Clinical trial NCT03486938
Conditions: Mild Cognitive Impairment Prodromal Alzheimer's Disease
Sponsor: AgeneBio
Start date: 2018-12-13; Completion date: 2022-11-02
Enrollment: 164 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to evaluate the efficacy of AGB101 on slowing cognitive and functional impairment as measured by changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score as compared with placebo in participants with mild cognitive impairment due to Alzheimer's Disease (MCI due to AD) also known as prodromal AD. Participants will be randomized to receive placebo or AGB101 (220 mg), once daily for 78 weeks. Secondary objectives are to assess the effect of AGB101 compared with placebo on clinical progression as measured by Mini-Mental State Examination (MMSE) and Functional Activities Questionnaire (FAQ).

Detailed description:

Arms: arm 1: Matching placebo to AGB101 tablet once daily, taken orally, for 78 weeks. arm 2: Single 220 mg AGB101 tablet once daily, taken orally, for 78 weeks.
Interventions: intervention 1: Placebo Oral Tablet intervention 2: AGB101 220 mg tablet
Intervention descriptions: intervention 1: Placebo oral tablet intervention 2: 220 mg AGB101 active compound

Protocol documents:
Prot_SAP_000.pdf: 
 
 
A multicenter, randomized, double-blind, placebo-controlled study evaluating the 
efficacy and safety of AGB101 (low-dose levetiracetam, 220 mg, extended release 
tablet) on slowing progression of mild cognitive impairment due to Alzheimer's 
disease 
 
 
NCT03486938 
 
 
Protocol Version 6.1  
19DEC2020 


 
 
 
-CONFIDENTIAL- 
This document and its contents are the property of and confidential to AgeneBio, Inc. 
Any unauthorized copying or use of this document is prohibited.
Protocol Title:  
A multicenter, randomized, double-blind, 
placebo-controlled study evaluating the efficacy and 
safety of AGB101 (low-dose levetiracetam, 220 mg, 
extended release tablet) on slowing progression of 
mild cognitive impairment due to Alzheimer’s 
disease 
Protocol Number: 
AGB101 MCD  
 
Clinical Phase: 
2B 
Protocol Version and Date: 
Version 6.1  19Dec2020 
US Investigational New Drug 
(IND) Number: 
 
113798 
Sponsor: 
AgeneBio, Inc. 
1340 Smith Ave., Suite 200 
Baltimore, MD 21209 
Phone: (410) 779-1260 
 


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SIGNATURE PAGE 
Protocol title: A multicenter, randomized, double-blind, placebo-controlled study 
evaluating the efficacy and safety of AGB101 (low-dose levetiracetam, 220 mg, extended 
release tablet) on slowing progression of mild cognitive impairment due to Alzheimer’s 
disease.  
The undersigned have reviewed the format and content of this protocol and have 
approved the clinical study protocol. 
Any modifications of the clinical study protocol must be agreed upon by the sponsor and 
the investigator and must be documented in writing. 
 
Sponsor Approval: 
Signature: 
 
 
Date: 
 
Name (print): 
 
 
 
 
 
 
 
 
 
Title: 
 
 
 
 
 
 
Investigator Agreement: 
I have read the clinical study protocol and agree to conduct the study as outlined 
herein. 
Signature: 
 
 
Date: 
 
Name (print): 
 
 
 
 
 
 
 
 
 
 
 
 
1/8/2021
Michela Gallagher
CEO AgeneBio, Inc.


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SYNOPSIS 
Protocol Title: 
A multicenter, randomized, double-blind, placebo-controlled 
study evaluating the efficacy and safety of AGB101 (low-dose 
levetiracetam, 220 mg, extended release tablet) on slowing 
progression of mild cognitive impairment due to Alzheimer’s 
disease.  
Protocol Number: 
AGB101 MCD 
Investigator(s)/Study 
Center(s):  
This study will be conducted at approximately 98 study sites in 
the Americas and Europe. Worldwide Clinical Trials, a 
contract research organization, will oversee operational aspects 
of this study on behalf of AgeneBio, Inc., the sponsor of the 
study. 
Phase of 
Development: 
Phase 2B 
Objectives: 
The objectives of this study are as follows:  
Primary objective  
 To assess the efficacy of AGB101 (low-dose levetiracetam, 
220 mg, extended release tablet) compared to placebo in 
subjects with mild cognitive impairment (MCI) due to 
Alzheimer’s disease (AD) using Clinical Dementia Rating-
Sum of Boxes (CDR-SB) scores. 
Secondary objectives  
 To assess the efficacy of AGB101 compared to placebo on 
daily functioning and cognition using Functional Activities 
Questionnaire (FAQ) and Mini Mental State Examination 
(MMSE) scores. 
 To assess the effect of AGB101 compared to placebo on 
neuronal injury, as measured by a change in the entorhinal 
cortex (EC) thickness, using magnetic resonance imaging 
(MRI).  
Additional secondary objectives 
 To assess the efficacy of AGB101 compared to placebo 
using CDR (global, memory box), Behavioral Pattern 


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Separation-Object (BPS-O) task, and International 
Shopping List Test (ISLT) scores.   
 To assess the effect of AGB101 compared to placebo on 
hippocampal volume using MRI. 
 To assess the effect of AGB101 compared to placebo on 
the levels of tau protein in the brain using the tau positron 
emission tomography (PET) marker 6-[18F]fluoro-3-(1H-
pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine 
([18F]MK-6240) in a subpopulation of approximately 56 
subjects.  
Exploratory Objective 
 To assess the effect of AGB101 on blood-based 
biomarkers of neurodegeneration using samples collected 
at week 78 or the early termination visit. 
Exploratory Objective (optional procedure to be performed 
only at Johns Hopkins University) 
 To assess the efficacy of AGB101 compared to placebo on 
hippocampal overactivity in subjects with MCI due to AD. 
Safety objective 
 To assess the safety and tolerability of AGB101 compared 
to placebo in subjects with MCI due to AD. 
Study Design: 
This is a multicenter, randomized, double-blind, placebo-
controlled, 78-week, fixed-dose study evaluating AGB101 
versus placebo as a treatment for slowing the progression of 
MCI due to AD. 
Planned Sample Size: A total of 160 subjects will be randomized (80/treatment 
group). 
Subject Selection 
Criteria: 
Eligibility criteria 
Inclusion criteria  
Subjects must meet all of the following inclusion criteria at 
screening: 
1. Subjects between 55 and 85 years old (inclusive) in good 
general health: 


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a. Willing and able to consent and participate for the 
duration of the study. 
b. Have eighth-grade education or good work history 
sufficient to exclude mental retardation. 
c. Have visual and auditory acuity adequate for 
neuropsychological testing. 
d. Have proficient fluency of the native local language 
to participate in all the neuropsychological test 
assessments. 
2. Have a study partner who has sufficient contact with the 
subject to be able to provide assessment of memory 
changes, who can accompany the subject to the screening 
and all major clinic visits for the duration of those visits, 
and who is able to provide an independent evaluation of 
the subject’s functioning. 
3. Have MCI due to AD as defined by all of the following 
criteria and consistent with the National Institute on 
Aging-Alzheimer’s Association criteria:  
a. MMSE scores between 24 and 30 (inclusive; 
exceptions may be made for subjects with < 8 years 
of education at the discretion of the sponsor). 
b. A memory complaint reported by the subject or 
his/her study partner. 
c. Evidence of lower memory performance based on 
the delayed recall portion of the ISLT. 
d. A Clinical Dementia Rating (CDR) score of 0.5 
with a memory box score of ≥ 0.5. 
e. Essentially preserved activities of daily living. 
f. Cognitive decline not primarily caused by vascular, 
traumatic, or medical problems (alternative causes 
of cognitive decline are ruled out). 
4. Permitted medications:  
a. With potential pro-cognitive effects, such as 
cholinesterase inhibitors and memantine, must be at 
a stable dose for ≥ 3 months prior to screening and 


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expected to remain stable throughout the study; 
estrogen replacement therapy, Ginkgo biloba, and 
vitamin E must be at a stable dose for ≥ 4 weeks 
prior to screening and expected to remain stable 
throughout the study. 
b. Other psychotropics, such as antidepressants and 
antipsychotics, must be at a stable dose for 
≥ 3 months prior to screening and expected to 
remain stable throughout the study. 
5. Willing and able to undergo imaging procedures: 
a. An amyloid-imaging PET scan with Neuroceq 
(florbetaben), Amyvid (florbetapir) or Vizamyl 
(flutemetamol) ([18F] isotope diagnostic agents) or 
documented evidence of an amyloid-positive PET 
scan. 
The amyloid PET scan performed at baseline must 
be read by a qualified physician with experience in 
reading amyloid PET scans, and it should be 
consistent with the presence of amyloid plaques. 
b. Repeated MRI scans (3 Tesla) with no 
contraindications to MRI. 
The MRI scan performed at baseline must be read 
by a physician with experience in evaluating 
brain-imaging studies in dementia. MRI scan 
results are consistent with the diagnosis of amnestic 
MCI due to AD with no clinically significant 
findings of non-AD pathology that could account 
for the observed cognitive impairment. 
6. Willing to allow collection of blood for apolipoprotein E 
(ApoE) genotyping (all sites). 
Exclusion criteria  
Subjects must not meet any of the following exclusion criteria 
at screening: 
1. Use of anticonvulsant medications or excluded 
psychotropic medications within 3 months prior to the 
baseline visit.  


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2. Participation in a therapeutic clinical study for any medical 
or psychiatric indications within 3 months (6 months for 
biologics) of the screening visit, or at any time during the 
study. 
Subjects must understand that they may only enroll in this 
clinical study once; they may not enroll in any other 
clinical study while participating in the current study, and 
they may not participate in a clinical study of a drug, 
biologic, therapeutic device, or medical food, in which the 
last dose/administration was received within 3 months 
(6 months for biologics) prior to screening. 
3. History of hypersensitivity or lack of tolerability to 
AGB101 (levetiracetam).  
4. Severe renal impairment (creatinine clearance of 
< 30 mL/minute) or undergoing hemodialysis.  
5. Any significant neurological disease other than suspected 
incipient AD, such as Parkinson’s disease, multi-infarct 
dementia, Huntington’s disease, normal pressure 
hydrocephalus, brain tumor, progressive supranuclear 
palsy, seizure disorder (lifetime history; infant febrile 
seizures are not exclusionary), subdural hematoma, 
multiple sclerosis, or history of significant head trauma 
followed by persistent neurologic deficits, or known 
structural brain abnormalities.  
6. Presence of pacemakers, aneurysm clips, artificial heart 
valves, ear implants, metal fragments, or foreign objects in 
the eyes, skin, or body that constitute a contraindication to 
having an MRI scan.  
7. Diagnosis of bipolar disorder, or major depression within 
the past 3 years, as described in the Diagnostic and 
Statistical Manual of Mental Disorders, 5th Ed (DSM-5).  
Psychotic features, agitation, or behavioral problems 
within the last 3 months that could lead to difficulty 
complying with the protocol. Subjects must not have a 
major depressive disorder or other types of depression that 
could confound diagnosis of MCI due to AD, or clinical 
assessments, in the opinion of the investigator. The 
Geriatric Depression Scale (long form score > 9 suggests 


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depression) results should be reviewed by the investigator 
to assist in this determination. 
8. Modified Hachinski Ischemic Scale (HIS) score > 4. 
9. History of schizophrenia (DSM-5 criteria). 
10. History of alcohol or substance abuse or dependence 
within the past 3 years (DSM-5 criteria). 
11. Any significant systemic illness or unstable medical 
condition that could lead to difficulty in complying with 
the protocol requirements.  
12. Any unstable medical condition that is likely to require 
new medical or surgical treatment during the course of the 
study and where such treatments might affect the collection 
of efficacy data. 
13. Clinically significant abnormalities in B12 or thyroid 
function test that might interfere with the study.  
A low B12 (below normative range for elderly) is 
exclusionary, unless follow-up labs (homocysteine and 
methylmalonic acid) indicate that it is not physiologically 
significant. If the B12 deficiency is treated, subjects may 
become eligible to participate in the study. 
14. Residence in a skilled nursing facility.  
Individuals in independent living communities, assisted 
living facilities, residential care facilities, or continuing 
care communities are eligible provided they engage in a 
sufficient spectrum of activity to permit assessment of all 
6 domains contributing to the Clinical Dementia 
Rating-Sum of Boxes (CDR-SB). Individuals in these 
facilities must also have a study partner who has the ability 
to observe the subject during the study and can participate 
in clinical evaluations.  
15. Any use of excluded medications (eg, antiepileptics, 
certain antidepressants or antipsychotics, antihistamines 
with anticholinergic properties, opiates). 
16. Participation in clinical studies using the ISLT, BPS-O 
task, or the trail making test (A, B) within 1 month of 
screening. 


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17. Female subjects must not be pregnant, lactating, or of 
childbearing potential (ie, they must be 2 years 
postmenopause or surgically sterile). 
Study Drug(s): 
Subjects will receive AGB101 or placebo in the morning in 
identically appearing oral dosage forms. One dose of AGB101 
will contain 220 mg of levetiracetam.  
Duration of 
Treatment: 
The duration of treatment will be 78 weeks. 


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Main Parameters of 
Efficacy: 
Primary endpoint  
Change in CDR-SB score from baseline to 78 weeks. 
Secondary endpoints: cognitive/functional  
 Change in FAQ score from baseline to 78 weeks. 
 Change in MMSE score from baseline to 78 weeks. 
Secondary endpoints: neuronal injury  
 Change in EC thickness on MRI from baseline to 
78 weeks. 
Additional secondary endpoints  
 Change in CDR global score from baseline to 78 weeks.  
 Change in CDR memory box score from baseline to 
78 weeks.  
 Change in BPS-O task score from baseline to 78 weeks.  
 Change in ISLT score from baseline to 78 weeks.  
 Change in EC volume on MRI from baseline to 78 weeks.  
 Change in hippocampal volume on MRI from baseline to 
78 weeks.  
 Change in [18F]MK-6240 in the brain from baseline at 
week 78.  
Exploratory endpoint:  
 Difference between treatment groups in blood-based 
biomarkers collected at week 78 or early termination 
visit. 
Exploratory endpoint: Functional MRI (optional procedure 
to be performed only at Johns Hopkins University) 
 Confirmation of target engagement demonstrated by 
reduction in hippocampal overactivity. 
Main Parameters of 
Safety: 
Safety endpoints 
 Change from baseline in vital signs (heart rate, respiratory 
rate, and blood pressure). 


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 Change from baseline in physical and neurological exams.  
 Change from baseline in safety labs and urinalysis.  
 Change from baseline in Columbia Suicide Severity Rating 
Scale. 
 Incidence of adverse events.  
Pharmacokinetic 
Parameters: 
AGB101 plasma pharmacokinetic sampling will be performed 
during the 26, 52, and 78-week visits. Time since the last dose 
will be recorded. 
Statistical Analyses: 
The primary goal of the study is to estimate the average 
treatment effect defined as the difference between the 
population mean outcome of the primary endpoint (CDR-SB 
change score from baseline to 78 weeks) comparing treatment 
to control. The primary null hypothesis is that the average 
treatment effect is zero. The alternative hypothesis is that the 
average treatment effect is not equal to zero.  
In the primary analysis, we will use a pre-specified, 
intention-to-treat estimator that simultaneously (i) adjusts for 
78-week outcomes missing at random (due to subject loss to 
follow up), and (ii) adjusts for chance imbalances in key 
baseline variables between the study arms. One advantage of 
this estimator is that it is consistent under weaker assumptions 
on missing outcomes than needed for the unadjusted estimator 
to be consistent. The nonparametric bootstrap (bias-corrected 
and accelerated method) will be used to construct 95% 
confidence intervals for the average treatment effect. Similar 
analyses will be conducted for each of the secondary 
endpoints, along with a gate-keeping multiple testing 
procedure for an ordered sequence of null hypotheses. 
ApoE genotyping will be used for post hoc subject 
stratification. There will be a preplanned subgroup analysis in 
which each efficacy measure will be looked at separately by 
ApoE genotype with two subgroups, those carrying one or 
more ApoE4 alleles and those with no ApoE4 alleles. 


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TABLE OF CONTENTS 
1 
INTRODUCTION .....................................................................................................21 
1.1 Background ............................................................................................................21 
1.2 Study Rationale ......................................................................................................21 
1.3 Dose Rationale .......................................................................................................23 
1.4 Study Endpoint Rationale ......................................................................................28 
1.5 Risks and Benefits for Subjects .............................................................................31 
2 
STUDY OBJECTIVES ..............................................................................................37 
2.1 Primary Objective ..................................................................................................37 
2.2 Secondary Objectives.............................................................................................37 
2.3 Additional Secondary Objectives ..........................................................................37 
2.4 Exploratory Objectives ..........................................................................................37 
2.5 Safety Objective .....................................................................................................37 
2.6 Study Hypothesis ...................................................................................................37 
3 
INVESTIGATIONAL PLAN ....................................................................................39 
3.1 Overall Study Design and Plan ..............................................................................39 
3.2 Study Duration .......................................................................................................40 
3.3 Selection of Study Population ................................................................................40 
3.3.1 Inclusion Criteria ...........................................................................................40 
3.3.2 Exclusion Criteria ..........................................................................................41 
3.3.3 Early Termination From Treatment ...............................................................43 
3.4 Treatments..............................................................................................................44 
3.4.1 Details of Study Treatments...........................................................................44 
3.4.2 Dosage Schedule ............................................................................................45 
3.4.3 Treatment Assignment (1:1 Randomization Placebo:AGB101) ....................45 
3.4.4 Drug Packaging and Blinding ........................................................................45 
3.4.5 Drug Inventory and Accountability ...............................................................46 
3.4.6 Treatment Compliance ...................................................................................47 
3.4.7 Prior and Ongoing Medical History and Treatments .....................................47 
3.5 Assessments ...........................................................................................................47 
3.5.1 Schedule of Assessments ...............................................................................47 


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3.5.2 Study Procedures ...........................................................................................52 
3.5.3 Early Termination Visit and Early Termination/Follow-up Visit..................55 
3.5.4 Efficacy Assessments.....................................................................................55 
3.5.5 Safety Assessments ........................................................................................57 
3.5.6 Additional Assessments .................................................................................58 
3.5.7 Pharmacokinetic Assessments .......................................................................59 
3.5.8 Appropriateness of Measurements .................................................................60 
4 
ADVERSE EVENT REPORTING............................................................................61 
4.1 Definitions and Criteria..........................................................................................61 
4.1.1 Adverse Events ..............................................................................................61 
4.1.2 Serious Adverse Events .................................................................................62 
4.1.3 Unexpected Adverse Drug Reactions ............................................................63 
4.1.4 Assessing Intensity and Relationship.............................................................63 
4.2 Reporting Procedures and Requirements ...............................................................64 
4.2.1 Adverse Events ..............................................................................................64 
4.2.2 Serious Adverse Events .................................................................................65 
4.3 Procedures for Documenting Pregnancy During Study .........................................66 
4.4 Sponsor Reporting of Suspected Unexpected Adverse Reactions to Regulatory 
Authorities..............................................................................................................67 
4.4.1 Unblinding Treatment Allocation ..................................................................67 
4.4.2 Fatal or Life-Threatening Serious Unexpected Adverse Reactions ...............67 
4.4.3 Other Serious Unexpected Adverse Reactions ..............................................68 
4.5 Reporting to Institutional Review Board and Independent Ethics Committee ......68 
5 
DATA MANAGEMENT AND STATISTICAL ANALYSIS ..................................69 
5.1 Data Management Considerations .........................................................................69 
5.2 Statistical Considerations .......................................................................................69 
5.2.1 Analysis Populations ......................................................................................69 
5.2.2 Protocol Deviations ........................................................................................70 
5.2.3 Subject Disposition ........................................................................................71 
5.2.4 Demographic and Baseline Characteristics ...................................................71 
5.2.5 Measurement of Treatment Compliance ........................................................71 


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5.2.6 Efficacy Analyses ..........................................................................................71 
5.2.7 Safety Analyses ..............................................................................................73 
5.3 Pharmacokinetic Analysis ......................................................................................76 
6 
STUDY MANAGEMENT ........................................................................................77 
6.1 Ethics and Consent .................................................................................................77 
6.1.1 Regulations and Guidelines ...........................................................................77 
6.1.2 Institutional Review Board/Independent Ethics Committee..........................77 
6.1.3 Informed Consent...........................................................................................77 
6.2 Indemnification ......................................................................................................77 
6.3 Discontinuation of the Study by the Sponsor ........................................................77 
6.4 Study Documentation.............................................................................................78 
6.5 Study Monitoring and Auditing .............................................................................78 
6.6 Data Safety and Monitoring Board ........................................................................78 
6.7 Retention of Records..............................................................................................79 
6.8 Use of Study Findings ............................................................................................79 
6.9 Publications ............................................................................................................79 
7 
REFERENCES ..........................................................................................................80 
8 
APPENDICES ...........................................................................................................86 
8.1 Accepted and Excluded Medications .....................................................................86 
8.2 Amyloid PET: Dosage, Administration, and PET Scan Acquisition Guidelines ..90 
8.3 MRI Scanning Procedures .....................................................................................93 
8.3.1 MRI Subject Pre-Scan Procedures .................................................................93 
8.3.2 MRI Subject Scan Protocol ............................................................................93 
8.3.3 MRI Subject Scan Procedures .......................................................................95 
8.4 PET Scanning Procedures for[18F]MK-6240 (Optional) .......................................95 
8.5 Site Qualification ...................................................................................................95 


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LIST OF TABLES 
Table 1: 
Pharmacokinetic Parameters for AGB101 (220 mg) ............................... 26 
Table 2: 
Predicted Pharmacokinetic Parameters of AGB101 (Levetiracetam) at 
Steady State After Once-Daily Administration of AGB101 Under Fasting and 
Fed Conditions ........................................................................................................ 27 
Table 3:  
Incidence (%) of Treatment-Emergent Adverse Events in 
Placebo-Controlled, Add-On Studies of Adults Experiencing Partial Onset 
Seizures by Body System ........................................................................................ 32 
Table 4:  
Adverse Events Most Commonly Resulting in Discontinuation or Dose 
Reduction ................................................................................................................. 33 
Table 5:  
Number (%) of Subjects With Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term ............................................................ 36 
Table 6:  
Details of the Study Drugs .......................................................................... 44 
Table 7:  
Schedule of Assessments ............................................................................. 48 
 
LIST OF FIGURES 
Figure 1: 
Mean Levetiracetam Concentration-Time Profiles Following 
Administration of AGB101 .................................................................................... 26 
Figure 2: 
Mean AGB101 (Levetiracetam) Concentration-Time Profiles After 
Single Dose (Actual Data) and Once-Daily Administration (Simulated Data at 
Steady State) of AGB101 Under a Fed Condition ............................................... 27 
Figure 3: 
Mean Simulated Steady State AGB101 (Levetiracetam) Concentration-
Time Profile of AGB101 Under the Fed Condition (B2) ..................................... 28 
Figure 4:  
Study Schema ........................................................................................... 39 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
[18F]MK-6240 
6-[18F]fluoro-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine 
3T 
3 Tesla 
Aβ 
beta amyloid 
AD 
Alzheimer’s Disease 
ADNI 
Alzheimer’s Disease Neuroimaging Initiative 
ADR 
adverse drug reaction 
AE 
adverse event 
AED 
antiepileptic drug 
AGB101 
low-dose levetiracetam, 220 mg, extended release tablet 
aMCI 
amnestic mild cognitive impairment 
ApoE 
apolipoprotein E 
AUC0-24 
area under the plasma concentration-time curve during 24 hours 
AUCextrap 
area under the plasma concentration-time curve extrapolated from 
time zero to time of last measurable concentration  
 
AUCinf 
area under the plasma concentration-time curve extrapolated from 
zero to infinity 
AUClast 
area under the plasma concentration-time curve from time of 
dosing to last measurable concentration 
BCa 
bias-corrected and accelerated method 
BID 
twice a day 
BOLD 
blood oxygen level dependent  
BP 
blood pressure 


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Abbreviation 
Definition 
BPS-O 
Behavioral Pattern Separation-Object 
CBC 
complete blood count 
CDR 
Clinical Dementia Rating 
CDR-SB 
Clinical Dementia Rating-Sum of Boxes 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL/F 
apparent total clearance of the drug from plasma after oral 
administration 
Clast 
last measurable plasma concentration 
Cmax 
maximum plasma drug concentration  
CNS 
central nervous system 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSM 
Diagnostic and Statistical Manual of Mental Disorders  
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
DSMB 
Data Safety and Monitoring Board  
EC 
entorhinal cortex 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EU 
European Union 
FAQ 
Functional Activities Questionnaire  
FDA 
Food and Drug Administration 


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Abbreviation 
Definition 
FLAIR 
fluid attenuation inversion recovery 
fMRI 
functional magnetic resonance imaging 
GCP 
Good Clinical Practice 
GDS  
Geriatric Depression Scale 
HIS 
Hachinski Ischemic Scale 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
IR-SPGR 
radiofrequency-spoiled gradient echo 
ISLT 
International Shopping List Test 
ITT 
intention-to-treat 
IWRS 
interactive web response System 
JHU 
Johns Hopkins University 
λz 
terminal disposition rate constant 
MCI 
mild cognitive impairment 
MedDRA 
Medical Dictionary for Regulatory Activities  
MMS 
Mini Mental State 
MMSE 
Mini Mental State Examination 
MP-RAGE 
magnetization-prepared gradient echo 


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Abbreviation 
Definition 
MRI 
magnetic resonance imaging 
MTL 
medial temporal lobe 
NIA-AA 
National Institute on Aging-Alzheimer’s Association 
PET 
positron emission tomography 
PK 
pharmacokinetic(s) 
RPM 
revolutions per minute 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SEM 
standard error of the mean 
SPGR 
radiofrequency-spoiled gradient echo 
SUSAR 
Suspected Unexpected Adverse Reactions  
T½ 
elimination half-life  
Tlast 
time to last measurable plasma concentration 
Tmax 
time to reach maximum plasma concentration following drug 
administration 
TEAE 
treatment-emergent adverse event 
TMLE 
targeted minimum loss based estimators  
US 
United States 
WCT 
Worldwide Clinical Trials 
 
 


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ADMINISTRATIVE STRUCTURE 
 
Medical Monitor: 
Stephen Kirzinger, MD 
Senior Medical Director 
Medical & Scientific Affairs 
Worldwide Clinical Trials (WCT) 
1000 Continental Drive 
King of Prussia, PA  19406 
Phone: (502)419-4732 
Email: stephen.kirzinger@worldwide.com 


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1 
INTRODUCTION 
1.1 
Background 
No effective therapies exist to halt or reverse Alzheimer's disease (AD). With a predicted 
prevalence of AD cases rising to >100 million worldwide by 2050 (Wimo and Prince 
2010), the need for such therapies is urgent. Data from the Alzheimer’s Disease 
Neuroimaging Initiative (ADNI) and other sources support the notion of existing AD 
pathology in the brain for at least a decade before a clinical diagnosis of AD is made 
(Perrin, Fagan, and Holtzman 2009; Tarawneh and Holtzman 2010; Weiner et al. 2015). 
By the time an AD diagnosis is made using clinical criteria for dementia, significant 
irreversible neurodegeneration has already occurred (Gómez-Isla et al. 1996). It is widely 
acknowledged that therapeutic intervention in the early stages of AD has the best 
prospect for modifying disease progression (Sperling et al. 2011). No such therapies have 
been approved based on studies in conditions that are precursors for dementia, such as in 
prodromal AD.  
By clinical, cognitive, and functional criteria, mild cognitive impairment (MCI) is an 
intermediate state between normal aging and a diagnosis of dementia, including probable 
AD. Impairment of episodic memory, that is the ability to acquire and retain information 
about life events that is greater than expected for a person’s age, is most commonly 
observed in subjects with MCI who progress to AD, and it has been used to define a 
subtype of MCI called amnestic mild cognitive impairment (aMCI) (Petersen 2011).  
In addition, evidence for the pathophysiology of AD, such as neuronal injury or 
neurodegeneration in specific loci in the brain (eg, temporal lobe) or evidence for 
amyloid by positron emission tomography (PET) imaging, was proposed for a diagnosis 
of MCI due to AD (Albert et al. 2011). MCI is a medical diagnosis as defined in the 
Diagnostic and Statistical Manual of Mental Disorders (DSM), 4th Ed, or a mild 
neurocognitive impairment due to AD as defined in the DSM 5th Ed (DSM-5). Currently, 
there are no approved treatments for MCI, including MCI due to AD. Thus, MCI due to 
AD represents an unmet medical need, which is both symptomatically and as a clinical 
diagnosis suitable for intervention to modify disease progression, in subjects at high risk 
for AD dementia.  
1.2 
Study Rationale 
The current study will enroll subjects with a diagnosis of MCI due to AD, as defined by 
the National Institute on Aging-Alzheimer’s Association (NIA-AA) criteria (Albert et al. 
2011). 
A distinctive condition in the MCI due to AD population is neural over-activity localized 
to the hippocampal formation by functional magnetic resonance imaging (fMRI) 
(Ewers et al. 2011; Sperling et al. 2011; Albert et al. 2011). Although modest 


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hippocampal over-activity is observed in preclinical (asymptomatic) conditions in older 
adults, (O’Brien et al. 2010; Yassa et al. 2011) a very prominent increase in hippocampal 
over-activity occurs in subjects with MCI due to AD compared with age-matched 
controls (Yassa et al. 2011; Bakker et al. 2012; Huijbers et al. 2015). In clinical studies, 
the magnitude of such hippocampal over-activity longitudinally predicts subsequent 
cognitive decline/conversion to dementia, (Dickerson et al. 2005; Miller et al. 2008; 
Sperling 2007) and hippocampal over-activity in subjects with MCI due to AD is 
significantly correlated with the extent of neuronal injury affecting AD-specific regions 
of the brain. Putcha et al. 2011 reported a significant correlation between greater 
hippocampal activation (fMRI) and more pronounced medial temporal lobe (MTL) 
atrophy (cortical thinning) indicative of AD-related neurodegeneration in subjects with 
MCI due to AD with a Clinical Dementia Rating (CDR) score of 0.5 selected by ADNI-1 
criteria. This supports a therapeutic rationale to reduce over-activity in order to slow or 
prevent neuronal injury.  
Current evidence from basic scientific research indicates a convergence of pathways 
involving the beta amyloid (Aβ) protein, the tau protein, and the process of aging itself 
that boosts hippocampal over-activity, contributing to the condition of MCI due to AD in 
subjects at high risk for progression to dementia. Levetiracetam has been shown to 
preserve synaptic function and control very early AD pathophysiology tied to Aβ and tau 
(Shi et al. 2013; Hall et al. 2015). It reduces aberrant over-activity in specific brain 
circuits that are highly vulnerable to early neurodegeneration caused by AD (Shi et al. 
2013; Hall et al. 2015).  
In animal models of age-related memory impairments and AD (Morris water maze, radial 
arm maze), levetiracetam reverses deficits in cognition and reductions of reelin 
expression in the entorhinal cortex (EC) of aged rats with memory impairments 
(Koh et al. 2010; Rose and Corbin 2010; unpublished data Gallagher M). The effect of 
levetiracetam on reelin expression is notable in light of evidence indicating that reelin 
reduction accelerates amyloid and tau pathology in the hippocampus (Kocherhans et al. 
2010). Reduced levels of reelin have also been shown in the EC of age-impaired (but not 
age-unimpaired) rhesus monkeys (Long et al. 2014). Reelin was shown to delay Aβ fibril 
formation and rescue cognitive deficits in a model of AD (Pujadas et al. 2014). Evidence 
of aberrant excitatory activity has been observed in experimental animal models relevant 
to AD, a condition first described in hAPP mice J20 (Palop et al. 2007; Busche et al. 
2012; Minkeviciene et al. 2009; Tabuchi et al. 2015). Levetiracetam administered at low 
doses to transgenic hAPP J20 mice resulted in an improved hippocampal system (eg, 
synaptic function, molecular markers, double-strand DNA breaks) and memory 
performance (Sanchez et al. 2012; Suberbielle et al. 2013).  
More recently, chronic use of low-dose levetiracetam (50 mg/kg/day for 30 days) was 
reported to reduce both amyloid and tau pathology in APPswe/PS1dE9 mice 


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(Shi et al. 2013). It is noteworthy that the effects of levetiracetam were not observed (no 
effect on brain markers or behavior) in control non-transgenic mice given the same drug 
treatment. Consistent with clinical and preclinical data, low-dose administration of 
levetiracetam was effective, while high dose had no effect (Sanchez et al. 2012). 
Importantly, a spectrum of other antiepileptic drugs (AEDs) with mechanisms of action 
different from levetiracetam (eg, ethosuximide, gabapentin, phenytoin, pregabalin, and 
vigabatrin) were ineffective in this AD model. More recently, chronic administration of 
low-dose levetiracetam rapidly and persistently reversed brain dysrhythmia and network 
hypersynchrony in hTau-A152T mice, suggesting that levetiracetam treatment is able to 
counteract tau-dependent neural network dysfunction (Das et al. 2018). 
1.3 
Dose Rationale 
Preclinical models of age-impaired laboratory rats with memory loss have demonstrated 
that increased activation in the CA3 subregion of the hippocampus is a dysfunctional 
condition contributing to memory impairment (Wilson et al. 2005; Wilson et al. 2006). In 
a preclinical model of memory loss due to aging and mouse models of AD pathology 
(J20 hAPP and APPswe/PS1dE9 mice), levetiracetam was shown to decrease excess 
neural activity and improve memory function (Koh et al. 2010; Sanchez et al. 2012; 
Shi et al. 2013). The levetiracetam dose levels leading to efficacious results in the 
age-impaired rat model ranged from 1.9 g/mL to 3.9 g/mL, and efficacy was lost at a 
higher exposure of 7.8 g/mL (Rosenzweig-Lipson et al. 2015). 
Based on preclinical efficacy results with low-dose levetiracetam and results from 
clinical use of Keppra XR (high-dose levetiracetam; 1000 mg/day to 3000 mg/day) for 
the treatment of epilepsy, a translational, proof-of-concept, phase 2 study was performed 
in subjects with MCI. This was an 8-week, randomized, double-blind, placebo-controlled, 
within-subject, crossover study evaluating the effects of low-dose levetiracetam on 
hippocampal over-activity and memory function in MCI (Bakker et al. 2012). A total of 
54 subjects completed the study. Subjects received both levetiracetam (62.5 mg twice a 
day [BID], 125 mg BID, or 250 mg BID) and placebo separately in periods of 2 weeks 
each. Twenty subjects completed the study in the 62.5 mg BID dose group, 17 subjects in 
the 125 mg BID dose group, and 17 subjects in the 250 mg BID dose group. At the end of 
each treatment period, participants completed a high-resolution fMRI scan while 
performing the 3 choice memory recognition task designed to assess the function of the 
hippocampal (DG/CA3) network (Bakker et al. 2008; Lacy et al. 2011). As in the rat 
model studies, low-dose levetiracetam (62.5 mg BID and 125 mg BID), but not high dose 
(250 mg BID), attenuated hippocampal over-activity and improved the task-related 
memory function (Bakker et al. 2015). The lower doses of levetiracetam that improved 
memory performance in the scanning task also normalized fMRI activation in the 
EC/DG/CA3 network both by reducing elevated DG/CA3 fMRI activity and by boosting 
decreased fMRI activation in the EC. Subjects who received the lower doses also showed 


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significant improvement in memory performance in the fMRI task. Drug blood levels 
from subjects receiving low-dose levetiracetam in the clinical study closely matched drug 
blood levels from preclinical aging/AD models (Koh et al. 2010; Sanchez et al. 2012; 
Bakker et al. 2012). In addition, matching high doses of levetiracetam in both the 
preclinical aging/AD studies and in subjects with aMCI were demonstrated to lack 
efficacy (Koh et al. 2010; Sanchez et al. 2012; Bakker et al. 2015) Based on these 
findings, AGB101 formulations (low-dose levetiracetam, 190 mg and 220 mg, extended 
release tablets) were developed to allow for once-daily dosing in subjects with aMCI. The 
current study is the first clinical study undertaken with the novel formulation. 
High-dose Keppra XR has been used for the treatment of epilepsy at doses of 
1000 mg/day to 3000 mg/day for more 15 years, with a favorable safety and efficacy 
profile in this subject population. Importantly, effective doses of levetiracetam used in the 
preclinical models of aMCI and AD are lower than those required clinically for 
antiepileptic activity. Consistent with preclinical findings, treatment with low-dose 
levetiracetam (62.5 mg BID or 125 mg BID) concurrently improved behavioral 
performance in the scanning task for memory function and normalized increased 
DG/CA3 activity. An analysis of the interaction for performance in the task by planned 
contrast showed that aMCI subjects who received levetiracetam at doses of 62.5 mg BID 
or 125 mg BID made fewer incorrect responses of 'old' while concomitantly increasing 
correct judgments of 'similar', compared with their control group counterparts (aMCI 
drug versus aMCI placebo by old versus similar; 62.5 mg BID (F[1,19] = 4.783, 
p = 0.041; 125 mg BID F[1,16] = 5.028, p = 0.039). Indeed, performance in the low-dose 
levetiracetam groups was not significantly different from healthy control subjects (aMCI 
drug versus control by old versus similar; 62.5 mg BID F[1,35] = 1.823, p = 0.186; 
125 mg BID F[1,32] = 1.945, p = 0.173).  
In contrast, subjects with aMCI who received high-dose levetiracetam (250 mg BID; 
Keppra starting dose for epilepsy) did not exhibit normalized DG/CA3 activity and did 
not improve in memory task performance, compared with subjects in the placebo group. 
In the memory task, they did not alter the proportion of old and similar responses to lures 
under drug treatment (aMCI drug versus aMCI placebo by old versus similar: 
F[1,16] = 1.492, p = 0.2396) and remained significantly different from healthy control 
subjects (aMCI drug versus control by old versus similar: F[1,32] = 5.208, p = 0.029).  
To confirm the finding that low-dose levetiracetam treatment effectively reduces 
hippocampal activation, a separate analysis was conducted in which voxel selection was 
based on a one-way analysis of variance study type in control subjects. This analysis 
resulted in an area of task-related activation similarly localized to the left DG/CA3 
subregion of the hippocampus. The effect of drug treatment was confirmed by comparing 
fMRI activation in the area of task-related activity in subjects with aMCI in the placebo 
and levetiracetam groups within each of the 3 aMCI cohorts. Confirming the treatment 


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effects, the analysis similarly showed that the levetiracetam 62.5 mg BID dose lowered 
but did not significantly reduce blood oxygen level dependent (BOLD) activation, 
compared with placebo (t = 1.503, p = 0.1492). The levetiracetam 125 mg BID dose 
significantly reduced BOLD activation during the correctly identified lure trials, 
compared with placebo (t = 2.192, p = 0.044). In contrast, the levetiracetam 250 mg BID 
dose showed no evidence of reducing activation (t = 0.1773, p = 0.8615). 
In addition to areas of task-related activity in the DG/CA3, analyses of the functional 
imaging data also revealed an area of reduced task-related activity in the left EC in both 
low-dose levetiracetam groups (62.5 mg BID and 125 mg BID). In the left EC, 
participants in the levetiracetam groups showed significantly decreased BOLD activation 
during those same lure studies, compared with their healthy control group counterparts 
(62.5 mg BID, t = 3.443, p = 0.002; 125 mg BID, t = 3.278, p = 0.003). After treatment, 
BOLD activation in the left EC was increased and normalized in aMCI participants 
during the critical lure studies, compared with their placebo counterparts. This increase 
was statistically significant in the 62.5 BID cohort (t = 3.318, p = 0.004) but not 
statistically significant in the 125 mg BID cohort (t = -1.60, p = 0.129). In both groups, 
fMRI activity in the left EC after drug treatment was no longer different from the activity 
observed in the left EC in the control subjects. 
The effects on BOLD activation in the left DG/CA3 and EC in the levetiracetam 62.5 mg 
BID and 125 mg BID cohorts were obtained with drug dose levels well below those used 
clinically for the treatment of epilepsy. Drug levels in aMCI subjects were determined to 
be 2.9 g/mL ± 0.29 g/mL (mean ± standard error of the mean [sem]) for the 62.5 mg 
BID cohort, 4.4 g/mL ± 0.53 g/mL (mean ± sem) for the 125 mg BID cohort, and 
7.91 g/mL ± 0.92 g/mL (mean ± sem). These drug exposure levels are well below 
typical ranges reported for efficacy with Keppra (high-dose levetiracetam) as an 
antiepileptic agent, where doses of 1000 mg/day to 3000 mg/day are typical, resulting in 
drug levels of 10 g/mL to 40 g/mL (Lyseng-Williamson 2011). 
Clinical experience with AGB 101 
Based on the findings from the phase 2 study, a novel extended-release tablet formulation 
of AGB101 was developed at a dose of 220 mg with a predetermined target plasma 
exposure range of 1.9 g/mL to 4.4 g/mL (based on animal and human aMCI data). A 
phase 1, 2-group, single-dose, 2-period, 2-way crossover, food-effect study of AGB101 
formulation was recently undertaken. The AGB101 maximum plasma drug concentration 
(Cmax) ranged from 3.02 µg/mL in the fasted condition to 3.16 µg/mL in the fed condition 
(Figure 1). The elimination half-life (T½) was similar under all conditions ranging from 
7.56 h to 8.09 h (Table 1), and it was comparable to the reported T½ of the levetiracetam 
extended release (~7 hours). Single-dose Cmax levels fell within the target range 
(1.9 µg/mL to 4.4 µg/mL).   


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Figure 1: Mean Levetiracetam Concentration-Time Profiles Following 
Administration of AGB101 
 
A2 = fasted condition in group 2/treatment A; B2 = fed condition in group 2/treatment B.  
 
Table 1: 
Pharmacokinetic Parameters for AGB101 (220 mg) 
 
AUCextrap = area under the plasma concentration-time curve extrapolated from time zero to time of last measurable 
concentration; AUCinf = area under the plasma concentration-time curve extrapolated from zero to infinity; 
AUClast = area under the plasma concentration-time curve from time of dosing to last measurable concentration; 
Clast = last measurable plasma concentration; Cmax = maximum plasma drug concentration; λz = terminal disposition 
rate constant; T½ = elimination half-life; Tlast = time to last measurable plasma concentration; Tmax = time to reach 
maximum plasma concentration following drug administration. 
Additional modeling studies were performed to predict exposures at a steady state. The 
AGB101 Cmax increased from 3.02 µg/mL to 3.84 µg/mL under the fasted condition and 


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from 3.16 µg/mL to 3.66 µg/mL under the fed condition (Figure 2 and Table 2). These 
maximal exposures all met the target criteria (1.9 µg/mL to 4.4 µg/mL). 
Figure 2: Mean AGB101 (Levetiracetam) Concentration-Time Profiles After Single 
Dose (Actual Data) and Once-Daily Administration (Simulated Data at 
Steady State) of AGB101 Under a Fed Condition 
 
Table 2: Predicted Pharmacokinetic Parameters of AGB101 (Levetiracetam) at 
Steady State After Once-Daily Administration of AGB101 Under Fasting 
and Fed Conditions 
 
AGB101 220 mg – Fasted (A2) 
AGB101 220 mg – Fed (B2) 
Parameter 
N 
Mean 
CV% 
N 
Mean 
CV% 
Cmax (µg/mL) 
26 
3.84 
19.20 
28 
3.66 
17.88 
Tmax (h) 
26 
3.46 
23.44 
28 
6.11 
27.95 
AUC0-24 (h* µg/mL) 
26 
57.60 
18.55 
28 
56.58 
18.47 
AUC0-24 = area under the plasma concentration-time curve during 24 hours; Cmax = maximum plasma drug 
concentration; Tmax = time to reach maximum plasma concentration following drug administration. 
Figure 3 depicts a steady-state modeling relative to the target range established for the 
AGB101 over time; the modeling was developed based on results from the phase 2 aMCI 
study and the age-impaired rat model. AGB101 meets the goal for the target range and 
maintains exposures between 1.9 µg/mL and 4.4 µg/mL for approximately 14 hours of 
the day. 
0
1
2
3
4
Mean Concentration (ug/mL)
0
4
8
12
16
20
24
Time (h)
Single Dose
Steady-State


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Figure 3: Mean Simulated Steady State AGB101 (Levetiracetam) Concentration-
Time Profile of AGB101 Under the Fed Condition (B2) 
 
Food effect: The presence of food did not significantly alter the pharmacokinetics (PK) of 
AGB101.  
Steady state: In general, based on the simulated mean concentration-time profiles and the 
mean Cmax from the simulated profiles, the predicted accumulation of levetiracetam in 
systemic circulation during once-daily administration of AGB101 formulation (220 mg) 
is consistent with the theoretical accumulation factor for once-daily administration of a 
drug with a T½ of approximately 8 hours (approximately 1.14), particularly under the fed 
condition. The simulations based on fasting data suggest a slightly higher accumulation 
factor (approximately 1.3). 
Overall conclusion: AGB101 (220 mg) is a novel extended-release formulation of 
levetiracetam suitable for once daily dosing in subjects with MCI due to AD. The 
extended-release formulation maintains exposures within the a priori-defined target range 
of 1.9 µg/mL to 4.4 µg/mL that aligns to the efficacy observed in the Phase 2 aMCI 
study. Importantly, the extended-release formulation exposures do not exceed the 
therapeutic efficacy range and do not approach the high-dose exposures associated with a 
lack of efficacy. The nominal impact of food on the rate and extent of absorption suggests 
that AGB101 may be administered without regard to food intake in a clinical study.  
1.4 
Study Endpoint Rationale 
The primary efficacy evaluation is the change in Clinical Dementia Rating-Sum of Boxes 
(CDR-SB) score over the course of treatment. The CDR (global score) is a rating scale 
used to characterize the degree of dementia severity. It ranges from 0 (“no dementia”) to 
3 (“severe dementia”). It is based on semi-structured interviews with both the subject 
thought to suffer from dementia and a knowledgeable informant (for example, an adult 
family member). For the CDR-SB score, cognitive functioning is rated in 6 domains: 
0
1
2
3
4
5
6
7
8
Mean Concentration (μg/mL)
0
4
8
12
16
20
24
Time (h)
Target Range
Too High – not efficacious


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memory, orientation, judgment and problem solving, community affairs, home and 
hobbies, and personal care. Each domain is rated on a 5-point scale of functioning as 
follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 
2, moderate impairment; and 3, severe impairment. For subjects with a global score of 
0.5, the subsequent “sum of boxes” score can help quantify the severity of cognitive and 
functional impairment within the range of MCI.  
CDR-SB has been shown to markedly progress (worsen) during MCI due to AD. In this 
regard, episodic memory impairment is related to CDR-SB progression (Albert et al. 
2007). Importantly, and consistent with a diagnosis of MCI due to AD, a positive Aβ 
status predicts greater progression on CDR-SB (Jack et al. 2010; Huijbers et al. 2015). 
Moreover, hippocampal over-activity also predicts progression on CDR-SB 
(Miller et al. 2008; Huijbers et al. 2015). If AGB101 is effective in slowing the 
progression of MCI due to AD, then subjects should show an improvement in (lowering), 
or a stabilizing of, their CDR-SB scores over the duration of the study (78 weeks). 
The secondary efficacy evaluation is the extent of neuronal injury as measured by the 
change in EC atrophy from baseline to 78 weeks. It has long been known that early 
pathological changes in the AD cascade occur in the EC (Braak and Braak 1991; Braak 
and Braak 1995; Braak et al. 1998). Consistent with the localization and spread of 
pathology, degeneration of EC neurons represents the earliest lesion in the brain that is 
characteristic of dementia due to AD. Quantitative studies of neuron numbers in autopsy 
brains well-characterized for AD pathology have shown that a substantial reduction in the 
numbers of EC neurons is observed in prodromal AD (CDR 0.5), with further progressive 
loss of EC neurons (> 90%) over the course of the disease (Gomez-Isla et al. 1996). 
Those findings are consistent with subsequent studies of autopsy brains (CDR 0.5) with 
50% or greater layer II neuron loss in the EC, as assessed by stereological analysis, and 
> 20% regional atrophy in the EC (Kordower et al. 2001; Price et al. 2001). Moreover, 
Kordower et al. 2001, reported that the layer II neuron loss and EC atrophy were 
significantly correlated with episodic memory status in neuropsychological tests of 
delayed recall, and the EC atrophy correlated significantly with performance on the Mini 
Mental Status Examination (MMSE). This evidence has reliably demonstrated that EC 
neurodegeneration and EC atrophy occurs in elderly subjects with MCI due to AD prior 
to the clinical diagnosis of dementia. 
In structural neuroimaging with magnetic resonance imaging (MRI), EC atrophy has been 
identified as a good biomarker for longitudinal progression in MCI due to AD and AD, 
with greater atrophy predicting more advanced disease severity (Zhou et al. 2015). In 
subsequent longitudinal studies using MRI, EC atrophy has been repeatedly shown as a 
strong predictor of further memory impairment and progression to Alzheimer’s dementia 
(Devanand et al. 2007; Burggren et al. 2011; Devanand et al. 2012; Ewers et al. 2012). 
Additionally, even minimal levels of EC atrophy detected by MRI are associated with 


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impairment on multiple memory tests, confirming that this atrophy has clinical relevance 
for individuals with MCI due to AD (Varon et al. 2011). 
Another useful biomarker for monitoring the progression of AD is the tau protein PET 
biomarker 6-[18F]fluoro-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine 
([18F]MK-6240). Post-mortem Braak staging, based on the anatomical localization of 
intraneuronal neurofibrillary tangles comprised of hyperphosphorylated tau protein, is a 
hallmark pathology defining the severity and progression of AD in the brain (Braak & 
Braak 1991). Recent studies using tau PET ligands have shown in vivo features in 
patients characteristic of Braak histopathological stages (Schwartz et al. 2016; Xia & 
Dickerson 2017). Notably, in patients in the prodromal stage of MCI, the tau PET tracer 
AV-1451 increased only in the entorhinal cortex (Braak Stage I & II) while patients with 
AD had increased binding in cortical areas consistent with later Braak stages (Cho et al. 
2016). [18F]MK-6240 has been developed for in vivo quantification of human 
neurofibrillary tangles (Collier et al. 2017; Hostetier et al. 2016; Walji et al. 2016) and 
has demonstrated binding consistent with AD tau pathology with an improved off target 
profile. Concurrent with the clinical use of tau PET tracers, evidence from AD preclinical 
models of human tau mutations has now demonstrated that chronically increased neural 
activity stimulates the release of tau and enhances the spread of tau pathology in the 
hippocampus and associated cortical circuits in a manner consistent with Braak staging 
(Wu et al. 2016). The longitudinal data that will be obtained with [18F]MK-6240 in a 
substudy is included to provide possible evidence for slowing of the progression of tau 
pathology in patients treated with AGB101 targeting excess neural activity compared to 
patients on placebo. Evidence for reduced progression of tau pathology in the substudy 
will bridge to patients in the Phase 3 protocol with the acquisition of structural 3T MRI 
longitudinal data in all subjects; structural atrophy in the brain with 3T MRI scans is 
expected to be observed in the entorhinal cortex (Tward et al. 2017) where increased 
binding in tau PET imaging is also expected to occur in the study population (Cho et al. 
2016). 
For this study, a subpopulation of approximately 56 subjects will participate, on an 
optional basis, to have the tau PET marker evaluated using the [18F]MK-6240 biomarker. 
Analyses of the two cognitive/functional secondary endpoints includes a fixed-sequence 
procedure with Type I error control, in which the Functional Activities Questionnaire 
(FAQ) and MMSE are separately considered in a sequential fashion (see Section 5.2.6.2). 
Assessments of EC and hippocampal atrophy are placed outside of this biostatistical 
gatekeeping process due to residual uncertain linkages between the neuropsychological 
test performance and structural neuroimaging assessments in this therapeutic area.  
A distinctive condition in the MCI due to AD population is neural over-activity localized 
to the hippocampal formation, as assessed by fMRI (Ewers et al. 2011; Sperling et al. 
2011; Albert et al. 2011). In clinical studies, the magnitude of such hippocampal over-


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activity longitudinally predicts subsequent cognitive decline/conversion to a dementia 
diagnosis (Dickerson et al. 2005; Miller et al. 2008; Sperling 2007) and hippocampal 
over-activity in MCI due to AD subjects is significantly correlated with the extent of 
neuronal injury affecting AD-specific regions of the brain. With respect to neuronal 
injury, Putcha et al. 2011 reported a significant correlation between greater hippocampal 
activation (fMRI) and more pronounced MTL atrophy (cortical thinning) indicative of 
AD-related neurodegeneration in MCI due to AD subjects. If the primary efficacy 
evaluation shows significant cognitive improvement, it could be due, in part, to the 
effects of AGB101 (low-dose levetiracetam) in reducing hippocampal over-activity to 
slow or prevent neuronal injury. This assessment will verify or dispute that prediction. 
1.5 
Risks and Benefits for Subjects 
Keppra is an antiepileptic drug approved for use in the United States (US) since 1999. 
Doses of 1000 mg/day to 3000 mg/day are typically used for this indication. As of 2011, 
Keppra was prescribed to nearly one quarter of all individuals with epilepsy. According 
to a survey of neurologists, Keppra performs best on categories such as 
safety/tolerability, as well as subject and physician benefits. 
In controlled clinical studies of adults with partial-onset seizures, the most frequently 
reported adverse events (AEs) from Keppra in combination with other AEDs included 
somnolence, asthenia, infection, and dizziness. Of the most frequently reported AEs, 
asthenia, somnolence, and dizziness appeared to occur predominantly during the first 
4 weeks of treatment with Keppra. AEs were usually mild-to-moderate in intensity.  
Keppra (adult doses 1000 mg/day-3000 mg/day) 
Partial onset seizures 
Table 3 lists treatment-emergent adverse events (TEAEs) that occurred in at least 1% of 
adult epilepsy subjects treated with Keppra who participated in placebo-controlled studies 
and were numerically more common than in individuals treated with placebo.  


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Table 3:  Incidence (%) of Treatment-Emergent Adverse Events in 
Placebo-Controlled, Add-On Studies of Adults Experiencing Partial 
Onset Seizures by Body System 
 
Other events reported by at least 1% of adult Keppra-treated subjects, but as or more 
frequent in the placebo group included: abdominal pain, accidental injury, amblyopia, 
arthralgia, back pain, bronchitis, chest pain, confusion, constipation, convulsion, diarrhea, 
drug level increased, dyspepsia, ecchymosis, fever, flu syndrome, fungal infection, 
gastroenteritis, gingivitis, grand mal convulsion, insomnia, nausea, otitis media, rash, 
thinking abnormal, tremor, urinary tract infection, vomiting, and weight gain. 
Time course of onset of AEs for partial-onset seizures 
Of the most frequently reported AEs in adults experiencing partial-onset seizures, 
asthenia, somnolence, and dizziness appeared to occur predominantly during the first 
4 weeks of treatment with Keppra. 
Discontinuation or dose reduction in well-controlled clinical studies 
In well-controlled adult clinical studies, 15.0% of subjects receiving Keppra and 11.6% 
of subjects receiving placebo either discontinued or had a dose reduction because of an 


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AE. Table 4 lists the most common (> 1%) AEs that resulted in discontinuation or dose 
reduction. 
Table 4:  Adverse Events Most Commonly Resulting in Discontinuation or Dose 
Reduction 
 
Myoclonic seizures 
In a well-controlled clinical study of adolescents (12 to 16 years of age) and adults with 
myoclonic seizures, the most frequently reported AEs associated with the use of Keppra 
in combination with other AEDs were somnolence, neck pain, and pharyngitis; these AEs 
were not observed an equivalent frequency among placebo-treated subjects. 
Other events occurring in at least 5% of Keppra-treated subjects with myoclonic seizures, 
but as or more frequent in the placebo group, were fatigue and headache. 
Keppra use in the elderly 
A total of 347 subjects age 65 or older have participated in clinical studies as of 
March 2015, and results from those studies showed no overall differences in 
safety-related measures due to age (Keppra XR 2015). Results from a study of 16 elderly 
subjects (age 61 to 88 years) showed a 28% decrease in total body clearance and an 
increase of 2.5 hours in T½, which were attributed largely to decreases in renal function 
typically found in the elderly. As Keppra is known to be substantially excreted by the 
kidneys, special care should be taken when administering Keppra to elderly individuals, 
as exposures are expected to be higher in that population.  
Published data are available on the safety, tolerability, and PK of Keppra in elderly 
healthy volunteers, elderly cognitively impaired subjects, and elderly subjects with 
epilepsy with or without comorbidity with AD. While not an exhaustive, the following 
summary captures important studies in the elderly reported in the literature.  
In a review by French et al. 2001, the safety and tolerability of Keppra was evaluated 
from an integrated summary of safety. In the cognition studies, subjects were randomized 
to receive Keppra (250 mg/day to 1500 mg/day; n = 394) or placebo (n = 344). The mean 


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age was 60 years, with 300 subjects (42%) being 65 years or older. The mean Keppra 
dose in subjects 65 years or older was 828 mg/day, and the average length of treatment 
was 41 days. Approximately 14% of subjects in the Keppra group and 7% of subjects in 
the placebo group experienced TEAEs that led to a dose reduction or discontinuation 
from the study. A higher incidence of AEs, particularly behavioral effects, was reported 
among subjects with epilepsy than elderly subjects with cognitive disorders who received 
lower doses of the drug.  
In an analysis of the UCB Keppra safety database, Cramer et al. 2003 reported a higher 
incidence of headache (5.2% versus 0.9%) and tremor (5.2% versus 0.5%) among elderly 
subjects with anxiety disorders compared with their younger counterparts.  
In a 1-year, open-label study, Keppra (1000 mg/day to 3000 mg/day) was administered as 
add-on therapy to 491 subjects with focal epilepsy age 65 years or older (Werhahn et al. 
2011). The mean age was 72 years (range, 65 to 101 years) and the mean daily dose was 
1573 mg, 1796 mg, and 2083 mg at 3 months, 6 months, and 12 months, respectively. 
Overall, Keppra was reported to be well tolerated. A total of 97 AEs were reported in 
53 subjects. Fatigue and restlessness were the most common AEs, occurring in 6 subjects 
each. Eighteen subjects (3.7%) discontinued the study because of intolerable AEs. Of the 
SAEs reported (n = 35), 1 (lack of efficacy) was regarded as probably related to Keppra, 
with the other 34 were regarded as unlikely related to the drug.  
The safety and cognitive effects of Keppra were evaluated in subjects with epileptic 
seizures comorbid with AD in a case-control design study (Cumbo and Ligori 2010). 
Subjects were administered Keppra (n = 38), phenobarbital (n = 28), or lamotrigine 
(n = 29), and compared with a control group (n = 68) of subjects with AD without 
epilepsy. The mean age was 72 years, and the mean daily dose of Keppra was 956 mg. 
AEs were mainly related to the central nervous system (CNS) and were mild in severity. 
Six (17%) Keppra-treated subjects reported AEs. None of the subjects dropped out of the 
study due to the AEs. Keppra caused fewer AEs than the other antiepileptic drugs. 
Keppra also improved cognitive performance related to the level of attention and oral 
fluency items, compared to baseline.  
In a 12-week, open-label, phase 4 study in subjects (n = 24) with epileptic seizures and 
AD or other cognitive problems, the mean age was 70 years (range, 50 to 84 years) and 
the median Keppra dose was 625 mg BID (Lippa et al. 2010). MMSE and AD assessment 
scale-cognitive scores improved relative to baseline. Fatigue was the most common AE. 
Five (21%) subjects experienced fatigue, and 4 of those subjects discontinued Keppra. 
Eleven of the 24 subjects were taking memantine, a cholinesterase inhibitor, or both 
Keppra and memantine. Keppra was regarded as well tolerated in this population.  
In a separate study, Contin et al. 2012 reported results on PK parameters in elderly 
subjects. A total of 105 elderly (age, 66 to 80 years), 70 very elderly (age, 81 to 
96 years), and 96 non-elderly (age, 30 to 65 years) subjects with epilepsy who had been 


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on Keppra for at least 1 month were included in the study. Median weight-normalized 
apparent total clearance of the drug from plasma after oral administration (CL/F) 
decreased from 1.23 mL/min kg in the nonelderly to 0.83 mL/min kg in the elderly and 
0.59 mL/min kg in the very elderly (P < 0.001). No sex differences were observed. 
Keppra CL/F significantly declined with age, with elderly and very elderly subjects 
requiring about 30% to 50% lower dose, respectively, compared with nonelderly subjects. 
Possibly-related AEs included somnolence, fatigue, confusion, irritability, paresthesias, 
and mental slowing, which were recorded in 14 (14.4%) nonelderly subjects, 14 (13.3%) 
elderly subjects, and 7 (10.0%) very elderly subjects.  
In a recent study, Werhahn et al. 2011 compared the efficacy and tolerability of Keppra 
to carbamazepine and lamotrigine in elderly subjects (> 60 years) with new onset focal 
epilepsy. The median daily dose of Keppra was 950 mg. At 58 weeks, the retention rate 
with Keppra was higher than that observed with carbamazepine and lamotrigine (61.5% 
versus 45.8% versus 55.6%, respectively). Subjects who received Keppra had a lower 
discontinuation rate (17.2%) due to AEs (fatigue, renal failure, and epileptic seizures), 
compared with those who received carbamazepine (32.2%) and lamotrigine (26.3%). The 
most common AEs (non-epilepsy related) in subjects who received Keppra were 
dizziness (29.5%), headache (25.4%), fatigue (25.4%), nasopharyngitis (16.4%), and 
nausea (9%).  
Postmarketing 
Postmarketing AE information has been obtained from the Keppra XR medication guide 
(Keppra XR 2015). The following AEs have been reported in subjects receiving Keppra 
worldwide: abnormal liver function test, agranulocytosis, choreoathetosis, drug reaction 
with eosinophilia and systemic symptoms, dyskinesia, erythema multiforme, hepatic 
failure, hepatitis, hyponatremia, leukopenia, muscular weakness, neutropenia, 
pancreatitis, pancytopenia (with bone marrow suppression identified in some of these 
cases), panic attack, thrombocytopenia, and weight loss. Alopecia has also been reported 
with Keppra use in epilepsy; however, recovery was reported in the majority of cases 
once the drug was discontinued. 
AGB101 (novel extended-release tablet formulation) 
In a recent phase 1, 2-group, single-dose, 2-period, 2-way crossover, food-effect study of 
AGB101 (190 mg and 220 mg) extended-release tablet formulation, 5 TEAEs were 
reported by 5 subjects over the course of the study; 2 of the AEs were reported in the 
190 mg dose group and 3 AEs were reported in the 220 mg dose group (Table 5). There 
were no serious AEs (SAEs) or AEs leading to study discontinuation. 


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Table 5:  Number (%) of Subjects With Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
 
AGB101 (220 mg) is the formulation that will be used in the current study. 
 
 
 
 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
 To assess the efficacy of AGB101 (low-dose levetiracetam, 220 mg, 
extended-release tablet) compared to placebo in subjects with MCI due to AD 
using CDR-SB scores. 
2.2 
Secondary Objectives 
 To assess the efficacy of AGB101 compared to placebo on daily functioning and 
cognition using FAQ and MMSE scores. 
 To assess the effect of AGB101 compared to placebo on neuronal injury, as 
measured by a change in the EC thickness, using MRI.  
2.3 
Additional Secondary Objectives 
 To assess the efficacy of AGB101 compared to placebo using CDR (global, 
memory box), Behavioral Pattern Separation-Object (BPS-O) task, and 
International Shopping List Test (ISLT) scores.   
 To assess the effect of AGB101 compared to placebo on hippocampal volume 
using MRI. 
 To assess the effect of AGB101 compared to placebo on the levels of tau protein 
in the brain using the tau PET marker [18F]MK-6240 in a subpopulation of 
approximately 56 subjects.  
2.4 
Exploratory Objectives 
 To assess the effect of AGB101 on blood-based biomarkers of 
neurodegeneration at week 78 or the early termination visit 
 (optional procedure to be performed only at Johns Hopkins University) To assess 
the efficacy of AGB101 compared to placebo on hippocampal overactivity in 
subjects with MCI due to AD. 
2.5 
Safety Objective 
 To assess the safety and tolerability of AGB101 compared to placebo in subjects 
with MCI due to AD. 
2.6 
Study Hypothesis 
AGB101 is hypothesized to slow the progression of MCI due to AD by restoring the 
entorhinal/hippocampal network balance. During this phase of the disease, fMRI studies 
show hippocampal over-activity and EC under-activity. As shown in the phase 2 study, 
AGB101 restores this network balance by attenuating hippocampal over-activity and 
restoring EC activity. Hippocampal over-activity predicts progression on CDR-SB 
(primary endpoint) and on EC atrophy (a neuronal injury secondary endpoint). By 


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restoring network balance, AGB101 is hypothesized to improve cognitive function 
(CDR-SB) and reduce neuronal injury (EC atrophy). 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a multicenter, randomized, double-blind, placebo-controlled, 78-week, fixed-dose 
study evaluating AGB101 versus placebo as a treatment for slowing the progression of 
MCI due to AD. 
The screening phase will occur 7 days to 42 days before the baseline visit (see Figure 4). 
After providing informed consent, subjects who meet entry criteria will be randomized 
1:1 during the final baseline visit to receive either placebo or AGB101. A total of 
160 subjects will be randomized (80/treatment group). Because of the PK and safety 
profile of AGB101, dosing will be initiated without titration and will be discontinued 
without tapering.  
The baseline visit will occur 1 day before the study start. Subjects will be given their 
assigned study drug and instructed to take their 1st dose the next morning. A telephone 
contact will be made 1 week after the baseline visit to assess the subjects’ medical status 
and inquire about any AEs/SAEs; similar telephone contacts will be made at weeks 17 
and 56 with the same purpose. Study clinic visits are divided into minor visits (“clinic 
minor”) at weeks 13, 39, and 65 and major visits (“clinic major”) at weeks 26, 52, and 78. 
The difference between these two types of visits is the number and kinds of assessments 
performed. The “clinic minor” visits consist of a few basic assessments, while the “clinic 
major” visits consist of more in-depth testing, neuropsychological testing, and blood 
draws. 
Subjects who enroll and subsequently discontinue the treatment before the 78-week visit 
will be followed up with a phone call at week 78 to assess their medical status and 
encourage them to come in to complete the early treatment termination/follow-up visit 
assessments.   
Figure 4:  Study Schema 
 
*Within 5 days ± 2 days of the last screening visit. 
**It includes phone contacts at weeks 1, 17, and 56. 


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3.2 
Study Duration 
The study includes up to a 5-week screening period and a 78-week treatment period 
consisting of 13 visits (3 screening visits, 1 baseline visit, 3 telephone call visits, and 
6 clinic visits). 
3.3 
Selection of Study Population 
The study population consists of subjects with a diagnosis of MCI due to AD (see 
Section 3.3.1 and Section 3.3.2).  
3.3.1 Inclusion Criteria 
Subjects must meet all of the following inclusion criteria at screening: 
1. Subjects between 55 and 85 years old (inclusive) in good general health: 
a. Willing and able to consent and participate for the duration of the study. 
b. Have eighth-grade education or good work history sufficient to exclude 
mental retardation. 
c. Have visual and auditory acuity adequate for neuropsychological testing. 
d. Have proficient fluency of the native local language to participate in all the 
neuropsychological test assessments. 
2. Have a study partner who has sufficient contact with the subject to be able to provide 
assessment of memory changes, who can accompany the subject to the screening visit 
and all major clinic visits for the duration of those visits, and who is able to provide 
an independent evaluation of the subject’s functioning. 
3. Have MCI as defined by all of the following criteria and consistent with the National 
Institute on Aging-Alzheimer’s Association criteria:  
a. MMSE scores between 24 and 30 (inclusive; exceptions may be made for 
subjects with <8 years of education at the discretion of the sponsor). 
b. A memory complaint reported by the subject or his/her study partner. 
c. Evidence of lower memory performance based on the delayed recall portion 
of the ISLT. 
d. A CDR score of 0.5 with a memory box score of ≥ 0.5. 
e. Essentially preserved activities of daily living. 
f. Cognitive decline not primarily caused by vascular, traumatic, or medical 
problems (alternative causes of cognitive decline are ruled out). 
4. Permitted medications:  
a. With potential pro-cognitive effects, such as cholinesterase inhibitors and 
memantine, must be at a stable dose for ≥ 3 months prior to screening and 
expected to remain stable throughout the study; estrogen replacement therapy, 


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Ginkgo biloba, and vitamin E must be at a stable dose for ≥ 4 weeks prior to 
screening and expected to remain stable throughout the study. 
b. Other psychotropics, such as antidepressants and antipsychotics, must be at a 
stable dose for ≥ 3 months prior to screening and expected to remain stable 
throughout the study. 
5. Willing and able to undergo imaging procedures: 
a. An amyloid-imaging PET scan with Neuroceq (florbetaben), Amyvid 
(florbetapir), or Vizamyl (flutemetamol) ([18F] isotope diagnostic agents) or 
documented evidence of an amyloid-positive PET scan. 
The amyloid PET scan performed at baseline must be read by a qualified 
physician with experience in reading amyloid PET scans, and it should be 
consistent with the presence of amyloid plaques. 
b. Repeated MRI scans (3 Tesla) with no contraindications to MRI. 
The MRI scan performed at baseline must be read by a physician with 
experience in evaluating brain-imaging studies in dementia. MRI scan results 
are consistent with the diagnosis of amnestic MCI due to AD with no 
clinically significant findings of non-AD pathology that could account for the 
observed cognitive impairment.  
6. Willing to allow collection of blood for apolipoprotein E (ApoE) genotyping (all 
sites). 
3.3.2 Exclusion Criteria 
Subjects must not meet any of the following exclusion criteria at screening: 
1. Use of anticonvulsant medications or excluded psychotropic medications within 
3 months prior to the baseline visit. 
2. Participation in a therapeutic clinical study for any medical or psychiatric indications 
within 3 months (6 months for biologics) of the screening visit, or at any time during 
the study.  
Subjects must understand that they may only enroll in this clinical study once; they 
may not enroll in any other clinical study while participating in the current study, and 
they may not participate in a clinical study of a drug, biologic, therapeutic device, or 
medical food, in which the last dose/administration was received within 3 months 
(6 months for biologics) prior to screening. 
3. History of hypersensitivity or lack of tolerability to AGB101 (levetiracetam). 
4. Severe renal impairment (creatinine clearance of < 30 mL/minute) or undergoing 
hemodialysis. 


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5. Any significant neurological disease other than suspected incipient AD, such as 
Parkinson’s disease, multi-infarct dementia, Huntington’s disease, normal pressure 
hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder (lifetime 
history; infant febrile seizures are not exclusionary), subdural hematoma, multiple 
sclerosis, or history of significant head trauma followed by persistent neurologic 
deficits, or known structural brain abnormalities. 
6. Presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, metal 
fragments, or foreign objects in the eyes, skin, or body that constitute a 
contraindication to having an MRI.  
7. Diagnosis of bipolar disorder, or major depression within the past 3 years, as 
described in the DSM-5.  
Psychotic features, agitation, or behavioral problems within the last 3 months that 
could lead to difficulty complying with the protocol. Subjects must not have a major 
depressive disorder or other types of depression that could confound diagnosis of 
MCI due to AD, or clinical assessments, in the opinion of the investigator. The 
Geriatric Depression Scale [GDS] (long form score > 9 suggests depression) results 
should be reviewed by the investigator to assist in this determination. 
8. Modified Hachinski Ischemic Scale (HIS) score > 4.  
9. History of schizophrenia (DSM-5 criteria). 
10. History of alcohol or substance abuse or dependence within the past 3 years (DSM-5 
criteria). 
11. Any significant systemic illness or unstable medical condition that could lead to 
difficulty in complying with the protocol requirements. 
12. Any unstable medical condition that is likely to require new medical or surgical 
treatment during the course of the study and where such treatments might affect the 
collection of efficacy data.  
13. Clinically significant abnormalities in B12 or thyroid function test that might interfere 
with the study. A low B12 (below normative range for elderly) is exclusionary, unless 
follow-up labs (homocysteine and methylmalonic acid) indicate that it is not 
physiologically significant. If the B12 deficiency is treated, subjects may become 
eligible to participate in the study. 
14. Residence in a skilled nursing facility. Individuals in independent living communities, 
assisted living facilities, residential care facilities, or continuing care communities are 
eligible provided they engage in a sufficient spectrum of activity to permit assessment 
of all 6 domains contributing to the CDR-SB. Individuals in these facilities must also 
have a study partner who has the ability to observe the subject during the study and 
can participate in clinical evaluations.  


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15. Any use of excluded medications (eg, antiepileptics, certain antidepressants or 
antipsychotics, antihistamines with anticholinergic properties, opiates). 
16. Participation in clinical studies using the ISLT, BPS-O task, or the trail making test 
(A, B) within 1 month of screening. 
17. Female subjects must not be pregnant, lactating, or of childbearing potential (ie, they 
must be 2 years postmenopause or surgically sterile). 
3.3.3 Early Termination From Treatment 
A subject who discontinues from treatment will complete the early termination visit 
assessments as shown in Table 7. The investigator will make every attempt to follow the 
subject to week 78 and complete the early termination/follow-up visit.  
A termination electronic case report form (eCRF) page should be completed for every 
subject who receives the study drug, whether or not the subject completes the study. The 
reason for early termination should be indicated on this form. The primary reason for early 
termination should be selected from the following standard categories: 
Adverse event (adverse reaction): Clinical or laboratory events occurred that, in the 
medical judgment of the investigator for the best interest of the subject, were grounds for 
discontinuation. This includes serious and non-serious AEs regardless of relation to the 
study drug. 
Death: The subject died. 
Withdrawal by subject: The subject or legal representative desired to withdraw from 
further participation in the study in the absence of an investigator-determined medical 
need to withdraw. If the subject gave a reason for withdrawing, it should be recorded in 
the eCRF. 
Withdrawal by study partner: The study partner desired to withdraw from further 
participation in the study in the absence of an investigator-determined medical need to 
withdraw. If the study partner gave a reason for withdrawing, it should be recorded in the 
eCRF. 
Lack of Efficacy: The subject or legal representative (or study partner) indicated a lack of 
efficacy as the primary reason warranting discontinuation from the study. 
Noncompliance with study drug: The subject was noncompliant in taking the prescribed 
study drug. Efforts to ensure compliance with the protocol including reminders, phone 
calls, and counseling should be recorded. Subjects who discontinue treatment will not be 
automatically discontinued from the study. Every effort should be made to bring subjects 
back for study visits unless the subject withdraws consent. 


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Physician decision: The study physician may determine that the subject should no longer 
continue in the study if continuation would pose a safety risk for either the subject, study 
partner, or another person. In this case, the reason for the concern should be recorded. 
Protocol deviation: The subject’s findings or conduct failed to adhere to the protocol 
requirements (eg, drug noncompliance, failure to return for defined number of visits). 
The deviation necessitated early discontinuation from treatment. 
Lost to follow-up: The subject stopped coming for visits and study personnel were unable 
to contact the subject. The efforts to contact the subject should be documented.  
Terminated by Sponsor: The subject was discontinued due to the study being terminated 
by the sponsor. 
Other: The subject was discontinued for a reason other than those listed above, such as 
theft or loss of study drug. 
3.4 
Treatments 
3.4.1 Details of Study Treatments 
Information about the study drugs is provided in Table 6 below. 
Table 6:  Details of the Study Drugs 
 
Study drug 
Placebo 
Name 
AGB101 
Not applicable 
Manufacturer 
AgeneBio, Inc. 
AgeneBio, Inc. 
Dose(s) 
1 x 220 mg 
Not applicable 
Route 
Oral 
Oral 
Formulation 
Light yellow to peach 
coated capsule shaped 
tablet debossed with 
“AGB” 
Light yellow to peach 
coated capsule shaped 
tablet debossed with 
“AGB” 
Strength(s) 
220 mg 
Not applicable 
AGB101 = low-dose levetiracetam, 220 mg, extended release. 
The sponsor will provide all the drug supplies. Subjects will be receiving AGB101 or 
placebo in the morning in identically appearing oral dosage forms. One dose of AGB101 


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will contain 220 mg of levetiracetam. A 102-day supply will be provided at each of the 
clinical visits. 
3.4.2 Dosage Schedule 
Subjects will be administered a single morning daily dose of placebo or AGB101 for 
78 weeks. Given the low dose being used, AGB101 dosing will be initiated without 
titration and will be discontinued without tapering. 
3.4.3 Treatment Assignment (1:1 Randomization Placebo:AGB101) 
A central randomization list will be used for the treatment assignment.  
After signing informed consent, subjects will be assigned a unique 10-digit subject 
identification number (XXX-CC-SSS-EE), with the first 3 digits for the study, the next 
2 digits for the country, the next 3 digits for the site, and the last 2 digits for the 
sequential order of enrollment at a given site. Subjects who are rescreened will receive a 
new identification number; the previous number will also be recorded by the site. After 
screening assessments are performed and eligibility is confirmed, eligible subjects will be 
randomized at baseline. Randomization will be accomplished by the study site using an 
interactive web response system (IWRS) to assign the next sequential randomization 
number within the relevant stratum to the eligible subject. Block randomization will be 
used at each site, with each block having a randomly chosen length of 4 or 6 (each with 
probability 1/2).  
3.4.4 Drug Packaging and Blinding 
The double-blind study drug will be packaged, labeled, and distributed to study sites by a 
designated vendor.  
The study drug supplied to subjects will be packaged in 3 bottles containing 34 tablets 
each. The study drug package labels will be in compliance with applicable regulatory 
requirements and will include the statements “Keep out of reach of children”, “Caution: 
New Drug – Limited by Federal (United States) law to investigational use”, and/or “For 
clinical trial use only” as appropriate, as well as any other locally mandated statements. 
Labels will be translated into the local language.  
At a minimum, labels will also include the following information: the name of the 
sponsor, study code, a unique identifier number, and appropriate contact information. A 
re-test or expiry date will be included in jurisdictions that require this information.  
The investigator may unblind a subject’s treatment assignment. If that happens, the 
following will apply: 
Such a measure should be taken only in the case of an emergency OR in the event of a 
serious medical condition when knowledge of the study drug is essential for the 
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In the event that a medical emergency or condition requires knowledge of the subject’s 
treatment assignment, the investigator will contact the medical monitor to discuss the 
potential need for unblinding. Unblinding will be done through the interactive voice 
response system/IWRS. The procedure for subject unblinding is provided in the study 
reference manual.  
If, for safety reasons, the investigator determines that the subject’s treatment must be 
immediately unblinded to provide adequate medical treatment, the investigator must 
inform the medical monitor about the unblinding as soon as possible, but without 
revealing the treatment assignment of the unblinded subject.  
The sponsor will be informed immediately of the decision to unblind any subject and will 
determine whether any additional measures need to be taken for the safety of subjects 
currently in the study.  
Any other requests to reveal a subject’s treatment identity must be requested from and 
approved by the sponsor.  
A subject will be withdrawn from the study if his or her treatment code is unblinded by 
the investigator. The date, time, and reason for the unblinding must be fully documented 
in the source documents and the eCRF.  
The sponsor, or designee, may unblind the treatment assignment for any subject if this is 
required to fulfill regulatory reporting obligations, such as expedited SAE reporting. 
Information about any subject for whom a code break or unblinding occurs will be 
provided to the Data Safety and Monitoring Board (DSMB) by the sponsor, or designee, 
within 15 days (within 7 days in the event of a fatal event). 
Information regarding unblinding treatment allocation in relation to reporting Suspected 
Unexpected Adverse Reactions (SUSARs) is provided in Section 4.4.1. 
3.4.5  Drug Inventory and Accountability 
Investigators must keep an accurate accounting of the number of study drug units 
delivered to the site, dispensed to subjects, returned to the investigator by the subject, and 
returned to the sponsor or other disposition during and at the completion of the study. 
Only an appropriately qualified person must dispense the study drug to subjects. The 
study drug is to be used in accordance with the protocol by subjects who are under the 
direct supervision of the investigator. Investigators should maintain records that 
adequately document that the subjects were provided the doses specified by the protocol 
and reconcile all study drugs received at the site before final disposition. At the end of the 
study, or as directed, all study drugs, including unused, partially used, and empty 
containers, will be returned to the sponsor. 


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3.4.6 Treatment Compliance 
Study drug containers must be returned at each visit, as compliance will be assessed by 
tablet count. Noncompliance is defined as taking < 80% or > 120% of the study drug 
during any outpatient evaluation period (visit to visit). The investigator may use clinical 
judgement in evaluating noncompliance with the study drug as a reason for early 
termination from the study. Subjects who discontinue treatment will not be automatically 
discontinued from the study. Every effort should be made to bring subjects back for study 
visits unless the subject withdraws consent. 
3.4.7 Prior and Ongoing Medical History and Treatments 
3.4.7.1 Prior and Ongoing Medical History 
Investigators should document all significant medical history that subjects experienced 
within 12 months of screening. Any illness present at the time informed consent is given 
should be regarded as concomitant illnesses. Illnesses first occurring or detected during 
the study and/or worsening of a concomitant illness during the study should be 
documented as AEs in the eCRF. 
3.4.7.2 Prior and Concomitant Treatments 
Prior treatments, defined as those received within 30 days before screening, should be 
recorded in the eCRF as prior medications. Concomitant treatments, defined as 
treatments received after the first dose of the study drug, should be recorded in the eCRF 
as concomitant medications. Any change in medication (including dose or frequency) 
should be recorded on the “Concurrent Medications Log” for the visit reported. If a 
subject begins an excluded medication, the site must document this by requesting an 
exception from the medical monitor.  
For a list of accepted and excluded medications, please refer to Appendix 8.1. Note that 
this is not an exhaustive list. For drugs not included on this list, inquire with the medical 
monitor. The medical monitor may grant exceptions for infrequent or trivial use.  
3.5 
Assessments 
Unless otherwise indicated, all assessments will be performed by the investigator or 
designated study personnel.   
3.5.1 Schedule of Assessments 
The study procedures are outlined in Table 7 and in Section 3.5.2. 


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Table 7:  Schedule of Assessments 
Study period 
Screening 
Baseline 
Treatment 
Early 
termina- 
tion 
 
Study visit number 
S 11 
S 21 
S 3/B 
MRI1 
B2 
W 
13 
W 13 
W 17 
W 26 
W 39 
W 52 
W 56 
W 65 
W 78 
ET4 
ET/ 
W 78 
Follow-
up5 
Study day/week 
D -42 to D -7 
D -1 
D 7 
± 2 
D 91 
± 5 
D 119 
± 5 
D 182 
± 5 
D 273 
± 5 
D 364 
± 5 
D 392 
± 5 
D 455 
± 5 
D 546 
± 5 
N/A 
W 78 
Visit type  
C 
I 
I 
C major 
T6 
C 
minor 
T6 
C 
major 
C 
minor 
C 
major 
T6 
C 
minor 
C 
major 
C  
major 
T/C 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ApoE genotyping (all 
sites) and DNA 
banking (JHU only; 
optional) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Physical and 
neurological exams 
(Height at Screening) 1  
X 
 
 
 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Vital signs and Body 
Weight 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Serum chemistry 
X 
 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
 
CBC 
X 
 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
 
Thyroid panel 
X 
 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
 
Liver function tests 
X 
 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
 


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Study period 
Screening 
Baseline 
Treatment 
Early 
termina- 
tion 
 
Study visit number 
S 11 
S 21 
S 3/B 
MRI1 
B2 
W 
13 
W 13 
W 17 
W 26 
W 39 
W 52 
W 56 
W 65 
W 78 
ET4 
ET/ 
W 78 
Follow-
up5 
Study day/week 
D -42 to D -7 
D -1 
D 7 
± 2 
D 91 
± 5 
D 119 
± 5 
D 182 
± 5 
D 273 
± 5 
D 364 
± 5 
D 392 
± 5 
D 455 
± 5 
D 546 
± 5 
N/A 
W 78 
Visit type  
C 
I 
I 
C major 
T6 
C 
minor 
T6 
C 
major 
C 
minor 
C 
major 
T6 
C 
minor 
C 
major 
C  
major 
T/C 
Urine drug screen  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ISLT7 
X 
 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
X 
MMSE 
X8 
 
 
X 
 
 
 
X 
 
X 
 
 
X8 
X8 
X8 
GDS 
X8 
 
 
X 
 
 
 
 
 
 
 
 
X8 
X8 
X8 
BPS-O task 
X9 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
X 
X 
Trail making test (A, B) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
FAQ 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
X 
X 
CDR (participant and 
study partner) 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
X 
X 
C-SSRS 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIS score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amyloid PET scan 
 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI structural:  
MP-RAGE or IR-SPGR 
 
 
X10, 11 
 
 
 
 
X 
(JHU 
only) 
 
X 
 
 
X10 
 
 
MRI structural: 
FLAIR, T2 
 
 
X10, 11 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 


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Study period 
Screening 
Baseline 
Treatment 
Early 
termina- 
tion 
 
Study visit number 
S 11 
S 21 
S 3/B 
MRI1 
B2 
W 
13 
W 13 
W 17 
W 26 
W 39 
W 52 
W 56 
W 65 
W 78 
ET4 
ET/ 
W 78 
Follow-
up5 
Study day/week 
D -42 to D -7 
D -1 
D 7 
± 2 
D 91 
± 5 
D 119 
± 5 
D 182 
± 5 
D 273 
± 5 
D 364 
± 5 
D 392 
± 5 
D 455 
± 5 
D 546 
± 5 
N/A 
W 78 
Visit type  
C 
I 
I 
C major 
T6 
C 
minor 
T6 
C 
major 
C 
minor 
C 
major 
T6 
C 
minor 
C 
major 
C  
major 
T/C 
[18F]MK-6240 (Tau 
protein marker, 
optional) 
 
 
 
X10 
 
 
 
 
 
 
 
 
X10 
 
 
fMRI (JHU only)12 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Study drug dispensing 
 
 
 
X13 
 
X 
 
X 
X 
X 
 
X 
 
 
 
PK sampling 
 
 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
 
Biomarker Blood Draw 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Prior/Concomitant 
medications14 
-------------------------------------------------------------------------------------X------------------------------------------------------------------------------------- 
AE/SAE reporting 
     -------------------------------------------------------------------------------------X------------------------------------------------------------------------------------- 
Abbreviations: AE=adverse event; ApoE=apolipoprotein E; B=baseline; B MRI=baseline magnetic resonance imaging; BPS-O=Behavioral Pattern Separation-Object; C=clinic 
visit; CBC=complete blood count; CDR=Clinical Dementia Rating; C major=major clinic visit; C minor=minor clinic visit; C-SSRS=Columbia Suicide Severity Rating Scale; 
D=day; DNA = deoxyribonucleic acid; ECG=electrocardiogram; ET=early termination; FAQ=Functional Activities Questionnaire; FLAIR=fluid attenuation inversion recovery; 
fMRI = functional magnetic resonance imaging; GDS=Geriatric Depression Scale; HIS=Hachinski Ischemic Scale; I=imaging visit; IR-SPGR=radiofrequency-spoiled gradient 
echo; ISLT=International Shopping List Test; JHU = Johns Hopkins University; M=month; MMSE=Mini Mental State Examination; MP-RAGE=magnetization-prepared gradient 
echo; MRI=magnetic resonance imaging; N/A=not applicable; PET=positron emission tomography; PK=pharmacokinetic; S=screening; SAE=serious adverse event; T=telephone 
contact; T/C=telephone contact/clinic visit; W=week. 
1 
The screening phase (S1, S2, S3/B MRI) will occur 7 days to 42 days prior to baseline. Subjects must meet all the criteria during all the screening visits in order to be enrolled 
in the study. Height without shoes will be recorded in inches or meters. 
2 
Baseline visit will occur on day -1 within 12 days ± 2 days of the S3/B MRI visit. S3/B MRI will occur up to 2 weeks prior to Baseline; the Tau scan needs to occur 1 or more 
days before the cognitive visit. 
3 
Week 1 visit will occur 7 days after the baseline visit.  


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4 
Subjects who discontinue treatment early (ie, at any time after randomization) will have the early termination visit assessments performed as soon as possible after treatment 
termination. 
5 
All subjects who enroll and subsequently discontinue treatment will be followed up with a phone call during week 78 to assess their medical status and encourage them to 
come in for a final CDR and neuropsychological assessments and AE reporting. 
6 
7 days after the baseline visit (week 1), day 119 (week 17), and day 392 (week 56), a phone call will be made to all the subjects to assess their medical status and inquire 
about any adverse events/serious adverse events.   
7 
There will be approximately a 20 minute wait time between the immediate recall and delayed recall portion of the ISLT.  
8 
The MMSE and the GDS will be administered, in this order, between the immediate recall and delayed recall portion of the ISLT.  
9 
A practice BPS-O will be administered at screening visit 1. 
10 
MRI/PET scans may be redone if the scan is not technically satisfactory (as judged by the imaging vendor) within 2 weeks of the original scan as long as the radiation 
exposure is within the limits approved by the IRB. 
11 
Previous MRI scans will not be allowed. A baseline for structural imaging will be established using procedures in this protocol.  
12 
fMRI will only be performed as an optional procedure at JHU. 
13 
Dosing begins the morning after the baseline visit. 
14 
Prior medications will only be recorded during the screening phase (S1, S2, S3/B MRI).  
 


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3.5.2 Study Procedures 
The following assessments will take place at the specified study visits. 
3.5.2.1 Screening Phase (Day -42 to -7) 
The assessments during the screening phase (screening, screening 2, screening 3/baseline 
MRI) will determine the subjects’ eligibility to enter the study and comply with the 
protocol requirements. Subjects must meet all the criteria during all the screening visits in 
order to be enrolled in the study.  
The following procedures will be performed and recorded during screening phase: 
Screening visit 1 (clinic visit) 
 Informed consent 
 Demographic information and medical history 
 Eligibility criteria 
 Blood sample for serum chemistry, complete blood count (CBC), thyroid panel, 
and liver function tests 
 Electrocardiogram (ECG) 
 Physical and neurological exams, and HIS score assessment  
 Vital signs and body weight 
 Urine sample for urinalysis and urine drug screen (amphetamines, 
benzodiazepines, cannabinoids, opiates, methadone, and alcohol) 
 ISLT, MMSE, GDS, practice BPS-O, CDR score (participant and study partner), 
Columbia Suicide Severity Rating Scale (C-SSRS), and HIS assessments 
 AEs/SAEs and prior medication reporting 
Screening visit 2 (imaging visit) 
 An amyloid-imaging PET scan with Neuroceq (florbetaben), Amyvid (florbetapir), 
or Vizamyl (flutemetamol) will be performed unless there is documented evidence 
of an amyloid-positive scan, and it will only be conducted on prospective 
participants who meet all the other eligibility criteria (see Appendix 8.2).  
 AEs/SAEs and prior medication reporting 
Screening visit 3/baseline MRI (imaging visit) 
 Baseline visit will occur on day -1 within 12 days ± 2 days of the S3/B MRI visit. 
S3/B MRI will occur up to 2 weeks prior to Baseline; the Tau scan needs to occur 
1 or more days before the cognitive visit. This MRI is to be conducted prior to the 
cognitive Baseline visit; up to 2 weeks can occur between S3/B and cognitive 
Baseline visit. 


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 A 3T MRI imaging scan will occur and will only be conducted on prospective 
participants who meet all the other eligibility criteria (see Appendix 8.3).  
3T MRI (structural: magnetization-prepared gradient echo [MP-RAGE] or 
radiofrequency-spoiled gradient echo [IR-SPGR], fluid attenuation inversion 
recovery [FLAIR] sequence, T2) (previous MRI scans will not be allowed).  
 A 3T task activated fMRI scan will occur during the same MRI session after 
completing the structural MRI sequences. An in-scanner version of the BPS-O will 
be used as the fMRI task (optional procedure at JHU only). 
 AEs/SAEs and prior medication reporting 
3.5.2.2 Randomization and Baseline Visit (Day -1 Within 12 Days ± 2 Days of the 
S3/B MRI Visit) 
The following procedures will be performed and recorded during the baseline visit: 
 Randomization of treatment assignment 
 Study drug dosing (begins the morning after the baseline visit). Subjects will be 
given their assigned study drug and instructed to take their 1st dose the next 
morning 
 Vital signs and body weight 
 Blood sample for ApoE genotyping (all sites) and DNA banking (optional 
procedure; JHU only) 
 A PET scan after injection with the tau PET marker [18F]MK-6240 (optional 
procedure) 
 MMSE, GDS, BPS-O task, trail making test (A and B), FAQ, CDR score 
(participant and study partner), and C-SSRS assessments 
 AEs/SAEs and concomitant medication reporting 
3.5.2.3 Weeks 1 (Baseline + 7 Days ± 2 Days), 17 (Day 119 ± 5 Days), and 56 
(Day 392 ± 5 Days) Phone Call  
A phone call will be made to all the subjects to evaluate at weeks 1, 17, and 56 (for Study 
Day and time window see Table 7): 
 Medical status 
 C-SSRS assessment 
 AEs/SAEs and concomitant medication reporting 
3.5.2.4 Weeks 13, 39, and 65 Visits “Clinic Minor” (Baseline + 13, 39, and 65 
Weeks ± 5 Days) 
The “clinic minor” visits will take approximately 1 hour each and will include a few 
basic assessments: 


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 Study drug dispensing 
 Physical and neurological exams 
 Vital signs and body weight  
 C-SSRS assessment 
 AEs/SAEs and concomitant medication reporting  
3.5.2.5 Weeks 26, 52, and 78 “Clinic Major” (Baseline + 26, 52, and 78 
Weeks ± 5 Days) 
The “clinic major” visits will take approximately 4 hours each and will include a few 
additional assessments, including neuropsychological testing and blood draws: 
 Study drug dispensing (weeks 26 and 52 only) 
 Physical and neurological exams 
 Vital signs and body weight 
 Blood sample for PK testing, serum chemistry, CBC, thyroid panel, and liver 
function tests 
 Urinalysis 
 3T MRI (structural: MP-RAGE or IR-SPGR) at week 26 (JHU only) and at weeks 
52 and 78 (all sites) 
 3T fMRI using scanner version of the BPS-O task at Baseline MRI and week 26 
only (optional procedures at JHU only) 
 ISLT, MMSE, BPS-O task, FAQ, CDR score (participant and study partner), and 
C-SSRS assessments 
 AEs/SAEs and concomitant medication reporting  
3.5.2.6 Week 78 Visit (Additional Assessments) 
The following additional assessments will be performed during the week 78 visit:  
 GDS assessment 
 ECG 
 Additional blood sample for biomarkers of neurodegeneration 
3.5.2.7 Week 78 Visit (Additional Imaging Assessments) 
The following additional imaging assessment will be performed during the week 78 visit: 
 PET scan after injection with the tau PET marker [18F]MK-6240 (optional 
procedure)  


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3.5.3 Early Termination Visit and Early Termination/Follow-up Visit 
Subjects who discontinue treatment (ie, at any time after randomization and before the 
week 78 visit) will have the early termination visit assessments performed as soon as 
possible after treatment termination. In addition, all subjects who enroll and subsequently 
discontinue will be followed up with a phone call during week 78 to assess medical status 
and encourage them to come in to complete the early termination/follow-up visit 
assessments.  
3.5.3.1 Early Termination Visit 
 ECG 
 Physical and neurological exams  
 Vital signs and body weight 
 Blood sample for PK testing, serum chemistry, CBC, thyroid panel, liver function 
tests and for blood-based biomarkers 
 Urinalysis 
 ISLT, MMSE, GDS, BPS-O task, FAQ, CDS (participant and study partner), and 
C-SSRS 
 AEs/SAEs and concomitant medication reporting 
3.5.3.2 Early Termination Follow-up Visit (Week 78) 
 Vital signs and body weight 
 ISLT, MMSE, GDS, BPS-O task, FAQ, CDR (participant and study partner), and 
C-SSRS 
 AEs/SAEs and concomitant medication reporting 
3.5.4 Efficacy Assessments  
3.5.4.1 Primary Efficacy Assessments  
The primary efficacy evaluation will be the change in CDR-SB score from baseline to 
78 weeks. This will be measured by asking the subject and their study partner a series of 
questions to collect information about the subject’s memory, orientation, judgment, and 
problem-solving ability, interest and knowledge of community affairs, home and hobbies, 
and ability to maintain personal care. In rating each of these domains, the assessment is 
based on the subject’s cognitive ability to function in these areas (“box score”). The 
change over the course of the treatment will be indicative of the relative efficacy of the 
test product. 
3.5.4.2 Secondary Efficacy Assessments 
The gated secondary efficacy assessments will consist of change in cognition/function, as 
measured by change in FAQ or MMSE from baseline to 78 weeks, and evaluation of 


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neuronal injury, as measured by change in AGB101 effects on EC thickness from 
baseline to 78 weeks. 
FAQ is a questionnaire administered to an informant who rates each subject’s 
performance over the preceding 4 weeks on 10 separate categories of instrumental 
activities of daily living: 1) writing checks, paying bills, keeping financial records; 2) 
assembling tax or business records; 3) shopping alone; 4) playing a game of skill; 5) 
making coffee or tea; 6) preparing a balanced meal; 7) keeping track of current events; 8) 
attending to and understanding a television program, book, or magazine; 9) remembering 
appointments, family occasions, medications; and 10) traveling out of the neighborhood. 
Performance in each category is rated as follows: 0- normal; 1- has difficulty, but does by 
self; 2-requires assistance; or 3-dependent (Pfeffer et al. 1982). 
MMSE is a sensitive, valid, and reliable 30-point questionnaire that measures and 
evaluates cognitive function and mental impairment. It involves presenting the subjects 
with simple questions and/or problems and evaluating their responses 
(Folstein et al. 1975).  
Other neuropsychological tests: 
 The ISLT is a 12-word, three-trial verbal list-learning test. The lists consist of 
shopping items selected to be language and regionally commonplace. The 
presentation of lists and the recording of responses are controlled by a laptop 
computer. Each list is randomly generated from a pool of 128 words. A different 
set of 12 words is chosen when a new list is required, with eight different lists 
without overlap. A trial finishes as soon as no further recall is possible or 
90 seconds has elapsed. The ISLT can reliably detect AD-related verbal learning 
and memory impairment in people from different cultures who read in different 
languages. 
 BPS-O task measures recognition memory by asking subjects to view a series of 
objects (phase 1) and then recall (phase 2) whether the objects being presented are 
old (ie, were originally presented in phase 1), new (were not presented in 
phase 1), or similar to those presented earlier in phase 1. The proportion of 
responses for each category (new items identified as “new”, repeated items 
identified as “old”, similar items identified as “similar”, and all incorrect response 
categories) is calculated.   
Neuroimaging evaluations:  
 EC thickness will be measured by imaging the brain (MRI) at set points 
throughout the study utilizing ADNI-2 imaging procedures. 
MRI measurements of brain structures have been shown to demonstrate brain atrophy 
correlated with neuronal loss in MCI and increasing rates of brain atrophy as subjects 
become more impaired. In this MCI study, rates of atrophy of the EC over time are used 
as a measure of disease progression and possible treatment effect. Structural MRI 
sequences (MP-RAGE/IR-SPGR) will be used to generate measures of rate of change in 


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the EC thickness in all study subjects, which will serve as a secondary endpoint for the 
treatment study. The core MRI protocol will consist of 3 structural MRI scans  from 
every subject at baseline, and weeks 52 and 78 on every MRI vendor system. For the 
purpose of exclusion, cerebrovascular disease, including white matter lesions and micro 
bleeds will be assessed using FLAIR and T2 sequences during the baseline assessment.  
All structural MRI acquisition methods and quality control procedures employed in this 
study will follow those employed in the ADNI-2 study to facilitate standardization and 
comparability (see Appendix 8.3). Summary descriptions of those methods are included 
below with deviations from the ADNI-2 procedures outlined explicitly. 
Hippocampal volume will also be measured with comparable techniques.  
PET Marker for tau protein evaluation: 
[18F]MK-6240 (optional): is a radiopharmaceutical that binds to tau protein and has been 
used to monitor the progression of AD. This procedure will be performed at baseline and 
week 78. A substudy of approximately 56 subjects is planned to have this procedure and 
evaluation performed to assess the value of this endpoint in future studies. 
fMRI scanning for functional evaluation 
Hippocampal network functioning will be measured by functional imaging (fMRI) at set 
points throughout the study utilizing published functional imaging procedures. Functional 
neuroimaging of the hippocampal subregions has been shown to provide a measure of 
increased activation in MCI associated with episodic memory impairments. In this MCI 
due to AD study, functional neuroimaging of the hippocampal network is used as a 
measure of disease progression and possible treatment effect. High-resolution functional 
neuroimaging methods will be used to measure relative levels of activation in the 
hippocampal subregions, specifically the DG/CA3 subregion in the context of 
performance on the BPS-O task. The fMRI protocol will consist of 8 runs of the 
functional MRI sequence that will be acquired during the MRI at baseline and week 26 
visits (optional at JHU site only). 
3.5.5 Safety Assessments 
3.5.5.1 Physical Examination  
Physical examinations will include examining the general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, heart, lungs, abdomen, lymph nodes, 
extremities, and nervous system. Neurological examinations will include examination of 
coordination, gait, patellar deep tendon reflexes, sensation, strength and muscle tone, and 
orientation. An AE form must be completed for all changes identified as clinically 
noteworthy. Height without shoes will be recorded in inches or meters at screening. 


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3.5.5.2 Vital Signs and Body Weight  
Vital signs will include body temperature (F or C), respiratory rate, supine (optional) and 
sitting radial pulse rates, and supine (optional) and sitting systolic and diastolic blood 
pressures (BPs). Supine recordings, if possible, will be made after the subject has been 
recumbent for 3 minutes. Body weight without shoes will be recorded in pounds or 
kilograms whenever vital signs are recorded. 
3.5.5.3 Electrocardiogram  
Standard 12-lead ECGs will be measured at screening, week 78, and ET. 
3.5.5.4 Laboratory Parameters  
The following clinical laboratory tests will be performed as indicated by the schedule of 
assessments (see Table 7): 
 Hematology: hemoglobin, hematocrit, CBC with differential, platelet count. 
 Chemistry: albumin, albumin/globulin ratio, alanine aminotransferase, alkaline 
phosphatase, aspartate aminotransferase, B12, bilirubin-direct, bilirubin-indirect, 
bilirubin-total, blood urea nitrogen, blood urea nitrogen/creatinine ratio, calcium, 
cholesterol, chloride, creatine kinase, creatinine, gamma-glutamyl transpeptidase, 
globulin, glucose, lactate dehydrogenase, phosphorus-inorganic, potassium, 
protein-total, sodium, triglycerides, and uric acid. 
 Urinalysis: pH of freshly voided specimen, specific gravity, protein, glucose, 
ketones, blood, and microscopic examinations of the sediment, and drug screen 
(amphetamines, benzodiazepines, cannabinoids, opiates, methadone, and alcohol). 
 Other: thyroid panel and liver function tests. 
Laboratory samples will be analyzed by a central laboratory to ensure consistent 
interpretation of results. Mailing instructions will be included in the laboratory manual. In 
the event of an unexplained clinically noteworthy abnormal laboratory test value as 
assessed by the investigator, the test should be repeated and followed up until the test 
value has returned to the normal range and/or an adequate explanation of the abnormality 
is found. 
3.5.6 Additional Assessments  
The long form GDS is a 30-item self-report assessment used to identify depression, 
specifically in an elderly population. The GDS questions are answered "yes" or "no", 
instead of a 5-category response set. This simplicity enables the scale to be used with ill 
or cognitively impaired individuals. A score of 0 to 9 is considered normal, while a score 
> 9 suggests depression.  
C-SSRS is a semi-structured interview designed to assess the severity and intensity of 
suicidal ideation, suicidal behavior, and non-suicidal self-injurious behavior over a 


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specified time period (eg, lifetime at baseline and since last visit at the additional visits). 
The assessment is completed by study staff with appropriate clinical training at scheduled 
visits as shown in the schedule of assessments (Table 7). If, at any visit following the 
baseline visit, there are any “YES” answers on items 4, 5, or any of the behavioral 
questions, a risk assessment should be done by a qualified clinician to determine whether 
it is safe for the subject to continue participation in the study.  
The modified HIS is a clinical tool used for screening to differentiate vascular dementia 
from degenerative forms of the disorder (MCI, AD). Subjects with a score of 7 or higher 
are more likely to have vascular dementia. A low HIS is less likely to indicate vascular 
dementia because ischemic lesions severe enough to produce dementia would be 
expected to be severe enough to cause the accompanying neurologic changes and 
elevation in the index (Hachinski et al. 1975). 
Trail making test is a neuropsychological test of visual attention and task switching. For 
part A, subjects connect a set of 25 sequentially numbered dots in order as fast as 
possible while still maintaining accuracy. For part B, subjects are asked to follow the 
same instructions but alternate between letters and numbers keeping each set in order. 
This will be conducted at baseline only. 
The additional blood draw at ET/week 78 visit will be used to provide samples for 
assessment of blood-based biomarkers that may reflect neurodegeneration.  Markers to be 
measured may include A-beta 1-40, A-beta 1-42, total tau, pTau 181, pTau 217 and 
neurofilament light chain (nfl). 
 
3.5.7 Pharmacokinetic Assessments 
A total of 3 samples will be collected for PK analysis at weeks 26, 52, and 78. In 
addition, approximately 40 mL of blood will be collected for screening and the 
end-of-study clinical laboratory evaluations. The total volume of blood collected will not 
exceed 300 mL.  
Blood samples (1 mL x 4 mL) will be collected in Vacutainer tubes containing 
dipotassium ethylenediaminetetraacetic acid as a preservative at 4 hours to 7 hours after 
dosing with AGB101 or placebo. The time and date of collection for each sample will be 
recorded.   
Blood samples will be centrifuged at approximately 3000 revolutions per minute (rpm) 
for 10 minutes at 4ºC. The resulting plasma samples will be harvested and transferred 
into approximately equal portions into 2 appropriately labeled polypropylene screw-cap 
tubes labeled “A” and “B”. PK samples will be placed in a freezer at -20ºC or lower 
within 60 minutes of the blood draw.  
Procedures for storage and shipment of the PK samples are provided in the PK Manual. 


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3.5.8 Appropriateness of Measurements 
All assessments that will be used in this study are commonly used, standard 
measurements frequently employed in studies investigating MCI and AD.


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4 
ADVERSE EVENT REPORTING  
Throughout the course of the study, all AEs will be monitored and recorded on an AE 
eCRF, including the AE’s description, start and end date, outcome, seriousness, severity, 
action taken, and relationship to the study drug. If AEs occur, the first concern is the 
safety of the study subjects. All AEs will be followed until resolved or stable and the 
outcome documented on the eCRF. 
4.1 
Definitions and Criteria 
4.1.1 Adverse Events 
Per International Conference on Harmonisation (ICH) E2A: An AE is any untoward 
medical occurrence in a subject or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
Events meeting the definition of an AE include: 
 Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition 
 New conditions detected or diagnosed after investigational product administration 
even though it may have been present prior to the start of the study 
 Signs, symptoms, or the clinical sequelae of a suspected drug interaction 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concomitant medication 
Clinically significant abnormal findings (laboratory test results, vital signs, physical 
examination findings, ECGs, radiologic exams, or other studies) should be recorded as 
AEs. A “clinically significant” finding is one that affects clinical management, including 
additional visits, monitoring or referrals, diagnostic tests or alteration of treatment, or that 
is considered clinically significant by the investigator. A clinically significant finding 
may be a change in a test that has previously been abnormal but now requires additional 
action. 
When a medical or surgical procedure is performed, the condition that leads to the 
procedure should be recorded as the AE. 
Events that do not meet the definition of an AE include: 
 Anticipated day-to-day fluctuations or expected progression of pre-existing 
disease(s) or condition(s) present or detected at the start of the study unless 


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judged by an investigator to be more severe than expected for the subject’s 
underlying condition 
 Abnormal laboratory, ECG, or vital sign measurements that are not labelled 
clinically significant (see definition above) 
 Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
 Pregnancy 
 Overdose in the absence of other AEs will not be reported as an AE in its own 
right 
Changes in C-SSRS during the course of the study indicating worsening should be 
evaluated by the investigator for clinical significance, and if clinically significant (eg, 
alteration in medical care or intervention is required), an associated AE should be 
recorded, if present. The AE should be the primary underlying clinical manifestation 
assessed as clinically significant, and not the change in score itself. 
Change in cognitive functioning (improvement or worsening) is also not considered to be 
an AE, since it is related to the underlying disease and the condition under study.  
4.1.2 Serious Adverse Events 
An SAE or reaction is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening 
 Requires inpatient hospitalization or prolongation of existing hospitalization, with 
the exception of: 
o Visits to the emergency room or hospital department that do not result in an 
overnight hospital admission 
o Elective surgery for a pre-existing condition that has not worsened 
o Routine health assessments requiring admission not associated with any 
deterioration in condition 
o Social admission (lack of housing, family circumstances, etc.) 
 Results in persistent or significant disability or incapacity 
 Is a congenital anomaly or birth defect 
 Is an important medical event (eg, intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result 
in hospitalization, development of drug dependency or drug abuse, or malignancy 
tumors [histologically different from the primary tumor]) 


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Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe.  
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization, but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also usually be considered serious. 
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. 
An SAE is not necessarily severe, eg, a hospitalization for a diagnostic procedure must be 
reported as an SAE even though the occurrence is not medically serious. By the same 
token, a severe AE is not necessarily serious: nausea of several hours’ duration may be 
rated as severe but may not be considered serious. 
4.1.3 Unexpected Adverse Drug Reactions 
An unexpected adverse drug reaction (ADR) is a reaction for which the nature or severity 
is not consistent with the applicable product information (see current Investigator’s 
Brochure). Until product information is amended, expedited reporting is required for 
additional occurrences of the reaction. Reports that add significant information on 
specificity or severity of a known, already documented SAE constitute unexpected 
events. For example, an event more specific or more severe than described in the 
Investigator's Brochure would be considered "unexpected.” Specific examples would be 
(a) acute renal failure as a labeled ADR with a subsequent new report of interstitial 
nephritis and (b) hepatitis with a first report of fulminant hepatitis. 
Guidance on reporting AEs and SAEs is described in Section 4.2. 
4.1.4 Assessing Intensity and Relationship 
All AEs will be assessed on 2 descriptive parameters: intensity and relationship to the 
study drug: 
1. Intensity refers to the severity of an event and references the impact on a subject’s 
functioning. 
2. Relationship refers to the likelihood that the event being assessed was caused by 
the study drug. 
Intensity 
Each AE will be classified according to the following criteria: 
Mild: 
The AE does not interfere in a significant manner with the 
subject’s normal level of functioning. 


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Moderate: 
The AE produces some impairment of functioning but is not 
hazardous to the subject’s health. 
Severe: 
The AE produces significant impairment of functioning or 
incapacitation and is a definite hazard to the subject’s health. 
When changes in the intensity of an AE occur more frequently than once a day, the 
maximum intensity for the experience should be noted. If the intensity category changes 
over a number of days, those changes should be recorded separately (with distinct onset 
dates). 
Relationship 
Each AE will be assessed as to its relationship to the study drug based on the following 
criteria. Although the attribution by the investigator will be collected for reported events, 
for analytic purposes a temporal association with the use of the study drug will be 
assumed sufficient for at least plausible association. 
Not related: 
No causal relationship exists between the study drug and 
the AE, but an obvious alternative cause exists, eg, the 
subject’s underlying medical condition or concomitant 
therapy. 
Related: 
There is a reasonable/plausible possibility that the AE 
may have been caused by the study drug. 
When assessing the relationship to the study drug, the following criteria will be 
considered: 
 Temporal relationship 
 Positive rechallenge 
 Positive dechallenge (resolution upon stopping the study drug, in absence of other 
intervention or treatment) 
 Known class effect 
 Biological plausibility 
 Lack of alternative explanation—concomitant drug or disease 
4.2 
Reporting Procedures and Requirements 
4.2.1 Adverse Events 
AE recording will begin at the first screening visit. Thereafter, AEs will be ascertained by 
asking the subject (and study partner) how he/she has been since the last visit. Any 


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AEs/SAEs occurring before the start of treatment (ie, before the first dose of the study 
drug) will be recorded and reported as such.  
Also, the sign, symptom, or disease present before starting the treatment period are only 
considered AEs if they worsen after starting the treatment period.  
If the investigator detects an AE in a study subject within 1 month of the last scheduled 
follow-up visit and considers the event possibly related or related to prior study 
treatment, the investigator should report it to WCT. 
The investigator should report all information about AEs on the AE/SAE section of the 
electronic data capture (EDC) system. Whenever possible, an AE will be reported using a 
diagnostic term (eg, “common cold” or “upper respiratory infection” rather than “runny 
nose, cough, mild fever”) and should be described with the attributes described in 
Section 4.1.4.  
4.2.2 Serious Adverse Events 
Each AE will be assessed to determine whether it meets seriousness criteria 
(Section 4.1.2). If the AE is considered serious, the investigator should report this event 
to WCT as outlined below and also to the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) according to its standard operating procedures. 
All information about SAEs will be collected and reported by entering the SAE 
information in the AE/SAE section of the EDC system. The investigator should send the 
initial report to WCT within 24 hours of becoming aware of the SAE and followed by 
follow-up reports as soon as possible, whether the events are deemed related to the study 
drug or not. The information provided in the EDC system should be as complete as 
possible, but minimally it must contain the following: 
 Subject number 
 Brief description of the SAE (diagnosis or signs/symptoms) 
 Serious criteria 
 Causality assessment 
 Assessment of the intensity of the event 
WCT Drug Safety will receive notification of the initial SAE via an e-mail alert 
generated from the EDC system. In the event of any temporary disruption of the EDC 
system, an alternative SAE reporting mechanism will be available to site personnel; in 
this instance, a paper SAE report form will be available. Site personnel will complete the 
paper SAE report form, scan and e-mail it within 24 hours to the following address: 
drugsafety@wwctrials.com.  


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Site personnel must complete the AE/SAE section with the SAE information as soon as 
the EDC system becomes available. SAEs that are ongoing should be followed until 
resolved or stabilized to a level acceptable to the investigator. 
The investigator is obliged to provide additional information as requested by the medical 
monitor or pharmacovigilance physician. In general, this will include a description of the 
event in sufficient detail to allow for a complete medical assessment of the case and 
independent determination of possible causality. In the case of a subject death, a 
summary of available autopsy findings, if performed, must be submitted as soon as 
possible to the contract research organization. However, any supporting information 
provided should not reveal a subject’s identity beyond the agreed study identifier. The 
investigator should ensure that information reported is accurate and consistent.  
Information not available at the time of the initial report (eg, an end date for the AE, 
laboratory values received after the report, or hospital discharge summary) must be 
documented on a follow-up form. All follow-up information must be reported in the same 
timelines as initial information.  
Any SAEs considered related to the study drug and discovered by the investigator at any 
interval after the study must also be reported to the sponsor within 24 hours following 
knowledge of the event. 
4.3 
Procedures for Documenting Pregnancy During Study 
Females of childbearing potential are to be excluded from this study. If a female sexual 
partner of a male subject becomes pregnant during the study, the investigator must notify 
WCT immediately of becoming aware of the pregnancy and will complete the pregnancy 
eCRF page. The investigator will also follow the progress of the pregnancy to term or 
termination and document the outcome of the pregnancy (health of the infant up to 
8 weeks of age). Male subjects should be instructed to notify the investigator if their 
female sexual partner becomes pregnant either during the treatment period of the study or 
within 3 months after the last dose of study drug. Although the pregnancy is not 
considered to be an AE or SAE, any pregnancy complications should be recorded as AEs 
or SAEs (if applicable). Any pregnancy should be followed through delivery for the 
observation of any SAE. Therefore, regardless of whether or not a pregnancy is actually 
considered an SAE, a pregnancy should be reported in the EDC. A paper CRF will be 
used as backup only. 
All data related to pregnancy, pregnancy outcome, and SAEs associated with pregnancy 
will be recorded in a safety database maintained by personnel responsible for 
pharmacovigilance at WCT. 


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4.4 
Sponsor Reporting of Suspected Unexpected Adverse Reactions to Regulatory 
Authorities  
SUSARs are AEs that are believed to be related to an investigational medicinal product 
and are both unexpected (ie, the nature or severity is not expected from the information 
provided in the Investigator's Brochure) and serious. As stated in the European Union 
(EU) ‘CT-3’ Communication from the Commission (2011/C 172/01) and the US Code of 
Federal Regulations (21 CFR 312.32), for there to be a reasonable possibility of a causal 
relationship between the event and the study drug, there must be facts (evidence) or 
arguments to suggest a causal relationship. Final assessment of expectedness for purposes 
of regulatory reporting is the responsibility of the sponsor.  
It is the responsibility of the sponsor to determine whether a reported SAE fits the 
classification of a SUSAR and to notify regulatory authority and investigators. 
Requirements and unblinding procedures for SUSAR reporting are described below. All 
SUSAR reporting, whether determined following unblinding during study conduct or 
apparent only after the study has ended, will adhere to European Directives 2001/20/EC, 
21 CFR 312.32 of the US CFR, Health Canada Food and Drug Regulation C.05.014, and 
other regions as applicable. 
4.4.1 Unblinding Treatment Allocation 
Generally, only SUSARs for which the treatment allocation of the subject is unblinded 
should be reported by the sponsor to the pertinent regulatory authorities.  
When an event may be a SUSAR, the blind should be broken only for that specific 
subject, and only if knowledge of the study drug assignment is material to the medical 
management of the AE (see Section 3.4.4). When unblinded to assist in the medical 
management, the blind for that subject should be maintained for individuals responsible 
for the ongoing conduct of the study (eg, management, monitors, and investigators) and 
those responsible for data analysis and interpretation of results at the conclusion of the 
study (eg, biometrics personnel).  
Unblinded information should only be accessible to those who need to be involved in the 
safety reporting to pertinent regulatory authorities, independent ethics 
committees/independent review boards (IECs/IRBs) and DSMBs, or individuals 
performing ongoing safety evaluations during the study. 
4.4.2 Fatal or Life-Threatening Serious Unexpected Adverse Reactions 
It is the responsibility of the sponsor to report fatal or life-threatening SUSARs to the 
pertinent regulatory authorities as soon as possible, but no later than 7 calendar days (or 
earlier, if locally mandated). These will be reported to the DSMB in parallel. 


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4.4.3 Other Serious Unexpected Adverse Reactions 
It is the responsibility of the sponsor to report other SUSARs to the pertinent regulatory 
authorities as soon as possible, but no later than 15 calendar days (or earlier if locally 
mandated). These will be reported to the DSMB in parallel. 
4.5 
Reporting to Institutional Review Board and Independent Ethics Committee 
The IEC/IRB will be notified of any SUSARs according to local regulations and within 
the designated timeframe.  
The investigator (or prospectively agreed to designee) is required to notify the IEC/IRB 
of any fatal SUSAR as soon as possible but no later than 7 calendar days after he/she first 
became aware of the reaction (or earlier if locally mandated).  
The investigator (or prospectively agreed to designee) is required to notify the IEC/IRB 
of any other SUSAR as soon as possible but no later than 15 calendar days after he/she 
first became aware of the reaction (or earlier if locally mandated).


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5 
DATA MANAGEMENT AND STATISTICAL ANALYSIS 
5.1 
Data Management Considerations 
An EDC system will be utilized in this study. The database will be designed, reviewed, 
and tested for user acceptance prior to the first study visit. Once data entry is completed 
at the site, WCT data management will review and check the data for completeness. 
Queries will be raised for inconsistencies found during the exhaustive process checking 
performed both electronically and by manual review. The statistical analysis of these data 
will be performed by the sponsor or its representative. All AEs will be coded using the 
latest version of the Medical Dictionary for Regulated Activities (MedDRA). 
Concomitant medications will be coded using the latest version of the World Health 
Organization Drug Dictionary. Data management activities, dates, and responsibilities 
will be outlined in the data management plan, which will be finalized prior to when the 
database goes live. 
5.2 
Statistical Considerations 
The statistical analysis will be undertaken by WCT in collaboration with AgeneBio, Inc. 
Dr. Michael Rosenblum will conduct the primary analysis. 
A detailed Statistical Analysis Plan (SAP) will be finalized and signed before the 
database lock, before the code for all subjects is broken, and before analysis of the study 
data are carried out. Any deviations from the analyses described below will be included 
in the SAP, which will be included in the clinical study report. 
5.2.1 Analysis Populations 
The enrolled set includes all subjects screened into the study who signed an Informed 
Consent Form (ICF) and who participated in screening activities, irrespective of whether 
they were randomized to treatment.  
The full analysis set includes all randomized subjects. All analyses of efficacy will be 
performed on the full analysis set, and these analyses will be considered the primary 
analyses of efficacy. In analyses based on the full analysis set, subjects will be analyzed 
as randomized. The reason the focus is on the full analysis set is to follow the 
intention-to-treat (ITT) principle. 
The safety analysis set includes all subjects who took at least one dose of the study drug 
following randomization. Safety will be analyzed using the safety analysis set. In 
analyses based upon the safety analysis set, subjects will be analyzed as treated. 
The per-protocol analysis set includes a subset of the full analysis set consisting of 
subjects who satisfy all of the inclusion/exclusion criteria, who correctly receive the 
treatment to which they are randomized, and who have completed all the visits up to and 
including the week 78 visit. In addition, significant protocol deviations defined in 


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Section 5.2.2 will be removed from the per-protocol analysis set. Analyses of efficacy 
based on the per-protocol analysis set will be considered secondary analyses of efficacy. 
Prior to the database lock, subject evaluability will be reviewed by the sponsor and 
detailed in the signed analysis population document. All subjects excluded from the 
per-protocol population and the reason for their exclusion will be listed. 
Assessing the Impact of COVID-19 on trial results:  
We will assess the impact of the four factors listed below on the trial results, following 
the FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Public Health Emergency Guidance for Industry, Investigators, and Institutional Review 
Boards (FDA 2020): 
1) Discontinuations due to COVID-19 
2) Study visits missed due to COVID-19 
Laboratory safety assessments that are unable to be done due to COVID-19 
restrictions will not be required for the subject to continue in study due to the long 
safety record of marketed levetiracetam. The site PI should conduct a careful 
interview with the participant and study partner to determine whether there have 
been any adverse events or change in the participants clinical condition. If no AEs 
or clinical concerns are present the PI should then document that the subject has 
no clinical symptoms of concern. Safety labs should be obtained at the earliest 
time permitted by COVID-19 restrictions or be obtained at next routine site visit 
if not a part of that assessment. 
3) Assessments that were conducted remotely rather than in person due to COVID-19 
4) Visits that were performed out of window due to COVID-19 
5.2.2 Protocol Deviations 
All protocol deviations will be assessed and documented on a case-by-case basis prior to 
the database lock. The following deviations will be summarized for the full analysis set:  
 Failure to meet the study entry criteria. 
 Treatment administration errors including improper administration of the study 
drug not supported by randomization; deviations from permitted dosage and 
regimen with the study drug. 
 Noncompliance with the study drug over the treatment period is defined as 
subjects who took < 80% or > 120% of the prescribed study drug, taking into 
account the number of days since the last study drug had been dispensed. The 
investigator may use clinical judgement in evaluating noncompliance with the 
study drug as a reason for early termination from the study. Subjects who 
discontinue treatment will not be automatically discontinued from the study. 


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Every effort should be made to bring subjects back for study visits unless the 
subject withdraws consent.  
 Significant noncompliance with the timing of the study visits, outside of a visit 
window. 
 Ingestion of prohibited medications after randomization. 
 
In addition, the following types of protocol deviations due to COVID-19 will be assessed, 
documented, and summarized: 
1) Discontinuations due to COVID-19 
2) Study visits missed due to COVID-19 
3) Assessments that were conducted remotely rather than in person due to COVID-19 
4) Visits that were performed out of window due to COVID-19 
5.2.3 Subject Disposition   
Subject disposition will be summarized using the full analysis set. The number of 
subjects in each analysis population, the number of subjects present at each scheduled 
visit, and the reason for the early discontinuation will also be summarized by treatment 
group.   
5.2.4 Demographic and Baseline Characteristics 
The comparability of treatment groups with respect to subject demographics and baseline 
assessments will be summarized in a descriptive manner. Formal statistical testing will 
not be performed. The baseline data will be summarized using the full analysis set.  
5.2.5 Measurement of Treatment Compliance 
Study drug containers must be returned at each visit, as compliance will be assessed by 
tablet counts. Noncompliance is defined as taking < 80% or > 120% of the study drug 
during any outpatient evaluation period (visit to visit).  
5.2.6 Efficacy Analyses 
5.2.6.1 Primary Efficacy Endpoint  
The primary endpoint is defined as the difference between the CDR-SB score measured 
at baseline and the week 78 visit. This is referred to as the CDR-SB change score. 
Following the ITT principle, the data analyzed are from the full analysis set. The primary 
goal of the study is to estimate the average treatment effect, defined as the difference 
between the population mean outcome of the primary endpoint under treatment 
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5.2.6.2 Secondary Efficacy Endpoints  
The two cognitive/functional secondary endpoints below will be tested using a fixed 
sequence procedure with Type I error controlled as described below. 
 Secondary endpoints: cognitive/functional 
o Change in FAQ score from baseline to 78 weeks 
o Change in MMSE score from baseline to 78 weeks 
 Secondary endpoints: neuronal injury 
o Change in EC thickness on MRI from baseline to 78 weeks 
 Additional secondary efficacy endpoints: 
o Change in CDR global score from baseline to 78 weeks 
o Change in CDR memory box score from baseline to 78 weeks 
o Change in BPS-O task score from baseline to 78 weeks 
o Change in ISLT score from baseline to 78 weeks 
o Change in EC volume on MRI from baseline to 78 weeks 
o Change in hippocampal volume on MRI from baseline to 78 weeks 
o Change in [18F]MK-6240 in the brain from baseline at week 78 
An overall false-positive (α) rate of 5% level for the key secondary efficacy endpoints 
will be maintained, in that no significance of key secondary endpoints will be claimed 
unless the primary statistical analysis is significant at the 5% level. In addition, the testing 
of the key secondary endpoints will be conducted in a hierarchical fashion, in that once a 
null hypothesis is not rejected, all subsequent key secondary hypothesis tests will be 
considered exploratory. The hierarchical ordering of the secondary endpoints will be 
specified in the SAP prior to study unblinding. 
5.2.6.3 Sensitivity Analysis to Missing Data and to Treatment Noncompliance 
A sensitivity analysis will be performed on the missing data at random assumption, based 
on the repeated measures pattern mixture model approach of Section 4 of the National 
Research Council, 2010. Specifically, for each arm, a sensitivity parameter will be 
suggested that represents the difference between the mean primary endpoint for those 
who drop out and those who do not at a given analysis time, conditional on the variables 
observed prior to that analysis time. The analysis times and variables used in the primary 
analysis will be restricted. The average treatment effect and p-value will be estimated for 
each pair of sensitivity parameters in a fine grid. The result will show how much of a 
deviation from the missing at random assumption is required to change the result from 
significant to non-significant. 


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Also, analyses will be conducted to estimate the average effect of assignment to the 
treatment versus control arms under perfect compliance with the study protocol 
(including treatment compliance and attending all visits). The analysis method (targeted 
maximum likelihood estimation) is the same as for the principal analysis described above 
except that there will be an indicator for treatment compliance at each visit and 
participants will be censored at the first visit at which they are either lost to follow-up or 
they are noncompliant with the study protocol. This analysis requires stronger 
assumptions than the principal analysis, and these assumptions will be clearly stated 
along with the results of this analysis.  
5.2.7 Safety Analyses 
5.2.7.1 Extent of Exposure 
Extent of exposure will be described by the number of days of exposure (last date of 
dosing minus first day of dosing plus 1), and the number of days of exposure to each dose 
of the study drug (last date of dosing minus first date of dosing plus 1 summed over each 
period of time where the subject receives the same dose) will be summarized. No 
allowance will be made for breaks in therapy for the calculation of the total number of 
days of exposure. If the date of last dosing is completely missing, then the date of last 
dosing will be taken for analysis purposes as the date the relevant medication was last 
dispensed. If only the month of the last dose is recorded, the first day of the month will be 
assumed as the last dosing date. 
5.2.7.2 Adverse Events 
AEs will be summarized by treatment group and by maximum dose, latest dose received 
prior to the onset of the AE, by visit and treatment period. 
A TEAE is defined as any AE that has an onset on or after the first dose of study drug, or 
any pre-existing condition that has worsened on or after the first dose of study drug, 
regardless of the causal relationship to the study drug. TEAEs will be attributed to a 
treatment using the following rules:  
All analyses of AEs will be performed by the study period, so that it is possible to 
identify AEs that may be related to withdrawal from study treatment. The summaries of 
AEs will be limited to TEAEs. For summaries of TEAEs, a TEAE will be assigned to a 
given period if the date of onset of the TEAE is on or after the date of the first visit 
during the period but before the date of the first visit of the next period.  
If the relationship of the AE to study drug is missing, it will be assumed to be related to 
the study drug for analysis purposes. 
The incidence of subjects reporting TEAEs, treatment-emergent SAEs, TEAEs related to 
study treatment, treatment-emergent SAEs related to study treatment, and TEAEs leading 


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to study discontinuation will be summarized using counts and percentages. The total 
number of TEAEs, treatment-emergent SAEs, TEAEs related to study treatment, 
treatment-emergent SAEs related to study treatment, and TEAEs leading to study 
discontinuation will also be summarized. 
AEs will be coded using MedDRA. The incidence of TEAEs and treatment-emergent 
SAEs will be summarized at the subject level by MedDRA primary system organ class 
and preferred term using counts and percentages. 
The incidence of TEAEs and treatment-related TEAEs will also be summarized by 
maximum severity and by closest relationship to study drug by MedDRA primary system 
organ class and preferred term. The summary will include the total number and 
percentage of subjects reporting a particular event. In counting the number of events 
reported, a continuous event, ie, an event reported more than once and which did not 
cease, will be counted only once; non-continuous TEAEs reported several times by the 
same subject will be counted as multiple events.  
The incidence of TEAEs resulting in dose reduction will be summarized by the latest 
dose received and also by treatment group. 
Withdrawal-related events will be tabulated separately. 
Narratives of deaths, SAEs, and other significant AEs will be provided in the relevant 
section of the study report.  
A complete subject listing of all AEs will be provided in the study report. This listing will 
include treatment, AE verbatim term, MedDRA primary system organ class and preferred 
term, the time of onset and cessation of the event relative to the first dose of study drug, 
duration of the AE, whether serious or not, severity, relationship to study drug, action 
taken, and outcome. 
5.2.7.3 Electrocardiographic Data 
A list of subjects with abnormal 12-lead ECG parameters at screening will be presented. 
Baseline ECG parameters (heart rate, cardiac rhythm, PR interval, QRS interval, 
QT interval, and QT interval corrected for heart rate) will be summarized for the final 
visit/early termination visit time point. For exploratory purposes, analyses of QT, QT 
interval corrected for heart rate using Fridericia’s formula, and QT interval corrected for 
heart rate using Bazett’s formula will be completed using accepted definitions for outliers 
(eg, frequency counts of interval changes from baselines ≥ 30 msec and ≥ 60 msec) as 
well as analyses of central tendency of active drug versus placebo and active dose versus 
placebo. 


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5.2.7.4 Laboratory Data 
Mean changes from baseline at each post-baseline time point for each laboratory variable 
will be presented. In addition, each reading will be classified as below, within, or above 
the normal range, based on ranges supplied by the laboratory used. Shift tables for the 
baseline and follow-up measurements will be presented and clinically significant changes 
will be summarized.  
Potentially clinically significant ranges will be defined in the SAP for selected 
parameters, and the number and percent of subjects meeting these criteria summarized. 
Tabular summaries will include only those subjects in whom the values represent a 
treatment-emergent worsening.  
Listings of laboratory parameters will be presented. Listings will flag results above and 
below the normal range as well as those that meet criteria for being potentially clinically 
significant (whether or not a treatment-emergent worsening). Separate listings for each 
hematology, chemistry, and urinalysis parameter will show results that meet criteria for 
being potentially clinically significant. In addition, for subjects who have one or more 
results that meet criteria, all laboratory results will be displayed. 
5.2.7.5 Vital Signs 
Summary statistics for the absolute vital sign value and the changes from baseline will be 
presented by treatment group for each visit. 
The number and percentage of subjects reporting potentially clinically meaningful 
observations will be summarized: 
 Systolic BP: supine ≤ 80 mmHg or ≥ 140 mmHg 
 Diastolic BP: supine ≤ 40 mmHg or ≥ 90 mmHg 
 Pulse rate: supine ≤ 50 bpm or ≥ 100 bpm 
 Respiration rate: < 8 or > 20 breaths per minute 
In addition, shift tables from baseline to each post-baseline visit in relation to the 
clinically meaningful ranges specified above will be presented for each of these vital sign 
parameters.  
5.2.7.6 Other Variables Related to Safety 
Change from baseline in C-SSRS is another endpoint related to safety. Changes in 
C-SSRS during the course of the study indicating worsening should be evaluated by the 
investigator for clinical significance, and, if clinically significant (eg, alteration in 
medical care or intervention is required), an associated AE should be recorded, if present. 
The AE should be the primary underlying clinical manifestation assessed as clinically 
significant, and not the change in score itself. 


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Changes from baseline in physical and neurological examinations are additional 
endpoints related to safety that will also be evaluated by the investigator for clinical 
significance, and, if clinically significant (eg, alteration in medical care or intervention is 
required), an associated AE should be recorded. 
5.3 
Pharmacokinetic Analysis 
A total of 3 samples will be collected for PK analysis at 26, 52, and 78 weeks. In 
addition, approximately 40 mL of blood will be collected for screening and month 18 
visit clinical laboratory evaluations. The total volume of blood collected will not exceed 
300 mL. Plasma levetiracetam concentrations will be reviewed to assess treatment 
compliance during the outpatient evaluation period, as described in Section 5.2.5. 


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6 
STUDY MANAGEMENT 
6.1 
Ethics and Consent 
6.1.1 Regulations and Guidelines 
The study will be performed in accordance with this protocol, US IND 21 CFR 312 or 
local national laws (as applicable), ICH guidelines for Good Clinical Practice (GCP), and 
the most recent guidelines of the Declaration of Helsinki. These guidelines are on file at 
WCT. 
6.1.2 Institutional Review Board/Independent Ethics Committee 
Conduct of the study must be approved by an appropriately constituted IRB or IEC. 
Approval is required for the study protocol, Investigator’s Brochure, protocol 
amendments, ICFs, subject information sheets, and advertising materials. No study drug 
will be shipped to a site until the sponsor or its representative has received written 
IRB/IEC authorization. 
6.1.3 Informed Consent 
For each study subject, a written ICF will be obtained before any protocol-related 
activities. Within this ICF, subjects will provide consent to all study-related procedures 
and the optional tau PET scan. A separate study partner ICF will be obtained at all sites. 
As part of this procedure, the investigator or a designated representative must explain 
orally and in writing the nature, duration, and purpose of the study, and the action of the 
study drug in such a manner that the subject and (if applicable) appointed guardian are 
aware of the potential risks, inconveniences, or AEs that may occur. Subjects should be 
informed that they may withdraw from the study at any time. They will receive all the 
information that is required by local regulations and ICH guidelines. The investigator or a 
designated representative will provide the sponsor or its representative with a copy of the 
IRB/IEC-approved ICF before the start of the study. 
6.2 
Indemnification 
The sponsor’s indemnification of the investigator and institution during the conduct of 
this study is addressed in a letter of indemnification provided as a separate document. 
Other indemnification or insurance will be provided as necessary under local regulations. 
6.3 
Discontinuation of the Study by the Sponsor 
The sponsor reserves the right to discontinue the study at a site or at multiple sites for 
safety or administrative reasons at any time. In particular, a site that does not recruit at a 
reasonable rate may be discontinued. Should the study be terminated and/or the site 
closed for whatever reason, all documentation and study drug pertaining to the study 
must be returned to the sponsor or its representative. 


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6.4 
Study Documentation 
By signing a copy of Food and Drug Administration (FDA) Form 1572 or other country-
specific regulatory forms, the investigator acknowledges that he/she has received a copy 
of the Investigator’s Brochure on AGB101 and assures the sponsor that he/she will 
comply with the protocol and the provisions stated in FDA Form 1572 and other country-
specific forms. No changes in this protocol can be made without the sponsor’s written 
approval. 
6.5 
Study Monitoring and Auditing 
This study will be monitored for quality assurance at all stages of its development by the 
clinical research personnel employed by the sponsor or its representative. Monitoring will 
include personal visits and telephone communication to assure that the investigation is 
conducted according to the protocol, standard operating procedures, guidelines of GCP, 
and applicable regulatory requirements. Quality control procedures will be applied to 
each stage of data handling to ensure that all data are reliable and have been processed 
correctly. On-site review of eCRFs will include a review of forms for completeness and 
clarity, and consistency with source documents available for each subject. Note that a 
variety of original documents, data, and records will be considered as source documents 
in this study.   
Medical advisors and clinical research associates or assistants may request to witness 
subject evaluations occurring as part of this protocol. The investigator and appropriate 
personnel will be periodically requested to attend meetings/workshops organized by the 
sponsor to assure acceptable protocol execution. The study may be subject to audit by the 
sponsor or by regulatory authorities. If such an audit occurs, the investigator must agree 
to allow access to required subject records. By signing this protocol, the investigator 
grants permission to personnel from the sponsor, its representatives, and appropriate 
regulatory authorities, for on-site monitoring of all appropriate study documentation, as 
well as on-site review of the procedures employed in eCRF generation, where clinically 
appropriate. 
6.6 
Data Safety and Monitoring Board 
The DSMB will meet periodically to review all the safety study data (AEs and clinical 
labs) by group, with the groups identified only as group A and group B (ie, DSMB 
members will be blinded to the treatment assignment). The DSMB will not see any 
efficacy data. If, during the course of the data review, the DSMB observes a separation of 
the two groups on any safety measure that suggests a pattern of AEs, the DSMB can 
request information on group assignment from the sponsor. If there is a difference 
between groups on some important safety finding, the DSMB can request information on 
group assignment. If no such difference emerges between groups, the DSMB will remain 
blinded to the treatment assignment until the last subject visit. A description of the 


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DSMB composition, its charter, and methods of analyses and communication will be 
provided in a companion document. 
6.7 
Retention of Records 
The investigator must arrange for retention of study records at the site. The nature of the 
records and the duration of the retention period (minimum 3 years) must meet the 
requirements of the relevant regulatory authority. In addition, because this is an 
international study, the retention period must meet the requirements of the most stringent 
authority. The investigator should take measures to prevent accidental or premature 
destruction of these documents.  
6.8 
Use of Study Findings 
By signing the study protocol, the investigator agrees to the use of results of the study for 
the purposes of national and international registration. If necessary, the authorities will be 
notified of the investigator’s name, address, qualifications, and extent of involvement. 
Reports covering clinical and biometric aspects of the study will be prepared by the 
sponsor or its representative. 
6.9 
Publications 
As a multicenter study, the sponsor intends to publish clinical data from all centers 
participating in the investigation. A publication committee selected by the sponsor will 
submit draft manuscripts to all participating investigators for their comments. In 
conformity with the Uniform Requirements for Manuscripts Submitted to Biomedical 
Journals published by the International Committee of Medical Journal Editors (see 
discussion in Kassirer & Angell 1991), investigators whose contribution consists solely in 
the collection of data will not be named individually as authors. Rather, those 
investigators will receive a collective authorship as the “AGB101 Study Group” and will 
be identified in a note. 
Individual investigators and/or their associates may subsequently publish additional 
findings of this study in scientific journals or present them at scientific meetings, 
provided that the sponsor is given ample opportunity to review any proposed abstract, 
manuscript, or slide presentation before its submission. This review is required to ensure 
that the sponsor is aware of all written and oral presentations of the data and does not 
imply any editorial review or restriction of the contents of the presentation or use. 
 
 


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7 
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8 
APPENDICES 
8.1 
Accepted and Excluded Medications 
The list included below is not exhaustive, but rather it provides examples in each drug 
class. For drugs not included on this list, inquire with the medical monitor. The medical 
monitor may grant exceptions in the use of otherwise excluded medications for infrequent 
or as needed use, provided they do not confound the safety and efficacy assessments. 
1. Acceptable: dose must be stable for 3 months prior to screening and maintained 
throughout the study 
Alzheimer’s  
Aricept (donepezil) 
   
Exelon (rivastigmine)  
 
Namenda (memantine) 
 
Namzaric (donepezil/memantine) 
Razadyne (galantamine) 
 
Vitamin E (4-week stable) 
 
Ginkgo biloba (4-week stable) 
 
Estrogen and estrogen-like drugs 
 
Antidepressants and anxiolytics (SSRIs, SNRIs, 5-HT1A inhibitors) 
Buspar (buspirone)  
Celexa (citalopram hydrobromide)  
Cymbalta (duloxetine)  
Effexor (venlafaxine HCl) 
Emsam (selegiline) 
Fluvoxamine maleate  
Lexapro (escitalopram hydrobromide) 
Marplan (isocarboxazid)  
Nefazodone HCl  
Parnate (tranylcypromine sulfate) 
Paxil (paroxetine HCl) 
Pexeva (paroxetine mesylate)  
Prozac (fluoxetine HCl) 
Sarafem (fluoxetine HCl)  
Wellbutrin, Zyban (bupropion HCl)  
Zoloft (sertraline HCl)  
 
Non-sedating antihistamines  
Claritin (loratadine) 
Zyrtec (cetirizine) 
Allegra (fexofenadine) 
 


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Antipsychotics (second-generation; limit to low doses) 
  
Abilify (aripiprazole) 
 
Geodon (ziprasidone) 
 
Risperdal (risperidone) 
 
Zyprexa (olanzapine) 
 
Incontinence drugs (limit to low doses; avoid if possible) 
Detrol (tolterodinel) 
Ditropan XL (oxybutynin)   
Enablex (darifenacin) 
Gelnique (oxybutynin)   
Oxytro (oxybutynin)  
Sanctura (atrospium) 
Vesicare (solifenacin) 
2. May be acceptable: for short-term use (<1 week; not within 2 weeks of screening, 
baseline, or major clinic visits) 
Antianxiety drugs (benzodiazepines)  
Ativan (lorazepam) 
Dalmane (flurazepam) 
Doral (quazepam) 
Halcion (triazolam) 
Klonopin (clonazepam)  
Librium (chlordiazepoxide)  
Restoril (temazepam)  
Serax (oxazepam)  
Valium (diazepam) 
Versed (midazolam) 
Xanax (alprazolam) 
 
Sleeping aids (sedative-hypnotics)  
Ambien, Ambien CR (zolpidem tartrate) 
Belsomra (suvorexant) 
Butisol sodium (butabarbital sodium) 
Carbtrital (pentobarbital and carbromal) 
Dalmane (flurazepam hydrochloride) 
Doral (quazepam) 
Edluar (zolpidem tartrate) 
Halcion (triazolam) 
Intermezzo (zolpidem)  
Lunesta (eszopiclone)  
Placidyl (ethchlorvynol)  
Prosom (estazolam)  
Restoril (temazepam)  


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Rozerem (ramelteon)  
Seconal (secobarbital sodium) 
Silenor (doxepin hydrochloride) 
Sonata (zaleplon) 
Zolpimist (zolpidem tartrate) 
Opioid analgesics 
Astramorph (morphine) 
Avinza (morphine)   
Exalgo (hydromorphone) 
Dilaudid (hydromorphone) 
Duragesic (fentanyl,  
Norco (hydrocodone) 
Opana (oxymorphone) 
OxyContin (oxycodone) 
Percocet (oxycodone)  
Vicodin (hydrocodone) 
 
Motion Sickness / vertigo / nausea / intestinal motility / IBS (anticholinergics)  
 
Antivert (meclizine) 
 
Bentyl (dicyclomine) 
Bonine (meclizine) 
Compazine (prochlorperazine) 
Lomotil (diphenoxylate with atropine) 
Tigan (trimethobenzamide) 
3. Excluded: not allowed within 3 months of screening or during the study 
Antiepileptic drugs  
Banzel (rufinamide) 
Depakote (valproic acid) 
Diamox (acetazolamide)  
Keppra (levetiracetam) – non-study medications 
Lamictal (lamotrigine)  
Lyrica (pregabalin) 
Neurontin (gabapentin) 
Potiga (ezogabine) 
Tegretol (carbamazepine)  
Topamax (topiramate)  
Trileptal (oxcarbazepine)  
Zonegran (zonisamide) 
 
Antidepressant (tricyclic antidepressants) and antipsychotic drugs  
Anafranil (clomipramine)  
Asendin (amoxapine) 
Aventyl (nortriptyline) 


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Elavil (amitriptyline) 
Etrafon (perphenazine/amitriptyline)  
Limbitrol (chlordiazepoxide/amitriptyline)  
Ludiomil (maprotiline) 
Pamelor (nortriptyline) 
Nardil (phenelzine sulfate)  
Norpramin (desipramine HCl) 
Remeron (mirtazapine) 
Seroquel (quetiapine) 
Sinequan (doxepin) 
Surmontil (trimipramine) 
Symbyax (olanzapine/fluoxetine)  
Tofranil (imipramine) 
Tofranil-PM (imipramine pamoate)  
Triavil (perphenazine/amitriptyline)  
Vivactil (protriptyline)  
 
Parkinson's disease drugs (dopamine agonists) 
Apokyn (apomorphine)  
Duopa (carbidopa/levodopa) 
Mirapex (pramipexole)   
Neupro (rotigotine)  
Parcopa (carbidopa/levodopa) 
Requip (ropinirole)  
Rytary (carbidopa/levodopa) 
Sinemet (carbidopa/levodopa) 
Stalevo (carbidopa/levodopa/entacapone) 
 
Parkinson's disease drugs (anticholinergics) 
 
Artane (trihexyphenidyl) 
Cogentin (benztropine) 
 
Levsin (Hyoscyamine) 
 
Symmetrel (amantadine) 
 
Antihistamines (first generation; used prn) 
Atarax (hydroxyzine) 
Benadryl (diphenhydramine) 
Chlor-Trimeton (chlorpheniramine)  
Clistin (carbinoxamine) 
Dimetane (brompheniramine) 
Priactin (cyproheptadine) 
Tavits (clemastine)  
Sominex (diphenhydramine) 
Vistaril (hydroxyzine) 


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Antipsychotics (first generation) 
 
Etrafon (perphazine) 
Haldol (haloperidol) 
Loxitane (loxapine) 
Mellaril (thioridazine) 
Navane (thiotixene) 
Prolixin (fluphenazine) 
Thorazine (chlorpromazine) 
 
Trilafon (perphenzaine) 
 
Stelazine (trifluoperazine) 
 
Antipsychotics (second generation with anticholinergic effects or sedation) 
 
Clozaril (clozapine) 
 
Seroquel (quetiapine) 
 
Antihypertensive with CNS side effects 
 
Catapres (clonidine) 
CNS=central nervous system; IBS=irritable bowel syndrome; prn=as needed; SNRIs=serotonin-norepinephrine 
reuptake inhibitors; SSRIs=selective serotonin reuptake inhibitors. 
8.2 
Amyloid PET: Dosage, Administration, and PET Scan Acquisition Guidelines 
Neuroceq (florbetaben) Dosage and Administration 
 Recommended activity for florbetaben is 300 megabecquerels (MBq; 
8.1 millicuries [mCi] ± 20%), maximum 30 µg mass dose, administered as a 
single intravenous bolus in a total volume of ≤ 10 mL through a short catheter 
(max ≤ 1.5 inches or less). Follow the injection with an intravenous flush of 0.9% 
sterile sodium chloride. 
 Inspect the radiopharmaceutical dose solution prior to administration and do not 
use it if it contains particulate matter or is discolored. 
 Use aseptic technique and radiation shielding to withdraw florbetaben solution. 
 Assay the dose in a suitable dose calibrator prior to administration. 
 Inject florbetaben through a short intravenous catheter (approximately 
≤ 1.5 inches) to minimize the potential for adsorption of the drug to the catheter. 
Portions of the florbetaben dose may adhere to longer catheters. 
Neuroceq (florbetaben) PET Scan Acquisition Guidelines 
 A 20-minute PET image, acquired as 4, 5-minute frames, should be acquired 
starting 90 minutes after florbetaben intravenous injection. The subject should be 


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supine and 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 trans-axial pixel sizes between 2 mm and 3 
mm. Images are to be read according to florbetaben reading methodology.  
Amyvid (florbetapir) Dosage and Administration 
 The recommended dose for florbetapir is 370 MBq (10 mCi), maximum 50 μg 
mass dose, administered as a single intravenous bolus in a total volume of 10 mL 
or less.  
 Follow the injection with an intravenous flush of 0.9% sterile sodium chloride.  
 Inspect the radiopharmaceutical dose solution prior to administration and do not 
use it if it contains particulate matter or is discolored. Use aseptic technique and 
radiation shielding to withdraw florbetapir solution.  
 Assay the dose in a suitable dose calibrator prior to administration.  
 Inject florbetapir through a short intravenous catheter (approximately 1.5 inches 
or less) to minimize the potential for adsorption of the drug to the catheter. 
Portions of the florbetapir dose may adhere to longer catheters.  
Amyvid (florbetapir) PET Scan Acquisition Guidelines 
 A 10-minute PET image should be acquired starting 30 to 50 minutes after 
florbetapir intravenous injection. The subject should be supine and 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.  
 Amyvid images should be interpreted only by readers who successfully complete 
a special training program. Training is provided by the manufacturer using either 
an in-person tutorial or an electronic process.  
 The objective of florbetapir image interpretation is to provide an estimate of the 
brain β-amyloid neuritic plaque density, not to make a clinical diagnosis. Image 
interpretation is performed independently of a patient’s clinical features and relies 
upon the recognition of unique image features.  
Vizamyl (flutemetamol) Dosage and Administration 
 The recommended dose for flutemetamol is 185 MBq (5 mCi) in a maximum 
dose volume of 10 mL, administered as a single intravenous bolus within 40 


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seconds. The maximum mass dose is 20 micrograms. Follow the injection with an 
intravenous flush of 5 to 15 mL of 0.9% sterile sodium chloride injection.  
 Use aseptic technique and radiation shielding to withdraw and administer 
flutemetamol solution.  
 Calculate the necessary volume to administer based on calibration time and dose 
using a suitably calibrated instrument.  
 Visually inspect flutemetamol for particulate matter and discoloration prior to 
administration. Do not administer flutemetamol if it contains particulate matter or 
is discolored.  
 Do not dilute flutemetamol.  
Vizamyl (flutemetamol) PET Scan Acquisition Guidelines 
 The recommended PET scan start time is 60 to 120 minutes after flutemetamol 
injection, using a PET scanner in 3-D mode with appropriate data corrections. A 
scan duration of 10 to 20 minutes is recommended. The time of initiation and the 
duration of the scan may vary depending on dose, imaging acquisition, and 
reconstruction parameters.  
 Position the patient supine with the brain (including the cerebellum) within a 
single field of view. The patient’s head should be tilted so that the anterior 
commissure-posterior commissure (AC-PC) plane is at right angles to the bore-
axis of the PET scanner, with the head positioned in a suitable head support. 
Reducing head movement with tape or other flexible head restraints may be 
employed. Iterative or filtered back-projection reconstruction is recommended 
with a slice thickness of 2 to 4 mm, matrix size of 128 x 128 with pixel sizes of 
approximately 2 mm. Where a post-smoothing filter is applied, a full width half 
maximum (FWHM) of not more than 5 mm is recommended; filter FWHM 
should be chosen to optimize the signal-to-noise ratio while preserving the 
sharpness of the reconstructed image.  
 Flutemetamol images should be interpreted only by readers who successfully 
complete the electronic or in-person training program provided by the 
manufacturer. The objective of flutemetamol image interpretation is to provide an 
estimate of the brain β-amyloid neuritic plaque density, not to make a clinical 
diagnosis. Image interpretation is performed independently of a subject’s clinical 
features and relies upon recognition of image features in certain brain regions.  
 Image interpretation is based upon the distribution of radioactive signal within the 
brain; clinical information is not a component of image assessment. Images are 
designated as positive or negative either by comparing radioactivity in cortical 
grey matter with activity in adjacent white matter, or based on the intensity in the 


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five regions mentioned above. Signal uptake in the cerebellum does not contribute 
to scan interpretation (for example, a positive scan may show retained cerebellar 
grey-white contrast even when the cortical grey-white contrast is lost). Images 
should be viewed with the minimum image intensity set to zero and the maximum 
set such that the signal level in the easily identifiable pons is at 90% of maximum.  
 Negative scans show more radioactivity in white matter than in grey matter, 
creating clear grey-white matter contrast.  
8.3 
MRI Scanning Procedures  
8.3.1 MRI Subject Pre-Scan Procedures 
a. All subjects should be screened by the study coordinator for standard MRI 
contraindications during screening and immediately prior to each MRI session. 
Contraindications include, but are not limited to, non-removable ferrous metal 
objects, aneurysm clips, pacemakers, and any other implanted medical or other 
devices, such as defibrillators, etc.   
b. Sedation will not be offered for the baseline MRI scan in this study. Subjects who 
experience significant claustrophobia or are otherwise uncomfortable with MRI scans 
should not participate in this study. When necessary to obtain a follow-up scan, 
sedation will be offered.  
c. Universal MRI safety precautions and local standard practice for monitoring subjects 
during the scan should be followed. This may include devices to monitor pulse and 
oxygen levels. 
d. Proper positioning of subjects into the scanner will be crucial for successful data 
acquisition, and each subject should be positioned in the same manner for each MRI 
scan. 
Subject should remove all upper-body clothing with metallic trim, zippers, buttons, or 
embroideries that may cause artifacts. A stereotactic marker (either vitamin E or fish oil 
capsule) should be placed on the subject’s right temple. Subjects should be provided with 
hearing protections and should be positioned without rotation in either plane. After 
positioning, the head should be immobilized using a Velcro strap across the forehead, or 
padding along the sides of the head, to reduce the possibility of motion. Align the center 
of the table by positioning cross-hairs on the subject’s nasion at every scanning session. 
Ensure subjects are high enough in the coil to prevent signal loss at the inferior aspect of 
the brain. Subjects should be reminded frequently throughout the scanning session to 
hold as still as possible. 
8.3.2 MRI Subject Scan Protocol 
All image sequence protocols for each scanner vendor will be provided electronically and 
should be loaded by the MRI support engineer. Scans acquired using a different sequence 


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definition will not be accepted. All scans will be performed in the straight axial or sagittal 
plane. No manual adjustments should be made. The following scans will be performed in 
the following order: 
a. Localizer scan 
b. Calibration/reference scan (if applicable) 
c. Accelerated sagittal MP-RAGE/IR-SPGR 
d. Repeated accelerated sagittal MP-RAGE/IR-SPGR 
e. FLAIR (baseline only) 
f. T2 (baseline only) 
g. Functional MRI scans (optional procedure performed only at JHU) 
a. Localizer scan  
A brief acquisition in 3 orthogonal planes for anatomical orientation. Multiple slices are 
acquired in the middle of each of the 3 planes. The head should be centered laterally 
along the inter-hemispheric fissure and centered on the thalamus for the anterior/posterior 
and superior/inferior planes. Sample images will be provided to ensure the subject is 
positioned correctly.  
Scans are only acquired in straight orthogonal planes. The head should be positioned as 
straight as possible in all 3 views. Oblique scans are not permitted. If the subject is not 
positioned correctly, positioning should be adjusted and a localizer scan repeated. 
b. Calibration/Reference Scan 
The MRI scanner should provide automated adjustment procedures for calibration and 
RF coil tuning and frequency adjustments after a subject is positioned in the scanner 
bore. Standard procedures provided by the manufacturer should be followed. 
c. Accelerated Sagittal 3D MP-RAGE/IR-SPGR 
The 3D MP-RAGE sequence will be utilized on the Siemens and Philips vendor systems, 
and the IR-SPRGR sequence will be used on the GE vendor system. 
The accelerated sagittal structural scan will be oriented as a straight sagittal scan with 
slice prescription from left to right. Acquisition should not be oblique to compensate for 
subject’s head tilt. The full head and skull should be included in the acquisition. The skull 
must be fully included superiorly and laterally. The entire cerebellum should be included 
inferiorly. The nose should be included in the anterior/posterior plane to avoid image fold 
over. The accelerated sagittal structural scan will be repeated to complete 2 identical 
structural scans. 
d. FLAIR and T2 
FLAIR and T2 scans will be completed during the baseline MRI. Orientation should be 
planned as a straight axial scan with slice prescription from inferior to superior. Scans 


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should not be oblique to adjust for the head tilt. Scans should be positioned on the mid-
sagittal slice from the tri-planar scout. The full brain must be covered. The slices should 
be placed to cover the cerebellum fully, as well as the full extent of the brain in the lateral 
and the anterior to posterior planes. If additional transverse slices are required to achieve 
full brain coverage, those slices should be added and acquired. 
8.3.3 MRI Subject Scan Procedures 
If a subject elects to discontinue the MRI procedure, every effort should be made to 
alleviate the source of discomfort and complete the MRI session. This includes making 
adjustments to the table, head coil, and padding. However, if the subject is still unable to 
complete the scan, then the MRI session should be terminated and recorded as incomplete 
with a description of the reasons for terminating the session. 
8.4 
PET Scanning Procedures for[18F]MK-6240 (Optional) 
[18F]MK-6240 Administration: Participants will receive a single intravenous bolus 
injection of 185 MBq (5 mCi) ± 10% of not more than 10 mL total volume followed by a 
10 mL normal saline (0.9% NaCl) flush.  
Scan Acquisition: The following procedure will be used for obtaining the [18F]MK-6240 
PET imaging scans: 
Subjects will receive the [18F]MK-6240 injection and should make themselves as 
comfortable as possible and should be encouraged to void frequently, walk, eat, and drink 
in an uptake room. At 90 minutes (acceptable starting range 90 to 110 minutes) following 
the injection, participants will undergo a continuous 30-minute brain scan consisting of 
6 × 300 sec frames to achieve a minimum of 10 minutes of artifact-free data.   
8.5 
Site Qualification 
Each site must be qualified for MRI/PET acquisition by the imaging vendor. Phantom 
scans will be used for MRI/PET site qualification.  
 


Certificate Of Completion
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AgeneBio, Inc - Part 11. 


 
 
A multicenter, randomized, double-blind, placebo-controlled study evaluating the 
efficacy and safety of AGB101 (low-dose levetiracetam, 220 mg, extended release 
tablet) on slowing progression of mild cognitive impairment due to Alzheimer's 
disease 
 
 
NCT03486938 
 
 
SAP Version 2.0 
21NOV2022