Conditions: Alzheimer's Disease
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 364
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the long-term safety and tolerability of ABBV-8E12 in participants with early AD.

Detailed description:

Arms:
arm 1: Participants who received 300 mg tilavonemab in Study M15-566 receive 1000 mg tilavonemab in Study M15-570 via intravenous (IV) infusion every 4 weeks for up to 5.5 years. arm 2: Participants who received 1000 mg tilavonemab in Study M15-566 continue on the same dose in Study M15-570 via IV infusion every 4 weeks for up to 5.5 years. arm 3: Participants who received 2000 mg tilavonemab in Study M15-566 continue on the same dose in Study M15-570 via IV infusion every 4 weeks for up to 5.5 years. arm 4: Participants who received placebo (PBO) in Study M15-566 receive 2000 mg tilavonemab in Study M15-570 via IV infusion every 4 weeks for up to 5.5 years.

Interventions: intervention 1: Tilavonemab
Intervention descriptions: intervention 1: solution for IV infusion

Protocol document:
Prot_000.pdf: 
ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
1
1.0
Title Page
Clinical Study Protocol M15-570
An Extension Study of ABBV-8E12 in Early 
Alzheimer's Disease
Incorporating Amendments 1 and 2
AbbVie Investigational 
  Product:
ABBV-8E12
Date:
20 October 2020
EudraCT Number:
2018-000268-26
Development Phase:
2
Study Design:
This is a Phase 2 extension of Study M15-566 evaluating the 
long-term safety and tolerability of ABBV-8E12 in subjects 
with early Alzheimer's disease
Investigators:
Multicenter trial:  Investigator information is on file at AbbVie
Sponsor:
AbbVie
Sponsor Contact for all Non-
Emergency Issues:
1 North Waukegan Road
North Chicago, IL 60064
Phone:
Fax:
Sponsor Emergency 
  Medical Contact:
1 North Waukegan Road
North Chicago, IL  60064
Phone:
Fax:
The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are 
provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial 
Application with the Competent Authority.
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
 
NCT03712787


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
2
1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date 
Original
09 April 2018
Amendment 1
24 January 2019
The purpose of this amendment is to:
●
Update Section 3.0 Introduction Clinical Experience to remove studies.
Rationale:  Study M15-562 and Study M15-563 have been completed and the 
PSP program is discontinued.
●
Update Section 3.2 Benefits and Risks to include language for the coronavirus 
disease-19 (COVID-19) pandemic.
Rationale:  To describe alternative processes that may be needed because of 
the COVID-19 pandemic.
●
Update Section 5.1 Overall Study Design and Plan:  Description to specify 
timing in schedule of activities.
Rationale:  To clarify the timing of the Day 1 visit of Study M15-570 in 
relation to Study M15-566 for study sites to follow.
●
Update Section 5.2.2 Exclusion Criteria to add a rationale for the exclusion 
criteria.
Rationale: to allow the TA MD to delegate responsibility.
●
Update Section 5.3.1.1 Study Procedures [Physical Examination, Neurological 
Examination, Vital Signs, 12-Lead Electrocardiogram (ECG), Abnormal 
Findings, Optional Lumbar Puncture, Magnetic Resonance Imaging (MRI), 
and Positron Emission Tomography (PET) Tau Imaging] 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 5.3.1.1 Study Procedures, Table 2 to specify optional tests.
 


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M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
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Rationale:  To clarify procedures that are not required if using Study M15-566 
Week 96 visit for Baseline.
●
Update Section 5.3.1.1 Study Procedures [Positron Emission Tomography 
(PET) Tau Imaging] to specify timing in schedule of activities.
Rationale: To clarify the timing of the tau PET scan for Day 1/Baseline for 
study sites to follow.
●
Update Section 5.3.1.1 Study Procedures to remove procedures.
Rationale:  To remove retinal imaging for amyloid and digital measures of 
cognition, actigraphy, and sleep because sleep and activity platforms will not 
be investigated.
●
Update Section 5.3.1.1 Study Procedures, Table 3 to specify timing of scales.
Rationale:  To confirm that the 24-item Alzheimer's Disease Cooperative 
Study/Activities of Daily Living scale adapted for patients with Mild Cognitive 
Impairment (ADCS-MCI-ADL-24), EuroQol 5 Dimensions 5 Levels Health 
State Instrument (EQ-5D-5L), and Columbia-Suicide Severity Rating Scale 
(C-SSRS) can be administered/assessed at any time during the visit.  This 
change was also created to align with Study M15-566.
●
Update Section 5.3.1.1 Study Procedures, EuroQuality of Life-5-level 
(EQ-5D-5L) to add language describing the scale.
Rationale:  To clarify the version of the scale.
●
Update Section 5.3.1.2 Collection and Handling of Biomarker and 
Pharmacogenetic Research Samples (Blood and Optional CSF Biomarker 
Samples; Optional Pharmacogenetic Research Samples) 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 5.3.2.1 Collection of Samples for Analysis (Optional CSF 
Samples for ABBV-8E12 Assay) to include language for the COVID-19 
pandemic.
Rationale:  To describe alternative processes that may be needed because of 
the COVID-19 pandemic.
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
4
●
Update Section 5.3.6.1 Biomarker Research Variables, Volumetric MRI to 
include language reflecting analysis.
Rationale:  To clarify the analysis and algin with the planned data analysis as 
described in Study M15-566 and the current SAP.
●
Update Section 5.3.6.1 Biomarker Research Variables to remove language.
Rationale:  To remove retinal imaging for amyloid because this will not be 
investigated.
●
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 specify timing of drug 
administration.
Rationale:  To clarify when study drug should be administered.
●
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 5.5.2 Identity of Investigational Product, Table 4 to add 
additional strength of study drug
Rationale:  To clarify the additional strength of 2000 mg/20 mL of 
ABBV-8E12
●
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 8.1.1 Analysis Data Sets, Data Set for Safety Analyses to 
remove language pertaining to analysis.
Rationale:  Removed because the cumulative safety data analysis will not be 
conducted for this study.  It will be considered in future aggregate safety 
analyses.
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
5
●
Update Section 8.1.1 Analysis Data Sets, Data Set for Biomarkers to include 
language pertaining to analysis.
Rationale:  To clarify the analysis in relation to Study M15-566.
●
Update Section 8.1.4 Safety Analysis to include language pertaining to 
analyses. 
Rationale:  Language replaced due to a change in statistical analysis plans.
●
Update Section 8.1.4.2 Analysis of Adverse Events to include language 
pertaining to analyses. 
Rationale:  Language replaced due to a change in statistical analysis plans.
●
Update Section 8.1.5 Biomarker Analyses to include language pertaining to 
analysis. 
Rationale:  Language replaced to reflect a part of the change in the method of 
analysis.
●
Update Section 8.1.5 Biomarker Analyses, Volumetric MRI Variables to 
include language pertaining to analysis. 
Rationale:  Language replaced to clarify the method of analysis.
●
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 Section 15.0 Reference List to replace reference.
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
6
Rationale:  The new reference establishes the validity and reliability of using 
the EuroQuality of Life-5-level (EQ-5D-5L) Proxy Version 1 in the Alzheimer's 
disease population.  It also compares the self-report and proxy-based version.
Other revisions were made to ensure consistency within the protocol and to provide 
further clarifications of study design and processes.
An itemized list of all changes made to this protocol under this amendment can be found 
in Appendix E.
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
7
1.2
Synopsis
AbbVie Inc.
Protocol Number:  M15-570
Name of Study Drug:  ABBV-
8E12
Phase of Development:  2
Name of Active Ingredient:  
ABBV-8E12
Date of Protocol Synopsis:  20 October 2020
Protocol Title:  An Extension Study of ABBV-8E12 in Early Alzheimer's Disease
Objectives:
The primary objective of this study is to assess the long-term safety and tolerability of ABBV-8E12 in 
subjects with early Alzheimer's disease (AD).
The secondary objective of this study is to assess the pharmacokinetics (PK) of ABBV-8E12 in subjects 
with early AD.
The exploratory objectives of this study are:

To assess the long-term efficacy of ABBV-8E12 in slowing disease progression in subjects 
with early AD. 

To assess the long-term effect of ABBV-8E12 on a range of disease-related and drug-related 
biomarkers in subjects with early AD.
Investigators:  Multicenter
Study Sites:  Up to 80 global sites
Study Population:  Adult subjects with early AD who completed Study M15-566
Number of Subjects to be Enrolled:  Approximately 400
Methodology:
Study M15-570 is a Phase 2 extension of the multiple dose, multicenter, multinational, randomized, 
double-blind, placebo-controlled study, Study M15-566, and is designed to evaluate the long-term safety 
and tolerability of ABBV-8E12 in subjects with early AD.  The study will consist of a 5-year treatment 
period and a follow-up period of approximately 20 weeks following the last study drug administration.
All subjects who complete the Treatment Period in Study M15-566 will be eligible to participate in this 
study according to the selection criteria.  Upon completion of baseline study procedures, eligible subjects 
will receive ABBV-8E12 via intravenous (IV) infusion on Day 1 of Study M15-570 as follows:  

Subjects who received placebo in Study M15-566 will receive 2000 mg ABBV-8E12 in 
Study M15-570;

Subjects who received 300 mg ABBV-8E12 in Study M15-566 will receive 1000 mg 
ABBV-8E12 in Study M15-570; and 

Subjects who received 1000 mg or 2000 mg ABBV-8E12 in Study M15-566 will continue on 
the same dose in Study M15-570. 
Note:  if any changes are made to alter Study M15-566 with regards to the treatment arms due to safety, 
efficacy, or other reasons, a corresponding change will be implemented in Study M15-570.  This change 
may include, but is not limited to, adding or dropping treatment arm(s).
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
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Methodology (Continued):
Subjects will receive study drug infusion every 4 weeks and undergo other study procedures and 
assessments as outlined in the Study Activities table (Appendix C).  Subjects will continue to receive 
treatment either until one of the discontinuation criteria is met, the sponsor discontinues the study, or the 
subject completes the 5-year treatment period of Study M15-570.  Refer to Section 5.4 for detailed 
description of discontinuation criteria.
Day 1 visit of Study M15-570 will be approximately 4 weeks but no more than 8 weeks after the 
Week 92 visit of Study M15-566.  Should this window be longer than 8 weeks, the subject may be 
considered for participation in Study M15-570 only with the approval of the AbbVie Therapeutic Area 
Medical Director (TA MD) or designee.  The investigators and subjects will remain blinded to the 
treatment assignments in Study M15-566 and will be blinded to the dose level of ABBV-8E12 in 
Study M15-570.
Safety will be closely monitored during the study conduct.  The study will also utilize an external data 
monitoring committee (DMC), which will review accumulating study data and make recommendations 
based on the emerging safety profile of ABBV-8E12.  The DMC membership, responsibilities, operating 
logistics, and timing of reviews will be documented in a charter that will be finalized prior to the 
first DMC review meeting.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:

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 institutional review board 
(IRB)/independent ethics committee (IEC) approved informed consent, prior to the conduct of 
any extension study-specific procedures (including any changes occurring in the subject's 
current therapeutic regimen).  In the absence of subject's ability to provide the informed 
consent, the informed consent must be obtained by a person who has the legal right to act on 
behalf of the subject following local regulations.

Subject completed the 96-week treatment period of Study M15-566. 

In the investigator's opinion, subject was compliant during participation in Study M15-566.

Subject has an identified, reliable study partner (e.g., caregiver, family member, social worker, 
or friend; preferably the same person for the duration of the study) who has frequent contact 
with the subject (at least 10 hours per week) and who will provide information as to the 
subject's cognitive and functional abilities.  The study partner has voluntarily signed the 
IRB/IEC approved study partner informed consent, prior to the conduct of any extension 
study-specific procedures.

If female, subject must be postmenopausal defined as:
o
Age ≥ 55 years with no menses for 12 or more months without an alternative medical 
cause.
OR
o
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy or 
hysterectomy).

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.
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
9
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion:

The subject has any significant change in his/her medical condition since participation in 
Study M15-566 that could interfere with the subject's participation in Study M15-570, could 
place the subject at increased risk, or could confound interpretation of study results.  The 
investigator must re-evaluate the subject for continuing participation and consider relevant 
factors including:
o
interim development of any clinically significant neurological, hematological, 
autoimmune, endocrine, cardiovascular, neoplastic, renal, hepatic, metabolic, psychiatric, 
pulmonary, gastrointestinal, or other major disorder
o
interim development of contraindication to or inability to tolerate brain MRI or PET scans

More than 8 weeks have elapsed since the subject received his/her last dose of study drug in 
Study M15-566 (i.e., Week 92 visit in Study M15-566).  In certain cases, subject may be 
eligible to enroll after approval by the TA MD or designee.

Subject is concurrently enrolled in another interventional clinical study (with the exception of 
Study M15-566) involving a therapeutic agent.

Subject is considered by the investigator, for any reason, to be an unsuitable candidate to 
receive ABBV-8E12 or the subject is considered by the investigator to be unable or unlikely to 
comply with the dosing schedule or study evaluations.
Investigational Product:
ABBV-8E12 (vial of 1000 mg/10 mL and vial of 2000 mg/20 mL)
Doses:
Dose 1:  1000 mg
Dose 2:  2000 mg
Doses will be given every 4 weeks.
Doses may be modified after evaluation by the DMC of the safety, 
tolerability, and available PK data.
Mode of Administration:
IV infusion
Reference Therapy:
Not applicable
Doses:
Not applicable
Mode of Administration:
Not applicable
Duration of Treatment:  5 years
Criteria for Evaluation:
Safety:
Adverse event monitoring, vital signs, physical examination, neurologic examination, electrocardiogram 
(ECG), laboratory tests, Columbia-suicide severity rating scale (C-SSRS), MRI, and immunogenicity 
assessments will be conducted. 
Subjects will be monitored closely for the occurrence of AEs and serious adverse events (SAEs) 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 (Appendix C).  The DMC will be in place to provide recommendations during the 
study.
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
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Criteria for Evaluation (Continued):
Efficacy:
Clinical Assessments:

Clinical Dementia Rating - Sum of Boxes (CDR-SB)

Repeatable Battery for Assessment of Neuropsychological Status (RBANS)

24-item AD Cooperative Study/Activities of Daily Living scale adapted for patients with mild 
cognitive impairment (ADCS-MCI-ADL-24)

EuroQuality of Life-5-level (EQ-5D-5L) Proxy Version 1
Pharmacokinetics:
Values for the following pharmacokinetic parameters will be estimated using mixed-effect modeling 
approach:  clearance (CL) and volume of distribution (V).  Additional parameters may be calculated if 
useful in the interpretation of the data.  Pharmacokinetic data from this study may be combined with data 
from other ABBV-8E12 studies for pharmacokinetic analyses.  Additional parameters may be calculated 
if useful in the interpretation of the data.
Immunogenicity:
Anti-drug antibodies (ADA) will be determined in serum for assessment of immunogenicity.
Biomarkers and Pharmacogenetics:
Exploratory research to assess effects of ABBV-8E12 on potential disease-related and drug-related 
biomarkers will be conducted.  Blood sampling, optional CSF sampling and MRIs for volumetric 
analysis will be done at designated time points throughout the study in order to obtain the data.  Also, tau 
PET scans will be collected in a subset of the subjects.  The potential CSF and plasma biomarkers will 
include, but are not limited to, the following:  tau and NFL concentrations; volumetric MRI measures for 
whole brain, hippocampus, temporal lobes 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.
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.  The values of other variables 
may be determined.  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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EudraCT 2018-000268-26
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Statistical Methods:
Safety:
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  The 
number and percentage of subjects reporting treatment-emergent AEs will be tabulated by MedDRA 
system organ class (SOC) and preferred term (PT) with a breakdown by treatment sequence.  
Tabulations will also be provided in which the number of subjects reporting an AE (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 SAE (including deaths) and 
AEs leading to premature discontinuation of the study drug will be tabulated according to the MedDRA 
SOC and preferred term by treatment sequence.  Treatment sequence differences between each 
ABBV-8E12 dose group will be analyzed using Fisher's exact test.  Differences between each 
ABBV-8E12 dose group 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.
Efficacy:
All efficacy analyses of comparisons will be performed with a 2-sided test at the significance level of 
0.050 unless otherwise specified.  All efficacy assessments that are taken no more than 45 days after the 
last dose of study drug will be included in the efficacy analyses.
The analysis of efficacy variables will be performed on the Study M15-570 ITT data set.  The analysis 
model is a likelihood-based, mixed effects model repeated measures (MMRM) analysis at 
Study M15-570 Baseline and each post-baseline observation using all observed data. This MMRM 
analysis will be applied to each efficacy variable with repeated measurements.  Details of the analysis 
will be described in the statistical analysis plan (SAP).
If applicable, delayed-start analysis will be conducted on the change from Baseline of Study M15-566 up 
to Week 96 in Study M15-570 on CDR-SB score.  An MMRM analysis model will be used.  Details of 
the analysis will be specified in the SAP.
Pharmacokinetics:
For ABBV-8E12 serum concentration data, descriptive statistics will be provided for each scheduled 
time of measurement with a breakdown by treatment sequence.
Data from this study may be combined with data from other studies for the population PK and exposure-
response analyses.  Population PK and exposure-response analyses of data from this study only may not 
be conducted.  The following general methodology will be used for the population PK and exposure-
response analyses.
Population PK analyses will be performed using the actual sampling time relative to the last 
administered dose. Pharmacokinetic models will be built using a non-linear mixed-effect modeling 
approach with the NONMEM software (Version 7, or higher version).  The structure of the starting PK 
model will be based on the PK analysis of data from previous studies.  Apparent CL and apparent V of 
ABBV-8E12 will be the PK parameters of major interest in the NONMEM analyses.  If necessary, other 
parameters may be fixed if useful in the analysis.
Immunogenicity:
The ADA titers will be tabulated by dose level and summarized as appropriate.
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
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Statistical Methods (Continued):
Biomarkers:
For each variable, descriptive statistics will be provided for each scheduled time of measurement with a 
breakdown by group as defined by treatment in Study M15-566 and treatment in Study M15-570, i.e.,:  

ABBV-8E12 1000 mg in Study M15-566, continuing the same in Study M15-570

ABBV-8E12 2000 mg in Study M15-566, continuing the same in Study M15-570

ABBV-8E12 300 mg in Study M15-566, ABBV-8E12 1000 mg in Study M15-570

Placebo in Study M15-566, ABBV-8E12 2000 mg in Study M15-570.
For the CSF concentrations of total and free tau and their ratio and for the plasma concentrations of total 
tau and NFL, an MMRM analysis will be performed for scheduled measurements after study drug 
administration of Study M15-570 begins.
The model for the MMRM analysis performed for the tau variables and plasma NFL will include 
classification by treatment sequence and by time of measurement.  There will be an effect for the 
interaction of treatment and time of measurement.  Except for the ratio of CSF free tau concentration to 
CSF total concentration, the baseline value will be a covariate.  For the ratio of CSF free to total tau, the 
value for baseline total tau concentration will be a covariate if this variable is found to be a significant 
covariate for the ratio in Study M15-566.  The subjects in each treatment sequence will be viewed as a 
random sample, and an appropriate structure for the covariance matrix of the measurements of a subject 
will be selected.
For volumetric MRI variables, descriptive statistics will be provided for the baseline value and the 
change from baseline for each of the scheduled times of measurement.  For each variable, an MMRM 
analysis will be performed for the changes from baseline.  The analysis will be much like that described 
for plasma total tau concentration, but with estimated total intracranial volume (eTIV) as a covariate in 
addition to the baseline value.
For each region of the brain for which SUVR values are obtained from PET scans, an analysis like that 
described for plasma total tau concentration will be performed.
 


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
Aβ
Amyloid
AD
Alzheimer's disease
ADA
Anti-drug antibody
ADCS-MCI-ADL-24
24-item Alzheimer's Disease Cooperative Study/Activities of Daily Living 
scale adapted for patients with mild cognitive impairment
ADL
activities of daily living
AE
Adverse event
ANOVA
Analysis of variance
aPTT
Activated partial thromboplastin time
AUC
Area under the concentration time curve
BMI
Body mass index
C2N
C2N diagnostics company
CBD
Corticobasal degeneration
CDR
Clinical dementia rating
CDR-SB
Clinical Dementia Rating Sum of Boxes
CL
Clearance
Cmax
Maximum observed serum concentration
CNS
Central nervous system
COVID-19
Coronavirus disease - 2019
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
CTE
chronic traumatic encephalopathy
Ctrough
Observed serum drug concentration at the end of a dose interval
DMC
Data monitoring committee
DNA
Deoxyribonucleic acid
DTP
Direct-to-patient
EC
Ethics committee
 


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ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EMA
European Medicines Agency
Emax
Maximum effect
EQ-5D-5L
EuroQol 5 Dimensions 5 Levels Health State Instrument
ERAC
Exposure-response analysis center
eTIV
Estimated total intracranial volume
GAM
generalized additive method
GCP
Good clinical practice
ICH
International Council on Harmonization
IEC
Independent ethics committee
IERC
Internal Executive Review Committee
IgG4
Immunoglobulin G4
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/IWB
Interactive Voice-Response/Interactive Web-Based
KD
Dissociation constant
LP
Lumbar puncture
MCI
Mild cognitive impairment
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed model repeated measures
MRI
Magnetic resonance imaging
NCS
Not clinically significant
NFL
Neurofilament light chain
NONMEM
nonlinear mixed effect modeling
PCS
Potentially clinically significant
PD
Premature discontinuation
PET
Positron emission tomography
 


ABBV-8E12
M15-570 Protocol Amendment 2
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PIN
personal identification number
PK
Pharmacokinetic
PRN
As needed
PSP
Progressive supranuclear palsy
PT
Preferred term
QTc
QT interval corrected
QTcF
Fridericia-corrected QT interval
RBANS
Repeatable battery for assessment of neuropsychological status
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
TA MD
Therapeutic area medical director
TEAE
Treatment-emergent Adverse Event
US
United States
V
Volume of distribution
V/F
apparent volume of distribution
VAS
visual analogue scale
vMRI
Volumetric magnetic resonance imaging
WBC
White blood cell count
WHO
World Health Organization
WHO DRUG
World Health Organization Drug Dictionary
 


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Definition of Terms
Treatment Visit Window
Visits during the Treatment Period may be scheduled within ± 4 days.
Study Drug Infusion
Study drug will be administered every 4 weeks for 5 years (65 infusions)
Treatment Period
Period of time to complete Day 1 through Week 260 or premature 
discontinuation (PD).
Post treatment Follow-up 
Period
Begins at the time of completion of the Treatment Period and continues up 
to 20 weeks.  Subjects can also enter the Post treatment Follow-up Period 
in this study if they prematurely discontinue from treatment.
 


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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 .....................................................................................................7
1.3
List of Abbreviations and Definition of Terms........................................13
2.0
Table of Contents...................................................................17
3.0
Introduction ...........................................................................21
3.1
Differences Statement..............................................................................23
3.2
Benefits and Risks....................................................................................24
4.0
Study Objectives....................................................................24
5.0
Investigational Plan...............................................................25
5.1
Overall Study Design and Plan:  Description ..........................................25
5.2
Selection of Study Population..................................................................27
5.2.1
Inclusion Criteria .....................................................................................27
5.2.2
Exclusion Criteria ....................................................................................28
5.2.3
Prior and Concomitant Therapy...............................................................29
5.2.3.1
Prohibited Therapy...................................................................................30
5.2.4
Contraception Recommendations and Pregnancy Testing.......................32
5.3
Efficacy, Pharmacokinetic, Biomarker, Pharmacogenetic and 
Safety Assessments/Variables..................................................................33
5.3.1
Efficacy and Safety Measurements Assessed ..........................................33
5.3.1.1
Study Procedures .....................................................................................33
5.3.1.2
Collection and Handling of Biomarker and Pharmacogenetic 
Research Samples ....................................................................................47
5.3.1.3
Confinement.............................................................................................49
5.3.1.4
Meals and Dietary Requirements.............................................................49
5.3.2
Drug and Anti-Drug Antibody Concentration Measurements.................49
5.3.2.1
Collection of Samples for Analysis .........................................................49
5.3.2.2
Measurement Methods.............................................................................51
5.3.3
Efficacy Variables....................................................................................51
5.3.4
Safety Variables.......................................................................................51
5.3.5
Pharmacokinetic Variables ......................................................................51
 


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5.3.6
Biomarker and Pharmacogenetic Research Variables .............................52
5.3.6.1
Biomarker Research Variables.................................................................52
5.3.6.2
Pharmacogenetic Research Variables......................................................53
5.3.7
Immunogenicity .......................................................................................54
5.4
Removal of Subjects from Therapy or Assessment.................................54
5.4.1
Discontinuation of Individual Subjects....................................................54
5.4.2
Discontinuation of Entire Study...............................................................56
5.5
Treatments................................................................................................56
5.5.1
Treatments Administered.........................................................................56
5.5.2
Identity of Investigational Product...........................................................58
5.5.2.1
Packaging and Labeling...........................................................................58
5.5.2.2
Storage and Disposition of Study Drugs..................................................59
5.5.2.3
Preparation/Reconstitution of Dosage Form............................................59
5.5.3
Method of Assigning Subjects to Treatment Groups...............................60
5.5.4
Selection and Timing of Dose for Each Subject......................................60
5.5.5
Blinding....................................................................................................60
5.5.6
Treatment Compliance.............................................................................62
5.5.7
Drug Accountability.................................................................................62
5.6
Discussion and Justification of Study Design..........................................62
5.6.1
Discussion of Study Design and Choice of Control Groups....................62
5.6.2
Appropriateness of Measurements...........................................................63
5.6.3
Suitability of Subject Population .............................................................63
5.6.4
Selection of Doses in the Study ...............................................................63
6.0
Complaints .............................................................................64
6.1
Medical Complaints.................................................................................65
6.1.1
Definitions................................................................................................65
6.1.1.1
Adverse Event..........................................................................................65
6.1.1.2
Serious Adverse Events ...........................................................................66
6.1.2
Adverse Event Severity............................................................................67
6.1.3
Relationship to Study Drug......................................................................67
6.1.4
Adverse Event Collection Period.............................................................68
6.1.5
Adverse Event Reporting.........................................................................69
6.1.6
Toxicity Management ..............................................................................71
 


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6.1.6.1
Allergic Reactions Management..............................................................72
6.1.6.2
Management of Adverse Events of the Nervous System.........................73
6.2
Product Complaint ...................................................................................74
6.2.1
Definition .................................................................................................74
6.2.2
Reporting..................................................................................................74
7.0
Protocol Deviations................................................................75
8.0
Statistical Methods and Determination of Sample 
Size ..........................................................................................75
8.1
Statistical and Analytical Plans................................................................75
8.1.1
Analysis Data Sets ...................................................................................76
8.1.2
Disposition, Demographics, and Other Baseline Characteristics ............77
8.1.3
Efficacy Analyses ....................................................................................78
8.1.4
Safety Analyses........................................................................................79
8.1.4.1
Study Drug Exposure and Compliance....................................................79
8.1.4.2
Analysis of Adverse Events.....................................................................79
8.1.4.3
Analysis of Laboratory Tests...................................................................80
8.1.4.4
Analysis of Vital Signs and Weight.........................................................80
8.1.4.5
Analysis of ECG Variables......................................................................81
8.1.4.6
Analysis of C-SSRS.................................................................................81
8.1.5
Biomarker Analyses.................................................................................82
8.1.6
Pharmacokinetics and Exposure-Response Analyses..............................83
8.1.6.1
Tabulations and Summary Statistics........................................................83
8.1.6.2
Population Pharmacokinetic and Exposure-Response Analysis..............84
8.1.7
Immunogenicity .......................................................................................85
8.1.8
Safety Interim Analysis............................................................................85
8.1.9
Preliminary Efficacy Analysis .................................................................86
8.2
Determination of Sample Size .................................................................86
8.3
Randomization Methods ..........................................................................86
9.0
Ethics.......................................................................................87
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) .............................................................................................87
9.2
Ethical Conduct of the Study...................................................................87
9.3
Subject Information and Consent.............................................................88
 


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10.0
Source Documents, Data Collection and Electronic 
Case Report Forms................................................................89
10.1
Source Documents ...................................................................................89
10.2
Data Collection/Electronic Case Report Forms.......................................89
11.0
Data Quality Assurance ........................................................90
12.0
Use of Information.................................................................91
13.0
Completion of the Study .......................................................92
14.0
Investigator's Agreement......................................................94
15.0
Reference List ........................................................................95
List of Tables
Table 1.
Medications That Require Special Consideration....................................31
Table 2.
Clinical Laboratory Tests.........................................................................39
Table 3.
Diagnostic Tools and Scale Administration Timing................................44
Table 4.
Identity of Investigational Product...........................................................58
List of Figures
Figure 1.
Study Schematic.......................................................................................27
Figure 2.
Adverse Event Collection ........................................................................69
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ............................................97
Appendix B.
List of Protocol Signatories......................................................................99
Appendix C.
Study Activities......................................................................................100
Appendix D.
Potentially Clinically Significant (PCS) Laboratory Value...................111
Appendix E.
Protocol Amendment:  List of Changes.................................................116
 


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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 (ADL), and a variety of neuropsychiatric and behavioral disturbances.  The 
aggregation and accumulation of tau appears to play a critical role in AD and, unlike 
accumulation of Aβ, 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 ADL 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  Results from trials 
of anti-Aβ antibody therapies 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 that may be already showing clinical symptoms of 
AD.
ABBV-8E12
ABBV-8E12 is a humanized immunoglobulin G4 (IgG4) monoclonal antibody against 
human microtubule-associated protein tau.  It targets soluble extracellular tau in the brain, 
 


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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 tau-associated neurodegenerative disorders.
A detailed discussion of the ABBV-8E12 preclinical and nonclinical data can be found in 
the Investigator's Brochure.4
Clinical Experience
Compassionate-Use Protocols
Prior to the regular Investigational New Drug Application (IND) submission, treatment 
was initiated under an Expanded Access IND (United States [US]) for one patient with 
PSP, and subsequently for one patient with CBD under a compassionate-use treatment 
protocol (Germany).  ABBV-8E12 was later administered to one patient with chronic 
traumatic encephalopathy (CTE) under an expanded access investigator-initiated protocol 
(US).
The PSP patient received 20 monthly infusions (highest dose 25 mg/kg), then died for 
reasons unrelated to study drug from 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 from 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.  The CTE patient has received 15 infusions of ABBV-8E12 ranging 
from 2.5 to 25 mg/kg.
 


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Phase 1 Single Ascending 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:  subdural hematoma 
resulting from a fall (15 mg/kg dose group), hospitalization due to a severe increase in 
agitation, anxiety, and perseverative behavior (25 mg/kg dose group), and hospitalization 
for hypertension (50 mg/kg dose group).
No subject experienced a systemic hypersensitivity reaction or injection site reaction, and 
there were no clinically relevant patterns of adverse event (AE) 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.
Phase 2 Multiple-Dose Study in Subjects with AD
Study M15-566 is an ongoing Phase 2, randomized, multicenter, double-blind, 
placebo-controlled, multiple-dose trial in which 3 dose levels of ABBV-8E12 are being 
evaluated (300, 1000 and 2000 mg).  A total of approximately 400 subjects (300 on 
ABBV-8E12 and 100 on placebo) are planned to participate in this study.
3.1
Differences Statement
Study M15-570 is the second study in which ABBV-8E12 will be administered to 
subjects with early AD after Study M15-566.  ABBV-8E12 will be administered for an 
extended treatment period of up to 5 years compared with up to 96 weeks in 
Study M15-566.  All subjects in Study M15-570 will be on active treatment (ABBV-8E12 
1000 or 2000 mg), whereas Study M15-566 is a placebo-controlled study.
 


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3.2
Benefits and Risks
There is a significant demand and unmet medical need for the development of disease-
modifying drugs for AD.  The aggregation and accumulation of tau appears to play a 
critical role in AD and correlates well with clinical disease progression.  ABBV-8E12 
may block tau seeds from propagating between cells and, therefore, may slow disease 
progression, thus providing a viable treatment option for patients with early AD. 
The safety profile of ABBV-8E12 to date has been favorable and no clinically relevant 
patterns of adverse events or abnormal laboratory findings have been observed.  Further, 
no ADAs were detected in post-dose samples in a SAD study in subjects with PSP.  Risks 
include infusion reactions and possibly life-threatening allergic reactions; however, no 
systemic hypersensitivity or injection site reactions have been reported to date.  
Evidence of efficacy demonstrated in preclinical studies and safety data from clinical 
studies obtained to date provide rationale for continuing assessment of safety and efficacy 
of ABBV-8E12.  The benefit-risk profile of ABBV-8E12 will be further defined in this 
trial as well as the ongoing Study M15-566.
In consideration of the coronavirus disease 2019 (COVID-19) pandemic, the benefits and 
risks to subjects participating in this study have been re-evaluated.  Based on the limited
information to date and due to the mechanism of action of ABBV-8E12, no additional risk 
is anticipated for study participants infected with SARS-Cov2 during the COVID-19 
pandemic.
4.0
Study Objectives
The primary objective of this study is to assess the long-term safety and tolerability of 
ABBV-8E12 in subjects with early AD.
The secondary objective of this study is to assess the pharmacokinetics (PK) of 
ABBV-8E12 in subjects with early AD.
 


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The exploratory objectives of this study are:
●
To assess the long-term efficacy of ABBV-8E12 in slowing disease 
progression in subjects with early AD. 
●
To assess the long-term effect of ABBV-8E12 on a range of disease-related 
and drug-related biomarkers in subjects with early AD.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This Phase 2 extension of a multiple dose, multicenter, multinational, randomized, 
double-blind study is designed to evaluate the long-term safety and tolerability of 
ABBV-8E12 in subjects with early AD.  The study will consist of a 5-year treatment 
period and a follow-up period of approximately 20 weeks following the last study drug 
administration.
All subjects who complete the Treatment Period in Study M15-566 will be eligible to 
participate in this study according to the selection criteria.  Upon completion of baseline 
study procedures, eligible subjects will receive ABBV-8E12 via intravenous (IV) infusion 
on Day 1 of Study M15-570 as follows:  
●
Subjects who received placebo in Study M15-566 will receive 2000 mg 
ABBV-8E12 in Study M15-570;
●
Subjects who received 300 mg ABBV-8E12 in Study M15-566 will receive 
1000 mg ABBV-8E12 in Study M15-570; and 
●
Subjects who received 1000 mg or 2000 mg ABBV-8E12 in Study M15-566 
will continue on the same dose in Study M15-570. 
Note:  if any changes are made to alter Study M15-566 with regards to the treatment arms 
due to safety, efficacy, or other reasons, a corresponding change will be implemented in 
Study M15-570.  This change may include, but is not limited to, adding or dropping 
treatment arm(s).
 


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Subjects will receive study drug infusion every 4 weeks and undergo other study 
procedures and assessments as outlined in the Study Activities table (Appendix C).  
Subjects will continue to receive treatment until one of the discontinuation criteria is met, 
the sponsor discontinues the study, or the subject completes the 5-year treatment period of 
Study M15-570.  Refer to Section 5.4 for detailed description of discontinuation criteria.
Day 1 visit of Study M15-570 (day of the first dose of Study M15-570) will be 
approximately 4 weeks but no more than 8 weeks after the Week 92 visit of 
Study M15-566.  Should this window be longer than 8 weeks, the subject may be 
considered for participation in Study M15-570 only with the approval of the therapeutic 
area medical director (TA MD) or designee.  The investigators and subjects will remain 
blinded to the treatment assignments in Study M15-566 and will be blinded to the dose 
level of ABBV-8E12 in Study M15-570.
For subjects who do not have extended interruptions in study drug administration between 
Study M15-566 and Study M15-570 (i.e., the duration between the last dose of study drug 
in Study M15-566 and the first dose of study drug in Study M15-570 is no more than 
8 weeks), certain procedures that were performed at the Week 96 Visit in Study M15-566 
do not need to be repeated for the Day 1 Visit in Study M15-570. 
Safety will be closely monitored during the study conduct.  The study will also utilize an 
external data monitoring committee (DMC), which will review accumulating study data 
and make recommendations based on the emerging safety profile of ABBV-8E12.  The 
DMC membership, responsibilities, operating logistics, and timing of reviews will be 
documented in a charter that will be finalized prior to the first DMC review meeting.
A schematic of the study design is shown in Figure 1.
 


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Figure 1.
Study Schematic
Detailed information regarding the regimens/treatments administered and assignment of 
the subjects to the treatment sequences can be found in Section 5.5.1 and Section 5.5.3.
5.2
Selection of Study Population
All subjects with early AD who complete Study M15-566, meet all inclusion criteria, and 
do not meet any exclusion criteria will be eligible for enrollment.
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 
institutional review board (IRB)/independent ethics committee (IEC) approved 
informed consent, prior to the conduct of any extension study-specific procedures 
(including any changes occurring in the subject's current therapeutic regimen).  In 
the absence of subject's ability to provide the informed consent, the informed 
consent must be obtained by a person who has the legal right to act on behalf of the 
subject following local regulations.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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2.
Subject completed the 96-week treatment period of Study M15-566. 
3.
In the investigator's opinion, subject was compliant during participation in 
Study M15-566.
4.
Subject has an identified, reliable study partner (e.g., caregiver, family member, 
social worker, or friend; preferably the same person for the duration of the study) 
who has frequent contact with the subject (at least 10 hours per week) and who will 
provide information as to the subject's cognitive and functional abilities.  The study 
partner has voluntarily signed the IRB/IEC approved study partner informed 
consent, prior to the conduct of any extension study-specific procedures.
5.
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).
6.
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.
Rationale for the Inclusion Criteria
1
In accordance with the harmonized Good Clinical Practice (GCP)
2 – 4
To select subject population appropriate for this study
5 – 6
The effects of ABBV-8E12 on pregnancy are currently unknown.
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
 


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1.
The subject has any significant change in his/her medical condition since 
participation in Study M15-566 that could interfere with the subject's participation 
in Study M15-570, could place the subject at increased risk, or could confound 
interpretation of study results.  The investigator must re-evaluate the subject for 
continuing participation and consider relevant factors including:
●
interim development of any clinically significant neurological, hematological, 
autoimmune, endocrine, cardiovascular, neoplastic, renal, hepatic, metabolic, 
psychiatric, pulmonary, gastrointestinal, or other major disorder
●
interim development of contraindication to or inability to tolerate brain MRI or 
positron emission tomography (PET) scan
2.
More than 8 weeks have elapsed since the subject received his/her last dose of 
study drug in Study M15-566 (i.e., Week 92 visit in Study M15-566).  In certain 
cases, subject may be eligible to enroll after approval by the TA MD or designee.
3.
Subject is concurrently enrolled in another interventional clinical study (with the 
exception of Study M15-566) involving a therapeutic agent.
4.
Subject is considered by the investigator, for any reason, to be an unsuitable 
candidate to receive ABBV-8E12 or the subject is considered by the investigator to 
be unable or unlikely to comply with the dosing schedule or study evaluations.
Rationale for Exclusion Criteria
1
To ensure the safety of the subjects
2
To allow the TA MD to delegate responsibility
2, 4
To select subject population appropriate for this study
3
These products may interfere with the PK 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 medically 
 


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necessary at any point during 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 in the electronic case report form (eCRF).
The AbbVie TA MD should be contacted with any questions regarding concomitant or 
prior therapy(ies).
5.2.3.1
Prohibited Therapy
There are no prohibited medications for this long-term extension study.  All concomitant 
medications, including any change in dose, must be recorded as described in 
Section 5.2.3.
Anticoagulants may be exclusionary for optional lumbar punctures (LPs).  Some subjects 
may be able to temporarily cease use of anticoagulant therapy in the limited duration 
surrounding the optional LP procedures.
Regularly scheduled or as needed (PRN) use of medications with psychotropic effects 
(some examples in Table 1, not a comprehensive list) should be considered in the context 
of the cognitive assessments and avoided when medically not necessary, so as not to 
confound interpretation of the assessments.  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 should not be administered within 48 hours of 
a PRN medication administration.
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. 
Subject should be discontinued from the study if she/he starts receiving an approved 
disease-modifying therapy for AD or a biologic medication for the treatment of AD.  
Refer to Section 5.4.1 for other discontinuation criteria.
 


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The AbbVie TA MD should be contacted if there are any questions regarding concomitant 
and prior medications.
Table 1.
Medications That Require Special Consideration
Anticoagulants (May Be Exclusionary for Optional 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 optional lumbar punctures.
Neuroleptics:
Generic Name:
Chlorpromazine
Fluphenazine
Loxapine
Perphenazine
Thioridazine
Thiothixene
Trifluoperazine
Clozapine
Haloperidol
Brand Name:
Thorazine
Prolixin
Loxitane
Etrafon, Trilafon
Mellaril
Navane
Stelazine
Clozaril
Haldol
Anticholinergic Agents:  
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
 


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Table 1.
Medications That Require Special Consideration (Continued)
Antiparkinsonian Medications:  
Generic Name:
Bromocriptine
Deprenyl/Selegiline
Levodopa
Pergolide
Pramipexole
Brand Name:
Parlodel
Eldepryl
Sinemet
Permax
Mirapex
Sedatives/Benzodiazepines:
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:
Generic Name:
Clonidine
Brand Name:
Catapres
Note:
Brand names may vary by country/region.
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
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 and 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 this study, each subject must have a study partner (e.g., caregiver, 
family member, social worker, or friend; preferably the same person for the duration of 
the study), 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.  In exceptional cases 
when the study partner is not available to accompany the subject to an applicable study 
visit, he/she may provide the information regarding subject's cognitive and/or functional 
abilities by telephone.  For subjects that prematurely discontinue the study, safety and 
efficacy assessments may be conducted remotely (for example, via telephone), where 
applicable.
Medical History Update
For all subjects, an update to the medical history (from that obtained in Study M15-566), 
including subject's history of cognitive impairment and any medications taken for AD or 
mild cognitive impairment (MCI), will be obtained on Day 1.  The updated medical 
history on Day 1 will serve as the baseline for clinical assessment.
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 Baseline 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 AEs.
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.
 


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Neurological Examination
A neurological examination will be performed at the times indicated in the Study 
Activities table (Appendix C).  The neurological exam performed on Day 1 will serve as 
the baseline for clinical assessment.  Symptoms identified during Day 1 will be recorded 
as AEs for Study M15-566; however, new symptoms or current symptoms that change in 
severity or frequency after Day 1 of study drug administration will be recorded as AEs for 
Study M15-570.
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
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.
 


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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 
(Appendix C).  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.
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 (NCS)
 


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●
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 (QTc) for heart 
rate will be determined using Fridericia-corrected QT interval (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 (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 follows:
●
Day 1 (Dose 1):
○
Pre-dose (within approximately 15 minutes before infusion begins)
○
Post-dose (within approximately 15 minutes after sodium chloride flush is 
completed)
●
Weeks 12, 24, 52, 104, 156, and 208:
○
Pre-dose (within approximately 15 minutes before infusion begins)
 


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●
Week 260 (Study Completion / Premature Discontinuation Visit):
○
May be done at any time during the visit 
Clinical Laboratory Tests
Samples will be obtained at a minimum for the clinical laboratory tests outlined in Table 2
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 2.
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 
mean corpuscular hemoglobin 
concentration 
Prothrombin time (PT)c
Activated partial thromboplastin
timec
PT/INR (prothrombin 
time/international 
normalized ratio)c
Blood urea nitrogen
Creatinine
Total bilirubin
Albumin
Aspartate aminotransferase
Alanine aminotransferase
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphate
Uric acid
Cholesterol
Total protein
Glucose
Triglycerides
Bicarbonate/CO2
Chloride
Thyroid Stimulating Hormone
(TSH)a
Thyroxine (T4)a
Vitamin B12 (cobalamin)a
Specific gravity
Ketones
Ph
Protein
Glucose
Blood
Microscopic examination, if 
dipstick results are positive
CSF Basic Labs with Optional 
LPsb
RBC, WBC with differential
Total Protein
Albumin
Glucose
Reference Tests if 
Vitamin B12 is Under the 
Lower Limit of Normal Range
Methylmalonic Acid
Homocysteine
CSF = Cerebrospinal fluid; INR = international normalized ratio; LP = Lumbar puncture; PT = Preferred term; 
RBC = Red blood cell count; T4 = Thyroxine; TSH = Thyroid stimulating hormone; WBC = White blood cell count
a.
Optional.  Not required if using Study M15-566 Week 96 visit for Baseline.
b.
Done locally according to the local laboratory specifications and capabilities.
c.
Only in subjects who undergo LPs.
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 AE.
 


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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 AEs.  Accordingly, for any values 
outside of the reference range, the investigator will indicate on the report if the result is 
clinically significant (CS) or 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 AE or document in source the reason(s) the 
finding was not considered an AE.
Any laboratory value that remains abnormal at premature discontinuation (PD)/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.
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.
Optional Lumbar Puncture 
LPs to collect cerebrospinal fluid (CSF) are optional procedures in Study M15-570.  
Subjects may still participate in the study even if they decide not to participate in this 
optional sample collection.
For all subjects who agree, LPs will be performed at time points indicated in the Study 
Activities table (Appendix C).  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 LP can be used at the discretion of the local clinical site staff.  Basic 
 


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neurochemical CSF analyses will be performed locally according to the local laboratory 
capabilities at the applicable clinical site after each LP/CSF collection.  These measures 
may include cell counts (Red blood cell count [RBC] and white blood cell count [WBC] 
with differential), total protein, albumin, and glucose.  Other CSF measurements 
(e.g., ABBV-8E12 concentration, tau, and other 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, bedrest, 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 LP include infection, damage to nerves in 
the back, and bleeding into the CSF space.  The risk of these is much less than 1%.5
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.
Magnetic Resonance Imaging
For all subjects, a 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.
MRI assessment at Day 1 will be used as baseline for evaluating changes during the study.  
Signal abnormalities on FLAIR or T2 weighted images will be evaluated to determine the 
presence of 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 starting from Baseline.
 


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The MRI scan should be done prior to the optional LP, if applicable.  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 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 time points indicated in the Study Activities table 
(Appendix C).  Subjects who did not complete tau PET imaging through Study M15-566 
and at Study M15-570 Day 1/Baseline will have tau PET imaging performed at 
subsequent visits only after discussion with the TA MD or designee.
Tau deposition in the brain, unlike Aβ, tracks closely with the cognitive decline of AD.  
Preclinical data suggests 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.
The tau PET scan for Day 1/Baseline should be carried out prior to administration of the 
first dose.
If the optional 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.
 


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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 obtained at the next onsite visit with 
the exception of Day 1/Baseline, which should be obtained prior to the administration of 
the first dose.
Diagnostic Tools and Rating Scales
Raters 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.  The objective of this certification/training is to establish uniformity across sites 
in the administration, interpretation and scoring of these rating instruments.  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(s), 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(s).  Individual exceptions to these requirements must 
be approved by the sponsor via the training vendor.  The recommended order of 
administration is Clinical Dementia Rating (CDR) followed by 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) and EuroQol 5 Dimensions 5 Levels Health 
State Instrument (EQ-5D-5L) may be administered/assessed at any subsequent time 
during the visit.  The timing and arrangements for the rating scales are presented in 
Table 3.  The order of the administration of scales at each visit should be consistent 
throughout the study.
 


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Table 3.
Diagnostic Tools and Scale Administration Timing
Scalea
Recommended Order of 
Administration
Approximate Administration 
Timeb (Minutes)
CDR
1
45 – 75
RBANS
2
25
ADCS-MCI-ADL-24
c
30 – 45
EQ-5D-5L
c
5
C-SSRS
c
5 – 20
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; EQ-5D-5L = EuroQol 5 Dimensions 5 Levels Health State Instrument; RBANS = Repeatable battery for 
assessment of neuropsychological status
a.
See Study Activities table in Appendix C for all time points.
b.
Breaks should be taken as necessary.
c.
Scale may be administered/assessed at any time during the visit.
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 the Study Activities table 
(Appendix C).
The diagnostic tools and rating scales include the following:
Clinical Dementia Rating (CDR)6
The CDR is a numeric scale used to quantify the severity of symptoms of dementia.  A 
qualified health professional will assess a subject'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 to 3 for each 
of the 6 areas.  The sum of these six areas, the CDR sum of boxes (Clinical Dementia 
Rating Sum of Boxes [CDR-SB]) score can range from 0 to 18.
The CDR-SB score will be calculated at each time point.  The CDR will be administered 
to both the subject and the study partner at the times indicated in the Study Activities table 
(Appendix C).
 


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24-Item Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale Adapted 
for Patients with Mild Cognitive Impairment (ADCS-MCI-ADL-24)7-10
The ADCS-MCI-ADL-24 is a 24-item study partner-based assessment of ADL designed 
specifically for MCI patients and is completed by a trained rater.  The scale assesses 
functional activities such as grooming, 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 ADL.  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 the Study Activities table (Appendix C).
Repeatable Battery for Assessment of Neuropsychological Status (RBANS)11
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,
4.
Attention – Digit Span and Coding, and
5.
Delayed Memory – List Recall, List Recognition, Story Memory, and Figure 
Recall.
 


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The RBANS has been shown to be effective at both detecting and characterizing dementia 
of different etiologies.  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 subject at the times indicated in the Study Activities 
table (Appendix C).
EuroQuality of Life-5-level (EQ-5D-5L)12,13
The EuroQuality of Life-5-level (EQ-5D-5L) Proxy Version 1 measures overall health 
status.  The caregiver (the proxy) will rate the patient's health status in their (the proxy's) 
opinion.  The scale contains a descriptive system comprised of 5 dimensions 
[(1) mobility, (2) self-care, (3) usual activities, (4) pain/discomfort, and 
(5) anxiety/depression].  These health states get scored on 5 levels of severity [(1) no 
problems, (2) slight problems, (3) moderate problems, (4) severe problems, and 
(5) unable to/extreme problems] and a visual analog scale (VAS) to evaluate current 
health state from 0 (worst imaginable) to 100 (best imaginable).  The descriptive profile 
can be converted into a value (EQ-Index) which ranges from 0 (death) to 1 (perfect 
health), with negative values indicating health states considered worse than death.  The 
EQ-5D-5L Proxy Version 1 will be administered at the times indicated in the Study 
Activities table (Appendix C).
Columbia-Suicide Severity Rating Scale14
The C-SSRS is a systematically administered instrument developed to track suicidal AEs 
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 may also be excluded from the study based 
on the clinical judgment of the investigator.
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 reference the table below for scales that 
may be administered remotely.
Scale
May be Administered Via Phone or Video Conference
ADCS-MCI-ADL-24
Yes
CDR
Yes
C-SSRS
Yes
EQ-5D-5L
Yes
RBANS
No
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; EQ-5D-5L = EuroQol 5 Dimensions 5 Levels Health State Instrument; RBANS = Repeatable Battery for 
Assessment of Neuropsychological Status
5.3.1.2
Collection and Handling of Biomarker and Pharmacogenetic 
Research Samples
Blood and Optional CSF Biomarker Samples
Blood and CSF samples will be collected at the times specified 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 5.3.6.1).
 


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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 scheduled on a day of dosing will be collected prior to the start of the 
infusion.  Blood samples collected at Year 5 (Study Completion)/PD Visit may be 
collected at any time during that visit.  Optional CSF samples will be collected by 
optional LP at the time points indicated in the Study Activities table (Appendix C).
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 or per local requirement.  The procedure for obtaining and 
documenting informed consent for exploratory research samples is discussed in 
Section 9.3.
 


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Optional whole blood samples (6.5 mL) for deoxyribonucleic acid (DNA) and ribonucleic 
acid (RNA) isolation will be collected from each consenting subject at the time points 
indicated in the Study Activities table (Appendix C).  All pharmacogenetic samples 
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.
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 PK assays of ABBV-8E12 will be provided by the 
central laboratory, the sponsor, or its designee.  The schedule for collection of blood 
samples is summarized in Appendix C. 
Blood Samples for ABBV-8E12 Assay
Blood samples, approximately 3 mL for ABBV-8E12 analysis will be collected by 
venipuncture as follows:
●
Day 1 and Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216 and 240 
 


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○
Prior to the start of the infusion. 
●
Week 260 (Study Completion)/PD Visit
○
Sample may be collected anytime during the day.
●
20 weeks post last dose (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:
●
Day 1 and Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 
○
Prior to the start of the infusion.
●
Week 260 (Study Completion)/PD Visit
○
Sample may be collected anytime during the day.
●
20 weeks post last dose (Post-Treatment Follow-Up Period)
○
Sample may be collected anytime during the day.
Optional CSF Samples for ABBV-8E12 Assay
CSF samples will be collected at times specified in the Study Activities table 
(Appendix C) by LP.  Information on the optional LP procedure can be found in the 
Lumbar Puncture section of Study Procedures section (Section 5.3.1.1).
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event blood samples for ABBV-8E12/ADA assays and the optional CSF for the 
ABBV-8E12 assay may not be performed due to study modifications related to the 
COVID-19 pandemic, these samples should be obtained at the next onsite visit.
 


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5.3.2.2
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 
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 ADA.
5.3.3
Efficacy Variables
Exploratory efficacy measures are described in Section 5.3.1.1 along with other study 
procedures and will be derived from assessments of CDR, RBANS, ADCS-MCI-ADL-24,  
and EQ-5D-5L.
5.3.4
Safety Variables
The following safety evaluations will be performed and safety information will be 
collected during the study:  Adverse event monitoring, vital signs, physical examination, 
neurological examination, ECG, laboratory tests, C-SSRS, and MRI assessments, and 
immunogenicity as determined by ADA responses in blood.
5.3.5
Pharmacokinetic Variables
Values for the following PK parameters will be estimated using a mixed-effect modeling 
approach:  clearance (CL) and volume of distribution (V).  Additional parameters may be 
calculated if useful in the interpretation of the data.  Pharmacokinetic data from this study 
may be combined with data from other ABBV-8E12 studies for PK analyses.
 


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5.3.6
Biomarker and Pharmacogenetic Research Variables
5.3.6.1
Biomarker Research Variables
Optional CSF and Plasma Concentration Variables
CSF samples will be assayed for free 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 tau.  CSF samples will also be analyzed for neurofilament light chain (NFL).  Plasma 
samples will be assayed for total tau and NFL to understand the relationship to disease 
progression and response to treatment.
CSF and blood samples may also be analyzed for biochemical or macromolecular factors 
(e.g., Aβ 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 main clinical study report, but may be described in a separate biomarker addendum.
Volumetric MRI
Baseline volumetric MRI (vMRI) measurements and measurements on change from 
baseline in vMRI measurements will be obtained.  The value itself for a given visit will be 
obtained by adding the baseline value to the value for change from baseline.  
Measurements will be obtained for whole brain, hippocampus, temporal lobes, and lateral 
ventricles.  Measurements may be obtained for additional regions.  The baseline 
measurement will be the same as the baseline measurement for Study M15-566, that is, 
 


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the last measurement obtained before the first study drug administration of 
Study M15-566.
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).  Additional variables (e.g., proportion of 
voxels within a target region that have a SUVR greater than a predetermined cutoff value) 
that reflect the extent or spread of tau pathology might also be assessed.  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.
5.3.6.2
Pharmacogenetic Research Variables
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 PK, 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.
 


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5.3.7
Immunogenicity
ADA levels will be determined for the assessment of immunogenicity.
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 AE or 
noncompliance with the protocol.
The subject will be discontinued from the study if any of the following occur:
●
Subject starts receiving an approved disease-modifying therapy for AD or a 
biologic medication for the treatment of AD.
●
Subject develops unacceptable toxicity.
●
Female subject becomes pregnant.
●
Investigator decides it is in the subject's best interest to discontinue.
●
Subject is noncompliant with the protocol based on the investigator or medical 
monitor assessment.
●
Subject withdraws consent.
●
Subject is lost to follow-up despite reasonable efforts by the investigator to 
locate the subject.
Subjects with the following AEs 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 AEs of nervous system will require 
discontinuation from further treatment with ABBV-8E12, initiation of 
appropriate medical therapy and follow-up.
 


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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 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.
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 AEs 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 AEs; 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 AE 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 AE is achieved.
For subjects who prematurely discontinue the study for reasons other than withdrawal of 
consent safety and efficacy assessments may be conducted remotely (for example, via 
telephone), where applicable.
 


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COVID-19 Pandemic-Related Acceptable Protocol Modifications
For subjects who miss 3 or more study drug doses due to the COVID-19 pandemic, the 
TA MD should be contacted to discuss continuation in the study.
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 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.  
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 every 4 weeks ± 4 days.  Subject weight will be 
obtained prior to study drug administration to determine the appropriate infusion rate as 
shown in the table below.
 


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Subject's Weight (inclusive)
Infusion Rate*
26.0 – 34.9 kg
2.1 mL/min or 126 mL/hr
35.0 – 44.9 kg
2.8 mL/min or 168 mL/hr
45.0 – 59.9 kg
3.6 mL/min or 216 mL/hr
60.0 – 89.9 kg
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.  Any subject weight between whole numbers should be rounded down to the 
lower number (i.e., select lower infusion rate/longer infusion time).
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
Infusion
ABBV-8E12 1000 mg
IV infusion every 4 weeks ± 4 days for 5 years
(Total of 65 infusions)
ABBV-8E12 2000 mg
Doses may be modified after evaluation by the DMC of the safety, tolerability, and available PK data or in accordance 
with changes made in Study M15-566.
The start and stop time of each study drug infusion will be recorded to the nearest minute.  
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 IRB/IEC requirements for home healthcare.  
Any prerequisite submissions or notifications to the site IRB/IEC and local competent 
health authority should be made and approved prior to the implementation of home 
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5.5.2
Identity of Investigational Product
Information about the ABBV-8E12 products to be used in this study is presented in 
Table 4.
Table 4.
Identity of Investigational Product
Investigational 
Product
Mode of 
Administration
Formulation
Strength
ABBV-8E12
Infusion
Solution for infusion in 
a vial
1000 mg/10 mL
ABBV-8E12
Infusion
Solution for infusion in 
a vial
2000 mg/20 mL
0.9% Sodium Chloride Injection/Solution for Infusion will be administered 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.  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 study, it 
will be labeled with a blinded dispensing label by the unblinded pharmacist or qualified 
designee as required.  Labels must remain affixed to the material.
 


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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.
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 AbbVie.  Study drug should 
be quarantined and not dispensed until AbbVie (or temperature excursion management 
system) deems drug as acceptable.  Study drug should be quarantined and not dispensed 
until AbbVie (or temperature excursion management system) deems drug as acceptable.
Investigational products (IPs) 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 doses will be performed by the unblinded site pharmacist or qualified 
designee.  Written instructions for the preparation of ABBV-8E12 solutions for infusion 
will be provided as a Pharmacy Manual separate from the protocol.
 


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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 enrolled in the study, the IVR/IWB system will retain the unique 5-digit 
subject number from Study M15-566.  The first digit will be 2, the second and third digits 
will be the site number (00, 01, 02, etc.) and the fourth and fifth digits will be assigned in 
ascending numerical order at each site.
Subjects in this study will receive ABBV-8E12 as follows:  
●
Subjects who received placebo in Study M15-566 will receive 2000 mg 
ABBV-8E12 in Study M15-570;
●
Subjects who received 300 mg ABBV-8E12 in Study M15-566 will receive 
1000 mg ABBV-8E12 in Study M15-570; and 
●
Subjects who received 1000 mg or 2000 mg ABBV-8E12 in Study M15-566 
will continue on the same dose in Study M15-570.
5.5.4
Selection and Timing of Dose for Each Subject
Selection of the doses for this study is discussed in Section 5.6.4.  Each subject will 
receive ABBV-8E12 as described in Section 5.5.3.  ABBV-8E12 will be administered 
every 4 weeks via IV infusion, preferably in the morning.
5.5.5
Blinding
The investigator and study site personnel (except the unblinded pharmacist) will remain 
blinded to the treatment throughout the course of the study.
 


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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 sequences.  For IP monitoring, there will be an 
unblinded AbbVie monitor for verification of unblinded documentation.  The unblinding 
procedure for the unblinded pharmacist/designee and the unblinded AbbVie monitor will 
be defined in a separate study-specific document.
The IVR/IWR 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 
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 for 
safety assessment.  SAS data sets blinded with respect to treatment assignment will be 
sent to an external statistical center by AbbVie.  The randomization schedules of 
Study M15-570 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.  The AbbVie Internal Executive Review Committee (IERC) 
may request access to closed reports if the DMC recommends that the study be 
discontinued or that the study design undergo major modifications, as outlined in the 
DMC charter.  All other AbbVie personnel will remain blinded to the treatment 
 


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assignment.  The AbbVie Primary Contact and the AbbVie IERC members will not be 
involved in any aspects of the trial or its management.
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 Pharmacy Manual separate 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 primarily designed to assess the long-term safety and tolerability of 
ABBV-8E12 in subjects with early AD when administered for up to 5 years.  Toxicity 
management in the parallel group design is described in Section 6.1.6.
 


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5.6.2
Appropriateness of Measurements
Standard PK, statistical, and clinical procedures will be utilized in this study.  
On-treatment safety evaluations (neurological examinations, AE monitoring, ECGs) are 
scheduled 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 selection criteria are intended to identify suitable subjects from those who 
participated in Study M15-566 and have the potential to benefit from treatment and not be 
exposed to undue risk.
5.6.4
Selection of Doses in the Study
The doses chosen for the study (1000 mg and 2000 mg) were selected based on the 
2 highest doses used in Study M15-566, which were determined based on available safety 
and tolerability data from the SAD study in subjects with PSP (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. 
The highest dose in Studies M15-566 and M15-570, 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.
In the 4-week preclinical mouse toxicology study, the highest dose tested was 250 mg/kg 
and the corresponding maximum observed serum concentration (Cmax) and area under the 
concentration time curve (AUC)0-168h were 3050 µg/mL and 298,000 hr•µg/mL (on 
 


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Day 22) after 4 doses administered weekly.  Assuming the PK of ABBV-8E12 is linear, 
the steady-state PK profiles were simulated at 1000 and 2000 mg following monthly 
administration of ABBV-8E12 based on the PK 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 1000 and 2000 mg is approximately 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 PK 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 dissociation constant (KD) of ABBV-8E12 
determined in vitro, it is estimated that the average tau binding in CSF by the antibody at 
predicted Ctrough and Cmax values over the 28-day period ranges from approximately 60% 
to 80% for 1000 mg and 75% to 90%, for 2000 mg ABBV-8E12 doses.
This study will enable further exploration of the safety profile of ABBV-8E12 at the 
1000 mg and 2000 mg dose levels.
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 IP must be reported to the sponsor 
(Section 6.2.2).  For AEs, please refer to Sections 6.1 through 6.1.6.  For product 
complaints, please refer to Section 6.2.
 


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6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of AEs on 
a routine basis throughout the study.  The investigator will assess and record any AE in 
detail including the date of onset, event diagnosis (if known) or sign/symptom, severity, 
time course (end date, ongoing, intermittent), relationship of the AE to study drug, and 
any action(s) taken.  For SAEs considered as having "no reasonable possibility" of being 
associated with study drug, the investigator will provide an "Other" cause of the event.  
For AEs to be considered intermittent, the events must be of similar nature and severity.  
Adverse event, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded.
All AEs will be followed to a satisfactory conclusion.
Subjects should be monitored for at least 30 minutes after the end of study drug infusions.  
Longer observation periods and more frequent vital sign checks may be required in 
subjects who experience infusion reactions.
6.1.1
Definitions
6.1.1.1
Adverse Event
An AE 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 AE 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 preexisting condition or illness is considered an AE.  Worsening in 
severity of a reported AE should be reported as a new AE.  Laboratory abnormalities and 
changes in vital signs are considered to be AEs only if they result in discontinuation from 
 


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the study, necessitate therapeutic medical intervention, meet protocol specific criteria for 
PCS laboratory values defined in Appendix D and/or if the investigator considers them to 
be AEs.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
AE if the surgery/procedure is being performed for a preexisting condition and the 
surgery/procedure has been preplanned prior to study entry.  However, if the preexisting 
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 AE.
6.1.1.2
Serious Adverse Events
If an AE meets any of the following criteria, it is to be reported to AbbVie as a SAE 
within 24 hours after the site becomes aware of the SAE:
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 SAEs with the outcome of death, the date and cause of death will be recorded on the 
appropriate case report form (CRF).
6.1.2
Adverse Event Severity
The investigator will use the following definitions to rate the severity of each AE:
Mild
The AE is transient and easily tolerated by the subject.
Moderate
The AE causes the subject discomfort and interrupts the subject's 
usual activities.
Severe
The AE 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 AE to 
the use of study drug:
 


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Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is sufficient evidence (information) to suggest a 
causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is insufficient evidence (information) to suggest a 
causal relationship.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an Other cause of event must be provided by the investigator for the SAE.
6.1.4
Adverse Event Collection Period
All AEs reported from the time of study drug administration until 20 weeks following 
discontinuation of study drug administration have elapsed (approximately 5 half-lives) 
will be collected, whether solicited or spontaneously reported by the subject.  In addition, 
SAEs and protocol-related nonserious AEs will be collected from the time the subject 
signed the study-specific informed consent.
Adverse event information will be collected as shown in Figure 2.
 




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For any subject safety concerns, please contact the physician listed below:
Primary Therapeutic Area Medical Director:
1 North Waukegan Road
North Chicago, IL  60064
Telephone Contact Information:
Office:
Mobile:
Email:
In emergency situations involving study subjects when the primary TA MD is not 
available by phone, please contact the 24-hour AbbVie Medical Escalation Hotline
where your call will be re-directed to a designated AbbVie TA MD.
Phone:  +1 (973) 784-6402
AbbVie will be responsible for Suspected Unexpected Adverse Reactions (SUSAR) 
reporting for the investigational medicinal product (IMP) in accordance with global and 
local guidelines and Appendix A of the Investigator's Brochure will serve as the 
Reference Safety Information (RSI).  The RSI in effect at the start of a DSUR reporting 
period serves as the RSI during the reporting period.  For follow-up reports, the RSI in 
place at the time of occurrence of the "suspected" serious adverse reaction will be used to 
assess expectedness.
SAEs that meet the reporting criteria, as dictated by local regulations, will be reported to 
both responsible ethics committees (ECs) and regulatory agencies as required by local 
regulations.  During the conduct of the study, the investigator should promptly provide 
written reports (e.g., International Council on Harmonization [ICH] Expedited Reports or 
 


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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 AEs and laboratory abnormalities that occur 
during the study must be evaluated by the investigator.  
A drug-related toxicity is an AE or laboratory value outside of the reference range that is 
judged by the investigator or AbbVie as a "reasonable possibility" of being related to the 
study drug (Section 6.1.3).  A toxicity is deemed "clinically significant" based on the 
 


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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.8  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.
6.1.6.1
Allergic Reactions Management
Subjects will be closely monitored for treatment-related AEs, including allergic reactions, 
during the infusion.  Subjects should be monitored on site until at least 30 minutes after 
 


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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.  Moderate infusion reactions resolving with supportive care 
should be discussed with the TA MD, and a reduction of the infusion rate for future 
administrations can be considered.
6.1.6.2
Management of Adverse Events of the Nervous System
Subjects will be closely monitored for AEs suggesting neurotoxicity.  Drug related AE 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 AEs 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 AEs of the nervous system, symptomatic 
neurological abnormalities and treatment-emergent MRI findings and 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.
 


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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 IP must be reported to the sponsor within 1 business 
day 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 AEs 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 
within 30 days, the site will need to provide justification and an estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
 


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7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol unless 
necessary to eliminate an immediate hazard to study subjects.  The principal investigator 
is responsible for complying with all protocol requirements, and applicable global and 
local laws regarding protocol deviations.  If a protocol deviation is identified after a 
subject has been enrolled, the principal investigator is responsible for notifying IEC/IRB 
regulatory authorities (as applicable), and the following AbbVie contacts:
Primary Contact:
Office:
Email:
Alternate Contact:
Mobile:
Email:
Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
General Considerations
Efficacy assessment will be an exploratory objective in this study.  The data analyses will 
be grouped by assigned treatment sequences/groups in Studies M15-566/M15-570:  
300/1000 mg, 1000/1000 mg, placebo/2000 mg, and 2000/2000 mg. If the one-sided 
unadjusted P value is ≤ 0.100 for the difference in treatment effect between ABBV-8E12 
2000 mg and placebo at Week 96 in Study M15-566, a delayed-start analysis will be 
 


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conducted.  The 2000/2000 mg group will be the early start group, and placebo/2000 mg 
will be the delayed-start group for the delayed-start analysis.  Details of the analysis plan 
will be specified in the statistical analysis plan (SAP).
8.1.1
Analysis Data Sets
Data Sets for Efficacy Analyses
Two data sets will be created for the efficacy analysis:  an intent-to-treat (ITT) data set 
and a delayed-start data set.
ITT Data Set:  The Study M15-570 ITT data set consists of all subjects who received any 
dose of study drug in Study M15-570.  All efficacy analyses will be conducted on the ITT 
data set using data from Study M15-570 alone unless otherwise specified.
Delayed-Start Data Set:  The delayed-start analysis data set includes all subjects from the 
Study M15-566 ITT data set who received placebo or ABBV-8E12 2000 mg in 
Study M15-566 regardless of whether they enroll in Study M15-570 or not.  For the 
delayed-start analysis, efficacy data from both Studies M15-566 and M15-570 will be 
included.
Data Set for Safety Analyses
The safety data set will consist of all subjects who received any dose of study drug in 
Study M15-570.  For safety analyses, the actual treatment received will be used instead of 
the treatment assignment at enrollment.
Data Set for Biomarkers
The subjects of the data set for biomarkers will be all subjects who have biomarker data 
for at least one scheduled visit later than Visit 1 of Study M15-570.  The data of a subject 
included for the analysis of a biomarker variable will include the baseline value of 
Study M15-566, which will also be the baseline value for Study M15-570, and all the data 
of Study M15-570 after Day 1 (day of the first dose of Study M15-570).
 


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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 sequence and for all treatment sequence combined for the 
safety data set.
The number and percentage of subjects who prematurely discontinue study drug will be 
summarized by treatment sequence and overall for safety data set for the primary reason 
as well as for all reasons collected.  In the summary, the number and percentage of 
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 sequence difference in subject's disposition.
Demographic and Other Baseline Characteristics
Demographics will be summarized for the ITT data set unless otherwise specified.  
Treatment sequence differences will be evaluated using overall tests.  No pairwise 
comparisons between treatment sequences 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 
sequence and for all treatment sequences combined.  The overall treatment sequence 
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 sequence and for all 
treatment sequences combined.  Fisher's exact test will be carried out to assess the overall 
comparability of treatment sequences based on two-sided tests.
 


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Efficacy and clinical measures taken at baseline (CDR-SB score, RBANS, 
ADCS-MCI-ADL-24, and EQ-5D-5L) will be summarized for the ITT data set only.  
One-way ANOVA will be used to assess the overall comparability of treatment sequences 
for all measurements.
Medical History
Medical history data, including subject's history of early AD or MCI, will be summarized 
for the safety data set 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 sequence 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 of comparisons will be performed with a 2-sided test at the 
significance level of 0.050 unless otherwise specified.  All efficacy assessments that are 
taken no more than 45 days after the last dose of study drug will be included in the 
efficacy analyses.
Analyses of the efficacy variables CDR-SB score, ADCS-MCI-ADL-24 total score, 
RBANS total scores, and EQ-5D-5L score will be performed on the Study M15-570 ITT 
data set.  The analysis model is a likelihood-based, mixed model repeated measures 
(MMRM) analysis at Study M15-570 Baseline and each post-baseline observation using 
all observed data.  This MMRM analysis will be applied to each efficacy variable with 
repeated measurements.  Details of the analysis will be described in the SAP.
 


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The delayed-start analysis will be conducted on the change from Baseline of 
Study M15-566 up to Week 96 in Study M15-570 on CDR-SB score.  An MMRM 
analysis model will be used.  Details of the analysis will be specified in the SAP.
8.1.4
Safety Analyses
Comparisons between treatment sequences (Study M15-566 and Study M15-570) of 
interest will not be performed.
All other safety assessments that are taken no more than 45 days after the last dose of 
study drug will be included in the safety evaluation of the Treatment Period, and all safety 
assessments that are taken more than 45 days but not more than 20 weeks after the last 
dose of study drug will be included in the safety evaluation for the Post-treatment 
Follow-up Visit.
8.1.4.1
Study Drug Exposure and Compliance
The number of doses of study drug will be summarized by treatment sequence and overall 
subjects.  The number and percentage of subjects with at least 90% compliance with study 
drug dosing (i.e., complete 90% of scheduled doses for each subject) will be summarized 
by treatment sequences and overall subjects.  No comparisons between treatment 
sequences will be performed.
8.1.4.2
Analysis of Adverse Events
The safety data set will be used for the AE summary.
Adverse event will be coded using the most current version of the MedDRA.  The number 
and percentage of subjects who report treatment-emergent adverse events (TEAEs) will be 
tabulated by the SOC and preferred term for the treatment sequences specified in 
Section 8.0.  No comparisons between treatment sequences will be performed.
The number and percentage of subjects who experienced treatment emergent SAEs 
(including deaths) and AEs leading to PD of study drug will be tabulated by the MedDRA 
 


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SOC and preferred term for treatment sequences specified in Section 8.0.  No 
comparisons between treatment sequences will be conducted for AE summaries.
A TEAE is defined as any AE that begins or worsens in severity on or after the date of the 
first dose of study drug and no more than 20 weeks after the date of the last study dose.
8.1.4.3
Analysis of Laboratory Tests
Analysis will be performed on the safety data set for laboratory tests.  Change from 
Baseline to each visit value and to the minimum, maximum, and final value will be 
presented for each continuous hematology, chemistry, and urinalysis parameter.  
Treatment differences between treatment sequence in change from Baseline to minimum, 
maximum, and final clinical laboratory evaluation will be analyzed using a 1-way 
ANOVA with treatment sequence as the main effect.  
For each treatment sequence, 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.  Laboratory 
observations will be categorized as normal, low, or high relative to the reference (normal) 
range associated with the laboratory that performed the assay.  Details will be specified in 
the SAP.  
The number and percentage of subjects in each treatment sequence who have values 
meeting predefined criteria for PCS (Appendix D) at any time after the first dose of study 
drug and no more than 20 weeks after the last dose of study drug will be summarized 
separately for hematology and chemistry variables.  No comparisons between treatment 
sequences will be performed for PCS analysis.
8.1.4.4
Analysis of Vital Signs and Weight
Analysis will be performed on the safety data set for vital signs and weight.  Vital sign 
variables for this study will be pulse rate, systolic blood pressure, diastolic blood pressure, 
body temperature, weight, and BMI.  
 


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Change from Baseline to each visit value and to the minimum, maximum, and final value 
will be presented for each vital sign and weight variable and analyzed using a 1-way 
ANOVA with treatment sequence as the main effect.  
The number and percentage of subjects in each treatment sequence who have values 
meeting predefined criteria for PCS (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 will be summarized.  No comparisons between treatment sequences will be 
conducted.
8.1.4.5
Analysis of ECG Variables
Analysis of ECG variables will be performed on the safety data set.  ECG variables for 
this study will be heart rate, PR, QRS, QT, and QTcF intervals.  Change from Baseline to 
final value will be presented for each ECG parameter and analyzed using a 1-way 
ANOVA with treatment sequence as the main effect.
The number and percentage of subjects in each treatment sequence who have values 
meeting predefined criteria for PCS (definitions will be provided in the SAP) at any time 
after the first dose of study drug will be summarized.
8.1.4.6
Analysis of C-SSRS
Analysis of C-SSRS will be performed on the safety data set.  The number and percentage 
of subjects in the following categories will be summarized for each treatment sequence 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), and
 


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●
Had suicidal ideation or behavior (defined as answering "Yes" to one or more 
suicidal ideation or behavior items).
8.1.5
Biomarker Analyses
For plasma concentration variables, CSF concentration variables, volumetric MRI 
variables, and tau PET variables identified in Section 5.3.6.1, descriptive statistics will be 
provided for each scheduled time of measurement with a breakdown by group as defined 
by treatment in Study M15-566 and treatment in this study.  That is, the 4 treatment 
sequences are as follows:
●
ABBV-8E12 1000 mg in Study M15-566, continuing the same in 
Study M15-570.
●
ABBV-8E12 2000 mg in Study M15-566, continuing the same in 
Study M15-570.
●
ABBV-8E12 300 mg in Study M15-566, ABBV-8E12 1000 mg in 
Study M15-570.
●
Placebo in Study M15-566, ABBV-8E12 2000 mg in Study M15-570.
The scheduled times of measurement will include the baseline measurement.  The 
baseline measurement will be the same as the baseline measurement for Study M15-566, 
that is, the last measurement obtained before the first study drug administration of 
Study M15-566.
For CSF free tau, total tau, the ratio of free tau to total tau, and plasma total tau and NFL, 
a MMRM analysis will be performed for the planned times of assessment after the 
first dose of study drug administration in Study M15-570.  The model will include 
classification by treatment (one of the 4 treatment sequences described above) and by time 
of measurement.  There will be an effect for the interaction of treatment and time of 
measurement.  Except for the ratio of CSF free tau concentration to CSF total tau 
concentration, the baseline value will be a covariate.  For the ratio of CSF free to total tau, 
the total tau baseline concentration will be a covariate if this variable is found to be a 
 


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significant covariate for the ratio in Study M15-566.  The subjects in each treatment 
sequence will be viewed as a random sample, and an appropriate structure for the 
covariance matrix of the measurements of a subject will be selected.
Volumetric MRI Variables
For each MRI variable, descriptive statistics will be provided for the baseline values, the 
values at the scheduled times of measurement after study drug administration in 
Study M15-570 begins, and changes from baseline at the scheduled times of 
measurement.  An MMRM analysis will be performed on the changes from baseline.  The 
analysis will be much like that described for plasma total tau concentration, but with 
estimated total intracranial volume (eTIV) as a covariate in addition to the baseline value.  
An appropriate structure for the covariance matrix will be selected.  For each of whole 
brain, hippocampus, temporal lobes, lateral ventricles and possibly other brain regions, the 
relationship with the primary efficacy variable CDR-SB, and possibly other efficacy 
variables, will be explored.
Tau PET Scan Variables
For each region of the brain for which SUVR values (i.e., tau load density) are obtained, 
an analysis like that described for plasma total tau concentration will be performed.  This 
analysis may also be performed on other variables for which values are determined, 
including measurements of extent or spread of tau load in the brain. 
For the SUVR of selected regions, the relationship with the primary efficacy variable 
CDR-SB will be explored.  This may be done also for other tau PET variables. 
8.1.6
Pharmacokinetics and Exposure-Response Analyses
8.1.6.1
Tabulations and Summary Statistics
For ABBV-8E12 serum concentration data, descriptive statistics will be provided for each 
scheduled time of measurement with a breakdown by treatment sequence as defined in 
Section 8.1.5.
 


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8.1.6.2
Population Pharmacokinetic and Exposure-Response 
Analysis
Data from this study may be combined with data from other studies for the population PK 
and exposure-response analyses.  Population PK and exposure-response analyses of data 
from this study only may not be conducted.  The following general methodology will be 
used for the population PK and exposure-response analyses.
Population PK analyses will be performed using the actual sampling time relative to the 
last administered dose.  Pharmacokinetic models will be built using a non-linear mixed-
effect modeling approach with the nonlinear mixed effect modeling (NONMEM) software 
(Version 7, or higher version).  The structure of the starting PK model will be based on 
the PK analysis of data from previous studies.  Apparent CL and apparent V of 
ABBV-8E12 will be the PK parameters of major interest in the NONMEM analyses.  If 
necessary, other parameters may be fixed if useful in the analysis.
The evaluation criteria described below will be used to examine the performance of 
different models.
1.
The objective function of the best model is significantly smaller than the alternative 
model(s).
2.
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 1) than the alternative model(s).
3.
Visual inspection of model fits, standard errors of model parameters and change in 
inter-subject and intra-subject error.
Once an appropriate base PK 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 apparent clearance or apparent oral 
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covariates (such as subject age, sex, body weight, concomitant medications, laboratory 
markers of hepatic or renal function) will be explored using either a stepwise forward 
selection method, or a generalized additive method (GAM), or another suitable 
regression/smoothing method at a significance level of 0.050.  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 nonlinear relationships of primary PK parameters with various covariates will 
be explored.
Relationships between exposure, biomarker, and clinical observations (efficacy or safety 
variables of interest) may be explored.  Initially, the time-course of placebo response will 
be modeled.  Subsequently the relationship between exposure (e.g., population PK model 
predicted average concentrations or AUC or trough concentrations of the individual 
model-predicted PK 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, maximum effect [Emax], sigmoid 
Emax) will be evaluated to characterize the exposure-response relationship based on the 
observed data.
Additional analyses will be performed if useful and appropriate.
8.1.7
Immunogenicity
The ADA titers will be summarized as appropriate with a breakdown by treatment 
(treatments as defined in Section 8.1.5).
8.1.8
Safety Interim Analysis
The DMC for Study M15-566 will serve as the DMC for Study M15-570.  The DMC will 
be responsible for providing assessments of safety at regular intervals.  An independent 
 


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statistical and data analysis center (SDAC) and an Exposure-Response Analysis Center 
(ERAC) external to AbbVie and with experience in producing statistical reports, 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.  After each DMC meeting, the chair of the DMC will 
communicate its recommendations to the designated AbbVie Primary Contact, as 
described in the DMC charter.  The AbbVie Primary Contact will triage the 
recommendations to either the AbbVie study team if the recommendation can be 
implemented without unblinded data review or the Internal Executive Review Committee 
(IERC) if unblinded data review is required.  The DMC, IERC, SDAC, and ERAC 
membership and responsibilities will be documented in the DMC charter.
8.1.9
Preliminary Efficacy Analysis
No formal interim efficacy analyses are planned for this study.  Other planned preliminary 
and exploratory analyses will be described in detail in the SAP.
8.2
Determination of Sample Size
The sample size for this study is dependent on the number of subjects who complete 
Study M15-566 and are qualified for enrollment into Study M15-570.  Approximately 
400 subjects will be randomized in Study M15-566; the number of subjects who enroll in 
Study M15-570 will be less than or equal to the total number of subjects enrolled in 
Study M15-566.
8.3
Randomization Methods
Not applicable.  Refer to Section 5.5.3 for method of assigning subjects to treatment 
groups.
 


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9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good clinical practice 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 ICH GCP.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Council for 
Harmonisation (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 
permitted by local regulations and the IRB/IEC.  Investigators should notify AbbVie if 
 


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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 study-related 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 activities.  A copy of each 
complete, signed, and dated informed consent will be given to the subject and their study 
partner and each original will be placed in the subject's study 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.
An informed consent, approved by an IRB/IEC, must be voluntarily signed and dated 
before optional pharmacogenetic samples are collected.  The nature of the testing should 
be explained and the subject given an opportunity to ask questions.  The informed consent 
 


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must be signed before the samples are collected and any testing is performed.  If the 
subject does not consent to provide the optional samples, 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 inspections, 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 CRF 
data for this study are being collected with an 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 Code of Federal Regulations Part 11.  The 
documentation related to the validation of the EDC system is available through the 
 


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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 investigators, and the study coordinators/project managers.  This meeting 
will include a detailed discussion and review of the protocol and essential documents, 
performance of study procedures, CRF completion, and specimen collection methods.
 


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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 IRB/IEC, 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.
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.
 


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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.
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, 
 


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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:
An Extension Study of ABBV-8E12 in Early Alzheimer's Disease
Protocol Date: 
20 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.
2.
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.
AbbVie.  ABBV-8E12 Investigator Brochure.
5.
Duits FH, Martinez-Lage P, Paquet C.  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.
6.
Morris JC.  The Clinical Dementia Rating (CDR):  current vision and scoring rules.  
Neurology.  1993;43(11):2412-4.
7.
Galasko D, Bennett D, Sano M, et al.  An inventory to assess activities of daily 
living for clinical trials in Alzheimer's disease.  The Alzheimer's Disease 
Cooperative Study.  Alzheimer Dis Assoc Disord.  1997;11 (Suppl 2):S33-9.
8.
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.
9.
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.
10.
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.
 


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11.
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.
12.
EuroQol Group.  EuroQol--a new facility for the measurement of health-related 
quality of life.  Health Policy.  1990;16(3):199-208.
13.
Jönsson L, Andreasen N, Kilander L, et al.  Patient- and proxy-reported utility in 
Alzheimer disease using the EuroQoL.  Alzheimer Dis Assoc Disord.  
2006;20(1):49-55.
14.
Columbia-Suicide Severity Rating Scale (C-SSRS) [homepage on the Internet].  
Columbia University Medical Center.  Available from:  
http//www.cssrs/Columbia.edu/.
 


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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
Neuroscience
Clinical Program Development
Statistics
Statistics
Pharmacokinetics
Medical Writing
 


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Appendix C.
Study Activities
Dose
Year 1
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
Dose 
14
Visits & Proceduresa
Day 1/
Baseline
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
40
Wk 
44
Wk 
48
Wk 
52
Subject/study partner ICFb
X
Medical history updatec
X
Treatment assignment
X
Physical examination
Xd
X
Vital signse
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weighte
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examination
Xd
X
X
X
12-lead ECG 
Xd
X
X
X
Clinical laboratory tests
Xd
X
X
X
Brain MRI
Xd
X
X
X
Optional LP/CSF collection
Xd
X
Tau PETf
Xd
X
Blood sample for ABBV-8E12 assay
Xd
X
X
X
ADA sample
Xd
X
X
X
Plasma and serum biomarker sample
Xd
X
X
X
Optional PG DNA and RNA sampleg
Xd
X
X
X
 


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Dose
Year 1
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
Dose 
14
Visits & Proceduresa
Day 1/
Baseline
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
40
Wk 
44
Wk 
48
Wk 
52
Administer IV study druga
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CDRh
Xd
X
X
RBANSh
Xd
X
ADCS-MCI-ADL-24h
Xd
X
EQ-5D-5Lh
X
X
C-SSRSe,h
Xd
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications reviewe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessmente
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 


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Dose
Year 2
Dose
15
Dose 
16
Dose 
17
Dose 
18
Dose 
19
Dose 
20
Dose 
21
Dose 
22
Dose 
23
Dose 
24
Dose 
25
Dose 
26
Dose 
27
Visits & Proceduresa
Wk
56
Wk
60
Wk
64
Wk
68
Wk
72
Wk
76
Wk
80
Wk
84
Wk
88
Wk
92
Wk
96
Wk
100
Wk
104
Subject/study partner ICFb
Medical history updatec
Treatment assignment
Physical examination
X
Vital signse
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weighte
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examination
X
X
12-lead ECG 
X
Clinical laboratory tests
X
X
Brain MRI 
O
X
Optional LP/CSF collection
X
Tau PETf
X
Blood sample for ABBV-8E12 assay 
X
X
ADA sample
X
X
Plasma and serum biomarker sample
X
X
Optional PG DNA and RNA sampleg
X
X
Administer IV study druga
X
X
X
X
X
X
X
X
X
X
X
X
X
CDRh
X
X
 


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Dose
Year 2
Dose
15
Dose 
16
Dose 
17
Dose 
18
Dose 
19
Dose 
20
Dose 
21
Dose 
22
Dose 
23
Dose 
24
Dose 
25
Dose 
26
Dose 
27
Visits & Proceduresa
Wk
56
Wk
60
Wk
64
Wk
68
Wk
72
Wk
76
Wk
80
Wk
84
Wk
88
Wk
92
Wk
96
Wk
100
Wk
104
RBANSh
X
ADCS-MCI-ADL-24h
X
EQ-5D-5Lh
X
C-SSRSe,h
X
X
X
Concomitant medications reviewe
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessmente
X
X
X
X
X
X
X
X
X
X
X
X
X
 


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Dose
Year 3
Dose 
28
Dose 
29
Dose 
30
Dose 
31
Dose 
32
Dose 
33
Dose 
34
Dose 
35
Dose 
36
Dose 
37
Dose 
38
Dose 
39
Dose 
40
Visits & Proceduresa
Wk
108
Wk
112
Wk
116
Wk
120
Wk
124
Wk
128
Wk
132
Wk
136
Wk
140
Wk
144
Wk
148
Wk
152
Wk
156
Subject/study partner ICFb
Medical history updatec
Treatment assignment
Physical examination
X
Vital signse
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weighte
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examination
X
X
12-lead ECG 
X
Clinical laboratory tests
X
Brain MRI 
O
X
Optional LP/CSF collection
Tau PETf
X
Blood sample for ABBV-8E12 assay 
X
X
ADA sample
X
X
Plasma and serum biomarker sample
X
X
Optional PG DNA and RNA sampleg
X
X
Administer IV study druga
X
X
X
X
X
X
X
X
X
X
X
X
X
CDRh
X
X
 


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Dose
Year 3
Dose 
28
Dose 
29
Dose 
30
Dose 
31
Dose 
32
Dose 
33
Dose 
34
Dose 
35
Dose 
36
Dose 
37
Dose 
38
Dose 
39
Dose 
40
Visits & Proceduresa
Wk
108
Wk
112
Wk
116
Wk
120
Wk
124
Wk
128
Wk
132
Wk
136
Wk
140
Wk
144
Wk
148
Wk
152
Wk
156
RBANSh
X
ADCS-MCI-ADL-24h
X
EQ-5D-5Lh
X
C-SSRSe,h
X
X
X
Concomitant medications reviewe
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessmente
X
X
X
X
X
X
X
X
X
X
X
X
X
 


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Dose
Year 4
Dose
41
Dose
42
Dose
43
Dose
44
Dose
45
Dose
46
Dose
47
Dose
48
Dose
49
Dose
50
Dose
51
Dose
52
Dose
53
Visits & Proceduresa
Wk 
160
Wk 
164
Wk 
168
Wk 
172
Wk 
176
Wk 
180
Wk 
184
Wk 
188
Wk 
192
Wk 
196
Wk 
200
Wk 
204
Wk 
208
Subject/study partner ICFb
Medical history updatec
Treatment assignment
Physical examination
X
Vital signse
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weighte
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examination
X
X
12-lead ECG 
X
Clinical laboratory tests
X
Brain MRI
O
X
Optional LP/CSF collection
Tau PETf
X
Blood sample for ABBV-8E12 assay 
X
X
ADA sample
X
X
Plasma and serum biomarker sample
X
X
Optional PG DNA and RNA sampleg
X
X
Administer IV study druga
X
X
X
X
X
X
X
X
X
X
X
X
X
CDRh
X
X
 


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Dose
Year 4
Dose
41
Dose
42
Dose
43
Dose
44
Dose
45
Dose
46
Dose
47
Dose
48
Dose
49
Dose
50
Dose
51
Dose
52
Dose
53
Visits & Proceduresa
Wk 
160
Wk 
164
Wk 
168
Wk 
172
Wk 
176
Wk 
180
Wk 
184
Wk 
188
Wk 
192
Wk 
196
Wk 
200
Wk 
204
Wk 
208
RBANSh
X
ADCS-MCI-ADL-24h
X
EQ-5D-5Lh
X
C-SSRSe,h
X
X
X
Concomitant medications reviewe
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessmente
X
X
X
X
X
X
X
X
X
X
X
X
X
 


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Dose
Year 5
Dose 
54
Dose 
55
Dose 
56
Dose 
57
Dose 
58
Dose 
59
Dose 
60
Dose 
61
Dose 
62
Dose 
63
Dose 
64
Dose 
65
Wk 260/
Study 
Completion 
PD Visit
20 Wk
Post-Last 
Dosei Follow-
Up Visit
Visits & Proceduresa
Wk 
212
Wk 
216
Wk 
220
Wk 
224
Wk 
228
Wk 
232
Wk 
236
Wk 
240
Wk 
244
Wk 
248
Wk 
252
Wk 
256
Subject/study partner ICFb
Medical history updatec
Treatment assignment
Physical examination
X
Vital signse
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weighte
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examination
X
X
X
X
12-lead ECG 
X
Clinical laboratory tests
X
X
X
Brain MRI 
O
X
X
X
Optional LP/CSF collection
X
Tau PETf
X
Blood sample for 
ABBV-8E12 assay 
X
X
X
X
ADA sample
X
X
X
X
Plasma and serum biomarker 
sample
X
X
X
X
Optional PG DNA and RNA 
sampleg
X
X
 


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Dose
Year 5
Dose 
54
Dose 
55
Dose 
56
Dose 
57
Dose 
58
Dose 
59
Dose 
60
Dose 
61
Dose 
62
Dose 
63
Dose 
64
Dose 
65
Wk 260/
Study 
Completion 
PD Visit
20 Wk
Post-Last 
Dosei Follow-
Up Visit
Visits & Proceduresa
Wk 
212
Wk 
216
Wk 
220
Wk 
224
Wk 
228
Wk 
232
Wk 
236
Wk 
240
Wk 
244
Wk 
248
Wk 
252
Wk 
256
Administer IV study druga
X
X
X
X
X
X
X
X
X
X
X
X
CDRh
X
X
X
X
RBANSh
X
X
ADCS-MCI-ADL-24h
X
EQ-5D-5Lh
X
X
C-SSRSe,h
X
X
X
X
Concomitant medications 
reviewe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessmente
X
X
X
X
X
X
X
X
X
X
X
X
X
X
O = Optional; Wk = Week
a.
Study drug will be administered on Day 1/Baseline visit, and then every 4 weeks thereafter until 1 of the discontinuation criteria is met, until the sponsor discontinues the 
study, or until the study reaches completion.  Visits during the Treatment Period may be scheduled within ± 4 days.  All dosing visits may be completed over 2 consecutive 
days at the discretion of the investigator with the second day to include the start and end of the infusion.
b.
Subject informed consent, or as applicable, legally authorized representative informed consent and subject assent, and study partner informed consent must be obtained prior 
to any Study M15-570 specific procedures being completed.
c.
Review medical history to confirm subject does not meet exclusion criteria prior to enrollment.
d.
Not required if procedure was conducted during the Week 96 visit in Study M15-566.  A repeat assessment/procedure may be required based on discussion with the TA MD 
or designee if subject is enrolling outside the 8 week window from the Week 92 visit in Study M15-566. 
e.
Vital signs, body weight, C-SSRS, concomitant medications review and AE assessment to be completed to administration of infusion.  
f.
Subjects who did not complete tau PET imaging through Study M15-566 and at Study M15-570 Day 1/Baseline will have tau PET imaging performed at subsequent visits 
only after discussion with TA MD or designee.  Tau PET imaging will only be collected for subjects at sites selected to participate in the tau PET assessment.
 


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g.
Optional pharmacogenetic DNA and RNA samples require consent.  Verify consent prior to sample collection.
h.
The recommended order of administration is CDR followed by RBANS.  When applicable, ADCS-MCI-ADL-24, EQ-5D-5L, and C-SSRS may be subsequently 
administered/assessed in any order.
i.
Post-treatment follow-up to occur approximately 20 weeks after the last dose.
Note:
For subjects who prematurely discontinue the study, safety and efficacy assessments may be conducted remotely (for example, via telephone), where applicable.
 












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Appendix E.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes
Section 1.2  Synopsis
Previously read:
AbbVie Inc.
Protocol Number:  M15-570
Name of Study Drug:  ABBV-8E12
Phase of Development:  2
Name of Active Ingredient:  ABBV-8E12
Date of Protocol Synopsis:  24 January 2019
Protocol Title:  An Extension Study of ABBV-8E12 in Early Alzheimer's Disease
Objectives:
The primary objective of this study is to assess the long-term safety and tolerability of ABBV-8E12 in 
subjects with early Alzheimer's disease (AD).
The secondary objective of this study is to assess the pharmacokinetics (PK) of ABBV-8E12 in subjects 
with early AD.
The exploratory objectives of this study are:

To assess the long-term efficacy of ABBV-8E12 in slowing disease progression in subjects 
with early AD. 

To assess the long-term effect of ABBV-8E12 on a range of disease-related and drug-related 
biomarkers in subjects with early AD.
Investigators:  Multicenter
Study Sites:  Up to 80 global sites
Study Population:  Adult subjects with early AD who completed Study M15-566
Number of Subjects to be Enrolled:  Approximately 400
Methodology:
Study M15-570 is a Phase 2 extension of the multiple dose, multicenter, multinational, randomized, 
double-blind, placebo-controlled study, Study M15-566, and is designed to evaluate the long-term safety 
and tolerability of ABBV-8E12 in subjects with early AD.  The study will consist of a 5-year treatment 
period and a follow-up period of approximately 20 weeks following the last study drug administration.
All subjects who complete the Treatment Period in Study M15-566 will be eligible to participate in this 
study according to the selection criteria.  Upon completion of baseline study procedures, eligible subjects 
will receive ABBV-8E12 via intravenous (IV) infusion on Day 1 of Study M15-570 as follows:  

Subjects who received placebo in Study M15-566 will receive 2000 mg ABBV-8E12 in 
Study M15-570;

Subjects who received 300 mg ABBV-8E12 in Study M15-566 will receive 1000 mg 
ABBV-8E12 in Study M15-570; and 

Subjects who received 1000 mg or 2000 mg ABBV-8E12 in Study M15-566 will continue on 
 


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the same dose in Study M15-570. 
Note:  if any changes are made to alter Study M15-566 with regards to the treatment arms due to safety, 
efficacy, or other reasons, a corresponding change will be implemented in Study M15-570.  This change 
may include, but is not limited to, adding or dropping treatment arm(s).
Methodology (Continued):
Subjects will receive study drug infusion every 4 weeks and undergo other study procedures and 
assessments as outlined in the Study Activities table (Appendix C).  Subjects will continue to receive 
treatment either until one of the discontinuation criteria is met, the sponsor discontinues the study, or the 
subject completes the 5-year treatment period of Study M15-570.  Refer to Section 5.4 for detailed 
description of discontinuation criteria.
Day 1 visit of Study M15-570 will be at least 4 weeks but no more than 8 weeks after the last dosing 
visit (Week 92) of Study M15-566.  Should this window be longer than 8 weeks, the subject may be 
considered for participation in Study M15-570 only with the approval of the AbbVie Therapeutic Area 
Medical Director (TA MD).  The investigators and subjects will remain blinded to the treatment 
assignments in Study M15-566 and will be blinded to the dose level of ABBV-8E12 in Study M15-570.
Safety will be closely monitored during the study conduct.  The study will also utilize an external data 
monitoring committee (DMC), which will review accumulating study data and make recommendations 
based on the emerging safety profile of ABBV-8E12.  The DMC membership, responsibilities, operating 
logistics, and timing of reviews will be documented in a charter that will be finalized prior to the 
first DMC review meeting.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:

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 institutional review board 
(IRB)/independent ethics committee (IEC) approved informed consent, prior to the conduct of 
any extension study-specific procedures (including any changes occurring in the subject's 
current therapeutic regimen).  In the absence of subject's ability to provide the informed 
consent, the informed consent must be obtained by a person who has the legal right to act on 
behalf of the subject following local regulations.

Subject completed the 96-week treatment period of Study M15-566. 

In the investigator's opinion, subject was compliant during participation in Study M15-566.

Subject has an identified, reliable study partner (e.g., caregiver, family member, social worker, 
or friend; preferably the same person for the duration of the study) who has frequent contact 
with the subject (at least 10 hours per week) and who will provide information as to the 
subject's cognitive and functional abilities.  The study partner has voluntarily signed the 
IRB/IEC approved study partner informed consent, prior to the conduct of any extension 
study-specific procedures.

If female, subject must be postmenopausal defined as:
o
Age ≥ 55 years with no menses for 12 or more months without an alternative medical 
cause.
OR
o
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy or 
hysterectomy).
 


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
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.
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion:

The subject has any significant change in his/her medical condition since participation in 
Study M15-566 that could interfere with the subject's participation in Study M15-570, could 
place the subject at increased risk, or could confound interpretation of study results.  The 
investigator must re-evaluate the subject for continuing participation and consider relevant 
factors including:
o
interim development of any clinically significant neurological, hematological, 
autoimmune, endocrine, cardiovascular, neoplastic, renal, hepatic, metabolic, psychiatric, 
pulmonary, gastrointestinal, or other major disorder
o
interim development of contraindication to or inability to tolerate brain MRI or PET scans

More than 8 weeks have elapsed since the subject received his/her last dose of study drug in 
Study M15-566 (i.e., Week 92 visit in Study M15-566).  In certain cases, subject may be 
eligible to enroll after approval by the TA MD.

Subject is concurrently enrolled in another interventional clinical study (with the exception of 
Study M15-566) involving a therapeutic agent.

Subject is considered by the investigator, for any reason, to be an unsuitable candidate to 
receive ABBV-8E12 or the subject is considered by the investigator to be unable or unlikely to 
comply with the dosing schedule or study evaluations.
Investigational Product:
ABBV-8E12 (1000 mg/10 mL)
Doses:
Dose 1:  1000 mg
Dose 2:  2000 mg
Doses will be given every 4 weeks.
Doses may be modified after evaluation by the 
DMC of the safety, tolerability, and available PK 
data.
Mode of Administration:
IV infusion
Reference Therapy:
Not applicable
Doses:
Not applicable
Mode of Administration:
Not applicable
Duration of Treatment:  5 years
Criteria for Evaluation:
Safety:
Adverse event monitoring, vital signs, physical examination, neurologic examination, electrocardiogram 
(ECG), laboratory tests, Columbia-suicide severity rating scale (C-SSRS), MRI, and immunogenicity 
assessments will be conducted. 
Subjects will be monitored closely for the occurrence of AEs and serious adverse events (SAEs) both 
during and after the IV infusion up to the final follow-up visit, at a minimum of approximately 20 weeks 
 


ABBV-8E12
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from the date of the last dose of study drug.  Monitoring will occur according to the protocol-defined 
Study Activities table (Appendix C).  The DMC will be in place to provide recommendations during the 
study.
Criteria for Evaluation (Continued):
Efficacy:
Clinical Assessments:

Clinical Dementia Rating - Sum of Boxes (CDR-SB)

Repeatable Battery for Assessment of Neuropsychological Status (RBANS)

24-item AD Cooperative Study/Activities of Daily Living scale adapted for patients with mild 
cognitive impairment (ADCS-MCI-ADL-24)

EuroQuality of Life-5-level (EQ-5D-5L)

Digital measures of cognition, actigraphy, and sleep (for subjects enrolled at participating sites)
Pharmacokinetics:
Values for the following pharmacokinetic parameters will be estimated using mixed-effect modeling 
approach:  clearance (CL) and volume of distribution (V).  Additional parameters may be calculated if 
useful in the interpretation of the data.  Pharmacokinetic data from this study may be combined with data 
from other ABBV-8E12 studies for pharmacokinetic analyses.  Additional parameters may be calculated 
if useful in the interpretation of the data.
Immunogenicity:
Anti-drug antibodies (ADA) will be determined in serum for assessment of immunogenicity.
Biomarkers and Pharmacogenetics:
Exploratory research to assess effects of ABBV-8E12 on potential disease-related and drug-related 
biomarkers will be conducted.  Blood sampling, optional CSF sampling and MRIs for volumetric 
analysis will be done at designated time points throughout the study in order to obtain the data.  Also, tau 
PET scans will be collected in a subset of the subjects.  Retinal images will be obtained in a subset of 
subjects.  The potential CSF and plasma biomarkers will include, but are not limited to, the following: 
tau and NFL 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.
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.  The values of other variables 
may be determined.  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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Statistical Methods:
Safety:
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  The 
number and percentage of subjects reporting treatment-emergent AEs will be tabulated by MedDRA 
system organ class (SOC) and preferred term (PT) with a breakdown by treatment sequence.  
Tabulations will also be provided in which the number of subjects reporting an AE (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 SAE (including deaths) and 
AEs leading to premature discontinuation of the study drug will be tabulated according to the MedDRA 
SOC and preferred term by treatment sequence.  Treatment sequence differences between each 
ABBV-8E12 dose group will be analyzed using Fisher's exact test.  Differences between each 
ABBV-8E12 dose group 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.
Efficacy:
All efficacy analyses of comparisons will be performed with a 2-sided test at the significance level of 
0.050 unless otherwise specified.  All efficacy assessments that are taken no more than 45 days after the 
last dose of study drug will be included in the efficacy analyses.
The analysis of efficacy variables will be performed on the Study M15-570 ITT data set.  The analysis 
model is a likelihood-based, mixed effects model repeated measures (MMRM) analysis at 
Study M15-570 Baseline and each post-baseline observation using all observed data.  This MMRM 
analysis will be applied to each efficacy variable with repeated measurements.  Details of the analysis 
will be described in the statistical analysis plan (SAP).
If applicable, delayed-start analysis will be conducted on the change from Baseline of Study M15-566 up 
to Week 96 in Study M15-570 on CDR-SB score.  An MMRM analysis model will be used.  Details of 
the analysis will be specified in the SAP.
Pharmacokinetics:
For ABBV-8E12 serum concentration data, descriptive statistics will be provided for each scheduled 
time of measurement with a breakdown by treatment sequence.
Data from this study may be combined with data from other studies for the population PK and exposure-
response analyses.  Population PK and exposure-response analyses of data from this study only may not 
be conducted.  The following general methodology will be used for the population PK and exposure-
response analyses.
Population PK analyses will be performed using the actual sampling time relative to the last 
administered dose.  Pharmacokinetic models will be built using a non-linear mixed-effect modeling 
approach with the NONMEM software (Version 7, or higher version).  The structure of the starting PK 
model will be based on the PK analysis of data from previous studies.  Apparent CL and apparent V of 
ABBV-8E12 will be the PK parameters of major interest in the NONMEM analyses.  If necessary, other 
parameters may be fixed if useful in the analysis.
Immunogenicity:
The ADA titers will be tabulated by dose level and summarized as appropriate.
 


ABBV-8E12
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Statistical Methods (Continued):
Biomarkers:
For each variable, descriptive statistics will be provided for each scheduled time of measurement with a 
breakdown by group as defined by treatment in Study M15-566 and treatment in Study M15-570, i.e.,:  

ABBV-8E12 1000 mg in Study M15-566, continuing the same in Study M15-570

ABBV-8E12 2000 mg in Study M15-566, continuing the same in Study M15-570

ABBV-8E12 300 mg in Study M15-566, ABBV-8E12 1000 mg in Study M15-570

Placebo in Study M15-566, ABBV-8E12 2000 mg in Study M15-570.
For the CSF concentrations of total and free tau and their ratio and for the plasma concentrations of total 
tau and NFL, an MMRM analysis will be performed to compare the effects of the 1000 and 2000 mg 
doses of ABBV-8E12 for scheduled measurements after the baseline assessment until Week 260.  The 
data set will contain the data of the first 2 groups identified above.  The data set will also include the data 
of the last group (those receiving placebo in Study M15-566 and ABBV-8E12 2000 mg in 
Study M15-570) beginning with Week 120 of Study M15-570, but with a shift in time by 96 weeks for 
the purposes of this analysis so that the shifted time indicates the length of time on ABBV-8E12 past 
96 weeks.  Thus, for this analysis, the Week 192 data of the last group will be considered the same as 
Week 96 data of the first 2 groups.  Data of the last group of Week 96 and earlier will not be included for 
this analysis.
The model for the MMRM analysis performed for the tau variables and plasma NFL will include 
classification by ABBV-8E12 dose and by time of measurement.  There will be an effect for the 
interaction of ABBV-8E12 dose and time of measurement.  Except for the ratio of CSF free tau 
concentration to CSF total concentration, the baseline value will be a covariate.  For the ratio of CSF free 
to total tau, the value for baseline total tau concentration will be a covariate if this variable is found to be 
a significant covariate for the ratio in Study M15-566.  The model will also have an effect to distinguish 
between subjects who were assigned to ABBV-8E12 treatment in Study M15-566 and those who were 
assigned to placebo in Study M15-566.  The subjects in each treatment sequence will be viewed as a 
random sample, and an appropriate structure for the covariance matrix of the measurements of a subject 
will be selected.
For volumetric MRI variables, descriptive statistics will be provided for the baseline value and the 
change from baseline for each of the scheduled times of measurement.  For each variable, an MMRM 
analysis will be performed for the changes from baseline.  The model will be much like that described 
for plasma total tau concentration, but with estimated total intracranial volume (eTIV) as a covariate in 
addition to the baseline value.  
For each region of the brain for which SUVR values are obtained from PET scans, an analysis like that 
described for plasma total tau concentration will be performed.
 


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Has been changed to read:
AbbVie Inc.
Protocol Number:  M15-570
Name of Study Drug:  ABBV-
8E12
Phase of Development:  2
Name of Active Ingredient:  
ABBV-8E12
Date of Protocol Synopsis:  20 October 2020
Protocol Title:  An Extension Study of ABBV-8E12 in Early Alzheimer's Disease
Objectives:
The primary objective of this study is to assess the long-term safety and tolerability of ABBV-8E12 in 
subjects with early Alzheimer's disease (AD).
The secondary objective of this study is to assess the pharmacokinetics (PK) of ABBV-8E12 in subjects 
with early AD.
The exploratory objectives of this study are:

To assess the long-term efficacy of ABBV-8E12 in slowing disease progression in subjects 
with early AD. 

To assess the long-term effect of ABBV-8E12 on a range of disease-related and drug-related 
biomarkers in subjects with early AD.
Investigators:  Multicenter
Study Sites:  Up to 80 global sites
Study Population:  Adult subjects with early AD who completed Study M15-566
Number of Subjects to be Enrolled:  Approximately 400
Methodology:
Study M15-570 is a Phase 2 extension of the multiple dose, multicenter, multinational, randomized, 
double-blind, placebo-controlled study, Study M15-566, and is designed to evaluate the long-term safety 
and tolerability of ABBV-8E12 in subjects with early AD.  The study will consist of a 5-year treatment 
period and a follow-up period of approximately 20 weeks following the last study drug administration.
All subjects who complete the Treatment Period in Study M15-566 will be eligible to participate in this 
study according to the selection criteria.  Upon completion of baseline study procedures, eligible subjects 
will receive ABBV-8E12 via intravenous (IV) infusion on Day 1 of Study M15-570 as follows:  

Subjects who received placebo in Study M15-566 will receive 2000 mg ABBV-8E12 in 
Study M15-570;

Subjects who received 300 mg ABBV-8E12 in Study M15-566 will receive 1000 mg 
ABBV-8E12 in Study M15-570; and 

Subjects who received 1000 mg or 2000 mg ABBV-8E12 in Study M15-566 will continue on 
the same dose in Study M15-570. 
Note:  if any changes are made to alter Study M15-566 with regards to the treatment arms due to safety, 
efficacy, or other reasons, a corresponding change will be implemented in Study M15-570.  This change 
may include, but is not limited to, adding or dropping treatment arm(s).
 


ABBV-8E12
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Methodology (Continued):
Subjects will receive study drug infusion every 4 weeks and undergo other study procedures and 
assessments as outlined in the Study Activities table (Appendix C).  Subjects will continue to receive 
treatment either until one of the discontinuation criteria is met, the sponsor discontinues the study, or the 
subject completes the 5-year treatment period of Study M15-570.  Refer to Section 5.4 for detailed 
description of discontinuation criteria.
Day 1 visit of Study M15-570 will be approximately 4 weeks but no more than 8 weeks after the 
Week 92 visit of Study M15-566.  Should this window be longer than 8 weeks, the subject may be 
considered for participation in Study M15-570 only with the approval of the AbbVie Therapeutic Area 
Medical Director (TA MD) or designee.  The investigators and subjects will remain blinded to the 
treatment assignments in Study M15-566 and will be blinded to the dose level of ABBV-8E12 in 
Study M15-570.
Safety will be closely monitored during the study conduct.  The study will also utilize an external data 
monitoring committee (DMC), which will review accumulating study data and make recommendations 
based on the emerging safety profile of ABBV-8E12.  The DMC membership, responsibilities, operating 
logistics, and timing of reviews will be documented in a charter that will be finalized prior to the 
first DMC review meeting.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:

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 institutional review board 
(IRB)/independent ethics committee (IEC) approved informed consent, prior to the conduct of 
any extension study-specific procedures (including any changes occurring in the subject's 
current therapeutic regimen).  In the absence of subject's ability to provide the informed 
consent, the informed consent must be obtained by a person who has the legal right to act on 
behalf of the subject following local regulations.

Subject completed the 96-week treatment period of Study M15-566. 

In the investigator's opinion, subject was compliant during participation in Study M15-566.

Subject has an identified, reliable study partner (e.g., caregiver, family member, social worker, 
or friend; preferably the same person for the duration of the study) who has frequent contact 
with the subject (at least 10 hours per week) and who will provide information as to the 
subject's cognitive and functional abilities.  The study partner has voluntarily signed the 
IRB/IEC approved study partner informed consent, prior to the conduct of any extension 
study-specific procedures.

If female, subject must be postmenopausal defined as:
o
Age ≥ 55 years with no menses for 12 or more months without an alternative medical 
cause.
OR
o
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy or 
hysterectomy).

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.
 


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion:

The subject has any significant change in his/her medical condition since participation in 
Study M15-566 that could interfere with the subject's participation in Study M15-570, could 
place the subject at increased risk, or could confound interpretation of study results.  The 
investigator must re-evaluate the subject for continuing participation and consider relevant 
factors including:
o
interim development of any clinically significant neurological, hematological, 
autoimmune, endocrine, cardiovascular, neoplastic, renal, hepatic, metabolic, psychiatric, 
pulmonary, gastrointestinal, or other major disorder
o
interim development of contraindication to or inability to tolerate brain MRI or PET scans

More than 8 weeks have elapsed since the subject received his/her last dose of study drug in 
Study M15-566 (i.e., Week 92 visit in Study M15-566).  In certain cases, subject may be 
eligible to enroll after approval by the TA MD or designee.

Subject is concurrently enrolled in another interventional clinical study (with the exception of 
Study M15-566) involving a therapeutic agent.

Subject is considered by the investigator, for any reason, to be an unsuitable candidate to 
receive ABBV-8E12 or the subject is considered by the investigator to be unable or unlikely to 
comply with the dosing schedule or study evaluations.
Investigational Product:
ABBV-8E12 (vial of 1000 mg/10 mL and vial of 2000 mg/20 mL)
Doses:
Dose 1:  1000 mg
Dose 2:  2000 mg
Doses will be given every 4 weeks.
Doses may be modified after evaluation by the DMC of the safety, 
tolerability, and available PK data.
Mode of Administration:
IV infusion
Reference Therapy:
Not applicable
Doses:
Not applicable
Mode of Administration:
Not applicable
Duration of Treatment:  5 years
Criteria for Evaluation:
Safety:
Adverse event monitoring, vital signs, physical examination, neurologic examination, electrocardiogram 
(ECG), laboratory tests, Columbia-suicide severity rating scale (C-SSRS), MRI, and immunogenicity 
assessments will be conducted. 
Subjects will be monitored closely for the occurrence of AEs and serious adverse events (SAEs) 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 (Appendix C).  The DMC will be in place to provide recommendations during the 
study.
 


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Criteria for Evaluation (Continued):
Efficacy:
Clinical Assessments:

Clinical Dementia Rating - Sum of Boxes (CDR-SB)

Repeatable Battery for Assessment of Neuropsychological Status (RBANS)

24-item AD Cooperative Study/Activities of Daily Living scale adapted for patients with mild 
cognitive impairment (ADCS-MCI-ADL-24)

EuroQuality of Life-5-level (EQ-5D-5L) Proxy Version 1
Pharmacokinetics:
Values for the following pharmacokinetic parameters will be estimated using mixed-effect modeling 
approach:  clearance (CL) and volume of distribution (V).  Additional parameters may be calculated if 
useful in the interpretation of the data.  Pharmacokinetic data from this study may be combined with data 
from other ABBV-8E12 studies for pharmacokinetic analyses.  Additional parameters may be calculated 
if useful in the interpretation of the data.
Immunogenicity:
Anti-drug antibodies (ADA) will be determined in serum for assessment of immunogenicity.
Biomarkers and Pharmacogenetics:
Exploratory research to assess effects of ABBV-8E12 on potential disease-related and drug-related 
biomarkers will be conducted.  Blood sampling, optional CSF sampling and MRIs for volumetric 
analysis will be done at designated time points throughout the study in order to obtain the data.  Also, tau 
PET scans will be collected in a subset of the subjects.  The potential CSF and plasma biomarkers will 
include, but are not limited to, the following:  tau and NFL concentrations; volumetric MRI measures for 
whole brain, hippocampus, temporal lobes 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.
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.  The values of other variables 
may be determined.  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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Statistical Methods:
Safety:
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  The 
number and percentage of subjects reporting treatment-emergent AEs will be tabulated by MedDRA 
system organ class (SOC) and preferred term (PT) with a breakdown by treatment sequence.  
Tabulations will also be provided in which the number of subjects reporting an AE (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 SAE (including deaths) and 
AEs leading to premature discontinuation of the study drug will be tabulated according to the MedDRA 
SOC and preferred term by treatment sequence.  Treatment sequence differences between each 
ABBV-8E12 dose group will be analyzed using Fisher's exact test.  Differences between each 
ABBV-8E12 dose group 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.
Efficacy:
All efficacy analyses of comparisons will be performed with a 2-sided test at the significance level of 
0.050 unless otherwise specified.  All efficacy assessments that are taken no more than 45 days after the 
last dose of study drug will be included in the efficacy analyses.
The analysis of efficacy variables will be performed on the Study M15-570 ITT data set.  The analysis 
model is a likelihood-based, mixed effects model repeated measures (MMRM) analysis at 
Study M15-570 Baseline and each post-baseline observation using all observed data.  This MMRM 
analysis will be applied to each efficacy variable with repeated measurements.  Details of the analysis 
will be described in the statistical analysis plan (SAP).
If applicable, delayed-start analysis will be conducted on the change from Baseline of Study M15-566 up 
to Week 96 in Study M15-570 on CDR-SB score.  An MMRM analysis model will be used.  Details of 
the analysis will be specified in the SAP.
Pharmacokinetics:
For ABBV-8E12 serum concentration data, descriptive statistics will be provided for each scheduled 
time of measurement with a breakdown by treatment sequence.
Data from this study may be combined with data from other studies for the population PK and exposure-
response analyses.  Population PK and exposure-response analyses of data from this study only may not 
be conducted.  The following general methodology will be used for the population PK and exposure-
response analyses.
Population PK analyses will be performed using the actual sampling time relative to the last 
administered dose.  Pharmacokinetic models will be built using a non-linear mixed-effect modeling 
approach with the NONMEM software (Version 7, or higher version).  The structure of the starting PK 
model will be based on the PK analysis of data from previous studies.  Apparent CL and apparent V of 
ABBV-8E12 will be the PK parameters of major interest in the NONMEM analyses.  If necessary, other 
parameters may be fixed if useful in the analysis.
Immunogenicity:
The ADA titers will be tabulated by dose level and summarized as appropriate.
 


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Statistical Methods (Continued):
Biomarkers:
For each variable, descriptive statistics will be provided for each scheduled time of measurement with a 
breakdown by group as defined by treatment in Study M15-566 and treatment in Study M15-570, i.e.,:  

ABBV-8E12 1000 mg in Study M15-566, continuing the same in Study M15-570

ABBV-8E12 2000 mg in Study M15-566, continuing the same in Study M15-570

ABBV-8E12 300 mg in Study M15-566, ABBV-8E12 1000 mg in Study M15-570

Placebo in Study M15-566, ABBV-8E12 2000 mg in Study M15-570.
For the CSF concentrations of total and free tau and their ratio and for the plasma concentrations of total 
tau and NFL, an MMRM analysis will be performed for scheduled measurements after study drug 
administration of Study M15-570 begins.
The model for the MMRM analysis performed for the tau variables and plasma NFL will include 
classification by treatment sequence and by time of measurement.  There will be an effect for the 
interaction of treatment and time of measurement.  Except for the ratio of CSF free tau concentration to 
CSF total concentration, the baseline value will be a covariate.  For the ratio of CSF free to total tau, the 
value for baseline total tau concentration will be a covariate if this variable is found to be a significant 
covariate for the ratio in Study M15-566. The subjects in each treatment sequence will be viewed as a 
random sample, and an appropriate structure for the covariance matrix of the measurements of a subject 
will be selected.
For volumetric MRI variables, descriptive statistics will be provided for the baseline value and the 
change from baseline for each of the scheduled times of measurement.  For each variable, an MMRM 
analysis will be performed for the changes from baseline.  The analysis will be much like that described 
for plasma total tau concentration, but with estimated total intracranial volume (eTIV) as a covariate in 
addition to the baseline value.
For each region of the brain for which SUVR values are obtained from PET scans, an analysis like that 
described for plasma total tau concentration will be performed.
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Add:
COVID-19
Coronavirus disease - 2019
DTP
Direct-to-patient
IERC
Internal Executive Review Committee
 


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Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Delete:
CRA
Clinical research associate
IRC
independent review committee
Section 3.0  Introduction
Subsection Clinical Experience
Heading "Phase 2 Multiple-Dose Study in Subjects with PSP"
Delete:  heading title and text
Phase 2 Multiple-Dose Study in Subjects with PSP
Study M15-562 is an ongoing Phase 2, randomized, multicenter, double-blind, 
placebo-controlled, multiple-dose trial in which 2 dose levels of ABBV-8E12 are being 
evaluated (2000 and 4000 mg).  A total of 330 subjects (220 on ABBV-8E12 and 110 on 
placebo) are planned to participate in this study.
Section 3.0  Introduction
Subsection Clinical Experience
Heading "Phase 2 Extension of Multiple-Dose Study in Subjects with PSP"
Delete:  heading title and text
Phase 2 Extension of Multiple-Dose Study in Subjects with PSP
Study M15-563 is an ongoing extension study of the Phase 2 Study M15-562 in which 
2 dose levels of ABBV-8E12 are being evaluated (2000 and 4000 mg).  Subjects who 
complete the treatment period in Study M15-562 and meet all entry criteria are eligible to 
participate in Study M15-563.  All subjects will be assigned to receive ABBV-8E12 
(2000 or 4000 mg) in 1:1 ratio.
Section 3.2  Benefits and Risks
Add:  new last paragraph
In consideration of the coronavirus disease 2019 (COVID-19) pandemic, the benefits and 
risks to subjects participating in this study have been re-evaluated.  Based on the limited 
 


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information to date and due to the mechanism of action of ABBV-8E12, no additional risk 
is anticipated for study participants infected with SARS-Cov2 during the COVID-19 
pandemic.
Section 4.0  Study Objectives
Second paragraph previously read:
The secondary objective of this study is to assess the pharmacokinetic (PK) of 
ABBV-8E12 in subjects with early AD.
Has been changed to read:
The secondary objective of this study is to assess the pharmacokinetics (PK) of 
ABBV-8E12 in subjects with early AD.
Section 5.1  Overall Study Design and Plan:  Description
Fifth paragraph, first and second sentence previously read:
Day 1 visit of Study M15-570 (day of the first dose of Study M15-570) will be at least 
4 weeks but no more than 8 weeks after the last dosing visit (Week 92) of 
Study M15-566.  Should this window be longer than 8 weeks, the subject may be 
considered for participation in Study M15-570 only with the approval of the therapeutic 
area medical director (TA MD).
Has been changed to read:
Day 1 visit of Study M15-570 (day of the first dose of Study M15-570) will be 
approximately 4 weeks but no more than 8 weeks after the Week 92 visit of 
Study M15-566.  Should this window be longer than 8 weeks, the subject may be 
considered for participation in Study M15-570 only with the approval of the therapeutic 
area medical director (TA MD) or designee.
Section 5.2.2  Exclusion Criteria
Criterion 2, last sentence previously read:
In certain cases, subject may be eligible to enroll after approval by the TA MD.
 


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Has been changed to read:
In certain cases, subject may be eligible to enroll after approval by the TA MD or 
designee.
Section 5.2.2  Exclusion Criteria
Subsection Rationale for Exclusion Criteria
Previously read:
1
To ensure the safety of the subjects
2, 4
To select subject population appropriate for this study
3
These products may interfere with the PK of the study drug.
Has been changed to read:
1
To ensure the safety of the subjects
2
To allow the TA MD to delegate responsibility
2, 4
To select subject population appropriate for this study
3
These products may interfere with the PK of the study drug.
Section 5.3.1.1  Study Procedures
Add:  new first paragraph
Study visits may be impacted due to the COVID-19 pandemic and 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.
 


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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.
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.
 


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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.
Table 2.  Clinical Laboratory Tests
Add:  new abbreviation "T4" and "TSH"
T4 = Thyroxine; TSH = Thyroid stimulating hormone
Table 2.  Clinical Laboratory Tests
Table note "a." previously read:
Baseline only.
Has been changed to read:
Optional.  Not required if using Study M15-566 Week 96 visit for Baseline.
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.
 


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Section 5.3.1.1  Study Procedures
Subsection Optional Lumbar Puncture
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
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 Tau Imaging
First paragraph, last sentence previously read:
Subjects who did not complete tau PET imaging at Day 1/Baseline will have tau PET 
imaging performed at subsequent visits only after discussion with the TA MD.
Has been changed to read:
Subjects who did not complete tau PET imaging through Study M15-566 and at 
Study M15-570 Day 1/Baseline will have tau PET imaging performed at subsequent visits 
only after discussion with the TA MD or designee.
 


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Section 5.3.1.1  Study Procedures
Subsection Positron Emission Tomography Tau Imaging
Third paragraph previously red:
The tau PET scan at Baseline should be carried out prior to administration of the 
first dose.
Has been changed to read:
The tau PET scan for Day 1/Baseline should be carried out prior to administration of the 
first dose.
Section 5.3.1.1  Study Procedures
Subsection Positron Emission Tomography 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 obtained at the next onsite visit with 
the exception of Day 1/Baseline, which should be obtained prior to the administration of 
the first dose.
Section 5.3.1.1  Study Procedures
Subsection Retinal Imaging for Amyloid
Delete:  subsection title and text
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 Aβ in the retinal epithelial layer.  Retinal Aβ plaques have 
been identified in postmortem eyes from AD patients and in Aβ overexpressing transgenic 
mice.  Preliminary data suggests amyloidogenic densities can be detected in the retina of 
early AD patients.  An exploratory retinal imaging test designed to detect trace amounts of 
Aβ may be conducted only at sites selected to participate by AbbVie based on scientific, 
 


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technical, and logistical considerations.  For all eligible subjects at participating sites, the 
retinal imaging test will be conducted at time points indicated in the Study Activities table 
(Appendix C).  Only retinal imaging for Aβ 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 optional 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.
Section 5.3.1.1  Study Procedures
Subsection Digital Measures of Cognition, Actigraphy, and Sleep
Delete:  subsection title and text
Digital Measures of Cognition, Actigraphy, and Sleep
Measures of cognition, actigraphy, and sleep will be conducted in a subset of sites 
selected to participate by AbbVie based on scientific, technical, and logistical 
considerations.  Details of sensor use and other digital measures will be described in a 
separate lab manual.
Table 3.  Diagnostic Tools and Scale Administration Timing
Table note "c." previously read:
When applicable, scale may be subsequently administered/assessed in any order prior to 
study drug administration.
Has been changed to read:
Scale may be administered/assessed at any time during the visit.
 


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Section 5.3.1.1  Study Procedures
Subsection Diagnostic Tools and Rating Scales
Heading "EuroQuality of Life-5-level (EQ-5D-5L)12,13"
Previously read:
The EuroQuality of Life-5-level (EQ-5D-5L) contains a health state descriptive part 
comprising 5 items, scored from 1 (no problems or symptoms) to 5 (serious problems or 
symptoms); a question about change in health state in the preceding 12 months, and a 
visual analog scale (VAS) to evaluate current health state (from 0, worst imaginable, to 
100, best imaginable).  The descriptive profile can be converted into a value (EQ-Index) 
which ranges from 0 (death) to 1 (perfect health), with negative values indicating health 
states considered worse than death.  It is administered to the subject by a clinician and 
takes approximately 8 minutes to complete.  The EQ-5D-5L will be administered to the 
subject at the times indicated in the Study Activities table (Appendix C).
Has been changed to read:
The EuroQuality of Life-5-level (EQ-5D-5L) Proxy Version 1 measures overall health 
status.  The caregiver (the proxy) will rate the patient's health status in their (the proxy's) 
opinion.  The scale contains a descriptive system comprised of 5 dimensions 
[(1) mobility, (2) self-care, (3) usual activities, (4) pain/discomfort, and 
(5) anxiety/depression].  These health states get scored on 5 levels of severity [(1) no 
problems, (2) slight problems, (3) moderate problems, (4) severe problems, and 
(5) unable to/extreme problems] and a visual analog scale (VAS) to evaluate current 
health state from 0 (worst imaginable) to 100 (best imaginable).  The descriptive profile 
can be converted into a value (EQ-Index) which ranges from 0 (death) to 1 (perfect 
health), with negative values indicating health states considered worse than death.  The 
EQ-5D-5L Proxy Version 1 will be administered at the times indicated in the Study 
Activities table (Appendix C).
 


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Section 5.3.1.1  Study Procedures
Subsection Diagnostic Tools and Rating Scales
Heading "Columbia-Suicide Severity Rating Scale14"
Subheading "COVID-19 Pandemic-Related Acceptable Protocol Modifications"
Add:  new subheading 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 reference the table below for scales that 
may be administered remotely.
Scale
May be Administered Via Phone or Video Conference
ADCS-MCI-ADL-24
Yes
CDR
Yes
C-SSRS
Yes
EQ-5D-5L
Yes
RBANS
No
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; EQ-5D-5L = EuroQol 5 Dimensions 5 Levels Health State Instrument; RBANS = Repeatable Battery for 
Assessment of Neuropsychological Status
Section 5.3.1.2  Collection and Handling of Biomarker and Pharmacogenetic 
Research Samples
Subsection Blood and Optional CSF Biomarker 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 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 5.3.2.1  Collection of Samples for Analysis
Subsection Optional CSF Samples for ABBV-8E12 Assay
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 samples for ABBV-8E12/ADA assays and the optional CSF for the 
ABBV-8E12 assay may not be performed due to study modifications related to the 
COVID-19 pandemic, these samples should be obtained at the next onsite visit.
Section 5.3.3  Efficacy Variables
Previously read:
Exploratory efficacy measures are described in Section 5.3.1.1 along with other study 
procedures and will be derived from assessments of CDR, RBANS, ADCS-MCI-ADL-24, 
EQ-5D-5L, and digital measures of cognition, actigraphy, and sleep.
Has been changed to read:
Exploratory efficacy measures are described in Section 5.3.1.1 along with other study 
procedures and will be derived from assessments of CDR, RBANS, ADCS-MCI-ADL-24,  
and EQ-5D-5L.
 


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Section 5.3.6.1  Biomarker Research Variables
Subsection Volumetric MRI
Second sentence previously read:
Measurements will be obtained for whole brain, hippocampus, and lateral ventricles.
Has been changed to read:
The value itself for a given visit will be obtained by adding the baseline value to the value 
for change from baseline.  Measurements will be obtained for whole brain, hippocampus, 
temporal lobes, and lateral ventricles.
Section 5.3.6.1  Biomarker Research Variables
Subsection Volumetric MRI
Fourth, fifth, and sixth sentence previously read:
Measurement of changes from baseline will be obtained for two different definitions of 
baseline.  One definition of the baseline is the same as that for Study M15-566, the last 
measurement prior to the first dose of the study.  For the other definition, the baseline 
MRI will be that for the extension study itself, the last MRI of Study M15-566 or one 
done on Day 1 of this study, as explained in Section 5.1.
Has been changed to read:
The baseline measurement will be the same as the baseline measurement for 
Study M15-566, that is, the last measurement obtained before the first study drug 
administration of Study M15-566.
Section 5.3.6.1  Biomarker Research Variables
Subsection Retinal Amyloid Imaging
Delete:  subsection title and text
Retinal Amyloid Imaging
Retinal optical images will be collected from each eye at the time points indicated in the 
Study Activities table (Appendix C) and subjected to image analysis.  The results of the 
 


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retinal imaging test will be compared to Aβ PET imaging results and reported in a 
separate addendum study report.
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
For subjects who miss 3 or more study drug doses due to the COVID-19 pandemic, the 
TA MD should be contacted to discuss continuation in the study.
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
Third and fourth paragraph previously read:
The start and stop time of each study drug infusion will be recorded to the nearest minute.  
Refer to the Pharmacy Manual for detailed instructions.  
Home infusion visits may be available depending on local regulations, logistical, and 
procedural considerations, and the investigator's assessment of the subject's suitability.  
These considerations and other relevant information will be detailed in a separate manual 
describing this provision.
 


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Has been changed to read:
The start and stop time of each study drug infusion will be recorded to the nearest minute.  
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 IRB/IEC requirements for home healthcare.  
Any prerequisite submissions or notifications to the site IRB/IEC and local competent 
health authority should be made and approved prior to the implementation of home 
infusions.
Table 4.  Identity of Investigational Product
Previously read:
Investigational 
Product
Mode of 
Administration
Formulation
Strength
Manufacturer
ABBV-8E12
Infusion
Solution for 
infusion in a vial
1000 mg/10 mL
AbbVie 
Deutschland 
GmbH & Co. KG, 
Ludwigshafen, 
Germany
 


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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
1000 mg/10 mL
ABBV-8E12
Infusion
Solution for infusion in 
a vial
2000 mg/20 mL
Section 5.5.5  Blinding
Second paragraph, second and third sentence previously read:
For IP 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.
Has been changed to read:
For IP monitoring, there will be an unblinded AbbVie monitor for verification of 
unblinded documentation.  The unblinding procedure for the unblinded 
pharmacist/designee and the unblinded AbbVie monitor will be defined in a separate 
study-specific document.
Section 5.5.5  Blinding
Subsection Unblinding of Data for the Data Monitoring Committee
Second sentence previously read:
The DMC will have full access to all data PRN for safety assessment.
Has been changed to read:
The DMC will have full access to all data for safety assessment.
 


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Section 5.5.5  Blinding
Subsection Unblinding of Data for the Data Monitoring Committee
Seventh sentence previously read:
An AbbVie internal review committee (IRC) may request access to closed reports if the 
DMC recommends that the study be discontinued or that the study design undergo major 
modifications, as outlined in the DMC charter.
Has been changed to read:
The AbbVie Internal Executive Review Committee (IERC) may request access to closed 
reports if the DMC recommends that the study be discontinued or that the study design 
undergo major modifications, as outlined in the DMC charter.
Section 5.5.5  Blinding
Subsection Unblinding of Data for the Data Monitoring Committee
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 and the AbbVie IERC members will not be involved in any 
aspects of the trial or its management.
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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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.
Section 7.0  Protocol Deviations
Contact Information previously read:
Primary Contact:
Office:
Email:
Alternate Contact:
Office:
Mobile:
Fax:
Email:
 


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Has been changed to read:
Primary Contact:
Office:
Email:
Alternate Contact:
Mobile:
Email:
Section 8.1.1  Analysis Data Sets
Subsection Data Sets for Safety Analyses
Subsection title previously read:
Data Sets for Safety Analyses
Has been changed to read:
Data Set for Safety Analyses
Section 8.1.1  Analysis Data Sets
Subsection Data Sets for Safety Analyses
First paragraph
Delete:  last sentence
There are two safety data sets:  a stand-alone data set and a cumulative data set.
Section 8.1.1  Analysis Data Sets
Subsection Data Sets for Safety Analyses
Delete:  second and third paragraph
Stand-Alone Data Set:  The stand-alone data set is the primary data set for safety analyses, 
and will contain data from Study M15-570 only, regardless of the treatment received in 
Study M15-566.  Baseline for the stand-alone data set will be the last observation on or 
 


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before the first dose of ABBV-8E12 in Study M15-570.  If no Baseline is recorded in 
Study M15-570, the last value in Study M15-566 will be used as the Baseline.
Cumulative Data Set:  The cumulative data set will consist of data from both 
Study M15-566 and Study M15-570.  It is the secondary data set for safety analyses.  For 
subjects who were in the placebo group in Study M15-566, their safety data from 
Study M15-566 will not be included in the cumulative data set but their safety data from 
Study M15-570 will be included.  For subjects who were in the placebo group in 
Study M15-566, Baseline will be the last observation prior to the first dose of study drug 
in Study M15-570.  For subjects who were in ABBV-8E12 treatment sequences in 
Study M15-566, Baseline for the cumulative data set will be their Baseline in 
Study M15-566.
Section 8.1.1  Analysis Data Sets
Subsection Data Set for Biomarkers
Add:  new subsection title and text
Data Set for Biomarkers
The subjects of the data set for biomarkers will be all subjects who have biomarker data 
for at least one scheduled visit later than Visit 1 of Study M15-570.  The data of a subject 
included for the analysis of a biomarker variable will include the baseline value of 
Study M15-566, which will also be the baseline value for Study M15-570, and all the data 
of Study M15-570 after Day 1 (day of the first dose of Study M15-570).
Section 8.1.2  Disposition, Demographics, and Other Baseline Characteristics
Subsection Subject Disposition
First paragraph previously read:
The number and percentage of subjects contributed by each country and site will be 
summarized for each treatment sequence and for all treatment sequence combined for the 
stand-alone data set.
 


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Has been changed to read:
The number and percentage of subjects contributed by each country and site will be 
summarized for each treatment sequence and for all treatment sequence combined for the 
safety data set.
Section 8.1.2  Disposition, Demographics, and Other Baseline Characteristics
Subsection Subject Disposition
Second paragraph, first sentence previously read:
The number and percentage of subjects who prematurely discontinue study drug will be 
summarized by treatment sequence and overall for stand-alone data set for the primary 
reason as well as for all reasons collected.
Has been changed to read:
The number and percentage of subjects who prematurely discontinue study drug will be 
summarized by treatment sequence and overall for safety data set for the primary reason 
as well as for all reasons collected.
Section 8.1.2  Disposition, Demographics, and Other Baseline Characteristics
Subsection Demographic and Other Baseline Characteristics
Last paragraph, first sentence previously read:
Efficacy and clinical measures taken at baseline (CDR-SB score, RBANS, 
ADCS-MCI-ADL-24, EQ-5D-5L, and exploratory measures of cognition, actigraphy, and 
sleep) will be summarized for the ITT data set only.
Has been changed to read:
Efficacy and clinical measures taken at baseline (CDR-SB score, RBANS, 
ADCS-MCI-ADL-24, and EQ-5D-5L) will be summarized for the ITT data set only.
 


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Section 8.1.2  Disposition, Demographics, and Other Baseline Characteristics
Subsection Medical History
Previously read:
Medical history data, including subject's history of early AD or MCI, will be summarized 
for the stand-alone data set using body systems and conditions/diagnoses as captured on 
the eCRF.
Has been changed to read:
Medical history data, including subject's history of early AD or MCI, will be summarized 
for the safety data set using body systems and conditions/diagnoses as captured on the 
eCRF.
Section 8.1.2  Disposition, Demographics, and Other Baseline Characteristics
Subsection Previous and Concomitant Medications
First sentence previously read:
Prior and concomitant medications will be coded by the most recent World Health 
Organization (WHO) Drug dictionary, and will be summarized by treatment sequence for 
the stand-alone data set.
Has been changed to read:
Prior and concomitant medications will be coded by the most recent World Health 
Organization (WHO) Drug dictionary, and will be summarized by treatment sequence for 
the safety data set.
Section 8.1.3  Efficacy Analyses
Second paragraph, first sentence previously read:
Analyses of the efficacy variables CDR-SB score, ADCS-MCI-ADL-24 total score, 
RBANS total scores, EQ-5D-5L score, and the relevant cognition, actigraphy, and sleep 
variables will be performed on the Study M15-570 ITT data set.
 


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Has been changed to read:
Analyses of the efficacy variables CDR-SB score, ADCS-MCI-ADL-24 total score, 
RBANS total scores, and EQ-5D-5L score will be performed on the Study M15-570 ITT 
data set.
Section 8.1.4  Safety Analyses
First, second, and third paragraph previously read:
Comparisons between treatment sequences (Studies M15-566/M15-570) of interest will 
be performed with a 2-sided test at the significance level of 0.050 unless otherwise 
specified.  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.
Unless otherwise specified, differences between treatment sequences in continuous safety 
variables (e.g., change from baseline to final observation on laboratory tests) will be 
assessed using an ANOVA model with treatment sequence as the main effect, and the 
differences between treatment sequences in binary safety variables will be evaluated using 
Fisher's exact test.
A treatment-emergent adverse event (TEAE) is defined as any AE that begins or worsens 
in severity on or after the date of the first dose of study drug and no more than 20 weeks 
after the date of the last study dose.
Has been changed to read:
Comparisons between treatment sequences (Study M15-566 and Study M15-570) of 
interest will not be performed.
Section 8.1.4.2  Analysis of Adverse Events
First paragraph previously read:
The stand-alone data set will be the primary data set for the AE summary.  Analyses that 
will be performed on the cumulative data set include the following:  Adverse event 
overview, AE incidence by Medical Dictionary for Regulatory Activities (MedDRA) 
 


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system organ class (SOC) and preferred term (PT), AE incidence in descending frequency 
by overall subjects, and SAE incidence by SOC and PT.
Has been changed to read:
The safety data set will be used for the AE summary.
Section 8.1.4.2  Analysis of Adverse Events
Second paragraph, second sentence previously read:
The number and percentage of subjects who report TEAEs will be tabulated by the SOC 
and preferred term for the treatment sequences specified in Section 8.0.  
Has been changed to read:
The number and percentage of subjects who report treatment-emergent adverse events 
(TEAEs) will be tabulated by the SOC and preferred term for the treatment sequences 
specified in Section 8.0.
Section 8.1.4.2  Analysis of Adverse Events
Add:  new last paragraph
A TEAE is defined as any AE that begins or worsens in severity on or after the date of the 
first dose of study drug and no more than 20 weeks after the date of the last study dose.
Section 8.1.4.3  Analysis of Laboratory Tests
First paragraph, first sentence previously read:
Analysis will be performed on the stand-alone data set for laboratory tests.  
Has been changed to read:
Analysis will be performed on the safety data set for laboratory tests.  
Section 8.1.4.4  Analysis of Vital Signs and Weight
First paragraph, first sentence previously read:
Analysis will be performed on the stand-alone data set for vital signs and weight.  
 


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Has been changed to read:
Analysis will be performed on the safety data set for vital signs and weight.  
Section 8.1.4.5  Analysis of ECG Variables
First paragraph, first sentence previously read:
Analysis of ECG variables will be performed on the stand-alone data set.  
Has been changed to read:
Analysis of ECG variables will be performed on the safety data set.  
Section 8.1.4.6  Analysis of C-SSRS
First sentence previously read:
Analysis of C-SSRS will be performed on the stand-alone data set.  
Has been changed to read:
Analysis of C-SSRS will be performed on the safety data set.  
Section 8.1.5  Biomarker Analyses
Second, third, and fourth paragraph previously read:
The scheduled times of measurement will include the baseline measurement.  For subjects 
who were treated with ABBV-8E12 in Study M15-566 and continuing the same treatment 
in Study M15-570, the baseline measurement will be the same as it was in 
Study M15-566, the last measurement prior to the first dose of the study.  For the 2 groups 
whose treatment in this study is a change from the treatment in Study M15-566, the 
baseline value will be that for the extension study itself, the last measurement of 
Study M15-566 or the predose measurement on Day 1 of Study M15-570, as explained in 
Section 5.1.  The descriptive statistics for a given time will provide information for both 
the data of the given time and the changes from Baseline, except for the vMRI variables, 
for which only a value for the change from Baseline will be available.
 


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For the CSF concentrations of total and free tau and their ratio and for the plasma 
concentrations of total tau and NFL, an MMRM analysis for scheduled measurements 
after the baseline assessment until Week 260 will be performed to compare the effects of 
the 1000 and 2000 mg doses of ABBV-8E12.  The data set will contain the data of the 
first 2 groups identified above.  The data set will also include data of the last group (those 
receiving placebo in Study M15-566, ABBV-8E12 2000 mg in Study M15-570) 
beginning with Week 120 of Study M15-570, but with a shift in time by 96 weeks for the 
purposes of this analysis so that the shifted time indicates the length of time on 
ABBV-8E12 past 96 weeks.  Thus, for this analysis, the Week 192 data of the last group 
will be considered the same as Week 96 data of the first 2 groups.  The Week 120 data of 
the last group will be considered the same as Week 24 data of the first 2 groups.  Data of 
the last group of Week 96 and earlier will not be included for this analysis.  
The model for the MMRM analysis performed for the tau variables and plasma NFL will 
include classification by ABBV-8E12 dose and by time of measurement.  There will be an 
effect for the interaction of ABBV-8E12 dose and time of measurement.  Except for the 
ratio of CSF free tau concentration to CSF total concentration, the baseline value will be a 
covariate.  For the ratio of CSF free to total tau, the total tau baseline concentration will be 
a covariate if this variable is found to be a significant covariate for the ratio in 
Study M15-566.  The model will also have an effect to distinguish between subjects who 
were assigned to ABBV-8E12 treatment in Study M15-566 and those who were assigned 
to placebo in Study M15-566.  The subjects in each treatment sequence will be viewed as 
a random sample and an appropriate structure for the covariance matrix of the 
measurements of a subject will be selected.
Has been changed to read:
The scheduled times of measurement will include the baseline measurement.  The 
baseline measurement will be the same as the baseline measurement for Study M15-566, 
that is, the last measurement obtained before the first study drug administration of 
Study M15-566.
 


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For CSF free tau, total tau, the ratio of free tau to total tau, and plasma total tau and NFL, 
a MMRM analysis will be performed for the planned times of assessment after the 
first dose of study drug administration in Study M15-570.  The model will include 
classification by treatment (one of the 4 treatment sequences described above) and by time 
of measurement.  There will be an effect for the interaction of treatment and time of 
measurement.  Except for the ratio of CSF free tau concentration to CSF total tau 
concentration, the baseline value will be a covariate.  For the ratio of CSF free to total tau, 
the total tau baseline concentration will be a covariate if this variable is found to be a 
significant covariate for the ratio in Study M15-566.  The subjects in each treatment 
sequence will be viewed as a random sample, and an appropriate structure for the 
covariance matrix of the measurements of a subject will be selected.
Section 8.1.5  Biomarker Analyses
Subsection Volumetric MRI Variables
Previously read:
Descriptive statistics will be provided for the baseline value and the change from baseline 
for volumetric MRI variables for each of the scheduled times of measurement.  For each 
variable, an MMRM analysis will be performed for the changes from baseline.  The 
model will be much like that described for plasma total tau concentration, but with 
estimated total intracranial volume (eTIV) as a covariate in addition to the baseline value.  
An appropriate structure for the covariance matrix will be selected.  For each of whole 
brain, hippocampus, lateral ventricles and possibly other brain regions, the relationship 
with the primary efficacy variable CDR-SB, and possibly other efficacy variables, will be 
explored.
Has been changed to read:
For each MRI variable, descriptive statistics will be provided for the baseline values, the 
values at the scheduled times of measurement after study drug administration in 
Study M15-570 begins, and changes from baseline at the scheduled times of 
measurement.  An MMRM analysis will be performed on the changes from baseline.  The 
analysis will be much like that described for plasma total tau concentration, but with 
 


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estimated total intracranial volume (eTIV) as a covariate in addition to the baseline value.  
An appropriate structure for the covariance matrix will be selected.  For each of whole 
brain, hippocampus, temporal lobes, lateral ventricles and possibly other brain regions, the 
relationship with the primary efficacy variable CDR-SB, and possibly other efficacy 
variables, will be explored.
Section 8.1.8  Safety Interim Analysis
Fifth, 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 internal review committee 
(IRC) if unblinded data review is required.  The DMC, IRC, SDAC, and ERAC 
membership and responsibilities will be documented in the DMC charter.
Has been changed to read:
After each DMC meeting, the chair of the DMC will communicate its recommendations 
to the designated AbbVie Primary Contact, as described in the DMC charter.  The AbbVie 
Primary Contact will triage the recommendations to either the AbbVie study team if the 
recommendation can be implemented without unblinded data review or the Internal 
Executive Review Committee (IERC) if unblinded data review is required.  The DMC, 
IERC, SDAC, and ERAC membership and responsibilities will be documented in the 
DMC charter.
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 
 


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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 IRB/IEC.  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
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.
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 IRB/IEC, and the study site.
Section 15.0  Reference List
Item 13 previously read:
Schrag A, Selai C, Quinn N, et al.  Measuring quality of life in progressive supranuclear 
palsy.  In:  Jenkinson C, Peters M, Bromberg M, editors.  Quality of Life Measurement in 
Neurodegenerative and Related Conditions.  Cambridge:  Cambridge University Press; 
2011.  P. 52-9.
Has been changed to read:
Jönsson L, Andreasen N, Kilander L, et al.  Patient- and proxy-reported utility in 
Alzheimer disease using the EuroQoL.  Alzheimer Dis Assoc Disord.  2006;20(1):49-55.
 


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Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical
Clinical
Clinical
Clinical
Statistics
Statistics
Pharmacokinetics
Medical Writing
Has been changed to read:
Name
Title
Functional Area
Neuroscience
Clinical Program Development
Statistics
Statistics
Pharmacokinetics
Medical Writing
 


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Appendix C.  Study Activities
Previously read:
Dose
Year 1
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
Dose 
14
Visits & Proceduresa
Day 1/
Baseline
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
40
Wk 
44
Wk 
48
Wk
52
Subject/study partner ICFb
X
Medical history updatec
X
Treatment assignment
X
Physical examination
Xd
X
Retinal imaging scane
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weightf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examination
Xd
X
X
X
12-lead ECG 
Xd
X
X
X
Clinical laboratory tests
Xd
X
X
X
Brain MRI
Xd
X
X
X
Optional LP/CSF collection
Xd
X
Tau PETg
Xd
X
Blood sample for ABBV-8E12 assay
Xd
X
X
X
ADA sample
Xd
X
X
X
Plasma and serum biomarker sample
Xd
X
X
X
 


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Dose
Year 1
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
Dose 
14
Visits & Proceduresa
Day 1/
Baseline
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
40
Wk 
44
Wk 
48
Wk
52
Optional PG DNA and RNA sampleh
Xd
X
X
X
Administer IV study druga
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CDRi
Xd
X
X
RBANSi
Xd
X
ADCS-MCI-ADL-24i
Xd
X
EQ-5D-5Li
X
X
C-SSRSf,i
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Digital measurements of cognition, 
actigraphy, and sleepj
Xj
Xj
Xj
Concomitant medications reviewf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessmentf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 


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EudraCT 2018-000268-26
159
Dose
Year 2
Dose
15
Dose 
16
Dose 
17
Dose 
18
Dose 
19
Dose 
20
Dose 
21
Dose 
22
Dose 
23
Dose 
24
Dose 
25
Dose 
26
Dose 
27
Visits & Proceduresa
Wk
56
Wk
60
Wk
64
Wk
68
Wk
72
Wk
76
Wk
80
Wk
84
Wk
88
Wk
92
Wk
96
Wk
100
Wk
104
Subject/study partner ICFb
Medical history updatec
Treatment assignment
Physical examination
X
Retinal imaging scane
X
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weightf
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examination
X
X
12-lead ECG 
X
Clinical laboratory tests
X
X
Brain MRI 
X
X
Optional LP/CSF collection
X
Tau PETg
X
Blood sample for ABBV-8E12 assay 
X
X
ADA sample
X
X
Plasma and serum biomarker sample
X
X
Optional PG DNA and RNA sampleh
X
X
Administer IV study druga
X
X
X
X
X
X
X
X
X
X
X
X
X
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
160
Dose
Year 2
Dose
15
Dose 
16
Dose 
17
Dose 
18
Dose 
19
Dose 
20
Dose 
21
Dose 
22
Dose 
23
Dose 
24
Dose 
25
Dose 
26
Dose 
27
Visits & Proceduresa
Wk
56
Wk
60
Wk
64
Wk
68
Wk
72
Wk
76
Wk
80
Wk
84
Wk
88
Wk
92
Wk
96
Wk
100
Wk
104
CDRi
X
X
RBANSi
X
ADCS-MCI-ADL-24i
X
EQ-5D-5Li
X
C-SSRSf,i
X
X
X
Digital measurements of cognition, actigraphy, and 
sleepj
Xj
Xj
Concomitant medications reviewf
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessmentf
X
X
X
X
X
X
X
X
X
X
X
X
X
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
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Dose
Year 3
Dose 
28
Dose 
29
Dose 
30
Dose 
31
Dose 
32
Dose 
33
Dose 
34
Dose 
35
Dose 
36
Dose 
37
Dose 
38
Dose 
39
Dose 
40
Visits & Proceduresa
Wk
108
Wk
112
Wk
116
Wk
120
Wk
124
Wk
128
Wk
132
Wk
136
Wk
140
Wk
144
Wk
148
Wk
152
Wk
156
Subject/study partner ICFb
Medical history updatec
Treatment assignment
Physical examination
X
Retinal imaging scane
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weightf
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examination
X
X
12-lead ECG 
X
Clinical laboratory tests
X
Brain MRI 
X
X
Optional LP/CSF collection
Tau PETg
X
Blood sample for ABBV-8E12 assay 
X
X
ADA sample
X
X
Plasma and serum biomarker sample
X
X
Optional PG DNA and RNA sampleh
X
X
Administer IV study druga
X
X
X
X
X
X
X
X
X
X
X
X
X
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
162
Dose
Year 3
Dose 
28
Dose 
29
Dose 
30
Dose 
31
Dose 
32
Dose 
33
Dose 
34
Dose 
35
Dose 
36
Dose 
37
Dose 
38
Dose 
39
Dose 
40
Visits & Proceduresa
Wk
108
Wk
112
Wk
116
Wk
120
Wk
124
Wk
128
Wk
132
Wk
136
Wk
140
Wk
144
Wk
148
Wk
152
Wk
156
CDRi
X
X
RBANSi
X
ADCS-MCI-ADL-24i
X
EQ-5D-5Li
X
C-SSRSf,i
X
X
X
Digital measurements of cognition, actigraphy, 
and sleepj
Xj
Xj
Concomitant medications reviewf
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessmentf
X
X
X
X
X
X
X
X
X
X
X
X
X
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
163
Dose
Year 4
Dose
41
Dose
42
Dose
43
Dose
44
Dose
45
Dose
46
Dose
47
Dose
48
Dose
49
Dose
50
Dose
51
Dose
52
Dose
53
Visits & Proceduresa
Wk 
160
Wk 
164
Wk 
168
Wk 
172
Wk 
176
Wk 
180
Wk 
184
Wk 
188
Wk 
192
Wk 
196
Wk 
200
Wk 
204
Wk 
208
Subject/study partner ICFb
Medical history updatec
Treatment assignment
Physical examination
X
Retinal imaging scane
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weightf
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examination
X
X
12-lead ECG 
X
Clinical laboratory tests
X
Brain MRI
X
X
Optional LP/CSF collection
Tau PETg
X
Blood sample for ABBV-8E12 assay 
X
X
ADA sample
X
X
Plasma and serum biomarker sample
X
X
Optional PG DNA and RNA sampleh
X
X
Administer IV study druga
X
X
X
X
X
X
X
X
X
X
X
X
X
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
164
Dose
Year 4
Dose
41
Dose
42
Dose
43
Dose
44
Dose
45
Dose
46
Dose
47
Dose
48
Dose
49
Dose
50
Dose
51
Dose
52
Dose
53
Visits & Proceduresa
Wk 
160
Wk 
164
Wk 
168
Wk 
172
Wk 
176
Wk 
180
Wk 
184
Wk 
188
Wk 
192
Wk 
196
Wk 
200
Wk 
204
Wk 
208
CDRi
X
X
RBANSi
X
ADCS-MCI-ADL-24i
X
EQ-5D-5Li
X
C-SSRSf,i
X
X
X
Digital measurements of cognition, actigraphy, 
and sleepi
Xi
Xi
Concomitant medications reviewf
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessmentf
X
X
X
X
X
X
X
X
X
X
X
X
X
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
165
Dose
Year 5
Dose 
54
Dose 
55
Dose 
56
Dose 
57
Dose 
58
Dose 
59
Dose 
60
Dose 
61
Dose 
62
Dose 
63
Dose 
64
Dose 
65
Wk 260/
Study 
Completion 
PD Visit
20 Wk
Post-Last 
Dosek Follow-
Up Visit
Visits & Proceduresa
Wk 
212
Wk 
216
Wk 
220
Wk 
224
Wk 
228
Wk 
232
Wk 
236
Wk 
240
Wk 
244
Wk 
248
Wk 
252
Wk 
256
Subject/study partner ICFb
Medical history updatec
Treatment assignment
Physical examination
X
Retinal imaging scane
X
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weightf
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examination
X
X
X
X
12-lead ECG 
X
Clinical laboratory tests
X
X
X
Brain MRI 
X
X
X
X
Optional LP/CSF collection
X
Tau PETg
X
Blood sample for 
ABBV-8E12 assay 
X
X
X
X
ADA sample
X
X
X
X
Plasma and serum biomarker 
sample
X
X
X
X
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
166
Dose
Year 5
Dose 
54
Dose 
55
Dose 
56
Dose 
57
Dose 
58
Dose 
59
Dose 
60
Dose 
61
Dose 
62
Dose 
63
Dose 
64
Dose 
65
Wk 260/
Study 
Completion 
PD Visit
20 Wk
Post-Last 
Dosek Follow-
Up Visit
Visits & Proceduresa
Wk 
212
Wk 
216
Wk 
220
Wk 
224
Wk 
228
Wk 
232
Wk 
236
Wk 
240
Wk 
244
Wk 
248
Wk 
252
Wk 
256
Optional PG DNA and RNA 
sampleh
X
X
X
Administer IV study druga
X
X
X
X
X
X
X
X
X
X
X
X
CDRi
X
X
X
X
RBANSi
X
X
ADCS-MCI-ADL-24i
X
EQ-5D-5Li
X
X
C-SSRSf,i
X
X
X
X
Digital measurements of 
cognition, actigraphy, and 
sleepj
Xj
Xj
Xj
Concomitant medications 
reviewf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessmentf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Wk = Week
a.
Study drug will be administered on Day 1/Baseline visit, and then every 4 weeks thereafter until 1 of the discontinuation criteria is met, until the sponsor discontinues the 
study, or until the study reaches completion.  Visits during the Treatment Period may be scheduled within ± 4 days.  All dosing visits may be completed over 2 consecutive 
days at the discretion of the investigator with the second day to include the start and end of the infusion.
b.
Subject informed consent, or as applicable, legally authorized representative informed consent and subject assent, and study partner informed consent must be obtained prior 
to any Study M15-570 specific procedures being completed.
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
167
c.
Review medical history to confirm subject does not meet exclusion criteria prior to enrollment.
d.
Not required if procedure was conducted during the Week 96 visit in Study M15-566.  A repeat assessment/procedure may be required based on discussion with the TA MD if 
more than 4 weeks have passed since the Week 96 visit.
e.
Exploratory eye test for AD pathology may be conducted at participating sites and will be performed at Weeks 60 and 260 or Premature Discontinuation.
f.
Vital signs, body weight, C-SSRS, concomitant medications review and AE assessment to be completed prior to administration of infusion.  
g.
Subjects who did not complete tau PET imaging at Day 1/Baseline will have tau PET imaging performed at subsequent visits only after discussion with TA MD.  Tau PET 
imaging will only be collected for subjects at sites selected to participate in the tau PET assessment.
h.
Optional pharmacogenetic DNA and RNA samples require consent.  Verify consent prior to sample collection.
i.
The recommended order of administration is CDR followed by RBANS.  When applicable, ADCS-MCI-ADL-24, EQ-5D-5L, and C-SSRS may be subsequently 
administered/assessed in any order prior to study drug administration.
j.
Start of collection period for digital measures of cognition, actigraphy, and sleep.  Detailed instructions and other considerations will be provided in a separate manual.
k.
Post-treatment follow-up to occur approximately 20 weeks after the Completion or Premature Discontinuation (PD) visit.
Note:
for subjects who prematurely discontinue the study, safety and efficacy assessments may be conducted remotely (for example, via telephone), where applicable.
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
168
Has been changed to read:
Dose
Year 1
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
Dose 
14
Visits & Proceduresa
Day 1/
Baseline
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
40
Wk 
44
Wk 
48
Wk 
52
Subject/study partner ICFb
X
Medical history updatec
X
Treatment assignment
X
Physical examination
Xd
X
Vital signse
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weighte
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examination
Xd
X
X
X
12-lead ECG 
Xd
X
X
X
Clinical laboratory tests
Xd
X
X
X
Brain MRI
Xd
X
X
X
Optional LP/CSF collection
Xd
X
Tau PETf
Xd
X
Blood sample for ABBV-8E12 assay
Xd
X
X
X
ADA sample
Xd
X
X
X
Plasma and serum biomarker sample
Xd
X
X
X
Optional PG DNA and RNA sampleg
Xd
X
X
X
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
169
Dose
Year 1
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
Dose 
14
Visits & Proceduresa
Day 1/
Baseline
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
40
Wk 
44
Wk 
48
Wk 
52
Administer IV study druga
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CDRh
Xd
X
X
RBANSh
Xd
X
ADCS-MCI-ADL-24h
Xd
X
EQ-5D-5Lh
X
X
C-SSRSe,h
Xd
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications reviewe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessmente
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
170
Dose
Year 2
Dose
15
Dose 
16
Dose 
17
Dose 
18
Dose 
19
Dose 
20
Dose 
21
Dose 
22
Dose 
23
Dose 
24
Dose 
25
Dose 
26
Dose 
27
Visits & Proceduresa
Wk
56
Wk
60
Wk
64
Wk
68
Wk
72
Wk
76
Wk
80
Wk
84
Wk
88
Wk
92
Wk
96
Wk
100
Wk
104
Subject/study partner ICFb
Medical history updatec
Treatment assignment
Physical examination
X
Vital signse
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weighte
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examination
X
X
12-lead ECG 
X
Clinical laboratory tests
X
X
Brain MRI 
O
X
Optional LP/CSF collection
X
Tau PETf
X
Blood sample for ABBV-8E12 assay 
X
X
ADA sample
X
X
Plasma and serum biomarker sample
X
X
Optional PG DNA and RNA sampleg
X
X
Administer IV study druga
X
X
X
X
X
X
X
X
X
X
X
X
X
CDRh
X
X
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
171
Dose
Year 2
Dose
15
Dose 
16
Dose 
17
Dose 
18
Dose 
19
Dose 
20
Dose 
21
Dose 
22
Dose 
23
Dose 
24
Dose 
25
Dose 
26
Dose 
27
Visits & Proceduresa
Wk
56
Wk
60
Wk
64
Wk
68
Wk
72
Wk
76
Wk
80
Wk
84
Wk
88
Wk
92
Wk
96
Wk
100
Wk
104
RBANSh
X
ADCS-MCI-ADL-24h
X
EQ-5D-5Lh
X
C-SSRSe,h
X
X
X
Concomitant medications reviewe
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessmente
X
X
X
X
X
X
X
X
X
X
X
X
X
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
172
Dose
Year 3
Dose 
28
Dose 
29
Dose 
30
Dose 
31
Dose 
32
Dose 
33
Dose 
34
Dose 
35
Dose 
36
Dose 
37
Dose 
38
Dose 
39
Dose 
40
Visits & Proceduresa
Wk
108
Wk
112
Wk
116
Wk
120
Wk
124
Wk
128
Wk
132
Wk
136
Wk
140
Wk
144
Wk
148
Wk
152
Wk
156
Subject/study partner ICFb
Medical history updatec
Treatment assignment
Physical examination
X
Vital signse
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weighte
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examination
X
X
12-lead ECG 
X
Clinical laboratory tests
X
Brain MRI 
O
X
Optional LP/CSF collection
Tau PETf
X
Blood sample for ABBV-8E12 assay 
X
X
ADA sample
X
X
Plasma and serum biomarker sample
X
X
Optional PG DNA and RNA sampleg
X
X
Administer IV study druga
X
X
X
X
X
X
X
X
X
X
X
X
X
CDRh
X
X
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
173
Dose
Year 3
Dose 
28
Dose 
29
Dose 
30
Dose 
31
Dose 
32
Dose 
33
Dose 
34
Dose 
35
Dose 
36
Dose 
37
Dose 
38
Dose 
39
Dose 
40
Visits & Proceduresa
Wk
108
Wk
112
Wk
116
Wk
120
Wk
124
Wk
128
Wk
132
Wk
136
Wk
140
Wk
144
Wk
148
Wk
152
Wk
156
RBANSh
X
ADCS-MCI-ADL-24h
X
EQ-5D-5Lh
X
C-SSRSe,h
X
X
X
Concomitant medications reviewe
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessmente
X
X
X
X
X
X
X
X
X
X
X
X
X
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
174
Dose
Year 4
Dose
41
Dose
42
Dose
43
Dose
44
Dose
45
Dose
46
Dose
47
Dose
48
Dose
49
Dose
50
Dose
51
Dose
52
Dose
53
Visits & Proceduresa
Wk 
160
Wk 
164
Wk 
168
Wk 
172
Wk 
176
Wk 
180
Wk 
184
Wk 
188
Wk 
192
Wk 
196
Wk 
200
Wk 
204
Wk 
208
Subject/study partner ICFb
Medical history updatec
Treatment assignment
Physical examination
X
Vital signse
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weighte
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examination
X
X
12-lead ECG 
X
Clinical laboratory tests
X
Brain MRI
O
X
Optional LP/CSF collection
Tau PETf
X
Blood sample for ABBV-8E12 assay 
X
X
ADA sample
X
X
Plasma and serum biomarker sample
X
X
Optional PG DNA and RNA sampleg
X
X
Administer IV study druga
X
X
X
X
X
X
X
X
X
X
X
X
X
CDRh
X
X
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
175
Dose
Year 4
Dose
41
Dose
42
Dose
43
Dose
44
Dose
45
Dose
46
Dose
47
Dose
48
Dose
49
Dose
50
Dose
51
Dose
52
Dose
53
Visits & Proceduresa
Wk 
160
Wk 
164
Wk 
168
Wk 
172
Wk 
176
Wk 
180
Wk 
184
Wk 
188
Wk 
192
Wk 
196
Wk 
200
Wk 
204
Wk 
208
RBANSh
X
ADCS-MCI-ADL-24h
X
EQ-5D-5Lh
X
C-SSRSe,h
X
X
X
Concomitant medications reviewe
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessmente
X
X
X
X
X
X
X
X
X
X
X
X
X
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
176
Dose
Year 5
Dose 
54
Dose 
55
Dose 
56
Dose 
57
Dose 
58
Dose 
59
Dose 
60
Dose 
61
Dose 
62
Dose 
63
Dose 
64
Dose 
65
Wk 260/
Study 
Completion 
PD Visit
20 Wk
Post-Last 
Dosei Follow-
Up Visit
Visits & Proceduresa
Wk 
212
Wk 
216
Wk 
220
Wk 
224
Wk 
228
Wk 
232
Wk 
236
Wk 
240
Wk 
244
Wk 
248
Wk 
252
Wk 
256
Subject/study partner ICFb
Medical history updatec
Treatment assignment
Physical examination
X
Vital signse
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weighte
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examination
X
X
X
X
12-lead ECG 
X
Clinical laboratory tests
X
X
X
Brain MRI 
O
X
X
X
Optional LP/CSF collection
X
Tau PETf
X
Blood sample for 
ABBV-8E12 assay 
X
X
X
X
ADA sample
X
X
X
X
Plasma and serum biomarker 
sample
X
X
X
X
Optional PG DNA and RNA 
sampleg
X
X
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
177
Dose
Year 5
Dose 
54
Dose 
55
Dose 
56
Dose 
57
Dose 
58
Dose 
59
Dose 
60
Dose 
61
Dose 
62
Dose 
63
Dose 
64
Dose 
65
Wk 260/
Study 
Completion 
PD Visit
20 Wk
Post-Last 
Dosei Follow-
Up Visit
Visits & Proceduresa
Wk 
212
Wk 
216
Wk 
220
Wk 
224
Wk 
228
Wk 
232
Wk 
236
Wk 
240
Wk 
244
Wk 
248
Wk 
252
Wk 
256
Administer IV study druga
X
X
X
X
X
X
X
X
X
X
X
X
CDRh
X
X
X
X
RBANSh
X
X
ADCS-MCI-ADL-24h
X
EQ-5D-5Lh
X
X
C-SSRSe,h
X
X
X
X
Concomitant medications 
reviewe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessmente
X
X
X
X
X
X
X
X
X
X
X
X
X
X
O = Optional; Wk = Week
a.
Study drug will be administered on Day 1/Baseline visit, and then every 4 weeks thereafter until 1 of the discontinuation criteria is met, until the sponsor discontinues the 
study, or until the study reaches completion.  Visits during the Treatment Period may be scheduled within ± 4 days.  All dosing visits may be completed over 2 consecutive 
days at the discretion of the investigator with the second day to include the start and end of the infusion.
b.
Subject informed consent, or as applicable, legally authorized representative informed consent and subject assent, and study partner informed consent must be obtained prior 
to any Study M15-570 specific procedures being completed.
c.
Review medical history to confirm subject does not meet exclusion criteria prior to enrollment.
d.
Not required if procedure was conducted during the Week 96 visit in Study M15-566.  A repeat assessment/procedure may be required based on discussion with the TA MD 
or designee if subject is enrolling outside the 8 week window from the Week 92 visit in Study M15-566. 
e.
Vital signs, body weight, C-SSRS, concomitant medications review and AE assessment to be completed to administration of infusion.  
f.
Subjects who did not complete tau PET imaging through Study M15-566 and at Study M15-570 Day 1/Baseline will have tau PET imaging performed at subsequent visits 
only after discussion with TA MD or designee.  Tau PET imaging will only be collected for subjects at sites selected to participate in the tau PET assessment.
 


ABBV-8E12
M15-570 Protocol Amendment 2
EudraCT 2018-000268-26
178
g.
Optional pharmacogenetic DNA and RNA samples require consent.  Verify consent prior to sample collection.
h.
The recommended order of administration is CDR followed by RBANS.  When applicable, ADCS-MCI-ADL-24, EQ-5D-5L, and C-SSRS may be subsequently 
administered/assessed in any order.
i.
Post-treatment follow-up to occur approximately 20 weeks after the last dose.
Note:
For subjects who prematurely discontinue the study, safety and efficacy assessments may be conducted remotely (for example, via telephone), where applicable.
 

SAP_001.pdf: 
Tilavonemab (ABBV-8E12) 
M15-570 - Statistical Programming Plan 
                                 Version 2.0 -  30 July 2021 
1 
 
 
 
Statistical Programming Plan for 
 
Study M15-570 
An Extension Study of ABBV-8E12 in Early Alzheimer’s 
Disease 
 
Date:  30 July 2021 
 
Version 2.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NCT03712787


Tilavonemab (ABBV-8E12) 
M15-570 - Statistical Programming Plan 
                                 Version 2.0 -  30 July 2021 
2 
 
 
Table of Content 
 
1.0 
Purpose and Scope .................................................................. 3 
2.0 
Study-Specific Programming Guidelines .............................. 3 
2.1 
Definition of Analysis Sets ........................................................................ 3 
2.2 
Analysis Conventions ................................................................................ 3 
2.2.1 
Statistical Significance .............................................................................. 3 
2.2.2 
Visit Definitions ........................................................................................ 3 
3.0 
Version History ........................................................................ 7 
4.0 
Appendix .................................................................................. 8 
 
List of Tables 
Table 1  SPP Version History Summary.............................................................................. 7 
Table 2   List of tables and figures to be programmed ........................................................ 8 
 
 
 
 
 
 
 
 


Tilavonemab (ABBV-8E12) 
M15-570 - Statistical Programming Plan 
                                 Version 2.0 -  30 July 2021 
3 
 
1.0 
Purpose and Scope 
This statistical programming plan (SPP) provides details to further elaborate some statistical 
methods as outlined in the statistical analyses plan (SAP) version 2.0 for M15-570 study. The 
document describes analysis conventions to guide the statistical programming work. The analysis 
will be completed by AbbVie Data and Statistical Sciences for tilavonemab (ABBV-8E12) Study 
Protocol M15-570. 
2.0 
Study-Specific Programming Guidelines 
2.1 
Definition of Analysis Sets 
Data Set for Safety Analyses 
The safety data set will contain data from Study M15-570 only, regardless of the treatment 
received in Study M15-566.  Baseline for the safety data set will be the last observation before 
the first dose of tilavonemab in Study M15-570.  If no baseline is recorded in Study M15-570, 
the last value in Study M15-566 will be used as the baseline. 
2.2 
Analysis Conventions 
2.2.1 
Statistical Significance 
Unless otherwise specified, statistical tests will be two-sided for efficacy and safety analyses at 
0.05 level.   
2.2.2 
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 first study drug dose day; Rx Day is a positive value when 


Tilavonemab (ABBV-8E12) 
M15-570 - Statistical Programming Plan 
                                 Version 2.0 -  30 July 2021 
4 
 
the time point of interest is on or after the first study drug dose day.  There is no Rx Day 0.  With 
this defined algorithm, the day of the first dose of study drug will be Rx Day 1. 
RxEnd 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:  RxEnd Day = date of time point – 
last dose date.  With this defined algorithm, the day of the last dose of study drug will be RxEnd 
Day 0. 
Definition of Baseline and Final Observation 
For primary efficacy analyses on the ITT data set and for safety analyses on the safety data set of 
the Treatment Period, "baseline" shall refer to the last non-missing observation prior to the first 
dose of study drug of Study M15-570. 
• If the duration between Day 1 of Study M15-570 and the last dose (Week 92) of Study 
M15-566 is less than or equal to 45 days and no M15-570 Day 1 visit data, vital sign, 
laboratory, MRI,  and questionnaire data at visit Week 96 of  Study M15-566 will be used 
as the baseline for Study M15-570. If  M15-570 Day 1 visit data are available, Day 1 visit 
data will be used as the baseline.  
• If the duration between Day 1 of M15-570 and the last dose (Week 92) of Study M15-
566 is larger than 45 days, Day 1 visit data of Study M15-570 of vital sign, laboratory, 
MRI, and questionnaire data will be the baseline.  If M15-570 Day 1 visit data are not 
available, the last available data from M15-566 will be used as the baseline. 
• Day 1 visit data of M15-570 will always be the baseline of Study M15-570 for all other 
data (Adverse Event, ECG) and will not be impacted by the duration between Day 1 visit 
of Study M15-570 and Week 92 visit of Study M15-566. 
For all safety analyses, "final" for the Treatment Period shall refer to the last non-missing 
observation in the Treatment Period but no more than 45 days after the last dose of the study 
drug for safety variables.  The "final" for the post-treatment follow-up period for safety variables 


Tilavonemab (ABBV-8E12) 
M15-570 - Statistical Programming Plan 
                                 Version 2.0 -  30 July 2021 
5 
 
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. 
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 treatment 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 post-baseline visit is 7 times “X”  
where “X” is visit week number. For example, the nominal day for Week 12 visit is 7*12=84.   
For measurements that are planned to be collected at Weeks 12, 24, 48, 72, 96, 144, 192, 240, 
and 260, i.e. clinical laboratory tests, observations will be mapped to an analysis “Week” 
according to the following windows defined by Rx day. 
Week 12  
Rx Days 2 through 126 
Week 24  
Rx Days 127 through 252 
Week 48  
Rx Days 253 through 420 
Week 72      
Rx Days 421 through 588 
Week 96  
Rx Days 589 through 840 
Week 144      
Rx Days 841 through 1176 
Week 192  
Rx Days 1177 through 1512 
Week 240             Rx Days 1513 through 1750 
Week 260     
Rx Days > 1750 
For measurements that are planned to be collected at Weeks 12, 24, 48, 72, 96, 120, 144, 168, 
192, 216, 240 and 260, i.e. Brain MRI, observations will be mapped to an analysis “Week” 
according to the following windows defined by Rx day. 
Week 12  
Rx Days 2 through 126 
Week 24  
Rx Days 127 through 252 


Tilavonemab (ABBV-8E12) 
M15-570 - Statistical Programming Plan 
                                 Version 2.0 -  30 July 2021 
6 
 
Week 48                Rx Days 253 through 420 
Week 72   
Rx Days 421 through 588 
Week 96  
Rx Days 589 through 756 
Week 120  
Rx Days 757 through 924 
Week 144  
Rx Days 925 through 1092 
Week 168      
Rx Days 1093 through 1260 
Week 192      
Rx Days 1261 through 1428 
Week 216     
Rx Days 1429 through 1596 
Week 240     
Rx Days 1597 through 1750 
Week 260              Rx Days > 1750 
For measurements that are planned to be collected at Weeks 4, 4n (n=2, 3, …12), 52, 72, 96, 104, 
120, 144, 156, 168, 192, 208, 216, 240 and 260, i.e. body weight and C-SSRS, observations will 
be mapped to an analysis "Week" according to the following windows defined by Rx day. 
                  Week 4                  Rx Days 2 through 42 
Week 4n  
Rx Days 7*((n-1)*4+2)+1 through 7*(n*4+2) 
Week 52   
Rx Days 351 through 434 
Week 72   
Rx Days 435 through 588 
Week 96  
Rx Days 589 through 700 
Week 104  
Rx Days 701 through 756 
Week 120  
Rx Days 757 through 924 
Week 144  
Rx Days 925 through 1050 
Week 156  
Rx Days 1051 through 1134 
Week 168      
Rx Days 1135 through 1260 
Week 192      
Rx Days 1261 through 1400 
Week 208  
Rx Days 1401 through 1484 
Week 216             Rx Days 1485 through 1596 
Week 240             Rx Days 1597 through 1750 
Week 260             Rx Days > 1750 


Tilavonemab (ABBV-8E12) 
M15-570 - Statistical Programming Plan 
                                 Version 2.0 -  30 July 2021 
7 
 
For safety assessments that are planned to be collected during post-treatment follow-up period, 
observations will be mapped to an analysis “Week” according to the following windows defined 
by RxEnd day. 
             Post-Treatment Week 20 
45< RxEnd Days ≤140 
 
If more than 1 observation is included in a visit time window, the non-missing observation 
closest to the nominal day will be used in analyses.  If more than 1 observation occurs on the 
same day, the average will be calculated and used in analyses. 
3.0 
Version History 
Table 1  SPP Version History Summary 
Version 
Date of Approval 
Summary 
1.0 
10 Feb 2021 
Initial version 
2.0 
30 Jul 2021 
• 
Removed contents related to efficacy, biomarker 
analysis, PK analysis, and some safety sections to 
align with update SAP v2.0 for abbreviated CSR 
• 
Update TOC for abbreviated CSR 


Tilavonemab (ABBV-8E12) 
M15-570 - Statistical Programming Plan 
                                 Version 2.0 -  30 July 2021 
8 
 
4.0 
Appendix 
Table 22   List of tables and figures to be programmed 
Table 
Title 
TABLE 14.1__1 
SUBJECTS DISPOSITION (ALL ENROLLED SUBJECTS) 
TABLE 14.1__2.1 
ACCOUNTABILITY BY INVESTIGATOR (ALL ENROLLED SUBJECTS) 
TABLE 14.1__2.2 
SUMMARY OF REASONS FOR STUDY DISCONTINUATION (ALL ENROLLED SUBJECTS) 
TABLE 14.1__2.3 
SUMMARY OF REASONS FOR STUDY DRUG DISCONTINUATION (SAFETY DATA SET) 
TABLE 14.1__2.4 
LISING OF SUBJECTS WHO MISSED ≥ 3 STUDY DRUG INFUSIONS DUE TO COVID-19 PANDEMIC (Safety DATA SET) 
TABLE 14.1__2.5 
LISTING OF SUBJECTS NUMBERS, INVESTIGATIONAL SITE NAMES, AND VISIT INFORMATION FOR SUBJECTS WHO RECEIVED 
REMOTE VIRTUAL VISITS DUE TO COVID-19 PANDEMIC (SAFETY DATA SET)   
TABLE 14.1__2.6 
LISTING OF SUBJECTS NUMBERS, INVESTIGATIONAL SITE NAMES, AND VISIT INFORMATION FOR SUBJECTS WHO RECEIVED 
REMOTE VIRTUAL VISITS DUE TO COVID-19 PANDEMIC (SAFETY DATA SET)   
TABLE 14.1__3.1 
DEMOGRAPHIC CHARACTERISTICS - PART 1 (GENDER, RACE, ETHNICITY, AGE GROUPS AND BODY MASS INDEX GROUPS) 
(SAFETY DATA SET) 
TABLE 14.1__3.2 
DEMOGRAPHIC CHARACTERISTICS - PART 2 (AGE, WEIGHT, HEIGHT AND BODY MASS INDEX) (SAFETY DATA SET) 
TABLE 14.1__3.3 
DEMOGRAPHIC CHARACTERISTICS - PART 3 (ALCOHOL AND TOBACCO USE) (SAFETY DATA SET) 
TABLE 14.1__4 
SUMMARY OF BASELINE CHARACTERISTICS (ITT DATA SET) 
TABLE 14.1__5.1 
SUMMARY OF MEDICAL/SURGICAL HISTORY BY BODY SYSTEM AND CONDITION/DIAGNOSIS (SAFETY DATA SET) 
TABLE 14.1__5.2 
SUMMARY OF ALZHEIMER’S DISEASE HISTORY (SAFETY DATA SET) 
TABLE 14.1__5.3 
SUMMARY OF ALZHEIMER’S DISEASE FAMILY HISTORY (SAFETY DATA SET) 
TABLE 14.1__6 
SUMMARY OF PREVIOUS AND CONCOMITANT MEDICATION USE (SAFETY DATA SET) 
TABLE 14.1__7.1 
NUMBER OF SUBJECTS FOR STUDY DRUG INFUSIONS (SAFETY DATA SET) 
TABLE 14.1__7.2 
SUMMARY OF STUDY DRUG EXPOSURE (DAYS) (SAFETY DATA SET) 
TABLE 14.1__7.3 
SUMMARY OF MEAN VOLUME PERCENTAGE OF ADMINISTERED STUDY DRUG INFUSIONS (SAFETY DATA SET) 


Tilavonemab (ABBV-8E12) 
M15-570 - Statistical Programming Plan 
                                 Version 2.0 -  30 July 2021 
9 
 
TABLE 14.1__7.4 
SUMMARY OF TILOVANEMAB EXPOSURE AFFECTED BY COVID-19 PANDEMIC (SAFETY DATA SET) 
TABLE 14.3__1.1 
OVERVIEW OF TREATMENT-EMERGENT ADVERSE EVENTS AND ALL DEATHS (SAFETY DATA SET) 
TABLE 14.3__1.2 
NUMBER AND PERCENTAGE OF SUBJECTS WITH TREATMENT-EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN CLASS AND 
PREFERRED TERM (SAFETY DATA SET) 
TABLE 14.3__1.3 
NUMBER AND PERCENTAGE OF SUBJECTS WITH TREATMENT-EMERGENT ADVERSE EVENTS ASSESSED BY THE INVESTIGATOR 
AS HAVING REASONABLE POSSIBILITY OF BEING RELATED TO STUDY DRUG BY SYSTEM ORGAN CLASS AND PREFERRED TERM 
(SAFETY DATA SET) 
TABLE 14.3__1.4 
SUBJECTS WITH TREATMENT-EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN CLASS, PREFERRED TERM AND MAXIMUM 
RELATIONSHIP TO STUDY DRUG (SAFETY DATA SET) 
TABLE 14.3__1.5 
SUBJECTS WITH TREATMENT-EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN CLASS, PREFERRED TERM AND MAXIMUM 
SEVERITY (SAFETY DATA SET) 
TABLE 14.3__1.6 
NUMBER AND PERCENTAGE OF SUBJECTS WITH TREATMENT-EMERGENT ADVERSE EVENTS BY PREFERRED TERM IN 
DESCENDING ORDER OF INCIDENCE (SAFETY DATA SET) 
TABLE 14.3__1.7.1 
LISTING OF SUBJECT NUMBERS ASSOCIATED WITH EACH PT FOR ALL TREATMENT-EMERGENT ADVERSE EVENTS (SAFETY 
DATA SET) 
TABLE 14.3__1.7.2 
LISTING OF SUBJECT NUMBERS ASSOCIATED WITH EACH PT FOR ALL TREATMENT-EMERGENT ADVERSE EVENTS ASSESSED BY 
THE INVESTIGATOR AS HAVING REASONABLE POSSIBILITY OF BEING RELATED (SAFETY DATA SET) 
TABLE 14.3__2.1.1 
NUMBER AND PERCENTAGE OF SUBJECTS WITH SERIOUS TREATMENT-EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN 
CLASS AND PREFERRED TERM (SAFETY DATA SET) 
TABLE 14.3__2.1.2 
LISTING OF SERIOUS ADVERSE EVENTS (SAFETY DATA SET) 
TABLE 14.3__2.2.1 
NUMBER AND PERCENTAGE OF SUBJECTS WITH TREATMENT-EMERGENT ADVERSE EVENTS LED TO DISCONTINUATION OF 
STUDY DRUG BY SYSTEM ORGAN CLASS AND PREFERRED TERM (SAFETY DATA SET) 
TABLE 14.3__2.2.2 
LISTING OF ADVERSE EVENTS THAT LED TO DISCONTINUATION OF STUDY DRUG (SAFETY DATA SET) 
TABLE 14.3__2.3.1 
NUMBER AND PERCENTAGE OF SUBJECTS WITH FATAL ADVERSE EVENTS INCLUDING EATHS BY SYSTEM ORGAN CLASS AND 
PREFERRED TERM (SAFETY DATA SET) 
TABLE 14.3__2.3.2 
LISTING OF FATAL ADVERSE EVENTS (SAFETY DATA SET) 
TABLE 14.3__2.4 
LISTING OF SUBJECT DEATHS (SAFETY DATA SET) 
TABLE 14.3__3.1 
NUMBER AND PERCENTAGE OF SUBJECTS MEETING CRITERIA FOR POTENTIALLY CLINICALLY SIGNIFICANT HEMATOLOGY 
(SAFETY DATA SET) 
TABLE 14.3__3.2 
LISTING OF SUBJECTS MEETING CRITERIA FOR POTENTIALLY CLINICALLY SIGNIFICANT HEMATOLOGY (SAFETY DATA SET) 
TABLE 14.3__4.1 
NUMBER AND PERCENTAGE OF SUBJECTS MEETING CRITERIA FOR POTENTIALLY CLINICALLY SIGNIFICANT CHEMISTRY 
(SAFETY DATA SET) 


Tilavonemab (ABBV-8E12) 
M15-570 - Statistical Programming Plan 
                                 Version 2.0 -  30 July 2021 
10 
 
TABLE 14.3__4.2 
LISTING OF SUBJECTS MEETING CRITERIA FOR POTENTIALLY CLINICALLY SIGNIFICANT CHEMISTRY (SAFETY DATA SET) 
TABLE 14.3__5 
SUMMARY OF C-SSRS (SAFETY DATA SET) 
TABLE 14.3__6.1 
SUMMARY OF NUMBER AND PERCENTAGE OF SUBJECTS PERTAINING CEREBRAL EDEMA, MICRO- AND MACRO-
HAEMORRHAGES, WHITE MATTER HYPERINTENSITIES (SAFETY DATA SET) 
TABLE 14.3__6.2 
NUMBER AND PERCENTAGE OF SUBJECTS WITH PRESENCE AND INCREASING SEVERITY OF CEREBRAL OEDEMA (SAFETY DATA 
SET) 
TABLE 14.3__6.3 
NUMBER AND PERCENTAGE OF SUBJECTS WITH NEW MICRO-HEMORRHAGES SINCE THE LAST VISIT (SAFETY DATA SET) 
TABLE 14.3__6.4 
NUMBER AND PERCENTAGE OF SUBJECTS WITH WHITE MATTER HYPERINTENSITIES CHANGE (ARWMC SCORE) SINCE THE LAST 
VISIT (SAFETY DATA SET) 
TABLE 14.3__6.5 
DESCRIPTIVE STATISTICS OF NUMBER OF NEW MICRO-HEMORRHAGES AND CHANGES OF ARWMC SCORES OVER TIME (SAFETY 
DATA SET) 
TABLE 14.3__6.6 
LISTING OF SUBJECTS WITH POST-BASELINE MRI FINDINGS (SAFETY DATA SET) 
APPENDIX 16.2__1 
STUDY AND STUDY DRUG COMPLETION 
APPENDIX 16.2__2.1 
INCLUSION/EXCLUSION CRITERIA 
APPENDIX 16.2__2.2 
PROTOCOL DEVIATIONS 
APPENDIX 16.2__2.3 
PREGNANCY TEST 
APPENDIX 16.2__3 
SUBJECTS EXCLUDED FROM THE EFFICACY ANALYSIS 
APPENDIX 16.2__4.1 
SUBJECT DEMOGRAPHICS 
APPENDIX 16.2__4.2 
SUBJECT MEDICAL/SURGICAL HISTORY 
APPENDIX 16.2__4.3 
TOBACCO AND ALCOHOL USE 
APPENDIX 16.2__4.4 
NEUROLOGICAL EXAMINATION 
APPENDIX 16.2__4.5.1 
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS - BASELINE) SCORE 
APPENDIX 16.2__4.5.2 
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS - SINCE LAST VISIT) SCORE 
APPENDIX 16.2__4.6 
ALZHEIMER’S DISEASE HISTORY 
APPENDIX 16.2__5 
STUDY DRUG ADMINISTRATION 
APPENDIX 16.2__6.1 
ADVERSE EVENTS 


Tilavonemab (ABBV-8E12) 
M15-570 - Statistical Programming Plan 
                                 Version 2.0 -  30 July 2021 
11 
 
APPENDIX 16.2__6.2 
SUBJECT DEATHS 
APPENDIX 16.2__6.3 
CONCOMITANT NON-AD MEDICATIONS AND SUPPLEMENTS 
APPENDIX 16.2__6.4 
SERIOUS ADVERSE EVENTS RELEVANT MICROBIOLOGY DATA 
APPENDIX 16.2__6.5 
SERIOUS ADVERSE EVENTS RELEVANT LABORATORY DATA 
APPENDIX 16.2__6.6 
SERIOUS ADVERSE EVENTS ADDITIONAL NON-PROTOCOL DIAGNOSTIC/THERAPEUTIC PROCEDURES 
APPENDIX 16.2__7.1.1 
HEMATOLOGY DETERMINATIONS - PART 1 
APPENDIX 16.2__7.1.2 
HEMATOLOGY DETERMINATIONS - PART 2 
APPENDIX 16.2__7.1.3 
HEMATOLOGY DETERMINATIONS - PART 3 
APPENDIX 16.2__7.1.4 
HEMATOLOGY DETERMINATIONS - COMMENTS AND VALUES OUTSIDE THE REFERENCE RANGE 
APPENDIX 16.2
7.2.1 
CHEMISTRY DETERMINATIONS - PART 1 
APPENDIX 16.2__7.2.2 
CHEMISTRY DETERMINATIONS - PART 2 
APPENDIX 16.2__7.2.3 
CHEMISTRY DETERMINATIONS - PART 3 
APPENDIX 16.2__7.2.4 
CHEMISTRY DETERMINATIONS - PART 4 
APPENDIX 16.2__7.2.5 
CHEMISTRY DETERMINATIONS - PART 5 
APPENDIX 16.2__7.2.6 
CHEMISTRY DETERMINATIONS - COMMENTS AND VALUES OUTSIDE THE REFERENCE RANGE 
APPENDIX 16.2__7.3.1 
URINALYSIS DETERMINATIONS - PART 1 
APPENDIX 16.2__7.3.2 
URINALYSIS DETERMINATIONS - PART 2 
APPENDIX 16.2__7.3.3 
URINALYSIS DETERMINATIONS - PART 3 
APPENDIX 16.2__7.3.4 
URINALYSIS DETERMINATIONS - COMMENTS AND VALUES OUTSIDE THE REFERENCE RANGE 
APPENDIX 16.2__7.4 
VITAL SIGNS 
APPENDIX 16.2__7.5 
ELECTROCARDIOGRAM TEST RESULTS 
APPENDIX 16.2
7.6.1 
MRI RESULTS 
APPENDIX 16.2__7.6.2 
VOLUMETRIC MRI RESULTS 
APPENDIX 16.2__7.7 
TAU PET IMAGING RESULTS 
 


ABBV-8E12
M15-570 – Statistical Analysis Plan
Version 2.0 – 29 July 2021
1
1.0
Title Page
Statistical Analysis Plan
Study M15-570
An Extension Study of ABBV-8E12 in Early 
Alzheimer's Disease
Date:  29 July 2021
Version 2.0
 


ABBV-8E12
M15-570 – Statistical Analysis Plan
Version 2.0 – 29 July 2021
2
1.1
List of Abbreviations and Definition of Terms
AD
Alzheimer's Disease
AE
Adverse event
ALT
Alanine aminotransferase
APOE
Apolipoprotein E
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
BMI
Body mass index
BUN
Blood urea nitrogen
CSF
Cerebrospinal fluid
C-SSRS
Columbia-Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
INR
International normalized ratio
MCHC
Mean corpuscular hemoglobin concentration
MCI
Mild cognitive impairment
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MHIS
Modified Hachinski Ischemic Scale
MRI
Magnetic resonance imaging
NFL
Neurofilament light
PCS
Potentially clinically significant
PD
Premature discontinuation
PET
Positron emission tomography
PK
Pharmacokinetic
PT
Preferred Term
RBC
Red blood cell count
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SOC
System Organ Class
 


ABBV-8E12
M15-570 – Statistical Analysis Plan
Version 2.0 – 29 July 2021
3
SUV
Standardized uptake value
SUVR
Standardized uptake value ratio
TEAE
Treatment-emergent adverse event
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 .............................................................................6
4.0
Study Objectives, Design and Procedures.............................6
4.1
Objectives ..................................................................................................6
4.2
Study Design..............................................................................................7
4.3
Sample Size................................................................................................9
4.4
Interim Analyses ........................................................................................9
4.5
Safety Variables.......................................................................................10
4.6
Biomarker and Pharmacogenetic Research Variables .............................10
4.6.1
Biomarker Research Variables.................................................................10
5.0
Analysis Populations and Analysis Data Set.......................11
6.0
Demographics, Baseline Characteristics, Subject 
History, and Previous/Concomitant Medications ..............11
6.1
Demographic and Baseline Characteristics .............................................11
6.2
Medical History .......................................................................................12
6.3
Previous and Concomitant Medications ..................................................13
7.0
Subject Disposition................................................................14
8.0
Study Drug Exposure and Compliance...............................14
9.0
Efficacy Analysis....................................................................15
9.1
General Considerations............................................................................15
10.0
Safety Analysis.......................................................................16
10.1
General Considerations............................................................................16
10.2
Analysis of Adverse Events.....................................................................16
10.2.1
Adverse Event Overview .........................................................................16
10.2.2
Adverse Event Incidence .........................................................................17
10.2.3
Listing of Adverse Events........................................................................18
10.3
Analysis of Laboratory Tests...................................................................19
10.3.1
Potentially Clinically Significant Laboratory Values ..............................19
10.4
Analysis for Other Safety Variables ........................................................20
 


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10.4.1
Columbia-Suicide Severity Rating Scale (C-SSRS)................................20
10.4.2
Summary of MRI Safety Evaluations ......................................................20
11.0
Pharmacokinetic Analysis.....................................................20
12.0
Biomarker Analysis...............................................................21
13.0
Summary of Changes ............................................................21
List of Tables
Table 1.
Laboratory Tests ......................................................................................19
Table 2.
Study Activities........................................................................................22
List of Figures
Figure 1.
Study Schematic.........................................................................................9
List of Appendices
Appendix A.
Potentially Clinically Significant (PCS) Laboratory Value.....................33
Appendix B.
Criteria for Potentially Clinically Significant Vital Sign and 
Weight Values..........................................................................................34
Appendix C.
Criteria for Potentially Clinically Significant ECG Values.....................35
 


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3.0
Introduction
This analysis plan describes the statistical analyses to be completed by AbbVie Data and 
Statistical Science for ABBV-8E12 Study Protocol M15-570, that incorporates 
one amendment (original Protocol:  09 April 2018; Amendment 1:  24 January 2019; 
Amendment 2:  20 October 2020).
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.  The SAP v2.0 is 
updated to provide details of analysis for the abbreviated CSR.
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 objective of this study is:
●
To assess the long-term safety and tolerability of ABBV-8E12 in subjects with 
early Alzheimer's disease (AD).
The secondary objective of this study is:
●
To assess the pharmacokinetics (PK) of ABBV-8E12 in subjects with early 
AD.
The exploratory objectives of this study are:
●
To assess the long-term efficacy of ABBV-8E12 in slowing disease 
progression in subjects with early AD.
 


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●
To assess the long-term effect of ABBV-8E12 on a range of disease-related 
and drug-related biomarkers in subjects with early AD.
4.2
Study Design
This Phase 2 extension of a multiple dose, multicenter, multinational, double-blind study 
is designed to evaluate the long-term safety and tolerability of ABBV-8E12 in subjects 
with early AD.  The study will consist of a 5-year treatment period and a follow-up period 
of approximately 20 weeks following the last study drug administration.
All subjects who complete the Treatment Period in Study M15-566 will be eligible to 
participate in this study according to the selection criteria.  Upon completion of baseline 
study procedures, eligible subjects will receive ABBV-8E12 via intravenous (IV) infusion 
on Day 1 of Study M15-570 as follows:
●
Subjects who received placebo in Study M15-566 will receive 2000 mg 
ABBV-8E12 in Study M15-570;
●
Subjects who received 300 mg ABBV-8E12 in Study M15-566 will receive 
1000 mg ABBV-8E12 in Study M15-570; and
●
Subjects who received 1000 mg or 2000 mg ABBV-8E12 in Study M15-566 
will continue on the same dose in Study M15-570.
Note:  if any changes are made to alter Study M15-566 with regards to the treatment arms 
due to safety, efficacy, or other reasons, a corresponding change will be implemented in 
Study M15-570.  This change may include, but is not limited to, adding or dropping 
treatment arm(s).
Subjects will receive study drug infusion every 4 weeks and undergo other study 
procedures and assessments as outlined in the Study Activities table (Table 2).  Subjects 
will continue to receive treatment until one of the discontinuation criteria is met, the 
sponsor discontinues the study, or the subject completes the 5-year treatment period of 
Study M15-570.
 


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Day 1 visit of Study M15-570 (day of the first dose of Study M15-570) will be at least 
4 weeks but no more than 8 weeks after the last dosing visit (Week 92) of 
Study M15-566.  Should this window be longer than 8 weeks, the subject may be 
considered for participation in Study M15-570 only with the approval of the therapeutic 
area medical director (TA MD).  The investigators and subjects will remain blinded to the 
treatment assignments in Study M15-566 and will be blinded to the dose level of 
ABBV-8E12 in Study M15-570.
For subjects who do not have extended interruptions in study drug administration between 
Study M15-566 and Study M15-570 (i.e., the duration between the last dose of study drug 
in Study M15-566 and the first dose of study drug in Study M15-570 is no more than 
8 weeks), certain procedures that were performed at the Week 96 Visit in Study M15-566 
do not need to be repeated for the Day 1 Visit in Study M15-570.
Safety will be closely monitored during the study conduct.  The study will also utilize an 
external data monitoring committee (DMC), which will review accumulating study data 
and make recommendations based on the emerging safety profile of ABBV-8E12.  The 
DMC membership, responsibilities, operating logistics, and timing of reviews will be 
documented in a charter that will be finalized prior to the first DMC review meeting.
A schematic of the study design is shown in Figure 1.
 


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Figure 1.
Study Schematic
4.3
Sample Size
The sample size for this study is dependent on the number of subjects who complete 
Study M15-566 and are qualified for enrollment into Study M15-570. Enrollment of 
Study M15-566 has been completed with 453 subjects randomized.  The number of 
subjects who enroll in Study M15-570 could be up to 453.
4.4
Interim Analyses
Interim Efficacy Analysis
No interim analysis will be performed due to early termination of the study.
Safety Reviews
The DMC for Study M15-566 will serve as the DMC for Study M15-570. Before 
database lock of Study M15-566, DMC safety reviews of Study M15-570 data will follow 
the same schedule as the Study M15-566 DMC safety review meetings (i.e., data from 
both studies will be reviewed jointly depending on the pre-specified Study M15-566 
review time points).  The database snapshots will be taken for the safety interim reviews.  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  


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Once the database is locked for Study M15-566, there will be no further planned DMC 
reviews for Study M15-570.
4.5
Safety Variables
The following safety evaluations will be performed and safety information will be 
collected during the study: Adverse event, vital signs, ECG, laboratory tests, C-SSRS, and 
MRI assessments, and immunogenicity as determined by ADA responses in blood.
4.6
Biomarker and Pharmacogenetic Research Variables
4.6.1
Biomarker Research Variables
Plasma and Optional CSF Concentration Variables
CSF samples will be assayed for free and total tauA value for the ratio of free tau 
concentration to total tau concentration could be determined The assessments on free tau 
and the ratio of free tau to total tau could be done to investigate the binding of ABBV-
8E12 to tau.  CSF samples will also be analyzed for neurofilament light chain (NFL).  
Plasma samples will be assayed for total tau and NFL.
Volumetric MRI
Baseline volumetric MRI (vMRI) measurements and measurements on change from 
baseline in vMRI measurements will be obtained.  The baseline measurement will be the 
same as the baseline measurement for Study M15-566, that is, the last measurement 
obtained before the first study drug administration of Study M15-566.  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 
 


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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).  Additional variables (e.g., proportion of 
voxels within a target region that have a SUVR greater than a predetermined cutoff value) 
that reflect the extent or spread of tau pathology might also be assessed.  Due to the 
exploratory nature of these PET imaging endpoints, values will be obtained 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.
5.0
Analysis Populations and Analysis Data Set
Data Sets for Safety Analyses
Safety Data Set:  The Safety Data Set will contain data from Study M15-570 only, 
regardless of the treatment received in Study M15-566.  Baseline for the Safety Data Set 
will be the last observation on or before the first dose of ABBV-8E12 in Study M15-570.  
If no Baseline is recorded in Study M15-570, the last value in Study M15-566 will be 
used as the Baseline.
6.0
Demographics, Baseline Characteristics, Subject 
History, and Previous/Concomitant Medications
The data analysis will be conducted on Safety Data Set and among treatment groups 
defined as Studies M15-566/M15-570:  300/1000 mg, 1000/1000 mg, placebo/2000 mg, 
and 2000/2000 mg.
6.1
Demographic and Baseline Characteristics
The following demographic and baseline characteristics will be summarized for each 
treatment group.
●
Gender (male/female)
●
Race (white, black, American Indian/Alaska native, Native Hawaiian or other 
Pacific Islander, Asian, Other, Multi-Race)
 


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●
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 (kg/m2) (< 25, ≥ 25)
●
APOE allele status (ε2ε2, ε2ε3, ε2ε4, ε3ε3, ε3ε4, ε4ε4)
●
Baseline cholinesterase inhibitors (AChEI) medication or memantine use 
(AChEI includes donepezil, rivastigmine, and galantamine)
6.2
Medical History
Medical history data for this study is transferred from Study M15-566 and will be 
conducted on Safety Data Set.  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 and overall.  Subjects reporting more than one PT within a SOC 
will be counted only once for that SOC.
The following disease history variables will be summarized for each treatment group, and 
overall subjects.
●
Age at onset of symptoms of cognitive impairment (years)
●
Age when first diagnosed as having MCI due to AD or AD (years)
 


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●
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).
6.3
Previous and Concomitant Medications
Previous medications are defined as all medications with a start date before the first study 
drug infusion of M15-570, regardless of the end date of these mediations.  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 and overall subjects.
●
Previous AD or MCI medication:  donepezil, rivastigmine, galantamine, 
tacrine, memantine, investigational medicine or other.
●
Previous antipsychotic/neuroleptic medications
●
Previous anticholinergic medications
 


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●
Previous sedatives/benzodiazepines
●
Previous Parkinsonian medications
●
Concomitant antipsychotic/neuroleptic medications
●
Concomitant anticholinergic medications
●
Concomitant sedatives/benzodiazepines
●
Concomitant Parkinsonian medications 
●
Concomitant AChEIs (donepezil, rivastigmine, galantamine) or memantine for 
cognitive impairment.
7.0
Subject Disposition
For subjects who are enrolled in the study, the number and percentage of subjects in each 
enrollment disposition category (enrolled but not treated, prematurely discontinued and 
completed) will be summarized for each treatment group and overall 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 and overall subjects.
In addition, the following additional summaries will be presented for all enrolled subjects:
●
The number and percentage of subjects who are enrolled at each site.
●
The number and percentage of subjects who prematurely discontinued at each 
site.
8.0
Study Drug Exposure and Compliance
Study drug exposure will be summarized for each treatment group and overall subjects.  
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 
 


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taken a total of infusions ≤ 6, 7 to 12, 13 to 18, 19 to 24, 25 to 30, 31 to 36, 37 to 42, 43 to 
48, 49 to 54, 55 to 60, and ≥ 61 will be summarized.  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 years).
To evaluate impact of Coronavirus Disease 2019 (COVID-19) pandemic on study drug 
compliance, expected infusions (completers are expected to have 65 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 treatment group and 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, 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 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 
treatment group and overall subjects.
9.0
Efficacy Analysis
9.1
General Considerations
No efficacy analysis will be performed for this study due to early termination of the study. 
 


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10.0
Safety Analysis
10.1
General Considerations
No comparisons between treatment groups (Studies M15-566/M15-570) of interest will be 
performed unless otherwise specified.
All other safety assessments that are taken no more than 45 days after the last dose of 
study drug will be included in the safety evaluation of the Treatment Period, and all safety 
assessments that are taken more than 45 days but not more than 20 weeks after the last 
dose of study drug will be included in the safety evaluation for the Post-treatment 
Follow-up Visit.
The Safety Data Set will be the data set for all safety data analyses.
10.2
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. 
10.2.1
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 and 
overall subjects.
●
Any TEAE
●
Any TEAE that was rated 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
 


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●
Any fatal TEAE
●
All deaths
10.2.2
Adverse Event Incidence
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 
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 and overall subjects.  The PTs will be 
presented by decreasing frequency in overall subjects.
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 and overall subjects.
●
Any TEAE
●
Any serious TEAE
●
Any TEAE that led to discontinuation of study drug
●
Any TEAE assessed by the investigator to be 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 and overall subjects.  Subjects reporting more than one 
TEAE for a given PT will be counted only once for that term in the most severe category 
 


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reported.  If a subject has an adverse event with unknown severity, then the subject will be 
counted in the severity category of "unknown" even if the subject has another occurrence 
of the same event with a severity present.  The only exception is if 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.
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 and overall subjects.  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," even if the subject has 
another occurrence of the same event with a relationship present.  The only exception is 
that if a 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."
10.2.3
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 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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10.3
Analysis of Laboratory Tests
The laboratory tests with continuous values that will be analyzed are described in Table 1.
Table 1.
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/Carbon Dioxide (CO2) 
Chloride
Specific gravity
pH
10.3.1
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 at any time in the entire study.  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.
 


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10.4
Analysis for Other Safety Variables
10.4.1
Columbia-Suicide Severity Rating Scale (C-SSRS)
Number and percentage of subjects in the following categories will be summarized for 
each treatment group and overall subjects 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)
10.4.2
Summary of MRI Safety Evaluations
MRI safety evaluations will be summarized by treatment sequences placebo/2000mg, 
2000/2000mg, 300/1000mg, and 1000/1000mg 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-blinded period will be presented.  Listing 
of subjects with post-baseline MRI findings will be provided.
11.0
Pharmacokinetic Analysis
No pharmacokinetic analysis will be performed for this study due to early termination of 
the study. 
 


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12.0
Biomarker Analysis
No biomarker analysis will be performed for this study due to early termination of the 
study. 
13.0
Summary of Changes
Changes in the planed analyses from the latest version of the protocol (Protocol 
Amendment 2) have been incorporated into Statistical Analysis Plan version 2.0. 
Efficacy analysis, PK analysis, and biomarker analysis sections and some safety analyses 
were removed in SAP version 2.0.
 


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Table 2.
Study Activities
Dose
Year 1
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
Dose 
14
Visits & Proceduresa
Day 1/
Baseline
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
40
Wk 
44
Wk 
48
Wk 
52
Subject/study partner ICFb
X
Medical history updatec
X
Treatment assignment
X
Physical examination
Xd
X
Retinal imaging scane
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weightf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examination
Xd
X
X
X
12-lead ECG 
Xd
X
X
X
Clinical laboratory tests
Xd
X
X
X
Brain MRI
Xd
X
X
X
Optional LP/CSF collection
Xd
X
Tau PETg
Xd
X
Blood sample for ABBV-8E12 assay
Xd
X
X
X
ADA sample
Xd
X
X
X
Plasma and serum biomarker sample
Xd
X
X
X
Optional PG DNA and RNA sampleh
Xd
X
X
X
 


ABBV-8E12
M15-570 – Statistical Analysis Plan
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Table 2.
Study Activities (Continued)
Dose
Year 1
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
Dose 
14
Visits & Proceduresa
Day 1/
Baseline
Wk 
4
Wk
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
40
Wk 
44
Wk 
48
Wk 
52
Administer IV study druga
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CDRi
Xd
X
X
RBANSi
Xd
X
ADCS-MCI-ADL-24i
Xd
X
EQ-5D-5Li
X
X
C-SSRSf,i
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Digital measurements of cognition, actigraphy, and 
sleepj
Xj
Xj
Xj
Concomitant medications reviewf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessmentf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 


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M15-570 – Statistical Analysis Plan
Version 2.0 – 29 July 2021
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Table 2.
Study Activities (Continued)
Dose
Year 2
Dose
15
Dose 
16
Dose 
17
Dose 
18
Dose 
19
Dose 
20
Dose 
21
Dose 
22
Dose 
23
Dose 
24
Dose 
25
Dose 
26
Dose 
27
Visits & Proceduresa
Wk
56
Wk
60
Wk
64
Wk
68
Wk
72
Wk
76
Wk
80
Wk
84
Wk
88
Wk
92
Wk
96
Wk
100
Wk
104
Subject/study partner ICFb
Medical history updatec
Treatment assignment
Physical examination
X
Retinal imaging scane
X
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weightf
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examination
X
X
12-lead ECG 
X
Clinical laboratory tests
X
X
Brain MRI 
X
X
Optional LP/CSF collection
X
Tau PETg
X
Blood sample for ABBV-8E12 assay 
X
X
ADA sample
X
X
Plasma and serum biomarker sample
X
X
Optional PG DNA and RNA sampleh
X
X
 


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M15-570 – Statistical Analysis Plan
Version 2.0 – 29 July 2021
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Table 2.
Study Activities (Continued)
Dose
Year 2
Dose
15
Dose 
16
Dose 
17
Dose 
18
Dose 
19
Dose 
20
Dose 
21
Dose 
22
Dose 
23
Dose 
24
Dose 
25
Dose 
26
Dose 
27
Visits & Proceduresa
Wk
56
Wk
60
Wk
64
Wk
68
Wk
72
Wk
76
Wk
80
Wk
84
Wk
88
Wk
92
Wk
96
Wk
100
Wk
104
Administer IV study druga
X
X
X
X
X
X
X
X
X
X
X
X
X
CDRi
X
X
RBANSi
X
ADCS-MCI-ADL-24i
X
EQ-5D-5Li
X
C-SSRSf,i
X
X
X
Digital measurements of cognition, actigraphy, and sleepj
Xj
Xj
Concomitant medications reviewf
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessmentf
X
X
X
X
X
X
X
X
X
X
X
X
X
 


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M15-570 – Statistical Analysis Plan
Version 2.0 – 29 July 2021
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Table 2.
Study Activities (Continued)
Dose
Year 3
Dose
28
Dose 
29
Dose 
30
Dose 
31
Dose 
32
Dose 
33
Dose 
34
Dose 
35
Dose 
36
Dose 
37
Dose 
38
Dose 
39
Dose 
40
Visits & Proceduresa
Wk
108
Wk
112
Wk
116
Wk
120
Wk
124
Wk
128
Wk
132
Wk
136
Wk
140
Wk
144
Wk
148
Wk
152
Wk
156
Subject/study partner ICFb
Medical history updatec
Treatment assignment
Physical examination
X
Retinal imaging scane
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weightf
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examination
X
X
12-lead ECG 
X
Clinical laboratory tests
X
Brain MRI 
X
X
Optional LP/CSF collection
Tau PETg
X
Blood sample for ABBV-8E12 assay 
X
X
ADA sample
X
X
Plasma and serum biomarker sample
X
X
Optional PG DNA and RNA sampleh
X
X
 


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M15-570 – Statistical Analysis Plan
Version 2.0 – 29 July 2021
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Table 2.
Study Activities (Continued)
Dose
Year 3
Dose
28
Dose 
29
Dose 
30
Dose 
31
Dose 
32
Dose 
33
Dose 
34
Dose 
35
Dose 
36
Dose 
37
Dose 
38
Dose 
39
Dose 
40
Visits & Proceduresa
Wk
108
Wk
112
Wk
116
Wk
120
Wk
124
Wk
128
Wk
132
Wk
136
Wk
140
Wk
144
Wk
148
Wk
152
Wk
156
Administer IV study druga
X
X
X
X
X
X
X
X
X
X
X
X
X
CDRi
X
X
RBANSi
X
ADCS-MCI-ADL-24i
X
EQ-5D-5Li
X
C-SSRSf,i
X
X
X
Digital measurements of cognition, actigraphy, and 
sleepj
Xj
Xj
Concomitant medications reviewf
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessmentf
X
X
X
X
X
X
X
X
X
X
X
X
X
 


ABBV-8E12
M15-570 – Statistical Analysis Plan
Version 2.0 – 29 July 2021
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Table 2.
Study Activities (Continued)
Dose
Year 4
Dose
41
Dose
42
Dose
43
Dose
44
Dose
45
Dose
46
Dose
47
Dose
48
Dose
49
Dose
50
Dose
51
Dose
52
Dose
53
Visits & Proceduresa
Wk
160
Wk 
164
Wk 
168
Wk 
172
Wk 
176
Wk 
180
Wk 
184
Wk 
188
Wk 
192
Wk 
196
Wk 
200
Wk 
204
Wk 
208
Subject/study partner ICFb
Medical history updatec
Treatment assignment
Physical examination
X
Retinal imaging scane
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weightf
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examination
X
X
12-lead ECG 
X
Clinical laboratory tests
X
Brain MRI
X
X
Optional LP/CSF collection
Tau PETg
X
Blood sample for ABBV-8E12 assay 
X
X
ADA sample
X
X
Plasma and serum biomarker sample
X
X
Optional PG DNA and RNA sampleh
X
X
 


ABBV-8E12
M15-570 – Statistical Analysis Plan
Version 2.0 – 29 July 2021
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Table 2.
Study Activities (Continued)
Dose
Year 4
Dose
41
Dose
42
Dose
43
Dose
44
Dose
45
Dose
46
Dose
47
Dose
48
Dose
49
Dose
50
Dose
51
Dose
52
Dose
53
Visits & Proceduresa
Wk
160
Wk 
164
Wk 
168
Wk 
172
Wk 
176
Wk 
180
Wk 
184
Wk 
188
Wk 
192
Wk 
196
Wk 
200
Wk 
204
Wk 
208
Administer IV study druga
X
X
X
X
X
X
X
X
X
X
X
X
X
CDRi
X
X
RBANSi
X
ADCS-MCI-ADL-24i
X
EQ-5D-5Li
X
C-SSRSf,i
X
X
X
Digital measurements of cognition, actigraphy, and 
sleepi
Xi
Xi
Concomitant medications reviewf
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessmentf
X
X
X
X
X
X
X
X
X
X
X
X
X
 


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M15-570 – Statistical Analysis Plan
Version 2.0 – 29 July 2021
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Table 2.
Study Activities (Continued)
Dose
Year 5
Dose 
54
Dose 
55
Dose 
56
Dose 
57
Dose 
58
Dose 
59
Dose 
60
Dose 
61
Dose 
62
Dose 
63
Dose 
64
Dose 
65
Wk 260/
Study 
Completion 
PD Visit
20 Wk
Post-Last Dosek
Follow-Up Visit
Visits & Proceduresa
Wk 
212
Wk 
216
Wk 
220
Wk 
224
Wk 
228
Wk 
232
Wk 
236
Wk 
240
Wk 
244
Wk 
248
Wk 
252
Wk 
256
Subject/study partner ICFb
Medical history updatec
Treatment assignment
Physical examination
X
Retinal imaging scane
X
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weightf
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examination
X
X
X
X
12-lead ECG 
X
Clinical laboratory tests
X
X
X
Brain MRI 
X
X
X
X
Optional LP/CSF collection
X
Tau PETg
X
Blood sample for ABBV-8E12 
assay 
X
X
X
X
ADA sample
X
X
X
X
Plasma and serum biomarker 
sample
X
X
X
X
 


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M15-570 – Statistical Analysis Plan
Version 2.0 – 29 July 2021
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Table 2.
Study Activities (Continued)
Dose
Year 5
Dose 
54
Dose 
55
Dose 
56
Dose 
57
Dose 
58
Dose 
59
Dose 
60
Dose 
61
Dose 
62
Dose 
63
Dose 
64
Dose 
65
Wk 260/
Study 
Completion 
PD Visit
20 Wk
Post-Last Dosek
Follow-Up Visit
Visits & Proceduresa
Wk 
212
Wk 
216
Wk 
220
Wk 
224
Wk 
228
Wk 
232
Wk 
236
Wk 
240
Wk 
244
Wk 
248
Wk 
252
Wk 
256
Optional PG DNA and RNA 
sampleh
X
X
X
Administer IV study druga
X
X
X
X
X
X
X
X
X
X
X
X
CDRi
X
X
X
X
RBANSi
X
X
ADCS-MCI-ADL-24i
X
EQ-5D-5Li
X
X
C-SSRSf,i
X
X
X
X
Digital measurements of 
cognition, actigraphy, and sleepj
Xj
Xj
Xj
Concomitant medications reviewf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE assessmentf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Wk = Week
a.
Study drug will be administered on Day 1/Baseline visit, and then every 4 weeks thereafter until 1 of the discontinuation criteria is met, until the sponsor discontinues the 
study, or until the study reaches completion.  Visits during the Treatment Period may be scheduled within ± 4 days.  All dosing visits may be completed over 2 consecutive 
days at the discretion of the investigator with the second day to include the start and end of the infusion.
b.
Subject informed consent, or as applicable, legally authorized representative informed consent and subject assent, and study partner informed consent must be obtained prior 
to any Study M15-570 specific procedures being completed.
c.
Review medical history to confirm subject does not meet exclusion criteria prior to enrollment.
 


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Table 2.
Study Activities (Continued)
d.
Not required if procedure was conducted during the Week 96 visit in Study M15-566.  A repeat assessment/procedure may be required based on discussion with the TA MD if 
more than 4 weeks have passed since the Week 96 visit.
e.
Exploratory eye test for AD pathology may be conducted at participating sites and will be performed at Weeks 60 and 260 or Premature Discontinuation.
f.
Vital signs, body weight, C-SSRS, concomitant medications review and AE assessment to be completed prior to administration of infusion.
g.
Subjects who did not complete tau PET imaging at Day 1/Baseline will have tau PET imaging performed at subsequent visits only after discussion with TA MD.  Tau PET 
imaging will only be collected for subjects at sites selected to participate in the tau PET assessment.
h.
Optional pharmacogenetic DNA and RNA samples require consent.  Verify consent prior to sample collection.
i.
The recommended order of administration is CDR followed by RBANS.  When applicable, ADCS-MCI-ADL-24, EQ-5D-5L, and C-SSRS may be subsequently 
administered/assessed in any order prior to study drug administration.
j.
Start of collection period for digital measures of cognition, actigraphy, and sleep.  Detailed instructions and other considerations will be provided in a separate manual.
k.
Post-treatment follow-up to occur approximately 20 weeks after the Completion or Premature Discontinuation (PD) visit.
Note:
For subjects who prematurely discontinue the study, safety and efficacy assessments may be conducted remotely (for example, via telephone), where applicable.
 


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Version 2.0 – 29 July 2021
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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)
Uric acid
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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Version 2.0 – 29 July 2021
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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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M15-570 – Statistical Analysis Plan
Version 2.0 – 29 July 2021
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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