Clinical trial NCT02880956
Conditions: Alzheimer's Disease
Keywords: Early Alzheimer's Disease (AD) Mild Cognitive Impairment (MCI) Mild Alzheimer's Disease (AD) Tau Early dementia Tauopathies AD Neurodegenerative diseases Memory loss Nervous system diseases
Sponsor: AbbVie
Start date: 2017-01-26; Completion date: 2021-07-28
Enrollment: 453 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study seeks to evaluate the efficacy and safety of ABBV-8E12 in participants with early Alzheimer's disease (AD).

Detailed description:

Arms: arm 1: Placebo for ABBV-8E12 every 4 weeks for 96 weeks arm 2: ABBV-8E12 300 mg every 4 weeks for 96 weeks arm 3: ABBV-8E12 1000 mg every 4 weeks for 96 weeks arm 4: ABBV-8E12 2000 mg every 4 weeks for 96 weeks
Interventions: intervention 1: ABBV-8E12 intervention 2: placebo for ABBV-8E12
Intervention descriptions: intervention 1: ABBV-8E12 solution for IV infusion intervention 2: placebo solution for intravenous (IV) infusion

Protocol documents:
Prot_000.pdf: 


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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
18 May 2016
Administrative Change 1
18 August 2016
Administrative Change 2
12 May 2017
Administrative Change 3
12 February 2018
Amendment 1
19 March 2018
Amendment 2
15 November 2018
The purpose of this amendment is to:
●
Update Section 3.2 Benefits and Risks to include language for the coronavirus 
disease-19 (COVID-19) pandemic.
Rationale: To include study subjects infected with SARS-Cov2 (COVID-19).
●
Update Section 5.1 Overall Study Design and Plan: Description to remove 
sites in Japan from the study.
Rationale: Sites in Japan were planned for enrollment, but did not occur.
●
Update Section 5.3.1.1 Study Procedures [Physical Examination, Neurological 
Examination, Vital Signs, 12-Lead Electrocardiogram (ECG), Abnormal 
Findings, Lumbar Puncture (LP), Magnetic Resonance Imaging (MRI), 
Positron Emission Tomography (PET) Tau Imaging, Retinal Imaging for 
Amyloid, and Digital Clock Drawing Test (dCDT)] to include language for the 
COVID-19 pandemic.
Rationale: To describe alternative processes that may be needed because of 
the COVID-19 pandemic.
●
Update Section 5.3.1.2 Collection and Handling of Biomarker and 
Pharmacogenetic Research Samples [Apolipoprotein E (APOE) 
Pharmacogenetic Sample; Optional Pharmacogenetic Research Samples] to 
include language for the COVID-19 pandemic.


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Rationale: To describe alternative processes that may be needed because of 
the COVID-19 pandemic.
●
Update Section 5.4.1 Discontinuation of Individual Subjects to include 
language for the COVID-19 pandemic.
Rationale: To describe alternative processes that may be needed because of 
the COVID-19 pandemic.
●
Update Section 5.5.1 Treatments Administered to include language for the 
COVID-19 pandemic.
Rationale: To describe alternative processes that may be needed because of 
the COVID-19 pandemic.
●
Update Section 6.1.5 Adverse Event Reporting to include language for the 
COVID-19 pandemic.
Rationale:  To describe alternative processes that may be needed because of 
the COVID-19 pandemic.
●
Update Section 8.1.7.1 Tabulations and Summary Statistics to include 
summary of data for all subjects
Rationale:  To include a summary of all data collected from subjects in
Cohorts 1 and 2.
●
Update Section 9.2 Ethical Conduct of the Study to include language for the 
COVID-19 pandemic.
Rationale: To describe alternative processes that may be needed because of 
the COVID-19 pandemic.
●
Update Section 9.3 Subject Information and Consent to include language for 
the COVID-19 pandemic.
Rationale: To describe alternative processes that may be needed because of 
the COVID-19 pandemic.
●
Update Section 11.0 Data Quality Assurance to include language for the 
COVID-19 pandemic.
Rationale: To describe alternative processes that may be needed because of 
the COVID-19 pandemic.
●
Update footnote at Appendix C Study Activities to accommodate tau PET due 
to scheduling conflicts.


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Rationale: To schedule tau PET as close as possible to Weeks 44 (Dose 12) 
and 96 visits.
An itemized list of all changes made to this protocol under this amendment can be found 
in Appendix E.


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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M15-566
Name of Study Drug:  ABBV-8E12
Phase of Development:  2
Name of Active Ingredient:  ABBV-8E12
Date of Protocol Synopsis:  02 October 2020
Protocol Title:  A Phase 2 Multiple Dose, Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Efficacy and Safety of ABBV-8E12 in Subjects with Early Alzheimer's Disease
Objectives:
The primary objectives of this study are:

To assess the efficacy of ABBV-8E12 in slowing disease progression (cognitive and functional 
impairment) in subjects with Early Alzheimer's Disease (AD) as measured by the Clinical 
Dementia Rating – Sum of Boxes (CDR-SB).

To assess the long-term safety of ABBV-8E12 for up to 96 weeks in subjects with Early AD.
The secondary objectives of this study are:

To assess the pharmacokinetics of ABBV-8E12 in subjects with Early AD.

To assess the efficacy of ABBV-8E12 in slowing cognitive and functional impairment in 
subjects with Early AD as measured by the Mini-Mental State Examination (MMSE), 
Alzheimer's Disease Assessment Scale (14-Item) Cognition Portion (ADAS-Cog-14), 
Repeatable Battery for Assessment of Neuropsychological Status (RBANS), 24-Item 
Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted for Patients 
with Mild Cognitive Impairment (ADCS-MCI-ADL-24), Functional Activities Questionnaire 
(FAQ) and University of California San Diego Performance Based Skills Assessment, Brief 
Version (UPSA-Brief).

To assess the global impact of ABBV-8E12 on cognition, function and behavior as measured by 
Alzheimer's Disease Cooperative Study Clinical Global Impression of Change for Mild 
Cognitive Impairment (ADCS-CGIC-MCI).
The exploratory objectives of this study are:

To assess the effect of ABBV-8E12 on cerebrospinal fluid (CSF) and plasma tau protein.

To assess the effect of ABBV-8E12 on potential CSF and plasma biomarkers of disease 
progression.

To assess the efficacy of ABBV-8E12 in slowing the rate of regional and/or whole brain 
atrophy in subjects with Early AD as measured by volumetric magnetic resonance imaging 
(vMRI).

To assess any signals or trends for efficacy of ABBV-8E12 in removing tau deposits or slowing 
the accumulation and spread of tau deposits in the brain as measured by tau positron emission 
tomography (PET) in a subset of subjects.

To generate additional data for the correlation between retinal amyloid imaging and amyloid 
PET imaging in a subset of subjects.

To characterize the performance of a digital clock drawing test (dCDT) in measuring cognitive 
function and assess its correlation with other clinical rating scales and biomarkers in a subset of 
subjects.


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Investigators:  Multicenter
Study Sites:  Up to 80 global sites
Study Population:  Adult (55 – 85 years old) subjects with early AD.
Number of Subjects to be Enrolled:  Approximately 400
Methodology:
This Phase 2 multiple dose, multicenter, multinational, randomized, double-blind, placebo-controlled 
study is designed to evaluate the efficacy and safety of ABBV-8E12 in subjects with Early AD.  Subjects 
will be allowed to use medications to treat symptoms related to AD, if on a stable dose for at least 
12 weeks prior to randomization.  The study will consist of a screening period of up to 12 weeks, a 
96-week double-blind treatment period and a follow-up period of approximately 20 weeks following the 
last study drug administration (for those subjects who prematurely discontinue from treatment, decline to 
participate in or do not qualify for extended treatment).  At the end of the treatment period, eligible 
subjects who completed the 96-week treatment period may enter a planned separate extension study for 
extended treatment.  All activities for these subjects will be outlined in a separate extension study 
protocol.
Approximately 400 subjects with Early AD between 55 to 85 years of age will be eligible to participate 
in the study according to the selection criteria.  Upon completion of screening and baseline procedures, 
eligible subjects will be randomized to one of the 3 ABBV-8E12 dose arms (300 mg, 1000 mg or 
2000 mg) or placebo in a 1:1:1:1 ratio.  Doses will be administered every 4 weeks via IV infusion. 
This study will utilize a Data Monitoring Committee (DMC).  The DMC will consist of at least 2 non-
AbbVie clinicians, at least 1 non-AbbVie statistician, and at least 1 external pharmacokineticist.  The 
DMC will review unblinded safety data and make recommendations based on the emerging safety 
profile of ABBV-8E12 and on the results of the interim efficacy analyses.  The DMC membership, 
responsibilities and operating logistics will be documented in a charter that will be finalized prior to the 
first DMC review meeting.
Safety and tolerability will be monitored throughout the study.
The first 48 subjects enrolled into the study will be represented as Cohort 1 in this protocol while the 
subjects enrolled subsequently to Cohort 1 will be represented as Cohort 2.  More frequent 
pharmacokinetic sampling and safety monitoring by the DMC will be conducted for Cohort 1 subjects.
Eligible subjects will be enrolled into the Treatment Period of the study on Day 1 and receive their 
first infusion of study drug.  Subjects will return to the study site every 4 weeks for their study drug 
infusion, blood collection, study procedures and assessments as outlined in the Study Activities Table.  
Subjects will be observed on-site for at least 2 hours following each of the first 4 infusions of study drug 
and for at least 30 minutes after the end of infusion of all doses thereafter.  In addition, Cohort 1 subjects 
will return to the study site 5 and 15 days after both the first and fourth infusion of study drug for 
collection of additional safety assessments and pharmacokinetic samples.


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Methodology (Continued):
In addition to blinded safety data monitoring by the sponsor, the first four mandatory safety DMC 
reviews of unblinded safety data will take place after the 12th, 24th, 36th and 48th subject have been 
administered their second dose and results for the MRI scheduled at approximately 2 weeks after their 
second dose are available.  The data set will consist of all of the available safety and pharmacokinetic 
data in the study, including the data of any subjects from Cohort 2 who have received at least one dose 
of study drug.
Additional safety DMC reviews will occur after a total of approximately 100, 200, 300 and 400 subjects 
are randomized.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:

Male or female and age is between 55 and 85 years, inclusive, at Screening Visit 1.

Subject who meets the National Institute on Aging and the Alzheimer's Association (NIA-AA) 
clinical criteria for mild cognitive impairment or probable AD, and has:
o
Clinical Dementia Rating (CDR)-Global Score of 0.5 at Screening Visit 1
o
Mini-Mental State Examination (MMSE) score of 22 to 30, inclusive, at Screening Visit 1
o
Repeatable Battery for the Assessment of Neuropsychological Status-Delayed Memory 
Index (RBANS – DMI) score of 85 or lower

Subject has a positive amyloid PET scan.

Subject has a Modified Hachinski Ischemic Scale (MHIS) score of ≤ 4.

The subject has an identified, reliable study partner (e.g., family member), who has frequent 
contact with the subject and who will provide information as to the subject's cognitive and 
functional abilities.

If using medications to treat symptoms related to AD, doses must be stable for at least 12 weeks 
prior to randomization.
Main Exclusion:

Subject has any contraindications or inability to tolerate brain magnetic resonance imaging 
(MRI), PET scans or lumbar puncture (Cohort 1 only).

Subject has evidence of any other clinically significant neurological disorder other than Early 
AD including but not limited to Parkinson's disease, vascular dementia, significant 
cerebrovascular abnormalities, frontal-temporal dementia, Huntington's disease, normal 
pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural 
hematoma, multiple sclerosis, history of significant head trauma followed by persistent 
neurologic deficits or known structural brain abnormalities.

Subject has a screening MRI scan, interpreted by a radiologist with evidence of infection, 
infarction (including multiple lacunas in a critical memory structure), or other focal lesions.

In the opinion of the investigator, the subject has any clinically significant or uncontrolled 
medical or psychiatric illness, or has had an infection requiring medical intervention in the past 
30 days.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):

Subject has had a myocardial infarction, unstable angina, stroke, transient ischemic attack or 
required intervention for any of these conditions (e.g., coronary artery bypass graft, 
percutaneous coronary intervention via cardiac catheterization, thrombolytic therapy) within 
6 months of Screening Visit 1.
Investigational Product:
ABBV-8E12 (300 mg/15 mL)
ABBV-8E12 (1000 mg/10 mL)
Doses:
Doses will be given every 4 weeks.
Dose 1:  300 mg 
Dose 2:  1000 mg
Dose 3:  2000 mg
Doses may be modified after evaluation by the data monitoring 
committee of the safety, tolerability and available pharmacokinetic data.
Mode of Administration:
IV infusion
Reference Therapy:
Placebo (0.9% Sodium Chloride Injection/Solution for Infusion)
Doses:
Doses will be given every 4 weeks.
Mode of Administration:
Intravenous (IV) Infusion
Duration of Treatment:  96 Weeks
Criteria for Evaluation:
Efficacy:
Clinical Assessments:

Clinical Dementia Rating sum of boxes (CDR-SB)

Repeatable Battery for Assessment of Neuropsychological Status (RBANS)

University of California's Performance Based Skills Assessment, Brief Version (UPSA-Brief)

Mini Mental State Examination (MMSE)

Alzheimer's Disease Assessment Scale (ADAS-Cog-14)

Functional Activities Questionnaire (FAQ)

Neuropsychiatric Inventory (NPI)

24-item Alzheimer's Disease Cooperative Study/Activities of Daily Living scale adapted for 
patients with mild cognitive impairment (ADCS-MCI-ADL-24)

Alzheimer's Disease Cooperative Study Clinician's Global Impression of Change for Mild 
Cognitive Impairment (ADCS-CGIC-MCI)


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Criteria for Evaluation (Continued):
Pharmacokinetic:
The concentration of ABBV-8E12 will be determined in serum and CSF samples collected in the study.
Values for the following pharmacokinetic parameters will be estimated using non-compartmental 
methods:  maximum observed serum concentration (Cmax), the time to Cmax (peak time, Tmax), the area 
under the concentration time curve (AUC) over the dosing interval after the first and the fourth doses; 
the observed serum concentration at the end of a dose interval (Ctrough) after all doses.
A mixed-effect modeling approach will be used to estimate the population central value and the 
empirical Bayesian estimates of the individual values for ABBV-8E12 clearance (CL) and volume of 
distribution (V).
The concentration of ABBV-8E12 in CSF will be summarized after the fourth dose and after the final 
dose if administered at least 3 months after the previous LP for subjects in Cohort 1.  LPs will be 
optional for subjects in Cohort 2, and the concentration of ABBV-8E12 in these CSF samples will be 
summarized, if available.
Additional parameters may be calculated if useful in the interpretation of the data.
Immunogenicity:
Anti-drug antibodies will be determined in serum for assessment of immunogenicity.
Biomarkers and Pharmacogenetics:
Exploratory research to assess effects of ABBV-8E12 on potential biomarkers of disease progression 
will be conducted.  Blood sampling, CSF sampling and MRIs for volumetric analysis will be done at 
designated time points throughout the study in order to obtain the data.  Tau PET scans will be collected 
in a subset of the subjects.  Also, retinal optical images will be obtained in a subset of subjects, and data 
from a digital clock drawing test as a measure of cognitive function will be collected from a subset of 
subjects.  The potential biomarkers for which data will be obtained from all subjects will include, but are 
not limited to, the following:  tau, amyloid beta 40 and 42, and neurofilament light chain (NFL) plasma 
concentrations; volumetric MRI measures for whole brain, hippocampus and lateral ventricles; tau PET 
standardized uptake value ratio (SUVR) for hippocampus, entorhinal area, frontal, parietal, temporal, 
and occipital lobes.
The CSF concentration of total tau and free tau will be determined to assess binding of ABBV-8E12 to 
tau.
Apolipoprotein E (APOE) allele status will be determined for each subject and analyzed as a factor 
contributing to the subject's response to treatment.  Optional pharmacogenetic research samples will also 
be collected.
Tau PET imaging will be used to assess the amount of tau burden and the ability of ABBV-8E12 to slow 
the accumulation and spread of tau deposits in the brain for subjects at participating sites.  The amount 
of tau deposits in a given region will be assessed by calculating a SUVR.  Due to the exploratory nature 
of these PET imaging endpoints, analyses will be performed for multiple brain regions, which will 
include, but not necessarily be limited to, 4 composite meta-regions that correspond to anatomical 
definitions of Braak stages III, IV, V, and VI.  Additional variables will be assessed.


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Criteria for Evaluation (Continued):
Safety:
Adverse event monitoring (including infusion and allergic reactions), vital signs, physical examination, 
neurologic examination, electrocardiogram (ECG), laboratory tests, Columbia-Suicide Severity Rating 
Scale (C-SSRS) and MRI assessments. 
Subjects will be monitored closely for the occurrence of adverse events (AEs) and serious AEs (SAEs), 
including infusion/allergic reactions, both during and after the IV infusion up to the final follow-up visit, 
at a minimum of approximately 20 weeks from the date of the last dose of study drug.  Monitoring will 
occur according to the protocol-defined Study Activities Table and will include but not be limited to 
AEs, vital signs, complete neurologic exam and MRIs.  The DMC will be in place to provide 
recommendations during the study.
Statistical Methods:
Efficacy:
The efficacy variables will be the change from baseline up to the Week 96 observation on the CDR-SB 
score, ADAS-Cog-14 total score, RBANS total score, MMSE total score, NPI total score, 
ADCS-MCI-ADL-24 total score, FAQ score, UPSA-Brief and ADCS-CGIC-MCI scores.  The primary 
efficacy variable will be the change from baseline up to the Week 96 on the CDR-SB score.  The 
primary efficacy analysis is to compare each ABBV-8E12 dose group with placebo using a likelihood-
based, mixed-effects model repeated measures (MMRM) analysis of the change from baseline for each 
post-baseline observation using all observed data.  The model will include fixed, categorical effects for 
treatment, site, visit, and treatment-by-visit interaction, and baseline-by-visit interaction with continuous 
fixed covariate for the corresponding baseline score.  The primary comparison will be the contrast 
between each ABBV-8E12 dose group and placebo at the Week 96 Visit using two-sided tests.  A 
group-sequential graphical approach will be used to handle multiplicity of primary and secondary 
efficacy endpoints for multiple ABBV-8E12 doses and multiple analyses.  The treatment group 
difference at earlier visits will be assessed as secondary.  An unstructured (co)variance structure will be 
used to model the within-patient errors.  Satterthwaite's approximation will be used to estimate 
denominator degrees of freedom and the Type III sum-of-squares for the Least Square (LS) means will 
be used to estimate treatment group differences.  This MMRM analysis will be applied to each efficacy 
variable with repeated measurements.


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Statistical Methods (Continued):
Pharmacokinetic:
The concentration data at the end of the first four dose intervals in Cohort 1 will be summarized to 
investigate the change in serum concentration with repeated dosing.  The logarithmic transformation will 
be used if appropriate.  The model will have effects for dose level, week and the interaction of dose level 
and week.  For measures of exposure, an analysis of covariance will be performed on dose normalized 
parameters of Cohort 1.  It is anticipated that the logarithmic transformation will be employed.  Subjects 
will be classified by dose level.  Body weight will be a covariate, and there may be other covariates.  The 
hypothesis of dose proportionality will be tested within the framework of the model by testing the 
hypothesis of no difference between the highest and lowest doses.  Population pharmacokinetic analyses 
will be performed using a non-linear mixed-effect modeling approach with the nonlinear mixed effect 
modeling (NONMEM) software (version VII, or higher version).  The structure of the starting 
pharmacokinetic model will be based on the pharmacokinetic analysis of data from previous studies and 
Cohort 1 of this study.  Apparent CL and V of ABBV-8E12 will be the pharmacokinetic parameters of 
major interest in the NONMEM analyses.
CSF concentration data after the fourth dose and the final dose in Cohort 1 and Cohort 2 (if available) 
will be tabulated and summarized by dose level.
Immunogenicity:
The anti-drug antibody (ADA) titers will be tabulated by dose level and summarized as appropriate.
Biomarker:
For CSF total tau and free tau concentrations and for their ratio, and for CSF NFL concentration, an 
analysis of covariance (ANCOVA) will be performed for each scheduled time of evaluation after 
treatment begins.  The model will have classification of subjects by treatment.    The covariate in these 
analyses will be the baseline value, except that for the analysis on the ratio of free tau and total tau 
concentrations, the covariate will be the baseline total tau concentration measurement.  An MMRM 
analysis will be performed for plasma/serum concentration variables, vMRI variables, and tau PET 
variables for the scheduled measurements during treatment (ending at Week 96).  For these analyses, the 
baseline value will be a covariate.  Hypothesis testing on the effects of ABBV-8E12 doses will be done 
within the framework of the model.  The primary tests will be a test on trend with dose (with placebo
considered a dose level) and a test on the difference between the highest dose and placebo.  The data will 
be transformed if there is a meaningful departure from the assumption of normality.
For some biomarker variables, the relationship to disease progression and response to treatment will be 
explored with disease state represented by the efficacy variable CDR-SB score and perhaps by some 
other variables.  The exploration on the relationship with disease progression will include an analysis of 
data of only the subjects treated with placebo.


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Statistical Methods (Continued):
Safety:
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  The 
number and percentage of subjects reporting treatment-emergent adverse events will be tabulated by 
MedDRA System Organ Class (SOC) and Preferred Term (PT) with a breakdown by treatment group.  
Tabulations will also be provided in which the number of subjects reporting an adverse event (MedDRA 
term) is additionally broken down by rating (mild, moderate or severe) and by whether possibly related 
to study drug.  The number and percent of subjects experiencing treatment-emergent SAEs (including 
deaths) and adverse events leading to premature discontinuation of the study drug will be tabulated 
according to the MedDRA SOC and preferred term by treatment group.  Treatment group differences 
between each ABBV-8E12 dose group and placebo will be analyzed using Fisher's exact test.  
Differences between each ABBV-8E12 dose group and placebo in change from baseline to minimum, 
maximum and final clinical laboratory evaluation, vital sign observation and ECG parameters will be 
analyzed by a one-way analysis of variance (ANOVA) with treatment as the main effect.


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
α
alpha
Aβ
amyloid
AD
Alzheimer's Disease
ADA
Anti-drug antibody
ADAS-Cog-14
Alzheimer's Disease Assessment Scale (14-Item) Cognition portion
ADCS-CGIC-MCI
Alzheimer's Disease Cooperative Study Clinician's Global Impression of 
Change for Mild Cognitive Impairment
ADCS-MCI-ADL-24
24-item Alzheimer's Disease Cooperative Study/Activities of Daily Living 
Scale Adapted for Patients with Mild Cognitive Impairment
AE
Adverse event
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
APOE
Apolipoprotein E
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
ATEMS
AbbVie Temperature Excursion Management System
AUC
Area under the concentration time curve
BMI
Body mass index
BUN
Blood urea nitrogen
C2N
C2N Diagnostics Company
CBD
Corticobasal degeneration
CDR
Clinical Dementia Rating
CDR-SB
Clinical Dementia Rating-Sum of Boxes
CDT
Clock drawing test
CFR
Code of Federal Regulations
CL
Clearance
Cmax
Maximum observed serum concentration
CNS
Central nervous system
COVID-19
Coronavirus disease-2019
CPK
Creatine phosphokinase


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CRA
Clinical research associate
CRF
Case report form
CS
Clinically significant
CSF
Cerebrospinal fluid
C-SSRS
Columbia-Suicide Severity Rating Scale
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
Observed serum drug concentration at the end of a dose interval
dCDT
Digital clock drawing test
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DSUR
Developmental Safety Update Report
DTP
Direct-to-Patient
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EMA
European Medicines Agency 
ERAC
Exposure-Response Analysis Center
eTIV
Estimated total intracranial volume
FAQ
Functional Activities Questionnaire
GAM
Generalized additive method
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transpeptidase
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HCV Ab
Hepatitis C virus antibody
HIV
Human immunodeficiency virus
iADLs
Instrumental Activities in Daily Living
IBRC
Internal Biomarker Review Committee
ICH
International Council on Harmonization
IEC
Independent Ethics Committee
IERC
Internal Executive Review Committee
IgG4
Immunoglobulin G4


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IMP
Investigational Medicinal Product
IND
Investigational New Drug Application
INR
International normalized ratio
IP
Investigational Product
IRB
Institutional Review Board
ITT
Intent-to-treat
IV
Intravenous
IVR
Interactive Voice-Response (system)
IWR
Interactive Web-Response (system)
LP
Lumbar puncture
LS
Least square
MCHC
Mean corpuscular hemoglobin concentration
MCI
Mild cognitive impairment
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MHIS
Modified Hachinski Ischemic Scale
MMA
Methylmalonic acid
MMRM
Mixed-effects model repeated measures
MMSE
Mini-Mental State Examination
MRI
Magnetic resonance imaging
N/A
Not applicable
NCS
Not clinically significant
NFL
Neurofilament light chain
NIA-AA
National Institute on Aging and the Alzheimer's Association
NOAEL
No observed adverse effects level
NONMEM
Nonlinear mixed effect modeling
NPI
Neuropsychiatric Inventory
PCR
Polymerase chain reaction
PCS
Potentially clinically significant
PD
Premature discontinuation
PET
Positron emission tomography
PIN
Personal identification number
PK
Pharmacokinetic
PRN
As needed


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PSP
Progressive supranuclear palsy
PT
Preferred Term
RBANS
Repeatable Battery for Assessment of Neuropsychological Status
RBANS-DMI
Repeatable Battery for Assessment of Neuropsychological Status-Delayed 
Memory Index
RBC
Red blood cell count
RNA
Ribonucleic acid
RSI
Reference Safety Information
SAD
Single-ascending dose
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SDAC
Statistical and Data Analysis Center
SmPC
Summary of Product Characteristics
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Reactions
SUV
Standardized uptake value
SUVR
Standardized uptake value ratio
T4
Thyroxine
TA MD
Therapeutic Area Medical Director
TEAE
Treatment-emergent adverse event
Tmax
Time to peak (maximum) observed serum concentration
TSH
Thyroid-stimulating hormone
UPSA Brief
University of California San Diego Performance Based Skills Assessment, 
Brief Version
V
Volume of distribution
vMRI
Volumetric magnetic resonance imaging
WBC
White blood cell count
WHO
World Health Organization


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Definition of Terms
Visit Window
Treatment Visits on Days 5, 15, 89 and 99 must be scheduled within 
± 2 days (these visits apply to Cohort 1 subjects only).  Visits on all other 
days during the treatment period may be scheduled within ± 4 days.
Study Drug Infusion
Study drug will be administered every 4 weeks for 96 weeks (24 infusions)
Treatment Period
Period of time to complete Day 1 through Week 96 or premature 
discontinuation.  
Post-treatment Follow-up 
Period
Beginning at the time of completion of the Treatment Period and continues 
up to 16 weeks, OR, if eligible, a planned separate extension study.  
Subjects will only enter the Post-treatment Follow-up Period in this study 
if they prematurely discontinue from treatment, do not qualify for, or 
decline to participate in the planned separate extension study.


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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................2
1.2
Synopsis .....................................................................................................5
1.3
List of Abbreviations and Definition of Terms........................................13
2.0
Table of Contents...................................................................18
3.0
Introduction ...........................................................................22
3.1
Differences Statement..............................................................................26
3.2
Benefits and Risks....................................................................................26
4.0
Study Objectives....................................................................27
5.0
Investigational Plan...............................................................28
5.1
Overall Study Design and Plan:  Description ..........................................28
5.2
Selection of Study Population..................................................................32
5.2.1
Inclusion Criteria .....................................................................................32
5.2.2
Exclusion Criteria ....................................................................................34
5.2.3
Prior and Concomitant Therapy...............................................................37
5.2.3.1
Prohibited Therapy...................................................................................38
5.2.4
Contraception Recommendations and Pregnancy Testing.......................40
5.3
Efficacy, Pharmacokinetic, Biomarker, Pharmacogenetic and 
Safety Assessments/Variables..................................................................41
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................41
5.3.1.1
Study Procedures .....................................................................................41
5.3.1.2
Collection and Handling of Biomarker and Pharmacogenetic 
Research Samples ....................................................................................63
5.3.1.3
Confinement.............................................................................................65
5.3.1.4
Meals and Dietary Requirements.............................................................65
5.3.2
Drug and Anti-Drug Antibody Concentration Measurements.................65
5.3.2.1
Collection of Samples for Analysis .........................................................65
5.3.2.2
Measurement Methods.............................................................................67
5.3.3
Efficacy Variables....................................................................................68
5.3.4
Safety Variables.......................................................................................68
5.3.5
Pharmacokinetic Variables ......................................................................68


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5.3.6
Biomarker and Pharmacogenetic Research Variables .............................69
5.3.6.1
Biomarker Research Variables.................................................................69
5.3.6.2
Pharmacogenetic Research Variables......................................................71
5.3.7
Immunogenicity .......................................................................................71
5.4
Removal of Subjects from Therapy or Assessment.................................72
5.4.1
Discontinuation of Individual Subjects....................................................72
5.4.2
Discontinuation of Entire Study...............................................................73
5.5
Treatments................................................................................................74
5.5.1
Treatments Administered.........................................................................74
5.5.2
Identity of Investigational Product...........................................................75
5.5.2.1
Packaging and Labeling...........................................................................76
5.5.2.2
Storage and Disposition of Study Drugs..................................................76
5.5.2.3
Preparation/Reconstitution of Dosage Form............................................77
5.5.3
Method of Assigning Subjects to Treatment Groups...............................77
5.5.4
Selection and Timing of Dose for Each Subject......................................78
5.5.5
Blinding....................................................................................................78
5.5.6
Treatment Compliance.............................................................................80
5.5.7
Drug Accountability.................................................................................80
5.6
Discussion and Justification of Study Design..........................................80
5.6.1
Discussion of Study Design and Choice of Control Groups....................80
5.6.2
Appropriateness of Measurements...........................................................81
5.6.3
Suitability of Subject Population .............................................................81
5.6.4
Selection of Doses in the Study ...............................................................81
6.0
Complaints .............................................................................83
6.1
Medical Complaints.................................................................................83
6.1.1
Definitions................................................................................................84
6.1.1.1
Adverse Event..........................................................................................84
6.1.1.2
Serious Adverse Events ...........................................................................85
6.1.2
Adverse Event Severity............................................................................86
6.1.3
Relationship to Study Drug......................................................................86
6.1.4
Adverse Event Collection Period.............................................................87
6.1.5
Adverse Event Reporting.........................................................................88
6.1.6
Toxicity Management ..............................................................................90


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6.1.6.1
Allergic Reactions Management..............................................................92
6.1.6.2
Management of Adverse Events of the Nervous System.........................92
6.2
Product Complaint ...................................................................................93
6.2.1
Definition .................................................................................................93
6.2.2
Reporting..................................................................................................93
7.0
Protocol Deviations................................................................94
8.0
Statistical Methods and Determination of Sample 
Size ..........................................................................................94
8.1
Statistical and Analytical Plans................................................................94
8.1.1
Analysis Data Sets ...................................................................................95
8.1.2
Disposition, Demographics, and Other Baseline Characteristics ............95
8.1.3
Efficacy Analyses ....................................................................................97
8.1.3.1
Primary Efficacy Analysis .......................................................................98
8.1.3.2
Secondary Efficacy Analysis ...................................................................98
8.1.4
Subgroup Analysis of CDR-SB Score .....................................................99
8.1.5
Biomarker Research Analyses .................................................................99
8.1.6
Safety Analyses......................................................................................102
8.1.6.1
Analysis of Adverse Events...................................................................103
8.1.6.2
Analysis of Laboratory Tests.................................................................103
8.1.6.3
Analysis of Vital Signs and Weight.......................................................104
8.1.6.4
Analysis of ECG Variables....................................................................104
8.1.6.5
Analysis of C-SSRS...............................................................................105
8.1.7
Pharmacokinetics ...................................................................................105
8.1.7.1
Tabulations and Summary Statistics......................................................105
8.1.7.2
Model and Tests.....................................................................................105
8.1.7.3
Missing Values and Model Violations...................................................107
8.1.7.4
Population Pharmacokinetic and Exposure-Response Analysis............108
8.1.8
Immunogenicity .....................................................................................110
8.1.9
Data Monitoring Committee (DMC) .....................................................110
8.1.10
Interim Analysis.....................................................................................111
8.2
Determination of Sample Size ...............................................................112
8.3
Randomization Methods ........................................................................112
9.0
Ethics.....................................................................................113


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9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................113
9.2
Ethical Conduct of the Study .................................................................113
9.3
Subject Information and Consent...........................................................114
10.0
Source Documents, Data Collection and Electronic 
Case Report Forms..............................................................115
10.1
Source Documents .................................................................................115
10.2
Data Collection/Electronic Case Report Forms.....................................115
11.0
Data Quality Assurance ......................................................116
12.0
Use of Information...............................................................117
13.0
Completion of the Study .....................................................118
14.0
Investigator's Agreement....................................................120
15.0
Reference List ......................................................................121
List of Tables
Table 1.
Safety and PK Procedures for Cohort 1...................................................31
Table 2.
Prohibited Medications ............................................................................38
Table 3.
Clinical Laboratory Tests.........................................................................48
Table 4.
Diagnostic Tools and Scale Administration Timing................................55
Table 5.
Identity of Investigational Product...........................................................75
List of Figures
Figure 1.
Study Schematic.......................................................................................30
Figure 2.
Adverse Event Collection ........................................................................87
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................125
Appendix B.
List of Protocol Signatories....................................................................127
Appendix C.
Study Activities......................................................................................128
Appendix D.
Potentially Clinically Significant (PCS) Laboratory Value...................133
Appendix E.
Protocol Amendment:  List of Changes.................................................138


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3.0
Introduction
Alzheimer's Disease
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease among the 
elderly population and the most common cause of dementia.  The latest figures estimate 
that over 46 million people are living with dementia worldwide.1  AD is pathologically 
defined by the extracellular accumulation of amyloid (Aβ), intracellular accumulation of 
tau, neuronal and synaptic loss, brain atrophy, and neuroinflammation.  The disease is 
clinically characterized by cognitive deterioration, progressive impairment of activities of 
daily living, and a variety of neuropsychiatric and behavioral disturbances.  Many lines of 
evidence from laboratories and clinics worldwide support the concept that an imbalance 
between production and clearance of Aβ1-42 is a very early and often initiating factor in 
AD many years or even decades before the onset of symptoms.  Once Aβ begins building 
up in the brain, a number of downstream events occur that probably play important roles 
in damaging axons, dendrites, synapses, intracellular signaling, synaptic transmission, and 
ultimately cell death.  In particular, the aggregation and accumulation of tau appears to 
play a critical role and unlike accumulation of amyloid, correlates well with clinical 
disease progression.
At present, approved pharmacological therapy for AD consists of symptomatic treatment 
with either cholinesterase inhibitors (donepezil, rivastigmine, galantamine) in the mild to 
moderate stages of the disease, or with an N-methyl-d-aspartate receptor antagonist 
(memantine) in the more severe stage.  These drugs provide only modest effects on 
cognitive function and activities of daily living in some patients.  Thus, even if patients 
receive the ideal therapy available today, the effect would not be long lasting and the 
patient's condition would eventually return to basal levels after a certain period of time.2,3  
For this reason, a huge demand and unmet medical need exist for the development of 
disease-modifying drugs for AD with the direct impact on the biology of the disease, 
which if possible, will change the course of the disease and reduce its associated burdens.  
While the best targets for such treatments remain to be determined, it is hypothesized that 
accumulation of Aβ into plaques in the brain is an early event in AD that is followed by 


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abnormal spreading of extracellular tau and tau's deposition into intracellular tangles.4  
There are several anti-Aβ antibody therapies currently in clinical trials, with several 
completing Phase III.5,6  Results from the anti-Aβ trials suggest that due to the early role 
of Aβ in AD, the antibody therapy needs to be administered before the onset of symptoms 
or at the earliest stages of cognitive impairment.  Since tau is generally thought to play a 
role at later stages of disease progression, there is a potential that an anti-tau therapeutic 
would be efficacious even when administered to patients who may be already showing 
clinical symptoms of AD.
ABBV-8E12
ABBV-8E12 is a humanized IgG4 monoclonal antibody against human microtubule-
associated protein tau.  It targets soluble extracellular tau in the brain, which has been 
implicated in the development and spreading of tau pathology.  Neurofibrillary tangles, a 
characteristic pathologic feature in AD and other neurological disorders such as 
progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), are formed 
inside of neurons by aggregated and post-translationally modified tau.  Based on 
preclinical evidence, ABBV-8E12 may be able to block soluble tau aggregates, or seeds, 
from propagating between cells and thereby decrease the spreading of tau pathology in 
brains with tauopathy.
Preclinical Efficacy
In preclinical studies, the mouse version of the ABBV-8E12 antibody (HJ8.5) that 
recognizes the same epitope was found to specifically block tau seeding activity from 
brain lysates of P301S transgenic mice in vitro.7  The P301S animal is a transgenic mouse 
model that carries a mutated human tau gene that leads to early onset frontotemporal 
dementia in humans.  In vivo, 3 months of treatment with HJ8.5 as a continuous 
intracerebroventricular infusion was associated with potent reductions in tau pathology, as 
evidenced by biochemical, histopathological, and functional/behavioral measures.  A 
similar study to assess the effects of peripherally (intraperitoneal) administered HJ8.5 
found that weekly intraperitoneal injections of HJ8.5 were highly effective at reducing 


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insoluble tau in the brain, reducing cortical and hippocampal atrophy, and improving 
sensorimotor function.8
Nonclinical Safety
ABBV-8E12 binds to human tau but not to tau protein from preclinical toxicology species 
(i.e., rhesus/cynomolgus monkey, canine, rabbit, rat or mouse).  Therefore, there is no 
pharmacologically relevant species in which to conduct toxicology studies to support 
safety of ABBV-8E12.  To assess toxicity in non-relevant species, a 4-week study in wild-
type mice was conducted at doses up to 250 mg/kg for 4 weeks via weekly intravenous 
(IV) injections.  There were no adverse effects at any dose level and the no adverse effects 
level (NOAEL) was 250 mg/kg.  It provided a margin of 3-fold over projected exposures 
at the highest dose of 2000 mg planned in this study. 
A detailed discussion of the preclinical toxicology and pharmacology can be found in the 
Investigator's Brochure.9
Clinical Experience
Prior to the regular Investigational New Drug (IND) submission, treatment was initiated 
under an Expanded Access IND (United States) for one patient with PSP, and 
subsequently for one patient with CBD under a compassionate use treatment protocol 
(Germany).
The PSP patient received 20 monthly infusions (highest dose 25 mg/kg), then died for 
reasons unrelated to study drug due to PSP complications.  The CBD patient who had a 
strong history of suicidal ideation and premeditation that preceded compassionate 
treatment with ABBV-8E12, received 3 monthly infusions (1 at 7.5 mg/kg, 2 at 
15 mg/kg), but died due to suicide 10 days after the second 15 mg/kg infusion.  No 
evidence of imaging abnormalities or other evidence of drug-related toxicity was detected 
in these 2 patients.


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Single Dose Study
The single-ascending dose (SAD) study (Study C2N-8E12-WW-104) investigated 5 dose 
levels (2.5 mg/kg, 7.5 mg/kg, 15 mg/kg, 25 mg/kg and 50 mg/kg) in 30 patients with PSP 
(n = 23 on ABBV-8E12, n = 7 on placebo).
Three serious adverse events (SAEs) were reported in this study.  In the 15 mg/kg dose 
group, one subject reported an SAE of a subdural hematoma resulting from a fall that was 
assessed as possibly related to study drug by the investigator.  The sponsor judged the 
SAE to be unlikely related to study drug, and likely related to the underlying PSP disease.  
In the 25 mg/kg dose group, one subject was hospitalized due to a severe increase in 
agitation, anxiety, and perseverative behavior; the subject was discontinued from the 
study after being unable to participate following the SAE.  The investigator and sponsor 
assessed that the worsening symptoms may represent progression of the patient's 
underlying disease, but that the study drug cannot be ruled out as a contributing factor, so 
the event was therefore assessed as possibly drug related.  In the 50 mg/kg dose group, 
1 subject was hospitalized for evaluation and treatment of hypertension.  This SAE was 
assessed by the investigator as moderate in severity, resolved without sequelae, and 
unrelated to study drug.
No subject experienced a systemic hypersensitivity reaction or injection site reaction, and 
there were no clinically relevant patterns of adverse events (AEs) or abnormal laboratory 
findings observed.  Based on available anti-drug antibody (ADA) data in
Study C2N-8E12-WW-104, no ADAs have been detected in post-dose samples on Day 14 
and Day 28.
The plasma pharmacokinetic data from Study C2N-8E12-WW-104 indicate dose-
proportional increases in area under the concentration time curve (AUC) from 2.5 to 
50 mg/kg.  The mean time to maximum plasma concentration (Tmax) ranged from 
0.3 hours to 4.6 hours, and half-life ranged from 27 to 37 days.


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Cerebrospinal fluid (CSF) concentrations increased with dose, and the CSF/plasma 
ABBV-8E12 ratio ranged from 0.181% to 0.385%.
3.1
Differences Statement
This is the first study in which ABBV-8E12 will be administered to subjects with Early 
AD and in which ABBV-8E12 will be administered for an extended treatment period of 
up to 96 weeks.
3.2
Benefits and Risks
ABBV-8E12 was administered under Protocol C2N-8E12-WW-104 to 23 subjects with 
PSP in single doses up to 50 mg/kg with no clinically concerning safety findings.  
In addition, 2 subjects received multiple doses of ABBV-8E12, one under an Expanded 
Access IND, Protocol C2N-8E12-EA-001 (United States) and the other under a single 
named trial application, Study C2N-8E12-DE-003 (Germany).  Treatment appeared to be 
well tolerated.  One subject received 20 monthly doses up to 25 mg/kg and one subject 
received 3 monthly doses up to 15 mg/kg.
No preclinical toxicology data are available in pharmacologically relevant species.  No 
adverse effects at any dose level were detected in the wild-type mouse toxicology study.  
Evidence of efficacy demonstrated in preclinical studies and safety data from clinical 
studies obtained to date provide rationale for continuing assessment of efficacy and safety 
in the current study.
The benefit-risk profile will be further defined in this trial.
In consideration of the coronavirus disease (COVID-19) pandemic, the benefits and risks 
to subjects participating in this study have been re-evaluated.  Based on the limited 
information to date, no additional risk is anticipated for study participants infected with 
SARS-Cov2 during the COVID-19 pandemic, due to the mechanism of action of 
ABBV-8E12.


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4.0
Study Objectives
The primary objectives of this study are:
●
To assess the efficacy of ABBV-8E12 in slowing disease progression 
(cognitive and functional impairment) in subjects with Early AD as measured 
by the Clinical Dementia Rating-Sum of Boxes (CDR-SB).
●
To assess the long-term safety of ABBV-8E12 for up to 96 weeks in subjects 
with Early AD.
The secondary objectives of this study are:
●
To assess the pharmacokinetics of ABBV-8E12 in subjects with Early AD.
●
To assess the efficacy of ABBV-8E12 in slowing cognitive and functional 
impairment in subjects with Early AD as measured by the Mini-Mental State 
Examination (MMSE), Alzheimer's Disease Assessment Scale (14-Item) 
Cognition Portion (ADAS-Cog-14), Repeatable Battery for Assessment of 
Neuropsychological Status (RBANS), 24-Item Alzheimer's Disease 
Cooperative Study/Activities of Daily Living Scale Adapted for Patients with 
Mild Cognitive Impairment (ADCS-MCI-ADL-24), Functional Activities 
Questionnaire (FAQ), University of California San Diego Performance Based 
Skills Assessment, Brief Version (UPSA-Brief), and Neuropsychiatric 
Inventory (NPI).
●
To assess the global impact of ABBV-8E12 on cognition, function and 
behavior as measured by Alzheimer's Disease Cooperative Study Clinical 
Global Impression of Change for Mild Cognitive Impairment (ADCS-CGIC-
MCI).
The exploratory objectives of this study are:
●
To assess the effect of ABBV-8E12 on CSF and plasma tau protein.
●
To assess the effect of ABBV-8E12 on potential CSF and plasma biomarkers 
of disease progression.


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●
To assess the efficacy of ABBV-8E12 in slowing the rate of regional and/or 
whole brain atrophy in subjects with Early AD as measured by volumetric 
magnetic resonance imaging (vMRI).
●
To assess any signals or trends for efficacy of ABBV-8E12 in removing tau 
deposits or slowing the accumulation and spread of tau deposits in the brain as 
measured by tau positron emission tomography (PET) in a subset of subjects
●
To generate additional data for the correlation between retinal amyloid 
imaging and amyloid PET imaging in a subset of subjects.
●
To characterize the performance of a digital clock drawing test (dCDT) in 
measuring cognitive function and assess its correlation with other clinical 
rating scales and biomarkers in a subset of subjects.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This Phase 2 multiple dose, multicenter, multinational, randomized, double-blind, 
placebo-controlled study is designed to evaluate the efficacy and safety of ABBV-8E12 in 
subjects with Early AD.  Subjects will be allowed to use medications to treat symptoms 
related to AD, if on a stable dose for at least 12 weeks prior to randomization.  The study 
will consist of a screening period of up to 12 weeks, a 96-week double-blind treatment 
period and a follow-up period of approximately 20 weeks following the last study drug 
administration (for those subjects who prematurely discontinue from treatment, decline to 
participate in or do not qualify for extended treatment).  At the end of the treatment 
period, eligible subjects who completed the 96-week treatment period may enter a planned 
separate extension study for extended treatment.  All activities for these subjects will be 
outlined in a separate extension study protocol.  
Approximately 400 subjects with Early AD between 55 to 85 years of age will be eligible 
to participate in the study according to the selection criteria described in Section 5.2.  
Upon completion of screening and baseline procedures, eligible subjects will be 
randomized to one of the 3 ABBV-8E12 dose arms (300 mg, 1000 mg or 2000 mg) or 


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placebo in a 1:1:1:1 ratio.  Doses will be administered every 4 weeks via IV infusion.  
Refer to Section 5.5.1 for details on infusion times.
This study will utilize a Data Monitoring Committee (DMC).  The DMC will consist of at 
least 2 non-AbbVie clinicians, at least 1 non-AbbVie statistician, and at least 
1 external pharmacokineticist.  The DMC will review unblinded safety data and make 
recommendations based on the emerging safety profile of ABBV-8E12 and on the results 
of the interim efficacy analyses.  The DMC membership, responsibilities and operating 
logistics will be documented in a charter that will be finalized prior to the first DMC 
review meeting.
Safety and tolerability will be monitored throughout the study.
The first 48 subjects enrolled into the study will be represented as Cohort 1 in this 
protocol while the subjects enrolled subsequently to Cohort 1 will be represented as 
Cohort 2.  More frequent pharmacokinetic (PK) sampling and safety monitoring by the 
DMC will be conducted for Cohort 1 subjects (Table 1).
Eligible subjects will be enrolled into the Treatment Period of the study on Day 1 and 
receive their first infusion of study drug.  Subjects will return to the study site every 
4 weeks for their study drug infusion, blood collection, study procedures and assessments 
as outlined in the Study Activities Table (Appendix C).  Subjects will be observed on-site 
for at least 2 hours following each of the first 4 infusions of study drug and for at least 
30 minutes after the end of infusion of all doses thereafter.  In addition, Cohort 1 subjects 
will return to the study site 5 and 15 days after both the first and fourth infusion of study 
drug for collection of additional safety assessments and PK samples.
In addition to blinded safety data monitoring by the sponsor, the first four mandatory 
DMC reviews of unblinded safety data will take place after the 12th, 24th, 36th and 48th
subject have been administered their second dose and results for the magnetic resonance 
imaging (MRI) scheduled at approximately 2 weeks after their second dose are available.  
The data set will consist of all of the available safety and pharmacokinetic data in the 


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study, including the data of any subjects from Cohort 2 who have received at least one 
dose of study drug.
Additional safety DMC reviews will occur after a total of approximately 100, 200, 300 
and 400 subjects are randomized.
A schematic of the study design is shown in Figure 1.
Figure 1.
Study Schematic


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Table 1.
Safety and PK Procedures for Cohort 1
Screening
Cohort 1, Doses 1 – 4
Visit 1
Dose 1
Dose 2
Dose 3
Dose 4
Weeks of Study Drug Exposure
N/A
0
0
2
4
8
12
12
14
Days –56 
to –8
Day 
1
Days
5 and 15
Day 29
Day 57
Day 
85
Days 
89 and 99
Neurological Exam
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
Xa
X
X
X
X
Xa
Clinical Laboratory Tests
X
X
X
X
X
Amyloid PET Scan
X
MRI
X
Xb
Xb
Lumbar Puncture/CSF Sample 
Collection
X
Xc
PK Sample Collection
Xd
X
X
X
X
Xd
X
X
ADA Sample Collection
Xe
X
Xe
Xe
Xe
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
AE/ConMed Review
X
X
X
X
X
X
X
X
X
ADA = anti-drug antibody; AE = adverse event; CSF = cerebrospinal fluid; C-SSRS = Columbia-Suicide Severity 
Rating Scale; ECG = electrocardiogram; MRI = magnetic resonance imaging; N/A = not applicable; PET = positron 
emission tomography; PK = pharmacokinetic
Visits on Days 5, 15, 89 and 99 must be scheduled within ± 2 days.  Visits on all other days may be scheduled within 
± 4 days.
a.
Pre-dose and within 15 minutes after the end of the infusion and prior to the PK sample collection.
b.
The MRI will be scheduled approximately 2 weeks following the dose and results must be available prior to the 
next scheduled dose.
c.
The lumbar puncture will be performed approximately 14 days after the fourth dose.
d.
Prior to the start of the infusion (0 hour, no more than 30 minutes prior to the start of the infusion), immediately 
after the end of the infusion (within 15 minutes) and 1 and 2 hours after the end of the infusion.
e.
Prior to the start of the infusion (0 hour, no more than 30 minutes prior to the start of the infusion).
Detailed information regarding the regimens/treatments administered and assignment of 
the subjects to the treatment groups can be found in Section 5.5.3.
This study was designed to enroll approximately 400 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 


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ethical considerations.  Therefore, if the target number of subjects has been enrolled, there 
is a possibility that additional subjects in screening will not be enrolled.
5.2
Selection of Study Population
Subjects will undergo screening procedures within 12 weeks prior to initial study drug 
administration.  Adult male and female subjects who meet the inclusion criteria and who 
do not meet any of the exclusion criteria will be eligible for enrollment into the study.
Subjects who have signed informed consent and did not randomize because they did not 
complete the study-specific procedures during the Screening Period or did not meet all 
entry criteria will be considered Screen Failures.  The reason(s) for screen failure will be 
recorded in the source documents and will be captured in the electronic case report form 
(eCRF).  Subjects who screen fail may be re-screened on a case-by-case basis after 
consulting the AbbVie Therapeutic Area Medical Director (TA MD) for approval.
5.2.1
Inclusion Criteria
A subject will be eligible for study participation if he/she meets the following criteria:
1.
Subject must be able to understand the nature of the study and has the opportunity 
to have any questions answered.  The subject has voluntarily signed the 
Independent Review Board (IRB)/Independent Ethics Committee (IEC) approved 
Informed Consent, prior to the conduct of any study procedures (including any 
changes occurring in the subject's current therapeutic regimen).  If based on the 
investigator's judgment at any point during the study the subject does not have an 
adequate capacity to provide consent, then the informed consent must be obtained 
by a person who has the legal right to act on behalf of the subject following local 
regulations.
2.
Male or female and age is between 55 and 85 years, inclusive, at Screening Visit 1.


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3.
Subject who meets the National Institute on Aging and the Alzheimer's Association 
(NIA-AA) clinical criteria for mild cognitive impairment or probable AD,10 and 
has:
●
Clinical Dementia Rating (CDR)-Global Score of 0.5 at Screening Visit 1
●
Mini-Mental State Examination (MMSE) score of 22 to 30, inclusive, at 
Screening Visit 1
●
Repeatable Battery for the Assessment of Neuropsychological Status-Delayed 
Memory Index (RBANS-DMI) score of 85 or lower
4.
Subject has a positive amyloid PET scan.
5.
Subject has a Modified Hachinski Ischemic Scale (MHIS) score of ≤ 4.
6.
Subject has an identified, reliable study partner (e.g., family member), who has 
frequent contact with the subject and who will provide information as to the 
subject's cognitive and functional abilities.  The study partner has voluntarily 
signed the IEC/IRB approved Study Partner Informed Consent, prior to the conduct 
of any study procedures.
7.
If female, subject must be postmenopausal defined as:
●
Age ≥ 55 years with no menses for 12 or more months without an alternative 
medical cause.
OR
●
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy).
8.
If the male subject is sexually active with female partner(s) of childbearing 
potential, he must agree, from Study Day 1 through 20 weeks after the last dose of 
study drug to practice the protocol specified contraception (Section 5.2.4) and must 
refrain from sperm donation.
9.
If using medications to treat symptoms related to AD, doses must be stable for at 
least 12 weeks prior to randomization.


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Rationale for the Inclusion Criteria
1
In accordance with the harmonized Good Clinical Practice (GCP)
7 – 8
The effects of ABBV-8E12 on pregnancy are currently unknown
2 – 6, 9
To select subject population appropriate for this study
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
1.
Subject has any visual, auditory or other impairment that in the Investigator's 
opinion would preclude collection of outcome measures.
2.
Subject has any contraindication to or inability to tolerate brain MRIs (e.g., a 
pacemaker or any other implanted device or condition that would preclude 
proximity to a strong magnetic field).
3.
Subject has any contraindication to or inability to tolerate a PET scan (includes 
current or recent participation in any procedures involving radioactive agents such 
that the total radiation dose exposure to the subject in any given year would exceed 
the local country limits of annual and total dose).
4.
Subject enrolled in Cohort 1 has any contraindications to or inability to tolerate 
lumbar punctures (e.g., use of anticoagulant medications such as warfarin and 
inability to temporarily cease use of such therapy for a limited duration 
surrounding lumbar punctures).
5.
Subject has evidence of any other clinically significant neurological disorder other 
than Early AD, including but not limited to:
●
Parkinson's disease
●
vascular dementia
●
significant cerebrovascular abnormalities
●
frontal-temporal dementia


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●
Huntington's disease
●
normal pressure hydrocephalus
●
brain tumor
●
progressive supranuclear palsy
●
seizure disorder
●
subdural hematoma
●
multiple sclerosis
●
history of significant head trauma followed by persistent neurologic deficits
●
known structural brain abnormalities
6.
Subject has a screening MRI scan, interpreted by a radiologist with evidence of 
infection, infarction (including multiple lacunas in a critical memory structure), or 
other focal lesions.
7.
Subject has a history of or currently has schizophrenia, schizoaffective disorder or 
bipolar disorder according to DSM-V or ICD-10 criteria.
8.
In the opinion of the investigator, the subject has any clinically significant or 
uncontrolled medical or psychiatric illness, or has had an infection requiring 
medical intervention in the past 30 days.
9.
Subject has significant current suicidal ideation within one year prior to Screening 
as evidenced by answering "yes" to questions 4 or 5 on the suicidal ideation portion 
of the Columbia-Suicide Severity Rating Scale (C-SSRS) completed at Screening 
or a history of suicidal attempts within the last 2 years.
10.
Subject has a positive screen for drugs of abuse or marijuana at Screening Visit.
11.
Subject has a current diagnosis or history of drug or alcohol abuse (by DSM-V 
criteria) within 24 months prior to screening visit.
12.
Subject has had a myocardial infarction, unstable angina, stroke, transient ischemic 
attack or required intervention for any of these conditions (e.g., coronary artery 
bypass graft, percutaneous coronary intervention via cardiac catheterization, 
thrombolytic therapy), within 6 months of Screening Visit 1.


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13.
Subject has a history or evidence of a malignancy within the 2 years prior to 
Screening Visit 1.  Subjects with some indolent malignancies (e.g., basal cell 
carcinoma or squamous cell carcinoma) or malignancies considered to be cured or 
not actively treated with anti-cancer therapy or radiotherapy may be permitted to 
enroll with the permission of the AbbVie TA MD.
14.
Subject has a positive test result for hepatitis B surface antigen (HBsAg) or 
hepatitis C virus antibody (HCV Ab) or known history of Human 
Immunodeficiency Virus (HIV) infection.
15.
Subject has had surgery under general anesthesia within 3 months prior to 
Screening or has a planned major surgical procedure scheduled during the period 
when the subject would be participating in this study.  The subject may 
subsequently be considered for the study following full recuperation from the 
surgical procedure.
16.
Receipt of an investigational product within a time period equal to 5 half-lives, if 
known, or within 6 weeks (for small molecules) or 6 months (for monoclonal 
antibodies or other biologics) prior to study drug administration.
17.
Subject has any history of prior receipt of active immunotherapy directed against 
tau or amyloid.
18.
Subject is taking specific exclusionary psychoactive medications or any other 
exclusionary medications as defined in Section 5.2.3.1.
19.
Subject has an abnormally low vitamin B12 (cobalamin), abnormal thyroxine (T4) 
or an abnormally high thyroid-stimulating hormone (TSH) at Screening that is 
considered clinically significant by the investigator.
20.
The investigator considers subject, for any reason, as an unsuitable candidate to 
receive ABBV-8E12 or unable or unlikely to comply with the dosing schedule or 
study evaluations.


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Rationale for Exclusion Criteria
1, 5 – 15, 
19, 20
These criteria were selected to ensure the appropriate subject population
2 – 4
To ensure the safety of the subjects
16 – 18
These products may interfere with the pharmacokinetics of the study drug
5.2.3
Prior and Concomitant Therapy
If a subject reports taking any over-the-counter or prescription medications, vitamins 
and/or herbal supplements or if administration of any medication becomes necessary from 
30 days prior to Screening through the end of the study, the name of the medication, 
dosage information including dose, route and frequency, date(s) of administration 
including start and end dates, and reason for use must be recorded.  The AbbVie TA MD 
must be notified if administration of any prohibited medication is reported during the 
study.
Permitted medications include (but are not limited to) the following:
●
Cholinesterase inhibitors and memantine are permitted if the dose is stable for 
12 weeks prior to randomization and no change is expected during the study.
●
Use of estrogen and estrogen-like compounds is allowed if the dose has been 
stable for 4 weeks prior to randomization.
●
Use of sedative/benzodiazepines (other than those listed in the prohibited 
medications Table 2) is allowed if the dose has been low and stable for 
4 weeks prior to randomization.
●
Use of narcotic analgesics is allowed if the dose has been low and stable for 
4 weeks prior to randomization:  (e.g., codeine, hydrocodone, meperidine, 
oxycodone, propoxyphene, and tramadol).
These medications should remain stable for the duration of the study unless a change in 
regimen is medically necessary.


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All concomitant medications, including any change in dose must be recorded with the 
reason for use, dates of administration, dosages and frequency in the eCRF.
5.2.3.1
Prohibited Therapy
Unless approved by the Investigator in consultation with the AbbVie TA MD, subjects 
should not receive the following medications (not a comprehensive list) described in 
Table 2.
Table 2.
Prohibited Medications
Anticoagulants (Exclusionary for Lumbar Punctures*) 
Generic Name:
Vitamin K antagonists
Enoxaparin sodium
Dabigatran
Rivaroxaban 
Apixaban
Edoxaban
Heparin 
Brand Name:
Warfarin, Acenocoumarol, Phenprocoumon
Lovenox
Pradaxa
Xarelto
Eliquis
Lixiana
*Some subjects may be able to temporarily cease use of anticoagulant therapy in the limited 
duration surrounding lumbar punctures.
Neuroleptics:  Prohibited Within 4 Weeks Prior to Screening and Throughout the Duration of the Study
Generic Name:
Chlorpromazine
Fluphenazine
Loxapine
Perphenazine
Thioridazine
Thiothixene
Trifluoperazine
Clozapine
Haloperidol
Brand Name:
Thorazine
Prolixin
Loxitane
Etrafon, Trilafon
Mellaril
Navane
Stelazine
Clozaril
Haldol (allowed if dose stable for 4 weeks prior to screening)


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Table 2.
Prohibited Medications (Continued)
Anticholinergic Agents:  Prohibited Within 4 Weeks Prior to Screening and Throughout the Duration of 
the Study
Generic Name:
Amantadine
Benztropine
Cyproheptadine
Dicyclomine
Diphenhydramine
Diphenoxylate with Atropine
Hydroxyzine
Hyoscyamine
Meclizine
Prochlorperazine
Trihexyphenidyl
Trimethobenzamide
Brand Name:
Symmetrel
Cogentin
Periactin
Bentyl
Benadryl, Sominex 2
Lomotil
Vistaril, Atarax
Levsin
Antivert, Bonine
Compazine
Artane
Tigan
Antiparkinsonian Medications:  Prohibited Within 4 Weeks Prior to Screening and Throughout the 
Duration of the Study
Generic Name:
Bromocriptine
Deprenyl/Selegiline
Levodopa
Pergolide
Pramipexole
Brand Name:
Parlodel
Eldepryl
Sinemet
Permax
Mirapex
Sedatives/Benzodiazepines:  Prohibited Within 4 Weeks Prior to Screening and Throughout the 
Duration of the Study
Generic Name:
Chlordiazepoxide
Clonazepam
Diazepam
Flurazepam
Meprobamate
Triazolam
Brand Name:
Librium
Klonopin
Valium
Dalmane
Miltown
Halcion
Antihypertensive Agents with Frequent Central Nervous System (CNS) Side Effects:  Prohibited 
Within 4 Weeks Prior to Screening and Throughout the Duration of the Study
Generic Name:
Clonidine
Brand Name:
Catapres
Note:
Brand names may vary by country/region.


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In general, dose changes or administration of additional medications with psychotropic 
effects (including opiates) on an as-needed (i.e., PRN) basis is prohibited.  In the 
exceptional case, low doses of anxiolytic/hypnotic agents, antipsychotic or opiate 
containing medications are permitted in the interest of patient safety or emergent 
symptom control; however, ongoing use of PRN medications should be discussed with the 
AbbVie TA MD.  If a subject requires PRN use of a medication with psychotropic effects, 
subject efficacy scales must not be administered within 48 hours of a PRN medication 
administration.  Depending on the time of dose administration, the next study visit should 
be rescheduled to assure an interval of at least 48 hours between PRN medication 
administration and psychometric assessments.  Each case of PRN medication 
administration must be documented with the reason for use, dates of administration, and 
dosages in the eCRF.  Regularly scheduled medications administered to a subject on a 
daily basis should not be delayed, and administration times should not be altered due to 
cognitive assessments.
The AbbVie TA MD should be contacted if there are any questions regarding concomitant 
and prior therapy(ies), or prohibited medications.
5.2.4
Contraception Recommendations and Pregnancy Testing
Pregnancy testing will not be required in this study.
If female, subject must be postmenopausal defined as:
●
Age > 55 years with no menses for 12 or more months without an alternative 
medical cause.
●
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy).
If male, subject must be surgically sterile (vasectomy with medical assessment confirming 
surgical success) or have a female partner who is postmenopausal or permanently sterile 
(bilateral oophorectomy, bilateral salpingectomy or hysterectomy), OR if sexually active 


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with female partner(s) of childbearing potential must agree from Study Day 1 through 
20 weeks after the last dose of study drug to practice contraception with:
●
Condom use.
●
True abstinence:  Refraining from heterosexual intercourse-when this is in line 
with the preferred and usual lifestyle of the subject.  (Note:  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods 
by the female partner and withdrawal are not acceptable).
●
Additionally, male subject agrees not to donate sperm from Study Day 1 
through 20 weeks after the last dose of study drug.
5.3
Efficacy, Pharmacokinetic, Biomarker, Pharmacogenetic 
and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Appendix C.
5.3.1.1
Study Procedures
Study visits may be impacted due to the COVID-19 pandemic may include changes such 
as phone or virtual visits, visits at alternative locations, or changes in the visit frequency 
and timing of study procedures.  Additional details are provided in the subsequent 
sections of this protocol.  Every effort should be made to ensure the safety of subjects and 
onsite staff, while maintaining the integrity of the study.  If visits cannot be conducted 
onsite due to travel restrictions or other pandemic-related reasons, the updates below on 
how to proceed should be followed.
Identification of Study Partner
To be eligible for screening, each subject must have a study partner (e.g., family member 
or friend), who has frequent contact with the subject (a minimum of 10 hours per week) 


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and who will provide information as to the subject's cognitive and functional abilities.  
The designated study partner must be sufficiently familiar with the subject (as determined 
by the investigator) to provide accurate data.  The site must obtain the name and contact 
information of the study partner and the source documents must record the study partner's 
consent to satisfy the responsibility of the study partner in this study.
Medical History
For all subjects, a complete medical history, including subject's history of cognitive 
impairment and any medications taken for AD or MCI, will be obtained at Screening.  In 
addition, history of alcohol and tobacco use will be obtained from each subject.  The 
medical history will be updated on Day 1.  The updated medical history on Day 1 will 
serve as the baseline for clinical assessment.
Ongoing concomitant medication (prescription or over-the-counter, including vitamins 
and herbal supplements) use and any medication stopped within 30 days prior to screening 
and any monoclonal antibodies or other biologics within 6 months prior to the study drug 
administration will also be recorded.
Hepatitis Screen
HBsAg and HCV Ab tests will be performed at Screening.  The hepatitis test panel will be 
performed by a certified laboratory.
Physical Examination
Physical examinations will be performed as indicated in the Study Activities Table 
(Appendix C).  A symptom-directed physical examination will be performed when 
necessary.  The last physical examination performed at screening prior to the first dose 
will serve as the baseline physical examination for clinical assessment.  Any significant 
physical examination findings after dosing begins will be recorded as adverse events.
Height will be measured at Screening; the subject will not wear shoes.


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Body weight will be measured as indicated in the Study Activities Table (Appendix C).  
The subject will wear lightweight clothing and no shoes during weighing.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event physical examinations may not be performed due to study modifications 
related to the COVID-19 pandemic, these examinations should be completed at the next 
onsite visit.
Neurological Examination
A neurological examination will be performed at the times indicated in the Study 
Activities Table.  The neurological exam performed on Day 1 will serve as the baseline 
for clinical assessment.  Symptoms identified during the Screening Period will not be 
recorded as adverse events; however, new symptoms or current symptoms that change in 
severity or frequency after the first day of study drug will be recorded as adverse events.
The neurological examination will assess:
●
Mental Status – assessment of orientation, speech, and memory
●
Cranial nerves – assessment of cranial nerves II-XII
●
Motor system – brief assessment of tone and strength, tremors
●
Sensory system – brief survey for light touch and temperature
●
Reflexes – assessment of deep tendon reflexes and plantar responses (Babinski 
sign)
●
Coordination – assessment of upper and lower extremities, including 
assessment for tremor
●
Gait – assessment of tandem gait
●
Station – assessment of posture and stability


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COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event neurological examinations may not be performed due to study modifications 
related to the COVID-19 pandemic, these examinations should be completed at the next 
onsite visit.
Vital Signs
Body temperature, blood pressure and pulse will be measured at the times indicated in the 
Study Activities Table (Appendix C).  The vital signs measurements just prior to dosing 
on Study Day 1 will serve as the baseline measurements for clinical assessment.
Blood pressure and pulse rate will be measured after the subject has been sitting for at 
least 5 minutes.  For visits in which both vital signs and blood sample(s) are collected, 
vital signs should be obtained prior to any blood collection.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event vital signs may not be obtained due to study modifications related to the 
COVID-19 pandemic, these measurements should be obtained at the next onsite visit.
12-Lead Electrocardiogram (ECG)
A 12-lead resting ECG will be obtained as indicated in the Study Activities Table.  For 
visits in which both ECGs and blood sample(s) are collected, ECGs should be obtained 
prior to any blood collection.  ECGs will be recorded after the subject has been supine for 
at least 5 minutes.  The subject should be instructed to remain completely stationary 
during the recording, without talking, laughing, deep breathing or swallowing during the 
time of recording (10 seconds).  The ECG measurements obtained on Day 1 will serve as 
the baseline for clinical assessment.
The ECGs will be read by a qualified local physician for an immediate safety assessment 
and also by the central reader who will provide a full report to the site within 
3 business days.


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COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event 12-lead ECG may not be performed due to study modifications related to the 
COVID-19 pandemic, this procedure should be completed at the next onsite visit.
Local ECG Reading:
A qualified physician at the study site will interpret and document his/her global 
interpretation on the ECG tracing, based on the following conventions, as appropriate:
●
Normal ECG
●
Abnormal ECG – not clinically significant
●
Abnormal ECG – clinically significant
This physician will sign and date the ECG tracings.  Each ECG should be reviewed by the 
physician before the study drug administration to ensure the tracing is interpretable and no 
acute, medically serious condition is present.  The investigator's (or physician designee's) 
initial interpretation of the ECG will be the basis of any decisions related to the study 
conduct and treatment of the study subjects (e.g., eligibility at baseline, AE assessment, 
etc.).
Central ECG Reading:
Site personnel will transmit ECG data to an ECG central laboratory for central processing 
and reading by a qualified cardiologist (central reader) who, also blinded by study drug 
assignment, will independently review each ECG.  QT interval corrected for heart rate 
(QTc) will be determined using Fridericia's correction method (QTcF).  The central ECG 
laboratory's data will be entered into the database.  The central reader will also provide the 
interpretation of the ECG (i.e., "Normal" or "Abnormal").  The central ECG laboratory 
will send the ECG report to the site within 3 business days.  The Investigator (or 
physician designee) will review the central reader's report/assessment and document 
his/her review by signing and dating the central ECG laboratory report.  The investigator 
should review and reconcile if necessary his/her interpretation of the ECG 


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(normal/abnormal) with the central ECG laboratory in case of relevant divergent 
assessments and reconcile as he/she determines is appropriate.
ECGs will be collected as single ECGs as follows:
Cohort 1 Subjects:
●
Screening
●
Day 1 (Dose 1)
○
Pre-dose (just prior to the start of infusion) and within 15 minutes after the 
end of infusion prior to the PK sample collection)
●
Days 5 and 15
○
Collection should be scheduled as close as possible to the corresponding 
time of the post infusion collection on Day 1.
●
Days 29 and 57 (Doses 2 and 3)
○
Pre-dose (just prior to the start of infusion)
●
Day 85 (Dose 4)
○
Pre-dose (just prior to the start of infusion) and within 15 minutes after the 
end of infusion (prior to the PK sample collection)
●
Weeks 24, 36, 48, and 72 (Doses 7, 10, 13 and 19 respectively)
○
Pre-dose (just prior to the start of infusion)
●
Week 96 (Study Completion Visit)
●
Follow-up (Week 104)
Cohort 2 Subjects:
●
Screening
●
Day 1 (Dose 1)
○
Pre-dose (just prior to the start of infusion) and approximately within 
15 minutes after the end of infusion).
●
Days 29, 57, 85 and Weeks 24, 36, 48, and 72 (Doses 2, 3, 4, 7, 10, 13 and 
19 respectively)


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○
Pre-dose (just prior to the start of infusion).
●
Week 96 (Study Completion Visit)
●
Follow-up (Week 104)
Urine Screens for Drugs of Abuse 
Urine specimens will be collected at times indicated in the Study Activities Table 
(Appendix C) to test for drugs of abuse by the central laboratory chosen for the study.  
Any subject testing positive for cocaine metabolites, phencyclidine, opiates, barbiturates, 
benzodiazepines, marijuana metabolites, amphetamines, or methadone prior to 
randomization, will be excluded from the study, unless the detected drug has been 
appropriately prescribed by a physician.  Additional drug screens may be obtained at the 
discretion of the investigator.  With the exception of subjects who are regularly taking 
opiates for pain control, any subjects testing positive during the study will be considered 
for premature discontinuation in consultation with the AbbVie TA MD.
Subjects should be instructed to abstain from drinking any alcoholic beverages for 
24 hours prior to each visit.
Clinical Laboratory Tests
Samples will be obtained at a minimum for the clinical laboratory tests outlined in Table 3
at the time points designated in the Study Activities Table (Appendix C).  
A certified laboratory will be utilized to process and provide results for the clinical 
laboratory tests.  Laboratory reference ranges will be obtained prior to the initiation of the 
study.  The baseline laboratory test results for clinical assessment for a particular test will 
be defined as the last measurement prior to the initial dose of study drug.


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Table 3.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysis
Hematocrit
Hemoglobin
Red blood cell (RBC) count
White blood cell (WBC) count
Neutrophils
Bands (if detected)
Lymphocytes
Monocytes
Basophils (if detected)
Eosinophils (if detected)
Platelet count (estimate not 
acceptable)
Mean corpuscular volume 
(MCV)
Mean corpuscular hemoglobin 
concentration (MCHC)
Prothrombin time (PT)
Activated partial thromboplastin 
time (aPTT)
PT/INR (Prothrombin 
Time/International 
Normalized Ratio)
Blood urea nitrogen (BUN)
Creatinine
Total bilirubin
Albumin
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphate
Uric acid
Cholesterol
Total protein
Glucose
Triglycerides
Bicarbonate/CO2
Chloride
Thyroid Stimulating Hormone 
(TSH)*
Thyroxine (T4)*
Vitamin B12 (cobalamin)*
Specific gravity
Ketones
Ph
Protein
Glucose
Blood
Microscopic examination, if 
dipstick results are positive
CSF Basic Labs**
RBC, WBC with differential
Total Protein
Albumin
Glucose
Reference Tests if 
Vitamin B12 is Under the 
Lower Limit of Normal 
Range
Methylmalonic Acid (MMA)
Homocysteine
Hepatitis Tests*
Hepatitis B surface antigen 
(HBsAg)
Hepatitis C virus antibody 
(HCV Ab)

Any positive HCV Ab test 
must be confirmed by a 
positive Hepatitis-C Viral 
ribonucleic acid (RNA) 
polymerase chain reaction 
(PCR) Qualitative test for 
HCV
*
Screening only.
**
Done locally according to the local laboratory specifications and capabilities.


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Abnormal Findings
For any laboratory test value outside the reference range that the investigator considers to 
be clinically significant:
●
The investigator will repeat the test to verify the out-of-range value.
●
The investigator will follow the out-of-range value to a satisfactory clinical 
resolution.
●
A laboratory test value that requires a subject to be discontinued from the 
study or requires a subject to receive treatment will be recorded as an adverse 
event.
For all laboratory abnormalities the investigator will determine if they indicate a new 
disease process, an exacerbation or worsening of an existing condition, or require further 
action to be taken and therefore need to be reported as adverse events.  Accordingly, for 
any values outside of the reference range, the Investigator will indicate on the report if the 
result is clinically significant (CS) or not clinically significant (NCS).  If a laboratory 
abnormality meets criteria for a potentially clinically significant (PCS) laboratory value, 
as defined in Appendix D, the investigator must either report an associated adverse event 
or document in source the reason(s) the finding was not considered an adverse event.
Any laboratory value that remains abnormal at Premature Discontinuation/End of Study 
and was judged to be clinically significant will be followed according to accepted medical 
standards until resolution of the abnormality.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event clinical laboratory tests may not be performed due to study modifications 
related to the COVID-19 pandemic, these tests should be completed at the next onsite 
visit.


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If laboratory tests cannot be performed, study drug may be administered to subjects if the
investigator has reviewed all prior laboratory results and confirms there are no safety 
concerns.
Lumbar Puncture (LP)
Lumbar punctures are required for subjects enrolled in Cohort 1 and are optional for 
subjects enrolled in Cohort 2.  For all Cohort 1 subjects and subjects agreeing to LPs in 
Cohort 2, LPs to collect CSF will be performed at time points indicated in the Study 
Activities Table (Appendix C).  Subjects will undergo a LP during Screening (preferably 
after all other entry criteria have been satisfied and after MRI and PET scan and any time 
prior to Day 1), after the 4th dose and after the final dose if administered at least 3 months 
after the previous LP.  A sample of CSF will be collected according to the CSF Collection 
Manual provided to the study site by the sponsor.  Computed tomography (CT)/fluoro-
guided lumbar puncture can be used at the discretion of the local clinical site staff.  Basic 
neurochemical CSF analyses will be performed locally according to the local laboratory 
capabilities at the applicable clinical site after each lumbar puncture/CSF collection.  
These measures may include cell counts (red blood cell [RBC] and white blood cell 
[WBC] with differential), total protein, albumin and glucose.  Other CSF measurements 
(e.g., ABBV-8E12 concentration, tau and other exploratory biomarkers) will be analyzed 
by the applicable designated laboratory.
Headaches occur commonly following withdrawal of CSF.  Subjects may be treated with 
the following, such as:  IV hydration, IV caffeine administration, bed-rest and analgesics.  
Uncommonly a blood patch (injection of some of the subject's blood to patch the CSF 
leak) may be needed.  Potential but rare risks of lumbar puncture include infection, 
damage to nerves in the back, and bleeding into the CSF space.  The risk of these is much 
less than 1%.11
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event lumbar puncture may not be performed due to study modifications related to 
the COVID-19 pandemic, this procedure should be completed at the next onsite visit.


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Magnetic Resonance Imaging (MRI)
For all subjects, a Magnetic Resonance Imaging (MRI) will be obtained at time points 
indicated in the Study Activities Table (Appendix C) and interpreted by a radiologist or 
neurologist.  Subjects will be queried to assure they do not have specific contraindications 
for MRI.  The Screening MRI should be completed after all other relevant screening 
procedures (except for the Amyloid PET and LP) have been completed and reviewed by 
the investigator.
The Screening MRI assessment will rule out the presence of any intracranial masses that 
might preclude the subject from undergoing a lumbar puncture and exclude focal or 
diffuse processes that could interfere with the diagnosis of AD or MCI, including signal 
abnormalities on FLAIR or T2 weighted images consistent with infectious, vascular, 
neoplastic or other degenerative processes.  The 3D T1 weighted sequences will also be 
acquired for volumetric analysis that will enable a quantitative assessment of the whole 
and regional brain volume.
On-treatment safety MRI analysis will be performed at the time points indicated in the 
Study Activities Table.  On-treatment volumetric MRI analysis will be performed at the 
time points indicated in the Study Activities Table (Appendix C) starting from Week 28.
The MRI scan should be done prior to the LP otherwise at least a 3-day window between 
the LP and the MRI appointment is necessary.  Details of the MRI procedures will be 
described in the MRI Procedures Manual provided by the Sponsor.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event MRI may not be performed due to study modifications related to the 
COVID-19 pandemic, this procedure should be completed at the next onsite visit.
Positron Emission Tomography (PET) Amyloid Imaging
For all subjects without an acceptable historical amyloid positive PET scan, an amyloid 
PET scan will be obtained at Screening.  The acceptability of the historical PET scan will 


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be determined by the central reader.  Even though amyloid is not a target for 
ABBV-8E12, amyloid imaging is included for subject selection to increase the diagnostic 
and prognostic accuracy in the early stages of AD.  It allows for a better differential 
diagnosis of cognitive impairment and identification of individuals that are at increased 
risk of progressive cognitive decline.
Subjects will be queried to assure they do not have specific contraindications for PET 
such as a history of radiation therapy within the past year, or a history of receiving 
radiation for research purposes within the past year.  The amyloid PET scan should be 
completed after all other relevant screening procedures including screening MRI scan 
have been completed and reviewed by the investigator.
If the LP and PET scan are done on the same day, the LP should be completed prior to the 
PET scan; otherwise there should be at least 12 hours between the LP and the PET scan.  
Details of PET procedures will be described in the Amyloid PET Procedures Manual 
provided by the Sponsor.
Positron Emission Tomography (PET) Tau Imaging
Tau PET imaging will be conducted only at sites selected to participate by AbbVie based 
on scientific, technical and logistical considerations.  For all eligible subjects, tau PET 
imaging will be conducted at Screening, after completion of Weeks 44 (Dose 12) and 96 
as indicated in the Study Activities Table (Appendix C).  Subjects who did not complete 
tau PET imaging during the screening period may still have tau PET imaging performed 
at subsequent visits.
Tau deposition in the brain, unlike amyloid, tracks closely with the cognitive decline of 
AD.  Preclinical data suggest that ABBV-8E12 decreases tau seeding activity in vitro and 
overall tau pathology in vivo.  Tau PET imaging will be used to assess any signals or 
trends of ABBV-8E12 to slow the accumulation (amount) and extent (spread) of tau 
deposits in the brain or potentially remove existing tau deposits 


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The tau PET scan at Screening should be carried out no longer than 12 weeks prior to 
administration of the first dose.
If the LP and tau PET scan are done on the same day, the LP should be completed prior to 
the tau PET scan; otherwise there should be at least 12 hours between the LP and the tau 
PET scan.  Details of tau PET procedures will be described in the tau PET Procedures 
Manual provided by the Sponsor.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event the tau PET scan may not be performed due to study modifications related to 
the COVID-19 pandemic, this procedure should be completed at the next onsite visit.
Retinal Imaging for Amyloid
Non-invasive retinal imaging is currently utilized to screen for a number of retinal 
diseases and is widely available.  Recently, retinal imaging has shown some utility in 
detecting trace amounts of beta amyloid in the retinal epithelial layer.  Retinal Aβ plaques 
have been identified in postmortem eyes from AD patients and in amyloid over-
expressing transgenic mice.  Preliminary data suggest amyloidogenic densities can be 
detected in the retina of early AD patients.  An exploratory retinal imaging test designed 
to detect trace amounts of amyloid may be conducted only at sites selected to participate 
by AbbVie based on scientific, technical and logistical considerations.  For all eligible 
subjects at participating sites, the retinal imaging test will be obtained during screening or 
within a 6-month window of initial randomization data.  An additional blood sample will 
also be collected.  This assessment will examine the relationship between retinal amyloid 
imaging and brain amyloid PET imaging results.  Only retinal imaging for amyloid will 
be conducted.  One eye drop will be administered in each eye for dilation.  As a result, the 
retinal imaging test should not be carried out prior to cognitive testing if scheduled on the 
same day.  If the retinal imaging test is scheduled during planned blood and CSF 
collections, the retinal imaging test should be completed after biofluid sampling.  Details 
for the retinal imaging procedure will be provided in a separate manual and will be 
conducted by trained site personnel.


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COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event the retinal scan may not be performed due to study modifications related to 
the COVID-19 pandemic, this procedure should be completed at the next onsite visit.
Diagnostic Tools and Rating Scales
Prior to the start of the study, designated raters will be certified in the use of all scales 
used in this study.  The objective of this certification/training is to establish uniformity 
across sites in the administration, interpretation and scoring of these rating instruments.  
Raters who cannot participate in pre-study certification/training or raters who become 
involved in the study after training at the investigator's meeting will not be permitted to 
perform any study-specified ratings until they have satisfactorily completed an 
individualized certification/training program designed by the central trainers, approved by 
AbbVie and supervised by the investigator or his/her designee.  It is the responsibility of 
the investigator to ensure that the raters at his/her site are appropriately trained and 
certified in the use of selected rating scales.  Every effort must be made by the 
investigative sites to ensure that each subject is rated by the same rater throughout their 
participation in the study.
AbbVie, in conjunction with the rater training vendor, will determine the minimum rater 
qualifications for each of the rating scales.  All raters must meet these qualifications prior 
to participation in the training process.  The qualifications of the raters will be verified 
through the training vendor.  Individual exceptions to these requirements must be 
approved by the Sponsor via the training vendor.  The order of the administration of 
scales at each visit should be consistent throughout the study.
Administration of selected scales will be audio recorded (as permitted by local 
regulations) to allow for central review of the data to ensure consistency and reliability.
Assessments will be performed at the times indicated in Table 4.


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Table 4.
Diagnostic Tools and Scale Administration Timing
Recommended 
Order of 
Administration
Approximate 
Administration 
Timea (Minutes)
Patient/ Study 
Partner
Screening 
Day –84 –
Day –8
Day –7 to 
Day 1 (Prior 
to Infusion)b
Week
12
Week 
24
Week
36
Week 
48
Week 
72
Week 
96
CDR
1
45 – 75
Both
X
X
X
X
X
X
RBANS
2
25
Patient
X
X
X
X
X
X
UPSA – Brief
3
10 – 15
Patient
X
X
X
ADAS-Cog-14
4
30 – 60
Patient
X
X
X
X
X
MMSE
5
10 – 15
Patient
X
X
X
X
X
X
ADCS-CGIC-MCI
6
10 – 15
Both
X
X
X
C-SSRSc
7
5 – 20
Patient
X
X
X
X
X
X
FAQ
d
6 – 10
Study partner
X
X
X
X
X
NPI  
d
15
Study partner
X
X
X
X
X
ADCS-MCI-ADL-24
d
30 – 45
Study partner
X
X
X
MHIS (I)
d
5
N/A clinician 
assessed
X
Digital clock drawing
d
5
Patient
X
X
X
X
X
X
X
X
ADAS-Cog-14 = Alzheimer's Disease Assessment Scale (14-Item) Cognition portion; ADCS-CGIC-MCI = Alzheimer's Disease Cooperative Study Clinician's Global Impression 
of Change for Mild Cognitive Impairment; ADCS-MCI-ADL-24 = 24-item Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted for Patients with 
Mild Cognitive Impairment; CDR = Clinical Dementia Rating; C-SSRS = Columbia-Suicide Severity Rating Scale; FAQ = Functional Activities Questionnaire; MHIS = Modified 
Hachinski Ischemic Scale; MMSE = Mini-Mental State Examination; N/A = not applicable; NPI = Neuropsychiatric Inventory; RBANS = Repeatable Battery for Assessment of 
Neuropsychological Status; UPSA Brief = University of California San Diego Performance Based Skills Assessment, Brief Version
a.
Breaks should be taken as necessary.
b.
Assessments will be done once during this time frame and can be administered on any day, but all must be done on the same day.
c.
The C-SSRS will be done at each visit throughout the study (see Study Activities Table Appendix C for all time points).
d.
Scale may be administered/assessed at any time during the visit.
I – Administered during Screening to assess inclusion criteria only.


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The diagnostic tools and rating scales include the following:
Clinical Dementia Rating (CDR)12
The Clinical Dementia Rating (CDR) is a numeric scale used to quantify the severity of 
symptoms of dementia.  A qualified health professional will assess a patient's cognitive 
and functional performance in six areas:  memory, orientation, judgment and problem 
solving, community affairs, home and hobbies, and personal care.  The CDR scale gives a 
score from 0 – 3 for each of the six areas.  The sum of these six areas, the CDR sum of 
boxes (CDR-SB) score can range from 0 – 18.
Using a scoring algorithm, a CDR global score (range from 0 – 3) will be generated.  The 
subject must have a CDR global score of 0.5 at Screening to be eligible for study 
participation.  The CDR-SB score will be calculated at each time point.  The CDR will be 
administered to both the patient and the study partner at the times indicated in Table 4.
Alzheimer's Disease Assessment Scale (14-Item) Cognition Portion; (ADAS-Cog-14)13
The ADAS-Cog was designed to assess the cognitive impairments most common in AD.  
The ADAS-Cog is a subscale of the ADAS, which focuses on cognitive functioning and 
memory. 
The ADAS-Cog-14 includes the original 11 items from the ADAS-Cog-11 [1.  Spoken 
language ability, 2.  Comprehension of spoken language, 3.  Recall of test instructions, 
4.  Word-findings difficulty in spontaneous speech, 5.  Following commands, 6.  Naming 
objects and fingers, 7.  Constructional praxis, 8.  Ideational praxis, 9.  Orientation, 
10.  Word-recall task, 11.  Word-recognition task] and includes three additional tasks 
[12.  Number cancellation task, 13.  Delayed word recall task, 14.  Executive functioning], 
for increased sensitivity in MCI patients.  The total score of the 14-item ADAS-cog 
ranges from 0 to 90, with a higher score representing greater impairment.  The ADAS-
Cog-14 will be administered to the patient at the times indicated in Table 4.


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Mini Mental State Exam (MMSE)14,15
The MMSE is a brief, 30-point questionnaire, administered by a trained rater, which 
provides a quantitative measure of cognitive status in adults and is widely used to screen 
for cognitive impairment and to estimate the severity of cognitive impairment at a given 
point in time in AD subjects.  The subject must have a score of 22 to 30, inclusive at 
Screening to be eligible for study participation.  Lower scores indicate greater 
impairment.  The MMSE will be administered to the patient at the times indicated in 
Table 4.
Functional Activities Questionnaire (FAQ)16,17
The FAQ measures level of assistance (functional disability) needed for carrying out 
instrumental activities in daily living (iADLs).  The FAQ score ranges from 0 – 30 and 
consists of 10 items (each scored from 0 – 3), which measure a specific iADL in the past 
4-weeks:  [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 from 0 – 3 as follows:  0 – normal; 1 – has difficulty, but does by 
self; 2 – requires assistance; or 3 – dependent.  The FAQ will be administered to the study 
partner by a trained interviewer.  Higher scores indicate a greater requirement of 
assistance.  The FAQ will be administered to the study partner at the times indicated in 
Table 4.
Neuropsychiatric Inventory (NPI)18-20
The NPI was developed to assess the presence of psychopathology in subjects with AD 
and other dementias.  The scale is based on responses from the study partner and should 
be administered in the absence of the subject.  The NPI is used to assess changes in the 
subject's behavior that have occurred in a defined period of time (4 weeks).  The NPI 
assesses 12 behavioral domains on the dimensions of frequency and severity.  Frequency 


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is rated on a scale where 0 = absent, 1 = occasionally, 2 = often, 3 = frequently, 4 = very 
frequently.  Severity is rated on a scale where 0 = absent, 1 = mild, 2 = moderate, 3 = 
severe.  For each of the domains, 3 scores will be obtained:  frequency, severity, and total 
(product of frequency and severity; ranges from 0 to 12).  A total NPI score can be 
calculated by summing the domain total scores (ranges from 0 to 144 with a lower score 
desirable).  The reliability, content validity and concurrent validity of the inventory has 
been established, and it has been shown to be sensitive to treatment effects.  The NPI will 
be administered to the study partner at the times indicated in Table 4.
24-Item Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted 
for Patients with Mild Cognitive Impairment (ADCS-MCI- ADL-24)21-23
The ADCS-MCI-ADL-24 is a 24-item, study partner-based assessment of activities of 
daily living designed specifically for AD patients and is completed by a trained rater.  The 
scale assesses functional activities such as cooking, household chores, shopping, keeping 
appointments, social interactions and hobbies.  Items are assessed according to whether 
they were performed in the past 4 weeks and, if so, some items are further assessed as to 
whether they were performed independently, with supervision, or with physical help.  
Scores on the ADCS-ADL-MCI range from 0 to 69, where higher score indicates greater 
capability to carry out activities of daily living.  The scale has good test-retest reliability, 
was designed for use across severities of AD, and has been demonstrated to detect drug 
effects in clinical trials.  The ADCS-MCI-ADL-24 will be administered to the study 
partner at the times indicated in Table 4.
Alzheimer's Disease Cooperative Study Clinical Global Impression of Change for Mild 
Cognitive Impairment (ADCS-CGIC-MCI)24,25
The instrument covers four major domains:  1.  General condition, 2.  Cognition, 
3.  Behavior, and 4.  Social and daily functioning.  Scoring is based on a 7-point Likert 
Scale:  1, marked improvement; 2, moderate improvement; 3, minimal improvement; 
4, no change; 5, minimal worsening; 6, moderate worsening; 7, marked worsening.  
Higher score indicates greater worsening.


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At baseline, the clinician interviews the subject and study partner about baseline status for 
later reference.  At baseline only, clinical information about the subject may be used, 
including medical history, physical and neurological examination, and other ratings done 
at screening.  At interval assessments, the subject is interviewed first, followed by the 
informant.  After completing the worksheets, the clinician records his/her clinical 
impression of change from baseline on the 7-item scale, referring only to his/her own 
baseline information when making the assessment, without consulting other study 
personnel and blinded to possible medication or adverse effects.  The instrument has 
5-items for baseline and 4-items for the post-baseline assessment.  The ADCS-CGIC-MCI 
will be administered to both the patient and the study partner at the times indicated in 
Table 4.
Modified Hachinski Ischemic Scale (MHIS)26,27
The MHIS is a brief clinical scale used to distinguish vascular dementia from non-
vascular dementia by assessing the presence of concurrent vascular risk factors, focal 
neurological symptoms or signs suggestive of prior stroke, or a history of strokes.  An 
experienced clinician will assess the MHIS for all subjects.  Subjects must have a score 
≤4 to be eligible for study participation.  The MHIS will be administered at the times 
indicated in Table 4.
Repeatable Battery for Assessment of Neuropsychological Status (RBANS)28
The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a 
25-minute, standardized neurocognitive battery with North American population-based 
normative data.  The RBANS measures five neurocognitive domains, with age-based 
scaling.  Twelve subtests measure cognitive decline or improvement across the following 
domains:
1.
Immediate Memory – List Learning and Story Memory,
2.
Visuospatial/Constructional – Figure Copy and Line Orientation,
3.
Language – Picture naming and Semantic Fluency,


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4.
Attention – Digit Span and Coding, and
5.
Delayed Memory – List Recall, List Recognition, Story Memory, and Figure 
Recall.
The RBANS has been shown to be effective at both detecting and characterizing dementia 
of different etiologies.  The Delayed Memory domain has been shown to be particularly 
sensitive to discriminating mild cognitive impairment (MCI) due to AD from controls, 
and also is predictive of cerebral amyloid burden.  The RBANS has been translated into 
over 25 different languages, with extensive clinical validity data from a wide variety of 
geographic regions.  The RBANS will be administered to the patient at the times indicated 
in Table 4.
University of California's Performance Based Skills Assessment, Brief Version (UPSA –
Brief)29
The UPSA-Brief is a performance-based instrument which uses a series of tasks and role-
play scenarios to evaluate a person's functional capacity in two areas of basic living skills 
(i.e., financial skills and communication skills).  The UPSA-Brief will be administered to 
the patient at the times indicated in Table 4.
Columbia-Suicide Severity Rating Scale30
The C-SSRS is a systematically administered instrument developed to track suicidal 
adverse events across a treatment study.  The instrument is designed to assess suicidal 
behavior and ideation, track and assess all suicidal events, as well as the lethality of 
attempts.  Additional features assessed include frequency, duration, controllability, reason 
for ideation, and deterrents.  The C-SSRS is considered a low-burden instrument as it 
typically takes less than 5 minutes to administer.  The C-SSRS questionnaire will be 
administered at the time points indicated in the Study Activities Table (Appendix C).
Any subject noted to have suicidal ideation with plan within the prior month, either via 
answering "yes" to questions 4 or 5 to the suicidal ideation portion of the C-SSRS or via 


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clinical interview, will be evaluated immediately by the study physician.  The AbbVie TA 
MD will also be informed.  Appropriate steps will be taken to protect the subject, 
including but not limited to possible discontinuation from the study and referral for 
appropriate psychiatric care.  Any such subject at Screening or on Day 1 will also be 
excluded from the study.
Digital Clock Drawing Test (dCDT)
The clock drawing test (CDT) is a well-established tool that assesses an individual's 
cognitive function and has been studied extensively in patients with various neurological 
disorders, including AD.31  In this study, a digitized ballpoint pen will be used to capture 
data points as subjects complete both the Command and Copy conditions of the CDT and 
associated software will be used to analyze the entire drawing process and final output.  
Preliminary data suggest that this approach may allow for the early detection of subtle 
nuances in cognitive performance beyond successful task completion as assessed in the 
traditional CDT.32
The dCDT will be conducted only at sites selected to participate by AbbVie based on 
scientific, technical, and logistical considerations.  For all eligible subjects, the test will be 
conducted by trained personnel at the Screening, Baseline, Week 12, Week 24, Week 36, 
Week 48, Week 72, and Week 96 visits as indicated in the Study Activities Table 
(Appendix C) and Table 4.  While it is ideal to have the dCDT administered starting with 
the Screening visit for all participating subjects, those who did not complete the test at 
Screening may do so at the subsequent visits.  Details for the administration procedure 
will be provided in a separate manual.  
The results of all screening and evaluations at the time of the first study drug 
administration must be within clinically acceptable limits, upon review by the investigator 
before a subject can be administered study drug.  Subjects will not be enrolled in the study 
if laboratory or other screening results are unacceptable.  Subjects who meet the inclusion 
criteria and do not meet any of the exclusion criteria will proceed to randomization 
(Section 5.5.3).  Patients who do not proceed to randomization may be asked to provide 


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an optional consent for sponsor to retain clinical and biomarker screening data for 
exploratory research.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If scale administration is not performed due to study modifications related to the 
COVID-19 pandemic, the scale(s) should be completed at the next onsite visit.  Should a 
virtual visit be conducted, the investigator should refer to the table below for scales that 
may be administered remotely.
Scale
May be Administered Via Phone or Video 
Conference
ADAS-Cog-14
No
ADCS-CGIC-MCI 
Yes
ADCS-MCI-ADL-24
Yes
CDR
Yes
C-SSRS
Yes
dCDT
No
FAQ
Yes
MMSE
No
NPI
Yes
RBANS
No
UPSA – Brief
No
ADAS-Cog-14 = Alzheimer's Disease Assessment Scale (14-Item) Cognition Portion; ADCS-CGIC-MCI = Alzheimer's 
Disease Cooperative Study Clinician's Global Impression of Change for Mild Cognitive Impairment; ADCS-MCI-ADL-
24 = 24-item Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted for Patients with Mild 
Cognitive Impairment; CDR = Clinical Dementia Rating; C-SSRS = Columbia-Suicide Severity Rating Scale; 
dCDT = Digital clock drawing test; FAQ = Functional Activities Questionnaire; MMSE = Mini-Mental State 
Examination; NPI = Neuropsychiatric Inventory; RBANS = Repeatable Battery for Assessment of Neuropsychological 
Status; USPA Brief = University of California San Diego Performance Based Skills Assessment, Brief Version


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5.3.1.2
Collection and Handling of Biomarker and Pharmacogenetic 
Research Samples
Blood and CSF Biomarker Samples
Blood and CSF samples will be collected as outlined in the Study Activities Table 
(Appendix C) and may be utilized to evaluate known and/or novel disease-related or drug-
related biomarkers.  The biomarker rationale will be discussed in the Biomarker Research 
Variables Section (Section 5.3.6).
All biomarker samples should be collected, processed, labeled and shipped as outlined in 
the study-specific laboratory manual, which will be provided separately.
AbbVie (or people or companies working with AbbVie) will store the samples in a secure 
storage space with adequate measures to protect confidentiality.  The samples may be 
retained while research on ABBV-8E12, or drugs of this class, or AD or related 
conditions continues, but for no longer than 20 years from the end of the study, or per 
local requirement.
Blood samples (10 mL) will be collected at Screening and (20 mL) prior to the start of the 
infusion (0 hour, no more than 30 minutes prior to the start of the infusion) at the time 
points indicated in the Study Activities Table (Appendix C).  Blood samples collected at 
Week 96 (Study Completion/PD Visit) may be collected at any time during that visit.
CSF samples (~24 mL) will be collected by lumbar puncture at the time points indicated 
in the Study Activities Table (Appendix C).  CSF samples collected at Week 14 will be 
approximately 14 days following the fourth dose.  In Cohort 2, CSF sample collection is 
optional.
Apolipoprotein E (APOE) Pharmacogenetic Sample
One (required) 4 mL whole blood sample will be collected from each subject at study 
Day 1 for APOE pharmacogenetic analysis.  This sample will not be used for any testing 
other than APOE genotypes. 


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COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event blood and optional CSF biomarker samples may not be collected due to study 
modifications related to the COVID-19 pandemic, these samples should be obtained at the 
next onsite visit.
Optional Pharmacogenetic Research Samples
Subjects will have the option to provide additional samples for pharmacogenetic research.  
Subjects may still participate in the main study even if they decide not to participate in 
this optional research.
AbbVie (or people or companies working with AbbVie) will store the optional 
pharmacogenetic research samples in a secure storage space with adequate measures to 
protect confidentiality.  The samples will be retained while research on ABBV-8E12 (or 
drugs of this class) or AD and related conditions continues, but for no longer than 
20 years after study completion.  The procedure for obtaining and documenting informed 
consent for exploratory research samples is discussed in Section 9.3.
Optional whole blood samples (6.5 mL) for deoxyribonucleic acid (DNA) and ribonucleic 
acid (RNA) isolation will be collected at Screening, Day 1, Day 85, Week 36, Week 48, 
Week 72 and Week 96 (Completion/PD) Visit from each consenting subject at the time 
points indicated in the Study Activities Table (Appendix C).
All pharmacogenetic samples (mandatory and optional) should be collected, processed, 
labeled and shipped as outlined in the study-specific laboratory manual, which will be 
provided separately.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event optional pharmacogenetic research samples may not be collected due to study 
modifications related to the COVID-19 pandemic, these samples should be obtained at the 
next onsite visit.


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5.3.1.3
Confinement
No overnight confinement will be required for this study.
5.3.1.4
Meals and Dietary Requirements
No meals will be provided as part of this study and there are no dietary requirements or 
restrictions for this study.
5.3.2
Drug and Anti-Drug Antibody Concentration Measurements 
5.3.2.1
Collection of Samples for Analysis
Specific instructions for collection of blood samples and subsequent preparation and 
storage of the serum samples for the pharmacokinetic assays of ABBV-8E12 will be 
provided by the central laboratory, the Sponsor, or its designee.  
Blood Samples for ABBV-8E12 Assay
Blood samples, approximately 3 mL for ABBV-8E12 analysis will be collected by 
venipuncture as follows:
For Subjects Enrolled in Cohort 1
●
Day 1 (Dose 1)
○
Prior to the start of the infusion (0 hour, no more than 30 minutes prior to 
the start of the infusion), immediately after the end of the infusion (within 
15 minutes) and 1 and 2 hours after the end of the infusion.
●
Days 5 and 15
●
Days 29 and 57 (Doses 2 and 3)
○
Prior to the start of the infusion (0 hour, no more than 30 minutes prior to 
the start of the infusion).
●
Day 85 (Dose 4)
○
Prior to the start of the infusion (0 hour, no more than 30 minutes prior to 
the start of the infusion), immediately after the end of the infusion (within 
15 minutes) and 1 and 2 hours after the end of the infusion.


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●
Days 89 and 99
●
Weeks 16, 24, 36, 48, and 72 (Doses 5, 7, 10, 13 and 19, respectively)
○
Prior to the start of the infusion (0 hour, no more than 30 minutes prior to 
the start of the infusion).
●
Week 96 (Study Completion/PD Visit)
○
Sample may be collected anytime during the day.
●
Weeks 104 and 112 (Post-Treatment Follow-up Period)
○
Sample may be collected anytime during the day.
For Subjects Enrolled in Cohort 2
●
Days 1, 29, 85 and Weeks 24, 36, 48, and 72 (Doses 1, 2, 4, 7, 10, 13 and 19, 
respectively)
○
Prior to the start of the infusion (0 hour, no more than 30 minutes prior to 
the start of the infusion)
●
Week 96 (Study Completion/PD Visit)
○
Sample may be collected anytime during the day
●
Weeks 104 and 112 (Post-Treatment Follow-Up Period)
○
Sample may be collected anytime during the day.
Blood Samples for ABBV-8E12 Anti-Drug Antibodies (ADA) Assays
Blood samples, approximately 3 mL for ABBV-8E12 ADA analysis will be collected by 
venipuncture as follows:
For Subjects Enrolled in Cohort 1:
●
Days 1, 29, 57, 85 and Weeks 16, 24, 36, 48, and 72 (Doses 1, 2, 3, 4, 5, 7, 
10, 13 and 19, respectively)
○
Prior to the start of the infusion (0 hour, approximately 30 minutes prior to 
the start of the infusion).
●
Days 15, 89 and 99
●
Week 96 (Study Completion/PD Visit)


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○
Sample may be collected anytime during the day.
●
Weeks 104 and 112 (Post-Treatment Follow-Up Period)
○
Sample may be collected anytime during the day.
For Subjects Enrolled in Cohort 2:
●
Days 1, 29, 85 and Weeks 24, 36, 48, and 72 (Doses 1, 2, 4, 7, 10, 13 and 19, 
respectively)
○
Prior to the start of the infusion (0 hour, approximately 30 minutes prior to 
the start of the infusion).
●
Week 96 (Study Completion/PD Visit)
○
Sample may be collected anytime during the day.
●
Weeks 104 and 112 (Post-Treatment Follow-Up Period)
○
Sample may be collected anytime during the day.
CSF Samples for ABBV-8E12 Assay
CSF collection in subjects enrolled in Cohort 1 is required and CSF collection in subjects 
enrolled in Cohort 2 is optional.  
CSF samples will be collected as outlined in the Study Activities Table (Appendix C) by 
LP.  The collection time and procedures of CSF samples can be found in the Lumbar 
Puncture section of Study Procedures Section (Section 5.3.1.1).  As described in the 
Collection and Handling of Biomarker and Pharmacogenetic Research Samples Section 
(Section 5.3.1.2), CSF samples (~24 mL) collected at Week 14 will be approximately 
14 days following the fourth dose.
5.3.2.2
Measurement Methods
Analysis of Serum and CSF Samples
Serum and CSF concentrations of ABBV-8E12 and relative titers of ABBV-8E12 ADA in 
serum will be determined using validated methods at the Bioanalysis Department at 
AbbVie.  Any additional analytes may be analyzed using non-validated methods.  Serum 


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samples collected for ABBV-8E12 and ABBV-8E12 ADA analysis may be used for 
future assay development or validation activities.  ABBV-8E12 ADA samples upon 
request may be used for the analysis of neutralizing ADAs.
5.3.3
Efficacy Variables
The primary efficacy variable is CDR-SB score; the primary efficacy measurement will 
be the change from baseline up to final evaluation at Week 96/PD of the CDR-SB score.
Secondary efficacy variables include the ADAS-Cog-14 total score, RBANS total score, 
MMSE total score, FAQ score, NPI total score, ADCS-ADL-MCI total score, UPSA-B 
and ADCS-CGIC score.  The secondary efficacy variables obtained from these measures 
are detailed in Section 8.0.
5.3.4
Safety Variables
The following safety evaluations will be performed and safety information will be 
collected during the study:  adverse event monitoring (including infusion and allergic 
reactions), vital signs, physical examination, neurological examination, ECG, laboratory 
tests, C-SSRS and MRI assessments.
5.3.5
Pharmacokinetic Variables
Values for the following pharmacokinetic parameters of ABBV-8E12 will be estimated 
using non-compartmental methods:  maximum observed serum concentration (Cmax), the 
time to Cmax (peak time, Tmax), the area under the concentration time curve (AUC) over 
the dosing interval after the first and the fourth doses; the observed serum concentration at 
the end of a dose interval (Ctrough) after all doses.
A mixed-effect modeling approach will be used to estimate the population central value 
and the empirical Bayesian estimates of the individual values for ABBV-8E12 clearance 
(CL) and volume of distribution (V).


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The concentration of ABBV-8E12 in CSF will be summarized after the fourth dose and 
after the final dose if administered at least 3 months after the previous LP for subjects in 
Cohort 1.  LPs will be optional for subjects in Cohort 2, and the concentration of 
ABBV-8E12 in these CSF samples will be summarized, if available.
Additional parameters may be calculated if useful in the interpretation of the data.
5.3.6
Biomarker and Pharmacogenetic Research Variables
5.3.6.1
Biomarker Research Variables
CSF and Plasma Concentration Variables
CSF samples will be assayed for neurofilament light chain (NFL), free tau and total tau, 
and the ratio of free tau concentration to total tau concentration will also be statistically 
analyzed.  The assessments on free tau and the ratio of free tau to total tau will be done to 
investigate the binding of ABBV-8E12 to CSF tau.  Plasma samples will be assayed for 
tau and NFL to understand the relationship to disease progression and response to 
treatment.  Plasma samples may also be analyzed for plasma Abeta 40 and Abeta 42 to 
study relationship with amyloid PET positivity.
CSF and blood samples may be analyzed for biochemical or macromolecular factors 
(e.g., amyloid beta) related to the pharmacodynamics and safety of ABBV-8E12.  
Additional CSF, plasma and/or serum evaluations may include analyzing biomarkers 
related to the pathway(s) targeted by the study drug or believed to be related to the disease 
or to drug response.  Biomarker samples may also be used for non-genetic exploratory 
research to assess and generate prognostic, predictive, pharmacodynamic, or surrogate 
biomarker signatures or develop assays.  In addition, the information learned from 
analyzing these samples may be used to investigate factors impacting response to 
treatment, scientific questions related to various disease where ABBV-8E12 may be 
investigated, or in the development of new therapies.  The results of biomarker testing 
may not be reported in the clinical study report.


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Volumetric MRI
Baseline vMRI measurements and measurements on change from baseline in vMRI 
measurements for MRIs from Week 28 through Week 96 will be obtained.  Measurements 
will be obtained for whole brain, hippocampus and lateral ventricles.  Measurements may 
be obtained for additional regions.
Tau PET Imaging
The amount of tau deposits in a given region will be assessed by calculating a 
standardized uptake value ratio (SUVR) of each region.  The SUVR is a ratio between the 
standardized uptake values (SUV) of a target brain region relative to that of cerebellar 
cortex, which is considered as the reference tissue devoid of tau.  The SUV is calculated 
by normalizing the concentration of radioactivity in the region (KBq/mL) to the injected 
dose (BMq) and the subject's body weight (kg).  Due to the exploratory nature of these 
PET imaging endpoints, analyses will be performed for multiple brain regions, which will 
include, but not necessarily be limited to, 4 composite meta-regions that correspond to 
anatomical definitions of Braak stages III, IV, V, and VI.  Additional variables (e.g., 
proportion of voxels within a target region that have a SUVR greater than a pre-
determined cutoff value) that reflect the extent or spread of tau pathology will be assessed. 
Retinal Amyloid Imaging
Retinal optical images will be collected from each eye for a subset of subjects and 
subjected to image analysis.  Retinal imaging will be conducted during screening or 
within a 6 month window of randomization date.  The results of the retinal imaging test 
will be compared to amyloid PET imaging results, may be pooled with additional external 
data and reported in a separate addendum study report.
Digital Clock Drawing Test 
Data from a dCDT as a measure of cognitive function will be obtained from a subset of 
subjects.  In addition to assessing the performance of the treatments with respect to this 
instrument, the correlation of dCDT measures with other clinical rating scales and 


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biomarkers will be assessed.  Results for dCDT will be reported in a separate addendum 
study report.
5.3.6.2
Pharmacogenetic Research Variables
APOE allele status will be determined for each subject and analyzed as a factor 
contributing to the subject's response to study treatment.  The APOE genotype results may 
be analyzed as part of a multi-study assessment of APOE and response to ABBV-8E12 
treatment.  The results may also be used for the development of diagnostic tests related to 
ABBV-8E12, or other drugs in development for AD or related conditions.  The APOE 
genotype results may not be included in the study summary.
The optional pharmacogenetic DNA and RNA samples may be analyzed for known and 
novel genetic (DNA), epigenetic (DNA), and transcription (RNA) factors contributing to 
AD or the subject's response to ABBV-8E12, in terms of pharmacokinetics, efficacy, 
tolerability and safety.  Such genetic factors may include genes and genetic expression for 
drug metabolizing enzymes, drug transport proteins, genes within the target pathway, or 
other genes believed to be related to AD or drug response.  Some genes currently 
insufficiently characterized or unknown may be understood to be important at the time of 
analysis.  The samples may be analyzed as part of a multi-study assessment of genetic 
factors involved in AD or the response to ABBV-8E12 or drugs of this class.  The 
samples may also be used for the development of diagnostic tests related to ABBV-8E12 
or other drugs for AD or related disorders.  The results of any pharmacogenetic analyses 
that are done may not be reported in the study summary.
5.3.7
Immunogenicity
Anti-drug antibody (ADA) levels will be determined for the assessment of 
immunogenicity.


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5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Each subject has the right to withdraw from the study at any time.  In addition, the 
investigator may discontinue a subject from the study at any time if the investigator 
considers it necessary for any reason, including the occurrence of an adverse event or 
noncompliance with the protocol.
Subjects with the following adverse events will be considered for treatment 
discontinuation:
●
Severe or life-threatening allergic reactions will require the immediate 
interruption of ABBV-8E12 treatment, permanent discontinuation from further 
treatment and initiation of appropriate medical therapy and follow-up.
●
Life-threatening drug related adverse events of nervous system will require 
discontinuation from further treatment with ABBV-8E12, initiation of 
appropriate medical therapy and follow-up.
All moderate and severe symptomatic neurological abnormalities and treatment-emergent 
MRI findings will be reported to AbbVie TA MD and subjects will be considered for 
discontinuation from treatment and may be permitted to continue in the study only after a 
management plan is discussed with the AbbVie TA MD.
Subjects with unexpected worsening of cognitive impairment or dementia will be reported 
to AbbVie TA MD and considered for discontinuation from treatment and may be 
permitted to continue in the study only after a management plan is discussed with the 
AbbVie TA MD.
Subjects at risk of suicide as indicated by answering yes to question 4 or 5 on the C-SSRS 
and/or determined by the investigator to be at risk of suicide should be discontinued from 
participation in the study and referred for appropriate follow-up care.


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In the event that a subject withdraws or is discontinued from the study, the primary reason 
for discontinuation and any other reason(s) for the discontinuation from the study will be 
recorded and a physical examination, neurological examination, body weight, vital signs 
measurement, ECG, laboratory analyses, C-SSRS and an assessment of adverse events 
will be performed as soon as possible after discontinuation from the study.  Additional 
blood samples for drug measurement may be collected at the time of discontinuation from 
subjects who are discontinued due to adverse events; the clock time, time in relation to 
dose, and date the sample was taken will be recorded.
If a subject is discontinued from the study with an ongoing adverse event or an unresolved 
laboratory result that is significantly outside of the reference range, the investigator will 
attempt to provide follow-up until a satisfactory clinical resolution of the laboratory result 
or adverse event is achieved.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Subjects who miss multiple study drug doses due to the COVID-19 pandemic may 
continue participation with approval from the TA MD.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.
A DMC will review unblinded safety data during the study.  Depending on the outcome of 
these evaluations, the DMC may make a recommendation to discontinue the entire study 
or stop enrollment in a single dose group prior to enrollment of the planned sample size.  


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The entire study will be discontinued if it is determined by AbbVie in consultation with 
the DMC that the continued exposure of subjects to study drug represents a significant 
safety risk.  Enrollment to a single dose group will be discontinued if it is determined by 
AbbVie in consultation with the DMC that the continued exposure of subjects to that dose 
of study drug represents a significant safety risk.  Alternatively, a recommendation may 
be made to reduce the dose in a single dose group.
5.5
Treatments
5.5.1
Treatments Administered
ABBV-8E12 will be given by IV infusion.  Subject weight will be obtained prior to study 
drug administration to determine the appropriate infusion rate as shown in the table 
below.
Subject's Weight in kg
Infusion Rate*
26.0 – 34.9 kg (inclusive)
2.1 mL/min or 126 mL/hr
35.0 – 44.9 kg (inclusive)
2.8 mL/min or 168 mL/hr
45.0 – 59.9 kg (inclusive)
3.6 mL/min or 216 mL/hr
60.0 – 89.9 kg (inclusive)
4.8 mL/min or 288 mL/hr
90.0 kg and over
7.2  mL/min or 432  mL/hr
*
Continue infusion until bag is empty.
Study drug will be administered by IV infusion, preferably in the morning but should be 
around the same time at each visit as follows:
Study Drug
Formulation
Placebo (0.9% Sodium Chloride 
Injection/Solution for Infusion)
IV infusion every 4 weeks for 96 weeks
(Total of 24 infusions)
ABBV-8E12 300 mg
ABBV-8E12 1000 mg
ABBV-8E12 2000 mg
Doses may be modified after evaluation by the data monitoring committee of the safety, tolerability and available 
pharmacokinetic data.


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The start and stop time of each study drug infusion will be recorded to the nearest minute.  
The start of study drug infusion occurs from ABBV-8E12 initiation up until the 
administration of the complete dose (including flush). The Pharmacy Manual may be 
referred to for detailed instructions.
Home Healthcare Service Due to the COVID-19 Pandemic
Subjects may be offered the option of home healthcare visits provided by a study nurse or 
third-party vendor based on the subject's suitability as assessed by the investigator and 
following the subject's written consent.  This option can only be offered in countries and 
sites that comply with local regulatory and IEC/IRB requirements for home healthcare.  
Any prerequisite submissions or notifications to the site IEC/IRB and local competent 
health authority should be made and approved prior to the implementation of home 
infusions.
5.5.2
Identity of Investigational Product
Information about the ABBV-8E12 and placebo products to be used in this study is 
presented in Table 5.
Table 5.
Identity of Investigational Product
Investigational Product
Mode of 
Administration
Formulation
Strength
ABBV-8E12
Infusion
Solution for infusion in 
a vial
300 mg/15 mL
1000 mg/ 10 mL
Placebo
Infusion
0.9% Sodium Chloride 
Injection/Solution for 
infusion, 250 mL
N/A
N/A = not applicable
0.9% Sodium Chloride Injection/Solution for Infusion will be administered to those 
subjects not receiving active ABBV-8E12 and as a vehicle for administration of 
ABBV-8E12.  0.9% Sodium Chloride Injection/Solution for Infusion will be supplied 
with commercially available material in either bags or bottles, locally sourced by the sites.  


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However, if mandated by local regulation, or in the case of exceptional circumstances 
when sites are unable to procure on their own, AbbVie may supply 0.9% Sodium Chloride 
Injection/Solution for Infusion if necessary. 
5.5.2.1
Packaging and Labeling
ABBV-8E12 will be provided in a glass vial as solution for infusion.  One vial will be 
packaged per carton.  Each vial and carton will be labeled with the information necessary 
per country requirement.  Labels must remain affixed to the vial and carton.  All blank 
spaces on the label will be completed by the site staff prior to dispensing to the subjects.
The commercially sourced 0.9% Sodium Chloride Injection/Solution for Infusion will not 
be labeled as an Investigational Medicinal Product (IMP) prior to the handling by the 
unblinded pharmacist or qualified designee.  Instead, after addition of ABBV-8E12 to the 
0.9% Sodium Chloride Injection/Solution for Infusion to be administered in the active 
arm, it will be labeled with a blinded dispensing label by the unblinded pharmacist or 
qualified designee as required.  0.9% Sodium Chloride Injection/Solution for Infusion 
without addition of ABBV-8E12, to be administered in the placebo arm, will be labeled 
with a blinded dispensing label by the unblinded pharmacist or qualified designee as well.  
Labels must remain affixed to the material.
If an IMP label on the 0.9% Sodium Chloride Injection/Solution for Infusion is mandated 
by local agencies, labels may be applied on the overwrap and will be removed by 
unblinded pharmacist prior to administration.
5.5.2.2
Storage and Disposition of Study Drugs
ABBV-8E12 must be stored at 2° to 8°C/36° to 46°F, must be protected from light and 
must not be frozen at any time.
0.9% Sodium Chloride Injection/Solution for Infusion should be stored per the locally 
approved commercial label, Summary of Product Characteristics (SmPC) or clinical study 
label. 


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A storage temperature log is to be maintained to document proper storage conditions.  The 
refrigerator temperature must be recorded on each business day.  All temperature 
excursions lasting longer than 30 minutes must be reported to the Sponsor immediately 
using the AbbVie Temperature Excursion Management System (ATEMS).  Study 
medication should be quarantined and not dispensed until AbbVie (ATEMS) deems the 
medication as acceptable.
Investigational products are for investigational use only, and are to be used only within 
the context of this study.  The study drug supplied for this study must be maintained under 
adequate security and stored under conditions specified on the label until dispensed for 
subject use or returned to AbbVie or representative.
5.5.2.3
Preparation/Reconstitution of Dosage Form
The preparation of blinded doses will be performed by the unblinded site pharmacist or 
qualified designee.  The prepared IP (placebo and ABBV-8E12) infusion bags should be 
covered by the blinding bags before dispensation.  Written instructions for the preparation 
of ABBV-8E12 solutions for infusion will be provided as separate document from the 
protocol.
5.5.3
Method of Assigning Subjects to Treatment Groups
Prior to enrolling subjects, each site will be provided with a user manual as well as a 
telephone number and user instructions for the Interactive Voice-Response/Interactive 
Web-Based (IVR/IWB) system.  Each user will receive a code number that will be used in 
combination with a personal identification number (PIN) to access the system by 
telephone and a unique username and confidential password to access the system through 
the internet.
As subjects are screened for the study, the IVR/IWB system will assign each subject a 
unique 5 digit subject number.  The first digit will be 2, the second and third digits will be 
the site number (01, 02, etc.) and the fourth and fifth digits will be assigned in ascending 
numerical order at each site.


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At the Day 1 visit, each subject will be randomly assigned to a double-blind treatment 
group through the IVR/IWB system after the site verifies that the subject is eligible to 
participate in the study.  The first dose of study drug will be administered after 
randomization at the same visit.  The randomization schedule will be computer-generated 
and implemented in IVR/IWB system before the start of the study by the AbbVie 
Statistical Department.
5.5.4
Selection and Timing of Dose for Each Subject
Selection of the dose for this study is discussed in Section 5.6.4.  Each subject will be 
randomized to one of four cohorts as described in Section 5.5.1.  ABBV-8E12 will be 
administered every 4 weeks via IV infusion at the research site in the morning.
5.5.5
Blinding
Placebo solution will be essentially identical in volume to the ABBV-8E12 solution.  The 
Investigator, study site personnel (except the unblinded pharmacist) and the subject will 
remain blinded to the treatment throughout the course of the study.  The study sponsor 
will remain blinded; however, a pharmacokineticist will be provided individual 
pharmacokinetic data from Cohort 1 after 48 weeks of treatment.  Subject identification 
numbers will be changed for the pharmacokinetic analysis to maintain the sponsor blind. 
ABBV-8E12 and 0.9% Sodium Chloride Injection/Solution for Infusion (if applicable) 
will be delivered to the unblinded pharmacist or qualified designee in an open-label 
format.  The unblinded pharmacist or qualified designee will prepare the dosing of 
ABBV-8E12 (in a blinded manner) following the available preparation instructions as 
appropriate based on the subject's assigned treatment group.  For blinding purposes, 
identical commercial 0.9% Sodium Chloride Injection/Solution for Infusion bag or bottle 
will be used in the placebo and ABBV-8E12 arms at each site.  The unblinded pharmacist 
or qualified designee will place a blinding bag over the infusion bag or bottle before 
dispensation following the written instructions provided as a separate document from the 
protocol.


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For investigational product monitoring, there will be an unblinded clinical research 
associate (CRA) for verification of unblinded documentation.  The unblinding procedure 
for the unblinded pharmacist/designee and the unblinded CRA will be defined in a 
separate study-specific document.
The IVR system will be programmed with blind-breaker instructions.  The study blind for 
a subject may be broken, if, in the opinion of the investigator, it is in the subject's best 
interest to know the study drug assignment.
AbbVie must be notified before breaking the blind, unless identification of the study drug 
is required for a medical emergency, i.e., situation in which the knowledge or the specific 
blinded treatment will affect the immediate management of the subject's conditions 
(e.g., antidote is available).  AbbVie must then be notified within 24 hours of the blind 
being broken.  The date and reason that the blind was broken must be recorded in the 
source documentation and on the eCRF, as applicable.
Unblinding of Data for the Data Monitoring Committee (DMC)
In order to ensure that the DMC will be fully informed, the DMC will be unblinded in its 
assessment of safety and efficacy data.  The DMC will have full access to all data as 
needed for safety assessment and all data included in interim efficacy analyses.  SAS data 
sets blinded with respect to treatment assignment will be sent to an external statistical 
center by AbbVie.  The study randomization schedules will be sent to an external 
statistical center under separate cover.  The external statistician will generate closed 
reports that will include unblinded information.  While the studies are ongoing, only the 
DMC and the external statistical center will have access to the closed reports.  An AbbVie 
Internal Executive Review Committee (IERC) may request access to closed reports if the 
discontinuation of the study, major modifications to the study design, or Phase 3 initiation 
is recommended by the DMC as outlined in the DMC charter.  All other AbbVie 
personnel will remain blinded to the treatment assignment.  The AbbVie Primary Contact 
for the DMC and the AbbVie IERC members will not be involved in any aspects of the 
trial or its management.


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5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will administer study 
drug only to subjects enrolled in the study in accordance with the protocol.  The study 
drug must not be used for reasons other than that described in the protocol.  Subjects will 
be supervised at the time of study drug administration.
5.5.7
Drug Accountability
The investigator or his/her representative will verify that study drug supplies are received 
intact and in the correct amounts.  This will be documented by signing and dating the 
Proof of Receipt or similar document.  A current (running) and accurate inventory of 
study drug will be kept by the investigator and will include shipping invoices and the date 
on which study drug is administered to the subject.  An overall accountability of the study 
drug will be performed and verified by an unblinded AbbVie monitor throughout the 
study and at the study site closeout visit.  Written instructions for IP accountability 
requirements will be provided in a separate document from the protocol.  Upon 
completion or termination of the study, all original containers (containing used study drug 
or containing unused study drug) will be destroyed at site, according to instructions from 
AbbVie and according to local regulations.  For those sites where local destruction of 
unused study drug is not feasible, sites will return the original containers of unused study 
drug to AbbVie according to instructions from AbbVie and according to local regulations.  
Labels must remain attached to the containers.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This study is designed to assess the safety and efficacy of ABBV-8E12 in subjects with 
Early AD for up to 96 weeks.  The inclusion of placebo administration and the double 
blind feature of the study will provide unbiased assessments.  There is no anticipated risk 
to subjects in the placebo group because participating in the study will not prevent 
subjects from taking approved medications for the treatment of AD.  The parallel-group 


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design with placebo control will provide a well-controlled unbiased assessment of the 
effect of ABBV-8E12 on clinical outcome measures and potential neuroimaging and CSF 
biomarkers that are associated with AD disease activity.  Toxicity management in the 
parallel group design is described in Section 6.1.6.
5.6.2
Appropriateness of Measurements
Standard pharmacokinetic, statistical and clinical procedures will be utilized in this study.  
On-treatment safety evaluations (neurological examinations, adverse event monitoring, 
ECGs) are scheduled at more frequent intervals for the first 48 subjects enrolled 
(Cohort 1) to promptly detect potential emerging safety signals.
Overall, choice of instruments to measure key domains of function, cognition, behavior 
and caregiver distress has been guided by published data on their use in MCI and AD 
patients.  These instruments have shown to be sensitive to the change in Early AD and 
MCI patients over a period of time.
5.6.3
Suitability of Subject Population
The target population is aimed to be still clinically very mildly affected but demonstrating 
observable disease burden that can be captured and monitored throughout the trial 
duration.  Confirmation of amyloid load on PET imaging will increase the diagnostic 
accuracy in the early stages of AD and together with onset of clinical symptoms will 
increase probability of cognitive decline due to initiation of tau spreading.  Several 
neuropathological studies suggested that at the onset of clinical symptoms tau spreading 
and aggregation has been already initiated but is still an ongoing and potentially 
interruptible process.
5.6.4
Selection of Doses in the Study
The doses chosen for the study were determined based on the safety and tolerability of the 
SAD study in patients with PSP that included single doses of ABBV-8E12 ranging from 
2.5 to 50 mg/kg.  All doses have been administered without notable treatment-related 
adverse effects or any evidence of safety findings.  In the 15 mg/kg dose group, 


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one subject reported an SAE of a subdural hematoma resulting from a fall that was 
assessed as possibly related to study drug by the investigator due to a temporal 
relationship with dosing.  The sponsor judged the SAE to be unlikely related to study 
drug, and likely related to the underlying PSP disease.  In the 25 mg/kg dose group, one 
subject was hospitalized due to a severe increase in agitation, anxiety, and perseverative 
behavior.  The subject had a prior history of anxiety and agitation during stressful events, 
such as medical procedures.  The investigator assessed the event as possibly drug related.  
In the 50 mg/kg dose group, one subject was hospitalized due to hypertensive 
cerebrovascular disease, which was a pre-existing condition for this subject.  The 
investigator assessed this event as not study drug related.
The highest dose, 2000 mg administered IV, is approximately 2-fold lower than the 
highest dose administered in the SAD study in patients with PSP (50 mg/kg based on a 
body weight of 80 kg).  This dose is also approximately equal to the maximal dose 
(25 mg/kg) administered every 4 weeks for 7 months to the 1 subject with PSP in the 
Expanded Access protocol.
The subject with PSP in the Expanded Access protocol began treatment at 1 mg/kg and 
received a total of 20 monthly ABBV-8E12 infusions.  The dosing regimen escalated in 
the following manner:  1 mg/kg for Month 1, 2.5 mg/kg for Month 2, 7.5 mg/kg for 
Month 3, 15 mg/kg for Months 4 – 11, 20 mg/kg for Months 12 – 13, and 25 mg/kg for 
Months 14 – 20.  Preliminary pharmacokinetic analysis estimated that half-life was 
approximately 13 to 21 days, and the accumulation ratio was around 1.7.  In the ongoing 
SAD study in patients with PSP, available pharmacokinetic data from the 2.5 mg/kg to 
25 mg/kg dose groups indicate dose proportional increases in exposure.  The plasma half-
life ranged from 17 to 24 days.  CSF concentrations measured 14 days after ABBV-8E12 
administration from the 2.5 mg/kg and 7.5 mg/kg dose groups increased with dose and the 
estimated CSF:plasma ratio was approximately 0.38%.
In the 4-week preclinical mouse toxicology study, the highest dose tested was 250 mg/kg 
and the corresponding Cmax and AUC0-168h were 3050 µg/mL and 298,000 hr•µg/mL (on 
Day 22) after 4 doses administered weekly.  Assuming the pharmacokinetics of 


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ABBV-8E12 is linear, the steady-state pharmacokinetic profiles were simulated at 300, 
1000, and 2000 mg following monthly administration of ABBV-8E12 based on the 
pharmacokinetic data from the 25 mg/kg dose group up to Day 56 in the ongoing SAD 
study in patients with PSP.  The predicted safety margin at the dose levels of 300, 1000, 
and 2000 mg is approximately 18-, 6- and 3-fold, respectively, for both Cmax and AUC.  In 
addition, the predicted AUC for a 1000 mg dose administered over 4 months and for a 
2000 mg dose administered over 2 months is no greater than the AUC following a single 
50 mg/kg dose predicted from the ongoing SAD study in patients with PSP.
Based on pharmacokinetics from the SAD study, it is possible to estimate the percent of 
tau in CSF that is bound by ABBV-8E12.  For this calculation, it is assumed that the CSF 
concentration for humanized antibodies is 0.2% of the plasma concentration and that the 
concentration of tau in CSF is 400 pg/mL.  Based on the KD of ABBV-8E12 determined 
in vitro, 300 mg will lead to approximately 30% – 55% of tau in CSF being bound by the 
antibody at predicted Ctrough and Cmax values.  Similar modeling was performed with 1000 
and 2000 mg ABBV-8E12 and estimated that the average tau binding over the 28 day 
period ranges from approximately 60% – 80% and 75% – 90%, respectively.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Sections 6.1
through 6.1.6.  For product complaints, please refer to Section 6.2.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 


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any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide an "Other" cause of the event.  For adverse events to be 
considered intermittent, the events must be of similar nature and severity.  Adverse 
events, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, meet protocol specific criteria for potentially clinically significant 
(PCS) laboratory values defined in Appendix D and/or if the investigator considers them 
to be adverse events.


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An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre-planned prior to study entry.  However, if the pre-
existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.
6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event within 24 hours of the site being made aware of the serious adverse 
event:
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study subject.  
Disability is not intended to include experiences of relatively 
minor medical significance such as headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).


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Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject and 
may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of subject, life-
threatening, hospitalization, prolongation of hospitalization, 
congenital anomaly, or persistent or significant 
disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.1.2
Adverse Event Severity
The investigator will use the following definitions to rate the severity of each adverse 
event:
Mild
The adverse event is transient and easily tolerated by the subject.
Moderate
The adverse event causes the subject discomfort and interrupts the 
subject's usual activities.
Severe
The adverse event causes considerable interference with the subject's 
usual activities and may be incapacitating or life-threatening.
6.1.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:
Reasonable 
Possibility
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.




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6.1.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
electronic data capture (EDC) RAVE® system.  Serious adverse events that occur prior to 
the site having access to the RAVE® system or if RAVE is not operable can be Emailed 
(this is the preferred route) or faxed to Clinical Pharmacovigilance within 24 hours of 
being made aware of the serious adverse event.
Email:  PPDINDPharmacovigilance@abbvie.com
FAX to:  +1 (847) 938-0660
For safety concerns, contact the Neuroscience Safety Team at:
Neuroscience Safety Team
Dept. R48S, Bldg. AP32
1 North Waukegan Road
North Chicago, IL  60064
Office:
+1 (847) 938-4191
Email:
SafetyManagement_Neuroscience@abbvie.com




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Expedited Reports or any additional reports required by local regulations) to the IEC/IRB 
of any changes that affect the conduct of the study and/or increase the risk to subjects.  
Written documentation of the submission to the IEC/IRB should also be provided to 
AbbVie.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
The investigator should capture COVID-19 infections as AEs.  If the event meets the 
criteria for a serious adverse event (SAE), reporting directions as described in Section 6.1
should be followed.
Supplemental study case report forms should be completed in the event of COVID-19 
related missed/virtual visits, study drug interruptions or discontinuations, or AEs 
(including capture of specific signs/symptoms of infection and testing results).
COVID-19 infections should be captured as AEs.  If the event meets the criteria for a 
serious adverse event (SAE), then the SAE reporting directions per the protocol and above
should be followed.  The following COVID-19 related supplemental eCRFs should be 
completed (for both serious and non-serious events):
●
COVID-19 Supplemental Signs/Symptoms
●
COVID-19 Status Form
If a subject has a confirmed or suspected COVID-19 infection and study drug was 
interrupted, the investigator should contact the sponsor emergency medical contact listed 
above before reintroducing study drug.
6.1.6
Toxicity Management
For the purpose of medical management, all adverse events and laboratory abnormalities 
that occur during the study must be evaluated by the investigator.  
A drug-related toxicity is an adverse event or laboratory value outside of the reference 
range that is judged by the investigator or AbbVie as a "reasonable possibility" of being 


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related to the study drug (Section 6.1.3).  A toxicity is deemed "clinically significant" 
based on the medical judgment of the investigator.  The following guidelines should be 
used for study drug-related toxicity management. 
Potential Drug-Related Toxicities
No potential drug related toxicities were identified from preclinical or clinical studies 
conducted to date.  Examples of safety concerns that could be hypothetically associated 
with ABBV-8E12 and safety concerns associated with monoclonal antibodies, in general, 
are summarized below.
On-Target Toxicities
The brain appears to be the only organ to express tau at significant levels.  Tau is an 
intracellular protein mainly expressed in neurons, although lower levels can be found in 
astrocytes and oligodendrocytes.  ABBV-8E12 is directed against extracellular tau and no 
function of extracellular tau has been reported.  No cellular uptake of mouse version of 
ABBV-8E12 antibody bound to tau aggregates was detected in preclinical studies.7  The 
likelihood of adverse on-target side effects of an anti tau immunotherapy is therefore 
anticipated to be low.
Non-Specific Off-Target Toxicities
Potential toxicities resulting from the non-human origin of ABBV-8E12 include allergic 
reactions or infusion reactions, including anaphylaxis or anaphylactoid reactions, flu-like 
symptoms, including fever, fatigue or loss of appetite, rash.  ABBV-8E12 is lacking the 
Fc effector function activity and therefore Fc-mediated antibody-dependent cellular 
cytotoxicity and complement-dependent cytotoxicity is not expected.  In addition, 
ABBV-8E12 exhibited a favorable in vitro immunosafety profile.  No infusion reactions 
have occurred in the single dose PSP clinical study or the Expanded Access protocol.


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6.1.6.1
Allergic Reactions Management
Subjects will be closely monitored for treatment-related adverse events, including allergic 
reactions, during the infusion.  For the 4 initial ABBV-8E12 infusions, subjects should be 
monitored on site until 2-hours post-infusion.  For subsequent infusions, subjects should 
be monitored on site until at least 30 minutes after the end of infusion.  Longer 
observation periods and more frequent vital sign checks may be required in subjects who 
experience infusion reactions.
Severe or life-threatening allergic reactions require the immediate interruption of 
ABBV-8E12 treatment and permanent discontinuation from further treatment.  
Appropriate medical therapy including epinephrine, corticosteroids, IV antihistamines, 
bronchodilators, and oxygen should be available for use in the treatment of such reactions.  
Subjects should be carefully observed until the complete resolution of all signs and 
symptoms.
Moderate allergic reactions will also require the interruption of ABBV-8E12 treatment.  
Once symptoms have resolved, the next scheduled infusion is allowed with a 50% 
reduction of the infusion rate.
6.1.6.2
Management of Adverse Events of the Nervous System
Subjects will be closely monitored for adverse events suggesting neurotoxicity.  Drug 
related adverse event is an adverse that is judged by the investigator or AbbVie as a 
"reasonable possibility" of being related to the study drug.
Life-threatening drug related adverse events of the nervous system will require 
discontinuation from further treatment with ABBV-8E12 and prompt notification of 
AbbVie TA MD.  Appropriate medical therapy will be initiated and subjects will be 
followed up until the resolution.
Subjects with moderate and severe drug related adverse events of the nervous system, 
symptomatic neurological abnormalities and treatment-emergent MRI findings and 


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subjects with unexpected worsening of cognitive impairment or dementia will be 
considered for discontinuation and may be permitted to continue in the study only after a 
management plan is discussed with the AbbVie TA MD.
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product.
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product or packaging issues.
Any information available to help in the determination of causality to the events outlined 
directly above should be captured.
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 24 hours of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and documented in source as required by the Sponsor.  Product 
Complaints associated with adverse events will be reported in the study summary.  All 
other complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition.  In instances where a return is requested, every effort should be made by the 
investigator to return the product within 30 days.  If returns cannot be accommodated 
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individual items are missing.  Study sites that do not enroll at least two subjects to each 
treatment group who have non-missing observations of CDR-SB score after 
randomization will be combined using an algorithm that will be described in the 
Statistical Analysis Plan (SAP).
8.1.1
Analysis Data Sets
Intent-to-Treat Data Set
The intent-to-treat (ITT) data set will include all randomized subjects who take at least 
one dose of study drug.  The data from the ITT data set will be analyzed by the treatment 
group assigned at the time of randomization, even if the subject does not receive the 
correct treatment, is not compliant with the protocol or does not follow through with the 
study until completion.  All efficacy analyses will be conducted on the ITT data set unless 
otherwise specified.
Safety Data Set
The safety data set will include all randomized subjects who take at least one dose of 
study drug.  For this analysis data set, actual treatment received will be used instead of 
treatment assignment at the time of randomization.  All safety analyses will be conducted 
on the safety data set unless otherwise specified.
8.1.2
Disposition, Demographics, and Other Baseline 
Characteristics
Subject Disposition
The number and percentage of subjects contributed by each country and site will be 
summarized for each treatment group and for all treatment groups combined for the safety 
data set.
The number and percentage of subjects who prematurely discontinue study drug will be 
summarized by treatment group and overall for the safety data set for the primary reason 
as well as for all reasons collected.  In the summary, the number and percentage of 


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subjects who discontinue due to any reason as well as due to each specific primary reason 
will be presented.  Subjects may report multiple reasons for prematurely discontinuing 
study drug, but the primary reason for discontinuation will be indicated in the eCRF and 
used to infer treatment group difference in subject's disposition.  Two-sided Fisher's exact 
tests will be used to perform pairwise comparisons between each ABBV-8E12 dose group 
and placebo with respect to the proportion of who discontinue for any reason and for each 
reason reported as primary.
Demographic and Other Baseline Characteristics
Demographics will be summarized for the ITT data set and the safety dataset unless 
otherwise specified.  Treatment group differences will be evaluated using overall tests.  
No pairwise comparisons between treatment groups will be performed for demographic 
and baseline characteristics variables unless the overall P value is ≤ 0.050.
For continuous demographic variables including age, weight, height, body mass index 
(BMI), descriptive statistics (number of subject with non-missing data, mean, standard 
deviation, median, and minimum and maximum) will be provided for each treatment 
group and for all treatment groups combined.  The overall treatment differences will be 
tested using one-way analysis of variance (ANOVA).
For categorical demographic variables including gender and race, number and percentage 
of subjects in each category will be provided for each treatment group and for all 
treatment groups combined.  Fisher's exact test will be carried out to assess the overall 
comparability of treatment groups based on two-sided tests.
Efficacy and clinical measures taken at baseline (CDR-SB score, scores for the ADAS-
Cog-14, MMSE, FAQ, UPSA-Brief, NPI, RBANS, ADCS-MCI-ADL-24 and ADCS-
CGIC-MCI) will be summarized for the ITT data set only.  One-way ANOVA will be 
used to assess the overall comparability of treatment groups for all measurements.


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Medical History
Medical history data, including subject's history of Early AD or MCI, will be summarized 
for the safety data sets using body systems and conditions/diagnoses as captured on the 
eCRF.
Previous and Concomitant Medications
Prior and concomitant medications will be coded by the most recent World Health 
Organization (WHO) Drug dictionary, and will be summarized by treatment group for the 
safety data set.  No statistical testing will be performed.  A subject who reports two or 
more uses of medication that belong to the same category defined by WHO Drug will be 
counted only once for that WHO category.
8.1.3
Efficacy Analyses
All efficacy analyses will be conducted on the ITT data set unless otherwise specified.  
Data collected more than 45 days after the last dose of the study drug will not be included 
in efficacy analyses.  Unless otherwise specified, for all efficacy analyses, "baseline" 
refers to the last non-missing observation prior to the first dose of study drug and "final" 
refers to the last non-missing observation after the first dose of study drug and no more 
than 45 days after the last dose of study drug.  Pairwise comparisons between each 
ABBV-8E12 dose group and the placebo group will be performed using two-sided tests.  
A group-sequential graphical approach33,34 will be applied for multiplicity control for 
multiple comparisons due to multiple endpoints, multiple ABBV-8E12 doses, and 
multiple interim analyses and final analysis.  The overall family-wise error rate will be 
controlled within 5%.  The detailed hypotheses testing procedure and multiplicity control 
method for the interim analyses and final analysis will be pre-specified in the SAP and the 
DMC Charter, which will be finalized and signed off before the first efficacy interim 
analysis of this trial.


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8.1.3.1
Primary Efficacy Analysis
The primary efficacy variable will be the change from baseline up to the Week 96 on the 
CDR-SB score.  The primary efficacy analysis is to compare each ABBV-8E12 dose 
group with placebo in using a likelihood-based, mixed-effects model, repeated measures 
(MMRM) analysis of the change from baseline for each post-baseline observation using 
all observed data.  The model will include fixed, categorical effects for treatment, site, 
visit, treatment-by-visit interaction, and baseline-by-visit interaction with continuous 
fixed covariates for baseline score.  The primary comparison will be the contrast between 
each ABBV-8E12 dose group and placebo at the Week 96 Visit using two-sided tests.  
The treatment group difference at earlier visits will be assessed as secondary.  An 
unstructured (co)variance structure will be used to model the within-patient errors.  
Satterthwaite's approximation will be used to estimate denominator degrees of freedom 
and the Type III sum-of-squares for the least squares (LS) means will be used to estimate 
treatment group differences.
8.1.3.2
Secondary Efficacy Analysis
Secondary Efficacy Analysis of the Primary Efficacy Variable
The change from baseline to each post-baseline observation on the CDR-SB scores will be 
summarized.  The change from baseline to final observation up to Week 96 on the CDR-
SB score will be analyzed by an analysis of covariance (ANCOVA) model with treatment 
and study site as the main effects and the baseline CDR-SB score as covariate.
Analyses for Secondary Efficacy Variables
The other secondary efficacy variables include ADAS-Cog-14 total score, scores of 
MMSE, NPI and ADCS-MCI-ADL-24 and scores of FAQ, UPSA-Brief, RBANS and 
ADCS-CGIC-MCI.
The change from baseline score on each secondary efficacy variable (with the exception 
of ADCS-CGIC-MCI) will be summarized and analyzed using the similar MMRM model 
described for the primary efficacy analysis.  The change from baseline to final observation 


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up to Week 96 for each secondary efficacy variable (with the exception of 
ADCS-CGIC-MCI) will also be analyzed using an ANCOVA model with treatment and 
study site as the main effects and the baseline value of analyzed variable as a covariate.  
The ADCS-CGIC-MCI score at each visit up to Week 96 will be summarized and 
analyzed using an MMRM model with fixed, categorical effects for treatment, site, visit 
and treatment-by-visit interaction.  The final ADCS-CGIC-MCI score up to Week 96 will 
be analyzed using an ANCOVA model with treatment and study site as the main effects.
The analyses will be performed in the ITT data set.
8.1.4
Subgroup Analysis of CDR-SB Score
To examine whether gender, age group, study site, country/geographic region or other 
baseline variables have an impact on response to treatment, subgroup analyses on CDR-
SB score will be conducted on change from baseline to last observations up to Week 96.  
Subgroup analyses will be performed using an ANCOVA model with the terms of 
treatment, site, subgroup variable, the treatment-by-subgroup variable interaction, and 
baseline score as a covariate.  The subgroup analysis for country/region will be performed 
using the same model but with the study site nested within geographic region.  The 
hypothesis that consistent response to treatment across strata of a subgroup variable will 
be tested at the significance level of 0.100 by examining the P value of the treatment-by-
subgroup interaction term in the ANCOVA model specified above.  The statistical 
comparison of each ABBV-8E12 dose group with placebo within each stratum will be 
performed when the statistical significance of the treatment-by-subgroup interaction term 
is achieved at 0.100 level.  The subgroup analysis will be conducted in the ITT data set.
8.1.5
Biomarker Research Analyses
CSF Concentration Variables
An ANCOVA will be performed on CSF concentrations for total tau, free tau, the ratio of 
free tau concentration to total tau concentration, and NFL for each scheduled time of 
evaluation during treatment (fourth dose interval and Week 96).  For the analysis for the 


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fourth dose interval, an analysis will be performed for the data of Cohort 1 alone and also 
for all available data.  The observations will be classified by treatment.  The baseline 
value (last value before the first dose of study drug) will be the covariate except for the 
analysis on the ratio of the free tau and total tau concentrations, in which case the 
covariate will be the baseline total tau concentration measurement.  If the probability 
distribution for a variable appears to have considerable non-symmetry (skewness 
coefficient > 0.75 in magnitude), a transformation will be sought so that the transformed 
variable has an approximately normal distribution.  Within the framework of the 
ANCOVA the means of the four treatments (with adjustment for baseline) will be 
estimated.  For each ABBV-8E12 dose level, the results of the test of the hypothesis of no 
difference between the dose and placebo will be reported.  Also, with the motivation to 
have a test with good power if the dose response curve is a monotonic function of dose, a 
test will be performed on a contrast in the four treatment means.  With µ0, µ1, µ2 and µ3
denoting the means for placebo, the 300 mg treatment, the 1000 mg treatment and 2000 
mg treatment, respectively, the hypothesis that –3µ0 – µ1 + µ2 + 3µ3 = 0 will be tested at 
significance level 0.05 against the two-sided alternative hypothesis.  The tests on the 
effects of the 1000 mg dose and the 300 mg dose will not be formally considered unless 
the statistic on the effect of the 2000 mg dose or the statistic on the contrast in the four 
means is significant at level 0.050.
Other CSF concentration variables of interest will be analyzed using methodology like 
that described for the analysis of total tau concentration.
Serum/Plasma Concentration Variables
Descriptive statistics will be provided for plasma concentrations of total tau and NFL.  
For each of these variables, an MMRM analysis will be performed on the data from the 
scheduled times of measurement.  The model will include the baseline value as a 
covariate, have classification of subjects by treatment, an effect for time (classification) 
and will include an effect for the interaction of treatment and time of measurement.  The 
initial model will also allow the regression coefficient for the baseline value to vary with 
time (an effect for interaction of time and the baseline value), but this feature will be 


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removed from the model if the statistic on this interaction is not significant at level 0.100.  
Within the framework of this model, the mean across the scheduled times of measurement 
and the mean for each individual time will be estimated for each treatment.  Also, tests on 
differences of effect among the dose levels (with placebo considered a dose level) will be 
performed within the framework of the model.  The primary tests will be on trend with 
dose (with placebo considered a dose level) and on the difference between the highest 
dose and placebo. 
For total tau and NFL, the relationship to disease progression and response to treatment 
will be explored with disease state represented by CDR-SB score and perhaps by other 
variables of interest.  The exploration on the relationship with disease progression will 
include an analysis of data from only the subjects treated with placebo. 
Descriptive statistics and some or all of the analyses described here may be provided for 
other variables.
vMRI Variables
Descriptive statistics will be provided for the baseline value, for each scheduled time after 
that and for the changes from baseline.  An analysis will be performed like that described 
for plasma NFL concentration, but with estimated total intracranial volume (eTIV) as a 
covariate in addition to the baseline value.  The regression coefficient for eTIV will not 
vary with time, as may be allowed for the vMRI baseline value.  An appropriate structure 
for the covariance matrix will be selected.
For each of whole brain, hippocampus and lateral ventricles, the relationship with the 
primary efficacy variable CDR-SB score, and possibly other efficacy variables, will be 
explored.  The exploration will include an analysis of data from only the subjects treated 
with placebo.  This may also be done for other regions.  


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Tau PET Scan Variables
For each region of the brain for which SUVR values are obtained, a joint analysis will be 
performed for the two scheduled times of evaluation during treatment (Week 44 and 
Week 96).  The analysis will be like that described for plasma NFL concentration.  For 
SUVR of selected regions, the relationship with the primary efficacy variable CDR-SB 
score will be explored.  The exploration will include an analysis of data from only the 
subjects treated with placebo.  This may be done also for other tau PET variables.
Consideration of Missing Values
The possibility of bias associated with missing data of subjects who prematurely 
discontinue treatment for reasons possibly related to study drug will be addressed.
8.1.6
Safety Analyses
All safety analysis will be performed on the safety data set unless otherwise specified.  
Comparisons between each ABBV-8E12 dose group and placebo will be performed with 
two-sided test at the significance level of 0.05, if applicable.  Pairwise comparisons for 
each ABBV-8E12 dose group versus placebo will be evaluated.
All safety assessments that are taken no more than 20 weeks after the last dose of study 
drug will be included in the safety evaluation for subjects who complete the double-blind 
Treatment Period or PD and do not roll over to the planned extension study.  If subjects 
enroll in the planned extension study, their safety information collected before the first 
dose of the planned extension study will be included in the safety evaluation for the 
double-blinded period.
Study Drug Exposure and Compliance
The number of doses on study drug will be summarized by treatment group and all 
treatment groups combined.  The number and percentage of subjects with at least 90% 
compliance with study drug (i.e., complete 90% of scheduled doses) will be summarized 
by treatment group and all treatment groups combined.


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Adverse Events
A treatment-emergent adverse event (TEAE) is defined as any adverse event that begins 
or worsens in severity on or after the first study drug dose date and no more than 
20 weeks after the last study drug dose date.
Unless otherwise specified, the treatment group differences in continuous safety variables 
(e.g., change from baseline to final observation on laboratory tests) will be assessed using 
an ANOVA model with the term of treatment, and the treatment group differences in 
binary safety variables will be evaluated using a Fisher's exact test.
8.1.6.1
Analysis of Adverse Events
Adverse events will be coded using the most current version of the Medical Dictionary for 
Regulatory Activities (MedDRA).  The number and percentage of subjects who report 
TEAEs will be tabulated by MedDRA system organ class (SOC) and preferred term (PT) 
for each treatment group, overall ABBV-8E12 and all treatment groups combined.  
Treatment group differences between each ABBV-8E12 dose group and placebo will be 
analyzed using Fisher's exact test.
The number and percent of subjects experiencing treatment-emergent SAEs (including 
deaths) and adverse events leading to premature discontinuation of study drug will be 
tabulated by MedDRA SOC and PT for each treatment group, overall ABBV-8E12 dose 
groups, and all treatment groups combined.  Treatment group differences between each 
ABBV-8E12 dose group and placebo will be analyzed using Fisher's exact test.
8.1.6.2
Analysis of Laboratory Tests
Change from baseline to each double-blind visit value and to the minimum, maximum and 
final double-blind value will be presented for each continuous hematology, chemistry and 
urinalysis parameter.  Treatment differences between each ABBV-8E12 dose group and 
placebo in change from baseline to minimum, maximum and final clinical laboratory 
evaluation will be analyzed using one-way ANOVA with treatment as the main effect.


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For each treatment group, shift tables will be generated showing the number and 
percentage of subjects with low, normal, high and missing values at baseline and final 
observation based on the reference ranges provided by each laboratory.
The number and percentage of subjects in each treatment group who have values meeting 
predefined criteria for potentially clinically significant values (definitions will be provided 
in the SAP) at any time after the first dose of study drug and no more than 20 weeks after 
the last dose of study drug or before the first dose in the planned extension study will be 
summarized separately for hematology and chemistry variables.
8.1.6.3
Analysis of Vital Signs and Weight
Vital sign variables include pulse, systolic blood pressure, diastolic blood pressure, body 
temperature, weight, and body mass index (BMI).
Change from baseline to each double-blind visit value and to the minimum, maximum and 
final double-blind value will be presented for each vital sign and weight variable and 
analyzed using one-way ANOVA with treatment as the main effect.
The number and percentage of subjects in each treatment group who have values meeting 
predefined criteria for potentially clinically significant values (definitions will be provided 
in the SAP) at any time after the first dose of study drug and no more than 20 weeks after 
the last dose of study drug or before the first dose in the planned extension study will be 
summarized.
8.1.6.4
Analysis of ECG Variables
ECG variables include heart rate, PR, QRS, QT and QTcF intervals.  Change from 
baseline to final double-blind value will be presented for each ECG parameters and 
analyzed by a one-way ANOVA with treatment as the main effect.
The number and percentage of subjects in each treatment group who have values meeting 
predefined criteria for potentially clinically significant values (defined in the SAP and 
DMC charter) at any time after the first dose of study drug will be summarized.


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8.1.6.5
Analysis of C-SSRS
Number and percentage of subjects in the following categories will be summarized for 
each treatment group by visit and for the entire study:
●
Answered 'Yes' to each C-SSRS item
●
Had suicidal ideation (defined as answering 'Yes' to one or more suicidal 
ideation items)
●
Had suicidal ideation only (defined as answering 'Yes' to one or more suicidal 
ideation items and answering 'No' to all suicidal behavior items)
●
Had suicidal behavior (defined as answering 'Yes' to one or more suicidal 
behavior items)
●
Had suicidal ideation or behavior (defined as answering 'Yes' to one or more 
suicidal ideation or behavior items
8.1.7
Pharmacokinetics
8.1.7.1
Tabulations and Summary Statistics
For the data of Cohort 1, serum concentrations of ABBV-8E12 and pharmacokinetic 
parameter values will be tabulated for each subject and each dose level, and summary 
statistics will be computed for each sampling time and each parameter by dose level.  
Also, for the serum concentration data of all subjects (Cohort 1 and Cohort 2), summary 
statistics will be provided for each scheduled time of sampling with breakdown by dose 
level.
CSF concentration data after the fourth dose and the final dose will be tabulated and 
summarized by dose level for Cohort 1. A summary of data for all subjects (Cohort 1 and 
Cohort 2) will also be included noting that CSF sample collection was optional for 
subjects in Cohort 2 per Amendment 1 of the protocol.
8.1.7.2
Model and Tests
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Change in Concentration with Repeated Dosing
The concentration data at the end the first four dose intervals in Cohort 1 will be 
summarized to investigate change in serum concentration with repeated dosing.  That is, 
the pre-dose ABBV-8E12 serum concentration data for the second through the 
fourth doses and the concentration at the end of the fourth dose interval will be 
summarized.  A MMRM analysis will be performed.  The logarithmic transformation will 
be used unless the data show that the logarithm has substantial non-symmetry 
(e.g., magnitude of skewness coefficient > 1.0) while untransformed concentration or 
another transformation has an approximately symmetric distribution.  The model will 
have effects for dose level, week and the interaction of dose level and week.  The 
concentration central value (back transformation of the LS mean of the transformed data) 
versus time curves for the three dose levels will be plotted on the same graph.  As a part 
of the investigation, hypothesis tests will be performed on the three changes in the mean 
(of the transformation) from the first three time points to the last time point.  Within the 
framework of the repeated measures analysis model, a test will be performed on the 
hypothesis of no interaction between the highest and lowest dose levels with time point.  
If this hypothesis is not rejected at level 0.05, the tests on the three mean changes will be 
performed on the time point main effects.  Otherwise, the tests will be performed for each 
dose level separately within the framework of the model.
A corresponding exploratory analysis over a longer period of time may also be performed 
on the pre-dose data of Cohorts 1 and Cohort 2 combined, beginning with Week 4 
(Dose 2) and ending with Week 72 (Dose 19), but restricted to the planned times of 
sampling of Cohort 2.  The emphasis will be estimation of any longer term trends that 
may be suggested by the data.
Dose Proportionality
An analysis will be performed on dose normalized Cmax, dose-normalized AUC and dose-
normalized Ctrough of the first and fourth dose intervals.  The logarithmic transformation 
will be employed for Cmax and AUC and will likely be used for Ctrough.  An ANCOVA will 


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be performed for each exposure variable for each of the first and fourth dose intervals, 
with the greater emphasis on the fourth dose interval.  Subjects will be classified by dose 
level, and body weight will be a covariate.  Other variables such as age and sex that might 
explain some of the variability among subjects will be considered.  A necessary condition 
for such a variable to be included in the final model is that the regression coefficient be 
significant at level 0.10.  The dependence among explanatory variable candidates will also 
be considered when selecting the final model.  Within the framework of the final model, 
the hypothesis of no difference between the means of the highest and lowest doses will be 
tested.
Accumulation Ratio
An analysis will be performed to estimate the accumulation ratio for Cmax and AUC from 
the first dose interval to the fourth dose interval.  For each of Cmax and AUC, a one-way 
ANOVA with classification by dose level will be performed on the change in the 
logarithm from first dose interval to the fourth dose interval.  If the test statistic on the 
dose level effect is significant at level 0.10, the estimate of the accumulation ratio will be 
provided for each dose level within the framework of the analysis of variance by 
exponentiation of the mean change in the logarithm (the geometric mean).  Along with the 
point estimate, a 95% confidence interval will be provided by exponentiation of 95% 
confidence limits for the mean change in the logarithm.  If the test statistic on dose level 
effect is not significant at level 0.10, a single estimate of the accumulation ratio will be 
given by exponentiation of the average of the mean changes for the three dose levels, with 
a 95% confidence interval also provided.
8.1.7.3
Missing Values and Model Violations
The possibility of bias from missing data of subjects who prematurely discontinue for 
reasons possibly related to study drug will be addressed.
It is anticipated that in a majority of cases of a missing individual concentration value in 
the first or fourth dose interval, estimates for pharmacokinetic variables (Cmax, AUC, etc.) 
will be determined without replacing missing individual concentration values, but simply 


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using the available data.  However, if a missing individual concentration value results in a 
value of a pharmacokinetic parameter that may be too low or too high to a meaningful 
degree, the value of the pharmacokinetic parameter will tentatively be considered missing.  
In this case, a value for the missing individual concentration may be imputed so that an 
appropriate value of the pharmacokinetic parameter can be included in the analysis.  The 
imputed value will be obtained using appropriate methodology that takes into account the 
individual characteristics of the subject.  Also, if the concentration value at the beginning 
or end of the dose interval is missing, a value must be imputed in order for a value of 
AUC to be determined.
Transformation of variables in order to avoid a meaningful degree of non-normality in the 
probability distributions is discussed in Section 8.1.5.  If an adequate transformation is not 
found for a variable, then a non-parametric analysis may be performed.
8.1.7.4
Population Pharmacokinetic and Exposure-Response 
Analysis
Data from this study may be combined with data from other studies for the population 
pharmacokinetic and exposure-response analyses.  Population pharmacokinetic and 
exposure-response analyses of only data from this study may not be conducted.  The 
following general methodology will be used for the population pharmacokinetic and 
exposure-response analyses.
Population pharmacokinetic analyses will be performed using the actual sampling time 
relative to dosing.  Pharmacokinetic models will be built using a non-linear mixed-effect 
modeling approach with the nonlinear mixed effect modeling (NONMEM) software 
(version VII, or higher version).  The structure of the starting pharmacokinetic model will 
be based on the pharmacokinetic analysis of data from previous studies and Cohort 1 of 
this study.  Apparent CL and volume of distribution (V) of ABBV-8E12 will be the 
pharmacokinetic parameters of major interest in the NONMEM analyses.  If necessary, 
other parameters may be fixed if useful in the analysis.


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The evaluation criteria described below will be used to examine the performance of 
different models.
●
The objective function of the best model is significantly smaller than the 
alternative model(s).
●
The observed and predicted concentrations from the preferred model are more 
randomly distributed across the line of unity (a straight line with zero intercept 
and a slope of one) than the alternative model(s).
●
Visual inspection of model fits, standard errors of model parameters and 
change in inter-subject and intra-subject error.
Once an appropriate base pharmacokinetic model (including inter- and intra-subject error 
structure) is developed, empirical Bayesian estimates of individual model parameters will 
be calculated by the posterior conditional estimation technique using NONMEM.  The 
relationship between these conditional estimates of CL and V values and potentially 
physiologically relevant or clinically meaningful covariates (such as subject age, sex, 
body weight, concomitant medications, laboratory markers of hepatic or renal function, 
etc.) will be explored using either stepwise forward selection method, or generalized 
additive method (GAM), or another suitable regression/smoothing method at a 
significance level of 0.05.  After identification of all relevant covariates, a stepwise 
backward elimination of covariates from the full model will be employed to evaluate the 
significance (at P < 0.005, corresponding to a decrease in objective function > 7.88 for 
one degree of freedom) of each covariate in the full model.
Linear or non-linear relationships of primary pharmacokinetic parameters with various 
covariates will be explored.
Relationships between exposure and clinical observations (primary efficacy variable) will 
be explored.  Exposure-response relationships for secondary efficacy variables and/or 
some safety measures of interest may also be explored.  Initially, the time-course of 
placebo response will be modeled.  Subsequently the relationship between exposure 
(e.g., population pharmacokinetic model predicted average concentrations or AUC or 


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trough concentrations of the individual model-predicted pharmacokinetic profiles, or 
some other appropriate measure of exposure) and drug effect will be explored after 
accounting for the time-course of placebo response.  Several classes of models 
(e.g., linear, log-linear, exponential, Emax, sigmoid Emax, etc.) will be evaluated to 
characterize the exposure-response relationship based on the observed data.
Additional analyses will be performed if useful and appropriate.
The possibility of bias from missing data of subjects who prematurely discontinue due to 
an adverse event will be addressed.
8.1.8
Immunogenicity
The ADA titers will be tabulated by dose level and summarized as appropriate.
Additional analyses will be performed if useful and appropriate.
8.1.9
Data Monitoring Committee (DMC)
A DMC will be employed for this study.  The DMC will be responsible for providing 
assessments of safety at regular intervals and will be conducting efficacy data reviews 
during the efficacy interim analyses.  The independent external Statistical and Data 
Analysis Center (SDAC) and Exposure-Response Analysis Center (ERAC) will be 
outside AbbVie organizations with experience in producing statistical reports that will be 
facilitating DMC meetings, conducting the analysis and preparing reports for the DMC.  
The DMC will provide recommendations about continuing, modifying, or stopping the 
trial for safety reasons or efficacy reasons.  The DMC membership and responsibilities 
will be documented in the DMC charter.  After each DMC meeting, the chair of the DMC 
will communicate its recommendations to the designated AbbVie Primary Contact or 
AbbVie IERC representative, as described in the DMC charter.  The AbbVie Primary 
Contact or the IERC representative will triage the recommendations to either the AbbVie 
Study Team if the recommendation can be implemented without unblinded data review or 
the IERC if unblinded data review is required.


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8.1.10
Interim Analysis
Interim analyses will be performed in this study to evaluate safety, target engagement, and 
efficacy of ABBV-8E12 treatment in the Early AD population.  Assessment of safety and 
efficacy data at interim will be conducted by the DMC.  Assessment of target engagement 
will be conducted by the AbbVie Internal Biomarker Review Committee (IBRC).
Safety Interim Reviews
The first four mandatory safety DMC reviews of unblinded safety data will take place 
after the 12th, 24th, 36th and 48th subject have been administered their second dose and 
results for the MRI scheduled at approximately 2 weeks after their second dose are 
available.  The data set will consist of all of the available safety and pharmacokinetic data 
in the study, including the data of any subjects from Cohort 2 who have received at least 
one dose of study drug when the data is cut.  Additional safety DMC reviews will occur 
after a total of approximately 100, 200, 300, and 400 subjects are randomized and every 
6 months thereafter until the study has completed.  Additional unplanned safety DMC 
reviews can occur at the discretion of the DMC and/or AbbVie.
The DMC chair will make recommendations to the AbbVie Primary Contact (who is not 
involved in the conduct of the trial) regarding continuing, modifying or terminating the 
trial due to safety concerns in accordance with the DMC charter.
Interim analysis for Target Engagement
An assessment of target engagement analysis for the first 48 Cohort 1 subjects will be 
conducted by the IBRC.  Biomarkers for target engagement will be defined as including 
both target binding (CSF free tau, CSF total tau, and plasma tau) and pharmacodynamic 
activity (CSF and plasma NFL).  An AbbVie internal biomarker team not involved in the 
study conduct and firewalled from the study team will perform detailed analysis on target 
engagement and provide the results to the IBRC.  This interim analysis results will guide 
the decision if an early futility analysis should be conducted.  Details of the target 
engagement analysis will be described in a separate biomarker analysis plan.


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Efficacy Interim Analyses
Efficacy interim analyses will be performed.  The DMC will be responsible for the interim 
efficacy reviews.  The DMC will make recommendations to the sponsor IERC 
representative regarding initiating of Phase 3 development, continuing the study to 
completion or terminating the study based on interim analysis results.
Futility stopping rules for the efficacy and decision rules for initiating phase 3 will be 
implemented in the efficacy interim analyses.  Details of interim analyses will be 
described in the SAP and DMC charter.
8.2
Determination of Sample Size
Approximately 400 Early AD subjects (100 subjects/group) will be enrolled and 
randomized into three ABBV-8E12 dose groups and placebo with 1:1:1:1 randomization 
ratio.  This sample size has about 80% power to detect an ABBV-8E12 treatment effect 
size (vs. placebo) of 0.45 for both the high dose and the middle dose and 0.28 for the low 
dose on CDR-SB score changes from baseline up to Week 96 using one-sided test at the 
2.5% significance level-with Bonferroni method to adjust multiplicity.35  This power 
assessment was based on the assumption that 25% subjects do not have post-baseline data 
and the calculation was conducted using Cytel EAST version 6.4.
8.3
Randomization Methods
Approximately 400 subjects will be enrolled into the study and randomized through the 
IVR/IWB system in a 1:1:1:1 ratio to one of the 3 ABBV-8E12 doses or placebo at the 
Day 1 Visit after the site verifies that the subject is eligible to participate in the study.  The 
first dose of study drug will be administered after randomization at the same visit.  
Subject randomization will be stratified by site.


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9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to International Conference on 
Harmonization (ICH) GCP.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki.  Responsibilities of the clinical 
investigator are specified in Appendix A.
In the event of a state of emergency due to the COVID-19 pandemic leading to difficulties 
in performing protocol-specified procedures, AbbVie will engage with study site 
personnel in an effort to ensure the safety of subjects, maintain protocol compliance, and 
minimize risks to the integrity of the study while trying to best manage subject continuity 
of care.  This may include alternative methods for assessments (e.g., contact by phone or 
virtual site visits), alternative locations (e.g., use of infusion centers), and the shipping of 
IP and/or supplies directly to subjects.  In all cases, these alternative measures must be 


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permitted by local regulations and the IEC/IRB.  Investigators should notify AbbVie if 
any urgent safety measures are taken to protect the subjects against any immediate 
hazards.
9.3
Subject Information and Consent
Prior to the initiation of any screening or study-specific procedures, the investigator or 
his/her representative will explain the nature of the study to the subject, their study 
partner, and the subject's representative (if applicable), and answer all questions regarding 
this study.  Each informed consent will be reviewed, signed and dated by the subject, the 
person who administered the informed consent, and any other signatories according to 
local requirements.  An informed consent statement will also be reviewed, signed and 
dated, by the subject's study partner prior to beginning any study related screening 
activities.  A copy of each informed consent will be given to the subject and their study 
partner and each original will be placed in the subject's medical record.  An entry must 
also be made in the subject's dated source documents to confirm that informed consent 
was obtained prior to any study-related procedures and that the subject received a signed 
copy.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
In the event a subject withdraws consent to participate from the study, stored biomarker 
and optional pharmacogenetic research samples will continue to be used for research and 
analysis.  In the event that a subject would like to withdraw consent for research using 
these samples, the subject may request that their samples be withdrawn.  Once AbbVie 
receives the request, remaining biomarker and optional pharmacogenetic research samples 
will be destroyed.  If the subject changes his/her consent, and the samples have already 
been tested, those results will still remain as part of the overall research data.


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An informed consent, approved by an IEC/IRB, must be voluntarily signed and dated 
before samples are collected for optional pharmacogenetic research.  The nature of the 
testing should be explained and the subject given an opportunity to ask questions.  The 
informed consent must be signed before the samples are collected and any testing is 
performed.  If the subject does not consent to provide samples for the pharmacogenetic 
exploratory research, it will not impact their participation in the study.
Due to the COVID-19 pandemic, protocol modifications in addition to those outlined in 
this protocol may become necessary.  If this situation arises, verbal consent may be added 
to the informed consent already included in this protocol.  Verbal consent would need to 
be obtained prior to making adaptations or substantial changes in study conduct in 
accordance with local regulations.
10.0
Source Documents, Data Collection and Electronic 
Case Report Forms
10.1
Source Documents
Source documents are defined as original documents, data, and records.  These may 
include hospital records, clinical and office charts, laboratory data/information, subject 
diaries or evaluation checklists, pharmacy dispensing and other records, recorded data 
from automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Source document data may be transcribed as required.  Data 
collected during this study must be recorded to the appropriate source document.
The investigator/institution will permit study-related monitoring, audits, IEC/IRB review, 
and regulatory inspection(s), providing direct access to source data documents.
10.2
Data Collection/Electronic Case Report Forms
Electronic case report forms (eCRFs) must be completed for each subject 
screened/enrolled in this study.  These forms will be used to transmit information 
collected during the study to AbbVie and regulatory authorities, as applicable.  The case 
report form (CRF) data for this study are being collected with an electronic data capture 


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(EDC) system called Rave® provided by the technology vendor Medidata Solutions 
Incorporated, NY, USA.  The EDC system and the study-specific eCRFs will comply with 
Title 21 CFR Part 11.  The documentation related to the validation of the EDC system is 
available through the vendor, Medidata, while the validation of the study-specific eCRFs 
will be conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of Internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.
11.0
Data Quality Assurance
Prior to enrolling any subject in the study, an initiation meeting will be held with AbbVie 
personnel, the investigator(s), and the study coordinators/project manager(s).  This 


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meeting will include a detailed discussion and review of the protocol and essential 
documents, performance of study procedures, CRF completion and specimen collection 
methods.
The AbbVie monitor will monitor the study site throughout the study according to a 
monitoring plan.  Source document review will be made against entries in RAVE and a 
quality assurance check will be performed to ensure that the investigator is complying 
with the protocol and regulations.  During the study, an ongoing review of the data will be 
conducted by a physician or representative at AbbVie.  Computer logic will be run to 
identify inconsistent study data.  Any necessary corrections will be made to the database 
via the appropriate change process.
During the COVID-19 pandemic, remote source document review of data may be 
employed if permitted by the local regulatory authority, the IEC/IRB, and the study site.
12.0
Use of Information
All information concerning ABBV-8E12 and AbbVie operations, such as AbbVie patent 
applications, formulas, manufacturing processes, basic scientific data, or formulation 
information, supplied by AbbVie and not previously published is considered confidential 
information.
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of 
ABBV-8E12.  This information may be disclosed as deemed necessary by AbbVie to 
other clinical investigators, other pharmaceutical companies, and to governmental 
agencies.  To allow for the use of the information derived from this clinical study and to 
ensure complete and thorough analysis, the investigator is obligated to provide AbbVie 
with complete test results and all data developed in this study and to provide direct access 
to source data/documents for study-related monitoring, audits, IEC/IRB review, and 
regulatory inspection.


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This confidential information shall remain the sole property of AbbVie, shall not be 
disclosed to others without the written consent of AbbVie, and shall not be used except in 
the performance of this study.
The investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study, including each subject's name, subject number, address, phone 
number and emergency contact information.  This list will be maintained at the study site 
with other study records under adequate security and restricted access, and will not be 
retrieved by AbbVie.
Any research that may be done using research samples from this study will be 
experimental in nature and the results will not be suitable for clinical decision making or 
patient management.  Hence, the subject will not be informed of individual results, should 
analyses be performed, nor will anyone not directly involved in this research.  
Correspondingly, researchers will have no access to subject identifiers.  Individual results 
will not be reported to anyone not directly involved in this research other than for 
regulatory purposes.  Aggregate data from research may be provided to investigators and 
used in scientific publications or presented at medical conventions.  Research information 
will be published or presented only in a way that does not identify any individual subject.
13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The investigator must retain any records related to the study according to local 
requirements.  If the investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.


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AbbVie will select the signatory coordinating investigator from the investigators who 
participate in each multicenter study.  Selection criteria for this signatory investigator will 
be based on level of participation, and significant knowledge of the clinical research, 
investigational drug, and study protocol.  The signatory investigator for the study will 
review and sign the final study report in accordance with the European Medicines Agency 
(EMA) Guidance on Investigator's Signature for Study Reports.
The end of study is defined as the date of the last subject's last visit.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for ABBV-8E12.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title:
A Phase 2 Multiple Dose, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study to Evaluate the Efficacy and Safety of 
ABBV-8E12 in Subjects with Early Alzheimer's Disease
Protocol Date:
02 October 2020
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1.
Anders Wimo MP.  World Alzheimer Report 2015.  Alzheimer's Disease 
International.  2015;1-87.
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Rogers SL, Farlow MR, Doody RS, et al.  A 24-week, double-blind, placebo-
controlled trial of donepezil in patients with Alzheimer's disease.  Donepezil Study 
Group.  Neurology.  1998;50(1):136-45.
3.
Raskind MA, Peskind ER, Wessel T, et al.  Galantamine in AD:  a 6-month 
randomized, placebo-controlled trial with a 6-month extension.  The Galantamine 
USA-1 Study Group.  Neurology.  2000;54(12):2261-8.
4.
Holtzman DM, Morris JC, Goate AM.  Alzheimer's disease:  the challenge of the 
second century.  Sci Transl Med.  2011;3(77):77sr1.
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Doody RS, Thomas RG, Farlow M, et al.  Phase 3 trials of solanezumab for mild-
to-moderate Alzheimer's disease.  N Engl J Med.  2014;370(4):311-21.
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Salloway S, Sperling R, Fox NC, et al.  Two phase 3 trials of bapineuzumab 
in mild-to-moderate Alzheimer's disease.  N Engl J Med.  2014;370(4):322-33.
7.
Yanamandra K, Kfoury N, Jiang H, et al.  Anti-tau antibodies that block tau 
aggregate seeding in vitro markedly decrease pathology and improve cognition in 
vivo.  Neuron.  2013;80(2):402-14.
8.
Yanamandra K, Jiang H, Mahan TE, et al.  Anti-tau antibody reduces insoluble tau 
and decreases brain atrophy.  Ann Clin Transl Neurol.  2015;2(3):278-88.
9.
AbbVie.  ABBV-8E12 Investigator's Brochure Edition 1.  22 April 2016.
10.
Albert MS, DeKosky ST, Dickson D, et al.  The diagnosis of mild cognitive 
impairment due to Alzheimer's disease:  recommendations from the national 
institute on aging-Alzheimer's association workgroups on diagnostic guidelines for 
Alzheimer's disease.  Alzheimers Dement.  2011;7(3):270-9.
11.
Duits FH, Martinez-Lage P.  Performance and complications of lumbar puncture in 
memory clinics:  results of the multicenter lumbar puncture feasibility study.  
Alzheimer's Dement.  2016;12(2):154-63.


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12.
Morris JC.  The Clinical Dementia Rating (CDR):  current vision and scoring rules.  
Neurology.  1993;43(11):2412-4.
13.
Skinner J, Carvalho JO, Potter GG, et al.  The Alzheimer's Disease Assessment 
Scale-Cognitive-Plus (ADAS-Cog-Plus):  an expansion of the ADAS-Cog to 
improve responsiveness in MCI.  Brain Imaging Behav.  2012;6(4):489-501.
14.
Folstein MF, Folstein SE, McHugh PR.  "Mini-mental state."  A practical method 
for grading the cognitive state of patients for the clinician.  J Psychiatr Res.  
1975;12(3):189-198.
15.
Tombaugh TN, McIntyre NJ.  The mini-mental state examination:  a 
comprehensive review.  J Am Geriatr Soc.  1992;40(9):922-35.
16.
Teng E, Becker BW, Woo E, et al.  Utility of the functional activities questionnaire 
for distinguishing mild cognitive impairment from very mild Alzheimer disease.  
Alzheimer Dis Assoc Disord.  2010;24(4):348-53.
17.
Pfeffer RI, Kurosaki TT, Harrah CH Jr, et al.  Measurement of functional activities 
in older adults in the community.  J Gerontol.  1982;37(3):323-9.
18.
Cummings JL, Mega M, Gray K, et al.  The Neuropsychiatric Inventory:  
comprehensive assessment of psychopathology in dementia.  Neurology.  
1994;44(12):2308-14.
19.
Cummings JL.  The Neuropsychiatric Inventory:  assessing psychopathology in 
dementia patients.  Neurology.  1997;48 (Suppl 6):S10-6.
20.
Kaufer DI, Cummings JL, Christine D, et al.  Assessing the impact of 
neuropsychiatric symptoms in Alzheimer's disease:  the Neuropsychiatric Inventory 
Caregiver Distress Scale. J Am Geriatr Soc.  1998;46(2):210-5.
21.
Galasko D, Bennett D, Sano M, et al.  An inventory to assess activities of daily 
living for clinical trials in Alzheimer's disease.  Alzheimer Dis Assoc Disord.  
1997;11 (Suppl 2):S33-9.
22.
Pedrosa H, De Sa A, Guerreiro M, et al.  Functional evaluation distinguishes MCI 
patients from healthy elderly people--the ADCS/MCI/ADL scale.  J Nutr Health 
Aging.  2010;14(8):703-9.


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23.
Perneczky R, Pohl C, Sorg C, et al.  Impairment of activities of daily living 
requiring memory or complex reasoning as part of the MCI syndrome.  Int J Geriatr 
Psychiatry.  2006;21(2):158-62.
24.
Schneider LS, Olin JT, Doody RS, et al.  Validity and reliability of the Alzheimer's 
Disease Cooperative Study-Clinical Global Impression of Change.  The 
Alzheimer's Disease Cooperative Study.  Alzheimer Dis Assoc Disord.  
1997;11 (Suppl 2):S22-32.
25.
Schneider LS, Raman R, Schmitt FA, et al.  Characteristics and performance of a 
modified version of the ADCS-CGIC CIBIC+ for mild cognitive impairment 
clinical trials.  Alzheimer Dis Assoc Disord.  2009;23(3):260-7.
26.
Hachinski VC, Iliff LD, Zilhka E, et al.  Cerebral blood flow in dementia.  Arch 
Neurol.  1975;32(9):632-7.
27.
Molsa PK, Paljarvi L, Rinne JO, et al.  Validity of clinical diagnosis in dementia:  a 
prospective clinicopathological study.  J Neurol Neurosurg Psychiatry.  
1985;48(11):1085-90.
28.
Randolph C, Tierney MC, Mohr E, et al.  The Repeatable Battery for the 
Assessment of Neuropsychological Status (RBANS):  preliminary clinical validity.  
J Clin Exp Neuropsychol.  1998;20(3):310-9.
29.
Gomar JJ, Harvey PD, Bobes-Bascaran MT, et al.  Development and cross-
validation of the UPSA short form for the performance-based functional 
assessment of patients with mild cognitive impairment and Alzheimer disease.  Am 
J Geriatr Psychiatry.  2011;19(11):915-22. 
30.
Columbia-Suicide Severity Rating Scale (C-SSRS) [homepage on the Internet].  
Columbia University Medical Center.  Available from:  
http//www.cssrs/Columbia.edu/.
31.
Grande L, Rudolph J, Davis R, et al.  Clock drawing: Standing the test of time.  In:  
Ashendorf Le Swenson (editor).  The Boston process approach to 
neuropsychological assessment.  Oxford:  Oxford University Press.  2013.


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32.
Muller S, Preische O, Heymann P, et al.  Increased diagnostic accuracy of digital 
vs. conventional clock drawing test for discrimination of patients in the early 
course of Alzheimer's disease from cognitively healthy individuals.  Front Aging 
Neurosci.  2017;9:101.
33.
Xi D, Tamhane A.  Allocating recycled significance levels in group sequential 
procedures for multiple endpoints.  Biomet J.  2015;57(1):90-107.
34.
Maurer W, Bretz F.  Multiple testing in group sequential trials using graphical 
approaches.  Stat Biopharm Res.  2013;5(4):311-20.
35.
Hochberg Y.  A sharper Bonferroni procedure for multiple tests of significance.  
Biometrika.  1988;75:800-2.


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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees (e.g., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.


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9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Clinical Program Development
Medical Writing
Statistics
Statistics
Pharmacokinetics
Neuroscience


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Appendix C.
Study Activities
Screening
Treatment Perioda (Year 1)
Visit 1
Visit 2
Dose 1
Dose 
2
Dose 
3
Dose 4
Dose 
5
Dose 
6
Dose 
7
Dose 
8
Dose 
9
Dose 
10
Dose 
11
Dose 
12
Dose 
13
Weeks of Study Drug Exposure
N/A
N/A
0
0
2
4
8
12
12
14
16
20
24
28
32
36
40
44
48
Day –84 to 
–8
Day –7 
to –1c
Day 
1c
Days 5d, 
15c,d
Day 
29c
Day 
57c
Day 
85c
Days 89d, 
99d
Day 
113c
Day 
141c
Day 
169c
Day 
197c
Day 
225c
Day 
253c
Day 
281c
Day 
309c
Day 
337c
Informed Consent and Study 
Partner identification
X
Medical/early AD History 
X
Drug Screen (Urine) and 
Hepatitis Screen
X
Weight & Heighte
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
Neurological Exam
X
X
C1
X
X
X
C1
X
X
X
X
X
Vital Signs
X
X
C1
X
X
X
C1
X
X
X
X
X
X
X
X
X
12-Lead ECGf
X
X
C1
X
X
X
X
X
X
Clinical Laboratory Tests
X
X
X
X
X
X
X
X
X
X
Randomizationg
X
Administer IV Study Drug
X
X
X
X
X
X
X
X
X
X
X
X
X
Amyloid PET Scan
X
Tau PET Scano
X
Xp
Retinal Imaging Scan
X
MRI
X
Xh
Xh
Xh
Xh


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Screening
Treatment Perioda (Year 1)
Visit 1
Visit 2
Dose 1
Dose 
2
Dose 
3
Dose 4
Dose 
5
Dose 
6
Dose 
7
Dose 
8
Dose 
9
Dose 
10
Dose 
11
Dose 
12
Dose 
13
Weeks of Study Drug Exposure
N/A
N/A
0
0
2
4
8
12
12
14
16
20
24
28
32
36
40
44
48
Day –84 to 
–8
Day –7 
to –1c
Day 
1c
Days 5d, 
15c,d
Day 
29c
Day 
57c
Day 
85c
Days 89d, 
99d
Day 
113c
Day 
141c
Day 
169c
Day 
197c
Day 
225c
Day 
253c
Day 
281c
Day 
309c
Day 
337c
Lumbar Puncture/CSF Sample 
Collectionr
X
Xi
APOE Pharmacogenetic Sample
X
Optional Pharmacogenetic 
Sample (DNA and RNA)j
X
X
X
X
X
Biomarker Plasma and Serum 
Sample
X
X
X
X
X
Blood Samples for ABBV-8E12 
Assayk
X
C1
X
C1
X
C1
C1
X
X
X
ADA Samplek
X
C1l
X
C1
X
C1
C1
X
X
X
Diagnostic Tools and Rating 
Scalesm
X
X
Xq
X
Xq
X
Columbia Suicide Severity Rating 
Scale
X
X
C1
X
X
X
C1
X
X
X
X
X
X
X
X
X
Concomitant Medication Review
X
X
X
C1
X
X
X
C1
X
X
X
X
X
X
X
X
X
Adverse Event Monitoringn
X
X
X
C1
X
X
X
C1
X
X
X
X
X
X
X
X
X


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Treatment Perioda (Year 2)
Post-Treatment 
Follow-Up 
Perioda,b
Dose 
14
Dose 
15
Dose 
16
Dose 
17
Dose 
18
Dose 
19
Dose 
20
Dose 
21
Dose 
22
Dose 
23
Dose 
24
Completion 
Visit/PD
Week 
104
Week 
112
Weeks of Study Drug Exposure
52
56
60
64
68
72
76
80
84
88
92
96
N/A
N/A
Day 
365c
Day 
393c
Day 
421c
Day 
449c
Day 
477c
Day 
505c
Day 
533c
Day 
561c
Day 
589c
Day 
617c
Day 
645c
Day 673c
Days 
729
Day 
785
Physical Exam
X
X
Neurological Exam
X
X
X
X
X
Weight & Heighte
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGf
X
X
X
Clinical Laboratory Tests
X
X
X
X
X
Administer IV Study Drug
X
X
X
X
X
X
X
X
X
X
X
MRI
Xh
X
Tau PET Scano
Xp
Lumbar Puncture/CSFr 
X
Optional Pharmacogenetic Sample (DNA and 
RNA)j
X
X
Biomarker Plasma and Serum Sample
X
X
Blood Samples for ABBV-8E12 Assayk
X
X
X
X
ADA Samplek
X
X
X
X
Diagnostic Tools and Rating Scalem,q
X
X
Columbia Suicide Severity Rating Scale 
X
X
X
X
X
X
X
X
X
X
X
X
X


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Treatment Perioda (Year 2)
Post-Treatment 
Follow-Up 
Perioda,b
Dose 
14
Dose 
15
Dose 
16
Dose 
17
Dose 
18
Dose 
19
Dose 
20
Dose 
21
Dose 
22
Dose 
23
Dose 
24
Completion 
Visit/PD
Week 
104
Week 
112
Weeks of Study Drug Exposure
52
56
60
64
68
72
76
80
84
88
92
96
N/A
N/A
Day 
365c
Day 
393c
Day 
421c
Day 
449c
Day 
477c
Day 
505c
Day 
533c
Day 
561c
Day 
589c
Day 
617c
Day 
645c
Day 673c
Days 
729
Day 
785
Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Monitoringn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C1 – Cohort 1 subjects only, Procedures should be conducted at approximately the same time as they would be conducted on the days of dosing.
a.
Visits on Days 5, 15, 89 and 99 must be scheduled within ± 2 days of the scheduled date.  Visits on all other days may be scheduled within ± 4 days of the scheduled date.
b.
Post-Treatment Visits to occur approximately 8 and 16 weeks after the Completion or Premature Discontinuation (PD) visit.
c.
Assessments on Day –7 to –1 will be done once during this time frame and can be administered on any day, but all should be done on the same day.  Assessments may also be 
completed on Day 1, but must be completed prior to the start of the study drug infusion.  At visits after Day 1 rating scales may be completed on any day within the visit 
window prior to the visit, but all rating scales should be completed on the same day.
d.
Only subjects enrolled in Cohort 1 will be required to return to the clinical site 5 and 15 days after doses 1 and 4.
e.
Height collected at Screening Visit 1 only.  On dosing days, weight will be collected prior to the start of the infusion.
f.
A detailed description for the timing of 12-Lead Single ECGs can be found in Section 5.3.1.1.
g
Randomization should be completed just prior to the first dose administration.
h.
The MRI will be scheduled approximately 2 weeks following the dose and results must be available prior to the next scheduled dose.
i.
The lumbar puncture will be performed approximately 14 days after the fourth dose.
j.
The optional Pharmacogenetic DNA and RNA samples require consent.  Verify consent prior to sample collection.
k.
A detailed description of the collection time points can be found in Section 5.3.2.1.
l.
ADA sample for Cohort 1 will only be collected on Day 15.
m.
See Table 4 for additional information on Diagnostic Tools and Rating Scales.
n.
A detailed description for procedures involving adverse event assessments can be found in Section 6.0.


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o.
Tau PET scan obtained only for subjects at sites selected to participate in the tau imaging assessment.
p.
Tau PET should be scheduled as close as possible to Weeks 44 (Dose 12) and 96 visits.
q.
On Weeks 12 and 36, only digital clock drawing test will be performed.
r.
The lumbar punctures at Screening Visit 1, Weeks 12 and 96 are optional for subjects in Cohort 2.












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Appendix E.
Protocol Amendment:  List of Changes
The summary of changes can be found in Section 1.1.
Specific Protocol Changes
Section 1.2  Synopsis
Subsection Methodology:
Fifth paragraph
Delete:  last sentence
Japanese subjects enrolled in Cohort J1 will follow safety and pharmacokinetic sample 
collection procedures of Cohort 1; however, the lumbar puncture will be optional for 
Cohort J1 subjects.
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Add:
COVID-19
Coronavirus disease-2019
DTP
Direct-to-Patient
IBRC
Internal Biomarker Review Committee
IERC
Internal Executive Review Committee
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Delete:
IRC
Independent Review Committee
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Abbreviation "MMA" previously read:
MMA
Methylmalonic acide


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Has been changed to read:
MMA
Methylmalonic acid
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Delete:
Sub-IRC
Sub-team of Internal Review Committee
Section 3.2  Benefits and Risks
Add:  new last paragraph
In consideration of the coronavirus disease (COVID-19) pandemic, the benefits and risks 
to subjects participating in this study have been re-evaluated.  Based on the limited 
information to date, no additional risk is anticipated for study participants infected with 
SARS-Cov2 during the COVID-19 pandemic, due to the mechanism of action of 
ABBV-8E12.
Section 5.1  Overall Study Design and Plan:  Description
Fifth paragraph
Delete:  last sentence
Japanese subjects enrolled in Cohort J1 will follow safety and PK sample collection 
procedures of Cohort 1; however, the lumbar puncture will be optional for Cohort J1 
subjects.
Table 1.  Safety and PK Procedures for Cohort 1 and Cohort J1
Table title previously read:
Safety and PK Procedures for Cohort 1 and Cohort J1
Has been changed to read:
Safety and PK Procedures for Cohort 1


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Table 1.  Safety and PK Procedures for Cohort 1 and Cohort J1
Header row, column "Cohort 1 and Cohort J1, Doses 1 – 4" previously read:
Cohort 1 and Cohort J1, Doses 1 – 4
Has been changed to read:
Cohort 1, Doses 1 – 4
Table 1.  Safety and PK Procedures for Cohort 1 and Cohort J1
Week of study drug exposure "Lumbar Puncture/CSF Sample Collectionf" 
previously read:
Lumbar Puncture/CSF Sample Collectionf
Has been changed to read:
Lumbar Puncture/CSF Sample Collection
Table 1.  Safety and PK Procedures for Cohort 1 and Cohort J1
Delete:  table note "f."
Lumbar puncture will be optional for Cohort J1.
Section 5.2.1  Inclusion Criteria
Criterion 3, first paragraph previously read:
Subject who meets the National Institute on Aging and the Alzheimer's Association (NIA-
AA) clinical criteria for mild cognitive impairment or probable AD,35 and has:
Has been changed to read:
Subject who meets the National Institute on Aging and the Alzheimer's Association (NIA-
AA) clinical criteria for mild cognitive impairment or probable AD,10 and has:


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Section 5.2.1  Inclusion Criteria
Criterion 6, last sentence previously read:
The study partner has voluntarily signed the IRB/IEC approved Study Partner Informed 
Consent, prior to the conduct of any study procedures.
Has been changed to read:
The study partner has voluntarily signed the IEC/IRB approved Study Partner Informed 
Consent, prior to the conduct of any study procedures.
Section 5.3.1.1  Study Procedures
Add:  new first paragraph
Study visits may be impacted due to the COVID-19 pandemic may include changes such 
as phone or virtual visits, visits at alternative locations, or changes in the visit frequency 
and timing of study procedures.  Additional details are provided in the subsequent 
sections of this protocol.  Every effort should be made to ensure the safety of subjects and 
onsite staff, while maintaining the integrity of the study.  If visits cannot be conducted 
onsite due to travel restrictions or other pandemic-related reasons, the updates below on 
how to proceed should be followed.
Section 5.3.1.1  Study Procedures
Subsection Physical Examination
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event physical examinations may not be performed due to study modifications 
related to the COVID-19 pandemic, these examinations should be completed at the next 
onsite visit.


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Section 5.3.1.1  Study Procedures
Subsection Neurological Examination
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event neurological examinations may not be performed due to study modifications 
related to the COVID-19 pandemic, these examinations should be completed at the next 
onsite visit.
Section 5.3.1.1  Study Procedures
Subsection Vital Signs
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event vital signs may not be obtained due to study modifications related to the 
COVID-19 pandemic, these measurements should be obtained at the next onsite visit.
Section 5.3.1.1  Study Procedures
Subsection 12-Lead Electrocardiogram (ECG)
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event 12-lead ECG may not be performed due to study modifications related to the 
COVID-19 pandemic, this procedure should be completed at the next onsite visit.


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Section 5.3.1.1  Study Procedures
Subsection Abnormal Findings
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event clinical laboratory tests may not be performed due to study modifications 
related to the COVID-19 pandemic, these tests should be completed at the next onsite 
visit.
If laboratory tests cannot be performed, study drug may be administered to subjects if the
investigator has reviewed all prior laboratory results and confirms there are no safety 
concerns.
Section 5.3.1.1  Study Procedures
Subsection Lumbar Puncture (LP)
First paragraph, first and second sentence previously read:
Lumbar punctures are required for subjects enrolled in Cohort 1 and are optional for 
subjects enrolled in Cohort 2 and Cohort J1.  For all Cohort 1 subjects and subjects 
agreeing to LPs in Cohort 2 and Cohort J1, LPs to collect CSF will be performed at time 
points indicated in the Study Activities Table (Appendix C).
Has been changed to read:
Lumbar punctures are required for subjects enrolled in Cohort 1 and are optional for 
subjects enrolled in Cohort 2.  For all Cohort 1 subjects and subjects agreeing to LPs in 
Cohort 2, LPs to collect CSF will be performed at time points indicated in the Study 
Activities Table (Appendix C).


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Section 5.3.1.1  Study Procedures
Subsection Lumbar Puncture (LP)
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event lumbar puncture may not be performed due to study modifications related to 
the COVID-19 pandemic, this procedure should be completed at the next onsite visit.
Section 5.3.1.1  Study Procedures
Subsection Magnetic Resonance Imaging (MRI)
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event MRI may not be performed due to study modifications related to the 
COVID-19 pandemic, this procedure should be completed at the next onsite visit.
Section 5.3.1.1  Study Procedures
Subsection Positron Emission Tomography (PET) Tau Imaging
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event the tau PET scan may not be performed due to study modifications related to 
the COVID-19 pandemic, this procedure should be completed at the next onsite visit.


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Section 5.3.1.1  Study Procedures
Subsection Positron Emission Tomography (PET) Tau Imaging
Heading "Retinal Imaging for Amyloid"
Subheading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new subheading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event the retinal scan may not be performed due to study modifications related to 
the COVID-19 pandemic, this procedure should be completed at the next onsite visit.
Table 4.  Diagnostic Tools and Scale Administration Timing
Abbreviation "UPSA - Brief" previously read:
UPSA - Brief = University of California San Diego Performance Based Skills 
Assessment, Brief Version
Has been changed to read:
UPSA Brief = University of California San Diego Performance Based Skills Assessment, 
Brief Version
Section 5.3.1.1  Study Procedures
Subsection Diagnostic Tools and Rating Scales
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If scale administration is not performed due to study modifications related to the 
COVID-19 pandemic, the scale(s) should be completed at the next onsite visit.  Should a 
virtual visit be conducted, the investigator should refer to the table below for scales that 
may be administered remotely.


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Scale
May be Administered Via Phone or Video 
Conference
ADAS-Cog-14
No
ADCS-CGIC-MCI 
Yes
ADCS-MCI-ADL-24
Yes
CDR
Yes
C-SSRS
Yes
dCDT
No
FAQ
Yes
MMSE
No
NPI
Yes
RBANS
No
UPSA – Brief
No
ADAS-Cog-14 = Alzheimer's Disease Assessment Scale (14-Item) Cognition Portion; ADCS-CGIC-MCI = Alzheimer's 
Disease Cooperative Study Clinician's Global Impression of Change for Mild Cognitive Impairment; ADCS-MCI-ADL-
24 = 24-item Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted for Patients with Mild 
Cognitive Impairment; CDR = Clinical Dementia Rating; C-SSRS = Columbia-Suicide Severity Rating Scale; 
dCDT = Digital clock drawing test; FAQ = Functional Activities Questionnaire; MMSE = Mini-Mental State 
Examination; NPI = Neuropsychiatric Inventory; RBANS = Repeatable Battery for Assessment of Neuropsychological 
Status; USPA Brief = University of California San Diego Performance Based Skills Assessment, Brief Version
Section 5.3.1.2  Collection and Handling of Biomarker and Pharmacogenetic 
Research Samples
Subsection Apolipoprotein E (APOE) Pharmacogenetic Sample
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event blood and optional CSF biomarker samples may not be collected due to study 
modifications related to the COVID-19 pandemic, these samples should be obtained at the 
next onsite visit.


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Section 5.3.1.2  Collection and Handling of Biomarker and Pharmacogenetic 
Research Samples
Subsection Optional Pharmacogenetic Research Samples
Heading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new heading title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event optional pharmacogenetic research samples may not be collected due to study 
modifications related to the COVID-19 pandemic, these samples should be obtained at the 
next onsite visit.
Section 5.4.1  Discontinuation of Individual Subjects
Subsection COVID-19 Pandemic-Related Acceptable Protocol Modifications
Add:  new subsection title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Subjects who miss multiple study drug doses due to the COVID-19 pandemic may 
continue participation with approval from the TA MD.
Section 5.5.1  Treatments Administered
Second paragraph previously read:
Study drug will be administered by IV infusion in the morning (if possible) at each visit as 
follows:
Has been changed to read:
Study drug will be administered by IV infusion, preferably in the morning but should be 
around the same time at each visit as follows:
Section 5.5.1  Treatments Administered
Last paragraph, last sentence previously read:
Refer to the Pharmacy Manual for detailed instructions.


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Has been changed to read:
The start of study drug infusion occurs from ABBV-8E12 initiation up until the 
administration of the complete dose (including flush). The Pharmacy Manual may be 
referred to for detailed instructions.
Section 5.5.1  Treatments Administered
Subsection Home Healthcare Service Due to the COVID-19 Pandemic
Add:  new subsection title and text
Home Healthcare Service Due to the COVID-19 Pandemic
Subjects may be offered the option of home healthcare visits provided by a study nurse or 
third-party vendor based on the subject's suitability as assessed by the investigator and 
following the subject's written consent.  This option can only be offered in countries and 
sites that comply with local regulatory and IEC/IRB requirements for home healthcare.  
Any prerequisite submissions or notifications to the site IEC/IRB and local competent 
health authority should be made and approved prior to the implementation of home 
infusions.
Table 5.  Identity of Investigational Product
Previously read:
Investigational 
Product
Mode of 
Administration
Formulation
Strength
Manufacturer
ABBV-8E12
Infusion
Solution for 
infusion in a vial
300 mg/15 mL
1000 mg/ 
10 mL
AbbVie Deutschland 
GmbH & Co. KG, 
Ludwigshafen, 
Germany
Placebo
Infusion
0.9% Sodium 
Chloride 
Injection/Solution 
for infusion, 
250 mL
N/A
Various*
(See below)
N/A = not applicable
*
Can be sourced from approved marketed products from various commercial manufacturers depending on 
availability.


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Has been changed to read:
Investigational Product
Mode of 
Administration
Formulation
Strength
ABBV-8E12
Infusion
Solution for infusion in 
a vial
300 mg/15 mL
1000 mg/ 10 mL
Placebo
Infusion
0.9% Sodium Chloride 
Injection/Solution for 
infusion, 250 mL
N/A
N/A = not applicable
Section 5.5.2.2  Storage and Disposition of Study Drugs
Third paragraph, third sentence previously read:
Malfunctions or any temperature excursion must be reported to the Sponsor immediately 
using the AbbVie Temperature Excursion Management System (ATEMS).
Has been changed to read:
All temperature excursions lasting longer than 30 minutes must be reported to the Sponsor 
immediately using the AbbVie Temperature Excursion Management System (ATEMS).
Section 5.5.5  Blinding
Subsection Unblinding of Data for the Data Monitoring Committee (DMC)
Seventh sentence previously read:
An AbbVie Independent Review Committee (IRC) may request access to closed reports if 
the discontinuation of the study, major modifications to the study design, or Phase 3 
initiation is recommended by the DMC as outlined in the DMC charter.
Has been changed to read:
An AbbVie Internal Executive Review Committee (IERC) may request access to closed 
reports if the discontinuation of the study, major modifications to the study design, or 
Phase 3 initiation is recommended by the DMC as outlined in the DMC charter.


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Section 5.5.5  Blinding
Subsection Unblinding of Data for the Data Monitoring Committee (DMC)
Last sentence previously read:
The AbbVie Representative and the AbbVie IRC members will not be involved in any 
aspects of the trial or its management.
Has been changed to read:
The AbbVie Primary Contact for the DMC and the AbbVie IERC members will not be 
involved in any aspects of the trial or its management.
Section 5.6.2  Appropriateness of Measurements
First paragraph, last sentence previously read:
On-treatment safety evaluations (neurological examinations, adverse event monitoring, 
ECGs) are scheduled at more frequent intervals for the first 48 subjects enrolled 
(Cohort 1) and for subjects enrolled in Cohort J1 to promptly detect potential emerging 
safety signals.
Has been changed to read:
On-treatment safety evaluations (neurological examinations, adverse event monitoring, 
ECGs) are scheduled at more frequent intervals for the first 48 subjects enrolled 
(Cohort 1) to promptly detect potential emerging safety signals.
Section 6.1.5  Adverse Event Reporting
Subsection COVID-19 Pandemic-Related Acceptable Protocol Modifications
Add:  new subsection title and text
COVID-19 Pandemic-Related Acceptable Protocol Modifications
The investigator should capture COVID-19 infections as AEs.  If the event meets the 
criteria for a serious adverse event (SAE), reporting directions as described in Section 6.1
should be followed.






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statistics will be provided for each scheduled time of sampling with breakdown by dose 
level.
CSF concentration data after the fourth dose and the final dose will be tabulated and 
summarized by dose level for Cohort 1. A summary of data for all subjects (Cohort 1 and 
Cohort 2) will also be included noting that CSF sample collection was optional for 
subjects in Cohort 2 per Amendment 1 of the protocol.
Section 8.1.9  Data Monitoring Committee (DMC)
Sixth and seventh sentence previously read:
After each DMC meeting, the chair of the DMC will communicate its recommendations 
to the designated AbbVie Contact, as described in the DMC charter.  The AbbVie Contact 
will triage the recommendations to either the AbbVie Study Team if the recommendation 
can be implemented without unblinded data review or the Independent Review Committee 
(IRC) if unblinded data review is required.
Has been changed to read:
The DMC membership and responsibilities will be documented in the DMC charter.  
After each DMC meeting, the chair of the DMC will communicate its recommendations 
to the designated AbbVie Primary Contact or AbbVie IERC representative, as described 
in the DMC charter.  The AbbVie Primary Contact or the IERC representative will triage 
the recommendations to either the AbbVie Study Team if the recommendation can be 
implemented without unblinded data review or the IERC if unblinded data review is 
required.
Section 8.1.10  Interim Analysis
First paragraph, last sentence previously read:
Assessment of target engagement will be conducted by an AbbVie sub-team of Internal 
Review Committee (sub-IRC).


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Has been changed to read:
Assessment of target engagement will be conducted by the AbbVie Internal Biomarker 
Review Committee (IBRC).
Section 8.1.10  Interim Analysis
Subsection Safety Interim Reviews
Last paragraph previously read:
The DMC chair will make recommendations to the AbbVie Contact (who is not involved 
in the conduct of the trial) regarding continuing, modifying or terminating the trial due to 
safety concerns in accordance with the DMC charter.
Has been changed to read:
The DMC chair will make recommendations to the AbbVie Primary Contact (who is not 
involved in the conduct of the trial) regarding continuing, modifying or terminating the 
trial due to safety concerns in accordance with the DMC charter.
Section 8.1.10  Interim Analysis
Subsection Interim analysis for Target Engagement
First sentence previously read:
An assessment of target engagement analysis for the first 48 Cohort 1 subjects will be 
conducted by the sub-IRC.
Has been changed to read:
An assessment of target engagement analysis for the first 48 Cohort 1 subjects will be 
conducted by the IBRC.


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Section 8.1.10  Interim Analysis
Subsection Interim analysis for Target Engagement
Third sentence previously read:
An AbbVie internal biomarker team not involved in the study conduct and firewalled 
from the study team will perform detailed analysis on target engagement and provide the 
results to sub-IRC.
Has been changed to read:
An AbbVie internal biomarker team not involved in the study conduct and firewalled 
from the study team will perform detailed analysis on target engagement and provide the 
results to the IBRC.
Section 8.1.10  Interim Analysis
Subsection Efficacy Interim Analyses
First paragraph, last sentence previously read:
The DMC will make recommendations to the sponsor representative regarding initiating 
of Phase 3 development, continuing the study to completion or terminating the study 
based on interim analysis results.
Has been changed to read:
The DMC will make recommendations to the sponsor IERC representative regarding 
initiating of Phase 3 development, continuing the study to completion or terminating the 
study based on interim analysis results.
Section 8.3  Randomization Methods
Last sentence previously read:
Subject randomization will be stratified by site except in Japan where all sites together 
will be treated as one "pseudo site" for randomization.
Has been changed to read:
Subject randomization will be stratified by site.


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Section 9.2  Ethical Conduct of the Study
Add:  new last paragraph
In the event of a state of emergency due to the COVID-19 pandemic leading to difficulties 
in performing protocol-specified procedures, AbbVie will engage with study site 
personnel in an effort to ensure the safety of subjects, maintain protocol compliance, and 
minimize risks to the integrity of the study while trying to best manage subject continuity 
of care.  This may include alternative methods for assessments (e.g., contact by phone or 
virtual site visits), alternative locations (e.g., use of infusion centers), and the shipping of 
IP and/or supplies directly to subjects.  In all cases, these alternative measures must be 
permitted by local regulations and the IEC/IRB.  Investigators should notify AbbVie if 
any urgent safety measures are taken to protect the subjects against any immediate 
hazards.
Section 9.3  Subject Information and Consent
Last paragraph, first sentence previously read:
An informed consent, approved by an IRB/IEC, must be voluntarily signed and dated 
before samples are collected for optional pharmacogenetic research.  
Has been changed to read:
An informed consent, approved by an IEC/IRB, must be voluntarily signed and dated 
before samples are collected for optional pharmacogenetic research.
Section 9.3  Subject Information and Consent
Add:  new last paragraph
Due to the COVID-19 pandemic, protocol modifications in addition to those outlined in 
this protocol may become necessary.  If this situation arises, verbal consent may be added 
to the informed consent already included in this protocol.  Verbal consent would need to 
be obtained prior to making adaptations or substantial changes in study conduct in 
accordance with local regulations.


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Section 11.0  Data Quality Assurance
Add:  new last paragraph
During the COVID-19 pandemic, remote source document review of data may be 
employed if permitted by the local regulatory authority, the IEC/IRB, and the study site.
15.0  Reference List
Add:  new Reference 10
Albert MS, DeKosky ST, Dickson D, et al.  The diagnosis of mild cognitive impairment 
due to Alzheimer's disease:  recommendations from the national institute on aging-
Alzheimer's association workgroups on diagnostic guidelines for Alzheimer's disease.  
Alzheimers Dement.  2011;7(3):270-9.
15.0  Reference List
Delete:  Reference 35
Albert MS, DeKosky ST, Dickson D, et al.  The diagnosis of mild cognitive impairment 
due to Alzheimer's disease:  recommendations from the national institute on aging-
Alzheimer's association workgroups on diagnostic guidelines for Alzheimer's disease.  
Alzheimers Dement.  2011;7(3):270-9.
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical
Medical Writing
Statistics
Pharmacokinetics
Clinical


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Has been changed to read:
Name
Title
Functional Area
Clinical Program Development
Medical Writing
Statistics
Statistics
Pharmacokinetics
Neuroscience
Appendix C.  Study Activities
Table note "p." previously read:
Tau PET should be scheduled as close as possible after Weeks 44 (Dose 12) and 96 visits.
Has been changed to read:
Tau PET should be scheduled as close as possible to Weeks 44 (Dose 12) and 96 visits.

SAP_001.pdf: 
ABBV-8E12
M15-566 – Statistical Analysis Plan
Version 3.0 – 19 May 2020
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1.0
Title Page
Statistical Analysis Plan
Study M15-566
A Phase 2 Multiple Dose, Multicenter, Randomized, 
Double-Blind, Placebo-Controlled Study to Evaluate 
the Efficacy and Safety of ABBV-8E12 in Subjects 
with Early Alzheimer's Disease
Date:  19 May 2020
Version 3.0
NCT02880956


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1.1
List of Abbreviations and Definition of Terms
AD
Alzheimer's Disease
ADA
Anti-drug-antibody
ADAS-Cog-14
Alzheimer's Disease Assessment Scale (14-Item) Cognition portion
ADCS-CGIC-MCI
Alzheimer's Disease Cooperative Study Clinician's Global Impression of 
Change for Mild Cognitive Impairment
ADCS-MCI-ADL-24
24-item Alzheimer's Disease Cooperative Study/Activities of Daily Living 
Scale Adapted for Patients with Mild Cognitive Impairment
AE
Adverse event
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
APOE
Apolipoprotein E
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC
Area under the concentration time curve
BMI
Body mass index
BUN
Blood urea nitrogen
CDR
Clinical Dementia Rating
CDR-SB
Clinical Dementia Rating-Sum of Boxes
Cmax
Maximum observed serum concentration
CSF
Cerebrospinal fluid
C-SSRS
Columbia-Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
Observed serum drug concentration at the end of a dose interval
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
ERAC
Exposure-Response Analysis Center
eTIV
Estimated total intracranial volume
FAQ
Functional Activities Questionnaire
FWER
Family wise error rate
IBRC
Internal Biomarker Review Committee


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IERC
Internal Executive Review Committee
INR
International normalized ratio
ITT
Intent-to-treat
LS
Least square
MCHC
Mean corpuscular hemoglobin concentration
MCI
Mild cognitive impairment
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MHIS
Modified Hachinski Ischemic Scale
MI
Multiple imputation
MMRM
Mixed-effects model repeated measures
MMSE
Mini-Mental State Examination
MRI
Magnetic resonance imaging
NFL
Neurofilament light
NPI
Neuropsychiatric Inventory
PCS
Potentially clinically significant
PD
Premature discontinuation
PET
Positron emission tomography
PK
Pharmacokinetic
PT
Preferred Term
RBANS
Repeatable Battery for Assessment of Neuropsychological Status
RBC
Red blood cell count
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SDAC
Statistical and Data Analysis Center
SOC
System Organ Class
SUV
Standardized uptake value
SUVR
Standardized uptake value ratio
TEAE
Treatment-emergent adverse event
Tmax
Time to peak (maximum) observed serum concentration
vMRI
Volumetric magnetic resonance imaging
WBC
White blood cell count


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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
List of Abbreviations and Definition of Terms..........................................2
2.0
Table of Contents.....................................................................4
3.0
Introduction .............................................................................7
4.0
Study Objectives, Design and Procedures.............................7
4.1
Objectives ..................................................................................................7
4.2
Study Design..............................................................................................9
4.3
Sample Size..............................................................................................20
4.4
Interim Analysis.......................................................................................20
4.5
Efficacy Variables....................................................................................22
4.6
Safety Variables.......................................................................................23
4.7
Pharmacokinetic Variables ......................................................................23
4.8
Biomarker and Pharmacogenetic Research Variables .............................23
4.8.1
Biomarker Research Variables.................................................................23
4.8.2
Pharmacogenetic Research Variables......................................................24
5.0
Analysis Populations and Analysis Datasets.......................25
5.1
Variables Used for Stratification of Randomization................................25
6.0
Analysis Conventions ............................................................25
6.1
Statistical Significance.............................................................................25
6.2
Visit Definitions.......................................................................................26
7.0
Demographics, Baseline Characteristics, Subject 
History, and Previous/Concomitant Medications ..............32
7.1
Demographic and Baseline Characteristics .............................................32
7.2
Medical History .......................................................................................34
7.3
Previous and Concomitant Medications ..................................................35
8.0
Subject Disposition................................................................36
9.0
Study Drug Exposure and Compliance...............................37
10.0
Efficacy Analysis....................................................................38
10.1
General Considerations............................................................................38
10.2
Primary Analysis of Primary Efficacy Endpoint .....................................38
10.3
Secondary Efficacy Analysis ...................................................................39


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10.3.1
Analysis of Secondary Efficacy Variables ..............................................39
10.4
Additional Efficacy Analysis...................................................................40
10.4.1
Sensitivity analysis of CDR-SB score .....................................................40
10.4.2
Listing of Randomized Subjects not Included in the Primary 
Efficacy Analysis .....................................................................................41
10.5
Combination of Sites with Fewer than 2 Subjects per Treatment 
Group .......................................................................................................41
10.6
Handling of Missing Data for Efficacy Assessments and 
Sensitivity Analysis of the Primary Efficacy Endpoint ...........................42
10.7
Handling of Multiplicity ..........................................................................44
10.8
Efficacy Subgroup Analysis ....................................................................48
11.0
Safety Analysis.......................................................................49
11.1
General Considerations............................................................................49
11.2
Analysis of Adverse Events.....................................................................49
11.2.1
Adverse Event Overview .........................................................................49
11.2.2
Adverse Event Incidence .........................................................................50
11.2.3
Listing of Adverse Events........................................................................51
11.3
Analysis of Laboratory Tests...................................................................52
11.3.1
Analysis of Mean Changes for Laboratory Tests.....................................52
11.3.2
Shifts Between Normal and Abnormal for Laboratory Tests ..................53
11.3.3
Potentially Clinically Significant Laboratory Values ..............................53
11.4
Analysis of Vital Signs and Weight.........................................................54
11.4.1
Vital Sign and Weight Mean Changes.....................................................54
11.4.2
Potentially Clinically Significant Vital Sign and Weight Values............54
11.5
Analysis of Electrocardiogram (ECG) Variables.....................................55
11.5.1
ECG Mean Changes.................................................................................55
11.5.2
Potentially Clinically Significant ECG Values........................................55
11.6
Analysis for Other Safety Variables ........................................................55
11.6.1
Columbia-Suicide Severity Rating Scale (C-SSRS)................................55
11.6.2
Analysis of CSF Lab Parameters .............................................................56
11.6.3
Summary of MRI Safety Evaluations ......................................................56
12.0
Pharmacokinetic Analysis.....................................................57
12.1
Determination of Values of Pharmacokinetic Parameters.......................57


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12.2
Tabulations and Summary Statistics........................................................58
12.3
Model and Tests.......................................................................................59
12.4
Missing Values and Model Violations.....................................................60
13.0
Analysis of Biomarker Research Variables ........................61
14.0
Summary of Changes ............................................................67
15.0
Reference List ........................................................................68
List of Tables
Table 1.
Safety and PK Procedures for Cohort 1...................................................12
Table 2.
Study Activities........................................................................................13
Table 3.
Diagnostic Tools and Scale Administration Timing................................19
Table 4.
Hypotheses Included in the Group-sequential Graphical Procedure .......45
Table 5.
Initial OBF P-Value Boundaries for CDR-SB Change from 
Baseline at Week 96.................................................................................47
List of Figures
Figure 1.
Study Schematic.......................................................................................11
Figure 2.
An Initial Graph for Alpha Allocation and Propagation..........................46
List of Appendices
Appendix A.
Potentially Clinically Significant (PCS) Laboratory Value.....................69
Appendix B.
Criteria for Potentially Clinically Significant Vital Sign and 
Weight Values..........................................................................................70
Appendix C.
Criteria for Potentially Clinically Significant ECG Values.....................71


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3.0
Introduction
This analysis plan describes the statistical analyses to be completed by AbbVie Clinical
Statistics and Programming for ABBV-8E12 Study Protocol M15-566, that incorporates 
two amendments (original Protocol; Administrative Change 1; Administrative Change 2; 
Administrative Change 3 (US-only); Amendment 1, Amendment 2).
This statistical analysis plan (SAP) provides details to further elaborate statistical methods 
as outlined in the protocol and describes analysis conventions to guide the statistical 
programming work. Population pharmacokinetic and exposure-response analysis for this 
study will be conducted separately and are not included in this SAP.
Analyses will be performed using SAS version 9.3 or higher (SAS Institute Inc., Cary, 
NC 27513) under the UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objectives of this study are:
●
To assess the efficacy of ABBV-8E12 in slowing disease progression 
(cognitive and functional impairment) in subjects with Early Alzheimer's 
Disease (AD) as measured by the Clinical Dementia Rating Sum of Boxes 
(CDR-SB).
●
To assess the long-term safety of ABBV-8E12 for up to 96 weeks in subjects 
with Early AD.
The secondary objectives of this study are:
●
To assess the pharmacokinetics of ABBV-8E12 in subjects with Early AD.
●
To assess the efficacy of ABBV-8E12 in slowing cognitive and functional 
impairment in subjects with Early AD as measured by the Mini-Mental State 
Examination (MMSE), Alzheimer's Disease Assessment Scale (14-Item) 
Cognition Portion (ADAS-Cog-14), Repeatable Battery for Assessment of 


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Neuropsychological Status (RBANS), 24-Item Alzheimer's Disease 
Cooperative Study/Activities of Daily Living Scale Adapted for Patients with 
Mild Cognitive Impairment (ADCS-MCI-ADL-24), Functional Activities 
Questionnaire (FAQ) and University of California San Diego Performance 
Based Skills Assessment, Brief Version (UPSA-Brief), and Neuropsychiatric 
Inventory (NPI).
●
To assess the global impact of ABBV-8E12 on cognition, function and 
behavior as measured by Alzheimer's Disease Cooperative Study Clinical 
Global Impression of Change for Mild Cognitive Impairment (ADCS-CGIC-
MCI).
The exploratory objectives of this study are:
●
To assess the effect of ABBV-8E12 on cerebrospinal fluid (CSF) and plasma 
tau protein.
●
To assess the effect of ABBV-8E12 on potential CSF and plasma biomarkers 
of disease progression.
●
To assess the efficacy of ABBV-8E12 in slowing the rate of regional and/or 
whole brain atrophy in subjects with Early AD as measured by volumetric 
magnetic resonance imaging (vMRI).
●
To assess any signals or trends for efficacy of ABBV-8E12 in removing tau 
deposits or slowing the accumulation and spread of tau deposits in the brain as 
measured by tau PET in a subset of subjects.
●
To generate additional data for the correlation between retinal amyloid 
imaging and amyloid positron emission tomography (PET) imaging in a subset 
of subjects.
●
To characterize the performance of a digital clock drawing test (dCDT) in 
measuring cognitive function and assess its correlation with other clinical 
rating scales and biomarkers in a subset of subjects.


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4.2
Study Design
This Phase 2 multiple dose, multicenter, multinational, randomized, double-blind, 
placebo-controlled study is designed to evaluate the efficacy and safety of ABBV-8E12 in 
subjects with Early AD.  Subjects will be allowed to use medications to treat symptoms 
related to AD, if on a stable dose for at least 12 weeks prior to randomization.  The study 
will consist of a screening period of up to 12 weeks, a 96-week double-blind treatment 
period and a follow-up period of approximately 20 weeks following the last study drug 
administration (for those subjects who prematurely discontinue from treatment, decline to 
participate in or do not qualify for extended treatment).  At the end of the treatment 
period, eligible subjects who completed the 96-week treatment period may enter a planned 
separate extension study for extended treatment.  All activities for these subjects will be 
outlined in a separate extension study protocol.
Approximately 400 subjects with Early AD between 55 to 85 years of age will be eligible 
to participate in the study according to the selection criteria described in protocol 
Section 5.2.  Upon completion of screening and baseline procedures, eligible subjects will 
be randomized to one of the 3 ABBV-8E12 dose arms (300 mg, 1000 mg or 2000 mg) or 
placebo in a 1:1:1:1 ratio.  Doses will be administered every 4 weeks via IV infusion.
This study will utilize a Data Monitoring Committee (DMC).  The DMC will consist of at 
least 2 non-AbbVie clinicians, at least 1 non-AbbVie statistician and at least 1 external 
pharmacokineticist.  The DMC will review unblinded safety data and make 
recommendations based on the emerging safety profile of ABBV-8E12.  The DMC will 
review the results of the interim efficacy analyses.  The DMC membership, 
responsibilities and operating logistics will be documented in a charter that will be 
finalized prior to the first DMC review meeting.
Safety and tolerability will be monitored throughout the study. The first 48 subjects 
enrolled into the study will be represented as Cohort 1 in this protocol while the subjects 
enrolled subsequently to Cohort 1 will be represented as Cohort 2. The protocol 
Amendment 2 states that Japanese subjects enrolled in J1 would follow safety and PK 


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sample collection procedures of Cohort 1.  However, the enrollment of the study has 
completed without enrolling Japanese subjects. Therefore, J1 is not described in this 
SAP. More frequent pharmacokinetic (PK) sampling and safety monitoring by the DMC 
will be conducted for Cohort 1 subjects (Table 1).
Eligible subjects will be enrolled into the Treatment Period of the study on Day 1 and 
receive their first infusion of study drug.  Subjects will return to the study site every 
4 weeks for their study drug infusion, blood collection, study procedures and assessments 
as outlined in the Study Activities Table (Table 2).  Subjects will be observed on-site for 
at least 2 hours following each of the first 4 infusions of study drug and for at least 
30 minutes after the end of infusion of all doses thereafter.  In addition, Cohort 1 subjects 
will return to the study sites, 5 and 15 days after both the first and fourth infusion of study 
drug for collection of additional safety assessments and PK samples.
In addition to blinded safety data monitoring by the sponsor, the first four mandatory 
DMC safety reviews of unblinded safety data will take place after the 12th, 24th, 36th and 
48th subject have been administered their second dose and results for the MRI scheduled 
at approximately 2 weeks after their second dose are available.  The dataset will consist of 
all of the available safety and pharmacokinetic data in the study, including the data of any 
subjects from Cohort 2 who have received at least one dose of study drug.  Additional 
DMC safety reviews will occur after a total of approximately 100, 200, 300 and 
400 subjects are randomized and every 6 months thereafter until the study completion.
A schematic of the study design is shown in Figure 1.


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Figure 1.
Study Schematic


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Table 1.
Safety and PK Procedures for Cohort 1
Screening
Cohort 1, Doses 1 – 4
Visit 1
Dose 1
Dose 2
Dose 3
Dose 4
Weeks of Study Drug 
Exposure
N/A
0
0
2
4
8
12
12
14
Days of study activities
Days –56 
to –8
Day 1
Days 5 
and 15
Day 29
Day 57
Day 85
Days 89 
and 99
Neurological Exam
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
Xa
X
X
X
X
Xa
Clinical Laboratory Tests
X
X
X
X
X
Amyloid PET Scan
X
MRI
X
Xb
Xb
Lumbar Puncture/CSF 
Sample Collection
X
Xc
PK Sample Collection
Xd
X
X
X
X
Xd
X
X
ADA Sample Collection
Xe
X
Xe
Xe
Xe
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
AE/ConMed Review
X
X
X
X
X
X
X
X
X
Visits on Days 5, 15, 89 and 99 must be scheduled within ± 2 days.  Visits on all other days may be scheduled 
within ± 4 days.
a.
Pre-dose and within 15 minutes after the end of the infusion and prior to the PK sample collection.
b.
The MRI will be scheduled approximately 2 weeks following the dose and results must be available prior to the 
next scheduled dose.
c.
The lumbar puncture will be performed approximately 14 days after the fourth dose.
d.
Prior to the start of the infusion (0 hour, no more than 30 minutes prior to the start of the infusion), immediately 
after the end of the infusion (within 15 minutes) and 1 and 2 hours after the end of the infusion.
e.
Prior to the start of the infusion (0 hour, no more than 30 minutes prior to the start of the infusion).


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Table 2.
Study Activities
Screening
Treatment Perioda (Year 1)
Visit 1
Visit 2
Dose 1
Dose 
2
Dose 
3
Dose 4
Dose 
5
Dose 
6
Dose 
7
Dose 
8
Dose 
9
Dose 
10
Dose 
11
Dose 
12
Dose 
13
Weeks of Study 
Drug Exposure
N/A
N/A
0
0
2
4
8
12
12
14
16
20
24
28
32
36
40
44
48
Day –84 
to –8
Day –7 
to –1c
Day 
1c
Days 
5d, 15c,d
Day 
29c
Day 
57c
Day 
85c
Days 
89d, 
99d
Day 
113c
Day 
141c
Day 
169c
Day 
197c
Day 
225c
Day 
253c
Day 
281c
Day
309c
Day 
337c
Informed Consent 
and Study Partner 
identification
X
Medical/early AD 
History 
X
Drug Screen (Urine) 
and Hepatitis Screen
X
Weight & Heighte
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
Neurological Exam
X
X
C1
X
X
X
C1
X
X
X
X
X
Vital Signs
X
X
C1
X
X
X
C1
X
X
X
X
X
X
X
X
X
12-Lead ECGf
X
X
C1
X
X
X
X
X
X
Clinical Laboratory 
Tests
X
X
X
X
X
X
X
X
X
X
Randomizationg
X
Administer IV Study 
Drug
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 2.
Study Activities (Continued)
Screening
Treatment Perioda (Year 1)
Visit 1
Visit 2
Dose 1
Dose 
2
Dose 
3
Dose 4
Dose 
5
Dose 
6
Dose 
7
Dose 
8
Dose 
9
Dose 
10
Dose 
11
Dose 
12
Dose 
13
Weeks of Study 
Drug Exposure
N/A
N/A
0
0
2
4
8
12
12
14
16
20
24
28
32
36
40
44
48
Day –84 
to –8
Day –7 
to –1c
Day 
1c
Days 
5d, 15c,d
Day 
29c
Day 
57c
Day 
85c
Days 
89d, 
99d
Day 
113c
Day 
141c
Day 
169c
Day 
197c
Day 
225c
Day 
253c
Day 
281c
Day 
309c
Day 
337c
Amyloid PET Scan
X
Tau PET Scano
X
Xp
Retinal Imaging Scan
X
MRI
X
Xh
Xh
Xh
Xh
Lumbar 
Puncture/CSF 
Sample Collectionr
X
Xi
APOE 
Pharmacogenetic 
Sample
X
Optional 
Pharmacogenetic 
Sample (DNA and 
RNA)j
X
X
X
X
X
Biomarker Plasma 
and Serum Sample
X
X
X
X
X


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Table 2.
Study Activities (Continued)
Screening
Treatment Perioda (Year 1)
Visit 1
Visit 2
Dose 1
Dose 
2
Dose 
3
Dose 4
Dose 
5
Dose 
6
Dose 
7
Dose 
8
Dose 
9
Dose 
10
Dose 
11
Dose 
12
Dose 
13
Weeks of Study 
Drug Exposure
N/A
N/A
0
0
2
4
8
12
12
14
16
20
24
28
32
36
40
44
48
Day –84 
to –8
Day –7 
to –1c
Day 
1c
Days 
5d, 15c,d
Day 
29c
Day 
57c
Day 
85c
Days 
89d, 
99d
Day 
113c
Day 
141c
Day 
169c
Day 
197c
Day 
225c
Day 
253c
Day 
281c
Day 
309c
Day 
337c
Blood Samples for 
ABBV-8E12 Assayk
X
C1
X
C1
X
C1
C1
X
X
X
ADA Samplek
X
C1l
X
C1
X
C1
C1
X
X
X
Diagnostic Tools and 
Rating Scalesm
X
X
Xq
X
Xq
X
Columbia Suicide 
Severity Rating Scale
X
X
C1
X
X
X
C1
X
X
X
X
X
X
X
X
X
Concomitant 
Medication Review
X
X
X
C1
X
X
X
C1
X
X
X
X
X
X
X
X
X
Adverse Event 
Monitoringn
X
X
X
C1
X
X
X
C1
X
X
X
X
X
X
X
X
X


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Table 2.
Study Activities (Continued)
Treatment Perioda (Year 2)
Post-
Treatment 
Follow-Up 
Perioda,b
Dose 
14
Dose 
15
Dose 
16
Dose 
17
Dose 
18
Dose 
19
Dose 
20
Dose 
21
Dose 
22
Dose 
23
Dose 
24
Completion 
Visit/PD
Week 
104
Week 
112
Weeks of Study Drug Exposure
52
56
60
64
68
72
76
80
84
88
92
96
N/A
N/A
Day 
365c
Day 
393c
Day 
421c
Day 
449c
Day 
477c
Day 
505c
Day 
533c
Day 
561c
Day 
589c
Day 
617c
Day 
645c
Day 673c
Days 
729
Day 
785
Physical Exam
X
X
Neurological Exam
X
X
X
X
X
Weight & Heighte
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGf
X
X
X
Clinical Laboratory Tests
X
X
X
X
X
Administer IV Study Drug
X
X
X
X
X
X
X
X
X
X
X
MRI
Xh
X
Tau PET Scano
Xp
Lumbar Puncture/CSFr
X
Optional Pharmacogenetic Sample 
(DNA and RNA)j
X
X
Biomarker Plasma and Serum 
Sample
X
X
Blood Samples for ABBV-8E12 
Assayk
X
X
X
X


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Table 2.
Study Activities (Continued)
Treatment Perioda (Year 2)
Post-
Treatment 
Follow-Up 
Perioda,b
Dose 
14
Dose 
15
Dose 
16
Dose 
17
Dose 
18
Dose 
19
Dose 
20
Dose 
21
Dose 
22
Dose 
23
Dose 
24
Completion 
Visit/PD
Week 
104
Week 
112
Weeks of Study Drug Exposure
52
56
60
64
68
72
76
80
84
88
92
96
N/A
N/A
Day 
365c
Day 
393c
Day 
421c
Day 
449c
Day 
477c
Day 
505c
Day 
533c
Day 
561c
Day 
589c
Day 
617c
Day 
645c
Day 673c
Days 
729
Day 
785
ADA Samplek
X
X
X
X
Diagnostic Tools and Rating 
Scalem,q
X
X
Columbia Suicide Severity Rating 
Scale 
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Monitoringn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C1 – Cohort 1 subjects only, Procedures should be conducted at approximately the same time as they would be conducted on the days of dosing.
a.
Visits on Days 5, 15, 89 and 99 must be scheduled within ± 2 days of the scheduled date.  Visits on all other days may be scheduled within ± 4 days of the scheduled date.
b.
Post-Treatment Visits to occur approximately 8 and 16 weeks after the Completion or Premature Discontinuation (PD) visit.
c.
Assessments on Day –7 to –1 will be done once during this time frame and can be administered on any day, but all should be done on the same day.  Assessments may also be 
completed on Day 1, but must be completed prior to the start of the study drug infusion.  At visits after Day 1 rating scales may be completed on any day within the visit 
window prior to the visit, but all rating scales should be completed on the same day.
d.
Only subjects enrolled in Cohort 1 will be required to return to the clinical site 5 and 15 days after doses 1 and 4.
e.
Height collected at Screening Visit 1 only.  On dosing days, weight will be collected prior to the start of the infusion.
f.
A detailed description for the timing of 12-Lead Single ECGs can be found in Section 5.3.1.1 in the protocol.


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Table 2.
Study Activities (Continued)
g
Randomization should be completed just prior to the first dose administration.
h.
The MRI will be scheduled approximately 2 weeks following the dose and results must be available prior to the next scheduled dose.
i.
The lumbar puncture will be performed approximately 14 days after the fourth dose.
j.
The optional Pharmacogenetic DNA and RNA samples require consent.  Verify consent prior to sample collection.
k.
A detailed description of the collection time points can be found in Section 5.3.2.1 in the protocol.
l.
ADA sample for Cohort 1 will only be collected on Day 15.
m.
See Table 3 for additional information on Diagnostic Tools and Rating Scales.
n.
A detailed description for procedures involving adverse event assessments can be found in Section 6.0 in the protocol.
o.
Tau PET scan obtained only for subjects at sites selected to participate in the tau imaging assessment.
p.
Tau PET should be scheduled as close as possible after Weeks 44 (Dose 12) and 96 visits.
q.
On Weeks 12 and 36, only digital clock drawing test will be performed.
r.
The lumbar punctures at Screening Visit 1, Weeks 12 and 96 are optional for subjects in Cohort 2.


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Table 3.
Diagnostic Tools and Scale Administration Timing
Recommended 
Order of 
Administration
Approximate 
Administration 
Timea (Minutes)
Patient/Study 
Partner
Screening 
Day –56 –
Day –8
Day –7 to 
Day 1 (Prior 
to Infusion)b
Week 
12
Week 
24
Week 
36
Week 
48
Week 
72
Week 
96
CDR
1
45 – 75
Both
X
X
X
X
X
X
RBANS
2
25
Patient
X
X
X
X
X
X
UPSA – Brief
3
10 – 15
Patient
X
X
X
ADAS-Cog-14
4
30 – 60
Patient
X
X
X
X
X
MMSE
5
10 – 15
Patient
X
X
X
X
X
X
ADCS-CGIC-MCI
6
10 – 15
Both
X
X
X
C-SSRSc
7
5 – 20
Patient
X
X
X
X
X
X
FAQ
d
6 – 10
Study partner
X
X
X
X
X
NPI
d
15
Study partner
X
X
X
X
X
ADCS-MCI-ADL-24
d
30 – 45
Study partner
X
X
X
MHISI
d
5
N/A clinician 
assessed
X
Digital clock drawing
d
5
Patient
X
X
X
X
X
X
X
X
a.
Breaks should be taken as necessary.
b.
Assessments will be done once during this time frame and can be administered on any day, but all must be done on the same day.
c.
The C-SSRS will be done at each visit throughout the study (see Table 2 Study Activities for all time points).
d.
Scale may be administered/assessed at any time during the visit.
I.
Administered during Screening to assess inclusion criteria only.


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4.3
Sample Size
Approximately 400 Early AD subjects (100 subjects/group) will be enrolled and 
randomized into three ABBV-8E12 dose groups and placebo with 1:1:1:1 randomization 
ratio.  This sample size has about 80% power to detect an ABBV-8E12 treatment effect 
size (vs. placebo) of 0.45 for both the high dose and the middle dose and 0.28 for the low 
dose on CDR-SB score changes from baseline up to Week 96 using one-sided test at the 
2.5% significance level with Bonferroni method to adjust multiplicity. This power 
assessment was based on the assumption that 25% subjects do not have post-baseline data 
and the calculation was conducted using Cytel EAST version 6.4.
4.4
Interim Analysis
DMC safety reviews, interim analysis for target engagement, and interim efficacy 
analyses will be performed in this study.  Assessment of safety and efficacy data at 
interims will be performed by the DMC.
Except for interim analysis for target engagement, an independent Statistical and Data 
Analysis Center (SDAC) and an independent Exposure-Response Analysis Center 
(ERAC) which are organizations outside AbbVie with experience in producing statistical 
reports will be responsible for generating and providing unblinded statistical tables, 
figures, and listings to the DMC for the interim reviews.  To maintain the integrity of the 
trial, a specific data access plan with a strict firewall will be in place to protect the 
unblinded data and the details will be described in the DMC charter and the Interim 
Unblinding Plan.
Safety Reviews
The first four mandatory DMC reviews of unblinded safety data will take place after the 
12th, 24th, 36th and 48th subject have been administered their second dose and results for 
the MRI scheduled at approximately 2 weeks after their second dose are available.  The 
data set will consist of all of the available safety and pharmacokinetic data in the study, 
including the data of any subjects from Cohort 2 who have received at least one dose of 


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study drug when the data is cut.  Additional DMC safety reviews will occur after a total of 
approximately 100, 200, 300 and 400 subjects are randomized and then approximately 
every six months thereafter until the study completion. Additional unplanned DMC 
safety reviews can occur at the discretion of the DMC and/or AbbVie.
The DMC will communicate their recommendations to the AbbVie Primary Contact (who 
is not involved in the conduct of the trial) regarding continuing, modifying or terminating 
the trial due to safety concerns in accordance with the DMC charter.  More details of 
safety reviews will be specified in the DMC Charter.
Interim Analysis for Target Engagement
An assessment of target engagement analysis for the first 48 Cohort 1 subjects will be 
conducted by an AbbVie Internal Biomarker Review Committee (IBRC).  Biomarkers for 
target engagement will include both target binding and pharmacodynamic activity 
biomarkers.  An AbbVie internal team will perform detailed analysis on target 
engagement.  This interim analysis results will guide the decision if an early futility 
analysis (Interim analysis 1) should be conducted. Details of the target engagement 
analysis will be described in a separate biomarker analysis plan.
Interim Efficacy Analyses
Three potential interim efficacy analyses could be performed when approximately 
8 subjects/group, 35 subjects/group (or 45% information) and 55 subjects/group (or 
75% information) complete Week 96 visit, respectively.  The number of subjects at each 
interim analysis is subject to change based on observed dropout rate at interim.  
Information fractions will be used to determine the number of subjects for each interim 
analysis.
The first interim efficacy analysis will be optional and for futility review only depending 
on interim target engagement and pharmacodynamic biomarker analysis results from 
Cohort 1 subjects.  The DMC will be informed by the IBRC chair regarding if the first 
efficacy review for futility is going to be conducted or not, and if conducted, the futility 


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criteria for the first interim efficacy analysis will be selected by the IBRC based on 
interim target engagement biomarker analysis results.
At the second and the third interim efficacy analyses, the DMC will make 
recommendations to trigger AbbVie Internal Executive Review Committee (IERC) review 
if pre-specified futility criteria or criteria for acceleration of Phase 3 development are met. 
The IERC is a group of executive R&D leaders responsible for reviewing important data 
from ongoing studies in order to make strategic and operational decisions. The IERC 
operates under its own standing charter which describes membership and IERC 
operations. The IERC will make one of the decisions listed below:
●
Continue Study M15-566 as is (no sponsor unblinding)
●
Terminating Study M15-566 due to futility 
●
Accelerate Phase 3 programs and continue Study M15-566 as is
If none of pre-specified criteria is met, the IERC will not review interim efficacy data.
Two-sided tests will be applied at interim efficacy analyses.  A group-sequential graphical 
approach will be used to handle multiplicity of comparing multiple ABBV-8E12 doses to 
placebo at interim analyses and final analysis.  Details of multiplicity control are specified 
in Section 10.7 of the SAP.
4.5
Efficacy Variables
The primary efficacy variable is the CDR-SB score change from baseline at Week 96.
Secondary efficacy variables include the ADAS-Cog-14 total score and subscale scores, 
RBANS total scale score and subtest scores, MMSE total score, FAQ total score, NPI 
total score, ADCS-MCI-ADL-24 total score, UPSA-Brief score and ADCS-CGIC-MCI 
scores.  The descriptions of the secondary efficacy variables are detailed in protocol 
Section 5.0. The key secondary efficacy variables are ADAS-Cog-14 total score and FAQ 
total score.


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4.6
Safety Variables
The following safety variables will be analyzed for the study:  adverse event, vital signs, 
C-SSRS, laboratory tests, ECG, and MRI safety evaluations.
4.7
Pharmacokinetic Variables
Values for the following pharmacokinetic parameters of ABBV-8E12 in Cohort 1 will be 
determined using non-compartmental methods:  maximum observed serum concentration 
(Cmax), the time to Cmax (peak time, Tmax), and the area under the concentration time curve 
(AUC) for the first and the fourth dose intervals.  For all subjects, the observed serum 
concentration at the end of a dose interval (Ctrough) will be obtained prior to study drug 
infusion on the days of dosing specified in Table 2 in all subjects.
4.8
Biomarker and Pharmacogenetic Research Variables
4.8.1
Biomarker Research Variables
Data to conduct research on disease-related and drug-related biomarkers will be obtained 
from blood and CSF samples, volumetric MRI, and tau PET imaging.  The biomarkers to 
be analyzed will include, but are not limited to, the following:
●
CSF samples will be assayed for free tau and total tau and plasma samples for 
total tau to investigate tau binding of ABBV-8E12.  In addition to a statistical 
analysis of tau concentrations, an analysis will be performed for the ratio of 
CSF free tau concentration to total tau concentration.  A statistical analysis 
will also be carried out for plasma total tau concentration.
●
CSF and plasma samples will be analyzed for NFL and perhaps for other 
biochemical or macromolecular factors related to the pharmacodynamics of 
ABBV-8E12.
●
Volumetric brain MRI will be performed at about 2 weeks after each of the 
doses scheduled for Weeks 28, 44 and 68 and at the Week 96 visit (end of the 
last dose interval) to assess regional volume change for the hippocampus, 
lateral ventricles, temporal lobes, and whole brain volume change.  Change of 
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●
For each of several regions of the brain, the amount of tau deposits will be 
assessed with the standardized uptake value ratio (SUVR) obtained from tau 
PET imaging. An SUVR is computed as the ratio of a target region value to a 
reference region value. Priority will be given to SUVR computed with the 
inferior part of the cerebellar gray matter as the reference region.  SUVR 
values will be determined for four composite meta- regions of interest (ROI) 
that correspond to anatomical definitions of Braak stages I, II, III, IV, V, and 
VI. Individual ROIs that make up these composite meta-ROIs are listed in 
detail in the Imaging Review Charter.  The SUVR value for a composite meta-
region will be a weighted average of the SUVR values for the individual ROIs 
of the composite meta-region.  In addition to SUVR computed using the 
inferior part of the cerebellar gray matter as the reference region, SUVR will 
also be computed using the following three reference regions: subcortical 
white matter, pons and the whole cerebellum.  If the analysis for a composite 
region gives evidence of an effect by 8E12, then an analysis will be performed 
for each individual ROI of the composite region.  An additional set of output 
metrics will be generated. These metrics will include Extent (tau positive 
fraction) defined as the number of tau positive voxels in a region divided by 
the total number of voxels in that region. Details of the quantitative analyses 
of tau PET scans, including the calculation of SUVR and amplitude/extent of 
SUVRs can be found in the Imaging Review Charter.
4.8.2
Pharmacogenetic Research Variables
APOE allele status will be determined for each subject and analyzed as a factor 
contributing to the subject's response to study treatment.  The APOE genotype results may 
be analyzed as part of a multi-study assessment of APOE and response to ABBV-8E12 
treatment.  The results may also be used for the development of diagnostic tests related to 
ABBV-8E12, or other drugs in development for AD or related conditions.  These analyses
results may not be included in the study summary.


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5.0
Analysis Populations and Analysis Datasets
Intent-to-Treat (ITT) Dataset
The intent-to-treat (ITT) dataset will include all randomized subjects who receive at least 
one dose of study drug infusion. The data from the ITT dataset will be analyzed by the 
treatment group assigned at the time of randomization, even if the subject does not receive 
the correct treatment, is not compliant with the protocol or does not follow through with 
the study until completion.  All efficacy analyses will be conducted on the intent-to-treat 
dataset unless otherwise specified.
Safety Dataset
The safety dataset will include all randomized subjects who receive any dose of study 
drug infusion.  For this analysis dataset, actual treatment received will be used instead of 
treatment assignment at the time of randomization.  All safety analyses will be conducted 
on the safety dataset unless otherwise specified.
5.1
Variables Used for Stratification of Randomization
Subject randomization is stratified by study site.
6.0
Analysis Conventions
6.1
Statistical Significance
Unless otherwise specified, statistical tests will be two-sided for efficacy and safety 
analyses.  The null hypotheses for efficacy will be rejected at the pre-specified 
significance level with the overall Type I family wise error rate (FWER) to be controlled 
at the two-sided 5% level.  P values will be rounded to five decimal points for primary 
and key secondary variables included in the FWER control and rounded to three decimal 
points for other analyses before assessing statistical significance.  All efficacy analyses 
will be conducted on the ITT dataset and all safety analyses will be conducted on the 
safety dataset unless otherwise specified.


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6.2
Visit Definitions
Definition of Rx Day (Days Relative to the First Dose of Study Drug)
Rx Day is calculated for each time point as the number of days between the day of the 
first dose of study drug and the specific time point.  For dates before the first dose date of 
study drug, Rx day = date of time point – first dose date; for dates on or after the first dose 
date of study drug, Rx day = date of time point – first dose date + 1.  Thus, Rx Day is a 
negative value when the time point of interest is prior to the day of the first study drug 
dose; Rx Day is a positive value when the time point of interest is on or after the day of 
the first study drug dose.  There is no Rx Day 0.  With this defined algorithm, the day of 
the first dose of study drug will be Rx Day 1.
Rx End Day is calculated for each post-treatment time point as the number of days 
between the day of the last dose of study drug and the specific time point: 
Rx End Day = date of time point – last dose date.  With this defined algorithm, the day of 
the last dose of study drug will be Rx End Day 0.
Definition of Baseline and Final Observation
Unless otherwise specified, for all efficacy analyses and for all safety analyses of the 
double-blind Treatment Period, "baseline" shall refer to the last non-missing observation 
prior to the first dose of study drug and "final" for the double-blind Treatment Period shall 
refer to the last non-missing observation but no more than 45 days after the last dose of 
the study drug for both efficacy variables and safety variables.  The "final" for the post-
treatment follow-up period for safety variables shall refer to the last non-missing 
observation greater than 45 days but no more than 20 weeks after the last dose of study 
drug.
Randomization and study drug administration are the last activities of Day 1 Visit after 
the site completes other study procedures and verifies that the subject is eligible to 
participate in the study.  From the definition of "baseline," it is clear that the baseline for a 
specific measurement is the last non-missing observation taken up to the Day 1 Visit (the 


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Randomization Visit).  At the computation level, the value of "baseline" for an efficacy or 
safety assessment is determined using the Rx Day associated with the visit.  Namely, 
baseline value is determined by taking the last non-missing observation obtained before 
the time of first dosing on Rx Day 1.  If an SAE occurs on the first dosing day, the event 
will be reported as a post-baseline event and the related safety assessments will be 
considered post-baseline data as well.
Definition of Analysis Windows
To perform longitudinal data analysis, observations that are obtained after the first day of 
study drug administration will be assigned to an analysis "week" associated with the 
Rx Days that are corresponding to the observations.  Unless otherwise specified, efficacy 
observations and safety observations no more than 45 days after the last dose of study 
drug will be included in analyses for the double-blind period.  Safety observations later 
than 45 days, but no more than 20 weeks, after the last dose of study drug will be included 
for the post-treatment follow-up period safety analysis.  The intervals presented below for 
each scheduled visit (Rx Days X through Y) include both Rx Days X and Y. The nominal 
day for each scheduled visit is defined in "Days of Study Activities" row in Table 2.
For measurements that are planned to be collected during the double-blind treatment 
period at Weeks 24, 48, 72 and 96, i.e., CDR, RBANS, ADAS-Cog-14, MMSE, FAQ and 
NPI, observations will be mapped to an analysis "week" according to the following 
windows defined by Rx day.
●
Week 24
Rx Days 2 through 252
●
Week 48
Rx Days 253 through 420
●
Week 72
Rx Days 421 through 588
●
Week 96
Rx Days > 588
For measurements that are planned to be collected during the double-blind treatment 
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24, observations will be mapped to an analysis "week" according to the following 
windows defined by Rx day.
●
Week 48
Rx Days 2 through 504
●
Week 96
Rx Days > 504 
For measurements that are planned to be collected during the double-blind treatment 
period at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 
84, 88, 92 and 96, i.e., body weight, observation will be mapped to an analysis "week"
according to the following windows defined by Rx day.
●
Week 4
Rx Days 2 through 42
●
Week 8 
Rx Days 43 through 70
●
Week 12
Rx Days 71 through 98
●
Week 16
Rx Days 99 through 126
●
Week 20
Rx Days 127 through 154
●
Week 24
Rx Days 155 through 182
●
Week 28
Rx Days 183 through 210
●
Week 32
Rx Days 211 through 238
●
Week 36
Rx Days 239 through 266
●
Week 40
Rx Days 267 through 294
●
Week 44
Rx Days 295 through 322
●
Week 48
Rx Days 323 through 350
●
Week 52
Rx Days 351 through 378
●
Week 56
Rx Days 379 through 406
●
Week 60
Rx Days 407 through 434
●
Week 64
Rx Days 435 through 462
●
Week 68
Rx Days 463 through 490
●
Week 72
Rx Days 491 through 518
●
Week 76
Rx Days 519 through 546


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●
Week 80
Rx Days 547 through 574
●
Week 84
Rx Days 575 through 602
●
Week 88
Rx Days 603 through 630
●
Week 92
Rx Days 631 through 658
●
Week 96
Rx Days > 658
For measurements that are planned to be collected during the double-blind treatment 
period at Weeks 2, 4, 8, 12, 14, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 
76, 80, 84, 88, 92, and 96, i.e., vital signs and C-SSRS, observations will be mapped to an 
analysis "week" according to the following windows defined by Rx day.
●
Week 2
Rx Days 2 through 21 (Cohort 1 subjects)
●
Week 4
Rx Days 22 through 42 (Cohort 1 subjects)
Rx Days 2 through 42 (Cohort 2 subjects)
●
Week 8
Rx Days 43 through 70
●
Week 12
Rx Days 71 through 91 (Cohort 1 subjects)
Rx Days 71 through 98 (Cohort 2 subjects)
●
Week 14
Rx Days 92 through 105 (Cohort 1 subjects)
●
Week 16
Rx Days 106 through 126 (Cohort 1 subjects)
Rx Days 99 through 126 (Cohort 2 subjects)
●
Week 20
Rx Days 127 through 154
●
Week 24
Rx Days 155 through 182
●
Week 28
Rx Days 183 through 210
●
Week 32
Rx Days 211 through 238
●
Week 36
Rx Days 239 through 266
●
Week 40
Rx Days 267 through 294
●
Week 44
Rx Days 295 through 322
●
Week 48
Rx Days 323 through 350
●
Week 52
Rx Days 351 through 378
●
Week 56
Rx Days 379 through 406


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●
Week 60
Rx Days 407 through 434
●
Week 64
Rx Days 435 through 462
●
Week 68
Rx Days 463 through 490
●
Week 72
Rx Days 491 through 518
●
Week 76
Rx Days 519 through 546
●
Week 80
Rx Days 547 through 574
●
Week 84
Rx Days 575 through 602
●
Week 88
Rx Days 603 through 630
●
Week 92
Rx Days 631 through 658
●
Week 96
Rx Days > 658
For measurements that are planned to be collected during the double-blind treatment 
period at Weeks 4, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84 and 96, i.e., clinical laboratory 
tests, observations will be mapped to an analysis "week" according to the following 
windows defined by Rx day.
●
Week 4
Rx Day 2 through 42
●
Week 8
Rx Day 43 through 70
●
Week 12
Rx Days 71 through 98
●
Week 16
Rx Day 99 through 126
●
Week 20
Rx Days 127 through 154
●
Week 24
Rx Days 155 through 210
●
Week 36
Rx Days 211 through 294
●
Week 48
Rx Days 295 through 378
●
Week 60
Rx Days 379 through 462
●
Week 72
Rx Days 463 through 546
●
Week 84
Rx Days 547 through 630
●
Week 96
Rx Days > 630


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For measurements that are planned to be collected during the double-blind treatment 
period at Weeks 2, 4, 8, 12, 24, 36, 48, 72 and 96, i.e., ECG, observation will be mapped 
to an analysis "week" according to the following windows defined by Rx day.
●
Week 2
Rx Days 2 through 21 (Cohort 1 subjects)
●
Week 4
Rx Days 22 through 42 (Cohort 1 subjects)
Rx Days 2 through 42 (Cohort 2 subjects)
●
Week 8
Rx Days 43 through 70
●
Week 12
Rx Days 71 through 126 
●
Week 24
Rx Days 127 through 210
●
Week 36
Rx Days 211 through 294
●
Week 48
Rx Days 295 through 420
●
Week 72
Rx Days 421 through 588
●
Week 96
Rx Days > 588
For vital sign measurements, C-SSRS, ECG, clinical laboratory tests, and MRI that are 
planned to be collected during the post-treatment follow-up period at Weeks 104, 
observations will be mapped to an analysis "week" according to the following windows 
defined by Rx End day.
●
Post-Treatment Week 8
Rx End Days > 45
For measurements that are planned to be collected during double-blind treatment period 
on Weeks 6, 14, 30, 46, 70 and 96, i.e., MRI observation will be mapped to an analysis 
"week" according to the following windows defined by Rx day.
●
Week 6
Rx Days 2 through 70
●
Week 14
Rx Days 71 through 154
●
Week 30
Rx Days 155 through 266
●
Week 46
Rx Days 267 through 406
●
Week 70
Rx Days 407 through 581


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●
Week 96
Rx Days > 581
If more than 1 observation is included in a visit time window, the observation that is 
closed to the nominal day of the visit will be used in the analysis.  If two observations 
have the same distance to the nominal day of the visit, the last non-missing observation 
will be used in analyses.  If more than 1 observation occurs on the same day, the average 
will be calculated and used in analyses.
7.0
Demographics, Baseline Characteristics, Subject 
History, and Previous/Concomitant Medications
7.1
Demographic and Baseline Characteristics
The following demographic and baseline characteristics will be summarized for each 
treatment group, for the combination of all ABBV-8E12 dose groups ("ABBV-8E12 
Overall") and for the combination of all treatment groups ("Total Subjects") for the safety 
dataset.
●
Gender (male/female)
●
Race (white, black, American Indian/Alaska native, Native Hawaiian or other 
Pacific Islander, Asian, Other, Multi-Race)
●
Education (high school or above, lower than high school)
●
Ethnicity (Hispanic or Latino)
●
Age (years)
●
Age group (< 65, ≥65)
●
Weight for all subjects (kg)
●
Weight for all male subjects (kg)
●
Weight for all female subjects (kg)
●
Height (cm)
●
Body mass index (BMI, kg/m2)
●
Body mass index category (BMI, kg/m2) (< 25, ≥25)
●
APOE allele status (ε2ε2, ε2ε3, ε2ε4, ε3ε3, ε3ε4, ε4ε4) 


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●
Baseline AD medication use: AChEI (donepezil, rivastigmine, galantamine)
and memantine
Alcohol and tobacco uses will be summarized for each treatment group, ABBV-8E12 
Overall and Total Subjects for the safety dataset.  For alcohol use, the number and 
percentage of subjects who are drinkers, ex-drinkers and non-drinkers (defined as those 
who have never been a drinker) will be presented.  For the tobacco use, the number and 
percentage of users, ex-users and non-users (defined as those who have never been a user) 
will be presented.  A subject reporting multiple use categories for the different types of 
tobacco (cigarette, pipe, cigar and chewing tobacco) will be counted in the tobacco user 
category.
The following baseline efficacy variables will be summarized for each treatment group, 
ABBV-8E12 Overall and Total Subjects for the ITT dataset.
●
CDR-SB score
●
ADAS-Cog-14 total score and subscale scores
●
FAQ total score 
●
UPSA-Brief score 
●
ADCS-MCI-ADL-24 total score
●
RBANS total scale score and subtest scores
●
MMSE total score 
●
NPI total score
●
ADCOMS score
ADCOMS score is a composite score which is a weighted linear combination of the 
remaining individual scale items from ADAS-cog, MMSE, and CDR-SB scales.  The 
weights for items are listed below.3


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Scale
Item name
Weights
ADAS-cog
Delayed word recall
0.008
Orientation
0.017
Word recognition
0.004
Word finding difficulty
0.016
MMSE
Orientation time
0.042
Drawing
0.038
CDR-SB
Personal care
0.054
Community affairs
0.109
Home and hobbies
0.089
Judgement and problem solving
0.069
Memory
0.059
Orientation
0.078
Categorical variables will be summarized by the number and percentage of subjects in 
each category and Fisher's exact test will be carried out to assess the comparability 
between treatment groups.  No comparisons of treatment groups will be performed for 
alcohol and tobacco uses.  Continuous variables will be summarized with descriptive 
statistics (number of non-missing observations, mean, standard deviation, median, 
minimum and maximum) and no comparisons between treatment groups will be 
performed.
7.2
Medical History
The conditions/diagnoses recorded in medical/surgery history eCRF will be coded using 
the most current version of the Medical Dictionary for Regulatory Activities (MedDRA).  
Data will be summarized and presented using system organ classes (SOCs) and preferred 
terms (PTs).  The SOC will be presented in alphabetical order and the PTs will be 
presented in alphabetical order within each SOC.  The number and percentage of subjects 
with a particular SOC and PT will be summarized for each treatment group, ABBV-8E12 
Overall and Total Subjects for the safety dataset.  Subjects reporting more than one PT 
within a SOC will be counted only once for that SOC.  No comparison among treatment 
groups will be performed.


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The following MCI due to AD or AD history variables will be summarized for each 
treatment group, ABBV-8E12 Overall and Total Subjects for the safety dataset.
●
Age at onset of symptoms of cognitive impairment (years) 
●
Age when first diagnosed as having MCI due to AD or AD (years)
●
Years since onset of symptoms of cognitive impairment (Date of Day 1 – Date 
of onset)
●
Years since MCI due to AD or AD diagnosis (Date of Day 1 – Date of 
diagnosis)
●
Family history of AD (None, biological mother, biological father, full sibling, 
biological child)
●
Years of formal education
Categorical variables will be summarized with the number and percentage of subjects in 
each category. Continuous variables will be summarized with descriptive statistics 
(number of non-missing observations, mean, standard deviation, median, minimum, and 
maximum).  No comparisons of treatment groups will be performed.
7.3
Previous and Concomitant Medications
Previous medications are defined as all medications with a start date before the first study 
drug infusion date.  Concomitant medications are defined as all medications, other than 
study drug, taken during the treatment period (i.e., from the first day of study drug 
administration through 45 days after the last day of study drug administration).  
Concomitant medication use for AD or MCI will be summarized into two categories:
taken both at baseline and post-baseline, not taken at baseline but taken post-baseline.  
Previous and concomitant medications will be coded using the World Health Organization 
(WHO) dictionary and will be summarized by generic name and Anatomical Therapeutic 
Chemical (ATC) classification system level 3.  The number and percentage of subjects 
who take at least 1 medication and who take at least 1 dose of each specific medication in 
the following categories will be summarized for each treatment group, ABBV-8E12 
Overall and Total Subjects.


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●
Previous AD or MCI medication: donepezil, rivastigmine, galantamine, 
Tacrine, memantine, investigational medicine or other.
●
Previous antipsychotic/neuroleptic medications
●
Previous anticholinergic medications
●
Previous sedatives/benzodiazepines
●
Previous Parkinsonian medications
●
Concomitant antipsychotic/neuroleptic medications
●
Concomitant anticholinergic medications
●
Concomitant sedatives/benzodiazepines
●
Concomitant Parkinsonian medications 
●
Concomitant cholinesterase inhibitors (donepezil, rivastigmine, galantamine) 
or memantine for cognitive impairment.
No comparisons of treatment groups will be performed.
8.0
Subject Disposition
The number of subjects who are screened will be summarized and screen failures will be 
summarized in Total Subjects and by each reason for screen failures.
For subjects who are randomized in the study, the number and percentage of subjects in 
each randomization disposition category (randomized but not treated, prematurely 
discontinued and completed) will be summarized for each treatment group, ABBV-8E12 
Overall and Total Subjects.
The number and percentage of subjects who prematurely discontinued study drug or 
prematurely discontinued from the study will be summarized by reason (primary or any 
reason) for each treatment group, ABBV-8E12 Overall and Total Subjects.
In addition, the following additional summaries will be presented for all randomized 
subjects:
●
The number and percentage of subjects who are enrolled at each site.


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The number and percentage of subjects who prematurely discontinued at each 
site.
9.0
Study Drug Exposure and Compliance
Summaries of study drug exposure and compliance will be prepared for the safety dataset.
Study drug exposure will be summarized for each ABBV-8E12 treatment group, 
ABBV-8E12 Overall.  Duration of exposure is calculated as the last study drug 
administration date minus the first study drug administration date + 30.  Total subject 
years of exposure is calculated by summing the duration of exposure across all subjects 
and dividing this sum by 365 (1 year will be considered to be 365 days).  The number and 
percentage of subjects who have taken a total of 1, 2, 3, 4 - 6, 7 - 9, 10 - 12, 13 - 15, 
16 - 18, 19 - 21, 22 - 24, > 24 infusions of study drug will be summarized.  No 
comparisons of treatment groups will be performed for this summary.  In addition, 
duration of exposure will be summarized with descriptive statistics (number of non-
missing observations, mean, standard deviation, median, minimum and maximum 
duration, and total subject-years).
To evaluate impact of COVID-19 pandemic on study drug compliance, expected infusions
(completers are expected to have 24 infusions, prematurely discontinued subjects are 
expected to have expected number of infusions based on discontinuation visit date) and
infusions missed due to COVID-19 pandemic will be summarized for each ABBV-8E12 
treatment group and ABBV-8E12 Overall (mean, minimum, maximum of expected 
infusions; mean, minimum, maximum of missed infusions, mean of the percentage of 
missed infusions relative to expected number of infusions will be tabulated) across all 
countries and by country.
At each scheduled dosing visit for ABBV-8E12 groups, the investigator will document 
whether the subject has received the entire dose infusion or not and the volume 
administered will be recorded in the eCRF if the entire dose is not administered.  The 
percentage of the assigned dose administered will be calculated at each visit.  The mean of 


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this percentage across infusions for each subject will be obtained.  The descriptive 
statistics (number of non-missing observations, minimum, mean, median, standard 
deviation, maximum) based on each subject's mean volume percentage of study drug 
infusion will be summarized for each ABBV-8E12 treatment group and ABBV-8E12 
Overall. 
10.0
Efficacy Analysis
10.1
General Considerations
All efficacy analyses will be conducted on the intent-to-treat dataset unless otherwise 
specified.  Data collected more than 45 days after the last dose of the study drug will not 
be included in efficacy analyses.
10.2
Primary Analysis of Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline to Week 96 visit on the 
CDR--SB score.  The primary analysis population will be subjects in the ITT dataset and 
the primary analysis will be a likelihood-based, mixed-effects model, repeated measures 
(MMRM) analysis of the change from baseline to each post-baseline assessment up to and 
including Week 96.  The model will include fixed, categorical effects for treatment, site, 
visit, baseline score-by-visit and treatment-by-visit interactions, with continuous fixed 
covariate for baseline score.  The primary comparison will be the contrast between each 
ABBV-8E12 dose group and placebo group at Week 96.  Contrasts between each 
ABBV-8E12 dose group and placebo at Weeks 24, 48, 72, and overall across the 
treatment period will be obtained and will be considered as secondary. An unstructured 
(co)variance structure will be used to model the within-patient errors.  The same 
(co)variance structure will also be used for all MMRM analyses for secondary efficacy 
variables.  Satterthwaite's approximation will be used to estimate denominator degrees of 
freedom.
The following statistics will be presented on the statistical table of MMRM analysis for 
change from baseline to each visit (Weeks 24, 48, 72, and 96):  descriptive statistics 


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(number of non-missing observations, mean, standard deviation, minimum and maximum) 
for each treatment group.  Within group LS mean and standard error will be presented for 
each treatment group.  LS mean, standard error, 95% confidence interval and two-sided 
P values for comparisons between each ABBV-8E12 dose group and placebo at each 
post-baseline visit will also be presented.  The LS mean, standard error, 95% confidence 
interval and two-sided P values of treatment difference comparing each ABBV-8E12 dose 
group with placebo across the treatment period will be included in the output as well.
10.3
Secondary Efficacy Analysis
10.3.1
Analysis of Secondary Efficacy Variables
The secondary efficacy variables include:
●
ADAS-Cog-14 total score and subscale scores
●
FAQ total score
●
ADCS-CGIC-MCI clinical global impression, cognition, behavior and 
functional abilities scores
●
UPSA-Brief score 
●
ADCS-MCI-ADL-24 total score
●
RBANS total scale score and subtest scores
●
MMSE total score 
●
NPI total score
●
ADCOMS
ADAS-Cog-14 total score and FAQ total score are key secondary efficacy variables and 
the Week 96 comparisons for each ABBV-8E12 dose vs placebo will be included in the 
multiplicity adjustment for the overall FWER control.  Other secondary efficacy variables 
will not be included in the multiplicity adjustment for the overall FWER control. The 
MMRM method used for the primary efficacy analysis will be applied to analyze the 
change from the baseline to each post-baseline assessment up to and including Week 96 
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the dependent variable is ADCS-CGIC-MCI score itself.  The model will include fixed, 
categorical effects for treatment, site, visit, baseline score-by-visit interaction and 
treatment-by-visit interactions, with continuous fixed covariate for baseline score in the 
model.  For the MMRM analysis of ADCS-CGIC-MCI scores, there is no baseline score 
and no baseline score-by-visit interaction in the model.  The comparison will be the 
contrast between each ABBV-8E12 dose group and placebo group at each post-baseline 
visit.
The following statistics will be presented in the statistical table of MMRM analysis for 
change from baseline to each post-baseline visit:  descriptive statistics (number of non-
missing observations, mean, standard deviation, minimum, and maximum) for each 
treatment group.  Within group LS mean and standard error for each post-baseline visit 
will be presented for each treatment group.  LS mean, standard error, 95% confidence 
interval and two-sided P values of treatment difference comparing each ABBV-8E12 dose 
group with placebo will also be presented for each post-baseline visit.  The LS mean, 
standard error, 95% confidence interval and two-sided P values of treatment difference 
comparing each ABBV-8E12 dose group with placebo across the treatment period will be 
included in the output.  P-values after considering multiplicity adjustment for the primary 
and key secondary variables will be presented in a separate table.
10.4
Additional Efficacy Analysis
10.4.1
Sensitivity analysis of CDR-SB score
Sensitivity analyses of CDR-SB score change from baseline will be conducted in ITT 
dataset in the final analysis.  Subjects who are randomized and dosed but failed to meet all
inclusion criteria or met any exclusion criteria will be excluded from these analyses.  In 
addition, the impact of COVID-19 on data collection in Study M15-566 should be 
considered as well. The following sensitivity analyses on CDR-SB score may be 
conducted:
●
Sensitivity analysis I: excluding subjects from ABBV-8E12 groups who 
missed more than two doses than expected (subjects who complete Week 96 


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visit and receive less than 22 doses, subjects who are prematurely discontinued
and receive more than two doses less than expected before the discontinue visit
date) or received less than 80% amount dosage than the assigned amount for 
more than two doses during the double-blind period. 
●
Sensitivity analysis II: include all subjects who have available CDR-SB score 
change from baseline regardless how many doses are missed or under-dosed or 
records are more than 45 days after the last dosing.
The MMRM analysis will be applied for these analyses and similar output will be 
generated for the sensitivity analyses of CDR-SB score. No multiplicity adjustment is 
needed for these analyses.
Sensitivity analysis will also be conducted on the CDR-SB score to evaluate the impact of 
missing data on the primary efficacy results.  Details of sensitivity analysis for missing 
data are specified in Section 10.6 of the SAP.
10.4.2
Listing of Randomized Subjects not Included in the Primary 
Efficacy Analysis
A listing of the randomized subjects that were not included in the primary efficacy 
analysis will be prepared.  The listing will include the reason(s) the subject was not 
included (did not receive study drug, had no baseline observation, and/or had no 
post-baseline observation within 45 days after the last dose of study drug).
10.5
Combination of Sites with Fewer than 2 Subjects per 
Treatment Group
When "site" is included as a factor in a statistical model, sites that do not have at least 
2 subjects per treatment group for the ITT dataset will be combined within each country 
as follows.
1.
Divide the sites into 2 groups with Group 1 including all sites that have at least 
2 subjects per treatment group and Group 2 including all remaining sites.  Sort each 
group in ascending order by total sample size and investigator number.


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2.
Starting at the top of the Group 2 list (i.e., the first site with the smallest sample 
size), combine the minimum number of sites required to achieve a pseudo-site that 
has at least 2 subjects per treatment group.  Continue this process until all Group 2 
sites have been grouped into pseudo-sites.
3.
If there is a site (or sites) left after Step 2, combine this site (or sites) with the last 
pseudo-site that is created.  For the situation where there is no previous pseudo-site 
exists, combine this site (or sites) with the first site on the sorted Group 1 list.
The naming of the pseudo-sites will be given by xxx99901, xxx99902, etc., where xxx is 
the country code.
The combined pseudo-sites will be used in all statistical models that include the "Site" as 
a factor.  However, the original site identification will be used in all summaries of subject 
disposition or discontinuation by Study Site and in all data listings.  In the summaries of 
the number and percentage of subjects contributed by each site in each treatment group 
for the ITT dataset, the name of pseudo-sites will also be displayed.
10.6
Handling of Missing Data for Efficacy Assessments and 
Sensitivity Analysis of the Primary Efficacy Endpoint
Missing Items for a Rating Scale
Unless otherwise specified, when an efficacy variable is a total score calculated from a set 
of individual items, the total score will be considered missing if any of the individual 
items are missing. 
Missing Visit Data
Before conducting any imputation of missing data, patterns of missing data for the 
primary endpoint CDR-SB score in placebo and three ABBV-8E12 arms will be assessed.  
Observed mean changes from baseline in CDR-SB score will be summarized over time 
for different missing patterns of longitudinal data (discontinued before Week 24 
assessment, discontinued after Week 24 assessment, discontinued after Week 48 


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assessment, discontinued after Week 48 assessment, discontinued after Week 72, 
completer). Number of subjects and percentage of subjects for each missing pattern will 
be summarized as well.
To evaluate robustness of the primary efficacy results on CDR-SB score changes from 
baseline, sensitivity analysis will be conducted using a multiple imputation (MI) method 
assuming a missing pattern that is mostly monotonic in this study and missing at random
(MAR).  The COVID-19 pandemic is interfering with the conduct of ongoing 
Study M15-566, with potential impact on treatment duration and the data collection, 
analysis and interpretation of clinical trial data. The probability of having missed visits 
and missing data due to COVID-19 infection or logistical restrictions related to the 
COVID-19 pandemic can be reasonably assumed to be unrelated to the unobserved values 
conditional on the observed data. Therefore, for the purpose of statistical analysis, it is 
reasonable to assume that these missing data are MAR and the MMRM analysis model 
that is based on MAR assumption is appropriate.
Sensitivity analysis will be conducted only if at least one ABBV-8E12 dose is statistically 
significant different from placebo after multiplicity adjustment for the primary endpoint in 
the primary efficacy analysis.
Sensitivity analysis using MI will be conducted in the following three steps:
1.
Use Monte Carlo Markov Chain (MCMC) methodology from PROC MI to impute 
the intermittent missing data so that a monotone missing pattern can be obtained 
for treatment group
2.
Impute missing data to create 20 complete datasets including observed CDR-SB 
change from baseline scores for subjects with scores for all 4 visits as well as 
observed and imputed change from baseline scores for subjects with missing visits
using the MI method


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3.
Analyze each imputed dataset generated in Step 1 with the same analysis model for 
the primary efficacy analysis of the primary endpoint and keep analysis results for 
each imputed dataset
4.
Combine analysis results across imputed datasets.
The MI method will be used to impute missing data at various visits overtime.  The MI 
method will be applied separately for each ABBV-8E12 dose arm and placebo arm.  
Multivariate regression models will be used to impute CDR-SB missing data for different
visits.  To impute missing values for CDR-SB score for Visit X, variables included in the 
imputation model are baseline CDR-SB score, CDR-SB score before discontinuation at 
Visit X, investigator sites.  A mean vector and variance covariance matrix based on all 
available cases will be used for the imputation.  If the monotonic missing pattern is not 
satisfied, the MCMC method will be used to create monotonic missing pattern by filling 
missing values between visits where data are observed. Imputed CDR-SB score needs 
satisfy the range requirement for the scale (integer and half integer value between 0 and 
18. If an imputed value is not in the range, it will be rounded down to 18 if greater than 
18 or rounded up to 0 if less than 0).  The MI will be implemented using PROC MI in 
SAS 9.4.  In Step 3, PROC MIANALYZE procedure will be used to combine MMRM 
analysis results based on 20 imputed datasets.
10.7
Handling of Multiplicity
Pairwise comparisons between each ABBV-8E12 dose group and the placebo group will 
be performed using two-sided tests.  A group-sequential graphical approach4,5 will be 
applied for multiplicity control for multiple comparisons due to multiple endpoints, 
multiple ABBV-8E12 doses and multiple interim analyses (IA) and final analysis. The 
overall family-wise error rate (FWER) will be controlled at the two-sided 5% level.
The primary endpoint and two ranked key secondary efficacy endpoints will be included 
for the FWER control in this study.  These endpoints are presented in Table 4. The initial 
alpha allocation to the primary hypotheses for three doses and alpha propagation among 


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hypotheses are presented in Figure 2. The ranked secondary endpoints hypotheses for a 
dose can be tested only if the primary endpoint hypothesis is rejected for that dose.  The 
primary endpoint hypothesis is the gatekeeper for testing the key secondary endpoints 
hypotheses and a higher ranked endpoint hypothesis is the gatekeeper for testing the lower 
ranked endpoint hypothesis for each dose.  O'Brien-Fleming (OBF) p-value boundaries 
will be used for all endpoints' hypotheses testing at interim and final analyses. The 
detailed group-sequential graphical testing procedure is described below. A summary 
table for multiplicity adjustment will be prepared. The table will include rejection 
boundary for each hypothesis at each analysis, observed p-value for testing each 
hypothesis at each analysis.
Table 4.
Hypotheses Included in the Group-sequential Graphical Procedure
Hypothesis 
Family
Endpoint
Comparative Hypotheses
Notation of 
Hypotheses
Primary 
family
CDR-SB score change from 
baseline at Week 96
ABBV-8E12 2000 mg vs. placebo
H11
ABBV-8E12 1000 mg vs. placebo
H21
ABBV-8E12 300 mg vs. placebo
H31
Secondary 
family
ADAS-Cog-14 total score change 
from baseline at Week 96
ABBV-8E12 2000 mg vs. placebo
H12
ABBV-8E12 1000 mg vs. placebo
H22
ABBV-8E12 300 mg vs. placebo
H32
FAQ total score change from 
baseline at Week 96
ABBV-8E12 2000 mg vs. placebo
H13
ABBV-8E12 1000 mg vs. placebo
H23
ABBV-8E12 300 mg vs. placebo
H33


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Figure 2.
An Initial Graph for Alpha Allocation and Propagation
Note:
Numbers inside each circle is the amount of alpha allocated initially for each hypothesis.  Numbers in 
rectangle boxes on arrow lines are weights for alpha propagation among hypotheses.
The steps to perform hypotheses testing procedure is summarized below: 
●
Step 0:  Set I = {H11, H21, H31, H12, H22, H32, H13, H23, H33}.  Initial 
alpha allocation weights w = (16/25, 8/25, 1/25) and corresponding alpha level 
(0.032, 0.016, 0.002) for CDR-SB change from baseline at Week 96 will be 
allocated to 2000 mg, 1000 mg and 300 mg doses (H11, H21, H31), 
respectively.  Zero alpha is allocated initially to all secondary endpoints'
hypotheses.  Initial propagation weights (g) between hypotheses are assigned 
and listed in Figure 2.  The p-value (two-sided) initial OBF rejection 
boundaries for 3 analyses (IA2, IA3, and final analyses) for the primary 


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endpoint are calculated using pre-allocated alpha levels with information 
fractions of 45%, 75% and 100% for IA2, IA3 and final analysis, respectively.  
The initial P-value boundaries for CDR-SB change from baseline at Week 96 
are presented in Table 5.  Initial OBF P-value rejection boundaries for all 
secondary endpoints are set to be (0.0, 0.0, 0.0) because no alpha is allocated 
for any secondary endpoint hypothesis.
Table 5.
Initial OBF P-Value Boundaries for CDR-SB Change from Baseline 
at Week 96
IA2
IA3
Final
ABBV-8E12 2000 mg (H11):  alpha = 0.032
OBF two-sided p-value boundary
0.00106
0.01126
0.02816
Cumulative alpha spending
0.00106
0.01166
0.032
ABBV-8E12 1000 mg (H21):  alpha = 0.016
OBF two-sided p-value boundary
0.00026
0.00472
0.01438
Cumulative alpha spending
0.00026
0.00482
0.016
ABBV-8E12 300 mg (H31):  alpha = 0.002
OBF two-sided p-value boundary
0.00001
0.00034
0.00188
Cumulative alpha spending
0.00001
0.00034
0.002
●
Stage k (k = IA2, IA3, Final):
Step 1:  obtain Week 96 p-values for the primary and key secondary endpoints.
Step 2:  compare p-values in step 1 against the boundaries for analysis at 
Stage k.  If one or more hypotheses are rejected, go to Step 3.  Otherwise, go to 
Step 5.
Step 3:  update the graph (Figure 2) using the method proposed by Bretz et al. 
(2009).6  If none of hypothesis is rejected, then go to Step 5 without updating 
the boundaries and Figure 2. The following are steps to update the graph with 
updated alpha allocation weights for each hypothesis and alpha propagation 
weights among hypotheses:


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○
I →I\{i}, i.e., update Set I after the ith hypothesis is rejected and excluded 
from Set I.
○
wj →wj + wigij, j ϵ I; 0, otherwise. wj is updated alpha allocation weight for 
hypothesis j, wi is alpha allocation weight for hypothesis i, gij is the alpha 
propagation weight from hypotheses i to j. 
○
gih = (gih+gjigih)/(1-gjigij), j,h ϵ I, j ≠h, gjigij < 1; 0, otherwise. gji is the 
alpha propagation weight from hypotheses j to i, gih is the alpha 
propagation weight from hypotheses i to h. 
Step 4:  calculate new OBF p-value boundaries for all endpoints with updated 
significant levels obtained in Step 3 and go to Step 2.
Step 5:  go to next stage (k + 1) and go to Step 1 or stop the testing.
10.8
Efficacy Subgroup Analysis
To examine whether gender, age group (< 65 vs ≥65 years old), APOE4 carrier status 
(carrier vs non-carrier), baseline AD medication use (use vs no use. AD medications are 
defined in Section 7.1), baseline amyloid PET level (baseline centiloid value < median vs 
≥median), and geographical region [North America (US and Canada) vs other countries]
have an impact on response to treatment, subgroup analyses on CDR-SB change score 
will be conducted using an ANCOVA model with the terms of treatment, subgroup 
variable, site (site is nested within a region for geographical region subgroup analysis), the 
treatment-by-subgroup variable interaction, and baseline score as a covariate.  The 
hypothesis that consistent response to treatment across strata of a subgroup variable will 
be tested at the significance level of 0.100 by examining the P value of the treatment-by-
subgroup interaction term in the ANCOVA model specified above.  The statistical 
comparison of each ABBV-8E12 dose group with placebo within each subgroup stratum 
will be performed when the statistical significance of the treatment-by-subgroup 
interaction term is achieved at 0.100 level. The subgroup analysis will be conducted on 
the ITT dataset.


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11.0
Safety Analysis
11.1
General Considerations
All safety analyses will be performed on the safety dataset.  Unless otherwise specified, 
treatment group differences in safety parameters are evaluated using two-sided test at the 
significance level of 0.050.  When statistical tests are performed, the comparisons will be 
between each ABBV-8E12 dose and placebo.  With the exception of adverse events, all 
safety assessments that are taken no more than 45 days after the last dose of study drug 
infusion will be included in the safety evaluation of the Double-blind Treatment Period.  
All safety assessments that are taken more than 45 days but no more than 20 weeks after 
the last dose of study drug infusion will be included in the safety evaluation for the Post-
Treatment Follow-Up Period.
11.2
Analysis of Adverse Events
All adverse events will be coded using the most current version of the Medical Dictionary 
for Regulatory Activities (MedDRA).  A treatment-emergent adverse event (TEAE) is 
defined as any adverse event that begins or worsens in severity on or after the first study 
drug dose date and no more than 20 weeks after the last study drug dose date.
11.2.1
Adverse Event Overview
The number and percentage of subjects experiencing one or more adverse events in the 
following adverse event categories will be summarized for each treatment group, 
ABBV-8E12 Overall.  No comparisons of treatment groups will be performed.
●
Any TEAE
●
Any TEAE that was rated as having reasonable possibility of being related to 
study drug by the investigator 
●
Any severe TEAE
●
Any serious TEAE
●
Any TEAE that led to discontinuation of study drug
●
Any fatal TEAE


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●
All deaths
11.2.2
Adverse Event Incidence
Treatment emergent adverse event (TEAE) incidence will be summarized and presented 
using primary MedDRA system organ classes (SOCs) and preferred terms (PTs).  The 
system organ classes will be presented in the alphabetical order and the preferred terms 
will be presented in the alphabetical order within each system organ class.  Subjects 
reporting more than one adverse event for a given MedDRA PT will be counted only once 
for that term.  Subjects reporting more than one adverse event within a SOC will be 
counted only once for the SOC total.  Subjects reporting more than one adverse event will 
be counted only once in the overall adverse event total.
The number and percentage of subjects experiencing one or more TEAEs will be 
summarized by PT for each treatment group, ABBV-8E12 Overall.  The PTs will be 
presented by decreasing frequency in ABBV-8E12 Overall.
The number and percentage of subjects experiencing one or more adverse events in the 
following adverse event categories will be summarized by primary SOC and PT for each 
treatment group, ABBV-8E12 Overall.  No comparisons of treatment groups will be 
performed.
●
Any TEAE
●
Any serious TEAE
●
Any TEAE that led to discontinuation of study drug
●
Any TEAE assessed by the investigator to have Reasonable Possibility of 
Being Related to study drug
The number of subjects experiencing one or more TEAEs will also be summarized by 
maximum severity category (mild, moderate, severe and unknown) and primary SOC and 
PT for each treatment group, ABBV-8E12 Overall.  Subjects reporting more than 
one TEAE for a given PT will be counted only once for that term in the most severe 


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category reported.  If a subject has an adverse event with unknown severity, then the 
subject will be counted in the severity category of "unknown" unless the subject has 
another occurrence of the same adverse event with the most extreme severity — "Severe."  
In this case, the subject will be counted under the "Severe" category.  No comparisons of 
treatment groups will be performed.
The number of subjects experiencing one or more TEAEs will also be summarized by 
maximum relationship category (Reasonable Possibility of Being Related, No Reasonable 
Possibility of Being Related and Unknown), as assessed by the investigator, and primary 
SOC and PT for each treatment group, ABBV-8E12 Overall.  Subjects reporting more 
than one TEAE for a given PT will be counted only once for that term in the most related 
category reported.  If a subject has an adverse event with unknown relationship, then the 
subject will be counted in the relationship category of "unknown," unless the subject has 
another occurrence of the same adverse event with a relationship assessment of 
"Reasonable Possibility of Being Related."  In this case, the subject will be counted under 
the "Reasonable Possibility of Being Related."  No comparisons between treatment 
groups will be performed.
11.2.3
Listing of Adverse Events
The following additional summaries of adverse events will be prepared.
●
List of subject numbers associated with each PT for all TEAEs
●
List of subject numbers associated with each PT for all TEAEs assessed by the 
investigator as having Reasonable Possibility of Being Related. 
●
Listing of all serious adverse events
●
Listing of all adverse events that led to discontinuation of study drug
●
Listing of all fatal adverse events
●
Listing of all deaths


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11.3
Analysis of Laboratory Tests
Analyses will be performed on the following continuous laboratory variables:
Hematology
Clinical Chemistry
Urinalysis
Hematocrit
Hemoglobin
Red blood cell (RBC) count
White blood cell (WBC) count
Neutrophils
Bands (if detected)
Lymphocytes
Monocytes
Basophils (if detected)
Eosinophils (if detected)
Platelet count (estimate not
acceptable)
Mean corpuscular volume
(MCV)
Mean corpuscular hemoglobin
concentration (MCHC)
Prothrombin time (PT) 
Activated partial thromboplastin
time (aPTT)
PT/INR (Prothrombin 
Time/International 
Normalized Ratio)
Blood urea nitrogen (BUN)
Creatinine
Total bilirubin
Albumin
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphate
Uric acid
Cholesterol
Total protein
Glucose
Triglycerides
Bicarbonate/Carbon Dioxide (CO2) 
Chloride
Specific gravity
pH
11.3.1
Analysis of Mean Changes for Laboratory Tests
Analyses of mean change from baseline to each double-blind visit value and to the 
minimum, maximum and final double-blind value will be presented for each continuous 
hematology, chemistry and urinalysis variable.  Analyses of mean change from final 
double-blind value to final post-treatment value will also be presented for each continuous 
hematology, chemistry and urinalysis variable.
For each mean change analysis, the mean and median change will be presented for each 
treatment group.  The mean change for each ABBV-8E12 dose group will also be 
compared to the mean change for the placebo group using an ANOVA with treatment as 


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the factor.  P values and 95% confidence intervals will be calculated based on pairwise 
contrasts within the ANOVA.
11.3.2
Shifts Between Normal and Abnormal for Laboratory Tests
Laboratory observations will be categorized as normal, low, or high relative to the 
reference (normal) range associated with the laboratory that performed the assay.  For 
each hematology and chemistry variable with a reference range, shift tables will be 
prepared for shifts from baseline to lowest, highest and final value during the entire study 
for each treatment group and ABBV-8E12 overall.  No comparisons of treatment groups 
will be performed.  The tables will present:
●
The numbers and percentages of subjects with low or normal observations at 
baseline who have a high observation at any post-baseline visit
●
The numbers and percentages of subjects with normal or high observations at 
baseline who have a low observations at any post-baseline visit
●
The numbers and percentages of subjects with low or normal observations at 
baseline who have a high observation at the final visit 
●
The numbers and percentages of subjects with normal or high observations at 
baseline who have a low observations at the final visit
11.3.3
Potentially Clinically Significant Laboratory Values
Criteria for potentially clinically significant (PCS) values have been predefined for
selected laboratory variables as outlined in Appendix A.  For each variable, a summary of 
the number and percentage of subjects in each treatment group who have at least 
one double-blind observation that meets the PCS criteria and is more extreme than their 
baseline value will be provided.  A listing will also be prepared that will include, for each 
variable, all observations for each subject that meet the PCS criteria for that variable at 
any time during the study.  No comparisons of treatment groups will be performed.


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11.4
Analysis of Vital Signs and Weight
Vital sign variables include:  diastolic blood pressure, systolic blood pressure and pulse 
rate and body temperature.  Weight variables include weight and BMI.
11.4.1
Vital Sign and Weight Mean Changes
Diastolic blood pressure, systolic blood pressure and pulse will be analyzed separately.  
Analyses of mean change from baseline to each double-blind visit value and to the 
minimum, maximum and final double-blind value will be presented for each vital sign and 
weight variable. Analyses of mean change from final double-blind value to final post-
treatment value will also be presented for each vital sign and weight variable.
For each mean change analysis, the mean and median change will be presented for each 
treatment group.  The mean change for each ABBV-8E12 dose group will also be 
compared to the mean change for the placebo group using an ANOVA with treatment as 
the factor.  P values and 95% confidence intervals will be calculated based on pairwise 
contrasts within the ANOVA.
11.4.2
Potentially Clinically Significant Vital Sign and Weight 
Values
Criteria for potentially clinically significant values have been predefined for selected vital 
sign and weight variables as outlined in Appendix A.  For each variable, a summary of the 
number and percentage of subjects in each treatment group who have at least one double-
blind observation that meets the PCS criteria and is more extreme than their baseline 
value will be provided.  A listing will also be prepared that will include, for each variable, 
all observations for each subject that met the PCS criteria for that variable at any time 
during the study.  No comparisons of treatment groups will be performed.


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11.5
Analysis of Electrocardiogram (ECG) Variables
Electrocardiogram (ECG) variables include:  heart rate (HR), PR interval, QRS interval, 
uncorrected QT interval, and QT interval corrected for heart rate using Fridericia's 
formula (QTcF).
11.5.1
ECG Mean Changes
Analyses of mean change from baseline to each double-blind visit value and to the 
minimum, maximum and final double-blind value will be presented for each ECG 
variable.  Analyses of mean change from final double-blind value to final post-treatment 
value will also be presented for each ECG variable.
For each mean change analysis, the mean and median change will be presented for each 
treatment group.  The mean change for each ABBV-8E12 dose group will also be 
compared to the mean change for the placebo group using an ANOVA with treatment as 
the factor.  P values and 95% confidence intervals will be calculated based on pairwise 
contrasts within the ANOVA.
11.5.2
Potentially Clinically Significant ECG Values
Criteria for potentially clinically significant values have been predefined for selected ECG 
variables as outlined in Appendix C.  For each variable, a summary of the number and 
percentage of subjects in each treatment group who have at least one double-blind 
observation that meets the PCS criteria and is more extreme than their baseline value will 
be provided.  Listings will also be prepared to include all observations for each variable 
for each subject that meet the PCS criteria for that variable at any time during the study.  
No comparisons of treatment groups will be performed.
11.6
Analysis for Other Safety Variables
11.6.1
Columbia-Suicide Severity Rating Scale (C-SSRS)
Number and percentage of subjects in the following categories will be summarized for 
each treatment group and ABBV-8E12 Overall by visit and for the entire study:


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●
Answered 'Yes' to each C-SSRS item
●
Had suicidal ideation (defined as answering 'Yes' to one or more suicidal 
ideation items)
●
Had suicidal ideation only (defined as answering 'Yes' to one or more suicidal 
ideation items and answering 'No' to all suicidal behavior items)
●
Had suicidal behavior (defined as answering 'Yes' to one or more suicidal 
behavior items)
●
Had suicidal ideation or behavior (defined as answering 'Yes' to one or more 
suicidal ideation or behavior items)
11.6.2
Analysis of CSF Lab Parameters
CSF variables include RBC and WBC with differential, total protein, albumin, glucose.  
Summary (number of non-missing observations, minimum, mean, median, standard 
deviation, maximum) of mean change from baseline to Week 12 (Cohort 1 subjects only) 
and mean change from baseline to final double-blind value will be presented for each CSF 
variable.
11.6.3
Summary of MRI Safety Evaluations
MRI safety evaluations will be summarized and compared between each ABBV-8E12 
dose and placebo based on MRI evaluations in the double-blinded period. The summaries 
include number and percentage of subjects with presence and severity of baseline and post 
baseline MRI findings of cerebral edema, microhemorrhages, and severe white matter 
disease as defined by a score of 3 on Age-Related White Matter Changes (ARWMC) 
scale and other structural abnormalities.  Descriptive statistics (mean, median, minimum, 
maximum) of number of new microhemorrhages or new lesions in the double-blind period 
will be presented.  Listing of subjects with post-baseline MRI findings will be provided.
No comparison will be performed for MRI safety summary.


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12.0
Pharmacokinetic Analysis
12.1
Determination of Values of Pharmacokinetic Parameters
Cmax for a dose interval will be the maximum observed concentration after the beginning 
of infusion of the dose and before the beginning of infusion of the next dose.  Tmax will be 
the time of Cmax relative to the beginning of infusion. The values of Cmax and Tmax will be 
considered missing if there is no measurement from a sample obtained before 3 hours 
after the end of infusion.
AUC for a dose interval will be obtained using straight lines between adjacent 
concentrations for times before 4 hours after the end of infusion.  An exponential curve 
will be used between the last time point of measurement before 4 hours after the end of 
infusion and the first time point of measurement after 4 hours after the end of infusion, 
and an exponential curve will be used between adjacent time points of measurement in the 
dose interval that come after this.  Actual times relative to the beginning of infusion will 
be used in the calculation of AUC.
The scheduled length of the first and fourth dose intervals is 672 hours.  If the actual 
length of a dose interval differs from the scheduled length by more than an hour, a value 
for the ABBV-8E12 concentration at the scheduled end of the dosing interval (672 hours 
after the start of infusion of the dose at the beginning of the dose interval) will be 
imputed.  In this case, the AUC will be calculated using the imputed value at the 
scheduled end of the dosing interval.  The imputed value will be obtained from 
interpolation with, or extrapolation of, the exponential curve defined by the last 
two concentration measurements in the dosing interval.
For the first dose interval, the concentration at the beginning of infusion of the dose will 
be assumed to be 0 even if the scheduled pre-dose blood sample is mistakenly obtained 
after the beginning of infusion.  For the fourth dose interval, the concentration of the pre-
dose sample will be used as the concentration at the beginning of infusion of the dose 
provided that the blood sample is obtained in the 30 minute interval before the beginning 
of infusion.  If the blood sample is obtained earlier than 30 minutes before the beginning 


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of infusion, for the calculation of AUC the concentration at the beginning of infusion will 
be Cobs X e–βt, where Cobs is the reported measurement for the pre-dose concentration, β is 
the rate constant determined from the exponential curve defined by the last 
two concentrations in the third dose interval and t the length of the time interval between 
the pre-dose blood sample and the beginning of infusion.  If the pre-dose sample for the 
fourth dose interval is mistakenly obtained after the beginning of infusion of the dose, a 
value for the concentration at the beginning of the dose interval (beginning of infusion) 
must be imputed unless the sample was obtained within a very few minutes of the 
beginning of infusion (< 15 minutes).  The other subjects in the same treatment group who 
have values for the concentrations at the beginning of the fourth dose interval, the 
beginning of the third dose interval and the end of the fourth dose interval may be used to 
obtain a linear regression model for the concentration at the beginning of the fourth dose 
interval, with the concentrations at the beginning of the third dose interval and the end of 
the fourth dose interval as explanatory (predictor) variables. The missing value may be 
replaced by the predicted value from the regression model.
12.2
Tabulations and Summary Statistics
For the data of Cohort 1, serum concentrations of ABBV-8E12 and pharmacokinetic 
parameter values will be tabulated for each subject and each dose level, and summary 
statistics will be computed for each sampling time and each parameter by dose level.  
Also, for the serum concentration data of all subjects, summary statistics will be provided 
for each scheduled time of sampling with breakdown by dose level.
CSF concentration data after the fourth dose and the final dose will be tabulated and 
summarized by dose level.
Summary statistics will consist of: number of observations (n), mean, standard deviation, 
coefficient of variation as a percentage (quotient of standard deviation and mean, 
multiplied by 100), minimum, median and maximum. In addition, the geometric mean 
will be given for Cmax and AUC.


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12.3
Model and Tests
Unless stated otherwise, hypothesis tests will be performed at significance level 0.050.
Change in Concentration with Repeated Dosing
The concentration data of the planned pre-infusion sampling times of Cohort 2 during 
Weeks 4 through 72 will be analyzed to investigate change in serum concentration over 
time.  The data of Cohort 1 will also be included in this analysis.  The logarithmic 
transformation will be used unless the data show that the logarithm has substantial non-
symmetry (e.g., magnitude of skewness coefficient > 1.0) while untransformed 
concentration or another transformation has an approximately symmetric distribution.  A 
MMRM analysis will be performed.  The model will have fixed effects for dose level, 
classification by time and the interaction of dose level and time.  The subjects will be 
viewed as a random sample, and an appropriate structure will be selected for the 
covariance matrix of the observations from a subject.  The concentration central value 
(back transformation of the estimate of the mean of the transformed data) versus time 
curves for the three dose levels will be plotted on the same graph.
Dose Proportionality
Analyses to address the issue of dose proportionality will be performed on the data of 
Cohort 1.  An analysis will be performed on each of dose normalized Cmax and dose-
normalized AUC for each of the first and fourth dose intervals.  An analysis will also be 
performed on dose-normalized Ctrough at Week 16.  The logarithmic transformation will be 
employed for Cmax and AUC and will likely be used for Ctrough.  An analysis of covariance 
(ANCOVA) will be performed for each exposure variable, with the greater emphasis on 
the fourth dose interval.  Subjects will be classified by dose level, and body weight will be 
a covariate.  Other variables such as age and sex that might explain some of the variability 
among subjects will be considered.  Except for body weight, a necessary condition for a 
variable to be included as a covariate in the final model is that the regression coefficient 
be significant at level 0.100.  The dependence among explanatory variable candidates will 


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also be considered when selecting the final model.  Within the framework of the final 
model, the hypothesis of no difference between the means of the highest and lowest doses 
will be tested.  If this hypothesis is rejected, corresponding tests will be conducted for the 
comparison of the middle dose to the lowest and highest doses.
12.4
Missing Values and Model Violations
The possibility of bias from missing data of subjects who prematurely discontinue for 
reasons possibly related to study drug will be addressed.  If it is concluded that there may 
be a bias of meaningful magnitude as a result of premature discontinuation, a value may 
be imputed for the missing pharmacokinetic parameter or missing concentrations, 
Sensitivity analyses might be carried out with the missing value replaced over a range of 
values.
In some cases of a missing individual concentration value, values of pharmacokinetic 
variables (Cmax, AUC, etc.) will be determined without replacing missing individual 
concentration values, but simply using the available data.  However, if a missing 
individual concentration value results in a value of a pharmacokinetic parameter that may 
be too low or too high to a meaningful degree, the value of the pharmacokinetic parameter 
will tentatively be considered missing.  In this case, a value for the missing individual 
concentration may be imputed so that an appropriate value of the pharmacokinetic 
parameter can be included in the analysis.  The imputed value will be obtained using 
appropriate methodology that takes into account the individual characteristics of the 
subject.  Also, if the concentration value at the beginning or end of the dose interval is 
missing, a value must be imputed in order for a value of AUC to be determined.
An imputed value will be obtained using appropriate methodology that takes into account 
the individual characteristics of the subject.  The data set from which the value is imputed 
will be restricted to that of subjects whose data could be considered a random sample 
from the probability distribution applicable to the subject with the missing data.  
Ordinarily, the data set from which the imputed value is obtained would be that of the 
treatment group to which the subject with the missing value is a member, or some 


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appropriate subset of the treatment group, using only subjects who do not have missing 
values of their own that would make them unsuitable for the purpose.
As stated in Section 12.4, it is expected that the logarithmic transformation will be used 
for dose-normalized AUC and dose-normalized Cmax and is likely to be used for pre-
infusion concentration (or Ctrough).  The primary purpose of a transformation will be to 
have a random variable with an approximately symmetric probability distribution, but an 
approximately symmetric distribution with apparently very heavy tails (e.g., kurtosis 
coefficient, as defined in the SAS Procedure Univariate, exceeding 9) would also be of 
concern.  If an adequate transformation is not found for a variable, then a non-parametric 
analysis may be performed.
13.0
Analysis of Biomarker Research Variables
Descriptive Statistics
Descriptive statistics will be provided for each variable by treatment and scheduled time 
of measurement.  The statistics will consist of: number of observations (n), mean, 
standard deviation, coefficient of variation as a percentage (quotient of standard deviation 
and mean, multiplied by 100), minimum, median and maximum.  If the logarithmic 
transformation is employed for the analysis of a variable, the geometric mean will also be 
reported.
Transformation of Variables for Analysis
If the probability distribution for a variable appears to have considerable non-symmetry 
(e.g., skewness coefficient > 1.00 in magnitude), a transformation will be sought that has 
an approximately normal distribution.  If a transformation is employed for the analysis, 
estimates of central values on the original scale (back transformation of SAS least squares 
means) will be provided.  If the logarithmic transformation is used, the comparison of a 
pair of treatments (usually with placebo as the reference treatment) will be in terms of the 
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Analysis of CSF Concentration Variables
An ANCOVA model will be used to evaluate CSF concentrations for total tau, free tau 
and the ratio of free tau concentration to total tau concentration for each scheduled time of 
evaluation during treatment (fourth dose interval and Week 96).  For the analysis for the 
fourth dose interval, an analysis will be performed for the data of Cohort 1 alone and also 
for all available data.  The observations will be classified by treatment.  The baseline 
value for total tau and free tau (last value before the first dose of study drug) will be the 
covariate in the case of total tau and free tau, but for the analysis on the ratio the covariate 
will be the baseline total tau concentration measurement.  If the probability distribution 
for a variable appears to have considerable non-symmetry (skewness coefficient > 0.75 in 
magnitude), a transformation will be sought so that the transformed variable has an 
approximately normal distribution.  For each ABBV-8E12 dose level, the results of the 
test of the hypothesis of no difference between the dose and placebo will be reported.  
Also, with the motivation to have a test with good power if the dose response curve is a 
monotonic function of dose, a test will be performed on a contrast in the four treatment 
means. With μ0, μ1, μ2 and μ3 denoting the means for placebo, the 300 mg treatment, the 
1000 mg treatment and 2000 mg treatment, respectively, the hypothesis that –3μ0 – μ1 + 
μ2 + 3μ3 = 0 will be tested at significance level 0.050 against the two-sided alternative 
hypothesis. The tests on the effects of the 1000 mg dose and the 300 mg dose will not be 
formally considered unless the statistic on the effect of the 2000 mg dose or the statistic 
on the contrast in the four means is significant at level 0.050.
CSF NFL concentration will be analyzed as described above for CSF total tau 
concentration.  The same will be done for other CSF concentration variables for which 
data are reported, provided that the proportion of measurements that are outside the limits 
of quantification and the magnitude of the lower limit do not make a conventional 
analysis of covariance inappropriate.


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Analysis of Serum/Plasma Concentration Variables
An analysis will be performed for plasma total tau concentration and for plasma NFL 
concentration.  If the data are reported for other plasma concentration variables, an 
analysis like that described for plasma total tau concentration will be performed, provided 
that the proportion of measurements that are outside the limits of quantification and the 
magnitude of the lower limit do not make the methodology inappropriate.
A MMRM analysis will be performed on the data from scheduled times of measurement. 
The model will include the baseline value as a covariate, have classification of subjects by 
treatment, an effect for time (classification) and will include an effect for the interaction 
of treatment and time of measurement.  The initial model will also allow the regression 
coefficient for the baseline value to vary with time (an effect for interaction of time and 
the baseline value), but this feature will be removed from the model if the statistic on this 
interaction is not significant at level 0.100.  The subjects of each treatment group will be 
viewed as a random sample, and an appropriate structure for the covariance matrix of the 
measurements of a subject will be selected.  Within the framework of this model, the 
mean across the scheduled times of measurement will be estimated for each treatment.  
Also, tests on differences of effect among the dose levels (with placebo considered a dose 
level) will be performed within the framework of the model. Tests on the dose level main 
effects will be performed as described for dose level effects in the analysis of covariance 
for CSF free tau concentration and CSF total tau concentration.  These same tests will be 
provided for each time of measurement in the framework of the MMRM model, and the 
tests for the individual times will be given the greater attention if the statistic on the 
interaction of treatment and time of measurement is significant at level 0.100.
Analysis of Volumetric MRI Variables
For volumetric MRI variables, descriptive statistics will be provided for the baseline 
value, for each scheduled time after that and for the changes from baseline. An MMRM 
analysis will be performed like that described for plasma NFL concentration, but with an 
additional covariate, estimated total intracranial volume (eTIV), in the model.  The 


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regression coefficient for eTIV will not vary with time, as may be allowed for the vMRI 
baseline value.
Analysis of Tau PET Scan Variables
For each region of the brain for which SUVR values are obtained, a joint analysis will be 
performed for the two scheduled times of evaluation during treatment (Week 44 and 
Week 96). The analysis will be like that described for plasma NFL concentration with 
some additional assumptions made.  The model will be that of a MMRM analysis even 
though there are only two times of measurement. The baseline value will be a covariate, 
with the regression coefficient assumed to be the same for the two times of measurement.  
Compound symmetry will be assumed for the covariance matrix of the error terms of the 
two times of measurement.  If data are reported for other continuous variables that reflect 
the extent of tau pathology, a similar approach will be used for their analysis.
Consideration of Premature Discontinuations
The possibility of bias from missing data of subjects who prematurely discontinue for 
reasons possibly related to study drug will be addressed.  If it is concluded that there may 
be a bias of meaningful magnitude as a result of premature discontinuation, sensitivity 
analyses may be carried out.  Also, some imputation of missing values for subjects who 
prematurely discontinue might be done.
Relationship with Disease State
For some of the exploratory biomarker variables, an analysis will be performed to explore 
the relationship to disease state/progression.  Disease state will be represented by 
CDR-SB score, and explorations may be carried out on the relationship between the 
biomarker variables and other measures of disease level.  The biomarker variables will 
include, but not necessarily be limited to, plasma total tau concentration, plasma NFL 
concentration, and the vMRI measures for whole brain, hippocampus, temporal lobe and 
lateral ventricles.  The relationship between change in CDR-SB score and change in 
biomarker will be explored.


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The schedule of visits for which the biomarker measurements are obtained are not the 
same as the schedule of visits on which the CDR-SB assessments are done.  For plasma 
concentration variables and vMRI variables, respectively, the visits defining the bivariate 
observations composing the data sets on which the analyses will be performed are shown 
in the two tables that follow.  Although there were times of evaluation before Week 48 for 
both plasma concentration biomarkers and CDR-SB, there was no pair of visits before 
Week 48 for which the blood sample for the biomarkers and the CDR-SB evaluation were 
judged to be close enough in time to form an acceptable bivariate observation.
Bivariate Observations for CDR-SB and Plasma Concentration Variable
Observation
Visit for CDR-SB Score
Visit for Plasma Concentration
1
Week 48
Week 48
2
Week 72
Week 72
3
Week 96
Week 96
Bivariate Observations for CDR-SB and vMRI
Observation
Visit for CDR-SB Score
Visit for vMRI Measurement
1
Week 24
Week 28
2
Week 48
Week 44
3
Week 72
Week 68
4
Week 96
Week 96
For each biomarker variable, the bivariate data of CDR-SB and the biomarker variable for 
each combination of treatment and time of observation will be plotted.  With each plot 
Spearman's rank correlation coefficient and the p-value for the test of independence will 
be provided.  An investigation of the relationship of CDR-SB with the biomarker variable 
for all of the times of observation jointly will be carried out in the framework of a 
MMRM analysis with decrease from baseline in CDR-SB score as the response variable 
and with change from baseline in the biomarker variable as a covariate (explanatory 
variable) that changes with time.  If a transformation is used for the analysis of the 
biomarker variable itself, that same transformation will be used for the biomarker variable 
in this analysis; that is, the covariate will be the change from baseline in the value of the 


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transformed variable.  The model will include classification by time of observation, which 
can also be thought of as the visit at which the CDR-SB evaluation was done.  The model 
will include classification by treatment and the interaction of treatment and time.  The 
initial model will have interaction of the covariate with treatment, allowing the regression 
coefficient of the covariate to depend upon treatment.  This interaction effect will be 
removed from the model if the statistic on the interaction is not significant at level 0.100 
in the analysis with the final choice of the structure for the covariance matrix of the error 
term, as discussed in the paragraph that follows.
The initial model will impose no restrictions on the covariance matrix for the error term 
(using Option UN with the SAS REPEATED statement).  A simpler structure for the 
covariance matrix will be considered, with the correlation coefficients for all pairs of 
times assumed to be the same while imposing no restrictions on the variances for the 
several times (using Option CSH with the SAS REPEATED statement). An approximate 
test of the hypothesis that the covariance matrix with the more complex model is same as 
the covariance matrix with the simpler model will be performed.  The approximate test 
will be that based upon the difference in the values of –2log (likelihood) for the 
two models, using the chi-square approximation for the null distribution, with degrees of 
freedom being the difference in the number of parameters required for the two structures 
of the covariance matrix.  If the test statistic is not significant at level 0.050, the simpler 
model will be tentatively adopted.  In that case, the compound symmetry structure (default 
option with the SAS REPEATED statement) will be considered.  The approximate test for 
the comparison of the two models will again be performed.  The compound symmetry 
model will be adopted only if the test statistic is not significant at level 0.050.  If the 
computational algorithm does not satisfactorily converge with a particular structure 
assumed for the covariance matrix, that structure will not be adopted, and only the simpler 
structure(s) will be considered.
If the final model contains an effect for the interaction of treatment and covariate, the 
estimate for each of the four regression coefficients and for the average of the 
four regression coefficients will be provided.  For each of the four regression coefficients 


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and for their average, a two-tailed test of the hypothesis that the regression coefficient (or 
the average) = 0 will be performed at significance level 0.050.  This will serve as a test of 
the hypothesis that the correlation coefficient between the CDR-SB change from baseline 
and the biomarker change from baseline is 0.  If the final model does not contain an effect 
for the interaction of treatment and covariate (a common regression coefficient for all 
four treatments), this hypothesis test will be performed on the single regression coefficient 
and will apply to placebo and all three ABBV-8E12 treatments.
To give further confidence in the assessment of the relationship of the biomarker variables 
with disease state and progression in the absence of treatment with ABBV-8E12, a 
MMRM analysis will be performed on the data set restricted to subjects on the placebo 
treatment.  The model and analysis will be simpler than that described above in that there 
will be no effects involving treatment.  In particular, there will be only a single regression 
coefficient.
14.0
Summary of Changes
Changes in the planed analyses from the latest version of the protocol 
(Protocol Amendment 1, Administrative Change 1, Administrative Change 2, 
Administrative Change 3, and Amendment 2) have been incorporated into Statistical 
Analysis Plan version 1.0.
In Statistical Analysis Plan version 2.0, changes of interim analysis (Section 4.4) and
impact of COVID-19 on statistical analysis (Section 10.4 and Section 10.6) have been 
incorporated. In Section 13.0, tau PET variables have been removed from the biomarkers 
specified for the exploration of relationship with disease state as represented by CDR-SB
since the number of subjects with tau PET data is now expected to be substantially smaller 
than was anticipated.
In Statistical Analysis Plan version 3.0, Braak stage I and II were included in 
Section 4.8.1. Analysis window definitions for vMRI, tau PET, CSF, and NFL were 


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removed in Section 6.2. Sensitivity analysis in Section 10.6 was updated.  Baseline 
amyloid centiloid value criterion for a subgroup analysis was updated in Section 10.8.
15.0
Reference List
1.
Little RJA. Pattern-mixture models for multivariate incomplete data. Journal of 
American Statistical Association. 1993;88:125-34.
2.
Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials with 
protocol deviation: a framework for relevant, accessible assumptions, and 
inference via multiple imputation. J Biopharm Stat. 2013;23(6):1352-71.
3.
Wang J, Logovinsky V, Hendrix SB, et al. ADCOMS: a composite clinical 
outcome for prodromal Alzheimer's disease trials.  J Neurol Neurosurg Psychiatry.  
2016;87(9):993-9.
4.
Xi D, Tamhane AC. Allocating recycled significance levels in group sequential 
procedures for multiple endpoints.  Biom J. 2015;57(1):90-107.
5.
Maurer W, Bretz F.  Multiple testing in group sequential trials using graphical 
approaches. Statistics in Biopharmaceutical Research. 2013;5(4):311-20.
6.
Bretz F, Maurer W, Brannath W, et al.  A graphical approach to sequentially 
rejective multiple test procedures.  Stat Med.  2009;28(4):586-604.


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Appendix A.
Potentially Clinically Significant (PCS) Laboratory Value
Clinical Laboratory Tests
Very Low (VL)
Very High (VH)
Hematology
Activated partial thromboplastin 
time
NA
> ULN
Hemoglobin
< 100 g/L (6.2 mmol/L)
> 40 g/L above ULN
Prothrombin Intl. Normalized
Ratio
NA
> ULN
Leukocytes
< 2 × 109/L
> 100 × 109/L
Lymphocyte
< 0.5 × 109/L
> 20 × 109/L
Neutrophil
< 1 × 109/L
NA
Platelets
< 75 × 109/L
NA
Chemistry
Bilirubin
NA
> 1.5 × ULN
Cholesterol
NA
> 12.92 mmol/L (500 mg/dL)
Creatinine
NA
> 1.5 × ULN
Calcium (corrected serum)
< 1.75 mmol/L (7.0 mg/dL)
> 3.1 mmol/L (12.5 mg/dL)
Glucose (fasting)
< 2.2 mmol/L (40 mg/dL)
> 13.9 mmol/L (250 mg/dL)
Potassium
< 3.0 mmol/L
> 6.0 mmol/L
Triglycerides
NA
> 5.7 mmol/L (500 mg/dL)
Urate
NA
> 590 umol/L (10 mg/dL)
Albumin
< 20 g/L
NA
Sodium
< 130 mmol/L
> 155 mmol/L
Phosphate
< 0.6 mmol/L (2.0 mg/dL)
NA
Enzymes
Alanine aminotransferase (ALT)
NA
> 3 × ULN
Alkaline phosphatase
NA
> 2.5 × ULN
Aspartate aminotransferase 
(AST)
NA
> 3 × ULN
NA = not applicable; ULN = upper limit normal
Adapted from the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published:  May 28, 2009 
(v4.03:  June 14, 2010).


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Appendix B.
Criteria for Potentially Clinically Significant Vital Sign and Weight 
Values
Vital Signs
Very Low (VL)
Very High (VH)
Systolic Blood Pressure 
(SBP) (mmHG)
≤ 90 and decreased ≥ 30 from 
baseline
≥ 180 and increased ≥ 40 from 
baseline
Diastolic Blood Pressure 
(DBP) (mmHG)
≤ 50 and decreased ≥ 20 from 
baseline
≥ 105 and increased ≥ 30 from 
baseline
Pulse (bpm)
≤ 45 and decreased ≥ 30 from 
baseline
≥ 120 and increased ≥ 30 from 
baseline
Temperature (C)
≥ 1.1 decrease from baseline
> 38.5 or increase ≥ 1.1 from 
baseline
Weight (kg)
Decreased ≥ 7% from baseline
Increased ≥ 7% from baseline


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Appendix C.
Criteria for Potentially Clinically Significant ECG Values
ECG Parameters
Significant Values
QTcF Interval (msec)
> 499
QTcF Interval Increased from Baseline (msec)
> 60