An Extension Study of a Phase IIa Study in Patients With Mild Alzheimer's Disease to Evaluate the Safety, Tolerability, Immunogenicity, and Efficacy of UBITh® AD Immunotherapeutic Vaccine (UB-311)
Phase: PHASE2
Conditions: Alzheimer's Disease
Sponsor: United Neuroscience Ltd.

 
 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
 
 
 
Investigational Product: 
UBITh® AD Immunotherapeutic Vaccine (UB-311) 
 
 
An Extension Study of a Phase IIa study in Patients with Mild Alzheimer’s 
Disease to Evaluate the Safety, Tolerability, Immunogenicity, and Efficacy of 
UBITh® AD Immunotherapeutic Vaccine (UB-311)  
 
 
 
 
Protocol Number:  
V203-AD-EXT 
Confidential 
Version: 1.1 
Date: 22-Jan-2018 
 
This document contains confidential information and is the property of United Neuroscience Ltd. (UNS). The 
receiver(s) of this document understood and agreed that this document is not to be disclosed to any 
unauthorized third party without written agreement issued by the sponsor. The need to disclose certain 
information contained in this document for the purpose of obtaining informed consent from potential subjects 
or his/her legally acceptable representative(s) of this study will be considered as exceptions.
 
 
 
 

 
 
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Clinical Trial Protocol: V203-AD-EXT 
 
Version: 1.1, Date: 22-Jan-2018 
 
Principal Investigators: 
Dr. Pei-Ning Wang（王培寧醫師） 
Department of Neurology, 
Taipei Veterans General Hospital, Taipei, Taiwan 
Dr. Ming-Jang Chiu（邱銘章醫師） 
Department of Neurology, 
National Taiwan University Hospital, Taipei, Taiwan 
Dr. Chin-Chang Huang（黃錦章醫師） 
Department of Neurology,  
Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan 
Dr. Chiung-Chih Chang（張瓊之醫師） 
Department of Neurology, 
Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan 
 
Sponsor: 
愛爾蘭商聯腦科學股份有限公司台灣分公司 
United Neuroscience Ltd., Taiwan Branch (Ireland) 
Taipei, Taiwan 
Product authorized by: 
愛爾蘭商聯腦科學股份有限公司 
United Neuroscience Ltd. (UNS) 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Clinical Trial Protocol: V203-AD-EXT 
 
Version: 1.1, Date: 22-Jan-2018 
 
Principal Investigator’s Signature Page  
 
I understood the obligations as a clinical trial investigator and agree to perform and report 
the study in compliance to the protocol, good clinical practice (GCP), and the current rules 
and regulations set forth by the applicable health authorities. 
 
Name 
 Affiliation 
 Signature 
 Date 
 
  
  
  
 

 
 
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Clinical Trial Protocol: V203-AD-EXT 
 
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Co-Investigator’s Signature Page  
 
I understood the obligations as a clinical trial investigator and agree to perform and report 
the study in compliance to the protocol, good clinical practice (GCP), and the current rules 
and regulations set forth by the applicable health authorities. 
 
Name 
 Affiliation 
 Signature 
 Date 
 
  
  
  

 
 
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Clinical Trial Protocol: V203-AD-EXT 
 
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Internal Signature Page 
 
I understood the obligations as an officer providing service in the organization(s) listed on the 
cover page of this document, and agreed to perform the study in my responsible aspects, in 
compliance to the protocol and good clinical practice (GCP) and the current rules and 
regulations set forth by the applicable health authorities. 
 
Affiliation 
 Name 
 Position 
 Signature 
 Date 
United Neuroscience 
Ltd., Taiwan 
  
  
  
  

 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ......................................................................................................................... 1 
LIST OF ABBREVIATIONS ................................................................................................................... 6 
SYNOPSIS ................................................................................................................................................ 9 
1. INTRODUCTION AND RATIONALE .......................................................................................... 14 
2 
OBJECTIVES .................................................................................................................................. 15 
3 
TRIAL DESIGN .............................................................................................................................. 15 
3.1 Description of the Protocol ................................................................................................. 15 
3.1.1 
Screening Period ............................................................................................................... 16 
3.1.2 
Treatment Period ............................................................................................................... 16 
3.1.3 
Follow-up Period ............................................................................................................... 16 
3.2 Endpoints........................................................................................................................... 16 
3.2.1 
Primary .............................................................................................................................. 16 
3.2.2 
Secondary .......................................................................................................................... 17 
2.2.3 
Exploratory ........................................................................................................................ 17 
3.3 Description of Blinding Methods ........................................................................................ 17 
3.4 Stopping Rules ................................................................................................................... 17 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................................... 19 
4.1 Number of Subjects ............................................................................................................ 19 
4.2 Inclusion Criteria ............................................................................................................... 19 
4.3 Exclusion Criteria .............................................................................................................. 19 
4.4 Subject Withdrawal Criteria .............................................................................................. 20 
5 
TREATMENT OF SUBJECTS ....................................................................................................... 22 
5.1 Description of Study Drug .................................................................................................. 22 
5.2 Dosing Regimens and Rationale ......................................................................................... 22 

 
 
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5.3 Handling of Study Drug ..................................................................................................... 22 
5.3.1 
Packing and Labelling ...................................................................................................... 22 
5.3.2 
Storage ............................................................................................................................... 22 
5.4 Drug Accountability ........................................................................................................... 22 
5.5 Concomitant Medicines ...................................................................................................... 23 
5.5.1 
Permitted Medicines .......................................................................................................... 23 
5.5.2 
Prohibited Medicines ........................................................................................................ 23 
5.6 Subject Compliance ........................................................................................................... 24 
6 
ASSESSMENT OF INVESTIGATIONAL PRODUCT .................................................................. 25 
6.1 Immunogenicity ................................................................................................................. 25 
6.1.1 
Anti-Aβ antibody measurement ........................................................................................ 25 
6.1.2 
Response rate..................................................................................................................... 25 
6.2 Safety ................................................................................................................................. 25 
6.3 Efficacy .............................................................................................................................. 25 
6.3.1 
Evaluation variables ......................................................................................................... 25 
6.3.2 
Efficacy assessment methods ............................................................................................ 26 
6.4 Measures to protect blinding of this trial ............................................................................ 27 
7 
ASSESSMENT OF SAFETY........................................................................................................... 28 
7.1 Safety Endpoints ................................................................................................................ 28 
7.1.1 
Local tolerability ............................................................................................................... 28 
7.1.2 
Clinical safety .................................................................................................................... 28 
7.1.3 
Adverse event collection .................................................................................................... 28 
7.1.4 
ECG ................................................................................................................................... 28 
7.1.5 
MRI .................................................................................................................................... 29 
7.1.6 
Safety laboratory ............................................................................................................... 29 

 
 
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7.2 Safety Instructions ............................................................................................................. 29 
7.2.1 
Local tolerability ............................................................................................................... 29 
7.2.2 
Monitoring of ARIA .......................................................................................................... 29 
7.3 Adverse Events Recording ................................................................................................. 29 
7.4 Adverse Events Monitoring ................................................................................................ 30 
7.5 Definitions of Adverse Event and Serious Adverse Event ................................................... 30 
7.6 Recording and Reporting of Adverse Event ....................................................................... 31 
7.7 Follow-up ........................................................................................................................... 33 
7.8 Obligation of the Sponsor ................................................................................................... 33 
8 
STUDY PROCEDURES .................................................................................................................. 34 
8.1 Study Visits ........................................................................................................................ 34 
8.1.1 
The Screening visit (-42 < Day < -1) ................................................................................ 34 
8.1.2 
Visit 1 (Week 1, Day 1) ...................................................................................................... 35 
8.1.3 
Visit 2 (Week 5, Day 29) .................................................................................................... 35 
8.1.4 
Visit 3 (Week 13, Day 85) .................................................................................................. 36 
8.1.5 
Visit 4 (Week 25, Day 169) ................................................................................................ 37 
8.1.6 
Visit 5 (Week 49, Day 337) ................................................................................................ 37 
8.1.7 
Visit 6 (Week 73, Day 505) ................................................................................................ 38 
8.1.8 
Visit 7 (Week 97, Day 673) ................................................................................................ 38 
8.1.9 
Visit 8 (Week 109, Day 757) .............................................................................................. 38 
8.2 Events and Time Schedule ................................................................................................. 40 
8.3 Blood Sample Collection .................................................................................................... 41 
9 
STATISTICS ................................................................................................................................... 42 
9.1 Analysis Variables .............................................................................................................. 42 
9.1.1 
Demographic and baseline characteristics ....................................................................... 42 

 
 
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9.1.2 
Immunogenicity variables ................................................................................................. 42 
9.1.3 
Efficacy variables .............................................................................................................. 42 
9.1.4 
Safety variables ................................................................................................................. 43 
9.2 Analysis Populations .......................................................................................................... 43 
9.2.1 
Efficacy populations ......................................................................................................... 43 
9.2.2 
Safety population ............................................................................................................... 43 
9.2.3 
Disposition of subjects....................................................................................................... 44 
9.3 Statistical Methods ............................................................................................................. 44 
9.3.1 
Demographic and baseline characteristics ....................................................................... 44 
9.3.2 
Treatment tolerability and compliance ............................................................................. 45 
9.3.3 
Analysis of immunogenicity variable ............................................................................... 45 
9.3.4 
Analysis of efficacy variables ............................................................................................ 45 
9.3.5 
Analysis of safety data ....................................................................................................... 45 
10 QUALITY CONTROL AND QUALITY ASSURANCE ................................................................ 48 
10.1 Responsibility of the Investigator(s) ................................................................................... 48 
10.2 Responsibility of the Sponsor ............................................................................................. 48 
10.3 Source Document Requirements ........................................................................................ 48 
10.4 Use and Completion of Case Report Forms (CRFs) and Additional Request ...................... 49 
11 ETHICS ........................................................................................................................................... 50 
11.1 Declaration of Helsinki and Ethical Review ........................................................................ 50 
11.2 Patient Information and Consent ....................................................................................... 50 
11.3 Patient Data Protection ...................................................................................................... 50 
12 DATA HANDLING AND RECORD KEEPING ............................................................................ 51 
12.1 Data Management .............................................................................................................. 51 
12.2 Record Retention in Study Sites ......................................................................................... 51 

 
 
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13 FINANCING AND INSURANCE ................................................................................................... 52 
14 PUBLICATION POLICY ............................................................................................................... 53 
15 REFERENCES ................................................................................................................................ 54 
 
 

 
 
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LIST OF ABBREVIATIONS 
ABBREVIATION 
TERM 
Aβ 
Amyloid β 
AChE 
Acetyl Cholinesterase 
AD 
Alzheimer’s Disease 
ADAS-Cog 
Alzheimer’s Disease Assessment Scale-Cognitive Subscale 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
ANOVA 
Analysis of Variance 
ARIA 
Amyloid-related Imaging Abnormalities 
ARIA-E 
Amyloid-related Imaging Abnormalities: Vasogenic Edema and/or Sulcal 
Effusion 
ARIA-H 
Amyloid-related 
Imaging 
Abnormalities: 
Microhemorrhage 
and 
Superficial Siderosis 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
BUN 
Blood Urine Nitrogen 
BW 
Body Weight 
CDR-SB 
Clinical Dementia Rating-Sum of Boxes 
CI 
Confidence Interval 
CNS 
Central Nerves System 
CpG-ODN 
Cytosine-phosphate-guanosine Oligodeoxynucleotide 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-reactive Protein 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAD 
Disability Assessment for Dementia 
dL 
Deciliter 
DNA 
Deoxyribonucleic Acid 
DOH 
Department of Health 
ECG 
Electrocardiogram 
EDTA 
Ethylenediamine Tetra Acetic Acid 
EIA 
Enzyme Immunoassay 
ELISPOT 
Enzyme-Linked ImmunoSpot  
ESR 
Erythrocyte Sedimentation Rate 
ET 
Early Termination 

 
 
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GCP 
Good Clinical Practice 
GFAP 
Glial fibrillary acidic protein 
HbA1c 
Glycosylated Hemoglobin 
HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B Virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
IL-6 
Interleukin-6 
IL-8 
Interleukin-8 
IM 
Intramuscular 
IQR 
Interquartile Range 
IRB 
Institutional Review Board 
IU 
International Unit 
kg 
Kilogram 
KS-CGMH 
Kaohsiung Chang Gung Memorial Hospital 
LK-CGMH 
Linkou Chang Gung Memorial Hospital 
m 
Meter 
MCI 
Mild Cognitive Impairment  
mcg, µg  
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mITT 
Modified Intention-to-treat 
mL 
Milliliter 
mm 
Millimeter 
MMSE 
Mini Mental State Examination 
MRI 
Magnetic Resonance Imaging 
n 
Number of Observations Available 
NCI 
National Cancer Institute 
NFH 
Neurofilament Heavy Chain 
NFL 
Neurofilament Light Chain 
NMDA 
N-methyl-D-aspartate 
NTB 
Neuropsychological Test Battery 
NTUH 
National Taiwan University Hospital 
PE 
Physical Examination 
PET 
Positron Emission Tomography 
PP 
Per-protocol 
PSD 
Power spectral densities 

 
 
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ROI 
Region of Interest 
S 
Screening 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SSRIs 
Selective Serotonin Reuptake Inhibitors 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SUVR 
Standard Uptake Value Ratio 
TEAE 
Treatment-emergent Adverse Event 
TNF-α 
Tumor necrosis factor-alpha 
TVGH 
Taipei Veterans General Hospital 
UCHL1 
Ubiquitin C-Terminal Hydrolase L1 
UNS 
United Neuroscience Ltd. 
ULN 
Upper limits of normal 
ULRR 
Upper Limit of Reference Range 
US FDA 
United States, Food and Drug Administration 
V 
Visit 
W 
Week 
WBC 
White Blood Cells 
WHO 
World Health Organization 

 
 
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SYNOPSIS 
PROTOCOL NUMBER 
V203-AD-EXT 
TITLE 
An Extension Study of a Phase IIa study in Patients with Mild 
Alzheimer’s 
Disease 
to 
Evaluate 
the 
Safety, 
Tolerability, 
Immunogenicity, and Efficacy of UBITh® AD Immunotherapeutic 
Vaccine (UB-311) 
STUDY SITES 
There will be four study sites: 
Site 1: Taipei Veterans General Hospital (TVGH) 
Principal Investigator: Dr. Pei-Ning Wang 
Site 2: National Taiwan University Hospital (NTUH) 
Principal Investigator: Dr. Ming-Jang Chiu 
Site 3: Linkou Chang Gung Memorial Hospital (LK-CGMH) 
Principal Investigator: Dr. Chin-Chang Huang  
Site 4: Kaohsiung Chang Gung Memorial Hospital (KS-CGMH) 
Principal Investigator: Dr. Chiung-Chih Chang 
STUDY OBJECTIVES 
To assess the long-term treatment effects of UB-311 on: 
1. Safety and tolerability of UB-311; 
2. Immunogenicity of UB-311; 
3. Change in cognitive and functional performance; 
4. Change in qEEG; 
5. Change of brain volume and cortical thickness 
6. Change in amyloid deposition evaluated by 18F-AV-45 PET 
imaging; 
7. Change in neurodegenerative biomarkers; 
8. Correlation between the titers of anti-Aβ antibody and 
anti-measles or anti-HBV cellular and humoral immune memory 
STUDY DESIGN 
This is a 108-week extension study in patients with mild 
Alzheimer’s disease (AD) who participated in V203-AD trial, a 
multicenter, randomized, double-blind, placebo-controlled phase IIa 
study of UB-311.  
Subjects from UB-311 treatment groups (Arm 1 with a 3-month 
treatment interval and Arm 2 with a 6-month treatment interval) in 
V203-AD study will receive total 3 doses of UB-311 at weeks 1, 49 
and 97 and 2 doses of placebo at weeks 5 and 13 as treatment group 
1. Subjects from placebo treatment group (Arm 3) in V203-AD 
study will receive total 5 doses of UB-311 at weeks 1, 5, 13, 49 and 
97 as treatment group 2. Subjects will be followed till Week 109. 
To maintain the blinding of V203-AD study, the first three 

 
 
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injections at weeks 1, 5 and 13 in this extension study will keep 
blinded before the end of V203-AD study.  
STUDY POPULATION 
Total expected number 
of subjects  
 
Inclusion criteria 
 
Subjects from V203-AD trial (maximum 42 subjects) will be 
eligible to join this extension study. 
 
Subjects may be included in the clinical trial only if they meet all of 
the following criteria: 
1. Patients who participated in V203-AD trial without major 
safety concerns; 
2. The last UB-311/placebo injection received in V203-AD study 
should be at least 24 weeks prior to the V1 of this extension 
study; 
3. Stable doses of permitted medications for 3 months before 
screening, such as acetyl cholinesterase (AChE) inhibitors, 
N-methyl-D-aspartate (NMDA) receptor antagonist, ergot 
alkaloids or their derivatives for cognitive enhancement; 
4. Female must either be post-menopausal (no menstrual period 
for >1 year), surgically sterilized or agree to avoid becoming 
pregnant during the entire period of this study; while sexually 
active fertile male must agree to use effective birth control 
methods throughout the study duration, if their sexual 
partner(s) are women of childbearing potential; 
5. With a caregiver who has frequent contact with the subject 
(e.g. an average of 10 hours per week or more) and agrees to 
sign the informed consent form (ICF) and to perform 
study-related AD scales; 
6. Both patient and his/her caregiver should sign the written 
informed consent before undergoing any study procedures; and 
7. Agree not to donate blood or blood products for transfusion 
during the study and for 3 months thereafter 
Exclusion criteria 
Subjects will be excluded from the clinical trial for any of the 
following reasons: 
1. Clinically 
significant 
neurological 
disease 
other 
than 
Alzheimer’s disease, such as Parkinson’s disease, multi-infarct 
dementia, 
Huntington’s 
disease, 
normal 
pressure 
hydrocephalus, brain tumor, progressive supranuclear palsy, 
seizure disorder, subdural hematoma, multiple sclerosis, or 
history of significant head trauma followed by persistent 
neurologic defaults or known structural brain abnormalities;  

 
 
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2. Screening magnetic resonance imaging (MRI) scan with 
evidence of central nerves system (CNS) infection, infarction, 
or other focal lesions, cerebrovascular disease, superficial 
siderosis, 
macrohemorrhage, 
microhemorrhages, 
multiple 
lacunes or lacunes in a critical memory structure accompanies 
with symptoms that the investigator determines to be a safety 
concern; 
3. Major depressive episode or manic episode as described in 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition (DSM-V) within the past 1 year before screening. 
Psychotic features, agitation or behavioural problems within 
the last 3 months before screening which could lead to 
difficulty in complying with the protocol; 
4. History of schizophrenia (DSM-V criteria);  
5. Any significant systemic illness or unstable medical condition 
which could lead to difficulty in complying with the protocol; 
6. History of alcohol or substance abuse or dependence within the 
past 2 years before screening (DSM-V criteria); 
7. History of autoimmune disease, including but not limited to 
ankylosing spondylitis, Sjogren’s syndrome, systemic lupus 
erythematosus, rheumatic arthritis, or multiple sclerosis; 
8. History of severe systemic disease that may affect a subject’s 
participation at the investigator’s discretion; 
9. History of anaphylaxis; other serious adverse reactions to any 
vaccine; or any serious allergic reactions to medications 
requiring treatment; 
10. Use of any prohibited medications within 4 weeks prior to 
screening; 
11. Use of any investigational drug within 4 weeks before 
screening; 
12. Previous exposure to any anti-Aβ immunotherapy except 
UB-311; 
13. History of cancer, including solid tumors and hematological 
malignancies (except basal cell and in situ squamous cell 
carcinomas of the skin that have been excised and resolved); 
14. Received blood or blood derivatives treatment within 3 months 
prior to screening;  
15. Current or recent participation (within 12 months before 
screening) in any procedures involving radioactive agents such 
that radiation exposure of the subject in any given year would 
exceed the whole-body limits of annual and total dose 

 
 
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commitment of 5 rems set forth in the US Code of Federal 
Regulations (CFR) Title 21 section 361.1; 
16. Abnormal clinical laboratory values judged by the investigator 
to be a safety concern to join the study 
INVESTIGATIONAL 
PRODUCT(S) 
The UB-311 (UBITh® AD Immunotherapeutic Vaccine) is supplied 
as a single-dose vial containing 300 µg in 0.5 mL solution.  
PRIMARY 
ENDPOINT(S) 
AND MAIN SECONDARY 
ENDPOINT(S) 
Primary endpoints: 
 Safety and tolerability: the incidence of adverse event 
(AE)/serious adverse event (SAE); and 
 The immunogenicity of UB-311 as measured by change in 
anti-Aβ antibody levels and response rate. 
Secondary endpoints: 
The treatment effects of UB-311 on: 
 The change in cognitive and global assessments, including: 
– Alzheimer’s Disease Assessment Scale-Cognitive Subscale 
(ADAS-Cog) 
– Mini-Mental State Exam (MMSE) 
– Clinical Dementia Rating-Sum of Boxes (CDR-SB)  
– Computerized cognitive tests 
 The change from baseline of V203-AD study in amyloid 
deposition by 18F-AV-45 PET imaging; 
Exploratory endpoints: 
 Titers of anti-Aβ1-42 monomer and anti-Aβ1-42 oligomer 
antibodies; 
 The change in qEEG; 
 The change of brain volume and cortical thickness; 
 The change in neurodegenerative biomarkers in blood such as 
Aβ40, Aβ42, tau, neurofilament heavy chain (NFH), neurofilament 
light chain (NFL), glial fibrillary acidic protein (GFAP) and 
ubiquitin C-Terminal Hydrolase L1 (UCHL1); 
 The correlation between titers of anti-Aβ antibody with 
anti-measles or anti-HBV antibodies and memory T cell 
responses for UBITh® 1 and UBITh® 2. 
STATISTICAL 
CONSIDERATIONS 
The overall treatment tolerability of UB-311 is defined as the 
percentage of number of administered doses divided by number of 
administered doses plus number of missed doses of subject(s) who 
drops out due to drug-related AE(s). It is calculated according to the 
following formula: 
100% x (A+B1+C+D)/ (A+B1+B2+C+D) 

 
 
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where  
A: number of administered doses of completers 
B1: number of administered doses of subject(s) who drops out 
due to drug-related AE(s) 
B2: number of missed doses of subject(s) who drops out due to 
drug-related AE(s) 
C: number of administered doses of subject(s) who drops out due 
to drug-unrelated AE(s) 
D: number of administered doses of subject(s) who drops out not 
due to AE(s) 
Analysis Population 
Modified intent-to-treat (mITT) population: all subjects who receive 
at least one dose of the study drug and have both baseline and at 
least one post-baseline assessment in any of the primary or 
secondary variables, irrespective of compliance with the study 
protocol and procedures. 
Per-protocol (PP) population: subjects who receive all planned doses 
of the study drug, complete the treatment period, fulfil all entry 
criteria, and have no key protocol deviation. 
Safety population: subjects exposed to at least one dose of the study 
drug. 
The analyses of primary safety variables and tolerability will be 
performed on safety population, and the analyses of immunogenicity 
and efficacy endpoints will be performed on both mITT and PP 
populations. 
For the analyses of immunogenicity, UB-311 response rate will be 
calculated and the change in antibody level will also be compared by 
a repeated-measures mixed-effects model. 
For the analyses of efficacy, continuous variables with repeated 
measures will be analyzed using a mixed-effects model. 
DURATION 
OF 
STUDY 
PERIOD 
Screening period: <6 weeks 
Treatment period: 96 weeks 
Follow-up period: 12 weeks 

 
 
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1. INTRODUCTION AND RATIONALE 
Alzheimer’s disease (AD), a progressive, multifactorial, and heterogeneous neurodegenerative 
disease, affects 47 million people worldwide and the number is projected to increase to more than 
131 million by 20501. Several early community-based studies have shown that AD is the most 
common cause of dementia in Taiwan with prevalence ranging from 1.7 to 4.4%2-4 and an incidence 
rate of about 0.817%5 in 2010.  
Alzheimer’s disease is characterized by extracellular aggregates of amyloid β (Aβ) protein and 
intracellular tangles of the neurofilament protein tau, both are toxic to neurons. Therefore, Aβ has 
been a major therapeutic target in Aβ immunotherapy. Although symptomatic therapies are 
available, there is still no proven treatment that can address a variety of neurobehavioral 
disturbances and reverse progression of AD6-7. It has been shown that reducing Aβ deposition is 
able to improve cognition function in animal models of AD. Recently released human clinical trial 
results of Aducanumab, a human monoclonal antibody targeting aggregated forms of β-amyloid 
developed by Biogen Inc8 also supports this notion. Unlike this passive immunity approach, the 
goal for an active Aβ immunotherapy is to stimulate an immune response to generate robust 
endogenous anti-Aβ antibodies that ultimately reduce brain Aβ levels. UBITh AD active 
immunotherapeutic vaccine (UB-311) is comprised of two Aβ1-14-targeting peptide immunogens 
(B-cell epitopes) each linked to proprietary, synthetic helper T-cell peptide epitopes (UBITh) 
formulated in a Th2-biased delivery system designed to minimize T-cell inflammatory reactivity9-12.  
Studies in small animals, baboons and macaques showed that anti-Aβ antibodies were generated 
with the expected N-terminus site-specificity by UB-311.  
The neurodegenerative processes in AD lead to the loss of synapses and dysfunction of brain 
electrical circuits. Quantitative electroencephalograhy (qEEG) is a clinical tool commonly used to 
non-invasively assess brain synaptic and circuit function. Studies have shown abnormal frequency 
power spectra and functional connectivity of resting state electroencephalographic (EEG) rhythms 
in subjects with AD compared to healthy age-matched elderly subjects. Alzheimer’s patients are 
typically characterized by a slowing of EEG, including an increase in delta and theta power and a 
decrease in alpha and beta13-15. EEG is thus a noninvasive, low cost and widely available biomarker 
to identify dementia and classify the degree of its severity by signal processing and analysis. qEEG 
will be used to track brain neurophysiology changes in this study. 
In addition to the imaging biomarker, 18F-AV-45 PET, peripheral blood based biomarker assays 
will also be performed throughout the study for AD progression and UB-311 therapeutic effect. 
These include Aβ40, Aβ42, Tau, Neurofilament heavy chain (NFH), Neurofilament light chain 
(NFL), glial fibrillary acidic protein (GFAP), and ubiquitin C-terminal Hydrolase L1 (UCHL1). 
In the phase I study (V118-AD) of UB-311, all 19 subjects completed the study and only 16 mild or 
moderate treatment-related AE episodes were reported in 9 subjects. Injection site reaction was the 
most frequently reported AE16. An UB-311 Phase IIa study (V203-AD) with an identical 3-arm, 
randomized, double-blind, placebo-controlled trial design is underway in Taiwan and 43 patients 
has been enrolled. In V203-AD study, subjects receive 7 doses of UB-311, 5 doses of UB-311 and 2 
doses of placebo or 7 doses of placebo utilizing 1:1:1 randomization scheme. Until Oct 2017, 25 
patients have completed the treatment period containing 7 injections of study drug and all patients 
have received 4 injections of study drug. To evaluate the long-term safety, tolerability and potential 
efficacy, patients who previously participated in V203-AD study will be eligible to participate in 

 
 
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the extension study and will receive 3 or 5 doses of UB-311 within a 96-week treatment period 
followed by a 12-week follow-up period. Assessments such as cognitive and global performance, 
amyloid PET imaging, EEG, brain volume/cortical thickness and fluid neurodegenerative 
biomarkers will be performed to evaluate the AD progression and treatment effect. 
 
2 
OBJECTIVES 
The primary objectives of this study are to assess the long-term safety and tolerability of UB-311 
treatment, and to evaluate the immunogenicity of UB-311 through measurement of anti-Aβ 
antibodies. 
The secondary objectives are to evaluate the effects of UB-311 on the changes of cognitive and 
global performance and to investigate whether UB-311 treatment results in group differences and 
changes in amyloid deposition in vivo evaluated by18F-AV-45 PET imaging. In addition, the change 
of qEEG, brain volume/cortical thickness and level of neurodegenerative biomarkers in blood will 
be assessed for AD progression and UB-311 efficacy evaluation. 
 
UBITh®1 and UBITh®2 epitopes are idealized T helper (Th) cell designs based on and modified 
from Th sites on measles virus F protein and hepatitis B surface antigen, respectively. To evaluate if 
subjects who previously infected with measles/HBV or immunized with measles/HBV vaccines will 
generated higher titer of anti-Aβ antibody by UB-311, titers of anti-measles and anti-HBV 
antibodies will be compared to the maximum titer of anti-Aβ antibody in subjects. In addition, an 
evaluation for T-cell memory status against UBITh® 1 and UBITh® 2 will also be performed in 
peripheral blood isolated monocytic cells.  
 
3 
TRIAL DESIGN 
This is a 108-week extension study of V203-AD multicenter Phase IIa trial.  
Individuals who participated in V203-AD trial will be eligible to join the extension study. 
 
3.1 Description of the Protocol 
The study comprises 3 periods as shown in Table 3.1 (please also see 8.2 Events and Time 
Schedule): 
 An up to 6-week screening period to complete screening visit, 
 A 96-week treatment period, and 
 A 12-week follow-up period. 
 
 
 
 

 
 
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Table 3.1 Clinical Schematic Diagram 
 
 
Screening 
Treatment 
Follow-up 
Visit 
S1 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Week 
-6 ~ -1  
1 
5 
13 
25 
49 
73 
97 
109 
Treatments 
 
 
 
 
 
 
 
 
 
1. For UB-311 treatment groups 
(arm 1 and 2) from V203-AD 
 
↑ 
↑P 
↑P 
 
↑ 
 
↑ 
 
2. For placebo group (arm 3) 
from V203-AD  
 
↑ 
↑ 
↑ 
 
↑ 
 
↑ 
 
↑: UB-311   ↑P: placebo 
 
3.1.1 Screening Period 
Subjects who completed the last injection in V203-AD study at least 24 weeks prior to the V1 of 
this extension study are screened within the screening period (Weeks -6~-1). All tests required for 
evaluating the eligibility of the subjects are performed at S1. If a subject’s last MRI scan in 
V203-AD study is within 3 months before the screening visit of this extension study, an MRI is not 
required for screening. The data of last MRI scan from V203-AD can be used for eligibility/safety 
evaluation in the extension study 
 
3.1.2 Treatment Period 
Subjects meeting all inclusion criteria and presenting no exclusion criteria enter the treatment 
period, from V1 (Week 1) to V7 (Week 97).  
Because the purpose of giving placebo in this extension study is to maintain the blindness of 
V203-AD study, placebo will not be given to subjects after unblinding of V203-AD study. 
 
3.1.3 Follow-up Period  
The follow-up period comprises 1 visit: V8 (Week 109)  
 
3.2 Endpoints 
3.2.1 Primary 
The primary endpoints of this study are:  
• Safety and tolerability of UB-311: incidence of adverse event (AE)/serious adverse event (SAE). 
• The immunogenicity of UB-311 as measured by 
– Change in anti-Aβ antibody levels  
– Response rate (see section 6.1.2 for definition) 
 

 
 
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3.2.2 Secondary 
The secondary endpoints are to measure the treatment effects of UB-311 on: 
 The change in cognitive and global assessments, including: 
 Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) 
 Mini-Mental State Exam (MMSE) 
 Clinical Dementia Rating-Sum of Boxes (CDR-SB)  
 Computerized cognitive tests 
 The change from baseline of V203-AD study in amyloid deposition by 18F-AV-45 PET imaging; 
 
2.2.3 Exploratory 
 Titers of anti-Aβ1-42 monomer and anti-Aβ1-42 oligomer antibodies; 
 The change in qEEG; 
 The change of brain volume and cortical thickness; 
 The change in neurodegenerative biomarkers such as Aβ40, Aβ42, tau, NFH, NFL, GFAP and 
UCHL1; and 
 The correlation between titers of anti-Aβ antibody and anti-measles or anti-HBV antibodies as 
well as memory T cell response for UBITh® 1 and UBITh® 2. 
 
The changes in anti-Aβ antibody levels, cognitive and global assessments, PET, qEEG, brain 
volume and cortical thickness and neurodegenerative biomarkers in blood will be compared 
between the 3 treatment groups from V203-AD study. If subjects agree to provide his/her remaining 
specimens from V203-AD for neurodegenerative biomarkers analysis, the data will be also 
compared from baseline in V203-AD study between 3 treatment groups. 
 
3.3 Description of Blinding Methods 
The UB-311 and placebo vials are indistinguishable by appearance. Knowing which study drug 
(UB-311 or placebo) is given in the second and third injections of the extension study will 
jeopardize the blindness of the V203-AD study, so we will reserve the blindness of the first three 
injections until the end of ongoing V203-AD study. Investigators do not have access to the 
information of randomization code and treatment arm of each subject until the V203-AD study is 
completed except under circumstances described in section 6.4. To maintain the blindness of 
V203-AD study, neither the investigator nor the sponsor will have access to the data that could 
potentially compromise study blindness before the end of V203-AD study. 
 
3.4 Stopping Rules 
The scientific measures of treatment that correspond to early termination are safety. 
In the event of an unexpected and suspected SAE that results in a life-threatening condition or death, 
the principal investigator(s) will assess the relationship between SAE and the study drug according 
to the subject’s clinical symptoms, clinical data, characteristics of the study medicine and safety 

 
 
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endpoints, such as MRI results. If the causality assessment confirms that the SAE is definitely 
related to the study drug, and the Institutional Review Board (IRB) and Department of Health 
(DOH) express consensus opinions, the clinical trial might be stopped. The subject will receive 
immediate clinical treatment for the adverse event and will not receive additional administrations of 
the study medicine. 
After this trial ends, all attempts should be made to follow up all subjects through telephone calls or 
by direct contact, in order to document any delayed or unresolved adverse drug reactions or adverse 
events. 

 
 
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4 SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 Number of Subjects 
Subjects from V203-AD trial (maximum 42 subjects) will be eligible to join this extension study.  
 
4.2 Inclusion Criteria 
For inclusion in the study subjects must fulfil all of the following criteria:  
1. Patients who participated in V203-AD trial without major safety concerns; 
2. The last UB-311/placebo injection received in V203-AD study should be at least 24 weeks 
prior to the V1 of this extension study; 
3. Stable doses of permitted medications for 3 months before screening, such as acetyl 
cholinesterase (AChE) inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonist, ergot 
alkaloids or their derivatives for cognitive enhancement; 
4. Female must either be post-menopausal (no menstrual period for >1 year), surgically sterilized 
or agree to avoid becoming pregnant during the entire period of this study; while sexually 
active fertile male must agree to use effective birth control methods throughout the study 
duration, if their sexual partner(s) are women of childbearing potential; 
5. With a caregiver who has frequent contact with the subject (e.g. an average of 10 hours per 
week or more) and agrees to sign the informed consent form (ICF) and to perform 
study-related AD scales; 
6. Both patient and his/her caregiver should sign the written informed consent before undergoing 
any study procedures; and 
7. Agree not to donate blood or blood products for transfusion during the study and for 3 months 
thereafter. 
 
4.3 Exclusion Criteria 
Any of the following is regarded as a criterion for exclusion from the study:  
1. Clinically significant neurological disease other than Alzheimer’s disease, such as Parkinson’s 
disease, multi-infarct dementia, Huntington’s disease, normal pressure hydrocephalus, brain 
tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, 
or history of significant head trauma followed by persistent neurologic defaults or known 
structural brain abnormalities;  
2. Screening magnetic resonance imaging (MRI) scan with evidence of central nerves system 
(CNS) infection, infarction, or other focal lesions, cerebrovascular disease, superficial 
siderosis, macrohemorrhage, microhemorrhages, multiple lacunes or lacunes in a critical 
memory structure accompanies with symptoms that the investigator determines to be a safety 
concern; 
3. Major depressive episode or manic episode as described in Diagnostic and Statistical Manual 
of Mental Disorders, Fifth Edition (DSM-V) within the past 1 year before screening. Psychotic 

 
 
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features, agitation or behavioural problems within the last 3 months before screening which 
could lead to difficulty in complying with the protocol; 
4. History of schizophrenia (DSM-V criteria);  
5. Any significant systemic illness or unstable medical condition which could lead to difficulty in 
complying with the protocol; 
6. History of alcohol or substance abuse or dependence within the past 2 years before screening 
(DSM-V criteria); 
7. History of autoimmune disease, including but not limited to ankylosing spondylitis, Sjogren’s 
syndrome, systemic lupus erythematosus, rheumatic arthritis, or multiple sclerosis; 
8. History of severe systemic disease that may affect a subject’s participation at the investigator’s 
discretion; 
9. History of anaphylaxis; other serious adverse reactions to any vaccine; or any serious allergic 
reactions to medications requiring treatment; 
10. Use of any prohibited medications within 4 weeks prior to screening; 
11. Use of any investigational drug within 4 weeks before screening; 
12. Previous exposure to any anti-Aβ immunotherapy except UB-311; 
13. History of cancer, including solid tumors and hematological malignancies (except basal cell 
and in situ squamous cell carcinomas of the skin that have been excised and resolved); 
14. Received blood or blood derivatives treatment within 3 months prior to screening; and 
15. Current or recent participation (within 12 months before screening) in any procedures involving 
radioactive agents such that radiation exposure of the subject in any given year would exceed 
the whole-body limits of annual and total dose commitment of 5 rems set forth in the US Code 
of Federal Regulations (CFR) Title 21 section 361.1. 
16. Abnormal clinical laboratory values judged by the investigator to be a safety concern to join the 
study  
 
4.4 Subject Withdrawal Criteria 
A subject may withdraw from the study treatment or the study due to the following reasons: 
1. Lost to follow up. 
2. The subject withdraws consent. 
3. Development of an imaging abnormality consistent with vasogenic edema, macrohemorrhage, 
or an area of superficial siderosis appears or a clinically symptomatic microhemorrhage. 
4. Development of intolerable adverse event due to study treatment as determined by the 
investigator and/or subject. 
5. Development of an intercurrent illness or condition for which the subject requires concomitant 
medications which are not allowed in the study. 
6. Discovery that the subject entered the study in violation of the protocol or occurrence of a 
protocol violation during the study that may affect safety at the investigator’s discretion. 

 
 
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7. Subject’s pregnancy. 
8. Subject’s death. 
9. The investigator feels that in the best interest of the subject’s health, the subject is to be 
withdrawn from the trial. 
10. Data not known before starting the trial become available and raise concern about the safety of 
the study drug such that continuation would pose potential risk to any particular subject. 
 
The type and timing of the data to be collected and follow-up for withdrawn subjects 
When a subject decides to withdraw from the study treatment or the study, he/she should be 
contacted to obtain information about the reason(s) for discontinuation and any adverse events. For 
subjects who withdraw from the study treatment or the study after study drug administration, efforts 
will be made, as appropriate and at discretion of investigator, to have an early termination (ET) visit 
arranged as soon as possible. All study procedures listed in Visit 8/ET (see sections 8.2) should be 
completed at the early termination visit when applicable. In addition, subjects will be encouraged to 
complete all remaining scheduled visits and procedures before the early termination visit. 
If a subject is withdrawn at a scheduled study visit, the early termination visit could be conducted 
on the same day. Besides, in the event of a drop-out after study drug administration, all attempts 
should be made to follow-up the subject through telephone calls or by direct contact until the end of 
this study (Week 109) in order to document any delayed adverse drug reactions or adverse events. 
 

 
 
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5 
TREATMENT OF SUBJECTS 
5.1 Description of Study Drug 
Study drug: UB-311 (UBITh® AD Immunotherapeutic Vaccine), 300 µg per 0.5 mL per vial. 
 
5.2 Dosing Regimens and Rationale 
Eligible subjects will receive total 3 or 5 doses of UB-311 depends on which treatment arm they 
were in V203-AD study. Subjects from placebo treatment group (Arm 3) in V203-AD study will 
receive total 5 doses of UB-311 at weeks 1, 5, 13, 49 and 97. Subjects from UB-311 treatment 
groups (Arm 1 and 2) in V203-AD study will receive total 3 doses of UB-311 at weeks 1, 49 and 97 
and 2 doses of placebo at weeks 5 and 13. Placebo will not be given to subjects after unblinding of 
V203-AD study. 
The long-term safety, tolerability and efficacy of UB-311 will be evaluated during the extension 
study. Considering the requirement of priming doses to elicit comparable anti-Aβ antibody titer, 
subjects from placebo treatment group (Arm 3) in V203-AD study will receive UB-311 at Weeks 5 
and 13 and UB-311 treatment groups (Arm 1 and 2) from V203-AD study will receive placebo at 
Weeks 5 and 13 to avoid unblinding of V203-AD study.  
UB-311/placebo will be given via intramuscular (IM) injection on alternate arms or at different sites, 
which will be recorded. 
 
5.3 Handling of Study Drug 
5.3.1 Packing and Labelling 
The drug is suitably packaged to protect it from alteration, contamination, and damage during 
storage, handling, and shipping. The treatment boxes containing UB-311/placebo are labelled with 
subject’s number, storage condition, and manufacturer and the vials are placed in the order of 
injection. The blindness of the first three injections will be reserved until the end of ongoing 
V203-AD study. 
 
5.3.2 Storage 
The study drugs have to be stored between 2°C and 8°C. The study drugs at each study site must be 
properly stored, under the responsibility of the investigator or the pharmacist in accordance with the 
storage conditions indicated on the label. The monitor should check the storage conditions during 
the monitoring visits. 
 
5.4 Drug Accountability 
The study drugs should be kept in pharmacy of each study site, and be administered to subjects in 
the clinical trial under the responsibility of the investigator. In addition, the investigator should keep 
accurate drug delivery records. Any study drug accidentally or deliberately destroyed should be 
accounted for and documented. Any discrepancies between the amounts dispensed and those 
returned should be explained. 

 
 
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After the end of the study, all used and unused vials of study drug should be packed, sealed, and 
returned to UNS. All remaining study drugs should be destroyed by UNS or its designee. 
 
5.5 Concomitant Medicines 
All concomitant medications should be recorded in the case report form (CRF). 
 
5.5.1 Permitted Medicines 
Permitted medicines/treatments are subject’s routinely used medications or the treatments which are 
judged by the investigator as not to affect the efficacy and safety assessments in the study. 
In addition, the following medications may be permitted: 
 Acetyl cholinesterase inhibitors (donepezil hydrochloride, rivastigmine tartrate, tacrine, 
galantamine); N-methyl-D-aspartate (NMDA) receptor antagonist (memantine); ergot alkaloids 
and their derivatives, must be on stable dose for at least 3 months prior to the screening visit. 
During the study period, subjects may adjust the dose of permitted medicines if determined to be 
needed by the investigators. 
 Ginkgo biloba 
 Piracetam (Nootropil) 
 Vitamin E (≤400 IU/day) 
 
5.5.2 Prohibited Medicines 
The following medications are prohibited within 4 weeks prior to the screening visit and during the 
study period: 
 Antiparkinson’s drugs (e.g. L-dopa, dopamine agonists, amantadine) 
 Neuroleptics, with the exception of haloperidol ≤2 mg/day, quetiapine ≤300 mg/day, risperidone 
≤2 mg/day, sulpiride ≤200 mg/day, and olanzapine ≤10 mg/day 
 Sedative/hypnotics (in exceptional cases where short-acting and intermediate-acting 
benzodiazepines are conditionally allowed, for example, midazolam in oral dosage ≤7.5 mg/day 
for sleep only, midazolam injection ≤5 mg/day for office procedures with sedation only, 
oxazolam ≤10 mg/day, alprazolam ≤1 mg/day, lorazepam ≤1 mg/day, bromazepam ≤12 mg/day 
with maximum starting dose of 1.5 mg, twice a day, estazolam ≤1 mg/day at bedtime for sleep 
only, and other hypnotics such as zolpidem ≤10 mg/day, and zopiclone ≤7.5 mg/day may be 
allowed during the study 
 Antidepressants (e.g. bupropion, imipramine, mirtazapine, nefazodone and trazodone) with the 
exception of selective serotonin reuptake inhibitors (SSRIs), e.g. fluoxetine, paroxetine, 
sertraline, fluvoxamine, escitalopram, citalopram and serotonin-norepinephrine reuptake 
inhibitors (SNRIs), e.g. venlafaxine, duloxetine, milnacipran, desvenlafaxine 
 Heparin or thrombolytic therapy starting from 4-week screening period 

 
 
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 Other treatments, including traditional herbal medicines and nutritional supplements, that may 
disturb the study result at investigator’s discretion 
 
5.6 Subject Compliance 
The compliance to the study treatments will be checked by the investigator and study drug 
administration will be recorded in the CRF. 
 

 
 
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6 
ASSESSMENT OF INVESTIGATIONAL PRODUCT 
6.1 Immunogenicity 
Immunogenicity is evaluated as one of the primary endpoints in this study. 
• Change in anti-Aβ antibody levels till the end of the study (Week 109) 
• Response rate (see section 6.1.2 for definition) 
 
6.1.1 Anti-Aβ antibody measurement 
For the immunogenicity assessment of the investigational product, UB-311, the level of anti-Aβ 
antibodies in the serum samples will be measured by a validated enzyme immunoassay 
manufactured by United Biomedical, Inc. (UBI). 
The level of anti-Aβ antibodies is assessed at every visit throughout the study period from V1 to V8 
except V4 and V6 (Weeks 1, 5, 13, 49, 97 and 109). For visits that UB-311/placebo is scheduled to 
be administrated (V1, V2, V3, V5 and V7), blood samples will be collected before the treatment. 
 
6.1.2 Response rate 
Antibody responder is defined as the study subject whose serum antibody titer is greater than the 
response threshold (see section 9.1.2 for definition) at any visit after V1. Response rate will be 
calculated as the percent of the number of antibody responders versus the total number of subjects. 
 
6.2 Safety 
The study-specific and general safety criteria are described in section 7.1 (Safety Endpoints). 
A patient card, including the relevant “24 hour alert system” telephone number, will be provided to 
every subject who participates in the study. 
 
6.3 Efficacy 
Efficacy variables are evaluated as secondary and exploratory endpoints in this study. 
 
6.3.1 Evaluation variables 
6.3.1.1 The change in cognitive and global assessments till the end of the study (Week 109) 
• Cognition: ADAS-Cog, MMSE and computerized cognitive test 
• Global: CDR-SB 
 
6.3.1.2 The change of amyloid burden in retention of 18F-AV-45  
The data will be expressed by mean regional standard uptake value ratio (SUVR) in the selected 
regions of interests (ROIs). The baseline of V203-AD study will be used to assess the change of 

 
 
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amyloid deposition during the study. 
 
6.3.1.3 The change in qEEG over the period extension study 
The absolute and relative power spectral densities (PSDs) will be calculated for each 1 second 
epoch (1-40 Hz bins), and also grouped into the standard EEG bandwidths: delta, theta, alpha, 
sigma, beta, and gamma. Additionally, the PSD variables will be averaged across brain regions of 
interest, including: frontal, central, parietal, anterior, temporal, and left/right brain regions. Global 
power in each band will be calculated by averaging power values for all channels.  
 
6.3.1.4 The change of brain volume and cortical thickness 
Alzheimer's disease leads to nerve cell death and tissue loss throughout the brain. Over time, the 
brain shrinks dramatically, affecting nearly all its functions. Therefore, the change of brain volume 
and cortical thickness will be evaluated via MRI scans.  
 
6.3.1.5 The change in neurodegenerative biomarkers over the period of extension study 
The concentration of neurodegenerative biomarkers such as Aβ40, Aβ42, tau, NFH, NFL, GFAP and 
UCHL1 will be measured and compared during the study to evaluate their correlation with disease 
progression and treatment efficacy of UB-311. 
 
6.3.1.6 The correlation between titers of anti-Aβ antibody and anti-measles or anti-HBV antibodies 
as well as memory T cell response for UBITh® 1 and UBITh® 2 
The titers of anti-measles and anti-HBV antibodies will be compared to the maximum titer of 
anti-Aβ antibody in subjects to evaluate the possible correlation between the titers of anti-Aβ 
antibody elicited by UB-311 and anti-measles or anti-HBV antibodies in subjects. 
Memory T cell response for UBITh® 1 and UBITh® 2 will be compared with titers of anti-measles 
or anti-HBV antibodies and anti-Aβ antibody. 
 
6.3.2 Efficacy assessment methods 
6.3.2.1 Rating scales 
All scales are rated by an independent clinical psychologist and/or study nurse who has to complete 
the training session specifically designed for this study. 
MMSE, ADAS-Cog and CDR/CDR-SB are evaluated at Weeks 1 (V1), 49 (V5) and 109 (V8). 
Computerized cognitive test is evaluated at Screening, Weeks 1 (V1), 25 (V4), 49 (V5), 73 (V6) 
and 109 (V8). 
 
6.3.2.2 18F-AV-45 retention measurement  
18F-AV-45 PET is conducted at week 97 (V7) to assess the change in amyloid burden over the 
period of V203-AD and the extension study.  

 
 
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In case of scanning failure, re-injection/re-scanning of 18F-AV-45 is allowed. 
 
6.3.2.3 EEG 
EEG is conducted at Screening, Weeks 1 (V1), 25 (V4), 49 (V5), 73 (V6) and 109 (V8). 
Five-minute eyes open and eye closed, the 3-choice vigilance task and the standard image 
recognition task will be performed by trained and certificated clinical personnel. 
 
6.3.2.4 Brain volume and cortical thickness 
The change of brain volume and cortical thickness is assessed by MRI imaging. MRI is scheduled 
at Screening, Week 13 (V3) and Week 97 (V7).  
 
6.3.2.5 Neurodegenerative biomarkers 
The level of different neurodegenerative biomarkers including Aβ40, Aβ42, tau, NFH, NFL, GFAP 
and UCHL1 is measured at Week 1 (V1), Week 49 (V5), Week 97 (V7) and Week 109 (V8). 
 
6.4 Measures to protect blinding of this trial 
In order to protect blinding of V203-AD study while it’s still ongoing, study drugs for this 
extension study will be labelled with individual subject number. In the event that an adverse effect 
is considered serious and related to the study drug, and knowing the assignment is essential for 
treating the subject, the investigator is allowed to contact UNS or CRO to call IVRS/IWRS from 
V203-AD study to obtain the treatment code of that individual subject. If the treatment assignment 
is unblinded, the investigator must notify UNS in writing and document the course of the events in 
the CRF. 
 
 

 
 
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7 
ASSESSMENT OF SAFETY 
7.1 Safety Endpoints 
• 
Local tolerability at the injection site 
• 
Amyloid-related imaging abnormalities (ARIA) including vasogenic edema and/or sulcal 
effusion (ARIA-E) and hemosiderin deposits (ARIA-H), such as microhemorrhage and 
superficial siderosis.  
• 
Other adverse events and serious adverse events 
• 
Vital signs 
• 
Physical examination 
• 
12-lead Electrocardiogram (ECG) 
• 
Laboratory tests: hematology, clinical chemistry, and inflammatory parameters 
 
7.1.1 Local tolerability 
Local tolerability at injection site will be evaluated by the investigator at 30-60 minutes 
post-injection at Weeks 1 (V1), 5 (V2), 13 (V3), 49 (V5) and 97 (V7). The subjects will record 
injection site reactions happening between 1 hour post-injection and 7 days post-injection in the 
patient diary (see Section 7.3). Subjects will be instructed not to rub or otherwise tamper with their 
injection site. 
 
7.1.2 Clinical safety 
Clinical safety will be assessed by physical examination and vital signs (including temperature, 
respiratory rate, heart rate, blood pressure, and body weight) at screening and at every visit 
throughout the study (V1 to V8). Neurology examination and vital signs will be assessed again 
30-60 minutes after study drug injection at Weeks 1 (V1), 5 (V2), 13 (V3), 49 (V5) and 97 (V7). 
   
7.1.3 Adverse event collection 
Adverse events and serious adverse events will be collected from the time of signing informed 
consent form and then at each visit until the end of the study.  
 
7.1.4 ECG 
A 12-lead ECG record is performed at Screening and at Weeks 49 (V5) and 109 (V8). The 12-lead 
ECGs should be performed after at least 10 minutes in supine position. The electrodes are to be 
positioned at the same place for each ECG recording. 
Both traces will be analyzed in comparison with the screening recorded trace at the end of the study. 
The original trace is kept as source data. In the CRF the assessment “normal”, “abnormal-clinically 
significant”, or “abnormal- not clinically significant” as determined by the investigator, is collected.  

 
 
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7.1.5 MRI 
MRI is performed at Screening and at Weeks 13 (V3) and 97 (V7) to monitor ARIA that may be 
induced by amyloid-modifying therapy. If a subject’s last MRI scan in V203-AD study is within 3 
months before the screening visit of this extension study, an MRI is not required for screening. The 
data of last MRI scan from V203-AD can be used for eligibility/safety evaluation in the extension 
study. 
 
7.1.6 Safety laboratory 
The following laboratory data are collected: 
• 
Hematology: complete blood count including differential cell count and absolute neutrophil 
count at Screening, Weeks 1 (V1), 5 (V2), 13 (V3), 49 (V5), 97 (V7) and 109 (V8). 
• 
Clinical chemistry: HbA1c at Screening; glucose AC, AST, ALT, bilirubin, sodium, total 
protein, BUN, creatinine, potassium, and albumin at Screening, Weeks 1 (V1), 5 (V2), 13 (V3), 
49 (V5), 97 (V7) and 109 (V8). 
• 
Inflammatory parameters: CRP and ESR at Screening, and at Weeks 5 (V2), 49 (V5) and 109 
(V8); TNF-α, IL-6, and IL-8 at Weeks 1 (V1), 5 (V2) and 109 (V8). 
For visits during which UB-311 or placebo is scheduled to be administered (V1, V2, V3, V5 and 
V7), blood samples will be collected before the treatment. 
 
7.2  Safety Instructions 
7.2.1 Local tolerability 
In the case where the investigator or the subject recognizes any signs of local intolerability, this 
should be recorded on the AE form in the CRF. 
 
7.2.2 Monitoring of ARIA 
Because vasogenic edema and other amyloid-related imaging abnormalities (ARIA) have been 
reported in clinical trials with multiple therapeutic avenues to lower Aβ burden in AD, subjects 
enrolled in this study will be followed for any suspected vasogenic edema (i.e. with symptoms 
and/or signs of headache, loss of coordination [ataxia], weakness or decreasing levels of 
consciousness) or ARIA. All Principal Investigators should be notified of the possible occurrence of 
ARIAs and the measures to be taken. 
The detailed procedures of MRI are described in a separate imaging manual by a Central Imaging 
Corelab. 
 
7.3 Adverse Events Recording 
During the scheduled visits, adverse events should be collected by means of standard questions (For 
example: Have you had any health problems since the previous visit?). Spontaneously reported 

 
 
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and/or observed adverse events and the responses to the questions should be recorded on the CRF 
with information about the degree of seriousness and any action taken. 
The patient diary will be used to record injection site reactions happening between 1 hour 
post-injection and 7 days post-injection. (Please also refer to the Injection Reaction Plan to acquire 
necessary information).  
All adverse events are to be coded to a “Preferred Term” and primary “System-Organ Class” using 
the Medical Dictionary for Regulatory Activities (MedDRA). AEs are reported and graded using 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 
4.03 or later. 
 
7.4 Adverse Events Monitoring 
Adverse events will be monitored by Contract Research Organization (CRO) based on its 
Monitoring Plan. All events will be managed and reported, and included in the final clinical study 
report.  
 
7.5 Definitions of Adverse Event and Serious Adverse Event 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject during the participation of the study, whether or not considered related to the medicinal 
product. An AE can therefore be any new or exacerbated unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease. The occurrence does not 
necessarily have to have a causal relationship with the treatment. 
A priori, efficacy endpoints as specified in the protocol will not be considered as AEs except if, 
because of the course or severity or any other features of such events, the investigator, according to 
his/her best medical judgment, considers these events as exceptional in this medical condition. 
Unexpected adverse drug experience is defined as any adverse drug experience, the specificity or 
severity of which is not consistent with the current investigator brochure; or, if an investigator 
brochure is not required or available, the specificity or severity of which is not consistent with the 
risk information described in the general investigative plan or elsewhere in the current application, 
as amended. “Unexpected”, as used in this definition, refers to an adverse drug experience that has 
not been previously observed (e.g., included in the investigator’s brochure) rather than from the 
perspective of such experience not being anticipated from the pharmacological properties of the 
pharmaceutical product. 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
 
Results in death or, 
 
Is life-threatening or, 
Note: The term "life-threatening" in the definition of "serious" refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event, which 
hypothetically might have caused death if it were more severe. 
 
Requires inpatient hospitalization or prolongation of existing hospitalization or, 
 
Results in persistent or significant disability/incapacity or, 

 
 
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 
Is a congenital anomaly/birth defect or, 
 
Is a medically important event: 
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. 
 
An adverse event fulfilling any one or more of these criteria should be reported as a serious adverse 
event, irrespective of the dose of drug given, and even if it is the result of an interaction or drug 
abuse. 
A distinction should be drawn between serious and severe adverse events. The term ‘severe’ is often 
used to describe the intensity (severity) of a specific event (as in mild, moderate, or severe 
myocardial infarction); the event itself, however, may be of relatively minor medical significance 
(such as severe headache). This is not the same as ‘serious,’ which is based on subject’s event 
outcome or action criteria usually associated with events that pose a threat to a subject’s life or 
functioning. The seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations. 
 
7.6 Recording and Reporting of Adverse Event 
All AEs and SAEs, regardless of seriousness or relationship to study drug(s), spanning from the 
first visit planned in the Clinical Trial Protocol/signature of the informed consent form up to the last 
(post treatment follow-up) visit, are to be reported and recorded on the corresponding page(s) or 
screen(s) included in the CRF. 
Laboratory, vital signs or ECG abnormalities are to be recorded as Adverse Events only if they are 
medically relevant: symptomatic, requiring corrective treatment, leading to discontinuation and/or 
fulfilling a seriousness criterion. 
The investigator may be asked to provide photocopies of the medical records for completing the AE 
or SAE report. The medical records submitted to the relevant parties will conceal the subjects’ 
names. It is the responsibility of the investigator to report AEs or SAEs by diagnosis terminologies, 
if possible. When the diagnosis is possible for the reported AE or SAE, no signs and symptoms used 
to establish that particular diagnosis should be reported. 
The investigator will be asked to determine the severity and causality of each AE and SAE based on 
the investigator’s clinical judgment. Adverse event reporting begins from date of consent and ended 
on the last day of the study period. The intensity of the AEs is graded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 as follows: 
 
Severity of AE 
Description 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 

 
 
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instrumental activities of daily living (ADL)*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
Activities of Daily Living (ADL): 
*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
**Self care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. 
 
The investigator makes a judgment regarding whether or not the AE is related to study drug, using 
the definitions below. The investigator is to evaluate any changes in laboratory values and make a 
determination as to whether or not the change is clinically important and whether or not the changes 
are related to study drug. However, even if the investigator determines there is no relationship to the 
study drug, the AE or clinically significant laboratory abnormality must still be recorded in the CRF 
along with the investigator’s assessment of relationship as follows: 
Relationship 
Description 
Unrelated 
The AE must definitely have been caused by the subject’s clinical state, or the study 
procedure/conditions (i.e. it had no association with the study drug) 
Unlikely 
The temporal association between the AE and the study drug was such that the study drug 
was not likely to have any reasonable association with AE. 
Possible 
The AE followed a reasonable temporal sequence from the time of drug administration, but 
could have been produced by the subject’s clinical state or the study procedures / conditions. 
Probable 
The AE followed a reasonable temporal sequence from the time of study drug administration, 
abated upon discontinuation of the study drug and could not be reasonably explained by the 
known characteristics of the subject’s clinical state. 
Definite 
The AE followed a reasonable temporal sequence from the time of study drug administration, 
abated upon discontinuation of the study drug and reappeared when the study drug is 
introduced. 
It is usually important for the investigators to take information of underlying diseases, concomitant 
drugs, temporal relationship of the onset of the event to the time of dosing the study medication, 
and re-challenging outcomes, into account when making a causal relation decision. 
It is the investigators’ responsibility to follow proactively the outcome of each AE/SAE until 
resolution or stabilization of the condition or lost of follow-up. 
Whether or not related to the study medication, all SAEs which happen during the study must be 
reported to the sponsor (UNS) and the CRO within the time frame (within 24 hours beginning from 
the investigator's knowledge of the event). 
An Adverse Event Form should be completed for all SAEs and forwarded to the CRO/sponsor 
within 24 hours. When new significant information is obtained as well as when outcome of an event 

 
 
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is known, the investigator should inform the CRO/sponsor. In applicable cases, sponsor may 
request a letter from the investigator summarizing events related to the case. Investigator should 
follow subjects as far as possible until an outcome to the events is known. 
The SAE/SUSAR (Suspected Unexpected Serious Adverse Reaction) will be reported to the 
regulatory authority and the Institutional Review Board (IRB) according to the Good Clinical 
Practice (GCP), regulatory, and IRB requirements. A SUSAR is defined as the SAE with the nature 
and severity of which is not consistent with the applicable product information (e.g., investigator’s 
brochure for an unapproved investigational medicinal product or package insert for an approved 
medicinal product). The investigator is responsible to communicate details of medical emergencies 
in trial subjects to the IRB. In case of a SAE/SUSAR results in death or a life-threatening event, the 
investigator should notify IRB at the assigned institution via a written document as soon as possible 
within 7 days of the initial recognition (followed by completing report within 8 days) and the other 
SAE/SUSARs within 15 days. Sponsor/CRO is responsible to inform the events to the regulatory 
authorities within the same time frame. 
 
7.7 Follow-up 
The investigator should take all appropriate measures to ensure the safety of the subjects; notably 
he/she should follow up the outcome of any AEs (clinical signs, laboratory values or other, etc.) 
until the return to normal or consolidation of the subject's condition. 
In case of any SAE, the subject must be followed up until clinical recovery is complete and 
laboratory results have returned to normal, or until progression has been stabilized. This may imply 
that follow-up will continue after the subject has left the clinical trial. 
In case of any SAE brought to the attention of the investigator at any time after the initiation of 
clinical trial and considered by him/her to be caused by the study drug with a reasonable possibility, 
this should be reported to the sponsor or the sponsor’s delegate within the time frame beginning 
from the investigator's knowledge of the event. 
 
7.8 Obligation of the Sponsor 
During the course of the study, the sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the study drug to the health authorities, IRBs as 
appropriate and to the investigators. 
In addition, the sponsor may report in an expedited manner all SAEs that are expected and at least 
reasonably related to the study drug to the authorities, according to local regulations. 
The sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report (CSR). 

 
 
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8 
STUDY PROCEDURES 
8.1 Study Visits 
The study consists of a screening period (up to 6 weeks), a treatment period (96 weeks) with 7 
visits, and a follow-up period (12 weeks). For V2 (Week 5) and V3 (Week 13), a time frame of ± 3 
days is acceptable using the day of V1 as reference (Day 1), i.e. if one visit date is changed, the next 
visit should take place according to the original schedule. For V4 (Week 25) to V8 (Week 109), a 
time frame of ± 14 days is acceptable using the day of V1 as reference. Out of visit/dosing window 
and missing visit/dose are considered as protocol deviations.  
 
8.1.1 The Screening visit (-42 < Day < -1) 
The Screening visit may take place no more than 42 days prior to V1. The subject receives verbal 
information concerning the aims and methods of the study, its constraints and risks, and the study 
duration. The written informed consent must be signed by the subject, the subject’s caregiver, and 
the investigator prior to any investigations. No screening procedures and assessments can be 
performed until the subject and the caregiver are fully informed of the study and sign the inform 
consent. Subjects, who are diagnosed with a medical condition during the screening process will be 
notified and referred for medical care.  
 
This visit includes: 
• Informed consent from the subject and the study caregiver 
• Inclusion/Exclusion criteria 
• Demographics (age and gender) 
• Complete medical history and concomitant diseases (general medical history: up to 30 days prior 
to screening visit; neurological and psychiatric: within 1 year prior to screening visit; surgery / 
Procedure: within 10 years prior to screening visit; other cancer history: life time base)  
• Concomitant and previous medication (within the last 3 months)  
• Record of AEs and SAEs 
• Physical examination and height 
• Vital signs, including temperature, respiratory rate, heart rate, blood pressure, and body weight 
• Structural MRI scanning (If a subject’s last MRI scan in V203-AD study is within 3 months 
before the screening visit of this extension study, an MRI is not required for screening.) 
• 12-lead ECG 
• Computerized cognitive test (two practices will be performed before the real test) 
• EEG 
• Blood collection for testing of: 
– CRP and ESR 

 
 
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– Clinical chemistry (HbA1c, glucose AC, AST, ALT, bilirubin, sodium, total protein, 
BUN, creatinine, potassium, and albumin) 
– Hematology (complete blood count including differential cell count and absolute 
neutrophil count) 
– Anti-measles and anti-HBV antibodies 
– Memory T cell response for UBITh® 1 and UBITh® 2 
 
8.1.2 Visit 1 (Week 1, Day 1) 
This visit (V1) should be scheduled within 6 weeks after S1 and includes: 
• Verification of Inclusion/Exclusion criteria and check for eligibility 
• Survey instruments 
– MMSE 
– CDR-SB 
– ADAS-Cog 
– Computerized cognitive test 
• EEG 
• Record of AEs and SAEs 
• Record of the use or change of any concomitant medications 
• Physical examination 
• Vital signs, including temperature, respiratory rate, heart rate, blood pressure, and body weight 
• Blood collection for: (before the UB-311 injection) 
– Anti-Aβ, anti-Aβ1-42 monomer and anti-Aβ1-42 oligomer antibodies 
– TNF-α, IL-6, and IL-8 
– Clinical chemistry (glucose AC, AST, ALT, bilirubin, sodium, total protein, BUN, 
creatinine, potassium, and albumin) 
– Hematology (complete blood count including differential cell count and absolute 
neutrophil count) 
– Neurodegenerative biomarkers (Aβ40, Aβ42, tau, NFH, NFL, GFAP and UCHL1) 
• Injecting study drug 
• Injection site assessments, vital signs (except body weight), and neurology examination of 
physical examination 30-60 minutes after injection 
 
8.1.3 Visit 2 (Week 5, Day 29) 

 
 
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This visit (V2) should be scheduled 4 weeks ± 3 days after V1 and includes: 
• Record of AE and SAE 
• Record of the use or change of any concomitant medications 
• Physical examination 
• Vital signs, including temperature, respiratory rate, heart rate, blood pressure, and body weight 
• Blood sampling for: (before the UB-311/placebo injection) 
– Anti-Aβ, anti-Aβ1-42 monomer and anti-Aβ1-42 oligomer antibodies 
– CRP, ESR, TNF-α, IL-6, and IL-8 
– Clinical chemistry (glucose AC, AST, ALT, bilirubin, sodium, total protein, BUN, 
creatinine, potassium, and albumin) 
– Hematology (complete blood count including differential cell count and absolute 
neutrophil count) 
• Injecting study drug 
• Injection site assessments, vital signs (except body weight), and neurology examination of 
physical examination 30-60 minutes after injection 
 
8.1.4 Visit 3 (Week 13, Day 85) 
This visit (V3) should be scheduled 12 weeks ± 3 days after V1 and includes: 
• Structural MRI scanning (should be scheduled < 14 days before the injection of study drug) 
• Record of AEs and SAEs 
• Record of the use or change of any concomitant medications 
• Physical examination 
• Vital signs, including temperature, respiratory rate, heart rate, blood pressure, and body weight 
• Blood collection for: (before the UB-311/placebo injection) 
– Anti-Aβ, anti-Aβ1-42 monomer and anti-Aβ1-42 oligomer antibodies 
– Clinical chemistry (glucose AC, AST, ALT, bilirubin, sodium, total protein, BUN, 
creatinine, potassium, and albumin) 
– Hematology (complete blood count including differential cell count and absolute 
neutrophil count) 
– Anti-measles and anti-HBV antibodies 
– Memory T cell response for UBITh® 1 and UBITh® 2 
• Injecting study drug 
• Injection site assessment, vital signs (except body weight), and neurology examination of 
physical examination 30-60 minutes after injection 

 
 
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8.1.5 Visit 4 (Week 25, Day 169) 
This visit (V4) should be scheduled 24 weeks ± 14 days after V1 and includes: 
• Record of AEs and SAEs 
• Record of the use or change of any concomitant medications 
• Physical examination  
• Vital signs, including temperature, respiratory rate, heart rate, blood pressure, and body weight 
• EEG 
• Computerized cognitive test 
 
8.1.6 Visit 5 (Week 49, Day 337) 
This visit (V5) should be scheduled 48 weeks ± 14 days after V1 and includes: 
• 12-lead ECG 
• Survey instruments 
– MMSE 
– CDR-SB 
– ADAS-Cog 
– Computerized cognitive test 
• EEG 
• Record of AEs and SAEs 
• Record of the use or change of any concomitant medications 
• Physical examination  
• Vital signs, including temperature, respiratory rate, heart rate, blood pressure, and body weight 
• Blood collection for: (before the UB-311 injection) 
– Anti-Aβ, anti-Aβ1-42 monomer and anti-Aβ1-42 oligomer antibodies 
– CRP and ESR 
– Clinical chemistry (glucose AC, AST, ALT, bilirubin, sodium, total protein, BUN, 
creatinine, potassium, and albumin) 
– Hematology (complete blood count including differential cell count and absolute 
neutrophil count) 
– Neurodegenerative biomarkers (Aβ40, Aβ42, tau, NFH, NFL, GFAP and UCHL1) 
• Injecting study drug 

 
 
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• Injection site assessment, vital signs (except body weight), and neurology examination of 
physical examination 30-60 minutes after injection  
 
8.1.7 Visit 6 (Week 73, Day 505) 
This visit (V6) should be scheduled 72 weeks ± 14 days after V1 and includes: 
• Record of AEs and SAEs 
• Record of the use or change of any concomitant medications 
• Physical examination  
• Vital signs, including temperature, respiratory rate, heart rate, blood pressure, and body weight 
• EEG 
• Computerized cognitive test 
 
8.1.8 Visit 7 (Week 97, Day 673) 
This visit (V7) should be scheduled 96 weeks ± 14 days after V1 and includes: 
• Structural MRI scanning (should be scheduled < 14 days before the injection of study drug) 
• 
18F-AV-45 PET scanning (a time frame of ±14 days is acceptable) 
• Record of AEs and SAEs 
• Record of the use or change of any concomitant medications 
• Physical examination  
• Vital signs, including temperature, respiratory rate, heart rate, blood pressure, and body weight 
• Blood sampling for: (before the UB-311 injection) 
– Anti-Aβ, anti-Aβ1-42 monomer and anti-Aβ1-42 oligomer antibodies 
– Clinical chemistry (glucose AC, AST, ALT, bilirubin, sodium, total protein, BUN, 
creatinine, potassium, and albumin) 
– Hematology (complete blood count including differential cell count and absolute 
neutrophil count) 
– Neurodegenerative biomarkers (Aβ40, Aβ42, tau, NFH, NFL, GFAP and UCHL1) 
• Injecting study drug 
• Injection site assessment, vital signs (except body weight), and neurology examination of 
physical examination 30-60 minutes after injection  
 
8.1.9 Visit 8 (Week 109, Day 757) 
This visit (V8) should be scheduled 108 weeks ± 14 days after V1 and includes: 

 
 
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• 12-lead ECG 
• Survey instruments 
– MMSE 
– CDR-SB 
– ADAS-Cog 
– Computerized cognitive test 
• EEG 
• Record of AEs and SAEs 
• Record of the use or change of any concomitant medications 
• Physical examination  
• Vital signs, including temperature, respiratory rate, heart rate, blood pressure, and body weight 
• Blood sampling for: 
– Anti-Aβ, anti-Aβ1-42 monomer and anti-Aβ1-42 oligomer antibodies 
– CRP, ESR, TNF-α, IL-6, and IL-8 
– Clinical chemistry (glucose AC, AST, ALT, bilirubin, sodium, total protein, BUN, 
creatinine, potassium, and albumin) 
– Hematology (complete blood count including differential cell count and absolute 
neutrophil count) 
– Neurodegenerative biomarkers (Aβ40, Aβ42, tau, NFH, NFL, GFAP and UCHL1) 
– Anti-measles and anti-HBV antibodies 
– Memory T cell response for UBITh® 1 and UBITh® 2 
 
 

 
 
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8.2 Events and Time Schedule 
Visit 
S 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8/ET 
Week 
-6~-1 
1/BL 
5 
13 
25 
49 
73 
97 
109/ET 
Day 
-42~-1 
1 
29±3 
85±3 
169±14 337±14 505±14 673±14 
757±14 
Vaccination/injection site 
assessment/ 
Neurology/vital signs1 
 
X 
X 
X 
 
X 
 
X 
 
ICF, medical history & concomitant 
disease, demographics 
X 
 
 
 
 
 
 
 
 
Incl./excl. criteria 
X 
X 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
X 
 
 
X 
MRI2 
X 
 
 
X 
 
 
 
X 
X** 
18F-AV-45 PET3 
 
 
 
 
 
 
 
X 
X** 
MMSE, CDR-SB and ADAS-Cog 
 
X 
 
 
 
X 
 
 
X 
Computerized cognitive test 
X 
X 
 
 
X 
X 
X 
 
X 
EEG 
X 
X 
 
 
X 
X 
X 
 
X 
AE/SAE 
X 
X 
X 
X  
X 
X 
X 
X 
X 
Previous and concomitant 
medicines 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PE4/vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-Measles antibody 
X 
 
 
X* 
 
 
 
 
X 
Anti-HBV surface antibody 
X 
 
 
X* 
 
 
 
 
X 
Memory T cell response test  
X 
 
 
X* 
 
 
 
 
X 
Clinical chemistry & hematology5 
X 
X* 
X* 
X* 
 
X* 
 
X* 
X 
Inflammatory6 
X 
X* 
X* 
 
 
X* 
 
 
X 
Anti-Aβ Ab level in serum 
 
X* 
X* 
X* 
 
X* 
 
X* 
X 
Anti-Aβ1-42 monomer & oligomer 
Antibodies 
 
X* 
X* 
X* 
 
X* 
 
X* 
X 
Neurodegenerative biomarkers 
(Aβ40, Aβ42, Tau, NFL, NFH, GFAP 
and UCHL1) 
 
X* 
 
 
 
X* 
 
X* 
X 
 
BL=baseline; ET=early termination; MRI=structure MRI 
1. 30-60 minutes after injection. Vital sign: not need to measure body weight. 
2. If a subject’s last MRI scan in V203-AD study is within 3 months before the screening visit of this extension study, an MRI is 
not required for screening. The data of last MRI scan from V203-AD can be used for eligibility/safety evaluation in the 
extension study. For V3 (Week 13) and V7 (Week 97), MRI should be scheduled <14 days before the injection of study drug.  
3. A time frame of ±14 days is acceptable for 18F-AV-45 PET scan. 
4. Including height (for S1 only) 
5. Clinical chemistry: HbA1c (for S1 only), glucose AC, AST, ALT, bilirubin, sodium, total protein, BUN, creatinine, potassium, 
and albumin at S1 and every visit throughout the study (V1 to V8); Hematology: complete blood count including differential 
cell count and ANC at S1and every visit throughout the study (V1 to V8). 
6. Inflammatory parameters: CRP and ESR: for S1, V2 (Week 5), V5 (Week 49) and V8 (Week 109); TNF-α, IL-6, and IL-8: for 
V1 (Week 1), V2 (Week 5) and V8 (Week 109). 
 
* 
 Blood specimens should be drawn before the UB-311/Placebo injection. 
**  For early termination visit only. 

 
 
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8.3 Blood Sample Collection 
For visits that UB-311 or placebo is scheduled to be administrated (V1, V2, V3, V5and V7), blood 
samples will be collected before the treatment. 
At Screening, V1, V2, V3, V5, V7 and V8/ET, different amount of blood will be collected in plain 
tube, SST II tube, NaF tube, EDTA or heparin tube. The details are described in the central 
laboratory’s handbook. 

 
 
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9 
STATISTICS 
The material of this section is the basis for the Statistical Analysis Plan (SAP) for the study. The 
SAP may be revised during the study to accommodate Clinical Trial Protocol amendments and to 
make changes to adapt to unexpected issues in study execution and data that may affect planned 
analyses. 
 
9.1 Analysis Variables 
9.1.1 Demographic and baseline characteristics 
The baseline value is defined as the last available value before the first injection of UB-311 in the 
extension study. 
Demographic characteristics are defined as follows: 
• 
Age (in years) to be derived as: (date of informed consent - date of birth)/365.25 
• 
Gender (male/female) 
• 
Body weight (kg) 
• 
Body Mass Index (BMI, kg/m2): weight in kg/(height in meters)2 
Disease characteristics including: 
• 
Disease duration (years): (date of informed consent – date of diagnosis)/365.25 
• 
Baseline scores of MMSE, CDR-SB, ADAS-Cog and computerized cognitive test 
 
Physical examination, medical history and concomitant disease, and previous and concomitant 
medication will be described at baseline. 
The baseline safety data of clinical chemistry and hematology, CRP, ESR, TNF-α, IL-6, IL-8, and 
number of microhemorrhages in the brain will also be summarized.   
 
9.1.2 Immunogenicity variables 
The level of anti-Aβ antibodies is one of the primary endpoints and is assessed at Week 1 (V1), 
Week 5 (V2), Week 13 (V3), Week 49 (V5), Week 97 (V7) and Week 109 (V8). The one-sided 
95% confidence interval (CI, right side) from all visits (V1 to V13) for subjects in Arm 3 (placebo 
group) of V203-AD study will be calculated as the threshold of response. Antibody responders will 
be defined as the subjects with serum antibody titer > response threshold at any visit after first 
injection of UB-311.  
 
9.1.3 Efficacy variables 
9.1.3.1 Rating scales 
MMSE, CDR-SB and ADAS-Cog are rated at Week 1 (V1), Week 49 (V5) and Week 109 (V8), 
while computerized cognitive test is assessed at the Screening visit, Week 1 (V1), Week 25 (V4), 

 
 
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Week 49 (V5), Week 73 (V6) and Week 109 (V8). Although the scores of two practices of 
computerized cognitive test at screening will be recorded, only the score of the real test will be used 
for data analysis. If a patient withdraws from the study prematurely during the study period or does 
not have any or some of the scores, the data will be treated as missing values, and no procedure for 
handling missing assessments will be applied.  
 
9.1.3.2 18F-AV-45 retention 
18F-AV-45 PET scanning is performed within ±14 days of V7 date. No procedure for handling 
missing assessments will be applied if there is a missing value. 
 
9.1.4 Safety variables 
The safety analysis will be based on the reported adverse events and other safety information 
including: 
• 
Local tolerability at injection site 
• 
Amyloid-related imaging abnormalities (ARIA) including vasogenic edema and/or sulcal 
effusion (ARIA-E) and hemosiderin deposits (ARIA-H), including microhemorrhage and 
superficial siderosis  
• 
Vital signs 
• 
Physical examination 
• 
12-lead ECG 
• 
Laboratory tests: hematology, clinical chemistry (glucose AC, AST, ALT, bilirubin, sodium, 
total protein, BUN, creatinine, potassium, and albumin), and inflammatory parameters (CRP, 
ESR, TNF-α, IL-6, and IL-8) 
 
9.2 Analysis Populations 
9.2.1 Efficacy populations 
The analyses of immunogenicity and efficacy endpoints will be performed by the treatment 
allocation and based on the modified intention-to-treat and per-protocol populations described 
below. 
Modified intention-to-treat (mITT) population: all subjects who receive at least one dose of the 
study drug, and have both baseline and at least one post-baseline assessment in any of the primary 
or secondary variables, irrespective of compliance with the study protocol and procedures. 
Per-protocol (PP) population: subjects who receive all planned doses of the study drug, complete 
the treatment period, fulfil all entry criteria, and have no key protocol deviation. 
 
9.2.2 Safety population 

 
 
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The safety population is the total treated population defined as all subjects exposed to at least one 
dose of the study drug, regardless of the amount of treatment administered.  
Safety endpoints and tolerability will be analyzed based on the safety population. 
 
9.2.3 Disposition of subjects 
The total number of subjects for each of the following categories will be presented in the clinical 
study report (CSR). 
• 
Screened subjects: all patients who have signed the inform consent 
• 
Enrolled subjects: subjects who are enrolled in the extension study 
• 
The safety population (as defined in Section 9.2.2) 
• 
The mITT population (as defined in Section 9.2.1) 
• 
The PP population (as defined in Section 9.2.1) 
 
A list of subjects prematurely withdrawn from the study, along with reasons for discontinuation, 
will be provided. 
 
9.3 Statistical Methods 
Continuous data will be summarized using the number of observations available (n), mean, standard 
deviation (SD), median, interquartile range (IQR), minimum, and maximum. 
Categorical data will be summarized using count and percentage. Missing data will not be 
categorized in the summaries. 
In general, descriptive statistics of quantitative efficacy and safety parameters (results and changes 
from baseline) by scheduled visit will be provided on observed cases, i.e. the inclusion of only 
subjects with non-missing assessments at a specific visit.  
All statistical tests will be two-sided at the alpha level of 0.05. 
 
9.3.1 Demographic and baseline characteristics 
9.3.1.1 Subject demographic characteristics, medical history and diagnoses 
Descriptive statistics will be used to summarize the demographic, baseline characteristics data and 
medical history for the safety population to describe the study population. 
Pathologies associated with past medical and surgical history will be classified into primary system 
organ classes and preferred terms using MedDRA and will be summarized using counts and 
percentages. The primary system organ classes and preferred terms will be sorted in decreasing 
order of frequency. 
 
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Medications will be classified into the following two groups: 
• 
Previous medications are those that the subject took within 3 months period prior to the 
Screening visit and prior to the first administration of UB-311 at Week 1 (V1). 
• 
Concomitant medications are those that the subject continued or started on or after the first 
injection of the study drug up to the end of the study. 
These medications will be classified into anatomic and therapeutic classes using the World Health 
Organization (WHO) Drug Dictionary. Subject will only be counted once within each anatomic and 
therapeutic class. 
Descriptive statistics including number of subjects and percentage will be provided.  
 
9.3.2 Treatment tolerability and compliance 
The overall treatment tolerability of UB-311 is defined as the percentage of number of administered 
doses divided by number of administered doses plus number of missed doses of subject(s) who 
drops out due to drug-related AE(s). It is calculated according to the following formula: 
100% x (A+B1+C+D) / (A+B1+B2+C+D) 
where  
A: number of administered doses of completers 
B1: number of administered doses of subject(s) who drops out due to drug-related AE(s) 
B2: number of missed doses of subject(s) who drops out due to drug-related AE(s) 
C: number of administered doses of subject(s) who drops out due to drug-unrelated AE(s) 
D: number of administered doses of subject(s) who drops out not due to AE(s) 
 
The overall compliance is defined as the actual dose (UB-311 or placebo) of injection compared to 
the prescribed dose of treatment during the study. It is calculated according to the following 
formula: 
100% x (Actual injection dose/Prescribed injection dose) 
 
9.3.3 Analysis of immunogenicity variable 
Immunogenicity analyses will be performed on the mITT and PP populations. The change in 
antibody level will be analyzed by a repeated-measures mixed-effects model.  
 
9.3.4 Analysis of efficacy variables 
Efficacy analyses will be performed on the mITT and PP populations. Descriptive statistics will be 
provided for all continuous variables at the scheduled visits. Continuous variables with repeated 
measures will be analyzed using a mixed-effects model. 
 
9.3.5 Analysis of safety data 

 
 
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The review of safety and tolerance will be performed on the safety population as defined in section 
9.3.2 Safety Population. 
The observation period will be divided into 2 segments: pre-treatment and post-treatment. 
• 
The pre-treatment period is defined as the time from the date of the informed consent to the 
time before the administration of first dose of UB-311 in the extension study. 
• 
The post-treatment period is defined as the time from after the first dose of UB-311 to the end 
of the study. 
 
9.3.5.1 Analysis of adverse event 
Pre-treatment AEs are defined as AEs that develop or worsen or become serious during the 
pre-treatment period. 
Treatment-emergent AEs (TEAEs) are defined as AEs that develop or worsen (according to the 
investigator’s judgement) or become serious during the post-treatment period. 
The primary focus of adverse event reporting in the CSR will be TEAEs. Pre-treatment AEs will be 
described separately. 
 
All adverse events 
All adverse events are to be coded to a “Preferred Term” and primary “System-organ Class” using 
the Medical Dictionary for Regulatory Activities (MedDRA).  
Summaries of all TEAEs will include: 
• 
The overview of AEs, summarizing number (%) of subjects with any TEAE/serious TEAE. 
• 
The number and percentage of subjects with at least one TEAE by System-organ Class and 
Preferred Term. 
• 
Summary of TEAEs by intensity (Grades 1 to 5), presented by System-organ Class and 
Preferred Term. 
• 
Summary of TEAEs by causal relationship to the study drug, by System-organ Class and 
Preferred Term. 
 
Serious adverse events 
Serious TEAEs will be summarized and presented as number and percent of subjects in the study. 
 
Adverse events leading to treatment discontinuation 
TEAEs leading to treatment discontinuation will be summarized and presented as number and 
percentage of subjects in the study. 
 

 
 
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Local tolerability at injection site 
The number and percentage of subjects with reaction at injection site will be summarized and 
presented. 
 
Vasogenic brain edema and amyloid imaging related abnormalities  
The number and percentage of subjects with amyloid-related imaging abnormalities (ARIA) will be 
summarized and presented. 
 
9.3.5.2 Analysis of laboratory variables 
The summaries will include subjects in the safety population who have at least one laboratory test 
performed during the post-treatment period and, when required by the definition of the abnormality, 
with an available baseline value and available laboratory normal ranges. For those descriptions, the 
baseline value will be the last available measure before the first UB-311 injection. 
Clinical laboratory values will be converted to standard international units. Descriptive statistics 
will be used to summarize the laboratory results and the changes from baseline by scheduled visit. 
 
9.3.5.3 Analysis of vital sign variables 
The summaries will include subjects in the safety population who have at least one parameter to be 
analyzed during the post-treatment period. Descriptive statistics will be used to summarize the 
results and the changes from baseline value by scheduled visit. 
 
9.3.5.4 Analysis of 12-lead ECG status 
Only ECG status (i.e. normal or abnormal (clinically significant or not clinically significant)) will 
be reported.  
 
9.3.5.5 Reason for withdrawal 
Reason for withdrawal will be tabulated.  
 
 
 

 
 
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10  QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Responsibility of the Investigator(s) 
The Investigator(s) undertake(s) to perform the clinical trial in accordance with this clinical trial 
protocol, International Conference on Harmonisation (ICH) guidelines for Good Clinical Practice 
(GCP) and the applicable regulatory requirements. 
The investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the sponsor (including security rules). The 
investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by sponsor representatives. 
If any circuit includes transfer of data, particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The investigator may appoint such other individuals, as he/she may deem appropriate as co- 
investigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All co-investigators shall be appointed and listed in a timely manner. The co-investigators 
will be supervised by and work under the responsibility of the Investigator. The investigator will 
provide them with a copy of the clinical trial protocol and all necessary information. 
 
10.2 Responsibility of the Sponsor 
The sponsor of this clinical trial is responsible to health authorities for taking all reasonable steps to 
ensure the proper conduct of the clinical trial protocol as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the case report forms. Thus, the main 
duty of the sponsor or sponsor’s delegate is to help the investigator and the sponsor maintain a high 
level of ethical, scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the sponsor or sponsor’s delegate to review study 
progress, investigator and subject compliance with clinical trial protocol requirements and any 
emergent problems. These monitoring visits will include but are not limited to review of the 
following aspects: subject informed consent, subject recruitment and follow-up, SAE 
documentation and reporting, AE documentation, study drug allocation, subject compliance with 
the study drug regimen, study drug accountability, concomitant therapy use and quality of data. 
 
10.3 Source Document Requirements 
According to the ICH guidelines for GCP, the sponsor or sponsor’s delegate must check the case 
report form (CRF) entries against the source documents, except for the pre-identified source data 
directly recorded in the CRF. The informed consent form will include a statement by which the 
patient allows the sponsor’s duly authorized personnel, the independent ethics committee 
(IRB/IEC), and the regulatory authorities to have direct access to original medical records which 
support the data on the CRF (eg, subject's medical file, appointment books, original laboratory 
records, etc.). These personnel, bound by professional secrecy, must maintain the confidentiality of 
all personal identity or personal medical information (according to confidentiality rules). 

 
 
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10.4 Use and Completion of Case Report Forms (CRFs) and Additional Request 
It is the responsibility of the investigator to maintain adequate and accurate CRFs (according to the 
technology used) designed by the sponsor to record (according to sponsor instructions) all 
observations and other data pertinent to the clinical investigation. All CRFs should be completed in 
their entirety in a neat, legible manner to ensure accurate interpretation of data. Should a correction 
be made, the correction will be recorded in the CRF. An audit trail will allow to identify the 
modification. 
 
 
 

 
 
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11 ETHICS 
11.1 Declaration of Helsinki and Ethical Review 
The study will be performed in accordance with the principles stated in the Declaration of Helsinki. 
The institutional review board (IRB) must approve the study protocol and informed consent form 
before the enrollment of subjects. The views of the IRB should be dated and filed. The names and 
titles of those who attend the IRB meeting should be attached. After receiving the approval letter 
from the IRB, the investigators have the responsibility to forward the copy of the approved letter to 
UNS before the commencement of the clinical trial. 
The investigator is responsible for informing the IRB of any serious adverse events and/or major 
amendments to the protocol as per local requirements. The investigator should file all 
correspondence with the IRB.  
 
11.2 Patient Information and Consent 
The investigator will ensure that the subject and his/her caregiver (must be a family member) are 
given full and adequate verbal and written information about the nature, purpose, possible risk and 
benefit of the clinical trial. Subjects and their caregivers must also be informed that they are free to 
discontinue their participation in the clinical trial at any time. The investigator must see the signed 
informed consent before enrolment. 
The subjects should have a copy of the ICF. If any modifications are to be made according to local 
requirements, the new version must be approved by UNS and IRB as well. 
 
11.3 Patient Data Protection 
In the CRFs, all patients should be identified by number, initials, date of birth and sex. The 
investigator is responsible for keeping a name list of all patients including patients’ numbers, full 
names and last known address. 
The subjects will be informed in ICF about the possibility of audits by authorized representatives of 
the UNS and/or regulatory authorities in which case a review of those parts of the hospital records 
relevant to the study may be required. However, the investigator will follow all applicable privacy 
laws in order to protect a subject’s privacy and confidentiality. 

 
 
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12 DATA HANDLING AND RECORD KEEPING 
12.1 Data Management 
The monitor and the investigator will ensure that the data are correctly and legibly recorded on the 
CRF. Monitors are responsible for the data editing. All data should be verified before data 
management. Any corrections should be verified and recorded by the investigator. 
The sponsor or its delegate will be responsible for data management of the trial. The responsibilities 
include database setup, entry screen generation, data entry and verification, data query/resolution, 
data cleanup, and data lock. Database will be converted into SAS dataset for statistical analysis. 
 
12.2 Record Retention in Study Sites 
The investigator must maintain all confidential study documentation, and take measures to prevent 
accidental or premature destruction of these documents. 
It is recommended that the investigator retain the study documents at least 2 years after the approval 
of a marketing application or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the study drug. 
However, applicable regulatory requirements should be taken into account in the event that a longer 
period is required. 
The investigator must notify the sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the investigator shall inform the sponsor and the relevant records shall be transferred to a mutually 
agreed upon designee. 

 
 
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13 
FINANCING AND INSURANCE 
The sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. The 
insurance of the sponsor does not relieve the investigator and the collaborators from maintaining 
their own liability insurance policy. An insurance certificate will be provided to the IRB or health 
authorities in countries requiring this document. 

 
 
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14 
PUBLICATION POLICY 
UNS follows local regulatory requirements relating to clinical trial registration and disclosure of 
results.  
UNS commits to seek publication of results of its completed applicable clinical trials on any 
marketed product in the peer-reviewed scientific literature, regardless of trial outcome. UNS 
supports recognized standards concerning authorship and publication.  
UNS will provide final statistical reports of protocol-derived outcomes to external authors. UNS 
reserves the right to review and comment on draft abstracts, manuscripts, presentations and other 
communications by external investigators regarding UNS-sponsored trials, prior to submission or 
public disclosure, in order to protect intellectual property and confidential information. As study 
sponsor, UNS does not approve or veto such publications.  
 

 
 
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15 
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