Conditions: Alzheimer's Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 43
Healthy volunteers: no

Brief summary:
The purpose of this Phase IIa study is to determine whether the AD Immunotherapeutic Vaccine (UB-311), targeting the amyloid beta peptide (N-terminal amino acids, 1-14), is safe and immunogenic in mild AD patients. In addition, the efficacy profiles will be evaluated as the secondary endpoint.

Detailed description:

Arms:
arm 1: Subjects will receive 7 doses of UB-311. arm 2: Subjects will receive 5 doses of UB-311 and 2 doses of placebo. arm 3: Subjects will receive 7 doses of placebo.

Interventions: intervention 1: UB-311 intervention 2: Placebo
Intervention descriptions: intervention 1: Intramuscular injection intervention 2: Intramuscular injection

Protocol document:
SAP_002.pdf: 
 
ICON Study Number: 3262-0001 
Page 1 of 21 
             Statistical Analysis Plan Version 4.0 Final 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
A Randomized, Double-blind, Placebo-controlled, 3-arm Parallel-group, 
Multicenter, Phase IIa Study to Evaluate the Safety, Tolerability, 
Immunogenicity, and Efficacy of UBITh® AD Immunotherapeutic 
Vaccine (UB-311) in Patients with Mild Alzheimer’s Disease 
 
 
 
 
 
 
Protocol Number: 
V203-AD 
Confidential 
Version: v4.0 Final 
Date: 31Oct2018 
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 exception. 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation or  
special term 
Explanation 
Aβ 
Amyloid β 
AD 
Alzheimer’s Disease 
ADAS-Cog 
Alzheimer’s Disease Assessment Scale-Cognitive Subscale 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study-Activities of Daily Living 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANOVA 
Analysis of Variance 
ARIA 
Amyloid-Related Imaging Abnormality 
ARIA-E 
Amyloid-related Imaging Abnormalities: Vasogenic Edema and/or 
Sulcal Effusion 
ARIA-H 
Amyloid-related Imaging Abnormalities: Microhemorrhage and 
Superficial Siderosis 
ARWMC 
Age-Related White Matter Changes 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
BUN 
Blood Urine Nitrogen 
BW 
Body Weight 
CDR 
Clinical Dementia Rating 
CDR-SB 
Clinical Dementia Rating-Sum of Boxes 
CI 
Confidence Interval 
CM 
Concomitant medicines 
CRP 
C-reactive Protein 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ESR 
Erythrocyte Sedimentation Rate 
HbA1c 
Glycosylated Hemoglobin 
HBsAg 
Hepatitis B Surface Antigen 
HIS 
Hachinski Ischemic Score 
IL 
Interleukin 
IL-6 
Interleukin-6 
IL-8 
Interleukin-8 
IMI 
ICON medical imaging 
IQR 
Interquartile Range 
IVRS/IWRS 
Interactive Voice/Web Response System 
kg 
Kilogram 
m 
Meter 


 
 
 
 
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mcg, µg 
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Miligram 
mITT 
Modified Intention-to-treat 
Min 
Minimum 
Max 
Maximum 
MMRM 
Mixed Model Repeated Measures 
mL 
Mililiter 
mm 
Milimeter 
MMSE 
Mini Mental State Examination 
n 
Number of Observations Available 
NPI 
Neuropsychiatric Inventory 
PET 
Positron Emission Tomography 
PP 
Per-protocol 
PVM 
Post-vaccine meningoencephalitis 
ROI 
Region of Interest 
S 
Screening 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SUVR 
Standard Uptake Value Ratio 
TEAE 
Treatment-emergent Adverse Event 
TNF-α 
Tumor necrosis factor-alpha 
UNS 
United Neuroscience Ltd. 
V 
Visit 
W 
Week 
WBC 
White Blood Cells 
WHO 
World Health Organization 


 
 
 
 
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AMENDMENT HISTORY 
 
Date 
Brief description of change 
03Jun2016 
Update per sponsor’s review comments. 
02Jul2018 
Update per sponsor’s review comments. 
07Jul2018 
Update per sponsor’s review comments. 
05Sep2018 
Update per sponsor’s review comments. 
12Oct2018 
Delete Center from mixed-effects model in section 5.9  
29Oct2018 
Add the words for “sensitivity analyses” in section 6 


 
 
 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..................................................................................................... 3 
TABLE OF CONTENTS ............................................................................................................ 6 
 
INTRODUCTION ......................................................................................................... 8 
1
 
STUDY OBJECTIVES AND ENDPOINTS................................................................. 8 
2
 
Primary Objectives ........................................................................................... 8 
2.1
 
Secondary Objectives ....................................................................................... 8 
2.2
 
Primary Endpoint(s) ......................................................................................... 8 
2.3
 
Secondary Endpoint(s) ..................................................................................... 8 
2.4
 
Exploratory Endpoints ...................................................................................... 9 
2.5
 
STUDY DESIGN .......................................................................................................... 9 
3
 
ANALYSIS VARIABLES ............................................................................................ 9 
4
 
Demographic and Baseline Characteristics ...................................................... 9 
4.1
 
Immunogenicity Variables ............................................................................. 10 
4.2
 
Efficacy Variables .......................................................................................... 10 
4.3
4.3.1 
SUVR Composite ...................................................................................... 11 
4.3.2 
Semi-Quantitative Visual Assessment ....................................................... 11 
4.3.3 
Regional SUVR ......................................................................................... 11 
 
Safety Variables.............................................................................................. 11 
4.4
 
STATISTICAL METHODS ........................................................................................ 12 
5
 
General ........................................................................................................... 12 
5.1
 
Handling of Dropouts or Missing Data .......................................................... 12 
5.2
 
Analysis Populations ...................................................................................... 14 
5.3
5.3.1 
Efficacy populations .................................................................................. 14 
5.3.2 
Safety population ....................................................................................... 14 
5.3.3 
Subgroups .................................................................................................. 14 
 
Protocol Deviation Reporting ......................................................................... 14 
5.4
 
Patient Disposition.......................................................................................... 15 
5.5
 
Enrollment by Site .......................................................................................... 15 
5.6
 
Subject Demographics and Baseline Characteristics ..................................... 15 
5.7
5.7.1 
Subject Demographic Characteristics, Medical History and Diagnoses .... 15 
5.7.2 
Physical Examination ................................................................................ 15 
5.7.3 
Medical History and Surgery History ........................................................ 15 
5.7.4 
Previous and Concomitant Medications/Therapy ...................................... 15 
5.7.5 
Baseline Efficacy and Safety Data ............................................................. 16 
 
Treatment Tolerability and Compliance ......................................................... 16 
5.8
 
Analysis of Immunogenicity Variable ............................................................ 16 
5.9
 
Analysis of Efficacy Data ............................................................................... 17 
5.10
 
Subgroup Analysis of Immunogenicity/Efficacy Data................................... 18 
5.11
 
Analysis of Safety Data .................................................................................. 18 
5.12


 
 
 
 
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5.12.1 
General ....................................................................................................... 18 
5.12.2 
Adverse Events .......................................................................................... 18 
5.12.3 
Clinical Laboratory Assessments ............................................................... 18 
5.12.4 
Vital Signs ................................................................................................. 19 
5.12.5 
12-lead ECG Status .................................................................................... 19 
5.12.6 
Imaging-Related Safety Endpoint .............................................................. 19 
 
Sample Size .................................................................................................... 20 
5.13
 
Interim Analysis ............................................................................................. 20 
5.14
 
Multiplicity ..................................................................................................... 20 
5.15
 
General Conventions for Tables, Listings and Figures .................................. 20 
5.16
 
CHANGES FROM THE PROTOCOL TO THIS SAP ............................................... 21 
6
 
 
 
 


 
 
 
 
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INTRODUCTION 
1
This statistical analysis plan (SAP) is consistent with the statistical methods section of the final 
study protocol (Version 5.0, dated 28Nov 2017) and includes additional detail of efficacy, and 
safety summaries to be included in the clinical study report (CSR). 
Specifically, this document will: 
1. 
Briefly review the objectives, design and endpoints of the study 
2. 
Define the analysis populations 
3. 
Define the rules for determining the outcome of the endpoints 
4. 
Provide an overview of the planned primary and secondary statistical analyses. 
The planned analyses identified in this SAP will be included in regulatory submission and/or 
future manuscripts. Any post-hoc, or unplanned analyses will be clearly identified in the respective 
CSR. The reader of this SAP is encouraged to also read the clinical protocol for details on conduct 
of this study, and the operational aspects of clinical assessments and timing for completing a 
subject in this study. 
 
STUDY OBJECTIVES AND ENDPOINTS 
2
 
Primary Objectives 
2.1
The primary objectives of this study are to assess the safety and tolerability of two regimens of 
UB-311, and to evaluate the immunogenicity of two regimens of UB-311 through measurement of 
anti-Aβ antibodies. 
 
Secondary Objectives 
2.2
The secondary objectives are to evaluate the effects of UB-311 on the changes of cognitive and 
functional performance over a period of 78 weeks, and to investigate whether UB-311 
treatment results in changes in amyloid deposition in vivo by 18F-AV-45 PET imaging. 
 
Primary Endpoint(s) 
2.3
The primary endpoints of this study are: 
 
Safety and tolerability of UB-311 during the study period. 
 
The immunogenicity of UB-311 as measured by 
o 
Change from baseline in anti-Aβ antibody levels by the end of study.  
o 
Response rate. 
 
Secondary Endpoint(s) 
2.4
The secondary endpoints are: 
 
The change from baseline in cognitive, functional, and global assessments by the end of 
study, including: 
o Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog)  
o Mini-Mental State Exam (MMSE) 
o Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL)  


 
 
 
 
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o Clinical Dementia Rating-Sum of Boxes (CDR-SB) 
o Neuropsychiatric Inventory (NPI) 
 
The change from baseline in amyloid deposition by the end of study, including: 
o Mean standard uptake value ratio (SUVR), a composite summary of selected brain 
regions by the end of study 
o Whole brain amyloid burden (positive or negative) determined by visual assessment 
 
Exploratory Endpoints  
2.5
 
The change of standard uptake value ratio (SUVR) by region by the end of study. 
 
AUC of anti-Aβ antibody levels by the end of study. 
 
STUDY DESIGN 
3
This is a 78-week, multicenter, randomized, double-blind, placebo-controlled Phase IIa study. 
Eligible subjects, 60 years or older with mild Alzheimer’s disease (AD), will be further screened 
by 18F-AV-45 PET scan for the presence of amyloid deposition. 
Enrolled subjects will be randomized into one of the 3 treatment arms in 1:1:1 ratio. Subjects 
assigned to Arm 1 will receive 7 doses of UB-311 at Weeks 0, 4, 12, 24, 36, 48, and 60. 
Subjects assigned to Arm 2 will receive 5 doses of UB-311 at Weeks 0, 4, 12, 36, and 60, and 
placebo at Weeks 24 and 48. Subjects assigned to Arm 3 will receive placebo at Weeks 0, 4, 12, 
24, 36, 48, and 60. Subjects will be followed until Week 78. Subjects enrolled in the Phase I trial 
with UB-311 will be excluded from the Phase IIa trial. 
 
ANALYSIS VARIABLES 
4
 
Demographic and Baseline Characteristics 
4.1
The baseline value is defined as the last available value before the first injection of study drug. The 
following demographic and baseline disease characteristics will be summarized by treatment, by 
study center and overall for the randomized and treated population. 
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 
 
Race 
Disease characteristics including: 
 
Disease duration (years): (date of informed consent– date of diagnosis)/365.25 
 
APOE genotype 
 
Baseline scores of ADAS-Cog total score, MMSE total score, ADCS-ADL total score, 
CDR/CDR-SB total score, NPI total score 
Inflammatory markers including: 


 
 
 
 
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 
CRP 
 
ESR 
 
TNF-α 
 
IL-6 
 
IL-8 
Physical examination, medical history and concomitant disease, previous and concomitant 
medication, and HIS score will be described at baseline. 
The baseline safety data of clinical chemistry and hematology, inflammatory markers and number 
of microhemorrhages in the brain will also be summarized. 
 
Immunogenicity Variables 
4.2
The level of anti-Aβ antibodies is one of the primary endpoints and is assessed at baseline (V1) 
and every following visit (V2 to V13). The one-sided 95% confidence interval (CI, right side) from 
all visits (V1 to V13) for subjects in Arm 3 (placebo group) 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 baseline. 
Response rate, treatment difference and its 90% CI will be calculated. 
The AUC of anti-Aβ antibodies will be served as exploratory endpoint. AUC will be calculated by 
the sum of individual trapezoid area under the curve of level of Aβ antibodies. In case of missing 
titer values, last observation carry forward will be used for AUC calculation. 
 
Efficacy Variables 
4.3
Efficacy variables are evaluated as secondary endpoints in this study. 
The change from baseline in cognitive, functional, and global assessments through the end of the 
study 
 
Cognition: ADAS-Cog 
o 
The ADAS-cog 13 contains 13 items, with a total scoring range of 0 – 85 and 
higher scores indicating greater dysfunction. 
 
Cognition: MMSE 
o 
The MMSE is a 30-point questionnaire that is used extensively in clinical and 
research settings to measure cognitive impairment and is commonly used in 
medicine and allied health to screen for dementia. It is also used to estimate the 
severity and progression of cognitive impairment and to follow the course of 
cognitive changes in an individual over time; thus making it an effective way to 
document a participant’s response to treatment. The total score range is 0 – 30 
and lower scores indicating greater impairment. 
 
Function: ADCS-ADL score is range of 0-78 and lower scores indicating greater 
impairment 
 
Global: CDR-SB 


 
 
 
 
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o 
The CDR-SB includes six domains (0-3 points/domain), with a total scoring 
range of 0 – 18 and higher scores indicating greater impartment. The CDR score 
is calculated at baseline for eligibility check. 
 
Behavior: NPI: 
o 
The NPI has 12 domains and for each domain, the relatives assess the frequency 
of the behaviour (4-point scale), the severity of the symptom (3-point scale) and 
the emotional stress for the caregiver (6-point scale). The total score of NPI is 0-
144 and lower scores indicates greater impairment. 
ADAS-Cog, ADCS-ADL, and NPI are rated at baseline (V1), Week 28 (V6), Week 52 (V10) and 
Week 78 (V13), while MMSE and CDR/CDR-SB are assessed at the first screening (S1), Week 24 
(V5), Week 48 (V9) and Week 78 (V13). 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. 
4.3.1 
SUVR Composite 
Mean SUVR change from baseline will be evaluated for a composite target region comprised of a 
weighted average of selected regions of interests such as frontal, temporal, parietal, occipital and 
precuneus. The corresponding reference region will be the whole cerebellum for the secondary 
endpoint. The SUVR is computed as the ratio of the target region signal to the reference region 
signal. 
4.3.2 
Semi-Quantitative Visual Assessment  
The semi-quantitative visual assessment method will be used to visually assess amyloid burden. 
The change form baseline in the proportion of PET positive subjects with visual read will be 
evaluated.  
4.3.3 
Regional SUVR 
Mean SUVR change from baseline will be evaluated for each of the selected brain regions of 
interest such as frontal, temporal, parietal, occipital and precuneus. The corresponding reference 
region will be the whole cerebellum. The SUVR is computed as the ratio of the target region signal 
to the reference region signal. 
 
 
Safety Variables 
4.4
The safety analysis will be based on the reported adverse events and other safety information 
including: 
 
Local tolerability at injection site 
 
Vital signs 
 
Physical examination 
 
12-lead ECG 
 
Laboratory tests: hematology, clinical chemistry (HbA1c, 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) 


 
 
 
 
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 
Imaging variables: 
o 
Amyloid-related imaging abnormality-E (ARIA-E) which includes parenchymal 
vasogenic edema and/or sulcal (leptomeninges) effusion 
o 
Amyloid-related imaging abnormality-H (ARIA-H) which includes hemosiderin 
deposits such as microhemorrhage and superficial siderosis 
o 
Post-vaccine meningoencephalitis (PVM) 
o 
Age-related white matter changes (ARWMC) 
o 
Non-ARIA abnormalities 
 
STATISTICAL METHODS 
5
 
General 
5.1
Continuous data will be summarized by treatment group using the number of observations 
available (n), mean, standard deviation (SD), median, interquartile range (IQR), minimum, and 
maximum. 
Categorical data will be summarized by treatment group 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. 
For undetected value, this study will take the minimum value that can be detected as the text value, 
eg, <3.5 will be treated as 3.5 and <0.012 will be treated as 0.012 when performing the summary 
and will list the original value in listing. 
 
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 study medication. 
 
The post-treatment period is defined as the time from after the first dose of study 
medication to the end of the study. 
All statistical tests will be two-sided at the alpha level of 0.05, unless otherwise specified. 
 
Handling of Dropouts or Missing Data 
5.2
Partial date of initial diagnosis will be imputed as below: 
 
If year is missing (or completely missing), do not impute; 
 
15th of the month will be used to impute the initial diagnosis date if only the day is 
missing; 
 
01July of the year will be used to impute as the initial diagnosis date if both the day and 
the month are missing; 
ADAS-Cog total score 
 The imputed total score of ADAS-Cog-13 when there is only one item is missing 
due to non- cognitive reasons is presented in:  


 
 
 
 
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Missing Question 
Imputed Total formula 
Word Recall 
Observed Total*(1+10/75) 
Orientation 
Observed total*(1+8/77) 
Word Recognition 
Observed total*(1+12/73) 
Delayed Word Recall 
Observed Total*(1+10/75) 
All other questions 
Observed total*(1+5/80) 
 If more than one of 13 items of ADAS-Cog are missing/NA, the total score will 
be set to missing. 
Concomitant Medications Start/End Date 
Partial missing start/end date to concomitant medications will be imputed as below:  
Start date of concomitant medications 
 If only the day of the month is missing, use the first day of the month to 
replace the missing part. 
 If both the day and the month are missing, January 1stwill be used to replace 
the missing part. 
 If Day, Month and Year are all missing, use a date one day before the first 
date of study drug. 
End date of concomitant medications 
 If only Day is missing, use the last day of the month. 
 If Day and Month are both missing, use the last day of the year. 
 If Day, Month and Year are all missing, assign ‘continuing’ status to stop date. 
Adverse Event Start/End Date 
Missing or partial missing date to the onset date of AE will be imputed as below: 
 If the AE onset date is completely missing, the AE start date will be imputed as the first 
date of study drug; 
 If the AE onset date is partial missing, then If both the year and the month are available 
and the year and the month are the corresponding year and month of the first dosing date, 
then the AE start date will be imputed as the first dosing date; 
o 
If both the year and the month are available and the year and the month are not 
equal to the corresponding year and month of the first dosing date, then the AE 
start date will be imputed as the 1st date of the month; 
o 
If only the year is available and the available year is the corresponding year of the 
first dosing date, then the AE start date will be imputed as the first dosing date; 
o 
If only the year is available, and the available year is not equal to the 
corresponding year of the first date of study drug, then the AE start date will be 
imputed as the January1st of the year; 
Adverse event end date will be imputed as below for the partial date only. 
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of the month; 
 If only the year is available, AE end date will be imputed as the December 31st of the 
year. 
 If the AE onset date is completely missing and status is “ongoing”, it will not be 
imputed 
 
Analysis Populations 
5.3
5.3.1 
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 randomized 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. 
5.3.2 
Safety population 
The safety population is the total treated population defined as all subjects randomized and 
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. 
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 
 Randomized subjects: subjects who receive a randomization number via IVRS/IWRS 
 The safety population 
 The mITT population 
 The PP population 
For the following two categories of subjects, counts, and percentages will be calculated for each 
treatment group using the number of randomized subjects in each group as denominator. 
 Subjects who have completed the 60-week treatment period 
 Subjects who discontinue the study drug during the treatment period 
A list of subjects prematurely withdrawn from the study, along with reasons for discontinuation, 
will be provided. 
5.3.3 
Subgroups 
While this study is not powered for subgroup analyses, select efficacy and safety endpoints will be 
analyzed by APOE4 carrier subgroups for exploratory purpose.  
 
Protocol Deviation Reporting 
5.4
There is a listing for describing the subjects with protocol violation. It will record the details of the 


 
 
 
 
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protocol deviation and its severity level. 
 
Patient Disposition 
5.5
The number and percentage of screened patients and screened-failure patient will be summarized 
for all subjects. 
The number and percentage of patients who completed the study and who discontinued the study 
will be summarized by treatment for all subjects. Discontinuations will be further summarized by 
reason. 
The number and percentage of patients in each analysis sets will be summarized by treatment. 
 
Enrollment by Site 
5.6
The number and percentage of patients in each study site will be summarized by treatment in 
mITT, PP and Safety population. 
 
Subject Demographics and Baseline Characteristics 
5.7
5.7.1 
Subject Demographic Characteristics, Medical History and Diagnoses 
The baseline value is defined as the last available value before the first injection of study drug. 
Descriptive statistics will be used to summarize the demographic, baseline characteristics data and 
medical history for the safety population to describe the study population by study center, 
treatment group and overall. 
The distribution of demographic and baseline characteristics among three treatment groups will be 
evaluated using chi-square or Fisher’s exact test for categorical variables and the Kruskal-Wallis 
test or analysis of variance (ANOVA) for continuous variables. 
Pathologies associated with past medical and surgical history will be classified into primary system 
organ classes and preferred terms using MedDRA 21.0 and will be summarized by study center, 
treatment group and overall using counts and percentages. The primary system organ classes and 
preferred terms will be sorted in decreasing order of frequency. 
5.7.2 
Physical Examination 
The number and percentage of abnormality at baseline will be summarized by treatment in Safety 
population. 
Shift from baseline for post treatment at scheduled visit will be summarized by treatment in safety 
population with number and percentage. 
5.7.3 
Medical History and Surgery History 
Previous/concomitant medical history and surgery history at baseline will be summarized for 
safety population by treatment with number and percent of patients by primary system organ class 
and preferred term. 
5.7.4 
Previous and Concomitant Medications/Therapy 
Medications will be classified into the following two groups: 
 Previous medications are those that the subject took within 3 months period prior to the 
first screening visit (S1) and prior to the first administration of the study drug at Week 0 


 
 
 
 
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(V1/baseline). 
 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. No statistical 
testing for between-group difference will be performed. 
5.7.5 
Baseline Efficacy and Safety Data 
For efficacy and safety analysis, the baseline for a given parameter is defined as the last available 
value prior to the first injection of the study medication. Baseline efficacy and safety variables will 
be summarized by treatment group, and overall. 
 
Treatment Tolerability and Compliance 
5.8
Overall treatment tolerability and compliance will be summarized in safety population. 
The overall treatment tolerability of UB-311 for each arm 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) 
 
Analysis of Immunogenicity Variable 
5.9
Anti-Aβ antibodies will be summarized by presenting summary statistics of raw data and change 
from baseline values (n, mean, standard deviation, median, range) at each scheduled visit in mITT 
Population and PP Population. 
The Kruskal-Wallis test or analysis of variance (ANOVA) for continuous variables for baseline 
information will be performed for comparing the un-adjusted change among Arm 1, Arm 2 and 
Arm 3. 
A repeated-measures mixed-effects model with treatment (Arm 1+ Arm 2 vs. Arm 3, Arm 1 vs. 
Arm 3 and, Arm 2 vs. Arm 3), study visit, time-by-treatment, APOE4 status, and baseline as a 


 
 
 
 
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covariate will be used to analyze change from baseline of anti-Aβ antibodies. The unstructured 
covariance will be used in the modelling of the within-patient errors in the analysis. For APOE4 
status subgroup analysis of MMRM, APOE4 factor will not be considered in the model. AUC of 
Anti-Aβ antibodies will be used an analysis of covariance (ANCOVA) model with treatment and 
baseline of Anti-Aβ antibodies as covariate. Antibody responders will be defined as the subjects 
with serum antibody titer > response threshold at any visit after baseline. The number and 
percentage of patients will be tabulated for each treatment group in mITT Population and PP 
Population at each post treatment scheduled visit. Treatment differences in the proportion antibody 
responders will be analyzed with the Chisq test. The one-sided 95% confidence interval (CI, right 
side) from all visits (V1 to V13) for subjects in Arm 3 (placebo group) will be calculated as the 
threshold of response. 
 
Analysis of Efficacy Data 
5.10
Efficacy analyses will be performed on the mITT and PP populations. For change from baseline of 
ADAS-Cog total score, MMSE total score, ADCS-ADL total score, CDR-SB total score, NPI total 
score, A repeated-measures mixed-effects model with treatment (Arm 1 + Arm 2 vs. Arm 3, Arm 1 
vs. Arm 3 and , Arm 2 vs. Arm 3), study visit, time-by-treatment, APOE4 status, and baseline as a 
covariate will be used to analyze change from baseline. The least square means using maximum 
likelihood estimate and its 95% will be provided. The unstructured covariance will be used in the 
modeling of the within-patient errors in the analysis. 
For change from baseline of mean SUVR, A repeated- measures mixed-effects model with 
treatment (Arm 1 + Arm 2 vs. Arm 3, Arm 1 vs. Arm 3 and, Arm 2 vs. Arm 3), study visit, time-
by-treatment, APOE4 status, and baseline as a covariate will be used to analyze change from 
baseline. The unstructured covariance will be used in the modeling of the within-patient errors in 
the analysis. 
For change from baseline of mean SUVR by region, A repeated- measures mixed-effects model 
with treatment (Arm 1 + Arm 2 vs. Arm 3, Arm 1 vs. Arm 3 and, Arm 2 vs. Arm 3), study visit, 
time-by-treatment, and baseline as a covariate will be used to analyze change from baseline. The 
unstructured covariance will be used in the modeling of the within-patient errors in the analysis. 
The p-values and confidence intervals for these efficacy endpoints were not adjusted for 
multiplicity, it should be used for screening purposes only, and that one side of 95% confidence 
intervals are provided to help gauge the precision of the estimates for treatment difference. 
The proportion of PET positive subjects with visual read will be provided by number and 
percentage for each treatment group in mITT Population and PP Population at each post treatment 
scheduled visit. Treatment differences will be analysed with the Chisq test. The one-sided 95% 
confidence interval (CI, right side) between (Arm 1 + Arm 2 vs. Arm 3, Arm 1 vs. Arm 3 and, 
Arm 2 vs. Arm 3) from all visits will be calculated. 
 


 
 
 
 
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Subgroup Analysis of Immunogenicity/Efficacy Data 
5.11
Subgroup analysis by APOE4 carrier will be performed for all immunogenicity and efficacy 
data, and the analysis model will be the same as the overall analysis. 
 
Analysis of Safety Data 
5.12
5.12.1 
General 
The review of safety and tolerance will be performed on the safety population as defined in 
Section 5.3.2 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 study medication. 
 The post-treatment period is defined as the time from after the first dose of study 
medication to the end of the study. 
The summary of safety results will be presented by each treatment group. 
5.12.2 
Adverse Events 
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 by subjects and events in each treatment group, will include: 
 The overview of AEs, summarizing number (n) and percentage (%) 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 and 
events in each treatment group. 
Adverse events leading to treatment discontinuation 
TEAEs leading to treatment discontinuation will be summarized and presented as number and 
percentage of subjects and events in each treatment group. 
Local tolerability at injection site 
The number and percentage of subjects and events with reaction at injection site will be 
summarized and presented by treatment group 
5.12.3 
Clinical Laboratory Assessments 
The summaries will include subjects in the safety population with at least one laboratory test 


 
 
 
 
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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 study 
drug injection. 
Descriptive statistics will be used to summarize the laboratory results and the changes from 
baseline by scheduled visit for each treatment group. Laboratory results will be listed.  
5.12.4 
Vital Signs 
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 for each 
treatment group. The listing will be provided for vital signs data. 
5.12.5 
12-lead ECG Status 
Only ECG status (i.e. normal or abnormal) will be reported. Descriptive statistics will be used 
to summarize the ECG status and the changes from baseline by scheduled visit for each 
treatment group. The listing will be provided for ECG data.  
5.12.6 
Imaging-Related Safety Endpoint 
Imaging abnormality events will include the following: 
 ARIA-E, ARIA-H, 
 ARWMC 
 PVM, and 
 Non-ARIA abnormalities 
 
All ARIA, PVM, ARWMC and non-ARIA abnormalities will be reported and analyzed as 
image related abnormalities. ARIA, PVM, ARWMC and non-ARIA abnormalities that 
appear following first administration of treatment will be reported as imaging related 
treatment- emergent abnormalities. 
An abnormality summary table will be provided for baseline and post-baseline visit by: 
 all imaging events including ARIA-E, ARIA-H, Non-ARIA, ARWMC, PVM 
 by treatment arm 
 by treatment arm and visit 
Frequency of ARIA (Presence Yes/No) (Total ARIA, ARIA-E only and ARIA-H only) 
will be provided with number and percent of patients for baseline visit. 
Frequency/Patient of ARIA (Total ARIA, ARIA-E only and ARIA-H only) will be 
summarized for safety population by treatment with number and percent of patients. 
New Events (since last visit) will be summarized for safety population by treatment with 
number and percent of patients. 
Improvement since baseline (ARIA-E and ARIA-H) will be summarized for safety 
population by treatment with number and percent of patients. 
PVM/ARWMC/non-ARIA abnormalities will be summarized for safety population by 
treatment with number and percent of patients. 
The number of ARIA-E/ARIA-H abnormalities will be summarized for safety population 
by treatment with n, mean, std dev, CV, Q1, median, Q3, Min, Max, L95 and U95. 
Distribution of number of ARIA-E/ARIA-H abnormalities by actual value, change from 
baseline will be summarized for safety population by treatment with number and percent 
of patients. 


 
 
 
 
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Visit value and change from baseline for ARIA-E, ARIA-H and total will be summarized 
for safety population by treatment with mean and standard deviation. 
Overall evaluation of change for ARIA-E/ARIA-H frequency by category (unchanged, 
improved and worsened) will be summarized for safety population by treatment with 
number and percent of patients. 
Number of occurrences ARIA-E/ARIA-H frequency by brain region (FL, PL, TL, OL, 
Cer, BS, Oth) will be summarized for safety population by treatment with number and 
percent of patients by visit. 
Overall evaluation of change for ARIA- E/ARIA-H frequency by type will be 
summarized for safety population by treatment with number and percent of patients. 
Overall change from baseline for ARWMC frequency by visit will be summarized for 
safety population by treatment with number and percent of patients. 
Visit value and Change from baseline for ARWMC will be summarized for safety 
population by treatment with n, mean, std dev, CV, Q1, median, Q3, Min, Max, L95 and 
U95. 
Overall change from baseline for post- vaccine meningoencephalitis frequency by visit 
will be summarized for safety population by treatment with number and percent of 
patients. 
 
Sample Size 
5.13
This early phase clinical trial is exploratory in nature; hence, the sample size is 
determined to assess the primary objective of safety, tolerability, and immunogenicity of 
UB-311. The total of 45 subjects is planned to be enrolled, 15 per arms. For each UB-311-
treated arm, 15 subjects are thought to be sufficient to detect an adverse event with an 
incidence of 7%. Furthermore, 30 subjects receiving UB-311 are anticipated to be able to 
detect an adverse event with an incidence of 4%.  
With the current sample sizes, there may be limited power to detect a reduction in mean 
SUVRs or regional SUVRs unless there is a dramatic clearance of pre-existing plaques, 
and extremely limited power to detect effects on cognitive and functional endpoints. 
These analyses are therefore considered exploratory. 
 
Interim Analysis 
5.14
There is no interim analysis for this study. 
 
Multiplicity 
5.15
There is only primary immunogenicity endpoint in this study, and all efficacy endpoint 
will be served as secondary endpoint, and p-Value and its confidence interval will be used 
for screening purpose, so there is no multiplicity adjustment performed. 
 
General Conventions for Tables, Listings and Figures 
5.16
For summary tables, unless otherwise specified, the number of decimal places provided in 
the SAS output will be based on the accuracy of the least accurate value in the raw data as 
follows: 
• 
n 
integer 
• 
Arithmetic mean 
1 decimal place more than the least accurate number in the raw data 
• 
SD 
2 decimal place more than the least accurate number in the raw data 
• 
CV(%) 
2 decimal places 
• 
Geometric mean 
1 decimal place more than the least accurate number in the raw data 
• 
Median 
1 decimal place more than the least accurate number in the raw data 
• 
Minimum 
same number of decimal places as raw data 


 
 
 
 
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• 
Maximum 
same number of decimal places as raw data 
• 
Confidence interval 
same number of decimals as the associated statistic 
• 
Geometric mean ratio 2 decimal places 
 
CHANGES FROM THE PROTOCOL TO THIS SAP 
6
Additional details and specifications have been included in this SAP to allow for better 
understanding of the intended methods. Additional analyses (including exploratory and 
subgroup assessments) for select variables have been added. Additional sensitivity analyses 
will be conducted to explore any effects related to the presence of data outliers. 
 

Prot_000.pdf: 
 
 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
 
 
 
Investigational Product: 
UBITh® AD Immunotherapeutic Vaccine (UB-311) 
 
 
A Randomized, Double-blind, Placebo-controlled, 3-arm Parallel-group, 
Multicenter, Phase IIa Study to Evaluate the Safety, Tolerability, 
Immunogenicity, and Efficacy of UBITh® AD Immunotherapeutic Vaccine 
(UB-311) in Patients with Mild Alzheimer’s Disease 
 
 
 
 
 
Protocol Number:  
V203-AD 
Confidential 
Version: 5.0  
Date: 28-Nov-2017 
 
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.
 
 
 


 
 
CONFIDENTIAL 
United Neuroscience Ltd. 
 
 
Clinical Trial Protocol: V203-AD 
 
Version: 5.0, Date: 28-Nov-2017 
 
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) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
CONFIDENTIAL 
United Neuroscience Ltd. 
 
 
Clinical Trial Protocol: V203-AD 
 
Version: 5.0, Date: 28-Nov-2017 
 
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 
 
  
  
  
 


 
 
CONFIDENTIAL 
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Clinical Trial Protocol: V203-AD 
 
Version: 5.0, Date: 28-Nov-2017 
 
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 
 
  
  
  


 
 
CONFIDENTIAL 
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Clinical Trial Protocol: V203-AD 
 
Version: 5.0, Date: 28-Nov-2017 
 
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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Clinical Trial Protocol: V203-AD 
i 
Version: 5.0, Date: 28-Nov-2017 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS .......................................................................................................................... i 
LIST OF ABBREVIATIONS .................................................................................................................. vi 
SYNOPSIS ................................................................................................................................................ x 
1 
INTRODUCTION AND RATIONALE ............................................................................................ 1 
2 
OBJECTIVES .................................................................................................................................... 4 
3 
TRIAL DESIGN ................................................................................................................................ 4 
3.1 Description of the Protocol ................................................................................................... 4 
3.1.1 
Screening Period ................................................................................................................. 4 
3.1.2 
Treatment Period ................................................................................................................. 5 
3.1.3 
Follow-up Period ................................................................................................................. 5 
3.2 Endpoints ............................................................................................................................. 5 
3.2.1 
Primary ................................................................................................................................ 5 
3.2.2 
Secondary ............................................................................................................................ 5 
3.3 Description of Blinding Methods .......................................................................................... 6 
3.4 Description of Randomization .............................................................................................. 6 
3.5 Stopping Rules ..................................................................................................................... 6 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ..................................................................... 7 
4.1 Number of Subjects .............................................................................................................. 7 
4.2 Inclusion Criteria ................................................................................................................. 7 
4.3 Exclusion Criteria ................................................................................................................ 8 
4.4 Subject Withdrawal Criteria ................................................................................................ 9 
5 
TREATMENT OF SUBJECTS ....................................................................................................... 11 
5.1 Description of Study Drug .................................................................................................. 11 
5.2 Dosing Regimens and Rationale ......................................................................................... 11 


 
 
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5.3 Handling of Study Drug ..................................................................................................... 11 
5.3.1 
Packing and Labelling ...................................................................................................... 11 
5.3.2 
Storage ............................................................................................................................... 12 
5.4 Drug Accountability ........................................................................................................... 12 
5.5 Concomitant Medicines ...................................................................................................... 12 
5.5.1 
Permitted Medicines .......................................................................................................... 12 
5.5.2 
Prohibited Medicines ........................................................................................................ 12 
5.6 Subject Compliance ........................................................................................................... 13 
6 
ASSESSMENT OF INVESTIGATIONAL PRODUCT .................................................................. 14 
6.1 Immunogenicity ................................................................................................................. 14 
6.1.1 
Anti-Aβ antibody measurement ........................................................................................ 14 
6.1.2 
Response rate..................................................................................................................... 14 
6.2 Safety ................................................................................................................................. 14 
6.3 Efficacy .............................................................................................................................. 14 
6.3.1 
Evaluation variables ......................................................................................................... 14 
6.3.2 
Efficacy assessment methods ............................................................................................ 15 
6.4 Measures to protect blinding of this trial ............................................................................ 15 
7 
ASSESSMENT OF SAFETY........................................................................................................... 16 
7.1 Safety Endpoints ................................................................................................................ 16 
7.1.1 
Local tolerability ............................................................................................................... 16 
7.1.2 
Clinical safety .................................................................................................................... 16 
7.1.3 
Adverse event collection .................................................................................................... 16 
7.1.4 
ECG ................................................................................................................................... 16 
7.1.5 
MRI .................................................................................................................................... 17 
7.1.6 
Safety laboratory ............................................................................................................... 17 


 
 
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7.2 Safety Instructions ............................................................................................................. 17 
7.2.1 
Local tolerability ............................................................................................................... 17 
7.2.2 
Monitoring of ARIA .......................................................................................................... 17 
7.3 Adverse Events Recording ................................................................................................. 18 
7.4 Adverse Events Monitoring ................................................................................................ 18 
7.5 Definitions of Adverse Event and Serious Adverse Event ................................................... 18 
7.6 Recording and Reporting of Adverse Event........................................................................ 19 
7.7 Follow-up ........................................................................................................................... 21 
7.8 Obligation of the Sponsor ................................................................................................... 21 
7.9 Data and Safety Monitoring Board..................................................................................... 22 
7.10 Risk Management .............................................................................................................. 23 
8 
STUDY PROCEDURES .................................................................................................................. 24 
8.1 Study Visits ........................................................................................................................ 24 
8.1.1 
The First Stage Screening (-42 < Day < 0) ...................................................................... 24 
8.1.2 
The Second Stage Screening (-42 < Day < 0) .................................................................. 25 
8.1.3 
Visit 1 (Week 0, Day 0 / baseline) ..................................................................................... 25 
8.1.4 
Visit 2 (Week 4, Day 28) .................................................................................................... 26 
8.1.5 
Visit 3 (Week 12, Day 84) .................................................................................................. 26 
8.1.6 
Visit 4 (Week 16, Day 112) ................................................................................................ 27 
8.1.7 
Visit 5 (Week 24, Day 168) ................................................................................................ 27 
8.1.8 
Visit 6 (Week 28, Day 196) ................................................................................................ 28 
8.1.9 
Visit 7 (Week 36, Day 252) ................................................................................................ 28 
8.1.10 Visit 8 (Week 40, Day 280) ................................................................................................ 29 
8.1.11 Visit 9 (Week 48, Day 336) ................................................................................................ 29 
8.1.12 Visit 10 (Week 52, Day 364) .............................................................................................. 30 


 
 
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8.1.13 Visit 11 (Week 60, Day 420) .............................................................................................. 31 
8.1.14 Visit 12 (Week 64, Day 448) .............................................................................................. 31 
8.1.15 Visit 13 (Week 78, Day 546) .............................................................................................. 32 
8.2 Events and Time Schedule.................................................................................................. 33 
8.3 Blood Sample Collection .................................................................................................... 34 
9 
STATISTICS ................................................................................................................................... 36 
9.1 Determination of Sample Size ............................................................................................ 36 
9.2 Analysis Variables .............................................................................................................. 36 
9.2.1 
Demographic and baseline characteristics ....................................................................... 36 
9.2.2 
Immunogenicity variables ................................................................................................. 37 
9.2.3 
Efficacy variables .............................................................................................................. 37 
9.2.4 
Safety variables ................................................................................................................. 37 
9.3 Analysis Populations .......................................................................................................... 37 
9.3.1 
Efficacy populations ......................................................................................................... 37 
9.3.2 
Safety population ............................................................................................................... 38 
9.3.3 
Disposition of subjects....................................................................................................... 38 
9.4 Statistical Methods ............................................................................................................. 38 
9.4.1 
Demographic and baseline characteristics ....................................................................... 39 
9.4.2 
Treatment tolerability and compliance ............................................................................. 39 
9.4.3 
Analysis of immunogenicity variable ............................................................................... 40 
9.4.4 
Analysis of efficacy variables ............................................................................................ 40 
9.4.5 
Analysis of safety data ....................................................................................................... 40 
10 QUALITY CONTROL AND QUALITY ASSURANCE ................................................................ 43 
10.1 Responsibility of the Investigator(s) ................................................................................... 43 
10.2 Responsibility of the Sponsor ............................................................................................. 43 


 
 
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Clinical Trial Protocol: V203-AD 
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10.3 Source Document Requirements ........................................................................................ 43 
10.4 Use and Completion of Case Report Forms (CRFs) and Additional Request ...................... 44 
11 ETHICS ........................................................................................................................................... 45 
11.1 Declaration of Helsinki and Ethical Review ........................................................................ 45 
11.2 Patient Information and Consent ....................................................................................... 45 
11.3 Patient Data Protection ...................................................................................................... 45 
12 DATA HANDLING AND RECORD KEEPING ............................................................................ 46 
12.1 Data Management .............................................................................................................. 46 
12.2 Record Retention in Study Sites ......................................................................................... 46 
13 FINANCING AND INSURANCE ................................................................................................... 47 
14 PUBLICATION POLICY ............................................................................................................... 48 
15 REFERENCES ................................................................................................................................ 49 
APPENDIX 1: IMAGING PROTOCOL .......................................................................................................... 51 
1 
Introduction ...................................................................................................................................... 51 
2 
MRI Methods .................................................................................................................................... 51 
3 
18F-AV-45 PET Methods .................................................................................................................... 53 
4 
Volumetric Magnetic Resonance Imaging (vMRI) for the Research Study ......................................... 54 
5 
Resting state fMRI (rs-fMRI) for the Research Study ......................................................................... 55 
6 
Reference .......................................................................................................................................... 55 
APPENDIX 2: RESEARCH STUDY PROTOCOL ............................................................................................. 56 
 


 
 
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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 
ADCS-ADL 
Alzheimer's Disease Cooperative Study-Activities of Daily Living 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ARWMC 
Age-Related White Matter Changes  
ALT 
Alanine Aminotransferase 
ANA 
Antinuclear Antibody 
ANC 
Absolute Neutrophil Count 
ANOVA 
Analysis of Variance 
aPTT 
Activated Partial Thromboplastin Time 
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 
Clinical Dementia Rating 
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 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAD 
Disability Assessment for Dementia 
dL 
Deciliter 
DNA 
Deoxyribonucleic Acid 
DOH 
Department of Health 


 
 
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DSMB 
Data and Safety Monitoring Board 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
e-CRF 
Electronic Case Report Form 
EDTA 
Ethylenediamine Tetra Acetic Acid 
EIA 
Enzyme Immunoassay 
ESR 
Erythrocyte Sedimentation Rate 
ET 
Early Termination 
FLAIR 
Fluid Attenuated Inversion Recovery 
fMRI 
Functional Magnetic Resonance Imaging 
GCP 
Good Clinical Practice 
GDS-SF 
Geriatric Depression Scale-Short Form 
GRE 
Gradient Refocused Echo 
HbA1c 
Glycosylated Hemoglobin 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
HIS 
Hachinski Ischemic Score 
HIV 
Human Immunodeficiency 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 
IVRS/IWRS 
Interactive Voice/Web Response System 
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 
Miligram 
mITT 
Modified Intention-to-treat 


 
 
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mL 
Mililiter 
mm 
Milimeter 
MMSE 
Mini Mental State Examination 
MP-RAGE 
Magnetization-prepared Rapid Gradient Echo 
MRI 
Magnetic Resonance Imaging 
n 
Number of Observations Available 
NCI 
National Cancer Institute 
NIA-AA 
National Institute on Aging–Alzheimer’s Association 
NINCDS-ADRDA 
National Institute of Neurological and Communicative Disorders and 
Stroke, and Alzheimer’s Disease and Related Disorders Association 
NMDA 
N-methyl-D-aspartate 
NPI 
Neuropsychiatric Inventory 
NTB 
Neuropsychological Test Battery 
NTUH 
National Taiwan University Hospital 
PE 
Physical Examination 
PET 
Positron Emission Tomography 
PP 
Per-protocol 
ROI 
Region of Interest 
PT 
Prothrombin Time 
RF 
Rheumatoid Factor 
rs-fMRI 
Resting State fMRI 
S 
Screening 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SHH 
Shuang Ho Hospital 
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 
UNS 
United Neuroscience Ltd. 
ULRR 
Upper Limit of Reference Range 
US FDA 
United States, Food and Drug Administration 
V 
Visit 
vMRI 
Volumetric Magnetic Resonance Imaging 
W 
Week 
WBC 
White Blood Cells 


 
 
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Clinical Trial Protocol: V203-AD 
ix 
Version: 5.0, Date: 28-Nov-2017 
 
WHO 
World Health Organization 


 
 
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United Neuroscience Ltd. 
 
 
Clinical Trial Protocol: V203-AD 
x 
Version: 5.0, Date: 28-Nov-2017 
 
SYNOPSIS 
PROTOCOL NUMBER 
V203-AD 
TITLE 
A 
Randomized, 
Double-blind, 
Placebo-controlled, 
3-arm 
Parallel-group, Multicenter, Phase IIa Study to Evaluate the Safety, 
Tolerability, Immunogenicity, and Efficacy of UBITh®  AD 
Immunotherapeutic Vaccine (UB-311) in Patients with Mild 
Alzheimer’s Disease 
STUDY SITES 
There will be five 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 
1. To assess the safety and tolerability of two regimens of UB-311; 
2. To evaluate the immunogenicity of two regimens of UB-311; 
3. To evaluate the effects of UB-311 on the changes of cognitive 
and functional performance over a period of 78 weeks; and 
4. To investigate whether UB-311 treatment results in changes in 
amyloid deposition in vivo by Florbetapir F18 (also known as 
18F-AV-45, Eli Lilly and Company) PET imaging. 
STUDY DESIGN 
This is a 78-week, multicenter, randomized, double-blind, 
placebo-controlled Phase IIa study. Eligible subjects, 60 to 90 years 
old with mild Alzheimer’s disease (AD), will be further screened by 
18F-AV-45 PET scan for the presence of amyloid deposition.  
Enrolled subjects will be randomized into one of the 3 treatment 
arms in 1:1:1 ratio. Subjects assigned to Arm 1 will receive 7 doses 
of UB-311 at Weeks 0, 4, 12, 24, 36, 48, and 60. Subjects assigned 
to Arm 2 will receive 5 doses of UB-311 at Weeks 0, 4, 12, 36, and 
60, and placebo at Weeks 24 and 48. Subjects assigned to Arm 3 
will receive placebo at Weeks 0, 4, 12, 24, 36, 48, and 60. Subjects 
will be followed till Week 78. 
Subjects enrolled in the Phase I trial with UB-311 will be excluded 
from the Phase IIa trial. 


 
 
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Clinical Trial Protocol: V203-AD 
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STUDY POPULATION 
Total expected number 
of subjects  
 
Inclusion criteria 
 
Approximately 45 subjects will be enrolled to receive study 
treatment, approximately 15 subjects per treatment arm. 
 
Subjects may be included in the clinical trial only if they meet all of 
the following criteria: 
1. Male or female aged between 60-90 years old; 
2. Probable Alzheimer’s disease based on the National Institute of 
Neurological and Communicative Disorders and Stroke and the 
Alzheimer’s Disease and Related Disorders Association 
(NINCDS-ADRDA) 
criteria 
and 
National 
Institute on 
Aging–Alzheimer’s Association (NIA-AA) guidelines; 
3. Mini-Mental State Examination (MMSE) scores between 20 
and 26 (inclusive); 
4. Clinical dementia rating (CDR) scores of 0.5 or 1; 
5. At least 6 years of education or sufficient work history (to 
exclude mental retardation); 
6. Visual and auditory acuity adequate for neuropsychological 
testing; 
7. 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; 
8. Hachinski ischemic score (HIS) <4 (original score); 
9. Geriatric Depression Scale-Short Form (GDS-SF) <6; 
10. Eastern Cooperative Oncology Group (ECOG) performance 
status 0-2; 
11. 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; 
12. 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), to perform study-related AD 
scales and to accompany or delegate a companion with the 
subject to all visits. A companion needs not to be a family 
member (with kinship); 
13. Both patient and his/her caregiver should sign the written 


 
 
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United Neuroscience Ltd. 
 
 
Clinical Trial Protocol: V203-AD 
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Version: 5.0, Date: 28-Nov-2017 
 
informed consent before undergoing any study procedures; 
14. Agree not to donate blood or blood products for transfusion 
during the study and for 3 months thereafter; and 
15. A positive of Aβ plaque on 18F-AV-45 PET by an imaging 
expert (confirmed during the second stage of screening per 
central independent review). 
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;  
2. Screening  magnetic resonance imaging (MRI) scan with 
evidence 
of 
central 
nerves 
system 
(CNS) 
infection, 
cerebrovascular disease, infarction, or other focal lesions, or a 
single 
area 
of 
superficial 
siderosis, 
or 
a 
prior 
macrohemorrhage, or more than four microhemorrhages, 
multiple lacunes or lacunes in a critical memory structure; 
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 


 
 
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Clinical Trial Protocol: V203-AD 
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screening; 
11. Use of any investigational drug within 4 weeks before 
screening; 
12. Current participation in clinical studies involving ADAS-Cog, 
MMSE, ADCS-ADL, CDR-SB, or NPI being collected more 
than one time per score per year; 
13. Previous exposure to any anti-Aβ immunotherapy; 
14. 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); 
15. Received blood or blood derivatives treatment within 3 months 
prior to screening; 
16. Positive serology for hepatitis B virus (HBV), hepatitis C 
virus(HCV), or human immunodeficiency virus (HIV); 
17. 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; 
18. Abnormal clinical laboratory values as listed below, and 
determined to be clinically significant by the investigator at the 
screening: 
– Serum antinuclear antibody (ANA) >1:80 
– Rheumatoid factor (RF) result is >17 IU/mL 
– Platelets <150,000 or >500,000/mm3 
– White blood cells (WBC) <3,000 or >10,500/mm3  
– Absolute neutrophil count (ANC) <1,500/mm3 
– Prothrombin time (PT) <9 or >13 seconds 
– Activated partial thromboplastin time (aPTT) <26.9 or 
>36.3 seconds 
– Serum creatinine >2 mg/dL 
– Glycosylated hemoglobin (HbA1c) >8.5% 
– Erythrocyte sedimentation rate (ESR) >age-adjusted upper 
limit of reference range (ULRR), i.e. over 50 years old: male 
>20 mm/hr, female >30 mm/hr; over 85 years old: male 
>30 mm/hr, female >42 mm/hr 
– C-reactive protein (CRP) >0.5 mg/dL  
– Aspartate aminotransferase (AST) >84 U/L 
– Alanine aminotransferase (ALT) >80 U/L 


 
 
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Clinical Trial Protocol: V203-AD 
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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 safety evaluations include physical 
examination, vital signs, Amyloid-related Imaging Abnormalities 
(ARIA), clinical chemistry & hematology tests, and incidence of 
adverse event (AE)/serious adverse event (SAE); and 
 The immunogenicity of UB-311 as measured by change from 
baseline in anti-Aβ antibody levels through the end of the study 
and response rate. 
Secondary endpoints: 
 The change from baseline in cognitive, functional, and global 
assessments through the end of the study, including: 
– Alzheimer’s Disease Assessment Scale-Cognitive Subscale 
(ADAS-Cog) 
– Mini-Mental State Exam (MMSE) 
– Alzheimer's Disease Cooperative Study-Activities of Daily 
Living (ADCS-ADL) 
– Clinical Dementia Rating-Sum of Boxes (CDR-SB)  
– Neuropsychiatric Inventory (NPI) 
 The change of amyloid burden from baseline to Weeks 52 and 78 
in retention of 18F-AV-45, determined by mean standard uptake 
value ratio (SUVR) of selected regions of interests (ROIs), such 
as frontal, temporal, parietal, occipital, and precuneus. 
STATISTICAL 
CONSIDERATIONS 
The overall treatment tolerability of UB-311 for each arm 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) 


 
 
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Clinical Trial Protocol: V203-AD 
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Analysis Population 
Modified intent-to-treat (mITT) population: all randomized 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 for each arm. 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: 60 weeks 
Follow-up period: 18 weeks 
 


 
 
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Clinical Trial Protocol: V203-AD 
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Version: 5.0, Date: 28-Nov-2017 
 
1 
INTRODUCTION AND RATIONALE 
Alzheimer’s disease (AD) is a chronic and progressive neurodegenerative disease set to become the 
largest socioeconomic burden of the developed world over the coming decades1. 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%2–6 and an incidence rate of about 0.54%7. 
The pathology of AD is characterized by a progressive loss of neurons and synapses with the 
presence of large numbers of extracellular amyloid plaques and intracellular neurofibrillary tangles. 
Although symptomatic therapies are available, there is still no proven treatment that can address a 
variety of neurobehavioral disturbances and reverse progression of AD1. Increased amyloid beta 
(Aβ) production or reduced Aβ catabolism has been implicated in the pathogenesis of AD. 
Therapeutic targets have focused on reducing Aβ deposition in brain and evidence shows that 
antibodies targeting Aβ can improve symptoms of AD. Results from successful immunotherapy 
with aggregated Aβ1-42 in transgenic mice overexpressing Aβ1-42 peptide led to the development of 
the first human active immunization trial with synthetic aggregated Aβ1-42 peptide AN1792 in 
combination with QS-21 adjuvant1,8. Analysis of AN1792-treated subjects showed that about 20% 
developed robust antibody response but available data on efficacy showed no significant effects on 
exploratory measures of cognition (Alzheimer's Disease Assessment Scale – Cognitive subscale 
[ADAS-Cog]) or disability (Disability Assessment for Dementia [DAD], Clinical Dementia Rating 
[CDR], Mini Mental State Examination [MMSE])1. However, significant improvements were 
observed in a nine component neuropsychological test battery (NTB), indicating less worsening of 
performance in anti-Aβ antibody responders. Improvements in memory were associated with 
increased antibody response and decreased tau in the cerebrospinal fluid in a small subset of 
patients. The AN1792-treated subjects were examined by magnetic resonance imaging (MRI) for 
cerebral volume changes; greater decrease of brain volume was noted without cognitive decline in 
antibody responders. Postmortem observations from three patients showed brain regions that were 
devoid of amyloid plaques. Unfortunately, the trial was halted after reports of acute 
meningoencephalitis in 18 of 300 patients treated with AN17921,8,9. 
However, antibodies did not appear to be the cause of meningoencephalitis since adverse reactions 
had no correlation with the generation of antibodies against Aβ1. Examination of two encephalitis 
cases postmortem revealed a marked CD4 positive T-cell infiltration suggesting that adverse 
reaction to Aβ immunotherapy was not due to humoral antibody response but due to T-cell 
mediated response to AN1792. Given that T-cell epitopes have been mapped to the carboxyl 
terminal domain of Aβ17-42, it was suggested that immunotherapy specifically targeting the active 
amino peptide terminal epitopes of Aβ and devoid of the carboxyl terminal domain may possibly 
reduce risk of T-cell mediated inflammatory response1,10. 
UBITh®  AD Immunotherapeutic Vaccine (UB-311) is a mixture of two synthetic peptides that 
include one of two active UBITh®  helper T-cell epitopes linked to a B-cell epitope from the first 14 
amino acids (Aβ1-14) of the amino terminal domain of Aβ with no epitope spreading to the carboxyl 
region in Aβ1-42
11,12. UBITh®  T-cell epitopes are derived from virus T-helper cell peptide epitopes 
rather than from Aβ peptide and thus the T helper cells activated by UB-311 are not likely to 
cross-react with Aβ11,12. The designated UBITh®  T-cell epitopes are promiscuous and highly potent 
and expected to provide a broader and stronger T-cell help than the T helper sites intrinsic to Aβ. 
UB-311 is formulated with mineral salts that have been licensed to be used as an adjuvant by U.S. 


 
 
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Clinical Trial Protocol: V203-AD 
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FDA. The T-cell response typically associated with this adjuvant is Th-2 response as evidenced by 
the stimulation of IL-4 cytokine secretion in mouse studies13,14. 
Specificity of UB-311 to amino terminal Aβ1-14 reduces the likelihood of a T-cell mediated 
inflammatory response as shown from the results of the preclinical studies in guinea pigs, baboons 
and macaques. Baboons aged more than 10 years immunized with UB-311 at Weeks 0, 3 and 6 and 
boosted at Weeks 78, 81 and 104 had no adverse reactions on observation. The treated baboons 
demonstrated high antibody titers with specificity to the Aβ1-14 domain, but not to the carboxyl 
domain at all dose levels. No unexpected adverse reactions at the injection site have been noted in 
any of the safety and immunogenicity studies conducted in guinea pigs and baboons. An acute and 
chronic toxicity study in Cynomolgous macaques demonstrated safety, tolerability and 
immunogenicity of UB-311. 
The dose selected for UB-311 is based on the data obtained from preclinical studies (Table 1). The 
anti-Aβ antibodies were detected in sera of four of six Macaques after one immunization at the 150 
μg/dose level at 3 weeks post injection and six of six Macaques at the 750 μg/dose level at 3 weeks 
post injection. The immunogenicity was also detected in sera of five of six baboons at the 300 
μg/dose level at 3 weeks post injection, and two of two baboons at the 1200 μg/dose level at 3 
weeks post injection. Therefore, the 300 μg/dose was considered as an appropriate dose and the 
doses over 750 μg were at the plateau of the optimal dose. Regarding the safety, no obvious adverse 
events occurred in the macaque groups receiving either 150 or 750 μg/dose; only some site 
reactogenicity occurred in the group receiving the higher dose, 750 μg/dose. Since human body 
weights are 10-fold to 20-fold higher than that of macaques, the safety associated with these doses 
will not be of concern. The 300 μg/dose was selected as the dose for further clinical evaluation 
because it was found to be safe, well tolerated and strongly immunogenic as shown by all available 
preclinical evidences. In the Phase I clinical trial, UB-311 has demonstrated satisfying safety and 
tolerability profiles when administered to patients with clinically documented mild to moderate 
Alzheimer’s disease (AD). It is also capable of eliciting antibodies with specificity to the 
N-terminus of the Aβ1-14 domain after administration by intramuscular route without causing any 
serious adverse events (SAEs) or intolerable adverse events (AEs). The response rate is 100%, 
using greater than one-sided 95% upper limit of the mean baseline titer as cutoff. 
 
Table 1. 
Species [BW] 
Peptide dose (μg) 
CpG ODN dose (μg)† 
Antibody titer Log10>2‡ 
per animal 
per kg BW 
per animal 
per kg BW§ 
3 weeks post 
1 dose† 
3 weeks post 
2 doses† 
Guinea pig 
[300 – 400 g] 
1 
2.5 – 3.3 
0.2 
0.5 – 0.7 
0 / 3 
0 / 3 
3 
7.5 – 10 
0.6 
1.5 – 2.0 
0 / 3 
0 / 3 
10 
25 – 33 
2.0 
5.0 – 6.7 
0 / 6 
5 / 6 
30 
75 – 100 
6 
15 – 20 
1 / 6 
6 / 6 
100 
250 – 333 
20 
50 – 67 
2 / 3 
3 / 3 
300 
750 – 1000 
60 
150 – 200 
2 / 3 
3 / 3 
Macaque 
[4 – 5 kg] 
150 
30 – 37.5 
60 
12 – 15 
4 / 6 
6 / 6 
750 
150 – 187.5 
150 
30 – 37.5 
6 / 6 
6 / 6 
Baboon 
300 – A¥ 
20 – 30 
60 
4 – 6 
3 / 4 
4 / 4 


 
 
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Clinical Trial Protocol: V203-AD 
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[10 – 15 kg] 
300 – B¥ 
20 – 30 
60 
4 – 6 
2 / 2 
2 / 2 
1200 
80 – 120 
240 
16 – 24 
2 / 2 
2 / 2 
†  For a 600 μg/mL peptide dosage, CpG ODN dosage is 120 μg/mL and aluminum content is 1600 μg/mL. 
‡  Log10 values >2 are scored as positive anti-Aβ titers. 
§  For use in humans, the concentration of the peptide:CpG ODN immunostimulatory complex is 300 μg peptide to 60 
μg CpG ODN delivered in 0.5 mL Adjuphos by intramuscular route. 
¥  Baboons immunized in Part A at 0 and 3 weeks and in Part B at 78 and 81 weeks (after 72 weeks rest period). 
BW=body weight; NA=not available. 
 
The definitive diagnosis of AD requires the presence of progressive dementia and the 
histopathological evidence from a biopsy or autopsy, i.e. neuritic plaques composed of Aβ 
aggregates and neurofibrillary tangles formed from phosphorylated tau protein15,16. The invention of 
Aβ imaging agent facilitates early evaluation of AD neuropathology and serves as a potential 
biomarker for clinical trials of disease-modifying therapies in AD. The 11C-labeled Pittsburgh 
compound B (11C-PiB) was the first positron emission tomography (PET) imaging agent to 
visualize Aβ plagues in living patients17,18. Rinne and colleagues have successfully demonstrated 
changes in Aβ load in AD patients treated with bapineuzumab, a passive immunotherapy targeting 
the N terminus of Aβ, by 11C-PiB PET19. However, its utilization is limited by a short half-life of 
20 minutes. Florbetapir F18 (also known as 18F-AV-45, Avid Radiopharmaceuticals, Inc. and Eli 
Lilly and Company), a radioactive diagnostic agent tagged with a radioisotope, fluorine-18, was 
recently approved by U.S. FDA with satisfying safety and effectiveness profiles, and a preferable 
half-life of 110 minutes as compared to 11C-PiB20. In this Phase IIa trial, the change of Aβ burden in 
brain as a proof-of-concept for the mechanism of UB-311 will be evaluated by using 18F-AV-45 
PET imaging. 
A follow-up report on a Phase I study showed that immunization with AN1792 could completely 
remove amyloid plaques as demonstrated by postmortem assessment, but patients still had the 
symptoms of end-stage dementia before death21. This finding suggests that clearance of amyloid 
plaques alone cannot repair existing damaged neurons and prevent disease progression. Increasing 
evidence from patients with mild-to-moderate AD has shown that the disease might be already 
beyond the disease-modifying effect of an immunotherapy22. Thus it would be reasonable to initiate 
treatment with disease-modifying effect before substantial neuronal loss or neuropathologic change 
that has damaged the brain. In the Phase I clinical trial with UB-311, a subset of older patients (age 
>60 years) with higher baseline MMSE scores (MMSE >20) showed both high antibody responses 
to the UB-311 vaccine after 3 dosages and improved clinical profiles as assessed by ADAS-Cog, 
MMSE and ADCS-CGIC scores23. Thus, subjects with mild AD are selected as the target patient 
population in this Phase IIa study to further demonstrate the safety and tolerability, establish the 
efficacy profiles, and explore other clinical benefits of UB-311. The Phase IIa clinical study will 
evaluate UB-311 as a promising candidate for active immunotherapy of mild Alzheimer’s disease. 


 
 
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Clinical Trial Protocol: V203-AD 
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2 
OBJECTIVES 
The primary objectives of this study are to assess the safety and tolerability of two regimens of 
UB-311, and to evaluate the immunogenicity of two regimens 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 
functional performance over a period of 78 weeks, and to investigate whether UB-311 treatment 
results in changes in amyloid deposition in vivo by 18F-AV-45 PET imaging. 
 
3 
TRIAL DESIGN 
This is a 78-week, randomized, double-blind, placebo-controlled, three-arm parallel-group, 
multicenter Phase IIa trial.  
Individuals who were enrolled in the Phase I trial will be excluded from the Phase IIa trial. 
 
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 first and second stage screenings, 
 A 60-week double-blind randomized treatment period, which includes 2 different UB-311 dosing 
regimen arms and 1 placebo arm, and 
 An 18-week follow-up period. 
 
Table 3.1 Clinical Schematic Diagram 
 
 
Screening 
Treatment 
Follow-up 
Visit 
S1 
S2 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 V11 V12 V13 
Week 
-6  ~  0 
0 
4 
12 
16 
24 
28 
36 
40 
48 
52 
60 
64 
78 
Treatment arms 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm 1 
 
 
↑ 
↑ 
↑ 
 
↑ 
 
↑ 
 
↑ 
 
↑ 
 
 
Arm 2 
 
 
↑ 
↑ 
↑ 
 
↑p 
 
↑ 
 
↑p 
 
↑ 
 
 
Arm 3 
 
 
↑p ↑p ↑p 
 
↑p 
 
↑p 
 
↑p 
 
↑p 
 
 
↑: UB-311  ↑p: placebo 
 
3.1.1 Screening Period 
Subjects with probable Alzheimer’s disease based on National Institute of Neurological and 
Communicative Disorders and Stroke, and Alzheimer’s Disease and Related Disorders Association 
(NINCDS-ADRDA) Criteria and National Institute on Aging–Alzheimer’s Association (NIA-AA) 
guidelines are screened at the first stage screening (S1, Weeks -6~0). All laboratory tests required 


 
 
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Clinical Trial Protocol: V203-AD 
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for evaluating the eligibility of the subjects are performed at S1. 
Subjects meeting inclusion criteria 1 to 14 and none of the exclusion criteria are eligible for the 
second stage screening (S2, Weeks -6~<0) for the positive of β amyloid (Aβ) plaques on 18F-AV-45 
PET by an imaging expert per central independent review (See Section 3 of Appendix 1 Imaging 
Protocol). 
 
3.1.2 Treatment Period 
Subjects meeting all inclusion criteria, presenting no exclusion criteria, and with Aβ imaging in the 
brain enter the treatment period, from V1 (Week 0) to V11 (Week 60). These subjects are 
randomized into one of the 3 treatment arms before treatment initiation at V1. 
 
3.1.3 Follow-up Period  
The follow-up period comprises 2 visits: V12 (Week 64) and V13 (Week 78).  
 
3.2 Endpoints 
 
3.2.1 Primary 
The primary endpoints of this study are:  
 Safety and tolerability of UB-311 during the study period. 
 The immunogenicity of UB-311 as measured by 
– Change from baseline in anti-Aβ antibody levels through the end of the study 
– Response rate (see section 6.1.2 for definition) 
 
3.2.2 Secondary 
The secondary endpoints are: 
 The change from baseline in cognitive, functional, and global assessments through the end of the 
study, including: 
– Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) 
– Mini-Mental State Exam (MMSE) 
– Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) 
– Clinical Dementia Rating-Sum of Boxes (CDR-SB)  
– Neuropsychiatric Inventory (NPI) 
 The change of amyloid burden from baseline to Weeks 52 and 78 in retention of 18F-AV-45, 
determined by mean standard uptake value ratio (SUVR) of selected regions of interests (ROIs), 
such as frontal, temporal, parietal, occipital, and precuneus. 


 
 
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3.3 Description of Blinding Methods 
The UB-311 and placebo vials are indistinguishable by appearance. Each treatment box is labeled 
with a number, which is generated by a computer program from UNS’s delegate CRO. Investigators 
do not have access to the randomization code except under circumstances described in section 6.4. 
To maintain the blind during the trial, neither the investigator nor the sponsor will have access to the 
data that could potentially compromise study blindness during the study. 
 
3.4 Description of Randomization 
The list of randomized numbers of treatment kits is generated centrally by UNS’s delegate CRO. 
UB-311 and/or placebo are packaged in accordance with this list. 
UNS’s delegate CRO provides a list of the randomized treatment box number and a randomization 
scheme to the Interactive Voice or Web Response System (IVRS/IWRS). The IVRS/IWRS 
generates the subject randomization list to allocate the treatments to subjects. 
Subjects are randomized to one of the three arms in 1:1:1 ratio, providing a projected equal 
distribution of subjects among groups. 
 
3.5 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 
endpoints, such as MRI results. If the causality assessment confirms that the SAE is definitely 
related to the study drug, and the committees of the Data and Safety Monitoring Board (DSMB), 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 
It is planned to recruit approximately 45 subjects (15 per arm) to receive study treatment in the 
78-week double-blind, placebo-controlled study. The randomization procedure continues until the 
target number of treated patients is reached. 
The screen failure rate is estimated to be 50%; therefore, to reach this number it is planned to screen 
at least 90 subjects. 
4.2 Inclusion Criteria 
For inclusion in the study subjects must fulfil all of the following criteria:  
1. Male or female aged between 60-90 years old. 
2. Probable Alzheimer’s disease based on the National Institute of Neurological and 
Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders 
Association (NINCDS-ADRDA) criteria and National Institute on Aging–Alzheimer’s 
Association (NIA-AA) guidelines. 
3. Mini-Mental State Examination (MMSE) scores between 20 and 26 (inclusive). 
4. Clinical dementia rating (CDR) scores of 0.5 or 1. 
5. At least 6 years of education or sufficient work history (to exclude mental retardation). 
6. Visual and auditory acuity adequate for neuropsychological testing. 
7. 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. 
8. Hachinski ischemic score (HIS) ≤4 (original score). 
9. Geriatric Depression Scale-Short Form (GDS-SF) <6. 
10. Eastern Cooperative Oncology Group (ECOG) performance status 0-2. 
11. 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. 
12. 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), to perform study-related 
AD scales and to accompany or delegate a companion with the subject to all visits. A 
companion needs not to be a family member (with kinship).  
13. Both patient and his/her caregiver should sign the written informed consent before undergoing 
any study procedures. 
14. Agree not to donate blood or blood products for transfusion during the study and for 3 months 
thereafter. 


 
 
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15. A positive of Aβ plaque on 18F-AV-45 PET by an imaging expert (confirmed during the second 
stage of screening per central independent review). 
 
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 MRI scan with evidence of central nerves system (CNS) infection, cerebrovascular 
disease, infarction, or other focal lesions, or a single area of superficial siderosis, or a prior 
macrohemorrhage, or more than four microhemorrhages, multiple lacunes or lacunes in a 
critical memory structure. 
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. Current participation in clinical studies involving ADAS-Cog, MMSE, ADCS-ADL, CDR-SB, 
or NPI being collected more than one time per score per year. 
13. Previous exposure to any anti-Aβ immunotherapy. 
14. 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). 
15. Received blood or blood derivatives treatment within 3 months prior to screening. 


 
 
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16. Positive serology for hepatitis B virus (HBV), hepatitis C virus (HCV), or human 
immunodeficiency virus (HIV). 
17. 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.  
18. Abnormal clinical laboratory values as listed below, and determined to be clinically significant 
by the investigator at the screening: 
– Serum antinuclear antibody (ANA) >1:80 
– Rheumatoid factor (RF) result is >17 IU/mL 
– Platelets <150,000 or >500,000/mm3 
– White blood cells (WBC) <3,000 or >10,500/mm3  
– Absolute neutrophil count (ANC) <1,500/mm3 
– Prothrombin time (PT) <9 or >13 seconds 
– Activated partial thromboplastin time (aPTT) <26.9 or >36.3 seconds 
– Serum creatinine >2 mg/dL 
– Glycosylated hemoglobin (HbA1c) >8.5% 
– Erythrocyte sedimentation rate (ESR) > age-adjusted upper limit of reference range 
(ULRR), i.e. over 50 years old: male >20 mm/hr, female >30 mm/hr; over 85 years old: 
male >30 mm/hr, female >42 mm/hr 
– C-reactive protein (CRP) >0.5 mg/dL 
– Aspartate aminotransferase (AST) >84 U/L 
– Alanine aminotransferase (ALT) >80 U/L 
 
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 13/ET (see sections 8.2 and 8.3) 
should be completed at the early termination visit when applicable, including: ECG, physical 
examination, vital signs, clinical chemistry and hematology tests, serum anti-Aβ antibody level 
evaluation, recordation of any AE/SAE, concomitant treatments (medications/therapy), imaging 
evaluations (18F-AV-45 PET and MRI), and neuropsychological tests (including MMSE, CDR-SB, 
ADAS-Cog, ADCS-ADL, and NPI). 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 78), 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. 
Placebo: delivery vehicle without UB-311 active peptides and CpG. 
 
5.2 Dosing Regimens and Rationale 
Eligible subjects are randomly assigned in 1:1:1 ratio to one of the following treatments:  
 Arm 1: UB-311 for a total of 7 intramuscular (IM) injections at Weeks 0, 4, 12, 24, 36, 48, and 
60. 
 Arm 2: UB-311 for a total of 5 IM injections at Weeks 0, 4, 12, 36, and 60. In order to maintain 
the blindness, subjects assigned to arm 2 will receive 2 IM injections of placebo at Weeks 24 and 
48. 
 Arm 3: placebo for a total of 7 IM injections at Weeks 0, 4, 12, 24, 36, 48, and 60. 
Injections will be given on alternate arms or at different sites, which will be recorded. 
The 300 µg of UB-311 in 0.5 mL sterile aqueous solution is the maximal concentration feasible in 
the current intramuscular injection formulation containing CpG-ODN and Adjuphos. Therefore, the 
dose escalation in the Phase IIa study will be based on the cumulative doses according to various 
treatment schedules instead of different amount of UB-311 per injection.   
A total of three injections of UB-311 at Weeks 0, 4, and 12 with a cumulative dose of 900 µg were 
evaluated in the Phase I clinical trial that showed acceptable safety, tolerability, immunogenicity, 
and positive clinical outcome in mild to moderate AD patients over a one–year period. In the Phase 
IIa study, the dose will be escalated based on increased number of injections than the Phase I study. 
Subjects assigned to Arm 1 will receive 7 injections of UB-311, 300 µg each at Weeks 0, 4, 12, 24, 
36, 48, and 60 with a cumulative dose of 2,100 µg. Subjects assigned to Arm 2 will receive 5 
injections of UB-311, 300 µg each at Weeks 0, 4, 12, 36, and 60 with a cumulative dose of 1,500 
µg.  
The Phase I study showed that three priming doses at Weeks 0, 4, and 12 successfully established 
sufficient immunogenicity against Aβ, thus the priming schedule was adopted for the current study. 
Additional doses for Arm 1 and Arm 2 at the frequency of 3 and 6 months, respectively, are 
intended to assess the requirement for maintaining elicited antibody levels. Furthermore, the dosing 
regimen of Arm 1 represents the most frequent injection schedule, allowing evaluation of safety and 
efficacy of the strongest antibody response.  
 
5.3 Handling of Study Drug 
 
5.3.1 Packing and Labelling 


 
 
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The treatment box for each subject includes 7 vials numbered in the order of injection. The boxes 
for Arm 1 contain 7 vials of UB-311. The boxes for Arm 2 contain 5 vials of UB-311 and 2 vials of 
placebo. The boxes for Arm 3 contain 7 vials of placebo. Each box and vial is labelled with the 
randomization code, storage condition, and manufacturer. 
 
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. 
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 (e.g. 
antihypertensives). 
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 and 
during the study period. 
 Ginkgo biloba 
 Piracetam (Nootropil) 
 Vitamin E (400 IU/day) 
 
5.5.2 Prohibited Medicines 


 
 
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The following medications are prohibited within 4 weeks prior to the first screening visit (S1) 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 
 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 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 from baseline in anti-Aβ antibody levels through the end of the study (Week 78) 
 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 
V13 (Weeks 0/baseline, 4, 12, 16, 24, 28, 36, 40, 48, 52, 60, 64, and 78). For visits that UB-311 or 
placebo is scheduled to be administrated (V1, V2, V3, V5, V7, V9, and V11), 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 9.2.2 for definition) at any visit after baseline. Response rate will be 
calculated as the percent of the number of antibody responders versus the total number of subjects 
for each arm. 
 
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 endpoints in this study. 
 
6.3.1 Evaluation variables 
6.3.1.1 The change from baseline in cognitive, functional, and global assessments through the end 
of the study 
 Cognition: ADAS-Cog and MMSE 
 Function: ADCS-ADL 


 
 
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 Global: CDR-SB 
 Behavior: NPI 
 
6.3.1.2 The change of amyloid burden from baseline to Week 52 and Week 78 in retention of 
18F-AV-45  
The data will be expressed by mean regional standard uptake value ratio (SUVR). 
 
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 and CDR/CDR-SB are evaluated at the first screening (S1), and at Weeks 24 (V5), 48 (V9) 
and 78 (V13). ADAS-Cog, ADCS-ADL, and NPI are evaluated at baseline (V1), and at Weeks 28 
(V6), 52 (V10) and 78 (V13). 
 
6.3.2.2 18F-AV-45 retention measurement  
18F-AV-45 PET is conducted at the second screening (S2), and at Weeks 52 (V10) and 78 (V13) to 
assess the change in Aβ burden from baseline to Weeks 52 and 78 (see Section 3 of Appendix 1 
Imaging Protocol).  
In case of scanning failure, re-injection/re-scanning of 18F-AV-45 is allowed. The detailed 
procedures of 18F-AV-45 PET are described in a separate manual, 18F-AV-45 PET Imaging 
Manual. 
 
6.4 Measures to protect blinding of this trial 
This is a double-blind study. In order to protect blinding, study drug will be labelled with individual 
unique randomization codes. 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 call IVRS/IWRS 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.  
The treatment arm for each subject will be coded so that the subject, investigator, and research staff 
do not know the arm assignment until the end of the study. Personnel related to analysis, statistics, 
and report writing will remain blinded before database lock. 


 
 
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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 0 (V1/baseline), 4 (V2), 12 (V3), 24 (V5), 36 (V7) 48 (V9), and 60 (V11). 
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 (S1 and S2) and at every 
visit throughout the study (V1 to V13). Neurology examination and vital signs will be assessed 
again 30-60 minutes after study drug injection at Weeks 0 (V1/baseline), 4 (V2), 12 (V3), 24 (V5), 
36 (V7), 48 (V9), and 60 (V11). 
   
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 the first screening (S1) and at Weeks 52 (V10) and 78 (V13). 
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. 


 
 
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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.  
 
7.1.5 MRI 
MRI is performed at the first screening (S1) and at Weeks 12 (V3), 24 (V5), 36 (V7), 48 (V9), 60 
(V11), and 78 (V13) to monitor ARIA and age-related white matter changes (ARWMC) that may 
be induced by amyloid-modifying therapy. Please refer to Appendix 1 Imaging Protocol for the 
detailed methods.  
 
7.1.6 Safety laboratory 
The following laboratory data are collected: 
 
Hematology: complete blood count including differential cell count and absolute neutrophil 
count at the first screening (S1) and every visit throughout the study (V1 to V13). 
 
Clinical chemistry: HbA1c at the first screening (S1); glucose AC, AST, ALT, bilirubin, 
sodium, total protein, BUN, creatinine, potassium, and albumin at the first screening (S1) and 
every visit throughout the study (V1 to V13). 
 
Inflammatory parameters: RF and ANA at the first screening (S1); CRP and ESR at the first 
screening (S1), and at Weeks 4 (V2), 16 (V4), 28 (V6), 40 (V8), 52 (V10), and 64 (V12); 
TNF-α, IL-6, and IL-8 at Weeks 0 (V1), 4 (V2), and 64 (V12). 
For visits that UB-311 or placebo is scheduled to be administered (V1, V2, V3, V5, V7, V9, and 
V11), 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. 


 
 
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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 
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, 


 
 
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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, 
 
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: 


 
 
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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 
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. 


 
 
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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 
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. 


 
 
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The sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report (CSR). 
 
7.9 Data and Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) with members independent from the sponsor and the 
clinical investigators is implemented in order to ensure the protection and safety of enrolled patients 
in the study. The DSMB members include: 
 An expert in the clinical aspects of the Alzheimer’s disease patient population being studied, 
 A biostatistician, and 
 An investigator with expertise in current clinical trials conduct and methodology. 
Each DSMB member will sign a Conflict of Interest Statement at the time they are invited to 
participate to declare that he/she does not have financial, proprietary, professional, or other interests 
that may affect impartial, independent decision-making by the DSMB. 
The DSMB is responsible for reviewing safety data, study conduct, and progress. Based on the 
review, the DSMB makes recommendations to the clinical investigators concerning the continuation, 
modification, or termination of the trial. In the V203-AD trial, the DSMB will convene for the first 
time after the 9th subject completes Visit 6, for the second time after the 18th subject completes Visit 
10, and for the third time after the 27th subject completes V13 to assess the safety data in the 
V203-AD trial. An emergency meeting of the DSMB may be called at any time by the DSMB Chair 
should questions on participants’ safety or other unanticipated problems arise. 
It is the responsibility of CRO or sponsor to ensure that the DSMB is informed about safety 
information relevant to the study. This includes providing the DSMB with preclinical data, results 
from the phase I study, and the phase IIa protocol before initiation of the trial, and a DSMB report 
at least one week prior to a scheduled meeting. The CRO is responsible for preparing the DSMB 
briefing materials, which consist of: 
 Subject recruitment, retention, and withdrawal information 
 AEs and SAEs 
– Tabulated by preferred term, intensity, seriousness, duration, treatment given, and the 
relationship to the study drug and study procedure 
– Individual events of particular concern 
 Tabulated clinical test results and laboratory values (e.g. raw values, changes/shifts from 
baseline, and clinical abnormalities), including clinical chemistry, hematology tests, and 12-lead 
electrocardiogram (ECG) 
 Vital signs and physical exam outcomes 
 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. 
Any other safety-related data requested by the DSMB 


 
 
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At the conclusion of a DSMB meeting, the DSMB will issue a summary report, which documents 
the review of data and outcomes across all sites took place on a given date. It should summarize the 
DSMB members’ opinions on the cumulative data reported from all participating sites without 
disclosure by treatment arm. It should also inform clinical investigators of the DSMB members’ 
conclusions with respect to progress or need for modification of the protocol. The summary report 
will be forwarded to each clinical investigator and the sponsor. The clinical investigator is required 
to transmit the summary report to his/her local IRB. 
 
7.10 Risk Management 
Postvaccination meningoencephalitis was reported in over 6% of patients treated with AN1792 for 
AD9,10. Based on the experiences of AN1792 clinical trials, the following measures are used to 
manage potential risks: 
1. Strict Enrollment Criteria 
Subjects with any evidence of CNS infection, infarction, other focal lesions, more than four 
microhemorrhages, multiple lacunes or lacunes in a critical memory structure by MRI, as well as 
having history of autoimmune disease will be excluded from the study. 
2. Sample Size 
A total of 45 subjects are planned to be enrolled. Among them, 30 subjects receiving UB-311 are 
anticipated to be able to detect an adverse event with an incidence of 4%. 
3. Regular MRI evaluations 
Brain MRI scans will be performed every 12 weeks during the treatment period and also at the 
end of study to ensure that any change or lesion in the brain, such as meningoencephalitis, 
vasogenic edema or microhemorrhage can be detected as early as possible.  
4. Regular Clinical Monitoring 
Clinical symptoms and laboratory data of hematology and clinical chemistry will be monitored 
closely throughout the study. Adverse events will be followed until conditions are resolved or 
stabilized. 
5. Establishment of DSMB 
DSMB will be implemented in this trial and DSMB meetings will be held as scheduled to ensure 
the protection and safety of enrolled subjects. DSMB meeting will also be held in response to 
any urgent safety events. 
6. Meningoencephalitis Management by Investigator 
If meningoencephalitis occurs, investigator will treat the subject with standard clinical 
procedures, such as giving bed rest, avoiding daylight, supplying fluid, and providing 
medications for pain control including anti-inflammatory, anti-convulsant and anti-emetic drugs. 
Corticosteroids may be prescribed to reduce tissue swelling or cerebral edema if necessary. 


 
 
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8 
STUDY PROCEDURES 
 
8.1 Study Visits 
The study consists of a screening period (up to 6 weeks) with 2 visits, a double-blind, 
placebo-controlled treatment period (60 weeks) with 11 visits, and a double-blind follow-up period 
(18 weeks) with 2 visits. From V2 (Week 4) to V12 (Week 64), a time frame of  3 days is 
acceptable using the day of V1 as reference (Day 0), i.e. if one visit date is changed, the next visit 
should take place according to the original schedule. For V13 (Week 78), a time frame of  7 days 
is acceptable using the day of V1 as reference. Out of visit/dosing window and missing visit/dose 
are considered as protocol deviations. Additional items for research purposes at each visit will be 
described in details in a separate research protocol (Appendix 2). 
 
8.1.1 The First Stage Screening (-42 < Day < 0) 
The first screening (S1) may take place no more than 42 days prior to randomization. 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 except for 18F-AV-45 PET imaging 
 Demographics (age, gender, race, years of education) 
 Complete medical history and concomitant diseases 
 Concomitant and previous medication (within the last 3 months)  
 Physical examination and height 
 Vital signs, including temperature, respiratory rate, heart rate, blood pressure, and body weight 
 Structural MRI scanning 
 12-lead ECG 
 Survey instruments 
– NINCDS-ADRDA 
– HIS score 
– MMSE 
– CDR / CDR-SB 


 
 
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– ECOG 
– GDS-SF 
 Record of adverse event (AE) and serious adverse event (SAE) 
 Blood collection for testing of: 
– HIV, HCV, and HBsAg 
– RF, ANA, CRP, ESR, PT, and aPTT 
– Serum pregnancy test (only for females with childbearing potential) 
– 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) 
 
8.1.2 The Second Stage Screening (-42 < Day < 0) 
This visit is scheduled between the first stage screening visit and visit 1 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  
 18F-AV-45 PET imaging  
 
8.1.3 Visit 1 (Week 0, Day 0 / baseline) 
This visit (V1) should be scheduled within 6 weeks after S1 and includes: 
 Verification of Inclusion/Exclusion criteria and check for eligibility 
 IVRS/IWRS call for randomization 
 Survey instruments 
– ADAS-Cog 
– ADCS-ADL 
– NPI 
 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) 


 
 
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– Anti-Aβ 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) 
– APO-E genotyping 
 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 2 (Week 4, Day 28) 
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 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 assessment, vital signs (except body weight), and neurology examination of 
physical examination 30-60 minutes after injection 
 
8.1.5 Visit 3 (Week 12, Day 84) 
This visit (V3) should be scheduled 12 weeks  3 days after V1 and includes: 
 Structural MRI scanning (should be scheduled < 7 days before the injection of study drug) 
 Record of AEs and SAEs 
 Record of the use or change of any concomitant medications 
 Physical examination 


 
 
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 Vital signs, including temperature, respiratory rate, heart rate, blood pressure, and body weight 
 Blood collection for: (before the UB-311/Placebo injection) 
– Anti-Aβ 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) 
 Injecting study drug 
 Injection site assessment, vital signs (except body weight), and neurology examination of 
physical examination 30-60 minutes after injection 
 
8.1.6 Visit 4 (Week 16, Day 112) 
This visit (V4) should be scheduled 16 weeks  3 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 
 Blood collection for: 
– Anti-Aβ 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) 
 
8.1.7 Visit 5 (Week 24, Day 168) 
This visit (V5) should be scheduled 24 weeks  3 days after V1 and includes: 
 Structural MRI scanning (should be scheduled < 7 days before the injection of study drug) 
 Survey instruments 
– MMSE 
– CDR-SB 
 Record of AEs and SAEs 
 Record of the use or change of any concomitant medications 


 
 
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 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 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) 
 Injecting study drug 
 Injection site assessment, vital signs (except body weight), and neurology examination of 
physical examination 30-60 minutes after injection  
 
8.1.8 Visit 6 (Week 28, Day 196) 
This visit (V6) should be scheduled 28 weeks  3 days after V1 and includes: 
 Survey instruments 
– ADAS-Cog 
– ADCS-ADL 
– NPI 
 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 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) 
 
8.1.9 Visit 7 (Week 36, Day 252) 
This visit (V7) should be scheduled 36 weeks  3 days after V1 and includes: 
 Structural MRI scanning (should be scheduled < 7 days before the injection of study drug) 


 
 
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 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/Placebo injection) 
– Anti-Aβ 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) 
 Injecting study drug 
 Injection site assessment, vital signs (except body weight), and neurology examination of 
physical examination 30-60 minutes after injection  
 
8.1.10 Visit 8 (Week 40, Day 280) 
This visit (V8) should be scheduled 40 weeks  3 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 
 Blood sampling for: 
– Anti-Aβ 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) 
 
8.1.11 Visit 9 (Week 48, Day 336) 
This visit (V9) should be scheduled 48 weeks  3 days after V1 and includes: 
 Structural MRI scanning (should be scheduled < 7 days before the injection of study drug) 
 Survey instruments 
– MMSE 


 
 
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– CDR-SB 
 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/Placebo injection) 
– Anti-Aβ 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) 
 Injecting study drug 
 Injection site assessment, vital signs (except body weight), and neurology examination of 
physical examination 30-60 minutes after injection  
 
8.1.12 Visit 10 (Week 52, Day 364)  
This visit (V10) should be scheduled 52 weeks  3 days after V1 and includes: 
 18F-AV-45 PET scanning (a time frame of  7 days is acceptable)  
 12-lead ECG 
 Survey instruments 
– ADAS-Cog 
– ADCS-ADL 
– NPI 
 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: 
– Anti-Aβ antibodies 
– CRP and ESR 
– Clinical chemistry (glucose AC, AST, ALT, bilirubin, sodium, total protein, BUN, 
creatinine, potassium, and albumin) 


 
 
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– Hematology (complete blood count including differential cell count and absolute 
neutrophil count) 
 
8.1.13 Visit 11 (Week 60, Day 420) 
This visit (V11) should be scheduled 60 weeks  3 days after V1 and includes: 
 Structural MRI scanning (should be scheduled < 7 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 sampling for: (before the UB-311/Placebo injection) 
– Anti-Aβ 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) 
 Injecting study drug 
 Injection site assessment, vital signs (except body weight), and neurology examination of 
physical examination 30-60 minutes after injection 
 
8.1.14 Visit 12 (Week 64, Day 448) 
This visit (V12) should be scheduled 64 weeks  3 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 
 Blood sampling for: 
– Anti-Aβ 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) 
 


 
 
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8.1.15 Visit 13 (Week 78, Day 546)  
This visit (V13) should be scheduled 78 weeks  7 days after V1 and includes: 
 Structural MRI scanning 
 18F-AV-45 PET scanning 
 12-lead ECG 
 Survey instruments 
– MMSE 
– CDR-SB 
– ADAS-Cog 
– ADCS-ADL 
– NPI 
 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: 
– Anti-Aβ 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) 
 


 
 
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8.2 Events and Time Schedule 
Visit 
S19 
S29 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
Week 
-6  ~  0 0/BL 
4 
12 
16 
24 
28 
36 
40 
48 
52 
60 
64 
78/ET 
Day 
-42  ~  0 
0 
283 843 1123 1683 1963 2523 2803 3363 3643 4203 4483 5467 
ICF, medical history & 
concomitant disease, 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Incl./excl. criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
MRI1 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
18F-AV-45 PET2 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
APO-E genotyping 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
NINCDS-ADRDA, HIS, 
GDS-SF, ECOG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMSE, CDR3/CDR-SB 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
ADAS-Cog, ADCS-ADL & 
NPI 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
AE/SAE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Previous and 
concomitant medicines 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PE4/vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV, HCV, HBsAg test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical chemistry5 & 
hematology5 
X 
 
X* 
X* 
X* 
X 
X* 
X 
X* 
X 
X* 
X 
X* 
X 
X 
Inflammatory6 
X 
 
X 
X* 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PT & aPTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-Aβ Ab level in 
serum 
 
 
X* 
X* 
X* 
X 
X* 
X 
X* 
X 
X* 
X 
X* 
X 
X 
Vaccination/injection 
site assessment/ 
Neurology/vital signs8 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
vMRI 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
fMRI 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Plasma Aβ40/42 levels 
 
 
X* 
X* 
X* 
X 
X* 
X 
X* 
X 
X* 
X 
X* 
X 
X 
Anti-Aβ1-42 monomer 
& oligomer 
Antibodies 
 
 
X* 
X* 
X* 
X 
X* 
X 
X* 
X 
X* 
X 
X* 
X 
X 
CSF tau & Aβ40/42 levels 
(optional) 
 
 
X* 
 
 
 
 
 
 
 
 
X 
 
 
X 
BL=baseline; ET=early termination; vMRI=volumetric magnetic resonance imaging; fMRI=functional magnetic resonance 
imaging 
1. For V3 (Week 12), V5 (Week 24), V7 (Week 36), V9 (Week 48), and V11 (Week 60), MRI should be scheduled <7 days before 
the injection of study drug. For V13, a time frame of  7 days is acceptable. 
2. For V13, a time frame of  7 days is acceptable. 
3. CDR: for S1 only 
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 V13); Hematology: complete blood count including differential 


 
 
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cell count and ANC at S1 and every visit throughout the study (V1 to V13). 
6. Inflammatory parameters: RF and ANA (for S1 only); CRP and ESR: for S1, V2 (Week 4), V4 (Week 16), V6 (Week 28), V8 
(Week 40), V10 (Week 52), and V12 (Week 64); TNF-α, IL-6, and IL-8: for V1, V2 (Week 4), and V12 (Week 64). 
7. For females with childbearing potential. 
8. 30-60 minutes after injection. Vital sign: not need to measure body weight. 
9. Criteria are screened at S1. Subjects meeting inclusion criteria 1 to 14 and none of the exclusion criteria are eligible for the S2. 
S1 and S2 should be done within 6 weeks before V1. 
* 
Blood or CSF specimens should be drawn before the UB-311/Placebo injection. 
8.3 Blood Sample Collection 
For visits that UB-311 or placebo is scheduled to be administrated (V1, V2, V3, V5, V7, V9, and 
V11), blood samples will be collected before the treatment. 
Visit 
S1 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
Week 
-6~0 0/BL 
4 
12 
16 
24 
28 
36 
40 
48 
52 
60 
64 
78/ET 
Day 
-42~0 
0 
283 843 1123 1683 1963 2523 2803 3363 3643 4203 4483 5467 
Vaccination 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Clotted Blood 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HCV, 
HBsAg, RF, 
ANA and 
serum 
pregnancy 
test1 
5 mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
chemistry2 
except HbA1c 
and Glucose 
AC, CRP3 
5 mL 5 mL 5 mL 5 mL 5 mL 5 mL 5 mL 5 mL 5 mL 5 mL 5 mL 5 mL 5 mL 
5 mL 
TNF-α, IL-6, and 
IL-8 
 
3.5 
ml 
3.5 
ml 
 
 
 
 
 
 
 
 
 
3.5 
ml 
 
Anti-Aβ, and 
anti- Aβ1-42 
monomer4 
and oligomer4 
 
2 mL 2 mL 2 mL 2 mL 2 mL 2 mL 2 mL 2 mL 2 mL 2 mL 2 mL 2 mL 
2 mL 
EDTA Blood 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology5 
and HbA1c6 
3 mL 3 mL 3 mL 3 mL 3 mL 3 mL 3 mL 3 mL 3 mL 3 mL 3 mL 3 mL 3 mL 
3 mL 
ESR 
3 mL 
 
3 mL 
 
3 mL 
 
3 mL 
 
3 mL 
 
3 mL 
 
3 mL 
 
APO-E 
genotyping 
 
3 mL 
 
 
 
 
 
 
 
 
 
 
 
 
Aβ40/42
4 
 
2 mL 2 mL 2 mL 2 mL 2 mL 2 mL 2 mL 2 mL 2 mL 2 mL 2 mL 2 mL 
2 mL 
NaF Blood 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Glucose AC 
2 ml 2 ml 2 ml 2 ml 
2 ml 
2 ml 
2 ml 
2 ml 
2 ml 
2 ml 
2 ml 
2 ml 
2 ml 
2 ml 
Citrated Blood 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT, aPTT 
2.7 
mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
BL=baseline; ET=early termination  
Note: In the case of testing failure, residual samples of the subject from other tests may be used for retesting. 


 
 
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1. Only for females with childbearing potential; 
2. Clinical chemistry: AST, ALT, bilirubin, sodium, total protein, BUN, creatinine, potassium, and albumin at S1 and every visit 
throughout the study (V1 to V13);  
3. CRP: for screening, V2 (Week 4), V4 (Week 16), V6 (Week 28), V8 (Week 40), V10 (Week 52), and V12 (Week 64); 
4. For research study; 
5. Hematology: complete blood count including differential cell count and ANC at S1 and every visit throughout the study (V1 to 
V13); 
6. HbA1c: for screening only. 


 
 
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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 Determination of Sample Size 
This early phase clinical trial is exploratory in nature; hence, the sample size is determined to assess 
the primary objective of safety, tolerability, and immunogenicity of UB-311. The total of 45 
subjects is planned to be enrolled, 15 per arms. For each UB-311-treated arm, 15 subjects are 
thought to be sufficient to detect an adverse event with an incidence of 7%. Furthermore, 30 
subjects receiving UB-311 are anticipated to be able to detect an adverse event with an incidence of 
4%. 
 
9.2 Analysis Variables 
 
9.2.1 Demographic and baseline characteristics 
The baseline value is defined as the last available value before the first injection of study drug. The 
following demographic and baseline disease characteristics will be summarized by treatment, by 
study center and overall for the randomized and treated population. 
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 
 
Race 
Disease characteristics including: 
 
Disease duration (years): (date of informed consent – date of diagnosis)/365.25 
 
APO-E genotype 
 
Baseline scores of ADAS-Cog, MMSE, ADCS-ADL, CDR/CDR-SB, and NPI 
 
18F-AV-45 retention (SUVR) 
 
Physical examination, medical history and concomitant disease, previous and concomitant 
medication, and HIS score 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.   


 
 
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9.2.2 Immunogenicity variables 
The level of anti-Aβ antibodies is one of the primary endpoints and is assessed at baseline (V1) and 
every following visit (V2 to V13). The one-sided 95% confidence interval (CI, right side) from all 
visits (V1 to V13) for subjects in Arm 3 (placebo group) 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 baseline. Response rate will be calculated for each arm. 
 
9.2.3 Efficacy variables 
 
9.2.3.1 Rating scales 
ADAS-Cog, ADCS-ADL, and NPI are rated at baseline (V1), Week 28 (V6), Week 52 (V10) and 
Week 78 (V13), while MMSE and CDR/CDR-SB are assessed at the first screening (S1), Week 24 
(V5), Week 48 (V9) and Week 78 (V13). 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.  
 
9.2.3.2 18F-AV-45 retention 
18F-AV-45 PET scanning is performed at the second screening (S2), Week 52 (V10), and Week 78 
(V13). No procedure for handling missing assessments will be applied if there is a missing value. 
 
9.2.4 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 (HbA1c, 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) 
 
9.3 Analysis Populations 
9.3.1 Efficacy populations 


 
 
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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 randomized 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. 
9.3.2 Safety population 
The safety population is the total treated population defined as all subjects randomized and 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. 
 
9.3.3 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 
 
Randomized subjects: subjects who receive a randomization number via IVRS/IWRS 
 
The safety population (as defined in Section 9.3.2) 
 
The mITT population (as defined in Section 9.3.1) 
 
The PP population (as defined in Section 9.3.1) 
For the following two categories of subjects, counts, and percentages will be calculated for each 
treatment group using the number of randomized subjects in each group as denominator. 
 
Subjects who have completed the 60-week treatment period  
 
Subjects who discontinue the study drug during the treatment period 
 
A list of subjects prematurely withdrawn from the study, along with reasons for discontinuation, 
will be provided. 
 
9.4 Statistical Methods 
Continuous data will be summarized by treatment group using the number of observations available 
(n), mean, standard deviation (SD), median, interquartile range (IQR), minimum, and maximum. 
Categorical data will be summarized by treatment group using count and percentage. Missing data 
will not be categorized in the summaries. 


 
 
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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. 
 
9.4.1 Demographic and baseline characteristics 
 
9.4.1.1 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 by study center, treatment 
group and overall. The distribution of demographic and baseline characteristics among three 
treatment groups will be evaluated using chi-square or Fisher’s exact test for categorical variables 
and the Kruskal-Wallis test or analysis of variance (ANOVA) for continuous variables.  
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 by study center, 
treatment group and overall using counts and percentages. The primary system organ classes and 
preferred terms will be sorted in decreasing order of frequency. 
 
9.4.1.2 Previous and concomitant medications/therapy 
Medications will be classified into the following two groups: 
 
Previous medications are those that the subject took within 24 week period prior to the first 
screening visit (S1) and prior to the first administration of the study drug at Week 0 
(V1/baseline). 
 
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. No statistical 
testing for between-group difference will be performed. 
 
9.4.1.3 Baseline efficacy and safety data 
For efficacy and safety analysis, the baseline for a given parameter is defined as the last available 
value prior to the first injection of the study medication. Baseline efficacy and safety variables will 
be summarized by study center, treatment group, and overall. 
 
9.4.2 Treatment tolerability and compliance 


 
 
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The overall treatment tolerability of UB-311 for each arm 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) 
 
9.4.3 Analysis of immunogenicity variable 
Immunogenicity analyses will be performed on the mITT and PP populations. Response rate will be 
provided for the two active treatment groups (Arm 1 and Arm 2) and the placebo group (Arm 3). 
The change in antibody level will be analyzed by a repeated-measures mixed-effects model.  
 
9.4.4 Analysis of efficacy variables 
Efficacy analyses will be performed on the mITT and PP populations. Descriptive statistics will be 
provided by treatment for all continuous variables at the scheduled visits. Continuous variables with 
repeated measures will be analyzed using a mixed-effects model to compare different treatment 
groups. 
 
9.4.5 Analysis of safety data 
 
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 study medication. 
 
The post-treatment period is defined as the time from after the first dose of study medication to 
the end of the study. 


 
 
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The summary of safety results will be presented by each treatment group. 
 
9.4.5.1 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 in each treatment group, 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 each 
treatment group. 
 
Adverse events leading to treatment discontinuation 
TEAEs leading to treatment discontinuation will be summarized and presented as number and 
percentage of subjects in each treatment group. 
 
Local tolerability at injection site 
The number and percentage of subjects with reaction at injection site will be summarized and 
presented by treatment group. 
 
Vasogenic edema and amyloid imaging related abnormalities  


 
 
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The number and percentage of subjects with amyloid-related imaging abnormalities (ARIA) will be 
summarized and presented by treatment group24. 
 
9.4.5.2 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 study drug 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 
for each treatment group. 
 
9.4.5.3 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 for each treatment group. 
 
9.4.5.4 Analysis of 12-lead ECG status 
Only ECG status (i.e. normal or abnormal) will be reported.  
 
9.4.5.5 Reason for withdrawal 
Reason for withdrawal will be tabulated by study center, treatment group and overall.  
 
 
 


 
 
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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 


 
 
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records, etc.). These personnel, bound by professional secrecy, must maintain the confidentiality of 
all personal identity or personal medical information (according to confidentiality rules). 
 
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.  
An Electronic Case Report Form (e-CRF) will be used in this study. Should a correction be made, 
the correction will be entered in the e-CRF overwriting the initial information. An audit trail will 
allow to identify the modification. 
Data are available within the system to the sponsor as soon as they are entered in the e-CRF. 
The computerized handling of the data by the sponsor after receipt of the CRFs may generate 
additional requests to which the investigator is obliged to respond by confirming or modifying the 
data questioned. The requests with their responses will be managed through the e-CRF. 
 
 


 
 
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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 e-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 
e-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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8. Schenk, D., Hagen, M. & Seubert, P. Current progress in beta-amyloid immunotherapy. Curr. 
Opin. Immunol. 16, 599–606 (2004). 
9. Gilman, S. et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an 
interrupted trial. Neurology 64, 1553–1562 (2005). 
10. Orgogozo, J.-M. et al. Subacute meningoencephalitis in a subset of patients with AD after 
Abeta42 immunization. Neurology 61, 46–54 (2003). 
11. Wang, C. Y. Immunogenic peptide composition for the prevention and treatment of 
Alzheimer’s 
Disease. 
(2004).at 
<http://webcache.googleusercontent.com/search?q=cache:ZcVbsodyWIgJ:www.freepatentsonli
ne.com/y2004/0247612.html+&cd=2&hl=zh-TW&ct=clnk&client=firefox-a> 
12. Wang, C. Y. et al. Site-specific UBITh amyloid-beta vaccine for immunotherapy of 
Alzheimer’s disease. Vaccine 25, 3041–3052 (2007). 
13. Agadjanyan, M. G. et al. Prototype Alzheimer’s disease vaccine using the immunodominant B 
cell epitope from beta-amyloid and promiscuous T cell epitope pan HLA DR-binding peptide. J. 
Immunol. 174, 1580–1586 (2005). 
14. Cribbs, D. H. et al. Adjuvant-dependent modulation of Th1 and Th2 responses to immunization 
with beta-amyloid. Int. Immunol. 15, 505–514 (2003). 
15. Ranginwala, N. A., Hynan, L. S., Weiner, M. F. & White, C. L., 3rd Clinical criteria for the 
diagnosis of Alzheimer disease: still good after all these years. Am J Geriatr Psychiatry 16, 
384–388 (2008). 


 
 
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16. Löppönen, M., Räihä, I., Isoaho, R., Vahlberg, T. & Kivelä, S.-L. Diagnosing cognitive 
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17. Klunk, W. E. et al. Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high 
affinity and readily enter the brain. Life Sci. 69, 1471–1484 (2001). 
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19. Rinne, J. O. et al. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients 
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22. Mangialasche, F., Solomon, A., Winblad, B., Mecocci, P. & Kivipelto, M. Alzheimer’s disease: 
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workgroup. Alzheimers Dement (2011).doi:10.1016/j.jalz.2011.03.003 
 


 
 
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APPENDIX 1: IMAGING PROTOCOL 
 
1 
Introduction 
Since amyloid-modifying therapeutic agents have entered Alzheimer’s disease (AD) clinical trials 
over the past decade, the occurrence of imaging abnormalities has required careful consideration by 
pharmaceutical companies and regulatory authorities. Brain imaging in AD has undergone 
revolutionary changes with the wide availability of an unprecedented array of new techniques. 
18F-AV-45 positron emission tomography (PET) exhibits high affinity specific binding to amyloid 
plaques. Since a negative 18F-AV-45 PET scan result reduces the likelihood that a patient’s 
cognitive impairment is due to AD, it can be an adjunct to other diagnostic evaluations. Various 
magnetic resonance imaging (MRI) methods are typically used in clinical trials of mild cognitive 
impairment (MCI)/AD for three purposes: 1) Eligibility and enrichment; 2) Safety: monitor side 
effects related to the study drug. 3) Efficacy: provide quantitative imaging biomarkers to assess 
drug effects on neurodegeneration longitudinally.  
It is standard practice in AD trials to exclude patients with radiological evidence of 
space-occupying lesions, major vascular disease or infarct. Since the clinical diagnosis of AD 
during life is frequently inaccurate outside of research centers, 18F-AV-45 PET may have value as 
an adjunct to clinical diagnosis. For some amyloid-modifying therapies, microhemorrhages are a 
risk factor for drug side effects. The safety MRI assessments focus on the recently described 
amyloid-related imaging abnormalities (ARIA) seen in therapies directed at amyloid pathway 
modification, “vasogenic edema” and/or sulcal effusion (ARIA-E) and hemosiderin deposits 
(ARIA-H), including microhemorrhages and superficial siderosis. The volumetric MRI (vMRI) 
acquisition and derived metrics assess the neurodegenerative consequences of the disease and 
potential therapeutic alteration on both regional and whole brain structures. Resting-state functional 
MRI (rs-fMRI) is an imaging method that reflects synaptic activity through changes in blood flow 
and the deoxyhemoglobin to oxyhemoglobin ratio, and the structures that are particularly vulnerable 
for early amyloid deposition in AD appear to overlap with the heteromodal cortices of the default 
mode network. 
2 
MRI Methods 
Each imaging site will be required to satisfy the requirements of MRI Site Qualification by 
completing a site specific technical evaluation form, completing imaging manual training and 
approval of all MRI scanners to be utilized for study subjects. Prior to site initiation, a MRI Imaging 
Manual, outlining image sequences and parameters will be created. All MRI imaging time points 
are to be acquired, reconstructed and submitted as described in the Imaging Manual. An Image 
Corelab will collect the MRI image data and an independent reviewer, with appropriate 
qualification, will make a qualitative and quantitative assessment of the screening MRI and safety 
MRI scans for each imaging time point. 
2.1 Screening MRI Scan 


 
 
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Beside results of laboratory test and ECG, the brain imaging performed at screening visit or during 
the screening stage must be available and free of any clinically significant abnormalities likely to 
interfere with the study conduct or evaluations. For all the brain imaging studies, sites should 
operate under the local institution regulations and policies for patient management and care and 
provide scans in digital imaging and communication in medicine format and ideally be able to 
transfer via secure internet connection to the imaging core lab. MRI scans should be acquired on 
either 1.5 or 3.0 Tesla scanners manufactured by General Electric Company, Philips or Siemens. 
Toshiba scanners may also be considered but the equipment should be less than 10 years old. The 
subject positioning should remain unchanged throughout the MRI examination. Proper subject 
positioning is crucial for successful reproduction of serial MRI exams. Therefore, it is important 
that each subject is positioned in the same manner for each and every MRI exam. 
Exclusion criteria: the first screening MRI scan with evidence of followings: 
 Central nerves system (CNS) infection (e.g., neurosyphilis, acquired immune deficiency 
syndrome or prion disease); 
 Major neurological disorder or degenerative conditions associated with significant cognitive 
impairment such as multiple sclerosis or Huntington’s disease; 
 Structural lesions (e.g., primary or secondary brain tumors, subdural hematoma or 
normal-pressure hydrocephalus);  
 Severe traumatic brain injury; 
 Cerebrovascular disease;  
 Multiple infarction (at least 2 different arterial territories involved), or a large intracerebral infact 
(>2 cm), or multiple lacunes, or lacunes in a critical memory structure (e.g., basal ganglia), or a 
large intracerebral hemorrhage (>2 cm) or more than four microhemorrhages; a single area of 
superficial siderosis;  
 
2.2 Safety MRI 
The purpose of safety MRI is used to monitor amyloid-related imaging abnormalities (ARIA) 
including vasogenic edema and sulcal effusions (ARIA-E) and microhaemorrhages and 
haemosiderin deposits (ARIA-H), as well as age-related white matter changes (ARWMC). Serial 
brain safety MRI scans should be performed regularly and at intervals of no more than every 3 
months. The MRI will be performed at the first screening and at weeks 12, 24, 36, 48, 60, and 78 to 
assess ARIA that may be induced by amyloid-modifying therapy.  
The Core MRI protocol consists of 3 types of sequences that are acquired in every subject and on 
every MRI vendor system, these are: (1) T1 weighted scan, (2) T2/ fluid attenuated inversion 
recovery (FLAIR), and (3) T2*-gradient refocused echo (GRE). T2/FLAIR imaging demonstrates 
ARIA-E with increased signal while the appearance of ARIA-H can be observed on long echo time 
GRE (T2*-GRE) sequences. The T2*-GRE should have a minimum Echo Time (TE) of 20 ms or 
greater and slice thickness of 5 mm or less. Microhemorrhages typically manifest as a focal, round, 
very low intensity (relative to adjacent brain) lesion in the brain parenchyma, detected on an 
appropriately weighted (T2 or T2*) MRI sequence, such as GRE sequences. Additional 
susceptibility weighting imaging (SWI) sequence may be imparted by post processing to improve 
microhemorrhages visualization2, obtaining high quality multi-site data that is consistent over time, 
and across different MRI systems.  


 
 
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The Imaging Corelab will qualify (and re-qualify after upgrades) each scanner on the MRI protocol. 
Correct specific classes of image artifacts in each image acquired; imaging intensity 
non-uniformity, image warping due to gradient nonlinearity, and scaling changes over time. 
3 
18F-AV-45 PET Methods 
Early phase human PET studies indicate that florbetapir binds to amyloid vulnerable brain regions 
in AD patients, similar to reported binding with 11C Pittsburgh Compound B (11C-PiB) in AD, with 
minimal cortical binding in normal control subjects3. The high correspondence of florbetapir 
binding and Aβ amyloid plaque load has been reported in a postmortem series4.  
Prior to site initiation, a PET Imaging Manual, outlining image acquisition and reconstruction 
parameters will be created. All PET imaging time points are to be acquired, reconstructed and 
submitted as described in the Imaging Manual. An Image Corelab will collect the PET image data 
and an independent reviewer, with appropriate qualification, will make a qualitative and 
quantitative assessment of the 18F-AV-45 PET amyloid deposition for each 18F-AV-45 PET 
imaging time point. 
3.1 PET/Computed Tomography (CT) Site Qualification 
Each imaging site will be required to satisfy the requirements of PET Site Qualification by 
completing a site specific technical evaluation form, completing imaging manual training and 
approval of all PET/CT scanners to be utilized for study subjects. Phantom imaging data (i.e. 
uniformity, Hoffman, Hot Sphere) is to be submitted prior to screening (ideally prior to site 
initiation) and then quarterly throughout the remaining study period. 
3.2 PET/CT Imaging Visit 
18F-AV-45 PET imaging will be acquired at the second stage screening and at week 52 and 
week 78 to assess the changes in Aβ burden from the baseline. Study subjects will receive a single 
intravenous bolus of approximately 370 MBq (10 mCi) of florbetapir (18F), followed by a 
10-minute PET brain image, beginning approximately 50 minutes post-dose injection at each scan 
visit5. The subject should be supine with the head positioned to center the brain, including the 
cerebellum, in the PET scanner field of view. Reducing head movement with tape or other flexible 
head restraints may be employed. Image reconstruction should include attenuation correction with 
resulting transaxial pixel sizes between 2 and 3 mm. In the event of scanning failure (i.e. excessive 
motion artifact, PET/CT scanner malfunction, or subject condition), the 18F-AV-45 PET/CT exam 
should be repeated.  
3.3 PET Central Independent Review 
For the PET eligibility review, sites are required to submit screening 18F-AV-45 PET scans 
acquired during the second stage screening immediately to the Imaging Corelab to confirm the 
presence of amyloid deposition and study eligibility. An independent reviewer will confirm the 
presence of amyloid deposition on the PET scans by conducting a visually qualitative assessment 
and making a determination for Aß+ (amyloid positive) or Aß- (amyloid negative). The 
Independent Reviewer will make the determination of Aß+ (amyloid positive) or Aß- (amyloid 
negative) based on a standard uptake value ratio (SUVR) threshold cutoff value (qAb-)5. 
Semi-quantitative visual rating 18F-AV-45 PET images will be conducted for each enrolled subject 
and all available visits: the Independent Reviewer (qualified nuclear medicine physician) will rate 


 
 
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each PET image independently for amyloid burden based on successive levels of 18F-AV-45 
retention. 
A quantitative analysis of PET image data will be performed utilizing PET software such as 
MIMNeuro for enrolled subjects and respective visits4. The 18F-AV-45 PET images will be fitted 
to region overlays to quantify the mean cortical to cerebellum SUVR calculated from cortical 
regions, such as frontal cortex, temporal cortex, precuneus, parietal cortex, anterior cingulate, and 
posterior cingulate, relative to the whole cerebellum reference region.  
18F-AV-45 PET follow up visits will be acquired at week 52 and week 78 to assess the changes in 
Aβ burden from the baseline. Semi-quantitative and quantitative analysis will be performed as 
described above.   
4 
Volumetric Magnetic Resonance Imaging (vMRI) for the Research Study 
Results of a study of vMRI versus cognitive testing demonstrate that vMRI could become the 
principal outcome measure for clinical trials in AD due to its precision6. The vMRI scan should 
cover the entire brain (including cerebellum) and skull, superiorly and laterally. In the 
anterior/posterior plane the nose should also be included, otherwise image folding will result and 
the exam may not be usable for the study. To ensure scanner stability and scan quality throughout 
the study, each site is required to perform on-going quality control scans on an MRI phantom (such 
as Alzheimer’s disease neuroimaging initiative phantom, American College of Radiology-ACR 
phantom, etc.) using the localizer and 3D T1-weighted scan prior to site scanning their first subject 
(prior to the screening), and then semi-annually throughout the remaining study period, as well as 
after any hardware upgrades to the scanner. If a site fails to perform these phantom scans prior to 
scanning study subjects, the study coordinator and the principal investigator at each site should be 
notified. 
The most important image set is the T1-weighted 3D volumetric acquisition. Isotropic voxels are 
desired to avoid a directional bias, but not required. The target voxel size is approximately 1 mm3, 
with a maximum of 1.5 mm in any one direction. The following is an example of a typical 
magnetization-prepared rapid gradient echo (MP-RAGE) sequence using a Siemens Trio 3-Tesla 
scanner for reference purpose: 128 slices, TR/TE = 2530/3.39 ms, slice thickness = 1.0 mm, flip 
angle = 7°, inversion time = 1100 ms, FOV = 256 × 256 mm, and in-plane matrix size = 256 × 256. 
Sites should acquire a 3D T1-weighted scan with scan parameters that are close to the MP-RAGE 
sequence mentioned above, compensating for differences in parameters based on their scanner 
manufacturer.  
Proper placement in the head coil is crucial because scans are acquired straight, not in an oblique 
orientation. It is mandatory to use the same position at the time of baseline and all subsequent visits. 
Position on mid-sagittal slice from tri-planar scout and make sure to get full brain coverage without 
image wrap: the skull must be fully included superiorly and laterally and the entire cerebellum 
should be included inferiorly. Every subject for the study must receive a clinical check by an on-site 
radiologist at each MRI facility. A request for a repeat MRI may be required in the event that the 
scans are found to be unacceptable due to subject motion or an incomplete MRI acquisition. Repeat 
MRI scans should be performed as quickly as possible. 
The vMRI data should be reviewed for quality at each site prior to sending the images to the Central 
Imaging Corelab, and if there are any artifacts, the scan should be repeated to get high quality 
images. Hippocampus and other brain regions (such as whole brain, ventricles) shall be assessed 


 
 
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using a semi-automatic, atlas based brain segmentation technique, and will be over-read by an 
independent reviewer (a qualified neuroradiologist), to capture volumetric measures. Volumetric 
data shall be corrected for differences in head size by dividing each measurement by the estimated 
total intracranial volume which is computed as the sum of the volumes of all four ventricles, the 
white matter, the gray matter, with the brain stem excluded. 
The vMRI will be conducted at the first screening, at week 48 and week 78. 
5 
Resting state fMRI (rs-fMRI) for the Research Study 
By measuring functional connectivity between spatially distinct brain regions, rs-fMRI can be used 
to evaluate brain function. Default mode network consists of the bilateral parietal cortex, the 
precuneus and posterior cingulate cortex, anterior cingulate cortex, medial prefrontal cortex, 
hippocampus, and thalamus7. Previous rs-fMRI studies have shown a disruption in functional 
connectivity between structures that are part of the default mode network at an early stage of AD 
and MCI8-10.  
The higher resolution and shorter TR greatly enhances the ability to capture the spatial and temporal 
variations of brain activity and connectivity. The following is the recommended protocol: whole 
brain volume at 2 × 2 × 2 mm resolution within a TR of 720 ms and TE of 33-34.6 ms. It also 
requires the use of a 32 channel head coil (such as Nova Medical). Eyes open; 72 slices; 20.8 cm 
(A-P) × 18 cm (R-L) FOV; Matrix 104 × 90; Flip angle 52°; scan time: ~15 min.  
The rs-fMRI data will be pre-processed, including spatial smoothing with a 6 mm Gaussian kernel 
to produce default and attention networks robustly. The default mode network will be assessed by 
correlating each voxel in individual datasets with low frequency fluctuations within seed regions 
placed in the brain. This method correlates the average BOLD time course of voxels within these 
regions with each other and with the time courses of all other voxels in the brain. 
The rs-fMRI should be conducted at the first screening, at week 48 and week 78. 
 
6 
Reference 
1. 
Wahlund LO, Barkhof F, Fazekas F, et al. A new rating scale for age-related white matter 
changes applicable to MRI and CT. Stroke; a journal of cerebral circulation. 2001; 
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Sperling RA, Jack CR, Jr., Black SE, et al. Amyloid-related imaging abnormalities in 
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Research Roundtable Workgroup. Alzheimer's & dementia : the journal of the Alzheimer's 
Association. 2011; 7(4):367-385. 
3. 
Wong DF, Rosenberg PB, Zhou Y, et al. In vivo imaging of amyloid deposition in 
Alzheimer disease using the radioligand 18F-AV-45 (florbetapir [corrected] F 18). Journal 
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51(6):913-920. 


 
 
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4. 
Clark CM, Schneider JA, Bedell BJ, et al. Use of florbetapir-PET for imaging beta-amyloid 
pathology. Jama. 2011; 305(3):275-283. 
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Johnson KA, Sperling RA, Gidicsin CM, et al. Florbetapir (F18-AV-45) PET to assess 
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Jack CR, Jr., Slomkowski M, Gracon S, et al. MRI as a biomarker of disease progression in 
a therapeutic trial of milameline for AD. Neurology. 2003; 60(2):253-260. 
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Damoiseaux JS, Rombouts SA, Barkhof F, et al. Consistent resting-state networks across 
healthy subjects. Proceedings of the National Academy of Sciences of the United States of 
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He Y, Wang L, Zang Y, et al. Regional coherence changes in the early stages of Alzheimer's 
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Wang K, Liang M, Wang L, et al. Altered functional connectivity in early Alzheimer's 
disease: a resting-state fMRI study. Human brain mapping. 2007; 28(10):967-978. 
 
APPENDIX 2: RESEARCH STUDY PROTOCOL 
A Research Study Adjunctive to a Randomized, Double-blind, Placebo-controlled, 3-arm 
Parallel-group, Multicenter, Phase IIa Study to Evaluate the Safety, Tolerability, Immunogenicity, 
and Efficacy of UBITh®  AD Immunotherapeutic Vaccine (UB-311) in Patients with Mild 
Alzheimer’s Disease (V203-AD). Protocol No.: V203-AD-Research.