Conditions: Rhinitis, Allergic, Seasonal
Keywords: Cedar pollinosis ASP4070 DNA plasmid vaccine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 150
Healthy volunteers: no

Brief summary:
The objective of this study was to evaluate the efficacy, safety, and dose-response of ASP4070 vaccinated in patients with cedar pollinosis.

Detailed description:
Subjects were vaccinated with ASP4070 or placebo at 2 week intervals. Clinical symptoms were evaluated after cedar pollen exposure in a chamber at 4, 8 and 12 weeks after the last vaccination to identify the timing of the onset of therapeutic effect.

Arms:
arm 1: Participants received ASP4070 4 mg 8 times by intradermal vaccination at 14-day intervals. arm 2: Participants received ASP4070 1 mg 8 times by intradermal vaccination at 14-day intervals. arm 3: Participants received Placebo 8 times by intradermal vaccination at 14-day intervals.

Interventions: intervention 1: ASP4070 intervention 2: Placebo
Intervention descriptions: intervention 1: Intradermal vaccination at 2-week intervals intervention 2: Intradermal vaccination at 2-week intervals

Protocol document:
Prot_000.pdf: 
Sponsor: API 
ISN/Protocol 4070-CL-0020 
- CONFIDENTIAL - 
09 Mar 2018 
Astellas 
Page 1 of 88 
 
 
 
Protocol for Phase II Dose-finding Study of ASP4070 
 
—A Randomized, Double-blind, Placebo-controlled, Dose-finding Study in Patients 
With Cedar Pollinosis Using an Environmental Exposure Chamber— 
 
ISN/Protocol 4070-CL-0020 
 
 
 
Sponsor: 
Astellas Pharma Inc. (API) 
2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 
 
 
 
 
 
 
 
 
 
 
 
Prepared on 09 Mar 2018 (Version 2.0) 
-------------------------------------------------------------------------------------------------------------------------------------- 
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 No unpublished information contained in this 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: API 
ISN/Protocol 4070-CL-0020 
- CONFIDENTIAL - 
09 Mar 2018 
Astellas 
Page 2 of 88 
Table of Contents 
I. 
SIGNATURES ······················································································· 8 
II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL ····························· 9 
III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ·················· 10 
IV. 
SYNOPSIS ··························································································· 13 
V. 
FLOW CHART AND SCHEDULE OF ASSESSMENTS ································· 22 
VI. 
ACCEPTABLE RANGE OF SCHEDULE OF ASSESSMENTS ························ 25 
1 
INTRODUCTION ·················································································· 27 
1.1 
Background ····················································································· 27 
1.1.1 
Target Disease and Other Treatment Methods and Their Problems ··············· 27 
1.1.2 
Characteristics of ASP4070 ····························································· 27 
1.2 
Non-clinical and Clinical Data ······························································· 28 
1.2.1 
Non-clinical Data ········································································· 28 
1.2.1.1 
Pharmacological Actions ·························································· 28 
1.2.1.2 
Toxicity ·············································································· 29 
1.2.1.3 
Pharmacokinetics ··································································· 29 
1.2.2 
Clinical Study Data ······································································ 29 
1.2.2.1 
Japanese Phase I Study (4070-CL-0010) ········································ 29 
1.2.2.2 
Overseas Phase I Studies ·························································· 30 
1.3 
Summary of Key Safety Information for Study Drugs ···································· 32 
1.4 
Risk-Benefit Assessment ······································································ 32 
2 
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ·································· 33 
2.1 
Study Objectives ··············································································· 33 
2.2 
Study Design and Dose Rationale ··························································· 33 
2.2.1 
Study Design ·············································································· 33 
2.2.2 
Dose Rationale ············································································ 35 
2.3 
Endpoints ························································································ 35 
2.3.1 
Primary Efficacy Endpoints ····························································· 35 
2.3.2 
Secondary Efficacy Endpoints ·························································· 36 
2.3.3 
Other Efficacy Endpoints ······························································· 37 
2.3.4 
Immune Response Endpoints ··························································· 37 
2.3.5 
Safety Endpoints·········································································· 38 
3 
STUDY POPULATION ··········································································· 38 


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- CONFIDENTIAL - 
09 Mar 2018 
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Page 3 of 88 
3.1 
Selection of Study Population ································································ 38 
3.2 
Inclusion Criteria ··············································································· 38 
3.3 
Exclusion Criteria ·············································································· 40 
4 
TREATMENT ······················································································ 43 
4.1 
Identification of Investigational Product ···················································· 43 
4.1.1 
Test Drug ·················································································· 43 
4.1.2 
Comparative Drug ········································································ 43 
4.2 
Packaging and Labeling ······································································· 43 
4.3 
Study Drug Handling ·········································································· 43 
4.4 
Blinding ························································································· 44 
4.4.1 
Blinding Method·········································································· 44 
4.4.2 
Confirmation of the Indistinguishability of the Study Drugs ······················· 44 
4.4.3 
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking ··················································································· 44 
4.4.4 
Breaking the Treatment Code for Emergency ········································ 45 
4.5 
Assignment and Allocation ··································································· 45 
5 
TREATMENTS AND EVALUATION ························································ 46 
5.1 
Dosing and Administration of Study Drug and Other Medications ····················· 46 
5.1.1 
Dose/Dose Regimen and Administration Period ····································· 46 
5.1.2 
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy) ··················································································· 46 
5.1.2.1 
Prohibited Medications/Therapies ··············································· 47 
5.1.2.2 
Rescue Drugs ········································································ 48 
5.1.2.3 
Prohibited Non-Medication Therapies ··········································· 48 
5.1.3 
Treatment Compliance··································································· 49 
5.1.4 
Restrictions During the Study ·························································· 49 
5.2 
Demographics and Baseline Characteristics ················································ 50 
5.2.1 
Demographics ············································································· 50 
5.2.2 
Medical History ··········································································· 50 
5.2.3 
Diagnosis of the Target Disease, Severity, and Duration of Disease ·············· 51 
5.3 
Efficacy Assessment ··········································································· 51 
5.3.1 
Nasal and Eye Symptoms During Chamber Period ·································· 51 
5.3.2 
Symptoms Survey After Chamber Period ············································· 52 
5.3.3 
Pollinosis Symptoms Survey During 2018 JRC Pollen Dispersal Season ········ 52 


Sponsor: API 
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- CONFIDENTIAL - 
09 Mar 2018 
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Page 4 of 88 
5.4 
Safety Assessment ············································································· 53 
5.4.1 
Adverse Events ··········································································· 53 
5.4.1.1 
Adverse Events (Primary Study Period) ········································· 53 
5.4.1.2 
Adverse Events (Long-term Safety Follow-up Period) ······················· 53 
5.4.2 
Local/Systemic Reaction Survey Diary ··············································· 53 
5.4.3 
Vital Signs ················································································· 53 
5.4.4 
Laboratory Assessments ································································· 54 
5.4.5 
Physical Examination ···································································· 54 
5.4.6 
Electrocardiogram (ECG) ······························································· 54 
5.5 
Adverse Events and Other Safety Aspects ·················································· 55 
5.5.1 
Definition of Adverse Events (AEs) ··················································· 55 
5.5.2 
Definition of Serious Adverse Events (SAEs) ······································· 56 
5.5.3 
Criteria for Causal Relationship to the Study Drug/Intradermal Injection 
Device ······················································································ 57 
5.5.4 
Criteria for Defining the Severity of an Adverse Event ····························· 57 
5.5.5 
Reporting of Serious Adverse Events (SAEs) ········································ 58 
5.5.6 
Follow-up of Adverse Events ··························································· 58 
5.5.7 
Procedure in Case of Pregnancy ························································ 58 
5.5.8 
Emergency Procedures and Management of Overdose ····························· 59 
5.5.9 
Supply of New Information Affecting the Conduct of the Study ·················· 59 
5.5.10 
Deviations From the Protocol and Other Actions Taken to Avoid Life-
Threatening Risks to Subjects ·························································· 60 
5.6 
Test Drug Concentration ······································································ 60 
5.7 
Other Measurements, Assessments or Methods ··········································· 60 
5.7.1 
Immune Response Assessment (Parameters) ········································· 60 
5.7.2 
Objective of Secondary Data Analysis ················································ 61 
5.7.2.1 
Sampling and Storage of Secondary Data Analysis Samples ················ 61 
5.7.2.2 
Disposal of Secondary Data Analysis Samples ································ 61 
5.7.2.3 
Disclosure of Secondary Data Analysis Results ······························· 61 
5.7.3 
Objective of Pharmacogenomics Research ··········································· 62 
5.7.3.1 
Sampling and Storage of Pharmacogenomics Sample ························ 62 
5.7.3.2 
Disposal of Pharmacogenomics Sample ········································ 62 
5.7.3.3 
Disclosure of Genetic Information ··············································· 63 
5.8 
Total Amount of Blood ········································································ 63 
5.9 
Phase II Second-Year Follow-up Study (4070-CL-0021) ································ 64 


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6 
DISCONTINUATION ············································································· 64 
6.1 
Discontinuation of Individual Subject(s) ··················································· 64 
6.2 
Discontinuation of the Site ···································································· 65 
6.3 
Discontinuation of the Study ································································· 65 
7 
STATISTICAL METHODOLOGY ···························································· 65 
7.1 
Sample Size ····················································································· 65 
7.2 
Analysis Set ····················································································· 66 
7.2.1 
Full Analysis Set (FAS) ································································· 66 
7.2.2 
Per Protocol Set (PPS) ··································································· 67 
7.2.3 
Safety Analysis Set (SAF) ······························································ 67 
7.2.4 
Immunological Analysis Set (IAS) ···················································· 67 
7.2.4.1 
IAS ··················································································· 67 
7.2.4.2 
IAS-2 ················································································· 67 
7.2.5 
Pollinosis Symptom Analysis Set (PSAS) ············································ 67 
7.3 
Demographics and Other Baseline Characteristics ········································ 67 
7.4 
Analysis of Efficacy ··········································································· 68 
7.4.1 
Analysis of Primary Endpoint ·························································· 68 
7.4.1.1 
Primary Analysis ··································································· 68 
7.4.1.2 
Secondary Analysis ································································ 68 
7.4.1.3 
Subgroup Analysis ································································· 69 
7.4.2 
Analysis of Secondary Endpoints ······················································ 69 
7.4.3 
Other Efficacy Endpoints Analysis ···················································· 70 
7.5 
Analysis of Immunological Response ······················································· 70 
7.6 
Analysis of Safety ·············································································· 70 
7.6.1 
Adverse Events ··········································································· 71 
7.6.2 
Local Reaction and Systemic Reaction ················································ 71 
7.6.3 
Laboratory Assessments ································································· 71 
7.6.4 
Vital Signs ················································································· 71 
7.6.5 
ECGs ······················································································· 71 
7.7 
Analysis of Pharmacokinetics ································································ 71 
7.8 
Other Analyses ················································································· 71 
7.8.1 
Secondary Data Analysis ································································ 71 
7.8.2 
Analysis of Pharmacogenomics Data ·················································· 72 
7.9 
Interim Analysis (and Early Discontinuation of the Clinical Study) ···················· 72 


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7.10 
Handling of Missing Data, Outliers, Visit Windows, and Other Information ········· 72 
7.10.1 
Time Points for Primary Study Period ················································ 72 
7.10.2 
Time Points for Pollinosis Symptoms Survey Period and Additional Study 
Period ······················································································ 74 
8 
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ···················· 74 
8.1 
Procedure for Clinical Study Quality Control ·············································· 74 
8.1.1 
Data Collection ··········································································· 74 
8.1.1.1 
Case Report Form ·································································· 74 
8.1.1.2 
Survey Diary ········································································ 75 
8.1.2 
Specification of Source Documents ··················································· 75 
8.1.3 
Clinical Study Monitoring ······························································ 76 
8.1.4 
Direct Access to Source Data/Documents ············································ 76 
8.1.5 
Data Management ········································································ 76 
8.2 
Ethics and Protection of Subject Confidentiality ·········································· 76 
8.2.1 
Institutional Review Board (IRB) ······················································ 76 
8.2.2 
Ethical Conduct of the Study ··························································· 77 
8.2.3 
Informed Consent of Subjects ·························································· 77 
8.2.3.1 
Subject Information and Consent ················································ 77 
8.2.3.2 
Subject Information and Consent on Secondary Data Analysis ·············· 77 
8.2.3.3 
Subject Information and Consent on Pharmacogenomics Research ········· 78 
8.2.3.4 
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ····························· 78 
8.2.4 
Subject Confidentiality ·································································· 79 
8.3 
Administrative Matters ········································································ 79 
8.3.1 
Arrangement for Use of Information and Publication of the Clinical Study ····· 79 
8.3.2 
Documents and Records Related to the Clinical Study ····························· 80 
8.3.3 
Protocol Amendment and/or Revision ················································ 82 
8.3.4 
Insurance of Subjects and Others ······················································ 82 
8.3.5 
Signatory Investigator for Clinical Study Report ···································· 82 
9 
QUALITY ASSURANCE ········································································· 82 
10 
STUDY ORGANIZATION ······································································· 83 
10.1 
Independent Data-Monitoring Committee (IDMC) | Data and Safety Monitoring 
Board (DSMB) | Monitoring Committee | Other Evaluation Committee(s) ··········· 83 
10.2 
Other Study Organization ····································································· 83 
10.3 
Registration of Subjects ······································································· 83 


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11 
REFERENCES ······················································································ 84 
12 
APPENDICES ······················································································· 85 
12.1 
Classification of Severity of Local Reactions at Vaccination Site ······················ 85 
12.2 
Classification of Severity of Systemic Reactions ·········································· 86 
12.3 
Classification of Severity of Pollinosis Symptoms ········································ 87 
12.4 
Events That Should Be Handled as Serious Adverse Events ···························· 88 
12.5 
Common Serious Adverse Events ··························································· 88 
 


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09 Mar 2018 
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I. 
SIGNATURES 
1. AGREEMENT BETWEEN THE SPONSOR’S RESPONSIBLE PERSON AND THE 
INVESTIGATOR 
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 (CHIKEN SEKININ ISHI) and responsible person of the Sponsor 
(CHIKEN IRAI SEKININSHA) inscribe in the bipartite agreement. 
This clinical study will be conducted in accordance with GCP for trials on gene, cellular, and 
tissue-based products. Of GCP-related terms presented in the protocol, those that are related 
to ASP4070 shall be read as though replaced by their corresponding terms related to GCP for 
trials on gene, cellular, and tissue-based products as shown below. 
 
GCP for trials on pharmaceutical 
products 
GCP for trials on gene, cellular, and 
tissue-based products 
Drug 
Product 
Adverse drug reaction 
Defect 
Toxicity 
Safety 
Pharmacological action 
Indication and performance 
Pharmacokinetics and drug metabolism 
Disposition 
Dosage and dose regimen 
Dosage, dose regimen, and usage 
 


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II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL 
Contact Information for the Sponsor  
Corporate Name: Astellas Pharma Inc. 
Location: 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 
Phone No.: 
 
Fax: 
 
Sponsor’s personnel: 
 
[Contact numbers during non-business hours and for emergency]:  
 Phone No.
 
 
Contact Information for the Contract Research Organization (CRO) 
Corporate name: 
 
Location: 
 
Phone No.: 
 
Fax: 
 
 
[Contact numbers during non-business hours and for emergency]:  
Phone No.: 
 
 


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III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
AE 
Adverse event 
ALB 
Albumin 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase (GPT) 
ANCOVA 
Analysis of covariance 
API 
Astellas Pharma Inc. 
AST 
Aspartate aminotransferase (GOT) 
BAT 
Basophil activation test 
BUN 
Blood urea nitrogen 
CK 
Creatine kinase 
Cl 
Chlorine 
Cre 
Creatinine 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
DNA 
Deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GCTP 
Good Gene, Cellular, and Tissue-based Products Manufacturing Practice 
GMP 
Good Manufacturing Practice 
γ-GTP 
γ-glutamyltranspeptidase 
HBs antigen 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
IAS 
Immunological analysis set 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IDMC 
Independent Data Monitoring Committee 
IFN-γ 
Interferon gamma 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IL 
Interleukin 
IRB 
Institutional Review Board 
ISN 
International study number 
ITI 
Immunomic Therapeutics, Inc. 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
JRC 
Japanese red cedar 
JRQLQ 
Japanese Rhinoconjunctivitis Quality of Life Questionnaire 
K 
Potassium 


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Abbreviations 
Description of abbreviations 
LAMP 
Lysosomal associated membrane protein 
LDH 
Lactate dehydrogenase 
MC 
Mountain cedar 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
Major histocompatibility complex 
Na 
Sodium 
PGx 
Pharmacogenomics 
PPS 
Per protocol set 
PSAS 
Pollinosis symptom analysis set 
QOL 
Quality of life 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
SCIT 
Subcutaneous immunotherapy 
SDA 
Secondary data analysis 
SFL 
Screen Failure Log 
SLIT 
Sublingual immunotherapy 
SOP 
Standard Operating Procedure 
T-Bil 
Total bilirubin 
T-Cho 
Total cholesterol 
TG 
Triglyceride 
Th 
T helper cell 
TNF 
Tumor necrosis factor 
TNNSMS 
Total non-nasal symptom medication score 
TNNSS 
Total non-nasal symptom score 
TNSMS 
Total nasal symptom medication score 
TNSS 
Total nasal symptom score 
TP 
Total protein 
TSMS 
Total symptom medication score 
TSS 
Total symptom score 
UA 
Uric acid 
WHODDE 
WHO Drug Dictionary Enhanced 
 


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Definition of Key Study Terms 
Terms 
Definition of terms 
Baseline 
Observed values/findings which are regarded observed starting point for 
comparison. 
Enroll 
To register or enter into a clinical trial. NOTE: Once a subject has been 
enrolled, the clinical trial protocol applies to the subject. 
Intervention 
The drug, therapy or process under investigation in a clinical study that is 
believed to have an effect on outcomes of interest in a study. (e.g., health-
related quality of life, efficacy, safety, pharmacoeconomics). 
Investigational 
period 
Period of time where major interests of protocol objectives are observed, and 
where the test drug or comparative drug (sometimes without randomization) 
is usually given to a subject, and continues until the last assessment after 
completing administration of the test drug or comparative drug. 
Screening period 
Period of time before entering the investigational period, usually from the 
time of starting a subject signing consent until just before the test drug or 
comparative drug (sometimes without randomization) is given to a subject. 
Randomization 
The process of assigning trial subjects to treatment or control groups using 
an element of chance to determine assignments in order to reduce bias. 
Screening 
A process of active consideration of potential subjects for enrollment in a 
trial. 
Screen failure 
Potential subject who did not meet one or more criteria required for 
participation in a trial. 
Study period 
Period of time from the first site initiation date to the last site completing the 
study. 
Variable 
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values. 
 


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IV. 
SYNOPSIS 
Date and Version # of Protocol Synopsis: 
Version 2.0, 09 Mar 2018 
 
Sponsor: 
Astellas Pharma Inc. (API), 
Protocol Number: 
4070-CL-0020 
Name of Study Drug:  
ASP4070 
Phase of Development:  
Phase II 
Title of Study: 
Phase II Dose-finding Study of ASP4070 
—A randomized, double-blind, placebo-controlled, dose-finding study in patients with cedar 
pollinosis using an environmental exposure chamber— 
Planned Study Period: 
Primary study period: From Apr 2017 to Jan 2018 
Pollinosis symptoms survey period: From 01 Feb 2018 to 31 Mar 2018 
Additional study period: From Apr 2018 to May 2018 
Long-term safety follow-up period: From Jan 2018 to Oct 2018 
Study Objective(s):  
To evaluate the efficacy, safety, and dose response for ASP4070 vaccinated in patients with cedar 
pollinosis. 
Planned Total Number of Study Centers and Location(s): 
1 study center, Japan 
Study Population: 
Patients with cedar pollinosis aged from 20 to 64 years 
Number of Subjects to be Enrolled / Randomized: 
Total number: 150 subjects 
ASP4070 4 mg group (4 mg × 8 times): 50 subjects 
ASP4070 1 mg group (1 mg × 8 times): 50 subjects 
Placebo group: 50 subjects 
Study Design Overview: 
A randomized, double-blind, placebo-controlled, dose-finding study 
The efficacy, safety, and dose response when ASP4070 (mixture containing equivalent amount of 
Cry j 1-LAMP plasmid and Cry j 2-LAMP plasmid, 4 mg/0.4 mL or 1 mg/0.4 mL) will be 
intradermally vaccinated 8 times at 14-day intervals will be evaluated with placebo (physiological 
saline) as the control. The study will conduct cedar pollen exposure using an environmental 
exposure chamber (OHIO Chamber; hereinafter, “chamber”), and the efficacy and dose response 
will be evaluated using clinical symptoms (nasal and eye symptoms) as indicators. 
Two factors, “Class from results of Japanese red cedar (JRC) pollen-specific immunoglobulin E 
(IgE) antibody test performed at Screening visit 1” and “Change in the mean of total 3 nasal 
symptom (sneezing, nasal discharge, and nasal congestion) score during 120 to 180 minutes after 
start of cedar pollen exposure in the chamber as compared to the score before cedar pollen 
exposure at Screening visit 2,” will be used as stratification factors to randomly allocate subjects 
into three groups—ASP4070 4 mg group, ASP4070 1 mg group, or placebo group—in a ratio of 
1:1:1, and the subjects will be vaccinated with the study drug. 
After a set period after the final vaccination of the study drug, re-exposure to cedar pollen in the 


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chamber will be conducted and the efficacy will be evaluated using clinical symptoms as 
indicators. Efficacy evaluation will be conducted 4, 8, and 12 weeks after the final vaccination to 
confirm the timing of effectiveness. The primary study period of the study will be until the end of 
the one week of post-observational period after the final evaluation in the chamber on Day 183 (12 
weeks after the final vaccination). 
The treatment code will be broken when the primary study period is completed and all data entered 
in case report forms are fixed. Even after code breaking, the study will be continued with the 
investigator, sub-investigator, study coordinator, and subjects remaining blinded. 
Subjects who have completed the primary study period will be the target of a survey on cedar 
pollinosis symptoms during the pollinosis symptoms survey period (01 Feb 2018–31 Mar 2018). 
Subjects will make entries in the Pollinosis Symptoms Survey Diary every day on information 
regarding nasal and eye symptoms. If a subject experiences intolerable nasal and eye symptoms 
during this period, then the use of rescue drugs will be allowed. 
An additional test of immune responses will be performed during the long-term safety follow-up 
period on subjects who have completed the pollinosis symptoms survey period and have provided 
additional consent to the additional test. The additional test will determine the parameters (specific 
IgE antibody [anti-JRC] and basophil activation test [BAT]) after the end of the cedar pollen 
dispersal season (May 2018). 
After the end of the primary study period, safety information (serious adverse event [SAE]) will be 
collected for approximately 9 months (1 year from the final vaccination of the study drug) as the 
long-term safety follow-up period. Safety information (SAE) will be collected for 1 year after the 
final vaccination of the study drug even from subjects who discontinue their participation in the 
study during the primary study period if they have received at least one vaccination of the study 
drug. 
Among subjects in the placebo group or optimal dose group (ASP4070 4 mg group or 1 mg group) 
who complete the primary study period, those who provide written consent again will be the target 
of a Phase II Second-Year Follow-up Study [4070-CL-0021] that is planned to be implemented. 
Inclusion/Exclusion Criteria: 
Inclusion: 
Subject is eligible for the study if all of the following 1 to 11 apply: 
1. Subject who has provided written consent using the informed consent form approved by the 
Institutional Review Board of the study site before starting any study-related procedure 
2. Subject of either sex who is aged from 20 to 64 years at the time of informed consent 
3. Subject who has nasal symptoms (sneezing, nasal discharge, or nasal congestion) and eye 
symptoms (itchy eyes or watery eyes) of pollinosis during the cedar pollen dispersal seasons in 
2016 and 2017 
4. Subject who has the Japanese red cedar (JRC) pollen-specific IgE antibody test result of Class 
3 or higher in the allergy test at Screening visit 1 
5. Subject who satisfies the following criteria for change in the mean of the nasal symptom score 
during 120 to 180 minutes after start of cedar pollen exposure in the chamber as compared to 
the score before cedar pollen exposure at Screening visit 2 
 
Total 3 nasal symptom score (3TNSS) worsens by 2 or more, 2 or more individual nasal 
symptom score (sneezing, nasal discharge, and nasal congestion) worsens by 1 or more 
6. Female subject must satisfy the following criteria 
Subject of non-childbearing potential must satisfy either of the following criteria: 
 
Subject who is post-menopausal (defined as at least 1 year without any menses) prior to 
Screening visit 1 


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 
Subject who is surgically sterile (hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy) 
Or, subject of childbearing potential (subject who does not meet the above definition of 
“female subject of non-childbearing potential”) must meet all of the following criteria: 
 
Subject must agree not to try to become pregnant during the primary study period or for 28 
days after the final vaccination of the study drug (whichever period is longer) 
 
Subject must have a negative urine pregnancy test at Screening visit 1 and on Day 1 (prior 
to vaccination) 
 
Subject must consistently use two forms of highly effective birth control* (at least one of 
which must be a barrier method) during the primary study period or for 28 days after the 
final vaccination of the study drug (whichever period is longer) if heterosexually active 
*Highly effective forms of birth control 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 
 
Calendar-based contraceptive methods (Knaus-Ogino or rhythm method) 
7. Female subject must agree not to breastfeed during the primary study period or for 28 days 
after the final vaccination of the study drug (whichever period is longer) 
8. Female subject must not donate ova during the primary study period or for 28 days after the 
final vaccination of the study drug (whichever period is longer) 
9. Male subject and their female spouse/partners who are of childbearing potential must be using 
highly effective contraception consisting of two forms of birth control* (at least one of which 
must be a barrier method) from the initial study drug vaccination until 28 days after the final 
vaccination of the study drug 
10. Male subject must not donate sperm from the initial study drug vaccination until 28 days after 
the final vaccination of the study drug 
11. Subject agrees not to participate in another intervention study while on treatment 
 
Subject is eligible for the additional test of the study if the following 12 and 13 both apply: 
12. Subject has completed the pollinosis symptoms survey period 
13. Subject has provided written consent using the informed consent form approved by the 
Institutional Review Board of the study site before starting any procedure related to the 
additional test of the study 
  
Waivers to the inclusion criteria will NOT be allowed. 
Exclusion: 
Subject will be excluded from participation if any of the following apply: 
1. Subject whose allergy test result to other antigens than JRC pollen (test result of IgE antibody 
specific to alnus, Japanese white birch, ragweed, artemisia, cocksfoot, dermatophagoides 
farinae, dermatophagoides pteronyssinus, Aspergillus, Candida, Alternaria, house dust 1, 
house dust 2, cat dander, and dog dander) is Class 4 or higher at Screening visit 1 
2. Subject who has received specific immunotherapy (including desensitization therapy) for cedar 
pollinosis in the past 
3. Subject who has received specific or non-specific immunotherapy within 5 years prior to 
Screening visit 1 
4. Subject who has received laser therapy/surgery for treating nasal symptoms within 3 years 


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prior to Screening visit 1 
5. Subject who has used the following drugs within 14 days prior to entering the chamber at 
Screening visit 2. 
Topical steroid, histamine H1-receptor antagonist, chemical mediator-isolation inhibitor, T 
helper cell 2 (Th2) cytokine inhibitor, thromboxane A2 synthesis inhibitor, thromboxane A2 
receptor antagonist, leukotriene receptor antagonist 
(Among the above drugs, use of medications for external use on the skin is allowed. However, 
use at the study drug vaccination site on the day before Day 1 is not allowed.) 
6. Subject who has used the following drugs within 84 days prior to entering the chamber at 
Screening visit 2 
Biological agents, such as antibiotics (anti-tumor necrosis factor alpha [TNFα] antibody, anti-
IgE monoclonal antibody, etc.) 
7. Subject who has used the following drugs within 84 days prior to the first vaccination of the 
study drug 
Systemic steroids and immunosuppressants (Use of medications for external use on the skin are 
allowed. However, use at the study drug vaccination site on the day before Day 1 is not 
allowed.) 
8. Subject who has received or is planning to receive vaccination of a live vaccine within 28 days 
prior to the first vaccination of the study drug, and/or subject who has received or is planning 
to receive vaccination of an inactivated vaccine/toxoid within 7 days prior to the first 
vaccination of the study drug 
9. Subject who has a history of serious allergic reactions, such as anaphylactic shock and 
generalized exanthema, caused by food and/or medical products (including vaccine) in the past 
10. Subject who has a positive immunological test result for hepatitis B surface antigen (HBs 
antigen) or hepatitis C virus (HCV) antibody at Screening visit 1 
11. Subject who has a complication of nasal disorder (nasal polyp, nasal septum deviation, chronic 
sinusitis, etc.) that may affect efficacy evaluation 
12. Subject who has autoimmune disease or other serious primary disease 
13. Subject who has been diagnosed with immunodeficiency in the past 
14. Subject who has a complication of seasonal allergic rhinitis, perennial allergic rhinitis, rhinitis 
medicamentosa, or non-allergic rhinitis against antigens other than cedar and cypress that 
require medical treatment 
15. Subject who has a complication of cardiovascular disease (including congestive cardiac failure, 
angina pectoris, and cardiac arrhythmias that require medical treatment) 
16. Subject who has a complication of hepatic disease (including viral hepatitis and drug-induced 
liver injury) 
17. Subject who has a complication of renal disease (including acute kidney injury, 
glomerulonephritis, and interstitial nephritis) 
18. Subject who has a complication of respiratory disease (including bronchial asthma and chronic 
bronchitis that require medical treatment) 
19. Subject who has a complication of malignant tumor or has been diagnosed with or has received 
treatment for malignant tumor within 5 years prior to the first vaccination of the study drug 
20. Subject who has been diagnosed with mental conditions, such as schizophrenia, bipolar 
disorder, and major depressive disorder, or dementia 
21. Subject who has a complication that may have an impact on the evaluation of local and 
systemic reactions 
22. Subject who has received vaccination of Cry j 2-LAMP vaccine 
23. Subject who has participated in a study of ASP4070 and received vaccination of the study drug 


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24. Subject who has participated in any clinical study or post-marketing clinical study of any other 
medical drug or device within 12 weeks (84 days) prior to Screening visit 1, or subject who is 
participating in such a study at present 
25. Subject who is an employee of the Sponsor or CRO or medical institution involved in the study 
26. Subject who is considered by the investigator or sub-investigator as unsuitable for study 
participation 
Waivers to the exclusion criteria will NOT be allowed. 
Investigational Product(s): ASP4070 
Dose(s) and Mode of Administration: 4 mg/0.4 mL or 1 mg/0.4 mL, 8 times by intradermal 
vaccination at 14-day intervals. 
Interdermal injection device manufactured by Terumo will be used for vaccination. 
Comparative Drug(s): Placebo (physiological saline) 
Dose(s) and Mode of Administration: 0.4 mL placebo, 8 times by intradermal vaccination at 
14-day intervals. 
Interdermal injection device manufactured by Terumo will be used for vaccination. 
Concomitant Medication Restrictions or Requirements: 
The use of the following medications will be prohibited: 
1. Until the end of the pollinosis symptoms survey period 
Immunotherapy specific to cedar pollinosis (including desensitization therapy) 
2. From 5 years prior to Screening visit 1 until the end of the pollinosis symptoms survey period 
Specific or non-specific immunotherapy 
3. From 14 days prior to entering the chamber at Screening visit 2 until the end of the pollinosis 
symptoms survey period 
Topical steroid, histamine H1-receptor antagonist, chemical mediator-isolation inhibitor, Th2 
cytokine inhibitor, thromboxane A2 synthesis inhibitor, thromboxane A2 receptor antagonist, 
leukotriene receptor antagonist 
(Among the above drugs, use of medications for external use on the skin will be allowed. 
However, use at the study drug vaccination site from the day before Day 1 until 28 days after 
the final vaccination of the study drug will not be allowed.) 
If a subject experiences intolerable nasal and eye symptoms during the pollinosis symptoms 
survey period, then the use of the following rescue drugs will be allowed. 
 
Tramazoline hydrochloride nasal drops 
 
Ketotifen fumarate eye drops 
 
Fexofenadine hydrochloride tablets 
4. From 84 days prior to entering the chamber at Screening visit 2 until the end of the pollinosis 
symptoms survey period 
Biological agents, such as antibiotics (anti-TNFα antibody, anti-IgE monoclonal antibody, etc.) 
5. From 84 days prior to the first vaccination of the study drug until the end of the pollinosis 
symptoms survey period and from the informed consent for the additional test until the 
completion of the additional test 
Systemic steroid/immunosuppressants 
(Use of medications for external use on the skin will be allowed. However, use at the study 
drug vaccination site from the day before Day 1 until 28 days after the final vaccination of the 
study drug will not be allowed.) 
6. From 28 days prior to the first vaccination of the study drug until 28 days after the final 
vaccination of the study drug 


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Live vaccine 
7. From 7 days prior to the first vaccination of the study drug until 28 days after the final 
vaccination of the study 
Inactivated vaccine/toxoid 
The following therapies will be prohibited: 
1. From 3 years prior to Screening visit 1 until the end of the pollinosis symptoms survey period 
 
Laser therapy/surgery for treating nasal symptoms 
2. From leaving the chamber at 4, 8, and 12 weeks after the final vaccination until the completion 
of the Symptoms Survey After Chamber 
 
Acts that physically remove pollen, such as nasal wash (including nebulizer use) and eye 
wash 
3. During the pollinosis symptoms survey period 
 
The use of objects that physically shield the body from pollen, such as masks/goggles 
This restriction does not apply to cases in which the investigator or sub-investigator deems 
the use to be unavoidable (such as medical personnel and factory workers), but the usage 
should be kept to the minimum. 
 
Acts that physically remove pollen, such as nasal wash (including nebulizer use) and eye 
wash 
Duration of Treatment: 
Vaccination of 8 times at 14-day intervals (Day 1, Day 15, Day 29, Day 43, Day 57, Day 71, 
Day 85, and Day 99) 
Formal Stopping Rules:  
Discontinuation Criteria for Individual Subjects 
1. Adverse events 
 
It is considered difficult for the subject to continue to participate in the study due to an AE. 
2. Consent withdrawal 
 
Subject withdraws consent for further treatment. 
3. Lost to follow-up 
 
Subject is lost to follow-up due to the subject’s personal reasons, such as moving away 
from the study site and busyness. 
 
Subject is lost to follow-up due to discontinuation of visits (or due to being unable to reach 
by any means). 
4. Protocol deviation 
 
Subject is found after vaccination to have been deviated from the inclusion/exclusion 
criteria and is judged unsuitable for further participation in the study. 
 
Another serious deviation from the protocol is found. 
5. Death 
 
Subject died. 
6. Other 
 
Subject is judged by the investigator or sub-investigator to be unsuitable for further 
participation in the study or a request is made by the Sponsor to discontinue study 
treatment due to safety reasons. 
Endpoints for Evaluation: 
Primary efficacy endpoint: 
Change in the mean of total 3 nasal symptom (sneezing, nasal discharge, and nasal congestion) 


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score (3TNSS) during 120 to 180 minutes (every 15 minutes, total of 5 time points) after start of 
cedar pollen exposure as compared to the score before cedar pollen exposure 
 
Secondary efficacy endpoints: 
 
Total 3 nasal symptom (sneezing, nasal discharge, and nasal congestion) score (3TNSS) 
 
Total 4 nasal symptom (sneezing, nasal discharge, nasal congestion, and itchy nose) score 
(4TNSS) 
 
Individual nasal symptom (sneezing, nasal discharge, nasal congestion, and itchy nose) score 
 
Total non-nasal symptom (itchy eyes and watery eyes) score (TNNSS) 
 
Individual eye symptom (itchy eyes and watery eyes) score 
 
Total symptom score (TSS) 
 
Time to occurrence of nasal or eye symptoms from start of cedar pollen exposure in the 
chamber 
 
Nasal discharge amount and sneezing count per 30 minutes during chamber exposure 
With regard to symptoms after leaving the chamber, a survey will be conducted on nasal and eye 
symptoms until 3 days after leaving the chamber. 
 
Other Efficacy Endpoints (For Pollinosis Symptoms Survey during the pollinosis symptoms survey 
period) 
Endpoints during the pollinosis symptoms survey period (01 Feb 2018–31 Mar 2018): 
 
Total 3 nasal symptom score (3TNSS) 
 
Individual nasal symptom (sneezing, nasal discharge, and nasal congestion) score 
 
Total non-nasal symptom score (TNNSS) 
 
Individual eye symptom (itchy eyes and watery eyes) score 
 
Total symptom score (TSS) 
 
Total nasal symptom medication score (TNSMS) 
 
Total non-nasal symptom medication score (TNNSMS) 
 
Total symptom medication score (TSMS) 
 
Troubles with daily life 
 
Japanese Rhinoconjunctivitis Quality of Life Questionnaire: JRQLQ No 1 
 
Overall evaluation by the subject 
 
Immune response endpoints (primary study period) 
Immunoglobulin G (IgG) antibody, specific IgG antibody (anti-JRC, anti-Cry j 1, and anti-Cry j 2), 
specific IgG4 antibody (anti-JRC), IgE antibody, specific IgE antibody (anti-JRC), anti-LAMP 
antibody, basophil activation test (BAT) 
 
Immune response endpoints (additional test) 
Specific IgE antibody (anti-JRC), basophil activation test (BAT) 
 
Safety endpoints 
 
Adverse events that occur during the primary study period. 
(Nasal and eye symptoms induced by cedar pollen exposure in the chamber will be separately 
collected as efficacy endpoints and will not be considered as AEs) 


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 
12-lead electrocardiogram, vital signs, laboratory assessments 
 
Local reactions and systemic reactions accompanying study drug vaccination that occur from 
each day of study drug vaccination until 14 days after vaccination 
 
SAEs that occur within approximately 9 months after the end of the primary study period (until 
12 months after the final vaccination of the study drug) (long-term safety follow-up period) 
Statistical Methods: 
Sample size justification:  
The number of subjects required for 80% probability of detecting superiority of the ASP4070 group 
over the placebo group was calculated. Among the study results of other drugs targeting patients 
with cedar pollinosis using a chamber, studies with published data that allow the effect size to be 
calculated were confirmed and the effect size was 0.668, 0.903, and 0.962 for bilastine, 
montelukast, and levocetirizine, respectively. Based on these effect sizes, with regard to the effect 
on the primary endpoint, the change in the mean of total 3 nasal symptom (sneezing, nasal 
discharge, and nasal congestion) score (3TNSS) during 120 to 180 minutes after entering the 
chamber to the score before cedar pollen exposure, the effect size of ASP4070 was assumed to be 
0.650. Using the significance level of the test to be 5% two-sided, when a hierarchical procedure is 
used for comparison with the placebo group in the order of high-dose group to low-dose group, if 
the effect size 0.650 is the same for the low-dose group as for the high-dose group, then the 
probability of detecting superiority of the low-dose group against the placebo group was calculated 
by simulation. Assuming the standard deviation to be 1, as a result of 10,000 simulations, the 
number of subjects required to ensure a detection power of over 80% was 48 subjects. Considering 
dropout cases, the number of subjects in each group was set to 50 subjects and 150 subjects in total. 
Efficacy: 
The FAS will be used for primary analysis. With regard to the change in the mean of total 3 nasal 
symptom (sneezing, nasal discharge, and nasal congestion) score (3TNSS) during 120 to 180 
minutes after start of cedar pollen exposure as compared to the score before cedar pollen exposure, 
the difference in the adjusted mean between each active drug group and the placebo group on Day 
183, two-sided 95% confidence interval and two-sided P value will be calculated using a mixed 
model for repeated measures assuming an unstructured covariance structure within subjects with 
explanatory variables being the vaccination group (ASP4070 4 mg, ASP4070 1 mg, and placebo), 
evaluation time (Day 127, Day 155, and Day 183), “Class from results of Japanese red cedar (JRC) 
pollen-specific IgE antibody test performed at Screening visit 1,” “Change in the mean of total 3 
nasal symptom (sneezing, nasal discharge, and nasal congestion) score during 120 to 180 minutes 
after start of cedar pollen exposure in the chamber as compared to the score before cedar pollen 
exposure at Screening visit 2,” and interaction of the vaccination group and evaluation time. 
With the significance level of the test to be 5% two-sided, the test will be conducted using 
hierarchical procedures in the following order: 
1. Comparison between the ASP4070 4 mg group and placebo group 
2. Comparison between the ASP4070 1 mg group and placebo group 
Pharmacokinetics: 
Not applicable 
Pharmacodynamics: 
Not applicable 
Immune response: 
With regard to Immune Response Endpoints, calculation of descriptive statistics or frequency 
tabulation by vaccination group and time point according to the scale and characteristics of the 
variables will be conducted. 


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Safety: 
With regard to adverse events and those whose relationship to the study drug cannot be ruled out, 
frequency tabulation by vaccination group will be conducted. With regard to laboratory test values, 
vital signs, etc., calculation of descriptive statistics or frequency tabulation by vaccination group 
and time point according to the scale and characteristics of the variables will be conducted. 
Interim analyses: 
Not applicable. 
 


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V. 
FLOW CHART AND SCHEDULE OF ASSESSMENTS 
Flow Chart 
 
 
● 
After code breaking, the Sponsor will be unblinded, but the study will be continued with 
the investigator, sub-investigator, study coordinator, and subjects remaining blinded. 
● 
Cedar pollinosis symptoms will be surveyed during the pollinosis symptoms survey 
period (01 Feb 2018–31 Mar 2018). 
● 
The additional test of immune responses will be performed during the long-term safety 
follow-up period on subjects who have completed the pollinosis symptoms survey period 
and have provided additional consent to the additional test. 
● 
Subjects will report whenever SAEs occur during the long-term safety follow-up period. 
Even if there is no contact from a subject, in principle, the subject will be asked about 
the occurrence of SAEs at 6 months and 12 months after the final vaccination. With 
regard to subjects who have discontinued the study during the primary study period, if 
the study drug had been vaccinated even once, then safety information (SAEs) will be 
collected for 1 year after the final vaccination. 
 
  
 
Primary study period 
Long-term safety follow-up period  
(12 months from the final study drug
vaccination) 
Screening period 
Study drug vaccination 
period 
Evaluation chamber 
period 
Additional 
tudy period 
Pollinosis symptoms 
survey period 
Screening 1 
Screening 3 
Screening 2 (Chamber) 
Chamber 
Chamber 
Chamber 
Post-observation 
Code breaking 
Pollinosis symptoms survey 
ASP4070 
4 mg group 
N = 50 
ASP4070 
1 mg group 
N = 50 
Placebo group 
N = 50 
8 vaccinations at 
2-week intervals  
(14-week vaccination 
period) 
3 evaluations at 
4-week intervals from 
the final study drug 
vaccination 
Additional test 


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Table 1: Schedule of Assessments 
Visit day 
 
Item 
Primary study period 
After 
Pollinosis 
Symptoms 
Survey 
Additional 
test 
Screening period 
Study drug vaccination period 
Evaluation 
chamber period 
Post-
observa- 
tion 
Disconti
nuation3) 
Screening 
visit 1 
Screening 
visit 21) 
Screening 
visit 32) 
Day 
1 
Day 
15 
Day 
29 
Day 
43 
Day 
57 
Day 
71 
Day 
85 
Day 
99 
Day 
127 
Day 
155 
Day 
183 
Period (Day) 
 
 
28 ± 7 
from 
Screening 
visit 24) 
1 
15 
± 3 
29 
± 3 
43 
± 3 
57 
± 3 
71 
± 3 
85 
± 3 
99 
± 3 
127 
± 7 
155 
± 7 
183 
± 7 
7 ± 3 
from 
Day 183  
– 
Apr 2018 
May 
201821) 
Informed consent 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
○20) 
 
Inclusion/exclusion criteria 
○ 
○ 
○ 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Target disease 
○ 
○ 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject demographics 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination5) 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Vaccination 
 
 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
 
 
 
 
 
 
 
Chamber evaluation 
 
○ 
 
 
 
 
 
 
 
 
 
○ 
○ 
○ 
 
 
 
 
Vital signs6),7) 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
 
○ 
 
 
12-lead electrocardiogram6) 
○ 
 
 
○ 
 
 
 
 
 
 
 
○ 
 
○ 
 
○ 
 
 
Immunological test8) 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
JRC allergy test9) 
○ 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Allergy test other than JRC8) 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (urine)6),10) 
○ 
 
 
○ 
 
○ 
 
○ 
 
○ 
 
○ 
○ 
○ 
 
○ 
 
 
Hematology test, blood biochemistry 
test, and urinalysis6),11) 
○ 
 
○ 
○ 
 
 
 
○ 
 
 
 
○ 
 
○ 
 
○ 
 
 
Consent for PGx12) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGx blood sampling6),13) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consent for SDA 
 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SDA blood sampling6),14) 
 
 
 
○ 
 
 
 
 
 
 
 
○ 
 
○ 
 
 
 
 
Parameters6),15),16) 
 
 
 
○ 
 
 
 
○ 
 
 
 
○ 
○ 
○ 
 
○ 
 
○22) 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
○ 
 
 
Local/Systemic Reaction Survey 
Diary17) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptoms Survey After Chamber 
Period Diary18) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pollinosis Symptoms Survey Diary19) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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○: To be performed 
1) 
Based on the results of tests and observations conducted at Screening visit 1, only those subjects who satisfy the Inclusion Criteria and do not fall under the 
Exclusion Criteria will be the target of Screening visit 2 onward. 
2) 
Based on the symptom score at the chamber evaluation at Screening visit 2, only those subjects who satisfy the inclusion criterion 5 will be the target of 
Screening visit 3 onward. 
3) 
Only those subjects who discontinue the study before Day 183 will be the target. In principle, discontinuation tests are conducted upon the decision to 
discontinue. 
4) 
Conducted no later than 7 days prior to Day 1. 
5) 
For visits with study drug vaccination, conduct physical examination (subjective symptoms, objective findings) 1 hour after study drug vaccination before 
allowing the patient to leave the clinic. 
6) 
For visits with study drug vaccination and chamber evaluation, conduct all other tests before vaccination and chamber evaluation. 
7) 
Refer to “5.4.3 Vital Signs” for test items. 
8) 
Refer to “5.2.2 Medical History” for test items. 
9) 
Refer to “5.2.3 Diagnosis of the Target Disease, Severity, and Duration of Disease” for test items. 
10) For female subjects only. Not required for subjects who are post-menopausal (defined as at least 1 year without any menses) at Screening visit 1 or subjects 
who are surgically sterile or have had hysterectomy or oophorectomy, and the possibility of pregnancy can be negated. 
11) Refer to “5.4.4 Laboratory Assessments” for test items. 
12) Obtain before conducting PGx blood sampling. 
13) To be conducted once during the period from Day 1 to Day 183. 
14) To be conducted only if blood is sampled when sample processing is possible. 
15) Refer to “5.7.1 Immune Response Assessment (Parameters)” for test items. 
16) BAT is to be conducted only if blood is sampled when sample processing is possible. If blood is not sampled on Day 1, then further blood sampling will be 
unnecessary. 
17) To be entered every day from each day of study drug vaccination to 14 days after vaccination. 
18) To be entered every day until 3 days after leaving the chamber (day of chamber evaluation, and 1, 2, and 3 days after leaving). 
19) Survey will be conducted with the target as subjects who have completed the primary study period. To be entered every day from 01 Feb 2018 to 31 Mar 
2018. 
20) Informed consent for the additional test. 
21) If a systemic steroid or an immunosuppressant (excluding external use on the skin) is used after the end of the pollinosis symptoms survey period up to 
informed consent for the additional test, the additional test will be performed 28 days after the last dose of the drug or later. 
22) The additional test will determine BAT and specific IgE antibody (anti-JRC) only. 
 


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VI. 
ACCEPTABLE RANGE OF SCHEDULE OF ASSESSMENTS 
The acceptable time ranges of tests and observations specified in the schedule of the primary 
study period are as follows. Pharmacogenomics (PGx) blood sampling will be conducted 
only once during the period from Day 1 to Day 183, and the acceptable range is the same as 
any other visit with blood sampling. The acceptable range is not specified for the 
discontinuation test; however, in principle, it will be conducted on the day when 
discontinuation is decided. 
[Vital signs (Axillary body temperature, sitting blood pressure, and sitting pulse rate)] 
Screening visit 1 
After consent is obtained 
Screening visit 2 
After Screening visit 1 + 1 day 
Screening visit 3 
28 days ±7 days from Screening visit 2 
and also until Day 1 − 7 days 
Day 1 
Until before study drug vaccination on Day 1 
Day 15, Day 29, Day 43, Day 57, 
Day 71, Day 85, Day 99 
Within ±3 days of the scheduled day 
Day 127, Day 155, Day 183 
Within ±7 days of the scheduled day 
[Hematology test, blood biochemistry test, and urinalysis] 
Screening visit 1 
After consent is obtained 
Screening visit 3 
28 days ± 7 days from Screening visit 2 
and also until Day 1− 7 days 
Day 1 
Until before study drug vaccination on Day 1 
Day 57 
Within ±3 days of the scheduled day 
Day 127, Day 183 
Within ±7 days of the scheduled day 
[12-lead electrocardiogram] 
Screening visit 1 
After consent is obtained 
Day 1 
Until before study drug vaccination on Day 1 
Day 127, Day 183 
Within ±7 days of the scheduled day 
[Pregnancy test (urine)] 
Screening visit 1 
After consent is obtained 
Day 1 
Until before study drug vaccination on Day 1 
Day 29, Day 57, Day 85 
Within ±3 days of the scheduled day 
Day 127, Day 155, Day 183 
Within ±7 days of the scheduled day 
[JRC allergy test] 
Screening visit 1 
After consent is obtained 
Screening visit 3 
28 days ±7 days from Screening visit 2 
and also until Day 1 − 7 days 


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[Allergy test other than JRC, immunological test] 
Screening visit 1 
After consent is obtained 
[Parameters] 
Day 1 
Until before study drug vaccination on Day 1 
Day 57 
Within ±3 days of the scheduled day 
Day 127, Day 155, Day 183 
Within ±7 days of the scheduled day 
[Evaluation in chamber] 
Screening visit 2 
After Screening visit 1 + 1 day 
Day 127, Day 155, Day 183 
Within ±7 days of the scheduled day 
[SDA blood sampling] 
Day 1 
Until before study drug vaccination on Day 1 
Day 127, Day 183 
Within ±7 days of the scheduled day 
 
The acceptable time range for the additional test is as follows. 
[Parameters] 
Additional test 
May 2018 
If a systemic steroid or an immunosuppressant (excluding external use on the skin) is used 
after the end of the pollinosis symptoms survey period up to informed consent for the 
additional test, the additional test will be performed 28 days after the last dose of the drug or 
later. 
 


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1 
INTRODUCTION 
1.1 
Background 
1.1.1 
Target Disease and Other Treatment Methods and Their Problems 
Japanese red cedar (JRC) is the main cause of pollinosis in Japan and its pollen may trigger 
cedar pollinosis. JRC pollen dispersal starts early in February and reaches its peak in March. 
The pollen grains of JRC are spherical and approximately 30 μm in diameter, and their major 
allergens include Cry j 1 and Cry j 2. 
JRC pollinosis exhibits typical type-1 allergic symptoms, such as nasal symptoms, including 
sneezing, nasal discharge, and nasal congestion, and eye symptoms, including itchy eyes and 
watery eyes, during the JRC pollen dispersal season. Therefore, it is known to significantly 
affect the QOL and work productivity of patients, and the prevalence of pollinosis in Japan is 
estimated to be over 20% [Environmental Health and Safety Division, Environmental Health 
Department, Ministry of the Environment, 2014]. Currently available treatment methods for 
cedar pollinosis include antigen removal/avoidance, drug therapy, surgical therapy, and 
allergen immunotherapy. It is possible to use cedar pollen masks to eliminate/avoid the 
antigen and thereby reduce exposure to cedar pollen. However, it is impossible to completely 
eliminate/avoid pollen. Although drugs with various different mechanisms of action have 
been available in the market to treat pollinosis at various levels of severity, drug therapy is 
not more than a symptomatic treatment that requires drugs to be continuously taken every 
year during the season while they have symptoms. Surgical therapy has the possibility of 
recurrence of allergic symptoms and has not yet reached the level of leading to a permanent 
cure or long-term remission of cedar pollinosis. Allergen immunotherapy includes 
subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), which were 
developed with the aim that patients may be able to achieve a permanent cure or long-term 
remission. However, this therapy may cause serious adverse reactions, such as anaphylaxis, 
and is inconvenient since long-term/frequent administration is required. Hence, the dropout 
rate of patients during treatment is high and it has not been widely adopted in clinical 
practice. 
For the reasons mentioned above, there is a growing need to develop a treatment method that 
is safer than any existing therapy and which provides a permanent cure or long-lasting 
symptom relief. The Allergy Measures Promotion Board of the Ministry of Health, Labour 
and Welfare (MHLW) has considered the development of a permanent cure through 
treatment, such as allergen immunotherapy, and therefore, developing new methods are 
necessary actions in the future. 
1.1.2 
Characteristics of ASP4070 
ASP4070 is a DNA vaccine against JRC pollinosis (pITI-JRC2*LAMP-vax) developed by 
Immunomic Therapeutics, Inc. (ITI), which may provide a new treatment option to patients 
who suffer from JRC pollinosis. It is a bivalent vaccine made up of two plasmids mixed in a 


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ratio of 1:1, each encoding one of the two major cedar allergens—Cry j 1 and Cry j 2—as a 
fusion protein with lysosome-associated membrane protein (LAMP). 
ASP4070 efficiently induces CD4+ T-cell response by co-localizing antigen protein with 
major histocompatibility complex (MHC) class II molecules [Geuze, 1998] localized in 
lysosomes [Marques et al., 2003]. Furthermore, the nucleic acid components of DNA 
vaccines are known to induce Type I interferon production [Ishii et al., 2008], and hence, it is 
predicted that T helper cell 1 (Th1) cell-dominated immune response is induced. Induction of 
Immunoglobulin E (IgE) production by an increase in allergen-specific Th2 cell response is 
considered to be the cause of the onset of allergies [Woodfolk and Platts-Mills, 2002], and it 
is anticipated that ASP4070 shifts the Th1/Th2 balance toward Th1 predominance and may 
suppress allergic symptoms. In addition, allergen expressed as a fusion protein with LAMP-1 
is known to be expressed only within lysosomes in the cytosol. In theory, it is unlikely to leak 
outside the cell and cause serious adverse reactions, such as anaphylaxis. Thus, ASP4070 is 
expected to resolve the safety problem, which is one of the concerns related to the existing 
allergen immunotherapies. Furthermore, patients are expected to receive therapeutic benefits 
with short-term treatment, and this vaccine has a high possibility of being convenient as well. 
ITI has previously conducted three phase I studies (Phase IA, Phase IB, and Phase IC) on the 
Cry j 2-LAMP vaccine (single component vaccine with only Cry j 2-LAMP plasmid) with 
Japanese or people of Japanese descent in the US, and all studies confirmed no problem with 
tolerability. 
API has previously conducted a Japanese phase I study [4070-CL-0010] with the aim of 
investigating the safety and immune response when ASP4070 is vaccinated in patients with 
JRC allergy. As a result of intramuscular (4 mg × 4 times, 4 mg × 1 time) and intradermal 
(4 mg × 4 times, 1 mg × 4 times, 4 mg × 1 time, 1 mg × 1 time) vaccination of ASP4070, this 
phase I study confirmed that there were no problems in tolerability among any of the groups. 
This study is a phase II dose-finding study [4070-CL-0020] to evaluate the efficacy and 
safety of ASP4070 in patients with JRC allergy using an environmental exposure chamber. 
 
1.2 
Non-clinical and Clinical Data 
1.2.1 
Non-clinical Data 
1.2.1.1 Pharmacological Actions 
The expression of Cry j 1-LAMP-1 fusion protein and Cry j 2-LAMP-1 fusion proteinin the 
cell was observed after introducing Cry j 1-LAMP plasmid and Cry j 2-LAMP plasmid into 
human embryonic kidney-derived 293T cell lines. Following the administration of ASP4070 
to mice, Cry j 1-specific IgG2a production and Cry j 2-specific IgG2a production were 
induced. However, Cry j 1- or Cry j 2-specific IgE production was not apparently induced. 
Furthermore, cultivation of spleen cells from ASP4070-administered mice in the presence of 
JRC pollen extract showed the production of interferon gamma (IFN-γ), but no clear 


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Interleukin-4 (IL-4) production was evident. The above results suggest that administration of 
ASP4070 to mice induces Th1 cell-dominated immune response to JRC pollen antigen. 
The effect of difference between the administration route and number of administration of 
ASP4070 on immunogenicity was investigated in mice. The production level of Cry j 1- and 
Cry j 2-specific IgG2a antibody by ASP4070 administration was the highest for intradermal 
administration as compared to intra muscular and subcutaneous administration. In addition, a 
total of 9 times of ASP4070 intradermal administration each week showed an increased 
production of Cry j 1- and Cry j 2-specific IgG2a antibody with increased number of 
administration. 
1.2.1.2 Toxicity 
With regard to toxicity studies, an 8-week intramuscular administration and a 4-week 
withholding study of Cry j 2-LAMP plasmid in rabbits (dose, 4.128 mg/body; administration, 
once every two weeks); a 4-week intramuscular administration study of Cry j 1-LAMP 
plasmid, Cry j 2-LAMP plasmid, and ASP4070 (bivalent vaccine containing both plasmids) 
in rabbits (dose, 2 mg/body for each plasmid and 4 mg/body for ASP4070; administration, 
once weekly); and a 13-week intramuscular administration study of ASP4070 in rabbits (dose, 
10 mg/body; administration. once weekly) were conducted. Neither of the studies showed 
toxic changes that may have been related to administration. Injection sites showed 
inflammatory reactions and although their incidence and severity were slightly higher than 
those in the vehicle control group, all inflammatory reactions detected were minimal or mild 
and reversible. Based on the degree of change at injection sites, it was considered that 
ASP4070 is unlikely to cause a clinically significant tissue injury. In the tissue distribution 
study of plasmid DNA in rabbits, the plasmid DNA copy number on Day 60 post-dose in any 
tissue was less than a threshold level at which chromosomal DNA integration needed to be 
examined, thereby suggesting an extremely low risk of chromosomal DNA integration. 
1.2.1.3 Pharmacokinetics 
A tissue distribution study of plasmid DNA was conducted in accordance with the FDA 
Guidelines (Guidance for Industry: Considerations for Plasmid DNA Vaccines for Infectious 
Disease Indications) to evaluate residual plasmid DNA. Following a single intramuscular 
dose of Cry j 2-LAMP plasmid to rabbits, a high level of plasmid DNA was observed at the 
injection site (muscle and subcutaneous tissue) and lymph nodes. Plasmid DNA level in the 
tissue decreased over time and was less than the quantification limit on Day 60 post-dose in 
most rabbits. 
1.2.2 
Clinical Study Data 
1.2.2.1 Japanese Phase I Study (4070-CL-0010) 
API has previously conducted a Japanese phase I study with the aim of investigating the 
safety and immune response when ASP4070 was vaccinated in 66 patients with JRC allergy. 
Refer to the Investigator’s Brochure for details. 


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This phase I study consisted of two parts: Part 1 and Part 2. Part 1 was an open-label, 
uncontrolled study to investigate the safety of intramuscular and intradermal vaccination of 
ASP4070 (4 mg × 4 times), and Part 2 was a placebo-controlled, double-blind, randomized 
parallel group comparative study to investigate the safety and immune response of 
intramuscular (4 mg × 4 times or 4 mg × 1 time) and intradermal (4 mg × 4 times, 1 mg × 4 
times, 4 mg × 1 time, or 1 mg × 1 time) vaccination of ASP4070. 
With regard to the safety, although AEs, such as local reaction and systemic reaction, 
occurred during Part 1 and Part 2 of the primary study, none was considered as major 
problems. There were no significant changes in laboratory assessments, vital signs, and 12-
lead electrocardiogram during Part 1 and Part 2. There were no significant problems with 
regard to the safety during the primary evaluation period and the long-term safety follow-up 
period. 
With regard to the immunological response, negative conversion in the skin prick test at the 
last observation in the primary study (Day 127) was reported in 4 patients, including 1 patient 
each in the intramuscular ASP4070 4 mg × 1 time, intradermal ASP4070 4 mg × 4 times, 
intradermal ASP4070 4 mg × 1 time, and intradermal ASP4070 1 mg × 1 time groups. No 
negative conversion in the skin prick test was found among patients receiving placebo in the 
intramuscular vaccination group or intradermal vaccination group. Various antibody levels, 
cytokines, and histamine release were measured but no differences in changes of these items 
were found among the treatment groups. All patients were negative to the anti-LAMP 
antibody at all time points in Part 1 and Part 2. 
In the additional investigation, pollinosis symptoms during JRC pollen dispersal season were 
investigated but no differences were found among the treatment groups in any of the 
endpoints. 
1.2.2.2 Overseas Phase I Studies 
ITI has previously conducted three phase I studies (Phase IA, Phase IB, and Phase IC) in the 
US using Cry j 2-LAMP vaccine (single component vaccine that includes only Cry j 2-
LAMP plasmid) targeting Japanese/people of Japanese descent. Refer to the Investigator’s 
Brochure for details. 
1.2.2.2.1 
Phase IA Study (US) 
Cry j 2-LAMP vaccine (4 doses of either 2 mg or 4 mg) was administered to 24 subjects in 
order to evaluate the safety and changes in immunologic biomarkers (skin prick test, etc.). Of 
the 24 subjects who lived in Japan, 18 subjects were positive to JRC pollen or mountain 
cedar (MC) pollen in the skin prick test, and 6 subjects were negative to both JRC pollen and 
MC pollen in the skin prick test. The skin prick test was performed before the start of the 
study and after vaccination of Cry j 2-LAMP vaccine 4 times (Day 132), and the results 
showed a conversion from positive to negative skin test in 14 of 17 subjects who had been 
positive to JRC pollen, MC pollen, or Cry j 2 at the start of the study. Among these subjects, 
a conversion to negative skin test was reported in 7 of 8 subjects who received 2-mg doses of 


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Cry j 2-LAMP vaccine and in 7 of 9 subjects who received 4-mg doses of Cry j 2-LAMP 
vaccine. All of the 6 subjects who had been skin test negative to all of JRC, MC, and Cry j 2 
at the start of the study did not experience a conversion to positive skin test but remained 
negative. With regard to the safety, 88 AEs were reported in 20 subjects. Most of these AEs 
occurred from Day 0 to Day 72, and only 2 AEs were reported from Day 73 to Day 132. The 
most frequent AE was injection site erythema (24 events in 11 subjects), followed by fatigue 
(14 events in 7 subjects), and headache (14 events in 7 subjects). The majority of AEs were 
mild in severity and none required treatment. No anti-LAMP antibodies were detected. There 
were no relevant changes in laboratory tests, vital signs, or physical examination. Thus, no 
significant concerns regarding the tolerability of Cry j 2-LAMP vaccine were identified. 
1.2.2.2.2 
Phase IB Study (US) 
The long-term safety of Cry j 2-LAMP vaccine and the safety of a booster injection of 
Cry j 2-LAMP vaccine (2 mg) were evaluated in 17 subjects who had received Cry j 2-
LAMP vaccine in the Phase IA study, and long-term changes in immunologic biomarkers 
were also evaluated. The skin prick test was performed before the start of this study and after 
a booster vaccination (Day 50 and Day 80). The results of the skin prick test indicated that 13 
subjects who were positive to JRC pollen or MC pollen at the start of the Phase IA study and 
subsequently participated in the Phase IB study were all negative at the start of this study. 
Among these subjects, the negative skin tests were maintained in 11 of 12 subjects who 
completed the study until Day 80. Among these 11 subjects, 2 of these subjects did not 
receive a booster injection of Cry j 2-LAMP vaccine but remained negative. A total of 4 
subjects who had a negative prick test result for JRC and MC before the start of the Phase IA 
study remained to have a negative result without converting to positive. With regard to the 
safety, 9 AEs were reported in 3 subjects. Furthermore, 6 of these events occurred in 2 
subjects after the booster vaccination of Cry j 2-LAMP vaccine. The reported AEs were mild 
or moderate in severity and eventually resolved. There were no clinically significant changes 
in laboratory assessments, vital signs, and physical examination, and there was no concern 
about the long-term safety and safety of booster vaccinations. 
1.2.2.2.3 
Phase IC Study (US) 
Cry j 2-LAMP vaccine (Group 2, 2.16 mg; Group 3, 1.08 mg) or physiological saline (Group 
1) was intradermally administered 4 times using the Biojector® 2000 device to 22 subjects, of 
whom 17 subjects were positive to any of JRC pollen, MC pollen, or Cry j 2 in the skin prick 
test and 5 subjects were negative to all JRC pollen, MC pollen, and Cry j 2 in the skin prick 
test, and the safety and changes in immune response biomarkers (skin prick test, etc.) were 
evaluated. The results of the skin prick test obtained from 10 subjects in Group 1 showed a 
conversion to negative skin test on Day 132 in 3 of 4 subjects who were positive to any one 
of JRC, MC, or Cry j 2 at screening. Among 9 subjects who completed the study until 
Day 132, a conversion from negative to positive skin test on Day 132 was found in 4 subjects 
who were negative to any one of JRC, MC, or Cry j 2 at screening. Among 6 subjects in 
Group 2, a conversion to negative skin test on Day 132 was found in 3 of 5 subjects (60%) 


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who were positive to JRC at screening. A conversion to negative skin test on Day 132 was 
also found in 1 of 4 subjects (25%) who were positive to MC at screening and 3 of 5 subjects 
(60%) who were positive to Cry j 2 at screening. Among 6 subjects in Group 3, a conversion 
to negative skin test on Day 132 was found in 1 of 2 subjects (50%) who were positive to 
JRC at screening. Among 3 subjects who were positive to MC at screening, 1 subject was 
still positive on Day 132 and 1 of the remaining 2 subjects (33%) was confirmed to be 
converted to negative skin test at discontinuation (Day 14), and the other subject remained 
positive at discontinuation (Day 102). Among 4 subjects who completed the study until Day 
132, a conversion from negative to positive skin test on Day 132 was found in 2 subjects who 
were negative to any one of JRC, MC, or Cry j 2 at screening. A conversion to negative skin 
test on Day 132 was also found in 1 of 3 subjects (33%) who were positive to Cry j 2 at 
screening. With regard to the safety, 321 AEs were reported across the three groups after the 
start of vaccination. No serious adverse events (SAEs) occurred. The most frequently 
reported AEs across the three groups included injection site-related AEs (257 events), most 
of which had already been reported in the Phase IA and Phase IB studies. No anti-LAMP 
antibodies were detected. There were no relevant changes in laboratory tests, vital signs, and 
physical examination. Thus, no significant concerns regarding the tolerability of Cry j 2-
LAMP vaccine were identified. 
 
1.3 
Summary of Key Safety Information for Study Drugs 
Summary of the safety information for the study drug as provided below. Refer to the 
Investigator’s Brochure for details. 
Although AEs, such as local reaction and systemic reaction, occurred during Japanese phase I 
study upon intramuscular or intradermal vaccination of ASP4070 2 mg or 4 mg, it was 
confirmed that there is no problem in the tolerability of up to 4 mg ASP4070. There were no 
problematic changes in laboratory assessments, vital signs, and 12-lead electrocardiogram 
during Part 1 and Part 2. In addition, during the long-term safety follow-up period, although 
an SAE (event name: benign parotid tumour) occurred in 1 subject in the ASP4070 4 mg × 1 
time (intramuscular vaccination) group, this was an event that occurred approximately 5 
months after the final vaccination and a relationship to the study drug was negated. 
Otherwise, there were no SAE and local reactions reported during the long-term safety 
follow-up period. 
In the US, signs of systemic symptoms, such as anaphylaxis, against the vaccine were not 
found in the Phase IA, Phase IB, and Phase IC studies using only Cry J 2-LAMP plasmid and 
there were no occurrences of other SAEs. In addition, the majority of AEs were transient 
injection site reactions and all were confirmed to have recovered without treatment. 
 
1.4 
Risk-Benefit Assessment 
ASP4070 is a DNA vaccine designed to express the antigen as a fusion protein with LAMP-1. 
ASP4070 can effectively induce CD4+ T-cell response by co-localization of the expressed 


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fusion protein with MHC Class II molecules localized in the lysosome [Geuze, 1998; 
Marques et al., 2003]. The nucleotide component of DNA vaccine is also known to induce 
Type I interferon production [Ishii et al., 2008], which may induce a Th1-dominant immune 
response. In reality, experiments with ASP4070 have shown that administration to mice leads 
to an increase in mice IgG2a antibody production that is induced and produced by Th1 cells, 
whereas IgE antibody that is induced and produced by Th2 cells was not induced. IgE 
production induced by the enhanced allergen-specific Th2 cell response is considered to be 
responsible for the onset of allergy [Woodfolk and Platts-Mills, 2002] and ASP4070 is 
expected to suppress allergic symptoms by rendering the Th1/Th2 balance to Th1-dominant. 
LAMP-1 fusion protein is known only to be expressed in lysosomes in cytoplasm [Marques 
et al., 2003], and in a study where antigen-LAMP-1 fusion protein expressing plasmid was 
administered to mice, antigen-LAMP-1 fusion protein was not detected in circulatory blood 
[Tan et al., 2006]. Therefore, the risk of anaphylaxis, which has been one of the concerns for 
conventional allergen immunotherapy, is considered to be low. 
Common AEs in previous clinical studies with Cry j 2-LAMP vaccine or ASP4070 included 
local reactions and systemic reactions that are normally observed with vaccination (refer to 
the Investigator’s Brochure for details). After study drug vaccination, the investigator or sub-
investigator should be watchful of these symptoms associated with vaccination and treat any 
symptoms as necessary to ensure the safety of subjects. 
In the environmental exposure chamber, JRC pollen that exists in the natural environment 
will be used and subjects will be exposed to JRC pollen levels approximately in the same 
level as observed within Tokyo Prefecture [Hashiguchi et al., 2009], and it is assumed that 
symptoms similar to those under the natural environment will occur with the pollen exposure. 
In addition, these symptoms may continue for 2 or 3 days after leaving the chamber. In case 
of unanticipated events, subjects will be continuously monitored during the assessment in the 
chamber and the investigator or sub-investigator will treat any symptoms as necessary to 
ensure the safety of subjects. 
 
2 
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS 
2.1 
Study Objectives 
To evaluate the efficacy, safety, and dose response for ASP4070 vaccinated in patients with 
cedar pollinosis. 
 
2.2 
Study Design and Dose Rationale 
2.2.1 
Study Design 
This study is a randomized, double-blind, placebo-controlled, dose-finding study. 


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The efficacy, safety, and dose response when ASP4070 (mixture containing equivalent 
amount of Cry j 1-LAMP plasmid and Cry j 2-LAMP plasmid, 4 mg/0.4 mL or 1 mg/0.4 mL) 
will be intradermally vaccinated 8 times at 14-day intervals will be evaluated with placebo 
(physiological saline) as the control. The study will conduct cedar pollen exposure using an 
environmental exposure chamber (OHIO Chamber; hereinafter, “chamber”), and the efficacy 
and dose response will be evaluated using clinical symptoms (nasal and eye symptoms) as 
indicators. 
Two factors, “Class from results of Japanese red cedar (JRC) pollen-specific IgE antibody 
test performed at Screening visit 1” and “Change in the mean of total 3 nasal symptom 
(sneezing, nasal discharge, and nasal congestion) score during 120 to 180 minutes after start 
of cedar pollen exposure in the chamber as compared to the score before cedar pollen 
exposure at Screening visit 2,” will be used as stratification factors to randomly allocate 
subjects into three groups—ASP4070 4 mg group, ASP4070 1 mg group, or placebo group—
in a ratio of 1:1:1, and the subjects will be vaccinated with the study drug. 
After a set period after the final vaccination of the study drug, re-exposure to cedar pollen in 
the chamber will be conducted and the efficacy will be evaluated using clinical symptoms as 
indicators. Efficacy evaluation will be conducted 4, 8, and 12 weeks after the final 
vaccination to confirm the timing of effectiveness. The primary study period of the study will 
be until the end of the one week of post-observational period after the final evaluation in the 
chamber on Day 183 (12 weeks after the final vaccination). 
The treatment code will be broken when the primary study period is completed and all data 
entered in case report forms are fixed. Even after code breaking, the study will be continued 
with the investigator, sub-investigator, study coordinator, and subjects remaining blinded. 
Subjects who have completed the primary study period will be the target of a survey on cedar 
pollinosis symptoms during the pollinosis symptoms survey period (01 Feb 2018–31 Mar 
2018). Subjects will make entries in the Pollinosis Symptoms Survey Diary every day on 
information regarding nasal and eye symptoms. If a subject experiences intolerable nasal and 
eye symptoms during this period, then the use of rescue drugs will be allowed. 
An additional test of immune responses will be performed during the long-term safety 
follow-up period on subjects who have completed the pollinosis symptoms survey period and 
have provided additional consent to the additional test. The additional test will determine the 
parameters (specific IgE antibody [anti-JRC] and basophil activation test [BAT]) after the 
end of the cedar pollen dispersal season (May 2018). 
After the end of the primary study period, safety information (SAE) will be collected for 
approximately 9 months (1 year from the final vaccination of the study drug) as the long-term 
safety follow-up period. Safety information (SAE) will be collected for 1 year after the final 
vaccination of the study drug even from subjects who discontinue their participation in the 
study during the primary study period if they have received at least one vaccination of the 
study drug. 


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Among subjects in the placebo group or optimal dose group (ASP4070 4 mg group or 1 mg 
group) who complete the primary study period, those who provide written consent again will 
be the target of a Phase II Second-Year Follow-up Study [4070-CL-0021] that is planned to 
be implemented. 
2.2.2 
Dose Rationale 
This study will intradermally vaccinate ASP4070 4 mg or ASP4070 1 mg 8 times at two-
week intervals (vaccination period of 14 weeks). 
With regard to the study drug vaccination amount, 4 mg, the maximum dose confirmed to 
have no problems regarding the tolerability in Japanese phase I study was designated as the 
high dose group, and additionally, to investigate dose-response relationship, 1 mg was to be 
investigated as the low dose group. Vaccination interval was the same as that in phase I 
studies and set at 2-week intervals. The number of vaccination was set to 8 times 
(vaccination period of 14 weeks) because an increase in immune response was confirmed 
upon an increase in the number of vaccinations from 7 to 9 times of vaccination, efficacy 
against seasonal allergies has been confirmed for up to 8 times of peptide immunotherapy 
developed in recent years, and patient burden is high for long-term treatment. 
During the phase I studies with vaccination up to 4 times, there was no trend suggesting an 
increase in AE incidence or aggravation of severity accompanying an increase in the number 
of vaccinations, and pre-clinical toxicity studies did not show any findings of changes related 
to toxicity with administration up to 13 times. 
Both intradermal and intramuscular vaccination have been confirmed in clinical studies 
conducted in the US and Japan as vaccination routes without any problems from the 
viewpoint of safety. In addition, many immune response-related cells, such as dendritic cells, 
exist in the epidermis, and intradermal vaccination has been reported to efficiently reinforce 
antigen recognition by the immune system and showed a higher immunogenicity than 
intramuscular vaccination [Hickling et al., 2011; Kenney et al., 2004]. Therefore, intradermal 
vaccination was selected for this study. 
 
2.3 
Endpoints 
2.3.1 
Primary Efficacy Endpoints 
Change in the mean of total 3 nasal symptom (sneezing, nasal discharge, and nasal 
congestion) score (3TNSS) during 120 to 180 minutes (every 15 minutes, total of 5 time 
points) after start of cedar pollen exposure as compared to the score before cedar pollen 
exposure 
Subjects will assess for each symptom (sneezing, nasal discharge, and nasal congestion) 
using the following score every 15 minutes from before cedar pollen exposure until 180 
minutes after cedar pollen exposure. 
0: None (no symptoms) 


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1: Mild (symptoms present but easily tolerated) 
2: Moderate (awareness of symptoms; bothersome, but tolerable) 
3: Severe (definite awareness of symptoms; difficult to tolerate, but does not interfere 
with the activities of daily living) 
4: Very severe (difficult to tolerate and interferes with the activities of daily living) 
[Rationale] 
The three main symptoms of sneezing, nasal discharge, and nasal congestion are the main 
pollinosis symptoms and the indicator of severity of these nasal symptoms is the total 3 nasal 
symptom score (3TNSS). In addition, results from other studies using a chamber have 
confirmed that clinical symptoms induced by cedar pollen exposure in the chamber reaches a 
plateau at 90 to 120 minutes after start of JRC pollen exposure. [Hashiguchi et al., 2009]. 
Based on the above, it was considered that clinical symptoms might be more accurately 
evaluated by cedar pollen exposure in the chamber. The primary endpoint was designated as 
the mean of total 3 nasal symptom score (3TNSS) at 120 to 180 minutes, which is after 
symptoms have stabilized. 
2.3.2 
Secondary Efficacy Endpoints 
● 
Total 3 nasal symptom (sneezing, nasal discharge, and nasal congestion) score (3TNSS) 
● 
Total 4 nasal symptom (sneezing, nasal discharge, nasal congestion, and itchy nose) 
score (4TNSS) 
● 
Individual nasal symptom (sneezing, nasal discharge, nasal congestion, and itchy nose) 
score 
● 
Total non-nasal symptom (itchy eyes and watery eyes) score (TNNSS) 
● 
Individual eye symptom (itchy eyes and watery eyes) score 
● 
Total symptom score (TSS) 
Subjects will score each symptom (sneezing, nasal discharge, nasal congestion, itchy nose, 
itchy eyes, and watery eyes) used for tabulation of the above items, using the indicators in 
“2.3.1 Primary Efficacy Endpoints.” 
The following items are also assessed. 
● 
Time to occurrence of nasal or eye symptoms (time point when the score of nasal or eye 
symptom worsens by one or more as compared to before JRC pollen exposure) from start 
of cedar pollen exposure in the chamber 
● 
Nasal discharge amount and sneezing count per 30 minutes during chamber exposure 
Nasal discharge amount is the difference in the weight of the tissue paper before and 
after use by subjects who are instructed to use pre-allocated tissues for blowing their 
nose. 
With regard to symptoms after leaving the chamber, a survey will be conducted on nasal and 
eye symptoms until 3 days after leaving the chamber. 


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2.3.3 
Other Efficacy Endpoints 
Endpoints during the pollinosis symptoms survey period (01 Feb 2018–31 Mar 2018): 
● 
Total 3 nasal symptom score (3TNSS) 
● 
Individual nasal symptom (sneezing, nasal discharge, and nasal congestion) score 
● 
Total non-nasal symptom score (TNNSS) 
● 
Individual eye symptom (itchy eyes and watery eyes) score 
● 
Total symptom score (TSS) 
● 
Total nasal symptom medication score (TNSMS) 
● 
Total non-nasal symptom medication score (TNNSMS) 
● 
Total symptom medication score (TSMS) 
● 
Troubles with daily life 
● 
Japanese Rhinoconjunctivitis Quality of Life Questionnaire: JRQLQ No 1 
● 
Overall evaluation by the subject 
For each symptom score, subjects will record the following items in their Pollinosis 
Symptoms Survey Diary every day. Section “12.3 Classification of Severity of Pollinosis 
Symptoms” will be referred to with regard to nasal and eye symptoms and troubles with daily 
life. 
● 
Nasal symptoms: Sneezing, nasal discharge, and nasal congestion, each graded with a 5-
level score of 0, 1, 2, 3, and 4. 
● 
Eye symptoms: Itchy eyes and watery eyes, each graded with a 4-level score of 0, 1, 2, 
and 3. 
● 
Troubles with daily life: 5-level score of 0,1, 2, 3, and 4. 
Total nasal symptom medication score, total eye symptom medication score, and total nasal 
and eye symptom medication score will be used for scoring rescue drug use status and for 
calculating endpoints. 
JRQLQ No 1 will be entered every 2 weeks during the pollinosis symptoms survey period for 
a total of 5 times. 
Overall evaluation by the subject is conducted by subjects after the end of the pollinosis 
symptoms survey period. 
● 
Overall evaluation by the subject: 5-level evaluation on overall evaluation of symptoms 
during the pollinosis symptoms survey period. 
2.3.4 
Immune Response Endpoints 
Immune response endpoints (primary study period) 
Immunoglobulin G (IgG) antibody, specific IgG antibody (anti-JRC, anti-Cry j 1, 
anti-Cry j 2), specific IgG4 antibody (anti-JRC), IgE antibody, specific IgE antibody 
(anti-JRC), anti-LAMP antibody, basophil activation test (BAT) 
 


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Immune response endpoints (additional test) 
Specific IgE antibody (anti-JRC), basophil activation test (BAT) 
2.3.5 
Safety Endpoints 
● 
AEs that occur during the primary study period 
(Nasal and eye symptoms induced by cedar pollen exposure in the chamber will be 
separately collected as efficacy endpoints and will not be considered as AEs) 
● 
12-lead electrocardiogram, vital signs, laboratory assessments 
● 
Local reactions and systemic reactions accompanying study drug vaccination that occur 
from each day of study drug vaccination until 14 days after vaccination 
● 
SAEs that occur within approximately 9 months after the end of the primary study period 
(until 12 months after the final vaccination of the study drug) (long-term safety follow-
up period) 
 
3 
STUDY POPULATION 
3.1 
Selection of Study Population  
Patients with cedar pollinosis aged from 20 to 64 years 
 
3.2 
Inclusion Criteria 
Subject is eligible for the study if all of the following 1 to 11 apply: 
1. Subject who has provided written consent using the informed consent form approved by 
the Institutional Review Board (IRB) of the study site before starting any study-related 
procedure 
2. Subject of either sex who is aged from 20 to 64 years at the time of informed consent 
3. Subject who has nasal symptoms (sneezing, nasal discharge, or nasal congestion) and 
eye symptoms (itchy eyes or watery eyes) of pollinosis during the cedar pollen dispersal 
seasons in 2016 and 2017 
4. Subject who has the JRC pollen-specific IgE antibody test result of Class 3 or higher in 
the allergy test at Screening visit 1 
5. Subject who satisfies the following criteria for change in the mean of the nasal symptom 
score during 120 to 180 minutes after start of cedar pollen exposure in the chamber as 
compared to the score before cedar pollen exposure at Screening visit 2 
● 
Total 3 nasal symptom score (3TNSS) worsens by 2 or more, 2 or more individual 
nasal symptom score (sneezing, nasal discharge, and nasal congestion) worsens by 1 
or more 


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6. Female subject must satisfy the following criteria 
Subject of non-childbearing potential must satisfy either of the following criteria: 
● 
Subject who is post-menopausal (defined as at least 1 year without any menses) 
prior to Screening visit 1 
● 
Subject who is surgically sterile (hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy) 
Or, subject of childbearing potential (subject who does not meet the above definition of 
“female subject of non-childbearing potential”) must meet all of the following criteria: 
● 
Subject must agree not to try to become pregnant during the primary study period or 
for 28 days after the final vaccination of the study drug (whichever period is longer) 
● 
Subject must have a negative urine pregnancy test at Screening visit 1 and on Day 1 
(prior to vaccination) 
● 
Subject must consistently use two forms of highly effective birth control* (at least 
one of which must be a barrier method) during the primary study period or for 28 
days after the final vaccination of the study drug (whichever period is longer) if 
heterosexually active 
*Highly effective forms of birth control 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 
● 
Calendar-based contraceptive methods (Knaus-Ogino or rhythm method) 
7. Female subject must agree not to breastfeed during the primary study period or for 28 
days after the final vaccination of the study drug (whichever period is longer) 
8. Female subject must not donate ova during the primary study period or for 28 days after 
the final vaccination of the study drug (whichever period is longer) 
9. Male subject and their female spouse/partners who are of childbearing potential must be 
using highly effective contraception consisting of two forms of birth control* (at least 
one of which must be a barrier method) from the initial study drug vaccination until 28 
days after the final vaccination of the study drug 
10. Male subject must not donate sperm from the initial study drug vaccination until 28 days 
after the final vaccination of the study drug 
11. Subject agrees not to participate in another intervention study while on treatment 
Subject is eligible for the additional test of the study if the following 12 and 13 both apply: 
12. Subject has completed the pollinosis symptoms survey period 
13. Subject has provided written consent using the informed consent form approved by the 
Institutional Review Board of the study site before starting any procedure related to the 
additional test of the study 


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Waivers to the inclusion criteria will NOT be allowed. 
[Rationale] 
1 and 13: Designated in consideration of ethics in accordance with the “Ordinance on Good 
Clinical Practice (GCP) for trials on gene, cellular, and tissue-based products” (MHLW 
ordinance No. 89, 30 Jul 2014) 
2: The age was set to 20 years or older, when subjects themselves have the ability to 
determine whether or not to participate in a clinical study. The upper limit was set to 64 
years because the study is targeting non-elderly patients. 
3 to 5: Designated to select JRC pollinosis patients who are the target of this study. 
6 to 10: Designated as general exclusion items to ensure the safety of subjects. 
11: Designated to appropriately conduct evaluation of this study. 
12: Designated to target subjects who have been investigated for cedar pollinosis symptoms 
during the pollinosis symptoms survey period. 
 
3.3 
Exclusion Criteria 
Subject will be excluded from participation if any of the following apply: 
1. Subject whose allergy test result to other antigens than JRC pollen (test result of IgE 
antibody specific to alnus, Japanese white birch, ragweed, artemisia, cocksfoot, 
dermatophagoides farinae, dermatophagoides pteronyssinus, Aspergillus, Candida, 
Alternaria, house dust 1, house dust 2, cat dander, and dog dander) is Class 4 or higher at 
Screening visit 1 
2. Subject who has received specific immunotherapy (including desensitization therapy) for 
cedar pollinosis in the past 
3. Subject who has received specific or non-specific immunotherapy within 5 years prior to 
Screening visit 1 
4. Subject who has received laser therapy/surgery for treating nasal symptoms within 3 
years prior to Screening visit 1 
5. Subject who has used the following drugs within 14 days prior to entering the chamber at 
Screening visit 2 
Topical steroid, histamine H1-receptor antagonist, chemical mediator-isolation inhibitor, 
T helper cell 2 (Th2) cytokine inhibitor, thromboxane A2 synthesis inhibitor, 
thromboxane A2 receptor antagonist, leukotriene receptor antagonist 
(Among the above drugs, use of medications for external use on the skin is allowed. 
However, use at the study drug vaccination site on the day before Day 1 is not allowed.) 
6. Subject who has used the following drugs within 84 days prior to entering the chamber at 
Screening visit 2 


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Biological agents, such as antibiotics (anti-tumor necrosis factor alpha [TNFα] antibody, 
anti-IgE monoclonal antibody, etc.) 
7. Subject who has used the following drugs within 84 days prior to the first vaccination of 
the study drug 
Systemic steroids and immunosuppressants (Use of medications for external use on the 
skin are allowed. However, use at the study drug vaccination site on the day before Day 
1 is not allowed.) 
8. Subject who has received or is planning to receive vaccination of a live vaccine within 
28 days prior to the first vaccination of the study drug, and/or subject who has received 
or is planning to receive vaccination of an inactivated vaccine/toxoid within 7 days prior 
to the first vaccination of the study drug 
9. Subject who has a history of serious allergic reactions, such as anaphylactic shock and 
generalized exanthema, caused by food and/or medical products (including vaccine) in 
the past 
10. Subject who has a positive immunological test result for hepatitis B surface antigen (HBs 
antigen) or hepatitis C virus (HCV) antibody at Screening visit 1 
11. Subject who has a complication of nasal disorder (nasal polyp, nasal septum deviation, 
chronic sinusitis, etc.) that may affect efficacy evaluation 
12. Subject who has autoimmune disease or other serious primary disease 
13. Subject who has been diagnosed with immunodeficiency in the past 
14. Subject who has a complication of seasonal allergic rhinitis, perennial allergic rhinitis, 
rhinitis medicamentosa, or non-allergic rhinitis against antigens other than cedar and 
cypress that require medical treatment 
15. Subject who has a complication of cardiovascular disease (including congestive cardiac 
failure, angina pectoris, and cardiac arrhythmias that require medical treatment) 
16. Subject who has a complication of hepatic disease (including viral hepatitis and drug-
induced liver injury) 
17. Subject who has a complication of renal disease (including acute kidney injury, 
glomerulonephritis, and interstitial nephritis 
18. Subject who has a complication of respiratory disease (including bronchial asthma and 
chronic bronchitis that require medical treatment) 
19. Subject who has a complication of malignant tumor or has been diagnosed with or has 
received treatment for malignant tumor within 5 years prior to the first vaccination of the 
study drug 
20. Subject who has been diagnosed with mental conditions, such as schizophrenia, bipolar 
disorder, and major depressive disorder, or dementia 


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21. Subject who has a complication that may have an impact on the evaluation of local and 
systemic reactions 
22. Subject who has received vaccination of Cry j 2-LAMP vaccine 
23. Subject who has participated in a study of ASP4070 and received vaccination of the 
study drug 
24. Subject who has participated in any clinical study or post-marketing clinical study of any 
other medical drug or device within 12 weeks (84 days) prior to Screening visit 1, or 
subject who is participating in such a study at present 
25. Subject who is an employee of the Sponsor or CRO or medical institution involved in the 
study 
26. Subject who is considered by the investigator or sub-investigator as unsuitable for study 
participation 
Waivers to the exclusion criteria will NOT be allowed. 
[Rationale] 
1 to 7, 11, 13, and 14: Designated because of the possibility of an effect on efficacy 
evaluation of the study drug. 
8 to 10, 12, and 15 to 20: Designated to ensure the safety of subjects. 
21: Designated because of the possibility of an effect on safety evaluation of the study drug. 
22 and 23: Designated because of the possibility of an effect on safety and efficacy 
evaluation of the study drug. 
24: Designated from ethical considerations and safety considerations for subjects. 
25: This criterion was set not to select anyone who would be disadvantaged by not 
participating in the study. 
26: This criterion was set in consideration of situations other than the above 1 to 25, where 
the investigator or sub-investigator judges a subject to be ineligible for participating in 
the study from a scientific and/or ethical perspective. 
Among subjects who satisfy all of the inclusion criteria 1 to 11 and do not fall under any of 
the exclusion criteria, subjects who were determined as reserve subjects will not proceed to 
procedures after Day 1 and are considered as completing their participation in the study when 
the number of subjects vaccinated with the drug reaches 150, the target number of subjects. 
 


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4 
TREATMENT 
4.1 
Identification of Investigational Product 
4.1.1 
Test Drug 
Code name 
ASP4070 
Non-proprietary name 
To be determined 
Dosage form and strength 
Clear and colorless injectable solution: 
4 mg/0.4 mL (containing 2 mg each of Cry j 1-LAMP plasmid 
and Cry j 2-LAMP plasmid) 
Lot No. 
See the procedures for handling the study products  
Storage condition 
Stored frozen (−20°C ± 5°C) and protected from light 
Expiration date 
See the procedures for handling the study products 
4.1.2 
Comparative Drug 
Code name 
Placebo 
Non-proprietary name 
Physiological saline 
Dosage form and strength 0.9% sodium chloride 
Lot No. 
See the procedures for handling the study products 
Storage condition 
Stored at room temperature 
Expiration date 
See the procedures for handling the study products 
 
4.2 
Packaging and Labeling 
All medications used in this study will be prepared, packaged, and labeled under the 
responsibility of qualified staff at API in accordance with API’s Standard Operating 
Procedures (SOPs), Good Gene, Cellular, and Tissue-based Products Manufacturing Practice 
(GCTP) guidelines (Good Manufacturing Practice [GMP] guidelines for the comparative 
drug), ICH GCP guidelines, and applicable local laws and regulations. 
(Package Form) 
ASP4070: 4 mg/0.4 mL vial 
Placebo: 
5 mL ampule 
 
4.3 
Study Drug Handling  
The head of the study site 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 products written by the Sponsor. 
● 
The study drug storage manager should prepare and retain records of the study drugs’ 
receipt, the inventory at the study site, the use by each subject, and the return to the 
Sponsor or alternative disposal of unused study drugs. These records should include 


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dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique 
code numbers assigned to the study drugs and subjects. 
● 
The study drug storage manager should prepare and retain records that document 
adequately that the subjects were provided the doses specified by the protocol, and 
reconcile all the study drugs supplied from the Sponsor. 
 
4.4 
Blinding 
4.4.1 
Blinding Method 
[Primary study period] 
The primary study period of this study is double blinded. Double blinding is conducted to 
hide which group subjects belong to —ASP4070 4 mg group, ASP4070 1 mg group, or 
placebo group. ASP4070 4 mg, ASP4070 1 mg, and placebo are all externally 
indistinguishable when filling the syringe. 
The study will not be blinded to the person in charge of randomization list management and 
study drug adjustment within the study site (hereinafter, “randomization list manager”), 
ancillary staff of the study site (ancillary randomization list manager), and sub-investigators 
who are in charge of study drug vaccination. Sub-investigators who are in charge of study 
drug vaccination will not be involved in this study other than vaccination to subjects, and 
other investigators will observe and evaluate subjects. However, sub-investigators who are in 
charge of study drug vaccination may conduct observation and evaluation at Screening visits 
until the sub-investigator starts to vaccinate subjects with the study drug. Details are provided 
in the “procedures for blinding compliance.” 
[Long-term safety follow-up study period (including pollinosis symptoms survey period and 
additional study period)] 
The treatment code will be broken when the primary study period is completed and all data 
entered in case report forms are fixed. Even after code breaking, the study will be continued 
with the investigator, sub-investigator, study coordinator, and subjects remaining blinded. 
4.4.2 
Confirmation of the Indistinguishability of the Study Drugs 
The randomization list manager will confirm the indistinguishability of the study drugs filled 
in the syringe at each study drug vaccination. 
4.4.3 
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking 
The treatment allocation manager (CRO) will prepare the randomization list. The treatment 
allocation manger will prepare and seal one original and two copies, and retain the original. 
The Sponsor will keep one copy in the sealed condition even after opening the original copy 
for code breaking. The randomization list manager will use one copy when adjusting study 


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drug dose and return the sealed copy to the treatment allocation manager after study drug 
vaccination to the final subject has been completed. The treatment allocation manager will 
also prepare and seal the treatment code for emergency when responding to a request from 
the study site. The sealed treatment code for emergency will be retained by the treatment 
allocation manager. 
In principle, code breaking will occur after the completion of vaccination of the study drug, 
all protocol-specified observation/assessments for the primary study period in all subjects, 
finalization of the Statistical Analysis Plan (SAP), and all data locked. The treatment 
allocation manager will unseal the randomization list (original), and the treatment allocation 
manager will submit the randomization list (original) and randomization list for study sites 
(copy) to the Sponsor. 
4.4.4 
Breaking the Treatment Code for Emergency 
In case of an emergency, such as the occurrence of an SAE, the investigator or sub-
investigator will be allowed to request the Sponsor to break the treatment code for an 
emergency. If the sub-investigator is requesting to break the treatment code for emergency, 
then in principle, prior approval of the investigator will be required. However, if it is difficult 
to obtain prior approval of the investigator, then the sub-investigator will report after the 
event. Upon request, the Sponsor will determine whether or not the treatment code for an 
emergency should be broken. If the code is to be broken, then the Sponsor will instruct the 
treatment allocation manager to break it. The sponsor will receive contact from the treatment 
allocation manager regarding the result of the emergency treatment code breaking, and the 
sponsor will inform the investigator or sub investigator of the result. Breaking of the 
treatment code for an emergency will be conducted in accordance with the procedure for 
breaking the emergency treatment code. 
 
4.5 
Assignment and Allocation 
The treatment allocation manager will prepare the randomization list prior to the initial 
vaccination of the study drug to the first subject, which randomly allocates randomization 
numbers to three groups in a ratio of 1:1:1 to ASP4070 4 mg group, ASP4070 1 mg group, or 
placebo group, with two factors as stratification factors, “Class of Japanese red cedar (JRC) 
pollen-specific IgE antibody test results at Screening visit 1” and “Change in the mean of 
total 3 nasal symptom (sneezing, nasal discharge, and nasal congestion) score during 120 to 
180 minutes after start of cedar pollen exposure in the chamber as compared to the score 
before cedar pollen exposure at Screening visit 2.” 
Subject allocation to randomization number will be conducted several times by the 
investigator or sub investigator (excluding sub-investigators who are in charge of study drug 
vaccination) and completed before the initial study drug vaccination of subjects. 
Specific procedures are provided in the “procedures for blinding compliance.” 


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5 
TREATMENTS AND EVALUATION 
5.1 
Dosing and Administration of Study Drug and Other Medications 
5.1.1 
Dose/Dose Regimen and Administration Period 
ASP4070 4 mg group: 0.4 mL of ASP4070 4 mg/0.4 mL will be intradermally vaccinated. 
ASP4070 1 mg group: 0.1 mL of ASP4070 4 mg/0.4 mL and 0.3 mL of physiological saline 
will be mixed and a total of 0.4 mL will be intradermally vaccinated. 
Placebo group: 0.4 mL of physiological saline will be intradermally vaccinated. 
Intradermal injection device manufactured by Terumo (Immucise® intradermal injection 
needle: Medical device approval No. 22700BZX00264000 and intradermal disposable 
syringe) will be used for study drug vaccination. For each vaccination, 0.2 mL each of the 
study drug will be vaccinated into two sites on each arm in principle. Vaccination sites will 
be in principle the upper arm deltoid. 
5.1.2 
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy) 
During the primary study period, the following items in the table below for all concomitant 
medications and treatments used after the start of the first vaccination of the study drug will 
be entered in the eCRF. 
Concomitant treatment  
Survey period 
Items to be entered in eCRF 
Medication 
All drugs 
From first vaccination of the 
study drug to completion of 
the primary study period 
Drug name, route of 
administration, reason for 
administration, and 
administration period 
Non-medication 
therapy 
All 
therapies 
From first vaccination of the 
study drug to completion of 
the primary study period 
Therapy name, reason for 
treatment, and treatment 
period 
The following items in the table below for rescue drugs and items that physically shield the 
body from JRC pollen, such as masks and goggles, used during the pollinosis symptoms 
survey period will be entered in the eCRF. From the end of the primary study period until the 
completion of the pollinosis symptoms survey period, if prohibited concomitant drugs are 
used, then the same items as for rescue drugs will be entered in the eCRF, and if prohibited 
concomitant therapies are used, then the therapy name and treatment period will be entered in 
the eCRF. 


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Concomitant treatment  
Survey period 
Items to be entered in eCRF 
Medication 
Rescue 
drugs 
Pollinosis symptoms survey 
period 
Drug name, daily dose, route 
of administration, and 
administration period 
Non-medication 
therapy 
Mask, 
goggles, 
etc. 
Pollinosis symptoms survey 
period 
Therapy name, use status 
(outdoor/indoor), and period 
of use 
If prohibited concomitant drugs are used from the informed consent for the additional test 
until the completion of the additional test, the items listed on the table below will be entered 
in the eCRF. For systemic steroids and immunosuppressants (excluding external use on the 
skin) used after the end of the pollinosis symptoms survey period up to informed consent for 
the additional test, entry in the eCRF is not necessary, but the drug name and administration 
period need to be confirmed. 
Concomitant treatment 
Survey period 
Items to be entered in eCRF 
Medication Prohibited 
concomitant drugs 
From informed 
consent for the 
additional test to the 
completion of the 
additional test 
Drug name, daily dose, route of 
administration, and administration 
period 
 
5.1.2.1 Prohibited Medications/Therapies 
The use of the following medications will be prohibited: 
1. Until the end of the pollinosis symptoms survey period 
Immunotherapy specific to cedar pollinosis (including desensitization therapy) 
2. From 5 years prior to Screening visit 1 until the end of the pollinosis symptoms survey 
period 
Specific or non-specific immunotherapy 
3. From 14 days prior to entering the chamber at Screening visit 2 until the end of the 
pollinosis symptoms survey period 
Topical steroid, histamine H1-receptor antagonist, chemical mediator-isolation inhibitor, 
Th2 cytokine inhibitor, thromboxane A2 synthesis inhibitor, thromboxane A2 receptor 
antagonist, leukotriene receptor antagonist 
(Among the above drugs, use of medications for external use on the skin will be allowed. 
However, use at the study drug vaccination site from the day before Day 1 until 28 days 
after the final vaccination of the study drug will not be allowed.) 
If a subject experiences intolerable nasal and eye symptoms during the pollinosis 
symptoms survey period, then the use of rescue drugs will be allowed. (Refer to “5.1.2.2 
Rescue Drugs”). 
4. From 84 days prior to entering the chamber at Screening visit 2 until the end of the 
pollinosis symptoms survey period 


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Biological agents, such as antibiotics (anti-TNFα antibody, anti-IgE monoclonal 
antibody, etc.) 
5. From 84 days prior to the first vaccination of the study drug until the end of the 
pollinosis symptoms survey period and from the informed consent for the additional test 
until the completion of the additional test 
Systemic steroid/immunosuppressants 
(Use of medications for external use on the skin will be allowed. However, use at the 
study drug vaccination site from the day before Day 1 until 28 days after the final 
vaccination of the study drug will not be allowed.) 
6. From 28 days prior to the first vaccination of the study drug until 28 days after the final 
vaccination of the study drug 
Live vaccine 
7. From 7 days prior to the first vaccination of the study drug until 28 days after the final 
vaccination of the study drug 
Inactivated vaccine/toxoid 
5.1.2.2 Rescue Drugs 
A daily dose of the following rescue drugs may be used for intolerable nasal and eye 
symptoms (in principle, a score of 4 for any of the nasal symptom score or a score of 3 for 
any of the eye symptom score) only on the day of occurrence during the pollinosis symptoms 
survey period. Prophylactic use of rescue drugs will be prohibited. Use status will be entered 
in the Pollinosis Symptoms Survey Diary. 
Drug name 
Use condition (to be used only if satisfying the conditions 
provided below) 
Tramazoline hydrochloride 
nasal drops 
Nasal congestion score 4 
Ketotifen fumarate eye drops 
Eye symptom (itchy eyes or watery eyes) score 3 
Fexofenadine hydrochloride 
tablets 
If fulfilling any of the following cases: 
 Nasal congestion or eye symptoms are intolerable even 
with the use of the above nasal/eye drops 
 Sneezing score 4 
 Nasal discharge score 4 
5.1.2.3 Prohibited Non-Medication Therapies 
The following therapies will be prohibited. 
1. From 3 years prior to Screening visit 1 until the end of the pollinosis symptoms survey 
period 
● 
Laser therapy/surgery for treating nasal symptoms 
2. From leaving the chamber at 4, 8, and 12 weeks after the final vaccination until the 
completion of the Symptoms Survey After Chamber 
● 
Acts that physically remove pollen, such as nasal wash (including nebulizer use) and 
eye wash 


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3. During the pollinosis symptoms survey period 
● 
The use of objects that physically shield the body from pollen, such as 
masks/goggles 
This restriction does not apply to cases in which the investigator or sub-investigator 
deems the use to be unavoidable (such as medical personnel and factory workers), 
but the usage should be kept to the minimum.  
● 
Acts that physically remove pollen, such as nasal wash (including nebulizer use) and 
eye wash 
5.1.3 
Treatment Compliance 
The sub-investigator who is in charge of study drug vaccination will adequately vaccinate the 
subject with the study drug. The date of vaccination will be recorded and entered in the eCRF. 
5.1.4 
Restrictions During the Study 
The investigator, sub-investigator, or study coordinator will instruct individual subjects to 
follow the “Requirements for Subjects” provided below during the study period. 
1. Visit control 
The subject will visit the study site at a specified schedule in the protocol. 
2. Contact regarding concomitant treatment (medication other than the study drug and non-
medication therapy) 
If the use of any concomitant treatment (medication [drugs other than the study drug and 
rescue drug during the pollinosis symptoms survey period] and non-medication therapy) 
is needed during the period from signing the informed consent form to completion of the 
pollinosis symptoms survey period, then the subject will contact the study site before 
using it, if possible, and follow instructions of the investigator or sub-investigator. 
3. Exercise 
The subject will not engage in strenuous exercise on the day of study drug vaccination. 
4. Alcohol intake 
The subject will not consume an excessive amount of alcohol on the day of study drug 
vaccination. 
5. Bathing 
The subject can take a bath or shower. The subject should be careful not to excessively 
stimulate the vaccination site on the day of vaccination. 
6. Contraception 
The potential effects of the study drug on pregnancy or on the health of the 
fetus/newborn child are unknown. Therefore, female subjects must consistently use two 
forms of highly effective birth control (at least one of which must be a barrier method) 
(refer to “3.2 Inclusion Criteria 6”) during the period from signing the informed consent 
form to completion of the primary study period or 28 days after the final study drug 
vaccination (whichever is longer), and male subjects and their female spouse/partners 
who are of childbearing potential must be using highly effective contraception consisting 


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of two forms of birth control (at least one of which must be a barrier method) during the 
period from the initial study drug vaccination until 28 days after the final study drug 
vaccination. 
7. Breastfeeding 
Female subjects must not breastfeed during the primary study period or for 28 days after 
the final vaccination of the study drug (whichever period is longer). 
8. Donation of ova/sperm 
Female subjects must not donate ova during the primary study period or for 28 days after 
the final vaccination of the study drug (whichever period is longer). 
Male subjects must not donate sperm from the initial study drug vaccination until 28 
days after the final vaccination of the study drug. 
9. Local/Systemic Reaction Survey Diary 
Subjects will make entries in the Local/Systemic Reaction Survey Diary every day from 
Day 1 until 14 days after the final vaccination of the study drug and bring it to the study 
site on each visit day. 
10. Symptoms Survey After Chamber Period Diary 
Subjects will make entries in the Symptoms Survey After Chamber Period Diary every 
day until 3 days after leaving the chamber and bring it to the study site on each visit day. 
11. Pollinosis Symptoms Survey Diary 
Subjects will make entries in the Pollinosis Symptoms Survey Diary every day from 01 
Feb 2018 to 31 Mar 2018. After the survey of pollinosis symptoms is completed, the 
overall evaluation will be immediately conducted. Subjects will bring the diary with 
entries to the study site on each visit day. 
12. Contact of safety information to medical institutions 
If any SAEs occur during study participation (including long-term safety follow-up 
period), then subjects will contact the medical institution. 
13. Other 
Subjects will not engage in anything that may fall under any of the exclusion criteria. 
 
5.2 
Demographics and Baseline Characteristics 
5.2.1 
Demographics 
The investigator or sub-investigator will investigate by a test and an interview regarding date 
of consent, age (at the time of consent), sex, height, and body weight at Screening visit 1 and 
enter in the eCRF. 
5.2.2 
Medical History 
Previous disease is defined as a disease that has been resolved by the time vaccination of the 
study drug starts, and concurrent disease is defined as a disease that persists at the time of the 
start of study drug vaccination. All concurrent diseases will be investigated and the diagnosis 
name will be recorded in the medical record or other source document and also entered in the 


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eCRF. Previous diseases will be confirmed based on the Inclusion Criteria and Exclusion 
Criteria but entry into eCRF will not be necessary. 
The following items should be examined at Screening visit 1 and confirmed that they do not 
fall under the Exclusion Criteria. 
● 
Immunological tests (HBs antigen, HCV antibody) 
● 
Allergy test other than JRC (specific IgE antibody to alnus, Japanese white birch, 
ragweed, artemisia, cocksfoot, dermatophagoides farinae, dermatophagoides 
pteronyssinus, Aspergillus, Candida, Alternaria, house dust 1, house dust 2, cat dander, 
and dog dander) 
5.2.3 
Diagnosis of the Target Disease, Severity, and Duration of Disease 
Information of the following will be obtained and recorded in the eCRF. 
● 
Target disease, target disease period, overall evaluation of cedar pollinosis in 2017 (good 
[almost no symptoms], fairly good [mild], normal [moderate], slightly bad [severe], 
extremely bad [most severe]) 
● 
Symptoms score upon chamber evaluation at Screening visit 2 and evaluation date 
Chamber evaluation at Screening visit 2 will be conducted using the same exposure 
conditions as that in chamber evaluation for efficacy evaluation and evaluated using the 
same scoring (refer to “5.3.1 Nasal and Eye Symptoms During Chamber Period”). 
JRC allergy test (specific IgE antibody against JRC) will be conducted at Screening visit 1 
and Screening visit 3 and the test result will be obtained directly by an electronic file from 
the centralized testing company. 
 
5.3 
Efficacy Assessment 
5.3.1 
Nasal and Eye Symptoms During Chamber Period 
With regard to nasal symptoms (sneezing, nasal discharge, nasal congestion, and itchy nose) 
and eye symptoms (itchy eyes and watery eyes) upon chamber evaluation at 4, 8, and 12 
weeks after the final vaccination of the study drug (exposure to JRC pollens, 8,000/m3; 
exposure duration, 180 minutes). Subjects will use the following score for assessment every 
15 minutes from before cedar pollen exposure until 180 minutes after cedar pollen exposure. 
Each symptom score at each time point and evaluation date will be entered in the eCRF. 
0: None (no symptoms) 
1: Mild (symptoms present but easily tolerated) 
2: Moderate (awareness of symptoms; bothersome, but tolerable) 
3: Severe (definite awareness of symptoms; difficult to tolerate, but does not interfere 
with the activities of daily living) 
4: Very severe (difficult to tolerate and interferes with the activities of daily living) 


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In addition, nasal discharge amount (measured by weight of the tissue paper before and after 
use by subjects who are instructed to use pre-allocated tissues for blowing their nose) and 
sneezing count per 30 minutes will be measured during chamber exposure and the results and 
evaluation date will be entered in the eCRF. 
5.3.2 
Symptoms Survey After Chamber Period 
A survey on nasal and eye symptoms until 3 days after leaving the chamber (day of chamber 
evaluation, 1, 2, and 3 days after leaving the chamber) will be conducted using the Symptoms 
Survey After Chamber Period Diary. Subjects will make a diary entry once every day using 
the symptoms score described in “5.3.1 Nasal and Eye Symptoms During Chamber Period” 
for evaluation. Each symptom score and evaluation date will be entered in the eCRF. 
5.3.3 
Pollinosis Symptoms Survey During 2018 JRC Pollen Dispersal Season 
Targeting subjects who have completed the primary study period, the following items will be 
evaluated regarding pollinosis symptoms during the pollinosis symptoms survey period (01 
Feb 2018–31 Mar 2018) using the Pollinosis Symptoms Survey Diary. Nasal and eye 
symptoms and troubles with daily life will be determined based on “12.3 Classification of 
Severity of Pollinosis Symptoms.” JRQLQ No 1 will be entered every 2 weeks during the 
pollinosis symptoms survey period (at the start of survey, 2, 4, and 6 weeks after the start of 
survey, and at the end of survey) for a total of 5 times. With regard to the following items, 
entries will be made into the eCRF. With regard to the use status of drugs other than rescue 
drugs, only information on prohibited medication will be entered into the eCRF. 
● 
Nasal symptoms: Sneezing, nasal discharge, and nasal congestion, each graded with a 5-
level score of 0, 1, 2, 3, and 4. 
● 
Eye symptoms: Itchy eyes and watery eyes, each graded with a 4-level score of 0, 1, 2, 
and 3. 
● 
Troubles with daily life: 5-level score of 0,1, 2, 3, and 4. 
● 
Rescue drug use status: Use/no use, drug name, administration route, use amount 
● 
Use status of drugs other than rescue drugs: Use/no use, drug name, administration route, 
use amount 
● 
Use status of items to physically shield from JRC pollen: Use/no use, therapy name, use 
status (outdoor/indoor) 
● 
Movement status to areas outside the Kanto region: Movement/no movement, area of 
movement 
● 
JRQLQ No 1 
● 
Overall evaluation by the subject: With regard to the overall evaluation of symptoms 
during the pollinosis symptoms survey period, evaluation will be conducted in 5 levels 
(good [almost no symptoms], fairly good [mild], normal [moderate], slightly bad 
[severe], and extremely bad [most severe]) after the end of the pollinosis symptoms 
survey period. 


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Furthermore, data on the JRC pollen dispersal amount that is publicized after the end of the 
JRC pollen dispersal season in 2018 will be obtained and used for analysis of efficacy 
evaluation of the pollinosis symptoms survey period. 
 
5.4 
Safety Assessment 
5.4.1 
Adverse Events 
5.4.1.1 Adverse Events (Primary Study Period) 
The survey period for AEs will be from obtaining informed consent until the end of the final 
observation of the primary study period. Nasal and eye symptoms induced by cedar pollen 
exposure in the chamber will be separately collected as efficacy endpoints and not considered 
as AEs. 
Refer to “5.5 Adverse Events and Other Safety Aspects” regarding information on collection 
of AEs and data handling. 
5.4.1.2 Adverse Events (Long-term Safety Follow-up Period) 
Long-term safety of ASP4070 will be investigated for 9 months from the last observation in 
the primary study period (for 12 months from the final vaccination of the study drug). If 
SAEs occur, then the subject will contact the study site. With regard to subjects who have 
discontinued the study during the primary study period, if the study drug had been vaccinated 
even once, then safety information (SAEs) will be collected for 1 year after the final 
vaccination. SAEs will be assessed in accordance with Section “5.5.2 Definition of Serious 
Adverse Events (SAEs).” Even if there is no contact from the subject, in principle, the 
subject will be asked about the occurrence of SAEs at 6 months and 12 months after the final 
vaccination of the study drug either when the subject visits the study site or by phone. 
5.4.2 
Local/Systemic Reaction Survey Diary 
The Local/Systemic Reaction Survey Diary will be used to survey the following designated 
items occurring from the date of study drug vaccination until 14 days after vaccination. 
Subjects will make an entry into the diary every day. 
● 
Local reactions: Pain, tenderness, erythema/redness, and induration/swelling 
● 
Systemic reactions: Nausea/vomiting, diarrhea, headache, fatigue, and myalgia 
5.4.3 
Vital Signs 
Axillary body temperature, sitting blood pressure, and sitting pulse rate at rest will be 
measured on each assessment day. See “Table 1: Schedule of Assessments” for the day of 
conducting the assessments. The measurement results and measurement date will be recorded 
in the eCRF. 


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5.4.4 
Laboratory Assessments 
Laboratory Assessments items to be conducted during the study are as follows. See “Table 1: 
Schedule of Assessments” for the day of conducting the assessments. Measurements will be 
conducted at the study site. 
1. Hematology test, blood biochemistry test, and urinalysis 
Test results will be obtained by an electronic file. The clinical significance of any 
laboratory assessments results that are outside the reference range will be determined and 
recorded by the investigator or sub-investigator. 
● 
Hematology 
Hb, Ht, RBC, WBC, differential leukocyte count (neutrophil, lymphocyte, monocyte, 
eosinophil, and basophil), PLT 
● 
Blood biochemistry 
TP, ALB, AST, ALT, γ-GTP, ALP, LDH, UA, T-Bil, BUN, Cre, CK, CRP 
(quantitative), Na, K, Cl, T-Cho, TG 
● 
Urinalysis 
Protein, glucose, occult blood, urobilinogen 
2. Pregnancy test (urine, only female subjects) 
The pregnancy test is not necessary for subjects who are post-menopausal (defined as at 
least 1 year without any menses) prior to Screening visit 1 or subjects who are surgically 
sterile or have had hysterectomy or oophorectomy, and the possibility of pregnancy can 
be negated. The test results and testing date will be entered in the eCRF. 
5.4.5 
Physical Examination 
The following will be assessed or examined. See “Table 1: Schedule of Assessments” for the 
day of conducting the assessments. 
1. Subjective symptoms 
The investigator, sub-investigator, or study coordinator will confirm subjective 
symptoms of the subject. The subject will report any “subjective symptom” that occurs 
during the primary study period to the investigator, sub-investigator, or study coordinator. 
2. Objective findings 
The investigator or sub-investigator will interview and/or examine the subject as much as 
possible at visit or when a subjective symptom is reported by the subject. 
Upon entry into the chamber, the investigator or sub-investigator will comprehensively 
determine whether there are any problems related to safety or whether there are any clinical 
symptoms that may affect pollinosis symptom evaluation from the subject’s subjective 
symptoms and objective findings. 
5.4.6 
Electrocardiogram (ECG) 
The investigator or sub-investigator will analyze the 12-lead ECG data and determine which 
of the following should be categorized: “Normal,” “clinically insignificantly abnormal,” or 


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“clinically significantly abnormal.” See “Table 1: Schedule of Assessments” for the day of 
conducting the assessments. The dates and results of measurements will be entered in the 
eCRF. If ECG data are assessed as “clinically insignificantly abnormal” or “clinically 
significantly abnormal,” then details of the abnormality will be entered in the eCRF. 
 
5.5 
Adverse Events and Other Safety Aspects 
5.5.1 
 Definition of Adverse Events (AEs) 
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. 
To identify all events that may be related to the procedures of the study and therefore require 
a change in study conduct, even if the subject has not received the drug, API will collect 
information on AEs. The collection of AEs will start when written consent is obtained and 
will be conducted until the completion of the last observation of the primary study period. 
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG 
data, physical exam) should be defined as an AE only if the abnormality meets one 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. 
Based on the entries in the Local/Systemic Reaction Survey Diary, if the investigator or sub-
investigator examines the subject and determines that the following items occurred from the 
date of study drug vaccination until 14 days after vaccination and a relationship with the 
study drug cannot be negated, then it will be evaluated as a local/systemic reaction at the 
vaccination site. 
● 
Local reactions: Pain, tenderness, erythema/redness, and induration/swelling 
● 
Systemic reactions: Nausea/vomiting, diarrhoea, headache, fatigue, and myalgia 
With regard to AEs observed after obtaining informed consent until starting the first 
vaccination of the study drug, the event name, date of onset, timing, seriousness, severity, 
date of resolution, and outcome will be recorded in the eCRF. 
With regard to AEs observed after starting the first vaccination of the study drug, the event 
name, presence/absence of local/systemic reaction, category of local/systemic reaction (if 
present), date of onset, timing, seriousness, severity, action(s) taken, date of resolution, 
outcome, causality with study drug/intradermal injection device, and reason for causality 


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assessment will be investigated and recorded in the eCRF. With regard to local reactions, the 
number of sites and timing of study drug vaccination that triggered the onset will be recorded 
in the eCRF. 
Seriousness (serious or non-serious), causal relationship to the study drug (not related, 
possible, probable), and severity (mild, moderate, severe, life-threatening) will be assessed in 
accordance with Sections “5.5.2 Definition of Serious Adverse Events (SAEs),” “5.5.3 
Criteria for Causal Relationship to the Study Drug/Intradermal Injection Device,” and “5.5.4 
Criteria for Defining the Severity of an Adverse Event,” respectively. 
If a diagnosis is made from the signs and/or symptoms, then the diagnosis should be recorded 
in preference to the listing of individual signs and symptoms. If a diagnosis is not made from 
the signs and/or symptoms, then the investigator or sub-investigator should record each sign 
and symptom as an individual AE. An AE that recurs after resolution or an AE that worsens 
in severity will be handled as a new AE. 
Nasal and eye symptoms induced by cedar pollen exposure in the chamber will be separately 
collected as efficacy endpoints and will be not considered as AEs. 
5.5.2 
Definition of Serious Adverse Events (SAEs) 
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 (an adverse event 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 adverse event 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) 
● 
Other medically important events 
Medical and scientific judgment should 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 one of the other outcomes listed in the 
definition above. These events, including those that may result in disability/incapacity, 
should also usually be considered serious. Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization; or development of drug dependency or drug abuse. 


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Any AE that falls under the criteria presented in Section “12.4 Events That Should Be 
Handled as Serious Adverse Events” should be handled as an SAE and reported in 
accordance with Section “5.5.5 Reporting of Serious Adverse Events (SAEs).” Additional 
information may be required. 
5.5.3 
Criteria for Causal Relationship to the Study Drug/Intradermal Injection 
Device 
Adverse events that fall under either “Possible” or “Probable” should be defined as “adverse 
events whose relationship to the study drugs could not be ruled out” or “adverse events 
whose relationship with the intradermal injection device 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). 
5.5.4 
Criteria for Defining the Severity of an Adverse Event 
Local reactions (pain, tenderness, erythema/redness, and induration/swelling) and systemic 
reactions (nausea/vomiting, diarrhoea, headache, fatigue, and myalgia) will be graded by 
reference to Sections “12.1 Classification of Severity of Local Reactions at Vaccination Site” 
and “12.2 Classification of Severity of Systemic Reactions.” 
Severity of other AEs will be assessed according to the following four levels: 
● 
Mild: 
No disruption of normal daily activities 
● 
Moderate: 
Affect normal daily activities 
● 
Severe: 
Inability to perform daily activities 
● 
Life-threatening: Necessity for urgent intervention 


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5.5.5 
Reporting of Serious Adverse Events (SAEs) 
In the case of a serious adverse event (SAE), the investigator or sub-investigator must report 
to the head of the study site and must contact the Sponsor/delegated CRO by telephone or fax 
immediately (within 24 hours of awareness). 
The investigator should complete and submit JUTOKUNA YUUGAIJISHOU 
HOUKOKUSHO containing all information that is required by the Regulatory Authorities to 
the Sponsor/delegated CRO by fax immediately (within 24 hours of awareness) and to the 
head of the hospital. If the faxing of JUTOKUNA YUUGAIJISHOU HOUKOKUSHO is not 
possible or is not possible within 24 hours, the Sponsor/delegated CRO should be informed 
by phone. 
Contact information for the Sponsor: 
, Astellas Pharma Inc. 
Fax: 
 
Phone No.: 
 
Contact information for the delegated CRO: 
 
Fax: 
 
5.5.6 
Follow-up of Adverse Events 
All AEs occurring after the initial study drug vaccination and all SAEs occurring during the 
long-term safety follow-up period are to be followed up by the investigator or sub-
investigator until resolved or judged to be no longer clinically significant, or until they are 
clearly determined as chronic. 
Even if the subject does not return to normal or level before study drug administration, the 
follow-up can be considered unnecessary or completed when the investigator or sub-
investigator deems the follow-up as unnecessary or completed and the reason is appropriately 
entered in the source reference material. 
5.5.7 
Procedure in Case of Pregnancy 
If a female subject becomes pregnant during the primary study period after the completion of 
the initial study drug vaccination or for 28 days after the final study drug vaccination 
(whichever is later), or the partner of a male subject becomes pregnant during the period from 
the completion of the final vaccination to 28 days after the final study drug vaccination, the 
investigator should 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 conception date, pregnancy result and neonatal data etc., should be included in this 
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. 


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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 should 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 after birth should be reported as an SAE regardless of 
its relationship with the study drug 
● 
If an infant dies more than 1 month after the birth, it should 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 
● 
Unless a congenital anomaly are identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination 
5.5.8 
Emergency Procedures and Management of Overdose 
If any symptom occurs due to ASP4070 overdose, then the investigator or sub-investigator 
will provide the subject with emergency care or general maintenance therapy depending on 
the symptom severity and perform appropriate examinations, such as vital signs, 12-lead 
ECG, and laboratory tests, to ensure the safety of the subject. These are only supportive 
measures, because there are no established ASP4070 overdose management methods. 
5.5.9 
Supply of New Information Affecting the Conduct of the Study 
1. When information is obtained regarding serious and unexpected adverse drug reactions 
that are specified in Article 273 of the Enforcement Regulations of the Pharmaceutical 
Affairs Law, in compliance with Article 80-2 Paragraph 6 of the Pharmaceutical Affairs 
Law, 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 “8.2.3.4 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 Investigator’s Brochure, 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. 


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5.5.10 
Deviations From the Protocol and Other Actions Taken to Avoid Life-
Threatening Risks to Subjects 
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 
 
5.7 
Other Measurements, Assessments or Methods 
5.7.1 
Immune Response Assessment (Parameters) 
The following parameters will be measured to confirm the immune response to ASP4070. 
Appropriate markers will be evaluated in an exploratory manner. See “Table 1: Schedule of 
Assessments” for the day of conducting the assessments. Measurement will be conducted at 
the centralized testing company and the date of blood sampling will be entered in the eCRF. 
The test result will be obtained directly by an electronic file from the centralized testing 
company after code breaking. 
BAT will be performed only if blood is sampled at a time/day when sample processing is 
possible. If blood sampling for BAT is not conducted on Day 1, then sampling for BAT will 
not be subsequently required. 
See “Table 1: Schedule of Assessments” for the time point of the additional test. The test 
result will be obtained directly by an electronic file from the centralized testing company. 
[Primary study period] 
● 
IgG antibody, specific IgG antibody(anti-JRC, anti-Cry j 1, anti-Cry j 2), specific IgG4 
antibody (anti-JRC), IgE antibody , specific IgE antibody (anti-JRC), anti-LAMP 
antibody, basophil activation test (BAT) 
[Additional test] 
● 
Specific IgE antibody (anti-JRC), basophil activation test (BAT) 


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5.7.2 
Objective of Secondary Data Analysis 
● 
Blood sampling for Secondary Data Analysis (SDA) will be conducted only if the 
content of analysis has been approved by the study site. The procedures described in 
Sections “5.7.2.1 Sampling and Storage of Secondary Data Analysis Samples,” “5.7.2.2 
Disposal of Secondary Data Analysis Samples,” “5.7.2.3 Disclosure of Secondary Data 
Analysis Results,” “8.2 Ethics and Protection of Subject Confidentiality,” and “8.3 
Administrative Matters” will be followed. 
● 
To conduct research on the action mechanism of the study drug against cedar pollinosis 
and measurement/analysis of exploratory biomarkers related to efficacy/safety evaluation, 
biological samples will be stored for a maximum of 2 years. 
5.7.2.1 Sampling and Storage of Secondary Data Analysis Samples 
Blood will be sampled at a time/day when sample processing is possible from those among 
subjects participating in the study who have provided written consent to collect and store 
blood samples for SDA. The date of consent and that of blood sampling for each subject will 
be fully recorded and entered in the eCRF. The investigator, sub-investigator, or study 
coordinator will take 19 mL of peripheral blood from the brachial vein three times during the 
study period (Day 1, Day 127, and Day 183) using a storage tube and a portion will be stored 
frozen at −80°C and the remainder stored at room temperature until the sample is collected 
from the study site. The sample collection/delivery institution will collect blood samples for 
SDA, temporarily store the samples frozen, and later deliver to the 
 
, which is the Secondary Data Analysis sample storage institution. The Secondary 
Data Analysis sample storage institution will receive the sampled blood and keep the samples 
frozen until analysis. However, the storage period of blood samples will be a maximum of 2 
years after data are locked. 
Anonymization of the sample: SDA in this study will anonymize the samples by a single 
code. The study site will allocate subject identification codes. 
5.7.2.2 Disposal of Secondary Data Analysis Samples 
When the storage period of the sample has ended, the investigator, sub-investigator, or study 
coordinator has received contact from the subject to withdraw consent to SDA, or the 
Sponsor has decided to dispose of the stored samples, the label on the sample tube from the 
relevant subjects will be immediately taken off and the Secondary Data Analysis sample 
storage institution will appropriately dispose of the sample. If SDA is conducted before the 
end of the storage period or withdrawal of consent, then data obtained from analysis will not 
be disposed. 
5.7.2.3 Disclosure of Secondary Data Analysis Results 
This study is exploratory and the results obtained from a biomarker research are considered 
as lacking in precision and reliability. Therefore, the results of this study will not be disclosed 
by the Sponsor to subjects and study sites. 


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5.7.3 
Objective of Pharmacogenomics Research 
● 
Blood sampling for pharmacogenomics research will be conducted only if the content of 
analysis has been approved by the study site. Follow the procedures in Sections “5.7.3.1 
Sampling and Storage of Pharmacogenomics Sample,” “5.7.3.2 Disposal of 
Pharmacogenomics Sample,” “5.7.3.3 Disclosure of Genetic Information,” “8.2 Ethics 
and Protection of Subject Confidentiality,” and “8.3 Administrative Matters.” 
● 
With regard to preparation for future studies on the efficacy or safety and the relationship 
with genomes/genes related to this test drug, the biological samples will be stored for a 
maximum of 15 years. 
● 
Biological samples will be collected and stored to enable exploratory research markers 
that predict drug response (efficacy and toxicity [adverse reactions]) by comprehensive 
analysis of genetic information from this clinical study and other clinical studies using 
this test drug in the future. 
● 
Genomic/gene analysis samples may be sampled to explore markers related to the 
occurrence of an adverse reaction if any serious adverse reactions are observed. 
5.7.3.1 Sampling and Storage of Pharmacogenomics Sample 
Blood will be sampled from those among subjects participating in the study who have 
provided written consent to collect and store blood samples for pharmacogenomics research. 
The investigator, sub-investigator, or study coordinator will take 5 mL of peripheral blood 
from the brachial vein one time between Day 1 and Day 183 using a storage tube and it will 
be stored at 4°C until the sample is collected from the study site. The date of consent and that 
of blood sampling for each subject will be fully recorded and entered in the eCRF. The 
sample collection/delivery institution will collect blood samples for pharmacogenomics 
research, temporarily store the samples frozen (approximately −20°C or lower), and deliver 
to the pharmacogenomics sample storage institution. The pharmacogenomics sample storage 
institution will receive the sampled blood and keep the samples frozen (approximately 
−80°C) until analysis in the future. However, the storage period of blood samples will be a 
maximum of 15 years after data are locked. 
Anonymization of the sample: Pharmacogenomics research in this study will anonymize the 
samples by a single code. The study site will allocate subject identification codes. 
5.7.3.2 Disposal of Pharmacogenomics Sample 
When the storage period of the sample has ended, the investigator, sub-investigator, or study 
coordinator has received contact from the subject to withdraw consent to pharmacogenomics 
research, or the Sponsor has decided to dispose of the stored samples, the label on the sample 
tube from the relevant subjects will be immediately taken off and the pharmacogenomics 
sample storage institution will appropriately dispose of the sample. If genomic/gene analysis 
is conducted before the end of the storage period or withdrawal of consent, data obtained 
from analysis will not be disposed. 


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5.7.3.3 Disclosure of Genetic Information 
Even if pharmacogenomics research is conducted in the future, this study is exploratory and 
gene analysis results (gene measurement results, relationship between genes and drug 
response) are considered as lacking in precision and reliability. Therefore, in principle, the 
results of gene analysis will not be disclosed by the Sponsor to subjects and study sites. 
 
5.8 
Total Amount of Blood 
The amount of blood to be collected in the study is as follows. Blood will be collected as 
needed if a follow-up of clinical laboratory values becomes necessary. 
[Primary study period] 
Test item 
Amount of 
blood per draw 
(mL) 
Frequency 
Total amount 
of blood 
(mL) 
Hematology 
2 
6 
12 
Blood biochemistry 
6 
6 
36 
Immunological tests 
3 
1 
3 
JRC allergy test 
2 
1 
2 
JRC allergy test 
Allergy test other than JRC 
6 
1 
6 
Parameters1) 
14 
5 
70 
Total 
129 
● 
If consent for pharmacogenomics research is obtained, then a further 5 mL will be 
sampled one time between Day 1 and Day 183. 
● 
If consent for SDA is obtained, then a further 19 mL each will be sampled on Day 1, 
Day 127, and Day 183. 
● 
If blood sampling for BAT is not conducted during the primary study period, blood 
sampling for the parameters will be 12 mL each time. 
● 
Reserve subjects will participate up to Screening visit 3, and the total amount of blood 
will be 27 mL. 
1) IgG antibody, specific IgG antibody (anti-JRC, anti-Cry j 1, anti-Cry j 2), specific IgG4 
antibody (anti-JRC), IgE antibody, specific IgE antibody (anti-JRC), anti-LAMP 
antibody, basophil activation test (BAT) 
 
[Additional study period] 
Test item 
Amount of 
blood per draw 
(mL) 
Frequency 
Total amount 
of blood 
(mL) 
Parameters2) 
4 
1 
4 
Total 
4 


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2) Specific IgE antibody (anti-JRC), basophil activation test (BAT) 
 
5.9 
Phase II Second-Year Follow-up Study (4070-CL-0021) 
To preliminarily collect information regarding the continued effect until the subsequent year 
and necessity for additional vaccinations in the subsequent year, and to collect safety data on 
subjects who are vaccinated for multiple years, a second-year, follow-up study is scheduled. 
In the second-year, follow-up study, subjects who have been allocated to the optimal dose 
group (ASP4070 4 mg group or 1 mg group) or placebo group in the study, completed the 
primary study period and also provided consent to participate in the second-year, follow-up 
study will be the target for one additional vaccination approximately one year after the final 
vaccination of this study. After obtaining consent for the second-year, follow-up study, 
chamber evaluation once before and after the study drug vaccination is scheduled to be 
conducted. 
 
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. 
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 involvement in the study at any time if the 
subject's clinical condition warrants it. 
If a subject is discontinued from the study with an ongoing adverse event or an unresolved 
laboratory result that is significantly outside of the reference range, the investigator will 
attempt to provide follow-up until the condition stabilizes or no longer is clinically 
significant. 
Discontinuation Criteria for Individual Subjects 
1. Adverse events 
● 
It is considered difficult for the subject to continue to participate in the study due to 
an AE. 
2. Consent withdrawal 
● 
Subject withdraws consent for further treatment. 
3. Lost to follow-up 
● 
Subject is lost to follow-up due to the subject’s personal reasons, such as moving 
away from the study site and busyness. 
● 
Subject is lost to follow-up due to discontinuation of visits (or due to being unable to 
reach by any means). 


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4. Protocol deviation 
● 
Subject is found after vaccination to have been deviated from the 
inclusion/exclusion criteria and is judged unsuitable for further participation in the 
study. 
● 
Another serious deviation from the protocol is found. 
5. Death 
● 
Subject died. 
6. Other 
● 
Subject is judged by the investigator or sub-investigator to be unsuitable for further 
participation in the study or a request is made by the Sponsor to discontinue study 
treatment due to safety reasons. 
 
6.2 
Discontinuation of the Site 
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the Sponsor and the head of the study site. 
 
6.3 
Discontinuation of the Study 
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If 
the Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination. 
 
7 
STATISTICAL METHODOLOGY 
The statistical analysis will be coordinated by the responsible biostatistician of the Sponsor. 
A Statistical Analysis Plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings, and figures to be produced. The SAP for the primary study 
period will be finalized before code breaking at the latest. Any changes from the analyses 
planned in SAP will be justified in the Clinical Study Report (CSR). A separate SAP will be 
written for the pollinosis symptoms survey period during the pollen dispersal season and 
additional study period. 
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. 
 
7.1 
Sample Size 
A total of 150 subjects, with 50 study drug vaccination subjects in each group 


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[Rationale] 
The number of subjects required for 80% probability of detecting superiority of the ASP4070 
group over the placebo group was calculated. Among the study results of other drugs 
targeting patients with cedar pollinosis using a chamber, studies with published data that 
allow the effect size to be calculated were confirmed and the effect size was 0.668 a), 0.903 b), 
and 0.962 c) for bilastine [Hashiguchi et al., 2017] , montelukast [Hashiguchi et al., 2012], 
and levocetirizine [Hashiguchi et al., 2013], respectively. Based on these effect sizes, with 
regard to the effect on the primary endpoint, the change in the mean of total 3 nasal symptom 
(sneezing, nasal discharge, and nasal congestion) score (3TNSS) during 120 to 180 minutes 
after entering the chamber to the score before cedar pollen exposure, the effect size of 
ASP4070 was assumed to be 0.650. Using the significance level of the test to be 5% two-
sided, when a hierarchical procedure is used for comparison with the placebo group in the 
order of high-dose group to low-dose group, if the effect size 0.650 is the same for the low-
dose group as for the high-dose group, then the probability of detecting superiority of the 
low-dose group against the placebo group was calculated by simulation. Assuming the 
standard deviation to be 1, as a result of 10,000 simulations, the number of subjects required 
to ensure a detection power of over 80% was 48 subjects. Considering dropout cases, the 
number of subjects in each group was set to 50 subjects and 150 subjects in total. 
a) With regard to the total 4 nasal symptom score (sneezing, nasal discharge, nasal congestion, and itchy 
nose) from 0 to 240 minutes after entering the environmental exposure chamber on Day 2 of 
administration, the mean for the bilastine 20 mg group and placebo group was 84.4 and 109.5, 
respectively, the standard deviation was 33.0 and 41.6, respectively, and the effect size was 0.668. 
b) With regard to the mean of the total 3 nasal symptom score (sneezing, nasal discharge, and nasal 
congestion) from 120 to 180 minutes after entering the environmental exposure chamber, the mean of the 
montelukast 7 days group and placebo group was 2.31 and 3.17, respectively, the standard deviation was 
0.17 and 0.20, respectively, and the effect size was 0.903. 
c) With regard to the AUC of the total 4 nasal symptom score (sneezing, nasal discharge, nasal congestion, 
itchy nose) from 0 to 180 minutes after entering the environmental exposure chamber, the mean of the 
levocetirizine single agent group and placebo group was 16.78 and 31.35, respectively, the standard 
deviation was 14.01 and 16.21, respectively, and the effect size was 0.962. 
 
7.2 
Analysis Set 
The following policies will apply to analysis sets in principle, but allocation of subjects to 
analysis sets will be determined in the Classification Meeting by reference to opinions or 
advice of medical experts as needed. 
7.2.1 
Full Analysis Set (FAS) 
The full analysis set will consist of all subjects who are randomized, are vaccinated with the 
study drug at least once, and have at least one measurement for efficacy evaluation obtained 
after vaccination of the study drug. This is the primary analysis set for efficacy analyses. 


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7.2.2 
Per Protocol Set (PPS) 
The per protocol set will consist of the subset of the FAS who do not meet criteria for the 
following PPS exclusion. 
● 
Violates Inclusion Criteria 
● 
Falls under Exclusion Criteria 
● 
Has not completed all the specified vaccinations 
● 
Has not been evaluated for efficacy on Day 183 
● 
Use of prohibited concomitant drug or non-medication therapy during the primary study 
period, which may affect efficacy evaluation 
● 
Other significant protocol deviation 
7.2.3 
Safety Analysis Set (SAF) 
For the statistical summary of the safety data, the safety analysis set (SAF) will be used. The 
SAF consists of all subjects who are vaccinated with the study drug at least once. 
7.2.4 
Immunological Analysis Set (IAS) 
7.2.4.1 IAS 
The immunological analysis set will consist of all subjects who are randomized, are 
vaccinated with the study drug at least once, and have at least one measurement for 
immunological response endpoint after vaccination of the study drug. 
7.2.4.2 IAS-2 
The immunological analysis set 2 (IAS-2) will consist of subjects who have provided 
additional consent for the additional test and have at least one measurement for 
immunological response endpoint during the additional study period. 
7.2.5 
Pollinosis Symptom Analysis Set (PSAS) 
The Pollinosis Symptom Analysis Set will consist of all subjects who are randomized, are 
vaccinated with the study drug at least once, and have at least one measurement for an 
endpoint on pollinosis symptoms during the pollen dispersal season after vaccination of the 
study drug. 
 
7.3 
Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized by treatment group for 
the FAS, PPS, SAF, IAS, and PSAS. Descriptive statistics will include number of subjects, 
mean, standard deviation, minimum, median and maximum for continuous endpoints, and 
frequency and percentage for categorical endpoints. 
 


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7.4 
Analysis of Efficacy 
The primary efficacy endpoint and secondary endpoints will be analyzed for the FAS and 
PPS. The results of statistical tests will be interpreted based on the FAS. The PPS will be 
used to assess the robustness of statistical test results based on the FAS. 
Analysis of Other Efficacy Endpoints will be conducted for the PSAS. 
7.4.1 
Analysis of Primary Endpoint 
7.4.1.1 Primary Analysis 
The FAS will be used for primary analysis. With regard to the change in the mean of total 3 
nasal symptom (sneezing, nasal discharge, and nasal congestion) score (3TNSS) during 120 
to 180 minutes after start of cedar pollen exposure as compared to the score before cedar 
pollen exposure, the difference in the adjusted mean between each active drug group and the 
placebo group on Day 183, two-sided 95% confidence interval and two-sided P value will be 
calculated using a mixed model for repeated measures assuming an unstructured covariance 
structure within subjects with explanatory variables being the vaccination group (ASP4070 
4 mg, ASP4070 1 mg, and placebo), evaluation time (Day 127, Day 155, and Day 183), 
“Class from results of Japanese red cedar (JRC) pollen-specific IgE antibody test performed 
at Screening visit 1,” “Change in the mean of total 3 nasal symptom (sneezing, nasal 
discharge, and nasal congestion) score during 120 to 180 minutes after start of cedar pollen 
exposure in the chamber as compared to the score before cedar pollen exposure at Screening 
visit 2,” and interaction of the vaccination group and evaluation time. 
With the significance level of the test to be 5% two-sided, the test will be conducted using 
hierarchical procedures in the following order: 
1. Comparison between the ASP4070 4 mg group and placebo group 
2. Comparison between the ASP4070 1 mg group and placebo group 
7.4.1.2 Secondary Analysis 
● 
Analysis that is the same as the analysis of primary endpoints described in “7.4.1.1 
Primary Analysis” will be conducted for the PPS. 
● 
Using the FAS and PPS, the summary statistics on the actual measured value and change 
from baseline for each evaluation time by vaccination group will be calculated. 
● 
Using the FAS and PPS, based on the mixed model for repeated measures described in 
“7.4.1.1 Primary Analysis,” the difference in the adjusted mean between each active drug 
group and the placebo group and two-sided 95% confidence interval will be calculated 
on Day 127 and Day 155. 
● 
Using the FAS and PPS, line plots for the mean for each evaluation time will be created. 
● 
Using the FAS and PPS, individual line plots for the actual measured value and change 
from baseline will be created. 


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7.4.1.3 Subgroup Analysis 
Exploratory subgroup analysis on baseline values, such as demographics and nasal and eye 
symptoms, will be conducted. 
7.4.2 
Analysis of Secondary Endpoints  
Analysis of secondary endpoints will be conducted for the FAS and PPS. 
1. Total 3 nasal symptom score (3TNSS), total 4 nasal symptom score (4TNSS), individual 
nasal symptom score, total non-nasal symptom score (TNNSS), individual eye symptom 
score, and total symptom score (TSS) for every 15 minutes 
● 
Summary statistics by vaccination group will be calculated for the actual measured 
value every 15 minutes and change from the score prior to cedar pollen exposure 
will be calculated. 
● 
Line plots for the mean will be created. 
● 
Individual line plots will be created. 
2. Change in the mean of the following scores during 120 to 180 minutes after start of cedar 
pollen exposure as compared to the score before cedar pollen exposure: total 4 nasal 
symptom score (4TNSS), individual nasal symptom score, total non-nasal symptom 
score (TNNSS), individual eye symptom score, and total symptom score (TSS) 
● 
Summary statistics by vaccination group will be calculated for the actual measured 
value and change from baseline for each evaluation period. 
● 
The difference in the adjusted mean between each active drug group and the placebo 
group and two-sided 95% confidence interval will be calculated for each evaluation 
time using a mixed model for repeated measures assuming an unstructured 
covariance structure within subjects with explanatory variables being the 
vaccination group, evaluation time, “Class from results of Japanese red cedar (JRC) 
pollen-specific IgE antibody test conducted at Screening visit 1,” “Change in the 
mean score during 120 to 180 minutes after start of cedar pollen exposure in the 
chamber as compared to the score before cedar pollen exposure at Screening visit 2,” 
and interaction of the vaccination group and evaluation time. 
● 
Line plots for the mean will be created for each evaluation time. 
● 
Individual line plots for the actual measured value and change from baseline will be 
created. 
3. Change in the mean of the following scores during 15 to 180 minutes after start of cedar 
pollen exposure as compared to the score before cedar pollen exposure: total 3 nasal 
symptom score (3TNSS), total 4 nasal symptom score (4TNSS), individual nasal 
symptom score, total non-nasal symptom score (TNNSS), individual eye symptom score, 
and total symptom score (TSS) 
● 
Summary statistics by vaccination group will be calculated for the actual measured 
value and change from baseline for each evaluation time. 
● 
Line plots for the mean will be created for each evaluation period. 


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● 
Individual line plots for the actual measured value and change from baseline will be 
created. 
4. Time to the occurrence of nasal or eye symptoms from start of cedar pollen exposure in 
the chamber  
● 
25, 50, 75 percentile of the predicted value and their 95% confidence interval will be 
calculated by the Kaplan–Meier method. If no symptoms occur, then the evaluation 
will be censored at 180 minutes. 
● 
A Kaplan–Meier plot value will be created. 
5. Nasal discharge amount and sneezing count per 30 minutes during chamber exposure 
● 
Summary statistics of the actual measurement value at every 30 minutes will be 
calculated for each evaluation time. 
● 
Number of subjects and percentage by severity at every 30 minutes will be 
calculated for each evaluation time. 
● 
Line plots for the mean will be created. 
● 
Individual line plots will be created. 
7.4.3 
Other Efficacy Endpoints Analysis 
Analysis of pollinosis symptoms during the JRC pollen dispersal season in 2018 will be 
conducted for the PSAS. 
● 
Summary statistics of the mean of individual symptom score and daily activity 
interference score will be calculated for each evaluation time. 
● 
Line plots of the mean of individual symptom score and daily activity interference score 
will be calculated. 
● 
Individual line plots of individual symptom score and daily activity interference score 
will be calculated. 
● 
A frequency table of JRQLQ No 1 will be prepared. 
● 
A frequency table of overall evaluation will be prepared. 
The transition of JRC pollen dispersal amount will be displayed together in line plots. 
 
7.5 
Analysis of Immunological Response 
Analysis of immunological response will be conducted for the IAS or IAS-2. 
● 
Summary statistics of the actual measured value and change from the baseline for 
continuous variables will be calculated for each evaluation time. 
● 
Frequency tables of continuous variables will be prepared for each evaluation time. 
● 
Individual line plots of the actual measured value and change from the baseline for 
continuous variables will be calculated. 
 
7.6 
Analysis of Safety 
Analysis of safety will be conducted for the SAF. 


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7.6.1 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number and percentage of AEs, SAEs, AEs leading to discontinuation, and 
AEs related to study drug will be summarized by system organ class, preferred term and 
vaccination group. The number and percentage of AEs by severity will also be calculated. All 
AEs will be listed. 
7.6.2 
Local Reaction and Systemic Reaction 
The number of occurrences of, and number and percentage of subjects with designated local 
reactions and systemic reactions will be summarized by symptom and vaccination group. The 
number of occurrences of, and number and percentage with subjects of designated local 
reactions and systemic reactions by severity will be calculated. 
7.6.3 
Laboratory Assessments 
For quantitative laboratory measurements descriptive statistics will be used to summarize 
results and change from baseline by vaccination group and evaluation time. Shifts relative to 
normal ranges from baseline to each evaluation time during treatment period in lab tests will 
also be tabulated. 
7.6.4 
Vital Signs 
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
by vaccination group and evaluation time. 
7.6.5 
ECGs 
The 12-lead ECG results will be summarized by vaccination group and evaluation time. 
 
7.7 
Analysis of Pharmacokinetics 
Not applicable 
 
7.8 
Other Analyses 
7.8.1 
Secondary Data Analysis 
SDA related to the action mechanism of the test drug against cedar pollinosis and 
efficacy/safety evaluation is scheduled to be conducted, but the content of analysis is not yet 
determined. The Sponsor will start the research when a specific content is determined. At that 
time, prior to the implementation of the research, the Sponsor will prepare a research plan for 
review by the Sponsor’s ethical review board for whether it is appropriate or not for research 
implementation from the ethical and scientific viewpoint and obtain approval. 


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7.8.2 
Analysis of Pharmacogenomics Data 
At present, the content of analysis for pharmacogenomics investigation is not yet determined. 
In the future, there is a possibility of exploratory investigation to determine whether there is a 
relationship between genetic analysis results and results of the study (clinical information: 
e.g., pharmacological activity, toxicity). The Sponsor will start the research when a specific 
content is determined. At that time, prior to the implementation of the research, the Sponsor 
will prepare a research plan (disposal method of reference material and timing) for review by 
the Sponsor’s ethical review board for whether it is appropriate or not for research 
implementation from the ethical and scientific viewpoint and obtain approval. 
 
7.9 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
No formal interim analysis is planned. 
 
7.10 
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
Final analytical handling of missing data, outliers, and analysis time points will be 
determined before database hard lock, considering the opinions and advice of medical experts 
as needed. Subjects or values excluded from analyses will be presented in the listing of 
individual values but will be excluded in the summarization, such as summary statistics. 
7.10.1 Time Points for Primary Study Period 
The acceptable time ranges for the time points for analysis are as follows. The day of the first 
vaccination of the study drug is defined as Day 1 and the day before the first vaccination is 
defined as Day −1. If multiple data are obtained at the same time point, then data obtained on 
the closest day to the scheduled day will be used for analysis. If data are present before and 
after the scheduled day with the same day difference, then data obtained after the scheduled 
day will be used for analysis. 


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[Vital Signs (Axillary body temperature, sitting blood pressure, and sitting pulse rate)] 
Timing 
Scheduled day 
Acceptable range 
Screening visit 1 
Date of informed consent 
After date of informed consent until 
the day before Screening visit 2 
Screening visit 2 
Visit date of Screening visit 
2 
After Screening visit 2 until −21 day 
of Screening visit 3 
Screening visit 3 
28 days from Screening 
visit 2 
28 days ±7 days from Screening visit 
2 and also until  
Day 1 − 7 days 
Day 1 
Day 1 
Until before study drug vaccination 
on Day 1 
Day 15, Day 29, Day 43, 
Day 57, Day 71, Day 85, 
Day 99 
Day 15, Day 29, Day 43, 
Day 57, Day 71, Day 85, 
Day 99 
Within ±3 days of the scheduled day* 
Day 127, Day 155, Day 183 
Day 127, Day 155, Day 183 
Within ±7 days of the scheduled day 
*: If the study drug is vaccinated, then data before study drug vaccination will be used. 
[Hematology test, blood biochemistry test, and urinalysis] 
Timing 
Scheduled day 
Acceptable range 
Screening visit 1 
Date of informed consent 
After date of informed consent until 
the day before Screening visit 2 
Screening visit 3 
28 days from Screening 
visit 2 
28 days ±7 days from Screening visit 
2 and also until 
Day 1 − 7 days 
Day 1 
Day 1 
Until before study drug vaccination 
on Day 1 
Day 57 
Day 57 
Within ±3 days of the scheduled day* 
Day 127, Day 183 
Day 127, Day 183 
Within ±7 days of the scheduled day 
*: If the study drug is vaccinated, then data before study drug vaccination will be used. 
[12-lead electrocardiogram] 
Timing 
Scheduled day 
Acceptable range 
Screening visit 1 
Date of informed consent 
After date of informed consent until 
the day before Screening visit 2 
Day 1 
Day 1 
Until before study drug vaccination 
on Day 1 
Day 127, Day 183 
Day 127, Day 183 
Within ±7 days of the scheduled day 
[Parameters] 
Timing 
Scheduled day 
Acceptable range 
Day 1 
Day 1 
Until before study drug vaccination 
on Day 1 
Day 57 
Day 57 
Within ±3 days of the scheduled day* 
Day 127, Day 155, Day 183 
Day 127, Day 155, Day 183 
Within ±7 days of the scheduled day 
*: If the study drug is vaccinated, then data before study drug vaccination will be used. 


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[Evaluation in chamber] 
Timing 
Scheduled day 
Acceptable range 
Screening visit 2 
Visit date for Screening 
visit 2 
After Screening visit 2 until −21 day 
of Screening visit 3 
Day 127, Day 155, Day 183 
Day 127, Day 155, Day 183 
Within ±7 days of the scheduled day 
7.10.2 Time Points for Pollinosis Symptoms Survey Period and Additional Study 
Period 
[Pollinosis symptoms during the JRC pollen dispersal season] 
Time points to evaluate pollinosis symptoms during the JRC pollen dispersal season in 2018 
will be determined before database hard lock, based on data, such as the collected symptom 
scores and data of JRC pollen dispersal amount. 
[Parameters] 
The acceptable time ranges for the time points for analysis are as follows. 
Timing 
Scheduled day 
Acceptable range 
Additional test 
16 May 2018 
From 01 May 2018 until 31 May 
2018 
 
8 
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS 
8.1 
Procedure for Clinical Study Quality Control 
8.1.1 
Data Collection 
8.1.1.1 Case Report Form 
The investigator, sub-investigator, or study coordinator will use the Electronic Data Capture 
(EDC) system for data entry. 
The investigator, sub-investigator, or study coordinator 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. The source documents should be appropriately maintained at the site. 
The monitor should verify the data in the eCRFs with source documents and confirm that 
there are no inconsistencies between them. 
Hematology test, blood biochemistry test and urinalysis, pregnancy test, and immunological 
tests will be performed at the study site, and JRC allergy test, allergy tests other than JRC, 
and parameter measurements will be performed at the centralized testing company. 
 
of API will electronically obtain the results of the hematology test, blood 
biochemistry test, and urinalysis from the study site and JRC allergy test and parameter 
measurements from the centralized testing company at a pre-determined time. The test result 
is obtained by an electronic file from the centralized testing company at the pre-determined 
time. 


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With regard to subjects who drop out before the initial study drug vaccination, the minimum 
demographics (sex, age, and informed consent date), AEs, reason for dropping out, and date 
of dropout will be entered in the Screen Failure Log (SFL). 
8.1.1.2 Survey Diary 
The investigator, sub-investigator, or study coordinator will confirm the Survey Diary 
(Local/Systemic Reaction Survey Diary, Symptoms Survey After Chamber Period Diary, and 
Pollinosis Symptoms Survey Diary) with entries by the subjects and the required items will 
be entered in the eCRF. 
Subjects will confirm the entered content at each hospital visit with the study coordinator and 
if there are any unclear entries, then additions or modifications will be made as necessary and 
the revision date will be written at the addition/modification and signed or sealed. 
8.1.2 
Specification of Source Documents 
Source data must be available at the site to document the existence of the study subjects and 
to 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 (e.g., age, sex, height, body weight) 
● 
Inclusion and exclusion criteria details 
● 
Participation in study and original signed and dated informed consent forms 
● 
Visit dates 
● 
Medical history and physical examination details 
● 
Key efficacy and safety data 
● 
Adverse events and concomitant medication 
● 
Results of relevant examinations (e.g., ECG charts, X-ray films etc.) 
● 
Laboratory printouts 
● 
Dispensing and return of study drug details 
● 
Reason for premature discontinuation 
● 
Randomization number 
● 
Local/Systemic Reaction Survey Diary 
● 
Symptoms Survey After Chamber Period Diary 
● 
Pollinosis Symptoms Survey Diary 
With regard to the following data, information entered in the eCRF will be considered as 
source data; however, if relevant information is recorded in the medical records, then 
information in the medical records will be handled as source data. 
● 
Details of AEs (time of onset, outcome, severity, seriousness, actions taken, other actions, 
and causal relationship to the study drug) 
● 
Day of last observation, day of discontinuation, reason for discontinuation 


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● 
Other comments entered in the eCRF (including comments in reports for follow-up 
observations, if follow-up observations for AEs are performed) 
8.1.3 
Clinical Study Monitoring 
The Sponsor or delegated 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 and relevant regulatory authorities. In 
these instances, they must provide all study-related records, such as source documents (refer 
to Section 8.1.2 “Specification of Source Documents”) when they are requested by the 
Sponsor monitors and auditors, the IRB, or regulatory authorities. The confidentiality of the 
subject's identities shall be well protected consistent 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 
 of the Sponsor in accordance with 
the standard operating procedures (SOPs) for data management. All study specific processes 
and definitions will be documented by Data Management. eCRF retrieval and correction 
process will be referenced in the CRF instructions. Coding of medical terms and medications 
will be performed using MedDRA and World Health Organization Drug Dictionary 
Enhanced (WHODDE) respectively. 
 
8.2 
Ethics and Protection of Subject Confidentiality 
8.2.1 
Institutional Review Board (IRB) 
Prior to the study contract, the protocol and various documents used for obtaining informed 
consent of subjects will be discussed and approved by the IRB of the study site to guarantee 
the protection of the rights, safety, and well-being of subjects. The contract with the study 
site will be concluded after the approval by the IRB. 


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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. 
Pharmacogenomics research will be conducted in accordance with the “Ethical Guidelines 
for Human Genome and Gene Analysis Research” (Notification No. 1 from the Ministry of 
Education, Culture, Sports, Science and Technology [MEXT], MHLW, and Ministry of 
Economy, Trade and Industry, 2004) and “Regarding Clinical Studies Using 
Pharmacogenomics” (Notification from Head of Evaluation and Licensing Division, 
Pharmaceutical and Food Safety Bureau, Ministry of Health and Labour, 30 Sep 2008) in 
addition to the above. 
SDA related to efficacy and safety evaluation using samples taken during the clinical study 
period will be conducted in accordance with the “Ethical Guidelines for Medical and Health 
Research Involving Human Subjects” (Notification No. 3 from MEXT and MHLW, 2014) in 
addition to items that must be adhered to during study implementation. 
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, signed (or a personal seal will be placed) 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 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 consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor, regulatory authorities, and other applicable 
individuals upon request. 
8.2.3.2 Subject Information and Consent on Secondary Data Analysis 
If SDA is approved at the study site, then other than consent to participating in the clinical 
study, consent will be required regarding SDA. Prior to the study implementation, the 
investigator will prepare the informed consent documents for subjects on SDA with the 
cooperation of the Sponsor and will revise this as needed. The prepared or revised informed 
consent document and other explanation documents will be submitted to the Sponsor and 
prior approval of the IRB/Independent Ethics Committee of the study site will be obtained. 


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Informed consent regarding SDA can only be obtained from subjects who have already 
consented to the clinical study. Separate from withdrawing consent to the clinical study, it is 
possible to withdraw consent to SDA only. With regard to consent to SDA, it is necessary to 
follow the instructions in “8.2.3.1 Subject Information and Consent.” 
If consent to SDA is withdrawn, then any samples for SDA that are remaining at the time of 
withdrawal of consent will be disposed. 
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor of the regulatory authorities, and other applicable 
individuals upon request. 
8.2.3.3 Subject Information and Consent on Pharmacogenomics Research 
If the pharmacogenomics research is approved at the study site, then other than consent to 
participating in the clinical study, consent will be required regarding the pharmacogenomics 
research. Prior to the study implementation, the investigator will prepare the informed 
consent documents for subjects on the pharmacogenomics research with the cooperation of 
the Sponsor and will revise this as needed. The prepared or revised informed consent 
document and other explanation documents will be submitted to the Sponsor and prior 
approval of the IRB/Independent Ethics Committee of the study site will be obtained. 
Informed consent regarding the pharmacogenomics research can only be obtained from 
subjects who have already consented to the clinical study. Separate from withdrawing 
consent to the clinical study, it is possible to withdraw consent to the pharmacogenomics 
research only. With regard to consent to the pharmacogenomics research, it is necessary to 
follow the instructions in “8.2.3.1 Subject Information and Consent.” 
If consent to the pharmacogenomics research is withdrawn, then any samples for the 
pharmacogenomics research that are remaining at the time of withdrawal of consent will be 
disposed. 
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor of the regulatory authorities, and other applicable 
individuals upon request. 
8.2.3.4 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information 
1. The investigator or his/her representative 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 to participate in the study 
(e.g., report of serious drug adverse drug reaction). The communication must be 
documented in the subject’s medical records and must document whether the subject is 
willing to remain in the study or not. 
2. The investigator must update their ICF and submit it for approval to the IRB. The 
investigator or his/her representative must obtain written informed consent from the 
subject on all updated ICFs throughout the primary study period. The investigator or 


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his/her designee must re-consent subjects with the updated ICF even if relevant 
information was provided orally. The investigator or his/her representative who obtained 
the written informed consent and the subject should sign or place a personal seal on and 
date the informed consent form. A copy of the signed 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 be made in the subject’s records documenting the re-consent 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. 
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 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 study monitors and auditors, 
may get to know matters related to subject's 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 Investigator’s Brochure 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. 
Publication of the study results is discussed in the Clinical Study Agreement. 
After agreement between investigator(s) and sponsor, the manuscript can be submitted for 
publication. 


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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, where applicable) 
● 
Investigator’s Brochure (and amendments, where applicable) 
● 
eCRFs and JUTOKUNA YUUGAIJISHOU HOUKOKUSHO 
● 
Study drug with all necessary documentation 
● 
Study contract 
In order to start the study, the investigator and/or study site is required to provide the 
following documentation to the Sponsor: 
● 
Agreement in the study protocol that is signed or sealed by the investigator 
● 
Current Curricula Vitae of the investigator 
● 
List of sub-investigators and study coordinators 
● 
IRB approval of the protocol, protocol amendments (if applicable) including a 
membership list with names and qualification (COPY) 
● 
Instruction and decision of the head of the study site 
● 
Study contract 
● 
Laboratory normal reference ranges (if applicable, signed and dated by the responsible 
laboratory employee) 
At the end of the study, the Sponsor is responsible for the collection of: 
● 
Study-related documentation 
The investigator will archive all study data (e.g., Subject Identification Code List, source data, 
electronic media containing eCRF data, and Investigator’s File) and relevant correspondence. 
These documents are to be kept on file for the appropriate term determined by local 
regulation. 
The records to be retained at the study sites are the ones listed as essential documents in GCP. 
These records shall be retained by the head of the study site 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. 
The head of the study site will retain the essential documents that should be stored at the 
study site in an appropriate manner according to the rules of the study site 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 stopped, until 
three years after the decision to discontinue development is notified) 
2. Until three years after discontinuation or termination of the study 
The following are the main documents to be retained at the study site. 
1. Source documents (clinical data, documents, and records for preparing the eCRF), 
hospital records, medical records, test records, memoranda, subject diary or check lists 
for evaluation, administration records, data recorded by automatic measuring instruments, 
reproductions or transcripts verified as precise copies, subject files and study-related 


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records kept at either a pharmacy, a laboratory, or medical technical office, as well as 
laboratory test slips, worksheets specified by the Sponsor, records of clinical 
coordinators, and records related to the clinical study selected from those verified in 
other departments or hospitals. 
2. Contracts, written informed consent forms, written information, and other documents or 
their copies prepared by the study personnel. A letter of request for clinical study 
(including a request for continuation/amendment), letter of request for review, notice of 
clinical study contract, clinical study contract, notification of discontinuation or 
completion of clinical study, written information for informed consent (including 
revisions), signed and dated written informed consent (including revisions), CVs of 
investigators, list of sub-investigators, list of signatures and print of seals (copy), 
electronic media containing eCRF data, etc. 
3. The protocol, documents obtained from the IRB related to the adequacy of conducting 
the clinical study by the head of the study sites (Article 51-1, MHLW Ordinance No. 89), 
documents obtained from the IRB related to the adequacy of conducting a clinical study 
whose period exceeds one year or the adequacy of continuously conducting the clinical 
study from which information on adverse drug reactions is obtained, and other 
documents obtained. An agreed-upon protocol (including revisions), Investigator’s 
Brochure (including revisions), operational procedures for the investigator, materials and 
information supplied by the Sponsor (e.g., AE report), matters reported by the 
investigator (revisions of the protocol, AE reports, etc.), operational procedures for the 
IRB, the list of names of the IRB members, materials for IRB review (including 
continuous deliberation), IRB review records (including continuous deliberation), the 
review result report of the IRB (including continuous deliberation), etc. 
4. Records of control for study drugs and other duties related to the clinical study. 
Procedure for controlling the study drugs, drug inventory and accountability record, 
vouchers for the receipt and return of the study drugs, and the prescriptions for 
concomitant medications. 
5. Records related to sample for SDA. 
To be able to handle withdrawal of consent of the subject regarding SDA and storage of 
samples for SDA, the study sites where SDA has been approved will store the list of 
subject identification code and informed consent document for SDA (including revised 
editions). 
6. Records related to sample for pharmacogenomics research. 
To be able to handle withdrawal of consent of the subject regarding pharmacogenomics 
research and storage of samples for pharmacogenomics research, the study sites where 
pharmacogenomics research has been approved will store the list of subject identification 
code and informed consent document for pharmacogenomics research (including revised 
editions) for a maximum of 15 years after data lock. 


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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 and/or revisions. Depending on the nature of the amendment, either 
approval of the IRB and regulatory authority or notification to the IRB and regulatory 
authority may be required. The changes will become effective only after the approval of the 
Sponsor, the investigator, and the IRB followed by the approval of the head of the study site. 
8.3.4 
Insurance of Subjects and Others 
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 site, the Sponsor will consult with the study site 
about handling the injury, based on the agreed study contract. Compensation for the 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 site 
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 site for the above study-related 
injury, or such compensation may be claimed, the study site 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. 
8.3.5 
Signatory Investigator for Clinical Study Report 
The signatories for the clinical study report are the Sponsor and medical expert. 
 
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, 
recorded, and reported in compliance with the protocol, GCP for trials on gene, cellular, and 
tissue-based products, and applicable regulatory requirement(s). 
The Sponsor or Sponsor’s designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. The audit may include on-site review of regulatory 
documents, eCRFs, and source documents. Direct access to these documents will be required 
by the auditors. 
  


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10 
STUDY ORGANIZATION 
10.1 
Independent Data-Monitoring Committee (IDMC) | Data and Safety 
Monitoring Board (DSMB) | Monitoring Committee | Other 
Evaluation Committee(s) 
Not applicable 
 
10.2 
Other Study Organization 
See attachments 
 
10.3 
Registration of Subjects 
Not applicable 
 


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09 Mar 2018 
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Page 84 of 88 
11 
REFERENCES 
Geuze HJ. The role of endosomes and lysosomes in MHC class II functioning. Immunol Today. 
1998;19:282-7. 
Hashiguchi K, Kanzaki S, Wakabayashi K, Tanaka N, Kawashima K, Suematsu K, et al. Efficacy of 
fluticasone furoate nasal spray and levocetirizine in patients with Japanese cedar pollinosis 
subjected to an artificial exposure chamber. J Drug Assess. 2013;2:94-105. 
Hashiguchi K, Okubo K, Wakabayashi K, Tanaka N, Watada Y, Suematsu K, et al. The assessment of 
the optimal duration of early intervention with montelukast in the treatment of Japanese cedar 
pollinosis symptoms induced in an artificial exposure chamber. J Drug Assess. 2012;1:40-7. 
Hashiguchi K, Tang H, Fujita T, Suematsu K, Tsubaki S, Nagakura H, et al. Validation study of the 
OHIO Chamber in patients with Japanese cedar pollinosis. Int Arch Allergy Immunol. 
2009;149:141-9. 
Hashiguchi K, Wakabayashi K, Togawa M, Saito A, Okubo K. Therapeutic effect of bilastine in 
Japanese cedar pollinosis using an artificial exposure chamber (OHIO Chamber). Allergol Int. 
2017;66:123-31. 
Hickling JK, Jones KR, Friede M, Zehrung D, Chen D, Kristensen D. Intradermal delivery of 
vaccines: potential benefits and current challenges. Bull World Health Organ. 2011;89:221-6. 
Ishii KJ, Kawagoe T, Koyama S, Matsui K, Kumar H, Kawai T, et al. TANK-binding kinase-1 
delineates innate and adaptive immune responses to DNA vaccines. Nature. 2008;451:725-9. 
Environmental Health and Safety Division, Environmental Health Department, Ministry of the 
Environment. [Manual for Pollinosis Environmental Health.] 2014. Japanese. 
Kenney RT, Frech SA, Muenz LR, Villar CP, Glenn GM. Dose sparing with intradermal injection of 
influenza vaccine. N Engl J Med. 2004;351:2295-301. 
Marques ET Jr, Chikhlikar P, de Arruda LB, Leao IC, Lu Y, Wong J, et al. HIV-1 p55Gag encoded in 
the lysosome-associated membrane protein-1 as a DNA plasmid vaccine chimera is highly 
expressed, traffics to the major histocompatibility class II compartment, and elicits enhanced 
immune responses. J Biol Chem. 2003;278:37926-36. 
Okuda M, Ohkubo K, Goto M, Okamoto H, Konno A, Baba K, et al. Comparative study of two 
Japanese rhinoconjunctivitis quality-of-life questionnaires. Acta Otolaryngol. 2005;125:736-44. 
Tan LK, Huang CH, Kuo IC, Liew LM, Chua KY. Intramuscular immunization with DNA construct 
containing Der p 2 and signal peptide sequences primed strong IgE production. Vaccine. 
2006;24:5762-71. 
Woodfolk JA, Platts-Mills TA. The immune response to intrinsic and extrinsic allergens: 
determinants of allergic disease. Int Arch Allergy Immunol. 2002;129:277-85. 
 








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12.4 
Events That Should Be Handled as Serious Adverse Events 
If any of the following events occurs during the study, then the event should be considered as 
an SAE and should be reported in accordance with the requirements detailed in Section 
“5.5.5 Reporting of Serious Adverse Events (SAE).” 
● 
Acute hepatic failure 
● 
Acute renal failure 
● 
Acute respiratory failure 
● 
Agranulocytosis 
● 
Anaphylaxis 
● 
Any malignancy 
● 
Aplastic anaemia 
● 
Transmission of an infectious agent via product 
● 
Congenital anomalies 
● 
Hepatic necrosis 
● 
Malignant hypertension 
● 
Pulmonary hypertension 
● 
Convulsion 
● 
Torsades de pointes 
● 
Toxic epidermal necrolysis 
● 
Ventricular fibrillation 
● 
Haemolytic anaemia 
● 
Bone marrow failure 
● 
Myocardial infarction 
● 
Cardiac arrest 
● 
Deafness 
● 
Blindness 
● 
Pancreatitis acute 
● 
Acute graft versus host disease 
● 
Septic shock 
● 
Sepsis 
● 
Rhabdomyolysis 
● 
Respiratory failure 
● 
Stevens-Johnson syndrome 
 
12.5 
Common Serious Adverse Events 
Not applicable 
 
 
(GPF 4.1) 

SAP_001.pdf: 
Sponsor: Astellas Pharma Inc.
SAP Final Version
ISN/Protocol 4070-CL-0020
22-Jun-2018
Astellas
Page 1 of 31
STATISTICAL ANALYSIS PLAN
Final Version, dated 22-Jun 2018
Phase II Dose-finding Study of ASP4070
—A Randomized, Double-blind, Placebo-controlled, Dose-finding Study in Patients With 
Cedar Pollinosis Using an Environmental Exposure Chamber—
< Pollinosis Symptoms Survey Period and Additional Study Period >
ISN: 4070-CL-0020
Astellas Pharma Inc. (API)
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 Inc.
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Page 2 of 31
Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 4
1
INTRODUCTION·················································································· 6
2
FLOW CHART AND VISIT SCHEDULE···················································· 7
3
STUDY OBJECTIVE(S) AND DESIGN······················································10
3.1
Study Objective(s) ············································································10
3.2
Study Design···················································································10
3.3
Randomization·················································································11
4
SAMPLE SIZE ····················································································11
4.1
Primary Study Period·········································································11
4.2
Pollinosis Symptoms Survey Period and Additional Study Period ·····················12
5
ANALYSIS SETS ·················································································12
5.1
Pollinosis Symptom Analysis Set (PSAS) ·················································12
5.2
Immunological Analysis Set (IAS-2) ·······················································13
6
ANALYSIS VARIABLES ·······································································13
6.1
Efficacy Endpoints············································································13
6.1.1
Pollinosis Symptoms Survey During 2018 JRC Pollen Dispersal Season········13
6.2
Immune Response Endpoints································································16
7
STATISTICAL METHODOLOGY ···························································16
7.1
General Considerations·······································································16
7.2
Study Population ··············································································16
7.2.1
Disposition of Subjects ·································································16
7.2.2
Demographic and Other Baseline Characteristics ···································17
7.3
Study Drugs····················································································18
7.4
Analysis of Efficacy ··········································································18
7.4.1
Analysis of Pollinosis Symptoms Survey ············································18
7.5
Analysis of Safety·············································································22
7.6
Analysis of PK·················································································22
7.7
Analysis of PD·················································································22
7.8
Subgroups of Interest ·········································································22
7.9
Other Analyses ················································································23


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7.9.1
Analyses of Immune Response ························································23
7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)····················24
7.11
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········24
7.11.1
Missing Data ·············································································24
7.11.2
Outliers ···················································································24
7.11.3
Visit Windows ···········································································24
7.11.4
Analysis Period for Pollinosis Symptoms ············································24
8
DOCUMENT REVISION HISTORY·························································25
9
REFERENCES ····················································································25
10
APPENDICES ·····················································································27
10.1
Appendix 1: Sample SAS code for logistic regression ···································27
10.2
Appendix 2: Key Contributors and Approvers ············································30


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I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
ANCOVA
Analysis of Covariance
BAT
Basophil Activation Test
BMI
Body Mass Index
CI
Confidence Intervals
CSR
Clinical Study Report
GD
Global Development
IAS-2
Immunological Analysis Set 2
ICH
International Conference on Harmonization
JRC
Japanese Red Cedar
JRQLQ
Japanese Rhinoconjunctivitis Quality of Life Questionnaire
LAMP
Lysosomal Associated Membrane Protein
LLOQ
Lower Limit of Quantitation
PD
Pharmacodynamic
PGx
Pharmacogenomics
PK
Pharmacokinetic
PSAS
Pollinosis Symptom Analysis Set
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SDA
Secondary Data Analysis
TLF
Tables, Listings and Figures
TNNSS
Total Non-nasal Symptom Score
TNNSMS
Total Non-nasal Symptom Medication Score
TNSMS
Total Nasal Symptom Medication Score
TNSS
Total Nasal Symptom Score
TSMS
Total Symptom Medication Score
TSS
Total Symptom Score
ULOQ
Upper Limit of Quantitation
WHO-DD
World Health Organization Drug Dictionary


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List of Key Terms
Terms
Definition of terms
Baseline
Observed values/findings which are regarded observed starting point for 
comparison.
Endpoint
A variable that pertains to the trial objectives
Investigational period
Period of time where major interests of protocol objectives are observed, 
and where the test drug or comparative drug (sometimes without 
randomization) is usually given to a subject, and continues until the last 
assessment after completing administration of the test drug or comparative 
drug.
Randomization
The process of assigning trial subjects to treatment or control groups using 
an element of chance to determine assignments in order to reduce bias.
Screening
A process of active consideration of potential subjects for enrollment in a 
trial.
Screening period
Period of time before entering the investigational period, usually from the 
time of starting a subject signing consent until just before the test drug or 
comparative drug (sometimes without randomization) is given to a subject.
Study period
Period of time from the first site initiation date to the last site completing the 
study.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.


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1
INTRODUCTION
This Statistical Analysis Plan (SAP) for the pollinosis symptoms survey period and 
additional study period contains a more technical and detailed elaboration of the principal 
features of the analysis 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 database hard lock at the end of the additional study 
period.
This statistical analysis is coordinated by the responsible biostatistician of GD, API. Any 
changes from the analyses planned in the SAP will be justified in the Clinical Study Report 
(CSR).


Sponsor: Astellas Pharma Inc.
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2
FLOW CHART AND VISIT SCHEDULE
●
After code breaking, the Sponsor will be unblinded, but the study will be continued with 
the investigator, sub-investigator, study coordinator, and subjects remaining blinded.
●
Cedar pollinosis symptoms will be surveyed during the pollinosis symptoms survey 
period (01 Feb 2018–31 Mar 2018).
●
The additional test of immune responses will be performed during the long-term safety 
follow-up period on subjects who have completed the pollinosis symptoms survey period 
and have provided additional consent to the additional test.
●
Subjects will report whenever SAEs occur during the long-term safety follow-up period. 
Even if there is no contact from a subject, in principle, the subject will be asked about 
the occurrence of SAEs at 6 months and 12 months after the final vaccination. With 
regard to subjects who have discontinued the study during the primary study period, if 
the study drug had been vaccinated even once, then safety information (SAEs) will be 
collected for 1 year after the final vaccination.


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Table 1: Schedule of Assessments
Visit day
Item
Primary study period
After 
Pollinosis 
Symptoms 
Survey
Additional 
test
Screening period
Study drug vaccination period
Evaluation 
chamber period
Post-
observa-
tion
Disconti
nuation3)
Screening 
visit 1
Screening 
visit 21)
Screening 
visit 32)
Day 
1
Day 
15
Day 
29
Day 
43
Day 
57
Day 
71
Day 
85
Day 
99
Day 
127
Day 
155
Day 
183
Period (Day)
28 ± 7 
from 
Screening 
visit 24)
1
15
± 3
29
± 3
43
± 3
57
± 3
71
± 3
85
± 3
99
± 3
127
± 7
155
± 7
183
± 7
7 ± 3 
from 
Day 183 
–
Apr 2018
May 
201821)
Informed consent
○
○20)
Inclusion/exclusion criteria
○
○
○
○
Randomization
○
Target disease
○
○
○
Subject demographics
○
Physical examination5)
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
Vaccination
○
○
○
○
○
○
○
○
Chamber evaluation
○
○
○
○
Vital signs6),7)
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
12-lead electrocardiogram6)
○
○
○
○
○
Immunological test8)
○
JRC allergy test9)
○
○
Allergy test other than JRC8)
○
Pregnancy test (urine)6),10)
○
○
○
○
○
○
○
○
○
Hematology test, blood biochemistry 
test, and urinalysis6),11)
○
○
○
○
○
○
○
Consent for PGx12)
PGx blood sampling6),13)
Consent for SDA
○
SDA blood sampling6),14)
○
○
○
Parameters6),15),16)
○
○
○
○
○
○
○22)
Adverse events
○
Local/Systemic Reaction Survey 
Diary17)
Symptoms Survey After Chamber 
Period Diary18)


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Pollinosis Symptoms Survey Diary19)
○: To be performed
1)
Based on the results of tests and observations conducted at Screening visit 1, only those subjects who satisfy the Inclusion Criteria and do not fall under the
Exclusion Criteria will be the target of Screening visit 2 onward.
2)
Based on the symptom score at the chamber evaluation at Screening visit 2, only those subjects who satisfy the inclusion criterion 5 will be the target of 
Screening visit 3 onward.
3)
Only those subjects who discontinue the study before Day 183 will be the target. In principle, discontinuation tests are conducted upon the decision to 
discontinue.
4)
Conducted no later than 7 days prior to Day 1.
5)
For visits with study drug vaccination, conduct physical examination (subjective symptoms, objective findings) 1 hour after study drug vaccination before 
allowing the patient to leave the clinic.
6)
For visits with study drug vaccination and chamber evaluation, conduct all other tests before vaccination and chamber evaluation.
7)
Refer to “5.4.3 Vital Signs” on the protocol for test items.
8)
Refer to “5.2.2 Medical History” on the protocol for test items.
9)
Refer to “5.2.3 Diagnosis of the Target Disease, Severity, and Duration of Disease” on the protocol for test items.
10) For female subjects only. Not required for subjects who are post-menopausal (defined as at least 1 year without any menses) at Screening visit 1 or subjects 
who are surgically sterile or have had hysterectomy or oophorectomy, and the possibility of pregnancy can be negated.
11) Refer to “5.4.4 Laboratory Assessments” on the protocol for test items.
12) Obtain before conducting PGx blood sampling.
13) To be conducted once during the period from Day 1 to Day 183.
14) To be conducted only if blood is sampled when sample processing is possible.
15) Refer to “5.7.1 Immune Response Assessment (Parameters)” on the protocol for test items.
16) BAT is to be conducted only if blood is sampled when sample processing is possible. If blood is not sampled on Day 1, then further blood sampling will be 
unnecessary.
17) To be entered every day from each day of study drug vaccination to 14 days after vaccination.
18) To be entered every day until 3 days after leaving the chamber (day of chamber evaluation, and 1, 2, and 3 days after leaving).
19) Survey will be conducted with the target as subjects who have completed the primary study period. To be entered every day from 01 Feb 2018 to 31 Mar 
2018.
20) Informed consent for the additional test.
21) If a systemic steroid or an immunosuppressant (excluding external use on the skin) is used after the end of the pollinosis symptoms survey period up to 
informed consent for the additional test, the additional test will be performed 28 days after the last dose of the drug or later.
22) The additional test will determine BAT and specific IgE antibody (anti-JRC) only.


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3
STUDY OBJECTIVE(S) AND DESIGN
3.1
Study Objective(s)
To evaluate the efficacy, safety, and dose response for ASP4070 vaccinated in patients with 
cedar pollinosis.
3.2
Study Design
This study is a randomized, double-blind, placebo-controlled, dose-finding study.
The efficacy, safety, and dose response when ASP4070 (mixture containing equivalent 
amount of Cry j 1-LAMP plasmid and Cry j 2-LAMP plasmid, 4 mg/0.4 mL or 1 mg/0.4 mL) 
will be intradermally vaccinated 8 times at 14-day intervals will be evaluated with placebo 
(physiological saline) as the control. The study will conduct cedar pollen exposure using an 
environmental exposure chamber (OHIO Chamber; hereinafter, “chamber”), and the efficacy 
and dose response will be evaluated using clinical symptoms (nasal and eye symptoms) as 
indicators.
Two factors, “Class from results of Japanese red cedar (JRC) pollen-specific IgE antibody 
test performed at Screening visit 1” and “Change in the mean of total 3 nasal symptom 
(sneezing, nasal discharge, and nasal congestion) score during 120 to 180 minutes after start 
of cedar pollen exposure in the chamber as compared to the score before cedar pollen 
exposure at Screening visit 2,” will be used as stratification factors to randomly allocate 
subjects into three groups—ASP4070 4 mg group, ASP4070 1 mg group, or placebo group—
in a ratio of 1:1:1, and the subjects will be vaccinated with the study drug.
After a set period after the final vaccination of the study drug, re-exposure to cedar pollen in 
the chamber will be conducted and the efficacy will be evaluated using clinical symptoms as 
indicators. Efficacy evaluation will be conducted 4, 8, and 12 weeks after the final 
vaccination to confirm the timing of effectiveness. The primary study period of the study will 
be until the end of the one week of post-observational period after the final evaluation in the 
chamber on Day 183 (12 weeks after the final vaccination).
The treatment code will be broken when the primary study period is completed and all data 
entered in case report forms are fixed. Even after code breaking, the study will be continued 
with the investigator, sub-investigator, study coordinator, and subjects remaining blinded.
Subjects who have completed the primary study period will be the target of a survey on cedar 
pollinosis symptoms during the pollinosis symptoms survey period (01 Feb 2018–31 Mar 
2018). Subjects will make entries in the Pollinosis Symptoms Survey Diary every day on 
information regarding nasal and eye symptoms. If a subject experiences intolerable nasal and 
eye symptoms during this period, then the use of rescue drugs will be allowed.
An additional test of immune responses will be performed during the long-term safety 
follow-up period on subjects who have completed the pollinosis symptoms survey period and 
have provided additional consent to the additional test. The additional test will determine the 


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Page 11 of 31
parameters (specific IgE antibody [anti-JRC] and basophil activation test [BAT]) after the 
end of the cedar pollen dispersal season (May 2018).
After the end of the primary study period, safety information (SAE) will be collected for 
approximately 9 months (1 year from the final vaccination of the study drug) as the long-term 
safety follow-up period. Safety information (SAE) will be collected for 1 year after the final 
vaccination of the study drug even from subjects who discontinue their participation in the 
study during the primary study period if they have received at least one vaccination of the 
study drug.
Among subjects in the placebo group or optimal dose group (ASP4070 4 mg group or 1 mg 
group) who complete the primary study period, those who provide written consent again will 
be the target of a Phase II Second-Year Follow-up Study [4070-CL-0021] that is planned to 
be implemented.
3.3
Randomization
The treatment allocation manager will prepare the randomization list prior to the initial 
vaccination of the study drug to the first subject, which randomly allocates subjects to three 
groups in a ratio of 1:1:1 to ASP4070 4 mg group, ASP4070 1 mg group, or placebo group, 
with two factors as stratification factors, “Class of Japanese red cedar (JRC) pollen-specific 
IgE antibody test results at Screening visit 1” and “Change in the mean of total 3 nasal 
symptom (sneezing, nasal discharge, and nasal congestion) score during 120 to 180 minutes 
after start of cedar pollen exposure in the chamber as compared to the score before cedar 
pollen exposure at Screening visit 2.”
The person in charge of subject allocation at the study site will use the randomization list
prepared by the treatment allocation manager to conduct allocation. Subject randomization 
will be conducted several times at the study site and completed before the initial study drug 
vaccination of subjects.
Specific procedures are provided in the “procedures for blinding compliance.”
4
SAMPLE SIZE
4.1
Primary Study Period
A total of 150 subjects, with 50 study drug vaccination subjects in each group
[Rationale]
The number of subjects required for 80% probability of detecting superiority of the ASP4070 
group over the placebo group was calculated. Among the study results of other drugs 
targeting patients with cedar pollinosis using a chamber, studies with published data that 
allow the effect size to be calculated were confirmed and the effect size was 0.668 a), 0.903 b), 
and 0.962 c) for bilastine [Hashiguchi et al., 2017] , montelukast [Hashiguchi et al., 2012], 
and levocetirizine [Hashiguchi et al., 2013], respectively. Based on these effect sizes, with 
regard to the effect on the primary endpoint, the change in the mean of total 3 nasal symptom 
(sneezing, nasal discharge, and nasal congestion) score (3TNSS) during 120 to 180 minutes 


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after entering the chamber to the score before cedar pollen exposure, the effect size of 
ASP4070 was assumed to be 0.650. Using the significance level of the test to be 5% two-
sided, when a hierarchical procedure is used for comparison with the placebo group in the 
order of high-dose group to low-dose group, if the effect size 0.650 is the same for the low-
dose group as for the high-dose group, then the probability of detecting superiority of the 
low-dose group against the placebo group was calculated by simulation. Assuming the 
standard deviation to be 1, as a result of 10,000 simulations, the number of subjects required 
to ensure a detection power of over 80% was 48 subjects. Considering dropout cases, the 
number of subjects in each group was set to 50 subjects and 150 subjects in total.
a) With regard to the total 4 nasal symptom score (sneezing, nasal discharge, nasal congestion, and itchy 
nose) from 0 to 240 minutes after entering the environmental exposure chamber on Day 2 of 
administration, the mean for the bilastine 20 mg group and placebo group was 84.4 and 109.5, 
respectively, the standard deviation was 33.0 and 41.6, respectively, and the effect size was 0.668.
b) With regard to the mean of the total 3 nasal symptom score (sneezing, nasal discharge, and nasal 
congestion) from 120 to 180 minutes after entering the environmental exposure chamber, the mean of the 
montelukast 7 days group and placebo group was 2.31 and 3.17, respectively, the standard deviation was 
0.17 and 0.20, respectively, and the effect size was 0.903.
c) With regard to the AUC of the total 4 nasal symptom score (sneezing, nasal discharge, nasal congestion, 
itchy nose) from 0 to 180 minutes after entering the environmental exposure chamber, the mean of the 
levocetirizine single agent group and placebo group was 16.78 and 31.35, respectively, the standard 
deviation was 14.01 and 16.21, respectively, and the effect size was 0.962.
4.2
Pollinosis Symptoms Survey Period and Additional Study Period
No statistical calculation has been made for the number of subjects in the pollinosis 
symptoms survey period and the additional study period. Subjects who have completed the 
primary study period will be included in the analysis for the pollinosis symptoms survey
period, and subjects who are obtained informed consent for the additional study period will
be included in the analysis for the additional study period.
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.
The following policies apply to analysis sets in principle, but allocation of subjects to 
analysis sets is determined in the Classification Meeting by reference to opinions or advice of 
medical experts as needed.
5.1
Pollinosis Symptom Analysis Set (PSAS)
The Pollinosis Symptom Analysis Set will consist of all subjects who are randomized, are 
vaccinated with the study drug at least once, and have at least one measurement for an 
endpoint on pollinosis symptoms during the pollen dispersal season after vaccination of the 
study drug.


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5.2
Immunological Analysis Set (IAS-2)
The immunological analysis set 2 (IAS-2) will consist of subjects who have provided 
additional consent for the additional test and have at least one measurement for 
immunological response endpoint during the additional study period.
6
ANALYSIS VARIABLES
6.1
Efficacy Endpoints
6.1.1
Pollinosis Symptoms Survey During 2018 JRC Pollen Dispersal Season
Endpoints during the pollinosis symptoms survey period (01 Feb 2018–31 Mar 2018):
6.1.1.1 Symptom Score
●
Total nasal symptom medication score (TNSMS; range: 0-19)
●
Total non-nasal symptom medication score (TNNSMS; range: 0-10)
●
Total symptom medication score (TSMS; range: 0-29)
●
Total nasal symptom score (TNSS; range: 0-12)
●
Total non-nasal symptom score (TNNSS; range: 0-6)
●
Total symptom score (TSS; range: 0-18)
●
Individual nasal symptom (sneezing, nasal discharge, and nasal congestion) score
●
Individual eye symptom (itchy eyes and watery eyes) score
●
Individual medication (Tramazoline hydrochloride nasal drops, Ketotifen fumarate eye 
drops, and Fexofenadine hydrochloride) score
●
Troubles with daily life
●
Proportion of subjects who did not use rescue medications
●
Proportion of subjects who used rescue medications within 7 days
●
Proportion of days with each rescue medication
○
Tramazoline hydrochloride nasal drops
○
Ketotifen fumarate eye drops
○
Fexofenadine hydrochloride
●
Proportion of days without Tramazoline hydrochloride nasal drops, Ketotifen fumarate 
eye drops, or Fexofenadine hydrochloride
●
Proportion of days without Tramazoline hydrochloride nasal drops or Fexofenadine 
hydrochloride
●
Proportion of days without nasal symptoms
●
Proportion of well days
●
Proportion of severe symptom days
●
Proportion of subjects who achieved mean TNSMS in score <3, <4
For each symptom score, subjects will record the following items in their Pollinosis 
Symptoms Survey Diary every day. Section “12.3 Classification of Severity of Pollinosis 
Symptoms” in the protocol will be referred to with regard to nasal and eye symptoms and 
troubles with daily life.


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●
Nasal symptoms: Sneezing, nasal discharge, and nasal congestion, each graded with a 5-
level score of 0, 1, 2, 3, and 4.
●
Eye symptoms: Itchy eyes and watery eyes, each graded with a 4-level score of 0, 1, 2, 
and 3.
●
Troubles with daily life: 5-level score of 0,1, 2, 3, and 4.
For total nasal symptom medication score, total eye symptom medication score, and total 
symptom medication score, usage of rescue medications will be scored and used for 
calculating the endpoints.
●
Medication for nasal symptoms:
○
Usage of Tramazoline hydrochloride nasal drops, Fexofenadine hydrochloride 
tablets or other same kind of medication, each scored as 3. If either of Tramazoline 
hydrochloride nasal drops or Fexofenadine hydrochloride tablets is used, other 
same kind of medication will not be scored for the same day.
○
Usage of mask, scored as 1.
●
Medication for eye symptoms:
○
Usage of Ketotifen fumarate eye drops or the same kind of medication, scored as 3.
If Ketotifen fumarate eye drops is used, other same kind of medication will not be 
scored for the same day.
○
Usage of goggle, scored as 1.
Proportion of days with each rescue medication, proportion of days without rescue 
medications, proportion of days without nasal symptoms, proportion of well days and 
proportion of severe symptom days will be calculated for each subject. The denominator is
the number of days the subject assessed. The day without nasal symptoms, the well day and 
the severe symptom day will be determined as below.
●
Day without nasal symptoms: the day on which all of nasal symptom scores are 0
●
Well day: the day on which all of nasal and eye symptom scores is 0 or 1 and no use of 
rescue medications
●
Severe symptom day: the day on which either of nasal symptom scores is 4 or either of 
eye symptom scores is 3
6.1.1.2 Japanese Rhinoconjunctivitis Quality of Life Questionnaire: JRQLQ No 1
JRQLQ No 1 will be entered every 2 weeks during the pollinosis symptoms survey period for 
a total of 5 times. JRQLQ No 1 consists of the following three parts.
JRQLQ I (nasal and eye symptoms): each graded with 5-level score of 0 for NO 
SYMPTOMS, 1 for MILD, 2 for MODERATE, 3 for SEVERE and 4 for VERY SEVERE
●
Runny nose
●
Sneezing
●
Blocked nose(nasal congestion)
●
Itchy Nose
●
Itchy Eyes


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●
Watery Eyes
JRQLQ II (QOL-related questionnaire): each graded with 5-level score of 0 for NO, 1 for 
SLIGHTLY, 2 for MODERATELY, 3 for GREATLY and 4 for VERY GREATLY
1.
Reduced productivity at work/home
2.
Poor mental concentration
3.
Reduced thinking power
4.
Impaired reading book/newspaper
5.
Memory deterioration
6.
Limitation of outdoor activity(e.g. sport, picnics)
7.
Limitation of going out
8.
Hesitation in communication
9.
Difficulty in conversations and speaking over the phone.
10.
Concerning people around
11.
Impaired sleeping
12.
Malaise
13.
Fatigue
14.
Low mood
15.
Frustration
16.
Depression
17.
Dissatisfied with life
JRQLQ III (General State): graded with 5-level score from 0 for FINE to 4 for CRYING
The following variables will be calculated for analysis.
●
Mean nasal and eye symptom score (Runny nose, Sneezing, Blocked nose(nasal 
congestion), Itchy Nose, Itchy Eyes and Watery Eyes)
●
Mean nasal symptom score (Runny nose, Sneezing, Blocked nose(nasal congestion), and 
Itchy Nose)
●
Mean eye symptom score (Itchy Eyes and Watery Eyes)
●
Mean 3 nasal and 2 eye symptom score (Runny nose, Sneezing, Blocked nose(nasal 
congestion), Itchy Eyes and Watery Eyes)
●
Mean score for each domain in the JRQLQ II
○
Usual Daily Activity: mean of items 1.-5.
○
Outdoor Activity: mean of items 6.-7.
○
Social Functioning: mean of items 8.-10.
○
Sleep Problem: item 11.
○
General Physical Problems: mean of items 12.-13.
○
Emotional Function: mean of items 14.-17.
6.1.1.3 Overall evaluation by the subject
Overall evaluation by the subject is conducted by subjects after the end of the pollinosis 
symptoms survey period.


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●
Overall evaluation by the subject: 5-level evaluation on overall evaluation of symptoms 
during the pollinosis symptoms survey period.
6.2
Immune Response Endpoints
Specific IgE antibody (anti JRC) and basophil activation test (BAT)
7
STATISTICAL METHODOLOGY
7.1
General Considerations
For continuous variables, descriptive statistics will include the number of subjects (n), mean, 
standard deviation, median, minimum, 25 percentile, 75 percentile and maximum. When 
needed, the use of other percentiles will be mentioned in the relevant section. 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%. 
All analyses will be presented by planned treatment group, unless specifically stated 
otherwise.
All statistical comparisons will be made using two sided tests at the α=0.05 significance level 
unless specifically stated otherwise.  All null hypotheses will be of no treatment difference, 
all alternative hypotheses will be two-sided, unless specifically stated otherwise. No 
multiplicity adjustment will be done. All p-values will be presented as supportive information.
All data processing, summarization, and analyses will be performed using SAS Drug 
Development (ver. 4.5), and PC-SAS (ver. 9.4). Specifications for table, figures, and data 
listing formats can be found in the TLF specifications for this study.
For the definition of subgroups of interest please refer to section 7.8.
The coding dictionary for concomitant medication is WHODDE (B2) V2016MAR.
The values below the lower limit of quantitation (LLOQ) or above the upper limit of 
quantitation (ULOQ) will be treated as described in the table below when descriptive 
statistics are calculated. 
Variable
Unit
LLOQ or ULOQ
Value used in analysis
Specific IgE Concentration 
(anti-JRC)
UA/ML
<0.10
0.10
7.2
Study Population
7.2.1
Disposition of Subjects
The following subject data will be presented:






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drops, Ketotifen fumarate eye drops, or Fexofenadine 
hydrochloride
Proportion of days without Tramazoline hydrochloride nasal 
drops or Fexofenadine hydrochloride
D
Proportion of days without nasal symptoms
D
Proportion of well days
A, B and C
Proportion of severe symptom days
A, B and C
Mean of TNSMS, TNNSMS, TSMS, TNSS, TNNSS, TSS, individual nasal and eye 
symptom scores, individual medication scores and score of troubles with daily life will be 
analyzed using an analysis of covariance (ANCOVA) model with treatment groups and the 
stratification factors as explanatory variables. The adjusted mean difference and its 95% 
confidence interval (CI) with p-values for ASP4070 group vs Placebo group will be 
presented. In addition, relative change will be calculated for reference.
Relative change (%) = (adjusted mean difference for ASP4070 group - Placebo group) / 
(adjusted mean for Placebo group calculated at mean values of covariates) x 100
<SAS code>
The following SAS code will be used for ANCOVA analysis:
PROC GLM;
   CLASS treatment strata;
   MODEL response=treatment strata;
   LSMEANS treatment / cl pdiff=control(‘placebo’);
RUN;
where variables in the model are:
-
treatment: Treatment group (ASP4070 4 mg, ASP4070 1 mg, and placebo)
-
strata: Class of Japanese red cedar (JRC) pollen-specific IgE antibody test results at 
Screening visit 1 (3, >=4) and Change in the mean of 3TNSS during 120 to 180 minutes 
after start of cedar pollen exposure as compared to the score before cedar pollen 
exposure at Screening visit 2 (<5, >=5)
-
response: Mean of TNSMS, TNNSMS, TSMS, 3TNSS, TNNSS, TSS, individual 
nasal and eye symptom scores, individual medication score and score of troubles with 
daily life
The day with each rescue medication, the day without rescue medications, the day without
nasal symptoms, well day and severe symptom day will be defined for each day as a binary 
variable (Yes/No). Those binary variables will be analyzed using generalized linear mixed 
model with logit link function and factors for treatment groups and the stratification factors 


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as a fixed effect and subjects as a random effect. The adjusted odds ratio and its 95% CI with 
p-value for ASP4070 group vs Placebo group will be presented.
<SAS code>
The following SAS code will be used for analysis of generalized linear model with logit 
link:
PROC GLIMMIX method=RSPL;
   CLASS treatment strata;
   MODEL response=treatment strata / link=logit dist=bin ddfm=kr2 oddsratio;
   RANDOM int / subject=usubjid;
   LSMEANS treatment / cl pdiff oddsratio;
RUN;
where variables in the model are:
-
treatment: Treatment group (ASP4070 4 mg, ASP4070 1 mg, and placebo)
-
strata: Class of Japanese red cedar (JRC) pollen-specific IgE antibody test results at 
Screening visit 1 (3, >=4) and Change in the mean of 3TNSS during 120 to 180 minutes 
after start of cedar pollen exposure as compared to the score before cedar pollen 
exposure at Screening visit 2 (<5, >=5)
-
usubjid: Subject Identifier
-
response: Binary variable (Yes/No) for the day with rescue medication, the day 
without rescue medications, the day without nasal symptoms, well day and severe 
symptom day
Proportion of subjects who did not use rescue medications and proportion of subjects who 
used rescue medications within 7 days will be presented for the analysis period D by 
treatment group, along with its 95% confidence interval based on the Clopper-Pearson 
method. This endpoint will also be analyzed using a logistic regression model with factors for 
treatment groups and the stratification factors as explanatory variables. The adjusted odds 
ratio and its 95% CI with p-value for ASP4070 group vs Placebo group will be presented. In 
addition, adjusted difference in proportion between ASP4070 group and Placebo group and 
its 95% CI will be calculated using predicted values from the logistic regression model [Ge et 
al., 2011] (for SAS code, see also Appendix 1).
<SAS code>
The following SAS code will be used for logistic regression analysis:
PROC LOGISTIC;
   CLASS treatment strata;
   MODEL response=treatment strata;


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RUN;
where variables in the model are:
-
treatment: Treatment group (ASP4070 4 mg, ASP4070 1 mg, and placebo)
-
strata: Class of Japanese red cedar (JRC) pollen-specific IgE antibody test results at 
Screening visit 1 (3, >=4) and Change in the mean of 3TNSS during 120 to 180 minutes 
after start of cedar pollen exposure as compared to the score before cedar pollen 
exposure at Screening visit 2 (<5, >=5)
-
response: Binary variable (Yes/No) for subjects who did not use rescue medications 
and proportion of subjects who used rescue medications within 7 days
Proportion of subjects who achieved mean TNSMS for the period B in score <3 and <4 will 
be presented by treatment group, along with its 95% confidence interval based on the 
Clopper-Pearson method. This endpoint will also be analyzed using a logistic regression 
model with factors for treatment groups and the stratification factors as explanatory variables. 
The adjusted odds ratio and its 95% CI with p-value for ASP4070 group vs Placebo group 
will be presented. In addition, adjusted difference in proportion between ASP4070 group and 
Placebo group and its 95% CI will be calculated in the similar way as above.
As for TNSMS, TNNSMS, TSMS, TNSS, TNNSS, TSS, individual nasal and eye symptom 
scores, individual medication scores and score for troubles with daily life per day, the 
following data will be presented graphically by treatment group: 
●
Individual results using spaghetti plot
●
Results using mean plot
In these plots JRC pollen counts will be overlaid on a right axis.
7.4.1.2 JRQLQ No 1
Results of JRQLQ No 1 will be summarized by treatment group and time point (1 Feb 2018, 
17 Feb 2018, 3 Mar 2018, 17 Mar 2018 and 31 Mar 2018).
Mean nasal and eye symptom score, mean nasal symptom score, mean eye symptom score
and mean 3 nasal and 2 eye symptom score in the JRQLQ I will be summarized using 
descriptive statistics.
Score for each questionnaire in the JRQLQ II will be summarized using descriptive statistics. 
Mean score for each domain will also be summarized.
Score for general state in the JRQLQ III will be summarized using descriptive statistics.
Frequency tabulations for general state in the JRQLQ III will also be created.
The following data will be presented graphically by treatment group:
●
Individual results using spaghetti plot
●
Results using mean (+/- SD) plot
In these plots JRC pollen counts will be overlaid on a right axis.






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7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)
Not applicable
7.11
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
Whether to replace missing data and outliers and how to choose the analysis time points will 
eventually be decided by the database hard lock, taking the opinions and advice of medical 
experts into consideration as needed. Subjects or values excluded from analyses will be 
presented in listing of individual values but excluded in summarization such as summary 
statistics.
Refer to the data specification document in which more details are provided.
7.11.1
Missing Data
No imputation of missing data will be done.
7.11.2
Outliers
All values will be included in the analyses.
7.11.3
Visit Windows
The acceptable time ranges for the time points for analysis are as follows. If multiple data are 
obtained at the same time point, then data obtained on the closest day to the scheduled day 
will be used for analysis. If data are present before and after the scheduled day with the same 
day difference, then data obtained after the scheduled day will be used for analysis.
[Parameters]
Analysis Time Point
Scheduled day
Acceptable range
Screening visit 1
Date of informed consent
After date of informed consent until 
the day before Screening visit 2
Screening visit 3
28 days from Screening 
visit 2
28 days ±7 days from Screening visit 
2 and also until 
Day 1 −7 days
Day 1
Day 1
Until before study drug vaccination 
on Day 1
Day 57
Day 57
Within ±3 days of the scheduled day*
Day 127, Day 155, Day 183
Day 127, Day 155, Day 183
Within ±7 days of the scheduled day
Additional Test
16 May 2018
From 1 May 2018 to 31 May 2018
*: If the study drug is vaccinated, then data before study drug vaccination will be used.
7.11.4
Analysis Period for Pollinosis Symptoms
The analysis periods used for analysis of pollinosis symptoms survey are defined as follows:


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Period
Description
Date
(Duration)
A
Peak symptom period*1 + 1 
week pre- and post-peak 
symptom period
From 18 Mar. 2018 to 31 Mar. 2018
(14 days)
B*2
Peak symptom period for JRC 
pollen*3 + 1 week pre- and 
post-peak symptom period
From 5 Mar. 2018 to 24 Mar. 2018
(20 days)
C*4
Peak JRC pollen dispersal 
period
From 24 Feb. 2018 to 31 Mar. 2018
(36 days)
D*5
Whole JRC pollen dispersal 
period
From 14 Feb. 2018 to 31 Mar. 2018
(46 days)
*1: Peak symptom period is defined as 7 consecutive days where the sum of daily average for 
TNSMS is the maximum during the pollinosis symptoms survey period (from 1 Feb. 2018 to 
31 Mar. 2018). Sum of daily average is calculated per 1 day interval.
*2: To avoid results being confounded by Japanese cypress pollen, peak symptom period for 
JRC pollen + 1 week pre- and post-peak symptom period was completed before the first day 
(25 Mar. 2018) of the first two consecutive days which there was a cypress pollen count of 
>=30/cm2/day.
*3: To avoid results being confounded by Japanese cypress pollen, peak symptom period for 
JRC pollen is defined as 7 consecutive days where the sum of daily average for TNSMS is 
the maximum from 1 Feb. 2018 until 24 Mar. 2018. Sum of daily average is calculated per 1
day interval.
*4: Peak JRC pollen dispersal period is defined as starting on the first day of the first two 
consecutive days during the pollinosis symptoms survey period (from 1 Feb. 2018 to 31 Mar.
2018) which there was a pollen count of >=30/cm2/day, and ending on the last day on which 
there was a pollen count of >=30/cm2/day.
*5: Whole JRC pollen dispersal period is defined as starting on the first day of the first two 
consecutive days during the pollinosis symptoms survey period (from 1 Feb. 2018 to 31 Mar.
2018) which there was a pollen count of >=1/cm2/day, and ending on the day before the first 
of three consecutive days on which there was a pollen count of 0/cm2/day.
8
DOCUMENT REVISION HISTORY
Version
Date
Changes
Comment/rationale for change
1.0
22-Jun-2018
NA
Document finalized
9
REFERENCES
Hashiguchi K, Kanzaki S, Wakabayashi K, Tanaka N, Kawashima K, Suematsu K, et al. Efficacy of 
fluticasone furoate nasal spray and levocetirizine in patients with Japanese cedar pollinosis 
subjected to an artificial exposure chamber. J Drug Assess. 2013;2:94-105.


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Hashiguchi K, Okubo K, Wakabayashi K, Tanaka N, Watada Y, Suematsu K, et al. The assessment of 
the optimal duration of early intervention with montelukast in the treatment of Japanese cedar 
pollinosis symptoms induced in an artificial exposure chamber. J Drug Assess. 2012;1:40-7.
Hashiguchi K, Wakabayashi K, Togawa M, Saito A, Okubo K. Therapeutic effect of bilastine in 
Japanese cedar pollinosis using an artificial exposure chamber (OHIO Chamber). Allergol Int. 
2017;66:123-31.
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)
Ge M, Durham LK, Meyer RD, et al. Covariate-adjusted difference in proportions from clinical trials 
using logistic regression and weighted risk differences. Drug Inf J 2011;45:481–93.


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10
APPENDICES
10.1
Appendix 1: Sample SAS code for logistic regression
ods output ParameterEstimates=tmp2_2(keep=Estimate) CovB=tmp2_3;
proc logistic data=tmp1 outdesign=tmp2_1(drop=AVAL);
class TRTPN(param=ref ref="3") STRATA1(param=ref ref="1") STRATA2(param=ref
ref="1");
model AVAL(event="1")=TRTPN STRATA1 STRATA2/ covb;
run;
proc iml;
   use tmp2_1;
     read all into X;
   close tmp2_1;
   use tmp2_2;
     read all into Est;
   close tmp2_2;
   use tmp2_3;
     read all into CovB;
   close tmp2_3;
   n=nrow(X);
   X1=X[,1]||j(n,1,1)||j(n,1,0)||X[,4]||X[,5];
   X2=X[,1]||j(n,1,0)||j(n,1,1)||X[,4]||X[,5];
   X3=X[,1]||j(n,1,0)||j(n,1,0)||X[,4]||X[,5];
   XB1=X1*Est;
   XB2=X2*Est;
   XB3=X3*Est;
   P1=exp(XB1)/(1+exp(XB1));


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   P2=exp(XB2)/(1+exp(XB2));
   P3=exp(XB3)/(1+exp(XB3));
   A1=P1#(1-P1);
   A2=P2#(1-P2);
   A3=P3#(1-P3);
   D1=t(A1)*X1/n;
   D2=t(A2)*X2/n;
   D3=t(A3)*X3/n;
   dif1=sum(P1-P3)/n; * proportion difference(TRTPN=1 - TRTPN=3) ;
   dif2=sum(P2-P3)/n; * proportion difference(TRTPN=2 - TRTPN=3) ;
   se1=sqrt( D1*CovB*t(D1) + D3*CovB*t(D3) -2*D3*CovB*t(D1) ); * standard error of 
proportion difference(TRTPN=1 - TRTPN=3) ;
   se2=sqrt( D2*CovB*t(D2) + D3*CovB*t(D3) -2*D3*CovB*t(D2) ); * standard error of 
proportion difference(TRTPN=2 - TRTPN=3) ;
   upper1=dif1+se1*probit(1-0.025); * upper bound of 95% CI of proportion 
difference(TRTPN=1 - TRTPN=3) ;
   upper2=dif2+se2*probit(1-0.025); * upper bound of 95% CI of proportion 
difference(TRTPN=2 - TRTPN=3) ;
   lower1=dif1-se1*probit(1-0.025); * lower bound of 95% CI of proportion 
difference(TRTPN=1 - TRTPN=3) ;
   lower2=dif2-se2*probit(1-0.025); * lower bound of 95% CI of proportion 
difference(TRTPN=2 - TRTPN=3) ;
   create diff var {dif1 se1 upper1 lower1 dif2 se2 upper2 lower2};
      append;
   close diff;


Sponsor: Astellas Pharma Inc.
SAP Final Version
ISN/Protocol 4070-CL-0020
22-Jun-2018
Astellas
Page 29 of 31
quit;


Sponsor: Astellas Pharma Inc.
SAP Final Version
ISN/Protocol 4070-CL-0020
22-Jun-2018
Astellas
Page 30 of 31
10.2
Appendix 2: Key Contributors and Approvers
List of Key Contributors and Approvers
Key Contributors
The following contributed to or reviewed this Statistical Analysis Plan as relevant to their 
indicated discipline or role.
Primary author (s)
 
 
Contributors and Reviewers
 
 
 
 
 
 
 


Sponsor: Astellas Pharma Inc.
SAP Final Version
ISN/Protocol 4070-CL-0020
22-Jun-2018
Astellas
Page 31 of 31
Author and Approver Signatories 
(E-signatures are attached at end of document)