufficient to 
Establish the Diagnosis of 
cGVHD)
Distinctive (Seen in cGVHD, but Insufficient 
Alone to Establish a Diagnosis of cGVHD)
Other Features
Common (seen with Both
Acute and Chronic 
GVHD)
Gastrointestinal 
Tract
Esophageal web 
Exocrine 
Anorexia 
Strictures or stenosis in the upper 
mid third of the esophagus†
Pancreatic insufficiency
Nausea 
Vomiting 
Diarrhea 
Weight loss 
Failure to thrive (infants and 
children)
Liver
Total bilirubin, 
Alkaline phosphatase > 2 x 
ULN
Alanine aminotransferase or 
aspartate aminotransferase >2 
x ULN
Lung
Bronchiolitis obliterans diagnosed 
with lung biopsy
Bronchiolitis obliterans diagnosed with
Bronchiolitis obliterans 
organizing pneumonia
Pulmonary function test and radiology‡
Muscles, fascia, 
joint
Fasciitis
Myositis or polymyositis‡
Edema
Joint stiffness or contractures 
secondary to sclerosis
Muscle cramps
Arthralgia or arthritis
Hematopoietic 
and immune 
systems
Thrombocytopenia
Eosinophilia
Lymphopenia
Hypo- or Hyper γ-
globulinemia
Autoantibodies 
(autoimmune hemolytic 
anemia and idiopathic 
thrombocytopenic purpura)
Table continued on next page


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Organ or Site
Diagnostic (Sufficient to 
Establish the Diagnosis of 
cGVHD)
Distinctive (Seen in cGVHD, but Insufficient 
Alone to Establish a Diagnosis of cGVHD)
Other Features
Common (seen with Both 
Acute and Chronic 
GVHD)
Other
Pericardial or 
Pleural effusions
Ascites
Peripheral neuropathy
Nephrotic syndrome
Myasthenia gravis
Cardiac conduction 
abnormality or 
cardiomyopathy
aGVHD: acute graft-versus-host disease; cGVHD: chronic graft-versus-host disease; GVHD: graft-versus-host disease; ULN: upper limit of normal
†In all cases, infection, drug effects, malignancy, or other causes must be excluded. 
‡Diagnosis of chronic GVHD requires biopsy or radiology conﬁrmation (or Schirmer test for eyes). 
Note: Other features can be acknowledged as part of the chronic GVHD symptomatology if the diagnosis is conﬁrmed. 
Reference:
Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al.  National institutes of health consensus development project on criteria for clinical trials in 
chronic graft-versus-host disease: 1. diagnosis and staging working group report. Biology of Blood and Marrow Transplantation. 2005; 11:945-55.  


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12.12 Appendix 12:  Grading of Chronic Graft versus Host Disease
Maximum grade of chronic GVHD
Limited - localized skin involvement and/or hepatic dysfunction due to cGVHD.
Extensive - 1 or more of the following:
●
Generalized skin involvement; or, 
●
Liver histology showing chronic aggressive hepatitis, bridging necrosis or cirrhosis; or, 
●
Involvement of the eye:  Schirmer’s test with < 5 mm wetting; or, 
●
Involvement of minor salivary glands or oral mucosa demonstrated on labial biopsy; or, 
●
Involvement of any other target organ.
References:
CIBMTR Form 2200 revision 2, June 2009.
Shulman HIM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE, et al. Chronic-graft-
versus-host syndrome in man: A long-term clinicopathologic study of 20 Seattle patients. AJM 
1980; 69:204-17.


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12.13 Appendix 13:  Organ Scoring and Global Scoring of Chronic Graft 
versus Host Disease 
Organ Scoring cGVHD
SCORE 0
SCORE 1
SCORE 2
SCORE 3
PERFORMANCE 
SCORE:
KPS   
      Asymptomatic and 
fully active ( KPS
100%)
      Symptomatic, fully 
ambulatory, restricted 
only in physically 
strenuous activity (KPS 
80%-90%)
     Symptomatic, 
ambulatory, capable of 
self-care, >50% of 
waking hours out of bed 
(KPS 60%-70%)
     Symptomatic, limited 
self-care, >50% of 
waking hours in bed 
(KPS <60%)
SKIN
Clinical features
      Maculopapular rash
      Lichen planus-like 
features
      Papulosquamous 
lesions or ichthyosis
      Hyperpigmentation
      Hypopigmentation
      Keratosis pilaris
      Erythema
      Erythroderma
      Poikiloderma
      Sclerotic features
      Pruritus
      Hair involvement
      Nail involvement
%BSA 
Involved
      No symptoms
    18% BSA with 
disease signs but NO 
sclerotic features
     19%-50% BSA OR
involvement with 
superficial sclerotic 
features “not 
hidebound” (able to 
pinch)
     50% BSA OR deep 
sclerotic features 
“hidebound” (unable to 
pinch) OR impaired 
mobility, ulceration or 
severe pruritus
MOUTH
     No symptoms
      Mild symptoms with 
disease signs but not 
limiting oral intake 
significantly 
       Moderate 
symptoms with disease 
signs with partial 
limitation of oral intake
     Severe symptoms with 
disease signs on 
examination with major 
limitation of oral intake
EYES
Mean tear test (mm):
      >10
      6-10
      < 5
      Not done
      No symptoms
      Mild dry eye 
symptoms not affecting 
ADL (requiring eye drops 
< 3 x per day) OR 
asymptomatic signs of 
keratoconjunctivitis sicca
       Moderate dry eye 
symptoms partially 
affecting ADL 
(requiring drops > 3 x 
per day or punctual 
plugs), WITHOUT 
vision impairment
       Severe dry eye 
symptoms significantly 
affecting ADL (special 
eyewear to relieve pain) 
OR unable to work 
because of ocular 
symptoms OR loss of 
visions caused by 
keratoconjunctivitis sicca
Table continued on next page


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SCORE 0
SCORE 1
SCORE 2
SCORE 3
GI Tract
       No symptoms
      Symptoms such as 
dysphagia, anorexia, 
nausea, vomiting, 
abdominal pain or 
diarrhea without 
significant weight loss 
(<5%)
       Symptoms 
associated with mild to 
moderate weight loss 
(5%-15%)
      Symptoms associated 
with significant weight 
loss >15%, requires 
nutritional supplement for 
most calorie needs OR 
esophageal dilation
LIVER
      Normal LFT
      Elevated Bilirubin, 
AP*, AST or ALT < 2 x 
ULN
      Bilirubin > 3 mg/dL
or Bilirubin, 
enzymes 2 x-5 x ULN
       Bilirubin or enzymes 
> 5 x ULN
LUNGS†
FEV1
DLCO
      No symptoms
       FEV1 > 80% OR 
LFS = 2
      Mild symptoms 
(shortness of breath after 
climbing 1 flight of steps)
      FEV1 60%-79% OR 
LFS = 3-5
      Moderate symptoms 
(shortness of breath 
after walking on flat 
ground)
      FEV1 40%-59% 
OR LFS = 6-9
       Severe symptoms 
(shortness of breath at 
rest; requiring 02)
       FEV1  < 39% OR 
LFS = 10-12
JOINTS AND FASCIA
       No symptoms
      Mild tightness of 
arms or legs, normal or 
mild decreased ROM
AND not affecting ADL
      Tightness of arms or 
legs OR joint 
contractures, erythema 
thought due to fasciitis, 
moderate decrease 
ROM AND mild to 
moderate limitation of 
ADL
       Contractures WITH
significant decrease of 
ROM AND significant 
limitation of ADL 
(unable to tie shoes, 
button shirts, dress self 
etc.)
GENITAL TRACT
      No symptoms
      Symptomatic with 
mild signs on exam AND
no effect on coitus and 
minimal discomfort with 
gynecologic exam
      Symptomatic with 
moderate signs on exam 
AND with mild 
dyspaareunia or 
discomfort with 
gynecologic exam
      Symptomatic WITH 
advanced signs (stricture, 
labial agglutination or 
severe ulceration) AND 
severe pain with coitus or 
inability to insert vaginal 
speculum
Other indicators, clinical manifestations or complications related to chronic GVHD (check all that apply and assign a 
score to its severity (0-3) base on its functional impact where applicable  (none - 0, mild - 1, moderate -2, severe - 3)
Esophageal stricture or web______
Pericardial Effusion ______
Pleural Effusion(s) ______
Ascites (serositis) ______
Nephrotic syndrome ______
Peripheral Neuropathy ______
Myasthenia Gravis ______
Cardiomyopathy ______
Eosinophilia > 500/ µL ______
Polymyositis ______
Cardiac conduction defects ______
Coronary artery involvement ______
Platelets < 100,000/µL ______
Progressive onset ______
OTHERS:  Specify: __________________________________________________________________________________
ADL: activities of daily living; BSA: bovine serum albumin; cGVHD: chronic graft-versus-host disease; DLCO: diffusing 
lung capacity of carbon monoxide; FEV1: forced expiratory volume ; GVHD: graft-versus-host disease; KPS: Karnofsky 
Performance Scale ; LFS: lung function score; PFT: pulmonary function testing; ROM: range of motion
Footnotes continued on next page


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Organ scoring of chronic GVHD. *AP may be elevated in growing children, and not reﬂective of liver dysfunction. 
†Pulmonary scoring is to be performed using both the symptom and PFT scale whenever possible, if performed based on 
symptoms.  When discrepancy exists between pulmonary symptom or PFT scores the higher value should be used for ﬁnal 
scoring. Scoring using the LFS is preferred, but if DLCO is not available, grading using FEV1 should be used. The LFS is a 
global assessment of lung function after the diagnosis of bronchiolitis obliterans has already been established.  The percent
predicted FEV1 and DLCO (adjusted for hematocrit but not alveolar volume) should be converted to a numeric score as 
follows: >80% = 1; 70%-79% = 2; 60%-69% = 3; 50%-59% = 4; 40%-49% = 5; < 40% = 6. The LFS = FEV1 score + 
DLCO score, with a possible range of 2-12.
Global Scoring of cGVHD
●
Mild:  1 or 2 organs or sites (except lung), with no clinically significant functional 
impairment (maximum of score 1 in all affected organs or sites).
●
Moderate:
o
At least 1 organ or site with clinically significant but no major disability 
(maximum score of 2 in any affected organ or site)  or;
o
3 or more organs or sites with no clinically significant functional impairment 
(maximum score of 1 in all affected organs or sites) or;  
o
A lung score of 1 
●
Severe:
o
Major disability caused by chronic GVHD (score of 3 in any organ or site);
o
A lung score of 2 or greater
Modified from Reference:
Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al.  National institutes of 
health consensus development project on criteria for clinical trials in chronic graft-versus-host 
disease: 1. diagnosis and staging working group report. Biology of Blood and Marrow 
Transplantation 2005;11:945-55.


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12.14 Appendix 14:  EQ-5D Questionnaire
Note that the below is an example; patients will be provided with forms to be completed.


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Appendix 14: EQ-5D Questionnaire continued








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12.16 Appendix 16:  Work Productivity and Activity Impairment 
Questionnaire:  General Health Version 2.0
The following questions ask about the effect of your health problems on your ability to work 
and perform regular activities. By health problems we mean any physical or emotional 
problem or symptom. Please fill in the blanks or circle a number, as indicated.
1.
Are you currently employed (working for pay)? ____  NO____  YES
If NO, check “NO” and skip to question 6.
The next questions are about the past 7 days, not including today.
2.
During the past 7 days, how many hours did you miss from work because of your health 
problems? Include hours you missed on sick days, times you went in late, left early, etc., 
because of your health problems. Do not include time you missed to participate in this 
study.
_____HOURS
3.
During the past 7 days, how many hours did you miss from work because of any other 
reason, such as vacation, holidays, time off to participate in this study?
_____HOURS
4.
During the past 7 days, how many hours did you actually work?
_____HOURS (If “0”, skip to question 6.)
5.
During the past 7 days, how much did your health problems affect your productivity 
while you were working? 
Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully 
as usual. If health problems affected your work only a little, choose a low number. 
Choose a high number if health problems affected your work a great deal.
Consider only how much health problems affected 
productivity while you were working.
Health problems 
had no effect on 
my work
Health problems 
completely 
prevented me from 
working
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER


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Appendix 16:  Work Productivity and Activity Impairment Questionnaire: General 
Health V2.0 (WPAI:GH) continued
6.
During the past 7 days, how much did your health problems affect your ability to do your 
regular daily activities, other than work at a job? 
By regular activities, we mean the usual activities you do, such as work around the 
house, shopping, childcare, exercising, studying, etc. Think about times you were limited 
in the amount or kind of activities you could do and times you accomplished less than 
you would like. If health problems affected your activities only a little, choose a low 
number. Choose a high number if health problems affected your activities a great deal. 
Consider only how much health problems affected your ability 
to do your regular daily activities, other than work at a job.
Health problems 
had no effect on 
my daily activities
Health problems 
completely 
prevented me from 
doing my daily 
activities
0
1
2
3
4
5
6
7
8
9
10
CIRCLE A NUMBER


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EudraCT number 2013-000903-18
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12.17 Appendix 17:  Definitions of Conditioning Regimens
Myeloablative conditioning regimen: regimens with total body irradiation single dose of 
≥500 cGY, fractionated dose of ≥ 800 cGY, busulfan doses of  > 9mg/kg, or melphalan doses 
of  > 150 mg/m2 given as single agents or in combination with other drugs.
Non-myeloablative (reduced-intensity) conditioning regimen: regimens with lower doses of 
total body irradiation, fractionated radiation therapy, busulfan, and melphalan than those used 
to define a myeloablative conditioning regimen (above).
Reference
Pasquini MC, Wang Z. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR 
Summary Slides, 2009.


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12.18 Appendix 18:  Liver Safety Monitoring and Assessment
Drug-induced liver injury (DILI) has been the most frequent single cause of safety-related 
marketing withdrawals for the past 50 years. Robust monitoring and expedited regulatory 
reporting of DILI during clinical trials are therefore required by the FDA (FDA Guidance, 
2009). However, monitoring and reporting of elevated liver function tests (LFTs) will be 
confounded in this trial because elevated LFTs are common in patients within 1 year after a 
hematopoietic cell transplant. Therefore, while LFTs will be monitored throughout this trial, 
extra pharmacovigilance will be performed only on those subjects that have marked elevations. 
Confirmed abnormalities will be characterized as marked where upper limit of normal (ULN):
ALT or AST
Total Bilirubin
Marked
> 20 x ULN
Or
> 10 x ULN
ALT: alanine aminotransferase; AST: aspartate aminotransferase; ULN: upper limit of normal
If laboratory testing for a subject enrolled in study and with normal serum aminotransferases 
(AT) and TBL has an increase of serum AT > 5x ULN or total bilirubin (TBL) > 2x ULN by 
either local or central laboratory, the medical monitor is to be notified within 24 hours. If the 
enrolled subject had abnormal AT or TBL at time of enrollment and there is an increase in the 
AT to > 5 x baseline or the TBL to > 2x baseline, the medical monitor is to be notified within 
24 hours. Alerts will be generated by the central laboratory regarding abnormalities to inform 
the Investigator, study monitor and study team. Notification to the medical monitor only needs 
to be done at the onset of LFT elevations. However, if the subject has normal LFTs for > 2 
weeks between the LFT elevations described above, the medical monitor is to be notified for 
each event.
If laboratory testing for a subject enrolled in the study reveals an increase of serum AT to > 
20x ULN, or TBL > 10x ULN, at least all 4 of the usual serum hepatic measures (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP] and 
TBL) is to be repeated by the central laboratory and the medical monitor is to be notified 
within 24 hours of the elevated LFTs. Testing should be repeated within 48 to 72 hours of 
notification of the test results. Alerts will be generated by the central laboratory regarding 
marked liver abnormality to inform the Investigator, study monitor and study team. Subjects 
should be asked if they have any symptoms suggestive of hepatobiliary dysfunction.
Follow-up Procedures
Confirmed marked abnormalities in hepatic functions should be thoroughly characterized by 
obtaining appropriate expert consultations, detailed pertinent history, PE and laboratory tests. 
The site is to complete the Liver Abnormality Case Report Form (LA-CRF) or an appropriate 
document. Information collected will include the following:
●
Diagnosis of condition causing the elevated LFTs
●
Central and local laboratory measurement of elevated LFTs (including AST, ALT, TBL, 
direct bilirubin, and ALP)
●
Concurrent medical conditions


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●
Concurrent medications
●
Prior conditioning medications with doses
●
Alcohol and illegal substance use
●
Hepatitis A, B, C and CMV and EBV testing to detect active replication of virus
●
Liver imaging and biopsy results, if performed
Confirmed marked abnormal LFTs should be repeated 2-3 times weekly and then weekly or 
less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.  
Study Discontinuation
In the absence of an explanation for increased LFTs, such as viral hepatitis, pre-existing or 
acute liver disease or exposure to other agents associated with liver injury, the subject may be 
discontinued from treatment. The Investigator may determine that it is not in the subject’s best 
interest to continue study participation. 
In addition, if close monitoring for a subject with marked hepatic laboratory tests is not 
possible, drug must be discontinued.
DMC Monitoring
In addition to the above, the DMC will assess unblinded events between the ASP0113 and 
placebo groups to determine if there appears to be a signal that the frequency or severity of 
liver events is greater in ASP0113 than placebo or/and than that reported in the literature.
Reference
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” issued by 
FDA on July 2009.


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12.19 Appendix 19:  Pharmacogenomics (PGx) Sub-Study
INTRODUCTION/BACKGROUND
PGx research aims to provide information regarding how naturally occurring changes in a 
subject’s gene and/or expression based on genetic variation may impact what treatment options 
are best suited for the subject. Through investigation of PGx by technologies such as 
genotyping, gene sequencing, statistical genetics and Genome-Wide Association Studies 
(GWAS), the relationship between gene profiles and a drug’s kinetics, efficacy or toxicity may 
be better understood. PGx research may identify which genes are involved in determining the 
way a subject may or may not respond to a drug.
STUDY OBJECTIVES
The PGx research that may be conducted in the future with acquired saliva samples is 
exploratory. The objective of this research will be to analyze or determine genes of relevance 
to clinical response, and toxicity/safety issues.
By analyzing genetic variations, it may be possible to predict an individual subject’s response 
to ASP0113 in terms of efficacy and/or toxicity.
STUDY POPULATION
Subjects who have consented to participate in this study may also participate in the optional 
pharmacogenomics sub-study. As part of this sub-study, subjects must provide separate written 
informed consent prior to providing any saliva samples that will be used at a later time for the 
pharmacogenomic analysis.
STUDY DESIGN
Site Sample Collection and Storage
Subjects who consent to participate in the PGx sub-study will provide 1 saliva sample at
baseline (V2) prior to dosing. Each sample will be identified with a unique identifier. Samples
will be collected and shipped to the Sponsor designated central laboratory for prolonged 
storage. Detailed collection, storage, and shipment procedures will be included in the 
Laboratory Manual for the study.
Central Laboratory and Research Laboratory Processing and Storage / Sample Coding
Once received at the banking CRO, the samples will be assigned a unique sample code (second 
code) and stored frozen. A table linking the subject number (first code) with the newly-
assigned sample code (second code) will be kept by the banking CRO. PGx analysis will be 
conducted using the second code only.
PHARMACOGENOMIC ANALYSIS
Details on the potential PGx analysis cannot be established yet. Astellas may initiate the PGx 
analysis in case evidence suggests that genetic variants may be influencing the drug’s kinetics, 


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efficacy and/or safety. Prior to initiating any analysis on the banked samples, the Astellas 
ethical committee (AREC) must approve the analysis plan.
DISPOSAL OF PHARMACOGENOMIC SAMPLES/DATA
All PGx samples collected will be stored for a period of up to 15 years following study 
database hardlock. If there is no requirement for analysis, the saliva sample will be destroyed 
after the planned storage period. The subject has the right to withdraw consent at any time. 
When a subject’s withdraw notification is received, the PGx sample will be destroyed. The 
results of any PGx analysis conducted on a sample prior to its withdrawal will be retained at 
Astellas indefinitely.
INFORMATION DISCLOSURE TO THE SUBJECTS
Retrospective PGx analysis may be conducted following the conclusion of the clinical study, if 
applicable. The results of the genetic analysis will not be provided to any investigators or 
subjects, nor can the results be requested at a later date. Any information that is obtained from 
the PGx analysis will be the property of Astellas. 


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12.20 Appendix 20:  Long-term Follow-up Questionnaire
Subjects will be contacted by telephone annually after the primary study period (Day 365) 
through 5.5 years post-transplant for long-term safety related to the DNA vaccine. Items to be 
assessed by telephone interview and available patient records include mortality, development 
of any new/recurrent cancer, development of infection requiring hospitalization, and local
immune-mediated reactions.
The following information will be collected at each of the contact time points:
1.
Subject mortality, including primary cause of death and date of death (if applicable).
2.
Development of any new/recurrent cancer (name).  
3.
Development of infection requiring hospitalization or resulting in death (name of 
infecting agent, or medications or laboratory data leading to diagnosis).  
o
The subject will be asked whether he/she has been diagnosed with any new medical 
conditions requiring hospitalization to solicit this information.
4.
Local immune-mediated reactions.  
o
The subject will be asked if he/she has had any redness or swelling at the sites of 
the study drug injections.


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12.21 Appendix 21:  Health Economic Assessment (Inpatient and 
Outpatient Utilization)
Are there any Inpatient Care visits to report? Yes No
If Yes, please record the number of days the patient was admitted to:  
Admission Unit/Floor
ICU Days_____________
                  # of Days
Step-down Unit Days______________
                                    # of Days
    Hospital General Medical/Surgical Ward Days_____________
                            # of Days
Was there an Emergency Room visit greater than 24 hours (without admittance)? Yes  No
If yes, please indicate the number of Emergency Room days____________
                     
# of days
Primary Reason (Diagnosis) for Admission:___________________
If a US site, please insert the ICD-9 code for the diagnosis.
If more than 1 Inpatient Care visit to report, please record diagnosis/ICD-9 code for each 
admission, and the number of days as noted above.
Are there any Non- Protocol- related Physician visits to report?
Yes No
If Yes, please indicate the number of visits:
Physician Visits_____________
# of visits
Are there any Emergency Room visits less than or equal to 24 hours to report?
Yes
No
If Yes, please indicate the number of visits:
ER visits (≤ 24 hours)__________
# of visits


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12.22 Appendix 22:  Karnofsky Performance Scale 
100%
Normal. No complaints. No evidence of disease.
90%
Able to carry on normal activity. Minor signs of disease.
80%
Normal activity with effort. Some signs and symptoms of disease.
70%
Cares for self. Unable to carry on normal activity or do active work.
60%
Requires occasional assistance, but is able to care for most personal needs.
50%
Requires considerable assistance and frequent medical care.
40%
Disabled. Requires special care and assistance.
30%
Severely disabled. Hospitalization is indicated, although death not imminent.
20%
Hospitalization necessary, very sick, active support treatment is necessary.
10%
Moribund. Fatal processes progressing rapidly.
0%
Dead.
Reference:
Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer, in 
Macleod cm (ed): Evaluation Of Chemotherapeutic Agents. New York, Columbia University 
Press, 1949 p 199-205.


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13
ATTACHMENT 1:  NON-SUBSTANTIAL AMENDMENT 1
I. The purpose of this amendment is:
Non-Substantial Changes
1.
Minor Administrative-type Changes
DESCRIPTION OF CHANGE: 
Include minor administrative-type changes, e.g., typos, format, numbering, consistency 
throughout the protocol.  
RATIONALE:
To provide clarifications to the protocol and to ensure complete understanding of study 
procedures.
2.
Update Selection Criteria in Synopsis
DESCRIPTION OF CHANGE:
Add acute undifferentiated leukemia (AUL) to the underlying diseases listed under inclusion 
criterion No. 6 of the Selection Criteria section in the Synopsis.
RATIONALE:
A portion of one of the inclusion criterion was inadvertently deleted from the synopsis 
section of the protocol. Therefore, the inclusion criterion is updated to match the full 
criterion that is provided in the body of the protocol (Section 3.2).
II.  Amendment Summary of Changes:
IV Synopsis, Selection Criteria
Inclusion Criterion #6
WAS:
6.  Subject has 1 of the following underlying diseases:
a. Acute myeloid leukemia (AML), with or without a history of myelodysplastic 
syndrome (MDS), in first or second complete remission [Appendix 6] or in early 
relapse (< 20% blasts in bone marrow with no circulating blasts in peripheral blood 
and no extramedullary leukemia).
b. Acute lymphoblastic leukemia (ALL), in first or second complete remission 
[Appendix 6]
c. Acute biphenotypic leukemia in first or second complete remission [Appendix 6]


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IS AMENDED TO:
6.  Subject has 1 of the following underlying diseases:
a.
Acute myeloid leukemia (AML), with or without a history of myelodysplastic 
syndrome (MDS), in first or second complete remission [Appendix 6] or in early 
relapse (< 20% blasts in bone marrow with no circulating blasts in peripheral blood 
and no extramedullary leukemia).
b. Acute lymphoblastic leukemia (ALL), in first or second complete remission 
[Appendix 6]
c.
Acute undifferentiated leukemia (AUL) in first or second complete remission 
[Appendix 6]
d. Acute biphenotypic leukemia in first or second complete remission [Appendix 6]
III.  Non-Substantial Amendment Rationale:
Rationale for Non-Substantial Designation
All revisions made to the protocol are administrative in nature and do not impact the safety 
or scientific value of the clinical study.


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[GPF v3.0]
14
SPONSOR’S SIGNATURES

SAP_001.pdf: 
A Randomized, Double-Blind, Placebo-Controlled, Phase 
3 Trial to Evaluate the Protective Efficacy and Safety of a 
Therapeutic Vaccine, ASP0113, in Cytomegalovirus 
(CMV)-Seropositive Recipients Undergoing Allogeneic, 
Hematopoietic Cell Transplant (HCT)
ISN/Protocol 0113-CL-1004
ClinicalTrials.gov Identifier: NCT01877655
Date of SAP: Final Version 3.0, dated 19 May 2017
Sponsor: Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062


Sponsor: Astellas Pharma Global Development
SAP Version 3.0
ISN/Protocol 0113-CL-1004
May 2017
Astellas
Page 1 of 45
STATISTICAL ANALYSIS PLAN
Final Version 3.0, dated 19-May-2017
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Evaluate the 
Protective Efficacy and Safety of a Therapeutic Vaccine, ASP0113, in Cytomegalovirus 
(CMV)-Seropositive Recipients Undergoing Allogeneic, Hematopoietic Cell Transplant 
(HCT)
ISN: 0113-CL-1004
EudraCT number: 2013-000903-18
IND number: 11381
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062
This confidential document is the property of the sponsor. No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor.


Sponsor: Astellas Pharma Global Development
SAP Version 3.0
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May 2017
Astellas
Page 2 of 45
Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 4
1
INTRODUCTION·················································································· 8
2
FLOW CHART AND VISIT SCHEDULE···················································· 9
3
STUDY OBJECTIVE(S) AND DESIGN······················································15
3.1
Study Objectives ··············································································15
3.2
Study Design···················································································15
3.3
Randomization·················································································15
4
SAMPLE SIZE·····················································································15
5
ANALYSIS SETS ·················································································16
5.1
Full Analysis Set ··············································································16
5.2
Modified Full Analysis Set ··································································16
5.3
Per Protocol Set ···············································································16
5.3.1
Reasons for Exclusion From PPS ·····················································17
5.4
Safety Analysis Sets ··········································································17
5.5
Pharmacokinetics Analysis Set (PKAS)····················································17
5.6
Pharmacodynamic Analysis Set (PDAS)···················································18
5.7
Immunogenicity Analysis Set ·······························································18
6
ANALYSIS VARIABLES ·······································································18
6.1
Efficacy Endpoints············································································18
6.1.1
Primary Efficacy Endpoint ·····························································18
6.1.2
Secondary Efficacy Endpoints·························································18
6.1.3
Exploratory Efficacy Endpoints ·······················································18
6.1.4
Immunogenicity Variables ·····························································22
6.2
Safety Variables ···············································································23
6.3
Pharmacokinetic Variables···································································24
6.4
Pharmacodynamic Variables·································································24
7
STATISTICAL METHODOLOGY ···························································24
7.1
General Considerations·······································································24
7.2
Study Population ··············································································25
7.2.1
Disposition of Subjects ·································································25
7.2.2
Protocol Deviations ·····································································25


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7.2.3
Demographic and Other Baseline Characteristics ···································25
7.2.4
Previous and Concomitant Medications ··············································26
7.2.5
Transplant Information ·································································26
7.3
Study Drug·····················································································27
7.4
Analysis of Efficacy ··········································································27
7.4.1
Analysis of Primary Endpoint ·························································27
7.4.2
Analysis of Key and Other Secondary Efficacy Endpoints ························29
7.4.3
Exploratory Endpoints ··································································31
7.5
Analysis of Safety·············································································33
7.5.1
Adverse Events ··········································································34
7.5.2
Local Reactogenicity Assessed by Subject···········································35
7.5.3
Clinical Laboratory Evaluation ························································35
7.5.4
Vital Signs················································································36
7.5.5
Pregnancies···············································································36
7.6
Analysis of PK·················································································36
7.7
Analysis of PD·················································································36
7.8
Safety Subgroups of Interest·································································36
7.9
Interim Analysis and Early Discontinuation of the Clinical Study······················37
7.9.1
Data Monitoring Committee ···························································37
7.9.2
Futility Analyses·········································································38
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········38
7.10.1
Missing Data ·············································································38
7.10.2
Outliers ···················································································39
7.10.3
Visit Windows ···········································································39
8
DOCUMENT REVISION HISTORY ·························································40
8.1
List of Changes in SAP Version 3.0 from Version 2 ·····································40
9
REFERENCES ····················································································42
10
APPENDICES ·····················································································43
Appendix 1: Handling of the Human Leukocyte Antigen (HLA) Mismatching··················43
Appendix 2: Signatures ··················································································45
List of In-text Tables
Table 1
Schedule of Assessments – Primary Study Period Visit 1 (Screening) – Day 365····10


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I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse Event
aGVHD
Acute Graft-versus-host Disease
ALP
Alkaline Phosphatase
ALT
Alanine Transaminase
ANCOVA
Analysis of Covariance
ASP0113
DNA vaccine being tested in this study
AST
Aspartate Transaminase
ATG
Anti-thromocyte Globulin
AVT
Antiviral Therapy
BDRM
Blind Data Review Meeting
BMI
Body Mass Index
BMTS
Bone Marrow Transplantation Subscale
cGVHD
Chronic Graft-versus-host Disease
CI
Confidence Intervals
CIF
Cumulative Incidence Function
CMH
Cochran-Mantel-Haenszel
CMV
Cytomegalovirus
CRF
Case Report Form
DBP
Diastolic Blood Pressure
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
eCRF
Electronic Case Report Form
EOD
End Organ Disease
EQ-5D
EuroQol – 5D
FACT-BMT
Functional Assessment of Cancer Therapy – Bone Marrow Transplant
FAS
Full Analysis Set
FDA
Food and Drug Administration
gB
Glycoprotein B
GVHD
Graft-versus-host Disease
H0
Null Hypothesis
H1
Alternative Hypothesis
HCT
Hematopoietic Cell Transplant
HCT-CI
Hematopoietic Cell Transplant Comorbidity Index
HEA
Health Economics Assessment


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Abbreviations
Description of abbreviations
HECOR
Health Economics and Clinical Outcomes Research
HLA
Human Leukocyte Antigen
HLT
High-Level Term
ICF
Informed Consent Form
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IgG
Immunoglobulin G
IRT
Interactive Response Technology
LLN
Lower Limit of Normal
MedDRA
Medical Dictionary for Regulatory Activities
mFAS
Modified Full Analysis Set
mL
Milliliter
m2
Meter squared
mm3
Millimeter cubed
mmHg
Millimeters of Mercury
mSAF
Modified Safety Analysis Set
NCI-CTCAE
National Institutes of Health Common Terminology Criteria for Adverse Events
PD
Pharmacodynamics
PE
Physical Examination
PGx
Pharmacogenomics
PK
Pharmacokinetic
pp65
Phosphoprotein 65
PPS
Per Protocol Set
PT
Preferred Term
QOL
Quality of Life
ROC
Receiver Operating Characteristic
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SOC
System Organ Class
TEAE
Treatment emergent Adverse Event
TLF
Tables, Listing, and Figures
ULN
Upper Limit of Normal
VE
Vaccine Efficacy 
WHO-DRL
World Health Organization Drug Reference List
WPAI: GH
Work Productivity and Activity Impairment Questionnaire: General Health


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List of Key Terms
Terms
Definition of terms
Adverse Event
An adverse event is any untoward medical occurrence in a subject 
administered a study drug which does not necessarily have a causal 
relationship with the treatment.
Baseline
The last measurement / evaluation on or prior to the first dose of randomized 
therapy is considered the baseline measure/evaluation.
Censored Data
The value of a measurement or observation which is only partially known, 
such as an event has not yet happened at the time of loss of contact before 
the study is completed.
CMV Infection
Replication of CMV (isolation of the virus or detection of viral protein or 
nucleic acid in any body fluid or tissue).
CMV Viremia
Presence of CMV in the blood.
End of Study in 
Primary Study Period
The point in time when the last protocol-defined assessment has been 
completed in the primary study period (excludes the Long-term Follow-up 
Period).
End of Treatment
The point in time when the subject receives the last dose of study drug.
Enrollment
The point in time when the subject signs the informed consent.
Hard Lock
Hard lock of a study database occurs after all issues discovered in final data 
review have been resolved and it is expected that no more changes to the 
study database will occur. Only after hard lock are treatment assignments 
unblinded. 
Long-term Follow-up
Period
The period of time from the Day 365 Visit (Visit 14) through the completion 
of the 4½ year additional safety follow-up.
Preemptive Therapy
A therapeutic treatment regimen where treatment for an infection/disease is 
initiated only after it is detected/confirmed.
Primary Analysis 
Period
The time between the first dosing of study drug through 1 year post 
transplant
Primary Study 
Withdrawal
A subject who is randomized but does not complete the Primary Study 
Period for any reason. 
Prophylactic Therapy
A therapeutic treatment regimen where treatment is administered prior to the 
detectable presence of infection or disease as a preventative measure.
Randomization
The action to allocate a subject to a treatment group. In this study, 
randomization occurs after the subject has met all inclusion and exclusion 
criteria between days -3 to -14 prior to the transplant date.
Screening
The process for identifying a candidate for the study and evaluating their 
eligibility to participate.
Screen Failure
A subject who signs the informed consent and undergoes the 
protocol-specific screening procedures, but does not fulfill the protocol 
inclusion and/or exclusion criteria. This subject should not be randomized.


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Serious Adverse Event
An adverse event is considered “serious” if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: results 
in death, is life threatening, results in persistent or significant disability / 
incapacity or substantial disruption of the ability to conduct normal life 
functions, results in congenital anomaly or birth defect, requires inpatient 
hospitalization or leads to prolongation of hospitalization, or is a medically 
important event.
Treatment Emergent 
Adverse Events for 
SAP
Adverse events occurring after the first dose of study drug and up to 1 year 
post-transplant. 


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1
INTRODUCTION
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis that is described in the protocol, and includes detailed 
procedures for executing the statistical analysis of the primary and secondary endpoints and 
other data. 
The SAP is finalized and signed prior to study unblinding. The list of changes from the Final 
Version 2.0 that affect the analysis is documented in Section 8
Any analytical changes from the final version of the SAP will be documented in the Clinical 
Study Report (CSR).


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2
FLOW CHART AND VISIT SCHEDULE
Flow Chart
Primary Study Period: Screening/ICF through 12-months Post-Transplant 
(Day 365/Visit 14)
1.
Screening visit and V2 (first dose) may occur either separately or on the same day. Eligibility will be 
determined using local laboratory results collected at the screening visit. The first dose of study drug 
must be administered prior to conditioning therapy. The dosing interval in relation to 
transplant/conditioning must be maintained.
2.
Local laboratory assessments may be repeated 1 time if abnormal within the 25 day screening period.
3.
The subject may be rescreened 1 time if the transplant is delayed and it will be outside the 25 day 
screening window. If outside the 25 day screening period, all screening procedures must be repeated.
4.
Baseline is date of first dose (V2). The day of transplant (donor cell infusion) is day 0 and all visit days 
are relative to day 0.
5.
Note that the day 365 visit must occur on day 365 +14 days (between day 365 to 379); it cannot occur 
prior to day 365.








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7.
Safety Laboratory will be drawn at the screening visit using the local laboratory. Safety laboratory will be done by a central laboratory at baseline, before doses 2-5, and at each 
follow-up time point for doses 2-5, and will include hematology and biochemistry, including a hepatic profile. Please refer to [Protocol Appendix 1] for a full list of routine safety 
parameters that will be tested, and to [Protocol Section 5.4.3] and the Laboratory Manual for further instruction on laboratory collection and processing.
8.
Screening for cytomegalovirus (CMV) immunoglobulin G (IgG) seropositivity by the local laboratory may be performed up to 30 days prior to transplant and before 
randomization.
9.
The modified hematopoietic cell transplant-comorbidity index (HCT-CI) score are to be completed during screening with history and laboratory from the screening visit. Local 
laboratory results are to be used in the assessment. Local laboratories may be repeated once to score the HCT-CI. Pulmonary function tests (PFTs) including forced expiratory 
volume (FEV1) and diffusing lung capacity of carbon monoxide (DLco), multi gated acquisition scan (MUGA), and/or echocardiograms performed within 6 months (180 days) 
prior to screening are to be used for scoring pulmonary and cardiac comorbidities. PFTs (FEV1 and DLco), MUGAs /or echocardiograms not performed within 6 months of 
screening will have to be repeated for scoring purposes. 
10.
For all females of childbearing potential, a urine or serum pregnancy test will be performed at screening, on the same day and prior to each dose, at visit 13, and at the primary 
study period completion/day 365 visit (V14). All pregnancy tests will be done locally. For subjects who receive mycophenolate mofetil, additional pregnancy testing should be 
done in accordance with local regulatory requirements.
11.
All AEs and SAEs will be collected from signing of the informed consent through 30 days post last dose of study drug. All events requiring adjudication (CMV end organ disease 
[EOD], initiation of CMV-specific antiviral therapy [AVT], and cause of death), grade 3 and higher grade AEs as well as all SAEs will be collected from 31 days post last dose of 
drug through 1 year post-transplant. A change in medical status or medical history from time of signing of informed consent through first dose of study drug is to be reported as 
an AE or SAE as applicable. In this study, the day 0 HCT is not considered an AE.  
12.
The EuroQol – 5D (EQ-5D), Functional Assessment of Cancer Therapy – Bone Marrow Transplant (FACT-BMT), and Work Productivity and Activity Impairment 
Questionnaire (WPAI) are to be completed by the subject prior to any other study assessments or visit procedures. Subjects are to complete these assessments in the following 
order: EQ-5D first, FACT-BMT second, WPAI:GH last. For all 3 patient-reported outcome measures, i.e. EQ-5D, FACT-BMT, WPAI, the answers must come from the subject. 
If the subject is unable to fill out the questionnaire, the assessment should not be performed. If the subject is unable to answer a question, the rest of the questionnaire still needs 
to be completed.
13.
Immunogenicity laboratories include collection of blood for the glycoprotein B (gB) antibody and phosphoprotein 65 (pp65) T-cell assays. Samples are to be drawn on visits V2, 
V5, V8, V9, V11 and V14. Samples for T-cell assays will not be collected if the absolute lymphocyte count is known to be < 500 mm3 by local or central laboratory 
measurement. If the visit coincides with a study drug administration, the sample will be drawn prior to injection.
14.
The platelet count must be at least ≥ 50000 mm3 (spontaneously or after platelet transfusion) performed by the local laboratory within 3 days prior to all study drug injections. 
Prior to all study drug injections, confirmation must be made that there is no medical contraindication to an IM injection. Results received in an equivalent local unit of measure 
must be converted to SI units.  If the subject’s platelet count does not meet this threshold at the time of the visit, the subject may return for the study drug injection and local 
reactogenicity assessment at a later time within the allowable window for the visit. If the subject’s platelet count does not meet this threshold during the visit window, the dose 
must be skipped and the corresponding follow-up safety laboratory and reactogenicity assessment should not be done. The second injection should be given as close to, but not 
prior to, day 14 as possible.
15.
Subjects who consent to participate in the pharmacogenomics (PGx) substudy will have a saliva sample collected during the baseline visit (V2), after randomization but prior to 
the first dose of study drug.
Footnotes continued on next page


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16.
Plasma viral load by the central laboratory will be monitored weekly (± 2 days) during days 0-100, every other week (±5 days) during days 101-180, every 30 days (±5 days) 
during days 181-365, at the initiation of CMV-specific AVT, when clinically indicated, and every time a viral load sample is sent to the local laboratory. When CMV-specific 
AVT is initiated, a central CMV viral load will be obtained a minimum of weekly until CMV-specific AVT is discontinued. Thereafter, the regularly scheduled viral load 
assessments will resume according to the scheduled protocol assessments.
17.
The first dose is to be given at day -14 to -3 prior to transplant and within 72 hours prior to the start of chemotherapy and radiation therapy for conditioning.
18.
The subject must be monitored directly for the first 15 minutes of the injection. The subject must be in the clinic, but does not require direct monitoring, from 15 minutes through 
1 hour after the injection.
19.
Local reactogenicity will be evaluated 1 hour (± 10 minutes) after each injection and for each of the 7 consecutive days following each injection beginning approximately 
24 hours following each dose (day 1-7 postdose). The assessments for each of the 7 consecutive days following an injection will be done by the subject and reported to the site via 
diary. When reactogenicity is reported as an AE, it is to be followed until resolution or medically stable. All local reactions ≥grade 3 (Protocol Appendix 7) require confirmation 
by a health care professional.
20.
The date of transplant (donor cell infusion) defines day 0 and all visit days are relative to day 0. Based on this schedule, V3 may occur prior to or after the day of transplant, 
day 0.  
21.
Transplant information includes recipient transplant volume infused, HLA typing of the donor and recipient, HLA cross match at time of transplant (as determined by the site’s 
standard method of determination and, if available), type of transplant, the number of CD34+ stem cells/kg infused if available, donor and recipient CMV serostatus, if available 
the hepatitis B virus (HBV) serostatus, hepatitis C virus (HCV) serostatus, and Epstein Barr Virus (EBV) serostatus of the donor and recipient; blood type of the donor and 
recipients. ABO cross match (if available), donor-recipient relatedness, donor gender, age, race (if available) and ethnicity (for the USA only and if available); donor product 
plasma, volume and RBC depletion status; and if available donor cell product CD3+, CD4+, CD8+ and CD56+ cell counts. For bone marrow recipients, the number of 
mononuclear cells transfused must also be included, if possible.
22.
Optional: A 20 mL peripheral blood sample from the CMV seropositive donors will be obtained prior to the stem cell donation for recipients participating in the main trial to test 
for CMV-specific T-cells (requires donors’ consent). For those donating peripheral stem cells, the donor blood sample is to be collected prior to the initiation of mobilization 
therapy (e.g., G-CSF). Not applicable to sites in Japan.
23.
Acute and chronic GVHD is to be assessed and graded/globally scored and the KPS will be used to assess performance status at baseline and V5, V7, V9, V11, and V13 
following transplant (day 0) through the primary study period completion/day 365 visit (V14) except when the visit is conducted by HHC. In addition, aGVHD needs to be 
assessed weekly through day 100. When a diagnosis of aGVHD is made for a subject, assessments are to continue weekly until resolution for maximal grade and stage by key 
organs. Local laboratories may be used for staging. When a diagnosis of cGVHD or aGVHD is made by a health care professional for a subject, the subject should return to the 
study center for evaluation and data collection, and assessments are to be done at each regularly scheduled protocol visit until resolution; the maximum score during the interval 
from the last assessment to the current assessment is to be recorded for assessments performed at the study site. 
24.
If the subject does not meet the criteria for dosing by day 40, V5 procedures (except study drug injection and local reactogenicity assessment) need to be completed within 5 days 
of day 40 (day 40 to 45) and V6 should be skipped.   
25.
The day 365 visit must occur on day 365 +14 days (between day 365 to 379); it cannot occur prior to day 365 for subjects who do not prematurely withdraw from both treatment 
and continued follow-up. For a subject who prematurely withdraws from the study (discontinues treatment with no continued follow-up), the study completion visit is to be 
completed within 14 days of study withdrawal.


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3
STUDY OBJECTIVE(S) AND DESIGN
3.1
Study Objectives
●
To evaluate the efficacy of ASP0113 compared with placebo as measured by a primary 
composite endpoint of overall mortality and CMV end organ disease (EOD) through 
1 year post-transplant.
●
To evaluate the safety of ASP0113 in subjects undergoing allogeneic HCT.
3.2
Study Design
Study 0113-CL-1004 is a Phase 3 randomized, double-blind, placebo-controlled trial. 
Randomized subjects will receive 5 injections of either ASP0113 or placebo in the following 
5 periods where the days are relative to the day of transplant (Day 0): Days -14 to -3, 14 to 
40, 60 ±5, 90 ±10 and 180 ±10. The first study drug injection will be given on the same day 
as, but prior to, the start of chemotherapy and radiation therapy for conditioning and the 
second injection should be given as close as possible to, but not prior to, Day 14. All study 
drug injections will be administered only when the platelet count is ≥ 50000 mm3
(spontaneously or after platelet transfusion) and when there is no medical contraindication to 
an intramuscular (IM) injection.
3.3
Randomization
At the Screening Visit, after the Informed Consent Form (ICF) has been signed, the subject 
receives a subject number assignment through the IRT for use throughout the study.
Subjects who subsequently meet all inclusion and none of the exclusion criteria will be 
randomly assigned to receive either ASP0113 or placebo. The randomization to treatment 
groups will be equally allocated in a 1:1 ratio and stratified by donor-recipient relatedness 
and donor CMV serostatus. 
The IRT vendor generates the randomization schedule. To obtain the randomized treatment 
assignment for a subject, the pharmacist or designee utilizes an IRT, which is available 7
days a week, 24 hours a day.
Randomization is done after the completion of the Screening period, and at least 14 to 3 days 
prior to the anticipated transplant day (Day 0). After submitting required information about 
the eligible subject, the drug kit number assignment is provided. Study drug assignment 
remains blinded to all site staff except the pharmacist and designated staff.
Randomization of subjects will continue until approximately 500 subjects have been received 
at least 1 dose of the study. Subjects who discontinue the study early after receiving the first 
dose of study drug will not be replaced. 
4
SAMPLE SIZE
In the primary analysis set of a Phase 2 study of the efficacy of ASP0113 in HCT, 7 subjects 
died and 2 additional subjects experienced CMV EOD out of 40 treated with ASP0113, for 


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an overall failure rate of 22.5%, while among the placebo subjects 11 subjects died and 1 
additional subject experienced CMV EOD out of 34, for an overall failure rate of 35.3%. 
To detect the estimated difference in mortality and CMV EOD from the phase 2 study 
(35.3% vs. 22.5%), the study needs a sample size of at least 424 (212 per arm) to have 80% 
power at the 2-sided significance level of 0.050. A trial of size 500 (250 per arm) is expected 
to have 86% power for the composite endpoint.
All calculations used nQuery Advisor 7.0, procedure PPT1 [2 group continuity corrected χ2
test of equal proportions (odds ratio = 1) (equal n’s)] with the assumptions described above.
5
ANALYSIS SETS
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses.
This SAP is for the data that is included for the primary analysis period which is defined as 
1-year period from the transplantation for the efficacy assessment while the safety analysis 
will be analyzed from the first study drug injection. Certain data summaries will consider the 
analysis windows as specified in the relevant sections. The analysis for the long-term follow 
up data will be developed in a separate SAP.
5.1
Full Analysis Set 
The Full Analysis Set (FAS) consists of all randomized subjects who receive at least 1 dose 
of randomized study drug. Subjects will be included in analyses using the FAS based on 
assigned treatment. Summaries of demographic and baseline characteristics will be provided 
for the FAS and the FAS will also be used for efficacy analyses.
5.2
Modified Full Analysis Set 
The Modified Full Analysis Set (mFAS) will consist of all subjects in the FAS, except for 
68 subjects who were included in the first time futility analysis. Summaries of demographic 
and baseline characteristics will be provided for the mFAS, and the mFAS will also be used 
for efficacy analyses. 
5.3
Per Protocol Set 
The Per-Protocol Set (PPS) includes subjects from the FAS who do not meet the prespecified 
PPS exclusion criteria as listed in Section 5.3.1 of this SAP.
The allocation of subjects to the PPS will be determined prior to database unblinding. An 
independent document for the Classification Specifications will be developed and signed. 
Final judgments on exclusion of subjects from the PPS will be made at the blinded data 
review meeting (BDRM), which will be held prior to treatment unblinding. 
The PPS set may be utilized for efficacy analyses applied to both FAS and mFAS, as 
appropriate.


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5.3.1
Reasons for Exclusion From PPS
The following reasons may lead to a subject’s exclusion from PPS:
●
Did not undergo HCT.
●
Received different study drug injection from randomized, or study drug is switched 
during the study
●
Administration of prohibited concomitant treatment as described in the Study Protocol.
●
Violation of the following inclusion or exclusion criteria which may affect the 
assessment of the efficacy of the study drug:
○
Inclusion criterion No 3, subject was CMV-seropositive HCT recipient as
confirmed by local laboratory at screening. 
○
Inclusion criteria No 4 and 5, subject did not undergo 1 of the procedures 
indicated in these inclusion criteria.
○
Inclusion criterion 6, subject did not have any of the indicated underlying 
conditions. 
○
Inclusion criterion 13, subject participated in another interventional study 
while on treatment. 
○
Exclusion criterion No 1, subject had active CMV disease or infection or had 
received treatment for active CMV disease or infection within 3 months 
(90 days) prior to transplant.
○
Exclusion criterion No 6, subject received any of the following substances or 
treatments: 

Alemtuzumab within 60 days prior to transplant, including 
conditioning regimen. 

T-cell depletion of donor cell product. 

Administration of a CMV vaccine, including any prior exposure to 
ASP0113.
○
Exclusion criterion No 7, subject received an allogeneic stem cell transplant 
within 1 year prior to transplant.
○
Exclusion criterion No 12, subject received a prior HCT and had residual 
cGVHD.
5.4
Safety Analysis Sets
The Safety Analysis Set (SAF) consists of all randomized subjects who received at least 
1 dose of study drug injection. Subjects will be included in the treatment group that the 
subject received as first injection. 
There will be 2 additional safety analysis sets. The Modified Safety Analysis Set (mSAF) 
will consist of all subjects in the SAF excluding the 68 subjects who were included in the 
first futility analysis. Another additional safety set will consist of the 68 excluded subjects 
and will be notated as xSAF. 
5.5
Pharmacokinetics Analysis Set (PKAS)
Pharmacokinetics are not applicable to this study.


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5.6
Pharmacodynamic Analysis Set (PDAS)
Pharmacodynamics are not applicable to this study.
5.7
Immunogenicity Analysis Set 
The Immunogenicity Analysis Set (IAS) will include subjects who received at least 1 dose of 
randomized study drug and for whom at least 1 post-transplant immunogenicity measurement 
is available.
The IAS will be used for analyses of the immunogenicity data.
6
ANALYSIS VARIABLES
6.1
Efficacy Endpoints
6.1.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the proportion of patients with composite of all-cause
mortality and adjudicated CMV EOD through 1 year post-transplant. 
6.1.2
Secondary Efficacy Endpoints
6.1.2.1 Key Secondary Efficacy Endpoints
The 2 key secondary efficacy endpoints are:
●
Time to first protocol-defined CMV viremia through 1 year post-transplant. CMV 
viremia is defined in the study protocol as CMV plasma viral ≥1000 IU/mL as assessed 
by the central laboratory.
●
Time to first use of adjudicated CMV-specific AVT after study drug first injection 
through 1 year post–transplant. 
6.1.2.2 Other Secondary Efficacy Endpoints
Additional secondary efficacy endpoints are:
●
Proportion of patients with a composite endpoint of CMV viremia and CMV-specific 
AVT use per the adjudication committee
●
Time to first event of either use of CMV-specific AVT or diagnosis of CMV EOD after
study drug first injection through one year post-transplant. This endpoint is a composite 
endpoint based on the independent adjudication committee assessments of CMV-specific 
AVT and CMV EOD.  
●
All-cause mortality at 1 year post-transplant
6.1.3
Exploratory Efficacy Endpoints
Exploratory efficacy endpoints include the following efficacy outcomes. 
●
Clinical outcomes:
○
Composite endpoint of all-cause mortality and adjudicated CMV EOD at 6 
months post-transplant 
○
All-cause mortality at 6 months post-transplant


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○
Incidence of adjudicated CMV EOD
○
Incidence of investigator-reported CMV EOD
○
Incidence of grade 3-4 aGVHD
○
Incidence of grade 3 treatment emergent viral, bacterial, or fungal infections 
other than CMV 
○
Maximum grade of aGVHD
○
Relapse mortality (death due to relapse of the subject’s primary disease)
○
Non-relapse mortality (death due to causes unrelated to the subject’s primary 
disease)
○
Incidence of engraftment (Yes/No)
○
Incidence of graft rejection/poor graft function
○
Incidence of relapse of primary disease requiring therapy
○
Number of episodes of protocol-defined CMV viremia [CMV plasma viral 
load ≥ 1000 IU/mL by the Abbott RealTime CMV assay as assessed by the 
central laboratory]
○
Association between CMV viremia and mortality
●
Duration of hospitalization(s), in days:
○
Total duration of ICU stays
○
Total duration of stays in step down units
○
Total duration of stays in hospital general medical/surgical ward
○
Total duration of all hospitalizations
●
Total number of days in emergency room and total number of visits to emergency room
Death will be classified as relapse mortality (adjudication CRF indicates ‘Death due to 
relapse of persistent disease’) or non-relapse mortality (‘Death not due to relapse of persistent 
disease’) by a blinded adjudication committee. If a death has not been adjudicated (e.g., 
discovered through public records search without a corresponding adverse event) then it will 
not be considered in either the relapse or the non-relapse mortality analyses.
In determining the number of episodes of protocol-defined CMV viremia, an episode will be 
considered to start when a viral load is load ≥1000 IU/mL and previous viral loads are <1000 
IU/mL. An episode will be considered to end when 2 consecutive viral loads < 1000 IU/mL 
separated by at least 1 week are observed. 
Treatment emergent infections are those occurring after the first dose of study drug and up to 
1 year post-transplant. 
Total duration of hospitalization will be the sum of hospitalization days added up over all the 
hospitalizations experienced by a subject within 1 year after transplantation, and will include 
days in intensive care, step down units and general medical/surgical wards. For comparing 
treatments, total duration of hospitalization will be normalized to days of hospitalization per 
year by dividing number of hospitalization days by the number of days of follow-up (starting 
from day of transplantation), times 365. For example, if a subject has a 3-day hospitalization 
and a 5-day hospitalization, and is lost to follow-up at 64 days post-transplant, then the value 
of 45.625 days/year will be used for this subject (365 x 8 / 64 = 45.625). 


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The same method of normalization will be used for total duration of stays in ICUs, total 
duration of stays in step down units, total duration of stays in hospital general 
medical/surgical ward, and total number of emergency room days. The number of emergency 
room visits will not be normalized.
6.1.3.1 Hospitalizations, Health Economic, and Quality of Life Variables
Health economics and clinical outcomes research variables include the following. Further
analyses of these endpoints will be described in a separate SAP.
●
Subjects’ quality of life variables 
○
EuroQol (EQ-5D) dimensions

Mobility 

Self-Care 

Usual Activities 

Pain/Discomfort 

Anxiety/Depression
○
Functional Assessment of Cancer Therapy – Bone Marrow Transplant 
(FACT-BMT)
○
Work Productivity and Activity Impairment Questionnaire: General Health 
(WPAI: GH)
●
Health Economic Assessment (HEA) 
The EQ-5D, FACT-BMT and WPAI: GH are assessed at each dosing visit, at V13 and at the 
Primary Study Period Completion/Day 365 Visit (V14). Information about administration of
these assessments can be found in the study protocol. 
Health economic information will be collected for subjects through the Primary Study Period 
Completion/Day 365 Visit (Visit 14).
6.1.3.1.1
Health Economic Assessments
Health Economic Assessments will include the following: concomitant medications and 
procedures, hospitalizations, nonscheduled clinic visits and emergency room visits. The 
information will be collected by the site via a retrospective review of the subject’s medical 
record. HEA data will include both data being routinely captured for the subject 
(e.g., concomitant medications) as well as data that will be used specifically for these 
analyses (e.g., information on hospitalizations).
6.1.3.1.2
EuroQol (EQ-5D)
The EQ-5D is an international standardized non-disease-specific (i.e., generic) instrument for 
describing and valuing health status. It is a measure of health-related quality of life (QOL), 
capable of being expressed as a single index value and specifically designed to complement 
other health status measures. The EQ-5D has 5 dimensions: Mobility, Self-Care, Usual 
Activities, Pain/Discomfort and Anxiety/Depression. Each dimension has 5 response levels 
(e.g., 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, 


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5=extreme problems). In addition, it has a visual analogue scale that elicits a self-rating by 
the respondent of his/her health status.
6.1.3.1.3
Functional Assessment of Cancer Therapy-Bone Marrow Transplant 
(FACT-BMT)
The Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) is a 
self-administered instrument designed to assess multi-dimensional aspects of QOL in bone 
marrow transplant (BMT) patients. It consists of the 27-item FACT-General (FACT-G) and 
the 23-item Bone Marrow Transplantation Subscale (BMTS). The FACT-G assesses 4
primary dimensions of QOL, including physical well-being (7 items), social-family 
well-being (7 items), emotional well-being (6 items) and functional well-being (7 items). 
A 5-point response scale ranging from 0 to 4 is used (0 = 'not at all'; 1 = 'a little bit'; 
2 = 'somewhat'; 3 = 'quite a bit'; and 4 = 'very much').
6.1.3.1.4
Work Productivity and Activity Impairment Questionnaire: General Health 
(WPAI: GH)
The Work Productivity and Activity Impairment Questionnaire: General Health (WPAI: GH) 
is a 6-question instrument designed to assess the effect of health problems (physical or 
emotional problem or symptom) on an individual’s ability to work and perform regular 
activities [see Protocol Appendix 16]. The WPAI: GH is assessed at each dosing visit, at V13 
and at the Primary Study Period Completion/Day 365 Visit (V14). 
Questions of the WPAI: GH are as follows.
1. Are you currently employed (working for pay)?
2. During the past 7 days, how many hours did you miss from work because of your health 
problems? Include hours you missed on sick days, times you went in late, left early, etc., 
because of your health problems. Do not include time you missed to participate in this study.
3. During the past 7 days, how many hours did you miss from work because of any other 
reason, such as vacation, holidays, time off to participate in this study?
4. During the past 7 days, how many hours did you actually work?
5. During the past 7 days, how much did your health problems affect your productivity while 
you were working?
Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully as 
usual. If health problems affected your work only a little, choose a low number. Choose a 
high number if health problems affected your work a great deal.
6. During the past 7 days, how much did your health problems affect your ability to do your 
regular daily activities, other than work at a job?
By regular activities, we mean the usual activities you do, such as work around the house, 
shopping, childcare, exercising, studying, etc. Think about times you were limited in the 


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amount or kind of activities you could do and times you accomplished less than you would 
like. If health problems affected your activities only a little, choose a low number. Choose a 
high number if health problems affected your activities a great deal.
If the answer to Question 1 is “No”, Questions 2 through 5 are skipped. The answers to 
Questions 2, 3, and 4 are given in hours. If the answer to Question 4 is “No”, Questions 5 is 
skipped. Question 5 is answered by circling a number from 0 to 10, with 0 representing 
“Health problems had no effect on my work” and 10 representing “Health problems 
completely prevented me from working”. Question 6 is likewise answered by circling a 
number from 0 to 10, with 0 representing “Health problems had no effect on my daily 
activities” and 10 representing “Health problems completely prevented me from doing my 
daily activities”.
WPAI: GH outcomes are expressed as impairment percentages, with higher numbers 
indicating worse outcomes, as follows. 
Q1 = currently employed.
Q2 = hours missed due to health problems.
Q3 = hours missed other reasons.
Q4 = hours actually worked.
Q5 = degree health affected productivity while working.
Q6 = degree health affected regular activities.
If Q1 = ‘Yes’ then the following are calculated. 
Percent work time missed due to health = 100% x Q2/(Q2+Q4).
Percent impairment while working due to health = 100% x Q5/10.
Percent overall work impairment due to health 
= 100% x Q2/(Q2+Q4)+[(1-(Q2/(Q2+Q4))x(Q5/10)]. 
If Q1 = ‘No’ then the above quantities should be considered missing values. 
For all subjects, the following will be calculated. 
Percent activity impairment due to health = 100% x Q6/10.
6.1.4
Immunogenicity Variables
An indicator of immunogenicity elicited by the vaccine is expected to be an increase in 
Gb-specific antibody levels and the T-cell response to the pp65 protein over time compared 
with the placebo group. 
Two immunogenicity assessments will be performed:
1. T-cell response to viral protein pp65 using cultured ELISpot .
2. Antibody response to gB antigen using an ELISA-based platform.


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Assessments will be done from peripheral blood mononuclear cells (T-cells) or serum samples 
(antibody) isolated over the course of the trial. Time points of the assessments are as follows:
On Visits V2, V5, V8, V9 and V11 and V14:
o
Samples for T-cell assays will not be collected if the Absolute Lymphocyte Count 
(ALC) is known to be < 500 mm3 by local or central laboratory measurement. 
o
If the visit coincides with a study drug administration, the sample will be drawn 
prior to injection.
Further details will be available in the Laboratory Manual.
6.2
Safety Variables
Safety will be assessed by evaluation of the following variables:
●
Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature 
and weight).
●
Adverse events using the NCI-CTCAE v. 4.03 grading scale.
●
Acute and non-acute Local reactogenicity signs and symptoms using the protocol-
specified reactogenicity scales, as described in Appendix 7 of the study protocol.
●
Clinical laboratory assessments.
●
Physical examinations.
●
Treatment emergent adverse events (TEAEs; frequency, severity, seriousness and 
relationship to study drug).
Per protocol, All AEs and SAEs will be collected from signing of the ICF through 30 days 
post last dose of study drug. All events requiring adjudication, Grade 3 and higher AEs and 
SAEs will be collected from 31 days post last dose of drug through 1 year post-transplant. 
TEAE is defined as an adverse event observed on the day or after the first injection up to 
1 year post-transplant. If the adverse event occurs on the day of the first injection of study 
drug and the onset check box is marked “Onset after first dose of study drug” or the onset 
check box is left blank in eCRF, then the adverse event will be considered treatment 
emergent. If the adverse event occurs on the day of the first injection of study drug and the 
onset check box is marked “Onset before first dose of study drug”, then the adverse event 
will not be considered treatment emergent. If a subject experiences an event both during the 
pre-investigational period and during the investigational period, the event will be considered 
as TEAE only if it has worsened in severity (i.e., it is reported with a new start date). 
The definition of TEAE for this SAP includes adverse events through 1 year post-transplant, 
regardless of the date of last study medication, rather than only 30 days after the last dose of 
study medication. This is because, as noted above, all events requiring adjudication, Grade 3 
and higher AEs and SAEs are collected through 1 year post-transplant. A drug-related TEAE 
is defined as any TEAE with possible or probable relationship to study treatment as assessed 
by the investigator. Any AE with a missing relationship per the investigator will be counted 
as study drug related AE in the summary. 


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Any AE with a missing severity per the investigator will be counted as severe, and any AE 
with a missing seriousness per the investigator will be counted as serious.
Astellas ‘Always Serious AE’ are identified by Astellas and then queries are issued to the
Investigator to consider upgrading the event to serious. If the investigator agrees to upgrade, 
then the site submits an SAE form for the event and adds the SAE number to RAVE. If they 
do not agree to upgrade the event, then only the SAE number is entered into RAVE. If an AE 
has an SAE number on RAVE it is considered Serious even if not indicated as such on the 
AE record.  
6.3
Pharmacokinetic Variables
Pharmacokinetics will not be analyzed in this study.
6.4
Pharmacodynamic Variables
Pharmacodynamics will not be analyzed in this study.
7
STATISTICAL METHODOLOGY
7.1
General Considerations
All statistical analyses and summary information will be generated according to this 
statistical analysis plan. Any analytical deviations from this plan will be documented in the 
clinical study report. All numerical rounding should be performed at the end of calculations. 
The p-values will be displayed with 3 significant digits. Statistical significance will be 
determined prior to rounding the p-value.
For continuous variables, descriptive statistics will include the number of subjects (n), mean, 
standard deviation (SD), median, minimum and maximum. Frequencies and percentages will 
be displayed for categorical data. Percentages by categories will be based on the number of 
subjects with no missing data ( i.e., will add up to 100%).
The analyses with the randomization stratification factors, donor-recipient relatedness 
(Related/Non-related) and donor CMV serostatus (Positive/Negative), that are used in the 
analyses will be based on the data from IRT. 
All statistical comparisons will be made using 2-sided tests at the α=0.05 significance level 
unless specifically stated otherwise. 
The analysis day will be calculated from the day of transplantation day (efficacy analysis 
day 0). Further details on data handling conventions are specified in Section 7.10  For 
patients who took study drug but did not receive HCT, the analysis day will be calculated 
from the first study drug injection day (safety analysis day 1).
This SAP includes the plan for data analysis for the primary study period (i.e., 1-year post 
transplantation) which is defined as data collected through day 380 (=365+14+1 day) from 
transplantation. The long-term follow-up period is not covered by this SAP and will be 
managed in a separate SAP.


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All data processing, summarization, and analyses will be performed using SAS® Version 9.4
or higher on Unix.
7.2
Study Population
7.2.1
Disposition of Subjects
Disposition of subjects will be summarized for the following:
●
Number and percentage of subjects with informed consent, discontinued before 
randomization, and randomized (overall only);
●
Number and percentage of subjects randomized in each analysis set, by treatment group
and overall;
●
Number and percentage of subjects completed and discontinued treatment, by reason for 
treatment discontinuation for randomized subjects, by treatment group; 
●
Number and percentage of subjects completed and discontinued the study, by reason for 
study discontinuation for randomized subjects and by treatment group; 
●
Number and percentage of subjects excluded from the PPS by reason for exclusion 
defined in Section 5.3.1, by treatment group for the FAS and mFAS
Number of subjects randomized in each country and site will be tabulated by treatment group
and overall.
7.2.2
Protocol Deviations
Protocol deviations as defined in the study protocol (Section 8.1.6 Protocol Deviations) will 
be assessed for all randomized subjects. The number and percentage of subjects meeting the
criteria will be summarized for each criterion and overall, by treatment group and total as 
well as by study site. Subjects deviating from a criterion more than once will be counted once 
for the corresponding criterion. Subjects who meet more than 1 criterion will be counted once 
in the overall summary. A data listing will be provided by site and subject. 
The unique protocol deviation criterion will be as follows:
PD1 - Entered into the study even though they did not satisfy entry criteria, 
PD2 - Developed withdrawal criteria during the study and was not withdrawn,
PD3 - Received wrong treatment or incorrect dose,
PD4 - Received excluded concomitant treatment. 
7.2.3
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized descriptively by the 
treatment group and overall for FAS, mFAS, PPS-FAS, PPS-mFAS, SAF, mSAF, and xSAF 
populations.
Descriptive statistics for age, weight, body mass index (BMI) and height at study entry will 
be presented. Frequency tabulations for sex, ethnicity, age group (Age < 65 years, Age ≥ 65 
years), race, BMI categories (<25, 25 to <30, and ≥30 kg/m2), ATG use, AML use, and 
myeloablative conditioning regimen will be done. Randomization strata donor-recipient 


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relatedness and donor CMV serostatus will be tabulated. Each of these combinations will also 
be tabulated. The ATG use (Yes/NO) and myeloablative or nonmyeloablative conditioning 
regimen will be tabulated from the eCRF according to the investigator’s assessment. 
Medical history is coded in MedDRA and will be summarized for treatment group and 
overall for SAF. One summary table will include SOC and PT and the other summary table 
will include PT in descending order of total group. 
7.2.4
Previous and Concomitant Medications
Previous and concomitant medications are coded with WHO-DRL, and will be summarized 
by therapeutic subgroup (ATC 2nd level) and chemical subgroup (ATC 4th level) and 
preferred WHO name by treatment group for the FAS and mFAS populations.
Previous medications are defined as medications that patients started and ended prior to first
administration of study medication. Concomitant medications are defined as any medications 
that patients took after the first dose of study medication and through 1-year post-
transplantation (i.e., 380 days from transplantation). Any previous medications that continued 
while study drug was given will be counted as both previous and concomitant medications.
Subjects taking the same medication multiple times will be counted once per medication and 
investigational period. A medication which can be classified into several chemical and/or 
therapeutic subgroups is presented in all chemical and therapeutic subgroups.
Antiviral therapies, including those used for reasons other than CMV infection, are of special 
interest. These medications will be summarized by reason for use. 
7.2.5
Transplant Information
The following characteristics of the transplant procedure will be summarized by treatment 
group and overall for FAS and mFAS populations
●
Recipient and donor HLA cross match at time of transplant 
●
Donor and recipient ABO and Rh blood types and cross match
●
Number of CD34+ stem cells/kg infused
●
Donor/recipient CMV serostatus
●
Hepatitis B virus, Hepatitis C virus, and Epstein-Barr Virus serostatus of the donor and 
recipient, if available
●
Donor-recipient relatedness
●
Modified HCT-CI total score assessed by the investigator
●
Product infused (bone marrow or peripheral blood stem cells)
●
Donor cell product CMV-specific T-cells (optional and requires informed consent from 
donor)
The number of HLA mismatches will be summarized overall and separately by type (A, B, 
and DR) as categorical data. For the overall number of HLA mismatches, the following 
categories will be used: 0, 1, 2, ≥3. The derivation of HLA mismatches is detailed in
Appendix 1


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7.3
Study Drug
For each treatment group, descriptive statistics of the number of doses of the drug subject 
received will be presented. Descriptive statistics of time from first dose to final dose of study 
drug will be presented by treatment group. Furthermore, the number of subjects receiving 
study drug at each scheduled dose will be presented. These summaries will be produced for 
the FAS, mFAS, PPS-FAS, PPS-mFAS, SAF, mSAF, and xSAF populations.
All injections of study medication are to be administered when the subject’s platelet count is 
≥ 50000 mm3 (spontaneously or after platelet transfusion) within 3 days prior to dosing. The 
numbers of subjects not receiving study drug injections due to this pre-condition will be 
summarized by treatment group. Additionally, the number of subjects who did receive 
injection although the subject’s platelet count is <50,000 mm3 will be tabulated.
7.4
Analysis of Efficacy 
7.4.1
Analysis of Primary Endpoint
7.4.1.1 Primary Analysis of the Primary Endpoint 
The primary endpoint which is the composite of all-cause mortality and adjudicated CMV 
EOD through 1 year post-transplant will be analyzed for the FAS population as the primary 
analysis. Deaths occurring up to day 365 from transplant will be counted. In other words 
deaths occurring on or before 365 days after transplant will be counted, although it could be 
reported later. Patients with CMV EOD that is assessed by the independent and blinded 
adjudication committee will be counted for the events that are observed up to day 380 from 
transplantation.
The odds ratio of the composite endpoint for the ASP0113 group over the placebo group will 
be compared to unity controlling for randomization stratifications of donor-recipient
relatedness and donor CMV serostatus by the Cochran-Mantel-Haenszel (CMH) test. The 
null (H0) and alternative hypotheses (H1) for this comparison are:
H0: Common Odds Ratio = 1.
H1: Common Odds Ratio ≠ 1.
The 2-sided p-values and the 95% confidence interval (CI) for the odds ratio from the CMH 
method will be calculated. The effect of ASP0113 will be considered statistically 
significantly superior to placebo if the p-value is less than 0.05.
Additionally, 1-RR with its 95% CI from the CMH method will be calculated as an additional 
descriptive summary.
For the purpose of the primary analysis, a subject who had a CMV EOD according to the 
adjudication committee and died will be counted in the mortality summary. A subject who 
died but the CMV EOD status is unknown will be counted toward the mortality summary. A 
subject with unknown survival status by day 365 will be counted a death if the subject does 
not have an adjudicated CMV EOD. A subject who is alive through day 365 and does not 
have the adjudicated CMV EOD will be counted as having no CMV EOD.


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This derivation plan is also shown in the following table: 
Composite Endpoint 
Derivation
Adjudicated CMV EOD is Yes
Adjudicated CMV EOD is not Yes
Survival Status=Died
Composite Endpoint=Yes 
(Count as Known Deaths)
Composite Endpoint=Yes 
(Count as Known Deaths)
Survival Status=Alive
Composite Endpoint=Yes 
(Count as Adjudicated CMV EOD)
Composite Endpoint=No 
Survival 
Status=Unknown
Composite Endpoint=Yes 
(Count as Adjudicated CMV EOD)
Composite Endpoint=Yes 
(Count as Unknown Survival Status)
An additional analysis will be repeated for the mFAS, PPS-FAS and PPS-mFAS.
7.4.1.2 Additional Analyses of the Primary Efficacy Endpoint
Additionally, the primary efficacy endpoint will be further evaluated using a different method 
and different data source for the FAS and mFAS analysis sets.
Time to first occurrence of the primary endpoint event will be analyzed in a Cox proportional 
hazards model where the time to event will be calculated in days from transplant to the 
earliest component observed. Subjects not experiencing the primary endpoint event will be 
censored at the time of their last follow-up visit. The last day of follow up visit will be 
defined as last known day alive. If a subject’s last known day alive is beyond day 380 and has 
no CMV EOD according to the adjudication committee, this subject will be censored on day 
380. The Cox model will include treatment group, donor/recipient relatedness, donor 
serostatus (the stratification factors for randomization). Additionally, 1- hazard ratio and its 
95% CI will be calculated.
Cumulative incidence functions (CIF) will be used to estimate the crude incidence of the 
primary endpoint by treatment group, and a Kaplan-Meier plot may also be considered.
7.4.1.3 Primary Analysis for Various Populations
As a supportive analysis for the primary efficacy endpoint of the composite endpoint of 
all-cause mortality and adjudicated CMV EOD through 1-year post-transplantation, the same 
CMH method as described in Section 7.4.1.1 will be further analyzed for the following 
analysis sets; mFAS, PPS-FAS and PPS-mFAS.
7.4.1.4 Subgroup Analysis 
Subgroup analyses on  the primary efficacy endpoint will be performed for FAS and mFAS 
analysis sets for the following subgroups:
●
Donor-Recipient Relatedness: (Related, Not Related)
●
Donor Serostatus: (Positive, Negative)
●
Age group: (Age<65 years, Age ≥65 years)
●
Sex: (Male, Female)
●
Race: (White, Black or African American, Asian, Other)
●
Geographic Region (North America, Europe, Asia, Australia)
●
ATG Use for Conditioning: (ATG Used, No ATG Used )


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●
Myeloablative Conditioning Regimen: (Yes, No)
●
AML Primary disease (Yes, No)
The observed odds ratio and its 95% CI based on the normal approximation for each level of 
subgroups will be calculated. 
The treatment-by-subgroup interaction will be evaluated using a logistic regression model 
with factors for treatment group, donor-recipient relatedness, donor CMV serostatus, the 
subgroup of interest, and treatment-by-subgroup interaction. If a subgroup with a level that 
has fewer than 10 patients within any treatment group, the level will be excluded when the 
interaction is assessed. The interaction will be evaluated at the significance level of 0.10. 
7.4.2
Analysis of Key and Other Secondary Efficacy Endpoints 
Two of the secondary efficacy endpoints will be considered as key secondary efficacy 
endpoints. 
7.4.2.1 Key Secondary Endpoint - Protocol-Defined CMV Viremia
The protocol-defined CMV viremia through 1 year post-transplant is defined as a CMV 
plasma viral load ≥1000 IU/mL by the central laboratory. The plasma viral load after 
transplantation through day 380 from transplantation day will be considered. A subject who 
has more than one time with CMV viral load ≥1000 IU/mL will be counted once. This 
endpoint will be analyzed by 2 statistical methods for FAS, mFAS and PPS-FAS.
A Cox proportional subdistributional hazards model will be used for the time-to-first 
protocol-defined CMV viremia through 1 year post-transplant. This model accounts for the 
competing risk of death, after which CMV Viremia can no longer be observed. A subject who 
has more than 1 incidence of having CMV viral load ≥1000 IU/mL will consider the first 
time of having this event. The Cox model will include treatment group, donor-recipient 
relatedness, donor CMV serostatus as factors in the model. From this model, 1 – Hazard 
Ratio and its 95% CI will be calculated. The p-value from this model will be calculated.
The treatment effect will also be evaluated with the following null hypothesis:
H0: 1-Hazard Ratio ≤ 20%.
While the alternative hypothesis is:
H1: 1-Hazard Ratio > 20%.
The p-value for the above hypothesis tests will use a Wald statistic using the Cox model 
parameter estimate for the treatment effect, θt:
Z = (θt – ln(1-20%))/S.E.(θt)
CIFs will be used to estimate the crude incidence of CMV Viremia by treatment group while 
accounting for the competing risk of death.
The analysis window extends to day 380 from the transplantation day in order to 
accommodate the protocol allowed visit windows. If a subject’s first event is after day 380, 
this subject will be censored on day 380 as the 1-year post transplantation is the primary 


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study period. A subject without an event will be censored on the last day of central laboratory 
assessment. In other words, if a subject has a central laboratory assessment beyond day 380 
that is negative, this subject will be censored on day 380. A subject who dies prior to 
reporting CMV Viremia will be handled using a competing risks model.
Additionally, the same CMH method as in the primary endpoint will be used to calculate 
odds ratio and its 95% CI and 1-relative risk and its 95% CI. The p-value from this method 
will also be calculated. 
7.4.2.2 Key Secondary Endpoint of Adjudicated CMV-Specific Antiviral Therapy
Subjects’ CMV-specific antiviral therapy (AVT) use will be adjudicated by the independent 
and blinded committee. This endpoint will be evaluated through 1 year post-transplant (i.e., 
through day 380 from transplantation) and will be considered as a key secondary efficacy
endpoint. This endpoint will be analyzed by 2 statistical methods for FAS, mFAS and PPS-
FAS.
A Cox proportional subdistributional hazards model will be used for time-to-first use of 
CMV-specific AVT through 1 year post-transplant. This model accounts for the competing 
risk of death, after which use of CMV-specific AVT can no longer be observed. If a subject 
used CMV-specific AVT more than once, the day of first use will be counted. If a subject did 
not use any CMV-specific AVT, the subject will be censored on the day of last study 
evaluation according to the end of study eCRF.
To evaluate the treatment effect compared to placebo, 1-Hazard Ratio, its 95% CI and 
p-value from the Cox model (as in Section 7.4.2.1) will be calculated.
CIFs will be used to estimate the crude incidence of CMV-specific AVT while accounting for 
the competing risk of death. 
Additionally, the same CMH method as in the primary endpoint will be used to calculate 
odds ratio and its 95% CI and 1-relative risk and its 95% CI. The p-value from this method 
will also be calculated.
7.4.2.3 Other Secondary Endpoints
7.4.2.3.1
CMV viremia and CMV-specific AVT Use
A composite endpoint of CMV viremia and CMV-specific AVT use per the adjudication 
committee will be analyzed as an additional secondary efficacy endpoint for FAS and mFAS 
analysis sets. The CMV viremia will be based on the protocol defined definition with plasma 
viral load ≥1000 IU/mL assessed by the central laboratory. Data that is observed through day
380 from transplantation will be included. 
This endpoint will be analyzed using the same CMH method as in the primary endpoint.
7.4.2.3.2
Time to CMV-specific Antiviral Therapy or End Organ Disease
A composite endpoint of time to first event between CMV-specific Antiviral Therapy (AVT)
use and CMV End Organ Disease (EOD) through 1 year post-transplant (i.e., through day 
380 from transplantation) will be analyzed for FAS and mFAS. Both CMV-specific AVT use 


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and CMV EOD will be based on the assessment of the adjudication committee. A subject 
without any event will be censored on the last study evaluation according to the end of study 
eCRF. A subject who dies prior to reporting CMV-specific AVT or EOD will be handled 
using a competing risks model.
This endpoint will be analyzed using the Cox proportional subdistributional hazards model 
and CIFs (to account for the competing risk of death) and CMH method, as described above 
for the key secondary endpoints. 
7.4.2.3.3
All-Cause Mortality
All-cause mortality will be analyzed by incidence and/or time to event approach for FAS and 
mFAS by treatment group.
All-cause mortality through 1-year post-transplantation summary will include all deaths and 
unknown survival status. For the known deaths, the adjudication committee assessed results 
will be summarized for the following category: Mortality due to the subject’s primary 
disease, and Mortality due to causes unrelated to the subject’s primary disease. 
All-cause mortality will be analyzed by 2 methods: time to event and the CMH method, as 
described for the primary analysis. For the time to event analysis, a subject with unknown 
survival status will be censored on the last day known alive. For the CMH analysis, subjects 
with unknown survival status by day 365 will be counted as dead.
7.4.3
Exploratory Endpoints
The analyses of all exploratory endpoints will be performed on the FAS and mFAS analysis 
sets. All endpoints derived from subjects’ visits will take an analysis window through day
380 from transplantation day while the mortality will be counted up to day 365.
7.4.3.1 Analyses of Clinical Outcomes Exploratory Endpoints
The following exploratory endpoints will be analyzed by incidence and/or time to event 
approach by treatment group. 
For the endpoint of adjudicated CMV EOD, and Investigator-reported CMV EOD, the 
summary will include incidence (i.e., number of episodes) where all events are added in 
addition to the number and percentage of subjects with at least one event. The proportion of 
subjects with an event will be analyzed by the CMH method and the odds ratio, its 95% CI 
and p-value will be calculated.  
●
Composite endpoint of all-cause mortality and adjudicated CMV EOD at 6 months 
post-transplant, using the same CMH approach as the primary endpoint. Deaths 
occurring up to day 180 from transplant will be counted. In other words deaths occurring 
on or before 180 days after transplant will be counted, although the death could be 
reported later. Patients with CMV EOD that is assessed by the independent and blinded 
adjudication committee will be counted for the events that are observed up to day 190 
from transplantation.


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●
All-cause mortality at 6 months post-transplant using time to event method, as described 
in Section 7.4.1.2  Deaths occurring up to day 180 from transplant will be counted. In 
other words deaths occurring on or before 180 days after transplant will be counted, 
although the death could be reported later.
●
Relapse mortality (death due to relapse of the subject's primary disease), using the same 
CMH approach as the primary endpoint.
●
Non-relapse mortality (death due to causes unrelated to the subject's primary disease), 
using the same CMH approach as the primary endpoint.
The proportion and number of subjects the events below will be descriptively summarized.
●
Proportion of grade 3-4 aGVHD
●
Proportion of engraftment (Yes/No)
●
Proportion of graft rejection/poor graft function
●
Proportion of relapse of primary disease requiring therapy
Additionally, number (percentage) of subjects by taking the maximum grade of aGVHD will 
be summarized.
Karnofsky Performance Scale (KPS) scores are collected at baseline and post-baseline. KPS 
scores will be descriptively summarized at baseline and the visits specified in schedule of 
assessments (Table 1), but KPS scores at any additional visits will only be listed.
The endpoint of grade 3 infections other than CMV will be summarized by the incidence 
counting all the events and number (percentage) of subjects. The number of subjects will be 
analyzed by the CMH method and the odds ratio, its 95% CI and the p-value will be 
calculated.
7.4.3.1.1
Association of CMV Viremia and Mortality
To estimate the association between CMV viremia and mortality, subjects in each treatment 
group will be cross-tabulated by viremia or no viremia within 1 year post-transplant, and by 
alive or dead at 1 year post-transplant. In addition, a multivariable Cox proportional hazards 
model will be constructed in a time-dependent manner. The model will be adjusted for the 
factors used to stratify the randomization. CMV viremia will be treated as a time-dependent
variable, starting at the time of the first occurrence of protocol-defined CMV viremia. The 
model for this analysis will include, in addition to CMV viremia, all the factors included in 
the final Cox regression model described earlier in this subsection.
7.4.3.1.2
Number of Episodes of Protocol-defined CMV Viremia
Number of episodes of protocol-defined CMV viremia [CMV plasma viral load ≥1000 
IU/mL by the Abbott RealTime CMV assay as assessed by the central laboratory] will be 
compared between treatments using the stratum-adjusted Kruskal-Wallis test, adjusting for 
donor-recipient relatedness and donor CMV status. 
Number of episodes of protocol-defined CMV viremia may be affected by duration of 
follow-up. Therefore, as a supporting analysis this variable will be compared between 


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treatments using a log-linear model with treatment, donor-recipient relatedness, and donor 
serostatus as factors and the log of time of follow-up as a covariate. 
7.4.3.2 Duration of Hospitalization, Health Economic, and Quality of Life Variables
Duration of hospitalizations, and days in emergency room, in days per year will be compared 
between treatments using descriptive statistics.
The number of emergency room visits, and Non-protocol-related physician visits, also will be 
compared between treatments using descriptive statistics.
The EQ-5D dimensions will be summarized as categorical variables by treatment arm at each 
visit and at final visit. Change from baseline in the EQ-5D VAS score will be summarized by 
treatment arm at each visit and at Final visit. 
Total FACT-BMT and the corresponding changes from baseline will be summarized by 
treatment arm at each visit and at Final Visit. 
The percent activity impairment due to health from the WPAI: GH and corresponding 
changes from baseline will be summarized by treatment arm at each visit and at Final Visit. 
Treatments will be compared with respect to each of these scales using analysis of covariance 
(ANCOVA) of change from baseline to final visit with treatment, donor-recipient relatedness, 
and donor CMV serostatus as factors and baseline value as a covariate. 
7.4.3.3 Immunogenicity Variables
T-cell responses to pp65 and gB-specific antibody levels will be summarized by visit and 
treatment group on the original scale. A plot of each of the immune responses over time by 
treatment will be produced. The comparisons between treatments will be made at each 
measurement visit using Wilcoxon rank sum test without adjusting for the multiplicity on the 
original scale. In addition, each of the immune response variables post baseline on the 
10 based log scale will be analyzed using repeated measures model, where the randomization 
stratum, treatment, time, and treatment by time interaction will be the explanatory variables. 
The self-consistent sandwich correlation structure will be used. If the test for the time by 
treatment interaction is significant (p value<0.1) the overall treatment group comparison will 
not be displayed in the plots.  
As an exploratory analysis, the relationship between immunogenicity variables and treatment 
outcome will be assessed using logistic regression method. The treatment outcome is if 
subject is free of CMV viremia through one year post-transplant. The optimal cutoff values of 
the respective immunogenicity variables that will define the treatment outcome will be 
explored in terms of maximizing the area under the receiver operating characteristic (ROC) 
curves.
All analyses of immunogenicity variables will be based on the IAS. 
7.5
Analysis of Safety
All analysis of safety will be presented by treatment group for the SAF unless specified 
otherwise.


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The safety data will be summarized relative to the date of the first study drug injection 
through day 380 from the transplantation day. The safety data that was measured through 
day 380 will be included. This analysis window will accommodate the protocol visit 
windows.
7.5.1
Adverse Events
The coding dictionary for this study will be MedDRA. Treatment-emergent adverse event 
will be defined as an adverse event observed on the day or after the first injection up to 1 year 
post-transplant. If the adverse event occurs on the day of the first injection of study drug and 
the investigator marks as “Onset after first dose of study drug” or the onset check box is left 
blank in eCRF, then the adverse event will be considered treatment emergent.  An overview 
table will include the following for the SAF, mSAF and xSAF :
●
Number and percentage of subjects with at least one TEAEs,
●
Number and percentage of subjects with drug related TEAEs,
●
Number and percentage of subjects with serious TEAEs,
●
Number and percentage of subjects with serious drug related TEAEs,
●
Number and percentage of subjects with TEAEs leading to death,
●
Number and percentage of subjects with drug related TEAEs leading to death,
●
Number and percentage of subjects with TEAEs leading to permanent discontinuation of 
study drug, 
●
Number and percentage of subjects with related TEAEs leading to permanent 
discontinuation of study drug, and
●
Number of deaths (on or before transplant Day 365 and after Day 365).
The number and percentage of subjects with TEAEs will be summarized for each treatment 
group. Summaries will be provided for:
●
TEAEs by SOC, HLT and PT (for SAF, mSAF and xSAF populations)
●
TEAEs by SOC, PT and CTCAE Grade
●
TEAEs by severity (mild, moderate and severe)
●
TEAEs by relationship to study drug assessed by investigator (Unlikely, possible and 
probable)
●
serious TEAEs assessed by investigator and including Astellas always SAE, 
●
study drug related (possible and probable) TEAEs assessed by investigator
●
study drug related (possible and probable) serious TEAEs by investigator and including 
Astellas always SAE
●
TEAEs leading to permanent discontinuation of study drug, 
●
study drug related (possible and probable) TEAEs leading to permanent discontinuation 
of study drug
●
TEAEs by PT in descending order of overall will be summarized 
●
TEAEs, PTs that equal or exceed a threshold of 5.0% in any treatment group, after 
excluding serious adverse events.


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For the same event, a subject reports different severity, the worst severity will be counted. 
For the same event, a subject reports different study drug relationship, the highest degree of 
relationship will be counted. 
Adverse Events of Interest
Adverse events of interest are as follows. 
●
Systemic reactions assessed by the sponsor medical review
●
Late onset reactions assessed by the sponsor medical review
●
Allergic and demyelinating reactions, to be identified using MedDRA SMQs for 
demyelination and anaphylactic.
●
Local reactogenicity: AEs that are deemed by the Investigator as being associated with a 
local reactogenicity events. These are identified by a check box in the AE eCRF. 
●
Acute local vaccine reactions, including injection site Pain, Tenderness, 
Erythema/Redness, and Induration/Swelling are assessed by the Investigator for 
60 minutes after each injection. For each subject, the reported grade on each scale 
following each injection, and overall the worst grade for each scale reported during the 
study will be summarized. 
7.5.2
Local Reactogenicity Assessed by Subject
Local (non-acute) vaccine reactions, including injection site Pain, Tenderness, Redness, and 
Swelling or Hardening are assessed by the subject for each of the 7 consecutive days 
following each injection beginning approximately 24 hours after the dose (day 1-7 post dose). 
Local reactogenicity assessments will be summarized by treatment. For each subject, the 
worst reported grade on each scale observed following each injection and overall during the 
study will be summarized by treatment. 
7.5.3
Clinical Laboratory Evaluation
Clinical laboratory data from central will be summarized by treatment group for SAF and
mSAF. The baseline value for clinical laboratory evaluations is the last non-missing 
measurement taken prior to, or on the same day as, the initial injection of study drug. 
Quantitative measurements from hematology and biochemistry will be summarized 
descriptively (n, mean, standard deviation, minimum, maximum and median for each 
treatment group at each visit). Additionally, a within-subject change will be calculated as the 
post-baseline measurement minus the baseline measurement and summarized. 
Each laboratory result from central laboratory will be classified as low (L), normal (N), or 
high (H) at each visit according to the laboratory supplied reference ranges. The number and 
percentage of subjects below and above reference range will be summarized for each 
treatment group at each visit. Additionally, for medically important parameters, shifts from 
baseline to post-baseline in either the Low or High direction, and at Final Visit, will be 
summarized. The post-baseline category will be determined by taking the lowest or highest 
category for a subject, depending on direction of worsening. The Final Visit will be the last 
value of a subject within the analysis period. 


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7.5.3.1 Liver function tests
The liver function test parameters from central laboratory will assessed by the categories 
listed below. The number and percentage of subjects who meet the following criteria at post-
baseline will be summarized. 
●
ALT or AST > 3xULN, > 5xULN, > 10xULN, >20xULN
●
ALT > 3xULN, > 5xULN, > 10xULN, >20xULN
●
AST > 3xULN, > 5xULN, > 10xULN, >20xULN
●
ALP > 1.5xULN, >3xULN
●
Total Bilirubin >2xULN
●
(ALT or AST > 3xULN) and Total Bilirubin > 1.5xULN
●
(ALT or AST > 3xULN) and Total Bilirubin > 2xULN
●
(ALT or AST > 3xULN) and ALP< 2xULN and Total Bilirubin > 2xULN
Any subjects who have at least one post-baseline value will be included in this summary. A 
subject may be counted more than once as the categories are not mutually exclusive (i.e., a 
subject with a value >10xULN will be counted also in the subsequent categories). The last 
3 criteria will be evaluated using the ALT and/or AST assessments that are conducted within 
3 days of the Total Bilirubin and ALP assessments, as applicable. 
7.5.4
Vital Signs
The baseline value for vital signs is the last measurement taken prior to the initial injection of 
study drug. 
Vital signs [systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse rate, 
respiratory rate, temperature and weight] will be summarized using mean, standard deviation, 
minimum, maximum and median by treatment group and visit. Additionally, a within-subject 
change will be calculated per visit and scheduled time as the post-baseline measurement 
minus the baseline measurement and summarized by treatment group and visit. 
7.5.5
Pregnancies
A detailed listing of all pregnancies will be provided.
7.6
Analysis of PK
Not applicable.
7.7
Analysis of PD
Not applicable. 
7.8
Safety Subgroups of Interest
The treatment emergent adverse events will be summarized by the treatment group for the 
subgroups defined based on the categorized variables listed below: 


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Grouping variable
Subgroups
Donor/Recipient Relatedness
Related
Not Related
Donor CMV Serostatus
Positive
Negative
Age group
Age < 65 years
Age ≥ 65 years
Sex
Female
Male
Race
White
Black or African American
Asian
Other
Geographic Region
North America
Europe
Asia
Australia
7.9
Interim Analysis and Early Discontinuation of the Clinical Study
Futility analyses will be conducted while the study is blinded by an independent data analysis 
center (DAC). Sponsor personnel will not have access to unblinded interim analysis data 
during the study unless the futility criterion is met and the sponsor needs to make a decision 
on discontinuing the trial.
7.9.1
Data Monitoring Committee
A DMC, independent of the Sponsor and Investigators, will be established to review the 
safety data throughout the study and to assess the futility of the study (See Section 7.9.2). 
The independent DMC statistician will have access to the randomization schedule. The DMC 
statistician and a separate independent data analysis center (DAC) will create or coordinate 
the unblinded deliverables for use by the DMC. The Sponsor will not have access to the 
unblinded tables and listings created for the DMC.
For details of the DMC refer to the DMC Charter.


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7.9.2
Futility Analyses
Futility analyses were conducted according the pre-specified plans described in the DMC 
Charter. See DMC Charter for additional details.
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
7.10.1
Missing Data
For the primary efficacy endpoint, the various sensitivity analyses will be conducted in order to 
assess the impact of missing data as described in the sections above.
For the endpoints where the time to event approach is used, a subject without an event will be 
censored according to the description planned for each endpoint.
For all-cause mortality, subjects with unknown survival status by day 365 will be counted as 
dead in the crude summary.
The start and stop dates of AEs and concomitant medication will be imputed to determine 
whether a medication is prior and/or concomitant and to determining whether an AE is/is not 
treatment emergent. Listings of the AEs and concomitant medications will present the patient 
reported partial dates; imputed dates will not be shown.
In case of missing partial start and stop dates for concomitant medications, the following 
rules will be used:
If the start date is missing or partial:
●
if the month is missing, use January 
●
if the day is missing, use the first day of the month under consideration
●
if the year is missing, use year of the informed consent date 
●
if the entire date is missing, use informed consent date 
If the stop date is missing or partial:
●
if the month is missing, use December 
●
if the day is missing, use the last day of the month under consideration
●
if the year or the entire date is missing, set the stop date to December 31st, 2099
If the imputed start date is after the stop date, then the imputed start date will be 1 day prior 
to the stop date.
For AEs, a missing or incomplete onset date will be imputed according to the following 
conventions. 
If an onset date is missing or only the year is known, the imputed onset date will be the date 
of first dose of study drug.
If only the year is known for the AE onset date, the imputed onset date will be the latest of 
the following non-missing dates:


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●
Date of first dose of study drug 
●
January 1 of the year of AE onset date 
If only the month and year is known for the onset date, set the surrogate onset date to the first 
day of that month and then apply the following rules. 
●
If the month and year of the onset date is prior to the month and year of the first dose of 
study drug, then the surrogate onset date will be the imputed onset date.
●
If the month and year of the onset date is on or after the month and year of the first dose 
of study drug, then the imputed onset date will be the latest of the following non-missing 
dates:
○
Date of first dose of study drug 
○
Surrogate onset date
If the imputed onset date is after the adverse event end date, the imputed onset date will be 
the same as the adverse event end date.
No imputation of missing data for other variables will be done.
7.10.2
Outliers
No outliers will be excluded from the analyses.
7.10.3
Visit Windows
All data collected up to 1-year post-transplant (i.e., day 380) will be included in the analysis, 
unless otherwise specified, except for mortality which is restricted to deaths occurring up to 
day 365 following the transplant. All data collected up to day 190 will be included in the 
6-month post-transplant analyses, except for mortality which is restricted to deaths occurring 
up to day 180 following the transplant.
For efficacy analysis, data will be analyzed from the transplant day (day 0); for safety 
analysis, data will be analyzed from the first injection of study drug.
The summary by visits will follow the visits according to the CRF.


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8
DOCUMENT REVISION HISTORY
8.1
List of Changes in SAP Version 3.0 from Version 2
The changes from the approved SAP Version 2 (Dated 15-Dec-2015) to Version 3.0 that 
impact analyses are listed with the rationale in the table below.
SAP 
Sections
Description
Rationale
5.1, 5.2, 
7.4.1.1
FAS is considered to be the primary analysis 
population
Consistency with protocol, and 
adherence to intent-to-treat 
principles.
5.3.1
Removed several reasons for exclusion from PPS
Deleted reasons that appear to be 
confounded with, or have little 
direct impact on, primary 
endpoint.
6.1.2.2
All-cause mortality at 1 year post-transplant was 
elevated from exploratory to secondary endpoint.
All-cause mortality is a 
component of the primary efficacy 
endpoint.
6.1.2.2, 
7.4.2.3
A composite endpoint of CMV viremia and CMV-
specific AVT use per the adjudication committee
has been added
To address suspicion of potential 
CMV-specific infection
6.1.3, 
7.4.3.1
Added exploratory endpoints: all-cause mortality at 
6 months, and composite endpoint of all-cause 
mortality and adjudicated CMV EOD at 6 months 
post-transplant.
In order to evaluate efficacy 
around the time of the last planned 
injection.
6.1.3
Removed a few exploratory endpoints:
-Incidence of severe cGVHD
-Maximum cGVHD
-Incidence of failure to engraft
-Time to engraftment
-Time to platelet recover
-Time to grade 3 treatment emergent viral, bacterial, 
or fungal infections other than CMV
Limited clinical relevance
7.1
Clarification of ‘1-year post transplant’ study period 
for death and non-death events.
Day 365 for mortality and Day 
380 for visit-based assessments to 
allow for protocol-allowed visit 
window.
7.2.4
Previous and concomitant medication summaries 
switched from safety (e.g., SAF) to efficacy (e.g., 
FAS) populations.
Medications are summarized for 
potential confounding of efficacy 
results.
7.4.1.1, 
7.4.1.2
Added 1-RR from CMH and 1-HR from Cox Model
Feedback from FDA


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7.5
Safety overview and TEAE summary by SOC, HLT 
and PT for SAF, mSAF, xSAF
All safety assessment to be done 
for SAF and mSAF. Summary 
based on xSAF were limited to 
high-level summaries as the xSAF 
population includes a limited 
number of subjects. 
7.5
Updated list of AE of Interest
Removed: Malignancies, Sinusoidal Obstruction 
Syndrome
Added: Systemic reactions, late onset reactions
Improve alignment with clinical 
objectives.


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9
REFERENCES
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics)
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics)


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10
APPENDICES
Appendix 1: Handling of the Human Leukocyte Antigen (HLA) 
Mismatching
The HLA antigens are located on the cell surface. The genes encoding the HLA antigens are 
on chromosome 6 and have co-dominant expression: both alleles of one gene locus result in a 
surface HLA antigen. HLA class I antigens consist of a heavy chain and a β2m unit and 
include the HLA-A, HLA-B and HLA-C antigens, while HLA class II antigens are 
constituted by two heavy chains and include the HLA-DR, HLA-DP and HLA-DQ antigens. 
All HLA genes (loci) are very polymorphic: each has various alleles (variants) that can be 
distinguished by DNA sequencing of gene DNA or by serological techniques for detection of 
the gene products (the HLA antigens on the cell surface): HLA typing.
The HLA types for HLA-A, HLA-B and HLA-DR are entered in the eCRF. Broad HLA 
types comprise of several fine specificities, the narrow types, but it is only the broad type 
codes (roughly equivalent to the serologically defined antigen or serotype (allotype)) that are 
entered into the eCRF.
Example:
Donor:
HLA A
HLA B
HLA DR
A11
A66
B5
-
DR5
DR6
Recipient:
HLA A
HLA B
HLA DR
A25
A32
B12
B5
DR5
DR7
Both codes for a locus will be considered identical (homozygote) if only one code is entered. 
In this case, the investigator will either enter the code twice or put a dash for the second entry 
(or leave the second entry blank). The order of the entries is unimportant. A mismatch 
between a donor and a recipient exists if the donor has an antigen which doesn’t appear in the 
recipient.
Calculation of the number of HLA mismatches:
For the comparison of the HLA types between the donor and the recipient, the following 
steps should be done to calculate the number of HLA mismatches:
1.
If the entry for a locus is a numeric code and a dash (or missing), then the dash for that 
locus is to be replaced (for calculation only) by the numeric code (homozygote).
2.
The following rules should be applied when calculating the number of mismatches 
within a HLA A, B, and DR locus:
●
If both codes are missing in either the donor or recipient, the number of mismatches is 
unknown (missing)
●
If the two codes are non-missing and identical for the recipient and the donor (without 
regard to the order) or the donor is homozygote and the donor code matches either 
one of the recipient’s codes then the number of mismatches is 0.


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Examples:
Donor
Recipient
Mismatch
A1   A2
A2   A1
0
A2   A2
A2   A1
0
●
If one code from the donor exists in the recipient but the other code is different 
between the donor and recipient or the donor has identical codes (homozygote) but 
they don’t match either code in the recipient, then the number of mismatches is 1. 
Examples:
Donor
Recipient
Mismatch
A2   A3
A2   A1
1
A2   A3
A2    A2
1
A2   A2
A3   A4
1
A2   A2
A1   A1
1
●
If the donor is not homozygote and all codes are different between the donor and the 
recipient then the number of mismatches is 2.
Example:
Donor
Recipient
Mismatch
A1   A2
A3   A4
2
3.
If the number of mismatches from any of the three loci are missing, then total number of 
HLA mismatches is missing.  Otherwise the total number of HLA mismatches is the sum 
of the mismatches from the three loci.