Conditions: Progressive Supranuclear Palsy
Keywords: PSP Steele-Richardson-Olszewski syndrome Tauopathy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 378
Healthy volunteers: no

Brief summary:
The purpose of this study was to assess efficacy, safety, tolerability, and pharmacokinetics of ABBV-8E12 in participants with progressive supranuclear palsy (PSP).

Detailed description:
This was a Phase 2, randomized, double-blind, placebo-controlled, multiple dose, multicenter study consisting of a screening period of up to 8 weeks (56 days), a 52-week double-blind treatment period, and a post-treatment follow-up period of approximately 20 weeks following last study drug administration (for those participants who prematurely discontinued from treatment, declined to participate in or did not qualify for participation in a long term extension \[LTE\] study). At the end of the treatment period, extended treatment was available for eligible participants who completed the 52-week treatment period and entered the separate long-term extension study (NCT03391765; Study M15-563). There were 3 cohorts in the study (Cohort 1, Cohort J1, and Cohort 2). Cohort 1 had augmented safety and pharmacokinetic (PK) assessments in the first 30 participants enrolled into the global study from countries other than Japan. Cohort J1 had augmented safety and PK assessments in the first 9 participants enrolled into the study from Japan. Cohort 2 consisted of all other participants enrolled in the global study not participating in Cohort 1 or Cohort J1.

This study was prematurely discontinued because the program for progressive supranuclear palsy was discontinued due to lack of efficacy of study drug.

Arms:
arm 1: 0.9% Sodium Chloride Injection/Solution for Infusion; intravenous infusions at Day 1, Day 15, and Day 29, then every 28 days for 52 weeks arm 2: Intravenous infusions at Day 1, Day 15, and Day 29, then every 28 days for 52 weeks; 300 mg/15 mL (participants in countries other than Japan or Spain); 1000 mg/10 mL (for participants in Japan or Spain) arm 3: Intravenous infusions at Day 1, Day 15, and Day 29, then every 28 days for 52 weeks; 300 mg/15 mL (participants in countries other than Japan or Spain); 1000 mg/10 mL (for participants in Japan or Spain)

Interventions: intervention 1: Placebo intervention 2: ABBV-8E12
Intervention descriptions: intervention 1: Participants with 44-49 kg body weight (BW) had an intravenous infusion rate of 3.5 mL/min or 210 mL/hr; those with 50-58 kg BW, 4.0 mL/min or 240 mL/hr; and those with a BW \>59 kg, 4.7 mL/min or 282 mL/hr. intervention 2: Participants with 44-49 kg body weight (BW) had an intravenous infusion rate of 3.5 mL/min or 210 mL/hr; those with 50-58 kg BW, 4.0 mL/min or 240 mL/hr; and those with a BW \>59 kg, 4.7 mL/min or 282 mL/hr. For participants in Cohort 2, ABBV-8E12 doses may have been decreased after the evaluation by the Data Monitoring Committee of available safety, tolerability and pharmacokinetic data.

Protocol document:
Prot_000.pdf: 
ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
1
1.0
Title Page
Clinical Study Protocol M15-562
A Randomized, Double-Blind, Placebo-Controlled 
Multiple Dose Study to Assess Efficacy, Safety, 
Tolerability, and Pharmacokinetics of ABBV-8E12 in 
Progressive Supranuclear Palsy
Incorporating Administrative Changes 1 and 2 (US 
Only), Amendments 1, 2, 2.01 (US Only), 2.01.01 (US 
Only), 2.02 (Germany Only), 2.02.01 (Germany Only), 
3, 3.01 (Germany Only), 3.02 (Japan Only), 4, and 5
AbbVie Investigational
  Product:
ABBV-8E12
Date:
13 December 2018
EudraCT Number:
2016-001635-12
Development Phase:
2
Study Design:
This is a Phase 2, randomized, double-blind, placebo-controlled 
study designed to evaluate the efficacy, safety, tolerability, 
immunogenicity, and pharmacokinetics of repeated dose 
administration of ABBV-8E12 in subjects with progressive 
supranuclear palsy (PSP).
Investigators:
Multicenter Trial:  Investigator Information is on file at AbbVie
Sponsor:
AbbVie
Sponsor/Emergency 
  Contact:
Medical Director
Neuroscience Development
AbbVie Inc. 
1 N Waukegan Road
North Chicago, IL 60064
Phone:
Fax:
Mobile:
Email:  
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.
NCT02985879


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
2
1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date 
Original
06 July 2016
Amendment 1
18 August 2016
Amendment 2
31 October 2016
Administrative Change 1
12 May 2017
Amendment 2.01 (US Only)
27 June 2017
Administrative Change 2 (US Only)
20 March 2018
Amendment 2.01.01 (US Only)
27 March 2018
Amendment 2.02 (Germany Only)
21 August 2017
Amendment 2.02.01 (Germany Only)
27 October 2017
Amendment 3
26 January 2018
Amendment 3.01 (Germany Only)
30 January 2018
Amendment 3.02 (Japan Only)
22 February 2018
Amendment 4
19 October 2018
The purpose of this amendment is to:
●
Update Section 5.3.1.1, Study Procedures, and Appendix C, Study Activities, 
to add Progressive Supranuclear Palsy (PSP) clinical features during the 
Screening Period.
Rationale:  To gather more specific data regarding PSP signs and symptoms 
prior to enrollment in the trial.
●
Update Appendix C, Study Activities, to add telephone contacts at Weeks 12, 
24, 36, and 52 for subjects who prematurely discontinue.
Rationale:  To learn about the condition of subjects since their premature 
discontinuation from the study.
Appendix B was revised to update the protocol signatories for this amendment.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
3
An itemized list of all changes made to the protocol under this amendment can be found 
in Appendix E.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
4
1.2
Synopsis
AbbVie Inc.
Protocol Number:  M15-562
Name of Study Drug:  ABBV-8E12
Phase of Development:  2
Name of Active Ingredient:  ABBV-8E12
Date of Protocol Synopsis:  13 December 2018
Protocol Title:  A Randomized, Double-Blind, Placebo-Controlled Multiple Dose Study to Assess 
Efficacy, Safety, Tolerability, and Pharmacokinetics of ABBV-8E12 in Progressive Supranuclear Palsy 
(PSP)
Objectives:  
The primary objectives of this study are:
!
To assess the efficacy of ABBV-8E12 in slowing disease progression in subjects with 
progressive supranuclear palsy as measured by the PSP Rating Scale (PSPRS).
!
To assess the long term safety and tolerability of ABBV-8E12 for up to 52 weeks in subjects 
with progressive supranuclear palsy.
The secondary objectives of this study are:
!
To assess the pharmacokinetics (PK) of multiple doses of ABBV-8E12 in subjects with 
progressive supranuclear palsy.
!
To assess the efficacy of ABBV-8E12 in slowing disease progression and functional impairment 
in subjects with progressive supranuclear palsy as measured by secondary endpoints.
!
To assess the efficacy of ABBV-8E12 in slowing regional and/or whole brain atrophy in 
subjects with progressive supranuclear palsy as measured by volumetric magnetic resonance 
imaging (MRI). 
The exploratory objectives of this study are:
!
To assess the efficacy of ABBV-8E12 in slowing disease progression and functional impairment 
in subjects with progressive supranuclear palsy as measured by exploratory endpoints.
!
To assess the effect of ABBV-8E12 on cerebrospinal fluid (CSF) and plasma tau protein levels.
!
To assess the effect of ABBV-8E12 on potential CSF and plasma biomarkers of disease 
progression.
Investigators:  Multicenter
Study Sites:  Approximately 60 multinational sites.
Study Population:  Adult male and female subjects with possible or probable progressive supranuclear 
palsy who meet all the inclusion criteria and who do not meet any exclusion criteria.
Number of Subjects to be Enrolled:  Approximately 330


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
5
Methodology:  
The study will consist of a screening period of up to 8 weeks, a 52-week double-blind treatment period 
and a post-treatment follow-up period of approximately 20 weeks following the last study drug 
administration (including those subjects who prematurely discontinue from treatment, decline to 
participate in or do not qualify for participation in a long term extension (LTE) study).  At the end of the 
treatment period, eligible subjects who completed the 52-week treatment period may enter a separate 
LTE study for extended treatment.  Upon completion of screening and baseline procedures, eligible 
subjects will be randomized to one of the 2 ABBV-8E12 dose arms (2000 mg or 4000 mg) or placebo in 
a 1:1:1 ratio.
The study will consist of 3 Cohorts.
Region
Cohort 1*
Cohort J1**
Cohort 2***
Global (not 
including Japan)
First 30 subjects enrolled#
NA
n = ~276
Japan
NA
First 9 subjects enrolled#
n = ~15
*
Cohort 1:  Augmented safety and PK assessments in the first 30 subjects enrolled into the global study from 
countries other than Japan.
**
Cohort J1:  Augmented safety and PK assessments in the first 9 subjects enrolled into the study from Japan.
*** Cohort 2:  All other subjects enrolled in the global study not participating in Cohort 1 or Cohort J1.
#
Augmented safety and pharmacokinetic assessments including additional study visits, more frequent 
neurological exams, vital signs, blood collections for safety labs, an additional lumbar puncture and MRI, and 
additional monitoring by the Data Monitoring Committee (DMC) will be performed in Cohort 1 and Cohort J1.
   
Eligible subjects will be enrolled into the Treatment Period of the study on Day 1 and receive their 
first infusion of study drug.  During the first 4 weeks, subjects will have 3 study drug infusions, the 
first on Day 1, the second at Day 15, and the third at Day 29.  Thereafter, subjects will return to the study 
site every 28 days for their study drug infusion, blood collection, study procedures and assessments.  
Subjects will be observed on-site for at least 2 hours following each of the first 4 infusions of study drug 
and for at least 30 minutes after the end of infusion of all doses thereafter. 
Subjects in Cohort J1 will be enrolled at least 2 days apart and will be confined for a minimum of 
24 hours following their first infusion.  Subjects will have another study visit to be assessed for safety 
2 days after the first infusion.  From the second to the fourth infusion, Cohort J1 subjects will be 
observed on-site for at least 2 hours following each infusion of study drug.  
Subjects in Cohort 2 will be observed on-site for at least 2 hours following each of the first 4 infusions of 
study drug.  Following the 4th infusion, all subjects in all cohorts will be observed on-site for at least 
30 minutes after the end of the infusion.
This study will utilize a DMC consisting of at least 2 external clinicians, at least 1 external statistician, 
and at least 1 external pharmacokineticist.  The DMC will review unblinded safety and efficacy data and 
make recommendations to the Sponsor based on the totality of available clinical data.  The DMC 
memberships, responsibilities and operating logistics will be documented in a charter that will be 
prepared prior to the first DMC review meeting.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
6
Methodology (Continued):
Safety and tolerability will be monitored throughout the study, specifically including conditions 
associated with infusions in general, and infusion reactions.  The first 39 subjects enrolled into the study 
will be represented as Cohort 1 (30 subjects) and Cohort J1 (9 subjects) in this protocol, while the 
subjects enrolled subsequently to Cohort 1 and Cohort J1 will be represented as Cohort 2.  More frequent 
PK sampling and safety monitoring by the DMC will be conducted for Cohort 1 and Cohort J1 subjects.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion Criteria:  
!
Male or female subject with age 40 years or greater at the time of signed consent.
!
Meets the following criteria for possible or probable progressive supranuclear palsy (Steele-
Richardson-Olszewski Syndrome):
o
gradually progressive disorder, with age at disease onset greater than or equal to 40 years
o
either or both of the following two items are met:
1.
vertical supranuclear gaze palsy
2.
slowing of vertical saccades AND postural instability with falls within the first 3 years 
of PSP symptoms
!
Presence of PSP symptoms for less than 5 years.  For the purpose of this inclusion criterion, a 
PSP symptom will be defined as any neurological, cognitive or behavior symptom consistent 
with known symptoms of PSP, occurring newly and subsequently progressing during the clinical 
course in the absence of another identifiable cause.
!
Subject is able to walk 5 steps with minimal assistance (stabilization of one arm or use of 
cane/walker).
!
Subject has an identified, reliable, study partner (e.g., caregiver, family member, social worker, 
or friend), who has frequent contact with the subject (at least 10 hours per week) and who can 
accompany the subject to study visits to provide information as to the subject's functional 
abilities.  The study partner has voluntarily signed the Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB) approved Informed Consent, prior to the conduct of any 
study procedures.
Main Exclusion Criteria:  
!
Male or female subject weighing less than 44 kg (97 lbs.) at screening will be excluded.
!
Mini-Mental State Examination (MMSE) score less than 15 at screening, or cognitive 
impairment that in the Investigator's opinion would preclude collection of outcome measures.
!
Any contraindication or inability to tolerate brain magnetic resonance imaging (MRI) (e.g., a 
pacemaker or any other implanted device or condition that would preclude proximity to a strong 
magnetic field).
!
During enrollment of Cohort 1 and Cohort J1, any contraindication or inability to tolerate 
lumbar punctures (e.g., use of anticoagulant medications such as warfarin) are exclusionary.  
During enrollment of Cohort 2, subjects who are not able to undergo lumbar puncture may be 
admitted with permission of the AbbVie Medical Director, and these subjects will not be 
required to undergo lumbar puncture during the study.
!
Subject resides at a skilled nursing or dementia care facility, or admission to such a facility is 
planned during the study period.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
7
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion (Continued):  
!
Evidence of any neurological disorder that could explain signs of PSP, including:
o
Signs of idiopathic Parkinson's disease (e.g., severe asymmetric parkinsonian signs, 
clinically significant tremor at rest, or prominent and sustained response to levodopa 
therapy)
o
Signs of multiple system atrophy (MSA) (e.g., prominent early cerebellar limb ataxia or 
unexplained symptomatic autonomic dysfunction)
o
Signs of Lewy body disease (e.g., hallucinations or delusions unrelated to dopaminergic 
therapy or other illness)
o
Probable Alzheimer disease according to National Institute of Neurological and 
Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders 
Association (NINCDS-ADRDA) criteria
o
History of repeated strokes with stepwise progression of parkinsonian features
o
History of major stroke
o
History of severe or repeated head injury
o
History of encephalitis
o
History of neuroleptic use (with the exception of clozapine or quetiapine) for a prolonged 
period of time or within the past 6 months
o
Oculogyric crises
o
Street-drug–related parkinsonism
o
Known history of autosomal dominant PSP due to a Microtubule Associated Protein Tau 
(MAPT) mutation
o
Known history of an autosomal dominant mutation associated with Frontotemporal Lobar 
Degeneration (FTLD) (e.g., an autosomal dominant mutation in C9ORF72 or GRN)
o
Significant other neurological disease on MRI that could account for PSP symptoms 
!
Evidence of any clinically significant neurological disorder other than PSP, including but not 
limited to significant cerebrovascular abnormalities, vascular dementia, motor neuron disease or 
Amyotrophic Lateral Sclerosis (ALS), Huntington's disease, normal pressure hydrocephalus, 
brain tumor, seizure disorder, multiple sclerosis, or known structural brain abnormalities.
!
The subject has a history of or currently has schizophrenia, schizoaffective disorder or bipolar 
disorder according to Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
(DSM-V) or International Classification of Diseases (ICD)-10 criteria.
!
Subject has had a significant illness or infection requiring medical intervention in the past 
30 days.
!
Any clinically significant hematological, autoimmune, endocrine, cardiovascular, neoplastic, 
renal, gastrointestinal, or other disorder that, in the Investigator's opinion, could interfere with 
the subject's participation in the study, place the subject at increased risk, or confound 
interpretation of study results.
!
Any history of prior receipt of active immunotherapy directed against tau.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
8
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion (Continued):  
!
Subject has received an investigational product (other than ABBV-8E12, also known as 
C2N-8E12) within a time period equal to 5 half-lives, if known, or within 6 weeks (for small 
molecules) or 6 months (for monoclonal antibodies or other biologics) prior to study drug 
administration.
!
Current enrollment in another interventional clinical study involving a therapeutic agent.
!
Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to 
receive ABBV-8E12 or that the subject is unable or unlikely to comply with the dosing schedule 
or study evaluations.
Investigational Product:
ABBV-8E12 (300 mg/15 mL)#
ABBV-8E12 (1000 mg/10 mL)
#
Dosage formulation will not be used in Japan and Spain.
Doses:
Doses will be given at Day 1, Day 15, Day 29, and every 28 Days 
thereafter.
Cohort 1 and Cohort J1:
!
Dose 1:  2000 mg
!
Dose 2:  4000 mg
Cohort 2 (expanded enrollment):
!
Dose 1:  2000 mg
!
Dose 2:  4000 mg
Doses may be decreased after the evaluation by the DMC of available 
safety, tolerability and PK data.
Mode of Administration:
Intravenous (IV) infusion
Reference Therapy:
Placebo (0.9% Sodium Chloride Injection/Solution for Infusion)
Doses:
Doses will be given at Day 1, Day 15, Day 29, and every 28 days 
thereafter.
Mode of Administration:
IV Infusion
Duration of Treatment:  52 Weeks
Criteria for Evaluation:
Efficacy:
Clinical and Cognitive Assessments:
Primary:
!
PSP Rating Scale (PSPRS)
Key Secondary:
!
Unified Parkinson's Disease Rating Scale (UPDRS) Part II
!
Clinical Global Impression of Change (CGI-C)
!
Midbrain atrophy as measured by volumetric MRI
!
Schwab and England Activities of Daily Living Scale (SEADL)


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
9
Criteria for Evaluation (Continued):  
Efficacy (Continued):
Clinical and Cognitive Assessments (Continued):
Additional secondary:
!
Clinical Global Impression of Severity (CGI-S) 
!
PSP Quality of Life Scale (PSP-QoL) 
!
PSPRS domain scores
!
Volumetric MRI of third ventricle, whole brain, frontal lobes, superior cerebellar peduncle, and 
brainstem
!
PSP Staging System (PSP-SS) (composite of dysphagia and gait items from PSPRS)
!
Time to loss of ability to walk independently as measured by PSPRS item 26
Exploratory
!
Natural History and Neuroprotection in Parkinson Plus Syndromes-Parkinson Plus Scale 
(NNIPPS-PPS) (not conducted in Japan)
!
Patient Global Impression of Change (PGI-C)
!
Letter fluency test (LFT) score
!
Repeatable Battery for Assessment of Neuropsychological Status (RBANS)
!
Color Trails Test (CTT) (Parts 1 and 2) score
!
EuroQuality of Life (EQ-5D) index score and Visual Analog Scale (VAS)
!
Exploratory quantitative MRI measures may additionally be evaluated, including diffusion 
tensor imaging (DTI) derived fractional anisotropy (FA) and diffusivity measures [radial 
diffusivity (RD), mean diffusivity (MD), and axial diffusivity] to assess changes in 
pathophysiology
!
Additional brain regions that are not listed under secondary assessments may be measured by 
volumetric MRI
!
CSF and plasma tau and neurofilament (NFL) biomarkers
Pharmacokinetics:
The concentration of ABBV-8E12 will be determined in serum and CSF samples collected in the study.
Values for the following pharmacokinetic parameters will be estimated using non-compartmental 
methods:  maximum observed serum concentration (Cmax), the time to Cmax (peak time, Tmax), the area 
under the concentration time curve (AUC) over the dosing interval after the first and the fifth doses in 
Cohort 1 and Cohort J1; the observed serum concentration at the end of a dose interval (Ctrough,
concentration prior to infusion on a day of dosing) in all cohorts.
A mixed-effect modeling approach will be used to estimate the population central value and the empirical 
Bayesian estimates of the individual values for ABBV-8E12 clearance (CL) and volume of distribution 
(V).
The concentration of ABBV-8E12 in CSF will be summarized after the fifth dose and after the final dose 
if administered at least 3 months after the previous LP for subjects in Cohort 1 and Cohort J1, and after 
final dose for subjects in Cohort 2. 
Additional parameters may be calculated if useful in the interpretation of the data.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
10
Criteria for Evaluation (Continued):
Immunogenicity:
Anti-drug antibodies will be determined in serum for assessment of immunogenicity.
Biomarkers:
CSF and Plasma Biomarkers:
!
Tau and NFL in CSF and plasma
!
Additional exploratory CSF and plasma-based pharmacodynamics (PD) analyses may be 
conducted based on sample availability
Imaging Biomarkers:
!
Regional and/or whole brain volume derived from MRI
!
Fractional anisotropy and diffusivity measures in brain regions of interest derived from diffusion 
tensor imaging
Safety:  
Adverse events (AE) and serious adverse events (SAE) will be monitored throughout the dosing period 
and for at least 20 weeks after the last dose.  Safety evaluations will include the following:  monitoring of 
adverse events (including infusion and allergic reactions), vital signs, physical examination, complete 
neurologic exam, cognitive assessments, Columbia-Suicide Severity Rating Scale (C-SSRS), laboratory 
abnormalities, electrocardiogram (ECG), brain magnetic resonance imaging (MRI) including fluid 
attenuated inversion recovery (FLAIR), and immunogenicity as determined by anti-drug antibody 
responses in blood.
Statistical Methods:
Efficacy:
The efficacy variables will be the change from baseline to Week 52 for each efficacy assessment.  The 
primary efficacy variable is the change on the PSPRS total score from baseline to Week 52.  The primary 
analysis is to compare each ABBV-8E12 dose group with placebo for all subjects in the study (including 
subjects in Cohort 1, Cohort J1, and Cohort 2) using a likelihood-based, mixed-effects model, repeated 
measures (MMRM) analysis of the PSPRS total score change from baseline for each post-baseline 
observation using all observed data.  The model will include fixed, categorical effects for treatment, site, 
visit, baseline score-by-visit interaction and treatment-by-visit interaction, with a continuous fixed 
covariate for baseline PSPRS total score.  The primary comparison will be the contrast between each 
ABBV-8E12 dose group and placebo at the Week 52 Visit using a graphic approach to control for 
multiplicity for primary and key secondary variables across 2 ABBV-8E12 doses.  The treatment group 
differences at earlier visits will be assessed as the secondary.  An unstructured (co)variance structure will 
be used to model the within-subject errors.  Satterthwaite's approximation will be used to estimate 
denominator degrees of freedom, and the Type III sum-of-squares for the Least Square (LS) means will 
be used to estimate treatment group differences.  This MMRM analysis will be applied to each efficacy 
variable with repeated measurements.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
11
Statistical Methods (Continued):
Pharmacokinetic:
The change in serum concentration across time will be considered in an analysis of Ctrough data, with the 
logarithmic transformation used if appropriate.  The pre-infusion concentration data for Days 15, 29 and 
85, plus Weeks 24 and 36 will be analyzed with a MMRM model.  For measures of exposure, an analysis 
of covariance will be performed on dose normalized parameters of Cohort 1 and Cohort J1.  It is 
anticipated that the logarithmic transformation will be employed.  Subjects will be classified by dose 
level and region, and the initial model will contain an effect for the interaction of dose level and region.  
Body weight will be a covariate. The model may have other covariates.  The hypothesis of dose 
proportionality will be tested within the framework of the model.
Population pharmacokinetic analyses will be performed using the actual sampling time relative to dosing.  
Pharmacokinetic models will be built using a non-linear mixed-effect modeling approach with the 
NONMEM software (version VII, or higher version).  The structure of the starting pharmacokinetic 
model will be based on the pharmacokinetic analysis of data from previous studies and Cohort 1 and 
Cohort J1 of this study.  Apparent CL and apparent volume of distribution (V) of ABBV-8E12 will be the 
pharmacokinetic parameters of major interest in the NONMEM analyses.  If necessary, other parameters, 
including the parameters describing absorption characteristics, may be fixed if useful in the analysis.  
CSF concentration data after the fifth dose (for subjects in Cohort 1 and Cohort J1) and the final dose will 
be summarized by dose level.
Immunogenicity:
The anti-drug antibody titers will be tabulated by dose level and summarized as appropriate.
Biomarker:  
An ANCOVA model will be used to evaluate CSF concentrations for total tau, free tau, and NFL for each 
scheduled time of evaluation during treatment.  Corresponding analyses on plasma measurements of total 
tau and NFL will be performed.  The observations will be classified by treatment and region, and the 
initial model will have an effect for the interaction of treatment and region.  The baseline value for total 
tau and free tau will be the covariate in the case of total tau and free tau, but for the analysis on the ratio 
the covariate will be the baseline total tau concentration measurement.  Within the framework of the 
analysis of covariance the means of the three treatments (with adjustment for baseline) will be estimated.  
The hypothesis of no difference between the higher ABBV-8E12 dose and placebo will be tested at 
significance level 0.050.  If this hypothesis is rejected, the hypothesis on no difference between the lower 
ABBV-8E12 dose and placebo will then be tested at significance level 0.050.
If the probability distribution for a variable appears to have considerable non-symmetry (e.g., skewness 
coefficient > 1.00 in magnitude), a transformation will be sought that has an approximately normal 
distribution.  If data for other variables are reported, descriptive statistics will be provided and 
appropriate analyses performed.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
12
Statistical Methods (Continued):
Safety:
Adverse events will be coded using the most current version of the Medical Dictionary for Regulatory 
Activities (MedDRA).  The number and percentage of subjects reporting treatment-emergent adverse 
events will be tabulated by MedDRA System Organ Class (SOC) and Preferred Term with a breakdown 
by treatment group.  Tabulations will also be provided by rating of severity (mild, moderate, and severe) 
and by whether possibly related to study drug.  The number and percent of subjects experiencing 
treatment-emergent serious adverse events (including deaths) and adverse events leading to premature 
discontinuation of the study drug will be tabulated according to the MedDRA SOC and preferred term by 
treatment group.  Treatment group differences between each ABBV-8E12 dose group and placebo will be 
analyzed by Fisher's exact test.  Differences between each ABBV-8E12 treatment group and placebo for 
mean laboratory, vital signs and ECG variables will be analyzed by a one-way analysis of variance 
(ANOVA) with treatment as the main effect.  The number and percentage of laboratory test values and 
measurements on vital signs that are potentially clinically significant, according to predefined criteria, 
will be tabulated as well.  Proportion of subjects who have suicidal behavior, suicidal ideation only, and 
suicidal behavior or ideation from the C-SSRS assessment will be summarized by treatment group.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
13
1.3
List of Abbreviations and Definition of Terms
Abbreviations
AD
Alzheimer's Disease
ADA
Anti-Drug-Antibody
AE
Adverse Event
ALS
Amyotrophic Lateral Sclerosis
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
ANOVA
Analysis of Variance
AP
Atypical Parkinsonism
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
ATEMS
AbbVie Temperature Excursion Management System
AUC
Area Under the Concentration Time Curve
B12
Cobalamin
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CBD
Corticobasal Degeneration
CGI-C
Clinical Global Impression of Change
CGI-S
Clinical Global Impression of Severity
CL
Clearance
Cmax
Maximum Observed Serum Concentration
CO2
Carbon Dioxide
COMT
Catechol-O-Methyltransferase
CPK
Creatine Phosphokinase
CPPM
Clinical Pharmacology and Pharmacometrics
CRA
Clinical Research Associate
CRF
Case Report Form
CS
Clinically Significant
CSF
Cerebrospinal Fluid
C-SSRS
Columbia-Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
14
Ctrough
Observed serum drug concentration at the end of a dose interval
CTT
Color Trails Test
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
DSM-V
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
DSS
Data and Statistical Sciences
DTI
Diffusion Tensor Imaging
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EMA
European Medicines Agency 
EQ-5D
EuroQol-5D
ERAC
Exposure-Response Analysis Center
FA
Fractional Anisotropy
Fc
Fragment Crystallizable
FLAIR
Fluid Attenuated Inversion Recovery
FSH
Follicle-Stimulating Hormone
FTLD
Frontotemporal Lobar Degeneration
GABA
Gamma-Aminobutyric Acid
GAM
Generalized Additive Method
GCP
Good Clinical Practice
GGT
Gamma-Glutamyl Transpeptidase
GRN
Progranulin
HbsAg
Hepatitis B Surface Antigen
HCV
Hepatitis C Virus
HCV Ab
Hepatitis C Virus Antibody
HIV
Human Immunodeficiency Virus
IB
Investigator Brochure
ICD
International Classification of Diseases
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IgG4
Subclass of IgG Antibody
IMP
Investigational Medicinal Product


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
15
IND
Investigational New Drug Application
INR
International Normalized Ratio
IP
Intraperitoneal
IRB
Institutional Review Board
IRC
Internal Review Committee
ITT
Intent-to-Treat
IU/L
International Units/Liter
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
IV
Intravenous
IVR/IWB
Interactive Voice-Response/Interactive Web-Based (system)
kD
Dissociation Constant
LAR
Legally Authorized Representative
LFT
Letter Fluency Test
LLN
Lower Limit of Normal
LP
Lumbar Puncture
LS
Least Square
LTE
Long-term Extension
MAPT
Microtubule Associated Protein Tau
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MD
Mean Diffusivity
MedDRA
Medical Dictionary for Regulatory Activities
MMA
Methylmalonic Acid
MMRM
Mixed-effect Model Repeated-Measures
MMSE
Mini-Mental State Examination
MRI
Magnetic Resonance Imaging
MSA
Multiple System Atrophy
NCS
Not Clinically Significant
NFL
Neurofilament
NFTs
Neurofibrillary Tangles
NINCDS-ADRDA
National Institute of Neurological and Communicative Disorders and Stroke 
and the Alzheimer's Disease and Related Disorders Association
NINDS-SPSP
National Institute of Neurological Disorders and the Society for Progressive 
Supranuclear Palsy


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
16
NNIPPS-PPS
Natural History and Neuroprotection in Parkinson Plus Syndromes-Parkinson 
Plus Scale
NOAEL
No Observed Adverse Effect Level
PCR
Polymerase Chain Reaction
PCS
Potentially Clinically Significant
PD
Pharmacodynamics
PGI-C
Patient Global Impression of Change
PIN
Personal Identification Number
PK
Pharmacokinetic
PPS
Pharmacovigilance and Patient Safety
PR
Measure of the time between the start of the P wave and the end of the R wave 
in the heart's electrical cycle
PRN
As Needed
PSP
Progressive Supranuclear Palsy
PSP-QoL
Progressive Supranuclear Palsy Health Related Quality of Life Scale
PSPRS
Progressive Supranuclear Palsy Rating Scale
PSP-SS
PSP Staging System
PT
Prothrombin Time
PT/INR
Prothrombin Time/International Normalized Ratio
PTT
Partial Thromboplastin Time
QRS
Measure of the time between the start of the Q wave and the end of the S wave 
in the heart's electrical cycle
QT
Measure of the time between the start of the Q wave and the end of the T wave 
in the heart's electrical cycle
QTc
Corrected QT
QTcF
QT corrected for heart rate using Fridericia's Method
RA
Regulatory Affairs
RBANS
Repeatable Battery for Assessment of Neuropsychological Status
RBC
Red Blood Cell count
RD
Radial Diffusivity
RNA
Ribonucleic acid
RSI
Reference Safety Information
SAD
Single-Ascending Dose
SAP
Statistical Analysis Plan
SDAC
Statistical and Data Analysis Center


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
17
SAE
Serious Adverse Event
SEADL
Schwab and England Activities of Daily Living Scale
SmPC
Summary of Product Characteristics
SNRIs
Serotonin-Norepinephrine Reuptake Inhibitors
SOC
System Organ Class
SSRIs
Selective Serotonin Reuptake Inhibitors
SUSAR
Suspected Unexpected Serious Adverse Reactions
SV1
Screening Visit 1
SV2
Screening Visit 2
T4
Thyroxine
TA MD
Therapeutic Area Medical Director
TEAE
Treatment-Emergent Adverse Event
TIA
Transient Ischemic Attack
Tmax
Peak Time
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
UPDRS
Unified Parkinson's Disease Rating Scale
US
United States
V
Volume of distribution
VAS
Visual Analog Scale
WBC
White Blood Cell count
WHO
World Health Organization
WOCBP
Women of Childbearing Potential
WPM
Words Per Minute
Definition of Terms
Visit Window
Visits on Days 5, 15, 89, and 99 must be scheduled within ± 2 days.  
Visits on all other days may be scheduled within ± 4 days.  Refer to 
Section 5.3.2.1 for acceptable PK and ADA windows.
Study Drug Infusion
Study drug will be administered at Day 1, Day 15, Day 29, and every 
28 Days thereafter
Scale Order
Certain scales follow a pre-defined order of administration.  Refer to 
Table 7 for recommended sequence.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
18
Study Drug Infusion Visit
A Study Drug Infusion Visit (i.e., defined as a study visit when study 
drug is administered) is deemed complete when all assessments per the 
Study Activities Table (Appendix C) are complete.  The visit may be 
completed over 2 consecutive days, with the second day to include the 
start and end of the infusion.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
19
2.0
Table of Contents
1.0
Title Page ...............................................................................1
1.1
Protocol Amendment:  Summary of Changes ......................................... 2
1.2
Synopsis................................................................................................. 4
1.3
List of Abbreviations and Definition of Terms...................................... 13
2.0
Table of Contents ................................................................ 19
3.0
Introduction......................................................................... 24
3.1
Differences Statement .......................................................................... 28
3.2
Benefits and Risks................................................................................ 28
4.0
Study Objective ................................................................... 29
5.0
Investigational Plan.............................................................30
5.1
Overall Study Design and Plan:  Description ........................................ 30
5.2
Selection of Study Population............................................................... 37
5.2.1
Inclusion Criteria.................................................................................. 38
5.2.2
Exclusion Criteria................................................................................. 40
5.2.3
Prior and Concomitant Therapy............................................................ 44
5.2.3.1
Prohibited Therapy............................................................................... 45
5.2.4
Contraception Recommendations and Pregnancy Testing ..................... 47
5.3
Efficacy, Pharmacokinetic, Biomarker, Pharmacogenetic and 
Safety Assessments/Variables............................................................... 49
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ............... 49
5.3.1.1
Study Procedures.................................................................................. 49
5.3.1.2
Collection and Handling of Biomarker and Pharmacogenetic 
Research Samples................................................................................. 71
5.3.1.3
Confinement......................................................................................... 72
5.3.1.4
Meals and Dietary Requirements.......................................................... 73
5.3.2
Drug and Anti-Drug Antibody Concentration Measurements................ 73
5.3.2.1
Collection of Samples for Analysis....................................................... 73
5.3.2.2
Measurement Methods ......................................................................... 77
5.3.3
Efficacy Variables................................................................................ 77
5.3.4
Safety Variables ................................................................................... 78
5.3.5
Pharmacokinetic Variables ................................................................... 78


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
20
5.3.6
Biomarker and Pharmacogenetic Research Variables............................ 79
5.3.6.1
Biomarker Research Variables.............................................................. 79
5.3.6.2
Pharmacogenetic Research Variables.................................................... 79
5.3.7
Immunogenicity ................................................................................... 80
5.4
Removal of Subjects from Therapy or Assessment ............................... 80
5.4.1
Discontinuation of Individual Subjects ................................................. 80
5.4.2
Discontinuation of Entire Study............................................................ 81
5.5
Treatments ........................................................................................... 82
5.5.1
Treatments Administered...................................................................... 82
5.5.2
Identity of Investigational Product........................................................ 83
5.5.2.1
Packaging and Labeling........................................................................ 84
5.5.2.2
Storage and Disposition of Study Drug................................................. 85
5.5.2.3
Preparation/Reconstitution of Dosage Form.......................................... 86
5.5.3
Method of Assigning Subjects to Treatment Groups ............................. 86
5.5.4
Selection and Timing of Dose for Each Subject .................................... 86
5.5.5
Blinding ............................................................................................... 87
5.5.6
Treatment Compliance ......................................................................... 89
5.5.7
Drug Accountability ............................................................................. 89
5.6
Discussion and Justification of Study Design........................................ 89
5.6.1
Discussion of Study Design and Choice of Control Groups .................. 89
5.6.2
Appropriateness of Measurements........................................................ 90
5.6.3
Suitability of Subject Population .......................................................... 90
5.6.4
Selection of Doses in the Study ............................................................ 90
6.0
Complaints........................................................................... 93
6.1
Medical Complaints ............................................................................. 93
6.1.1
Definitions ........................................................................................... 94
6.1.1.1
Adverse Event...................................................................................... 94
6.1.1.2
Serious Adverse Events........................................................................ 95
6.1.2
Adverse Event Severity ........................................................................ 96
6.1.3
Relationship to Study Drug................................................................... 96
6.1.4
Adverse Event Collection Period.......................................................... 97
6.1.5
Adverse Event Reporting...................................................................... 98
6.1.6
Pregnancy............................................................................................100


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
21
6.1.7
Toxicity Management..........................................................................100
6.1.7.1
Management of Adverse Events of the Nervous System ......................102
6.1.8
Collection of Data Regarding Known Complications of the 
Disease Under Study ...........................................................................103
6.2
Product Complaint...............................................................................104
6.2.1
Definition............................................................................................104
6.2.2
Reporting ............................................................................................104
7.0
Protocol Deviations ........................................................... 105
8.0
Statistical Methods and Determination of Sample 
Size ..................................................................................... 106
8.1
Statistical and Analytical Plans............................................................106
8.1.1
Analysis Data Sets...............................................................................106
8.1.2
Disposition, Demographics, and Other Baseline Characteristics ..........107
8.1.3
Efficacy Analyses................................................................................108
8.1.3.1
Primary Efficacy Analysis...................................................................111
8.1.3.2
Secondary Efficacy Analysis ...............................................................111
8.1.4
Subgroup Analysis of PSPRS Total Score ...........................................113
8.1.5
Biomarker Analyses ............................................................................114
8.1.6
Safety Analyses...................................................................................115
8.1.6.1
Analysis of Adverse Events.................................................................116
8.1.6.2
Analysis of Laboratory Tests...............................................................116
8.1.6.3
Analysis of Vital Signs and Weight .....................................................117
8.1.6.4
Analysis of ECG Variables..................................................................117
8.1.6.5
Analysis of C-SSRS ............................................................................117
8.1.7
Pharmacokinetics ................................................................................118
8.1.7.1
Tabulations and Summary Statistics ....................................................118
8.1.7.2
Model and Tests ..................................................................................118
8.1.7.3
Missing Values and Model Violations .................................................120
8.1.7.4
Population Pharmacokinetic and Exposure-Response Analysis............120
8.1.8
Immunogenicity ..................................................................................122
8.1.9
Data Monitoring Committee (DMC)....................................................122
8.1.10
Interim Analyses .................................................................................123
8.2
Determination of Sample Size .............................................................125


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
22
9.0
Ethics.................................................................................. 125
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ........................................................................................125
9.2
Ethical Conduct of the Study...............................................................126
9.3
Subject Information and Consent.........................................................126
10.0
Source Documents and Case Report Form 
Completion ........................................................................ 128
10.1
Source Documents...............................................................................128
10.2
Case Report Forms..............................................................................128
11.0
Data Quality Assurance .................................................... 129
12.0
Use of Information ............................................................ 130
13.0
Completion of the Study ................................................... 131
14.0
Investigator's Agreement.................................................. 132
15.0
Reference List.................................................................... 133
List of Tables
Table 1.
Description of Cohorts.......................................................................... 31
Table 2.
Safety Observation Period Following Infusions .................................... 33
Table 3.
Sample Size.......................................................................................... 35
Table 4.
Safety and PK Procedures for Cohort 1 and Cohort J1.......................... 36
Table 5.
Prohibited Medications......................................................................... 46
Table 6.
Clinical Laboratory Tests ..................................................................... 57
Table 7.
Diagnostic Tools and Scale Order and Duration of Administration ....... 63
Table 8.
Identity of Investigational Product........................................................ 84
Table 9.
Hypotheses Testing Order in the Graphical Testing Approach.............110
List of Figures
Figure 1.
Study Schematic................................................................................... 35
Figure 2.
Adverse Event Collection..................................................................... 98
Figure 3.
A Graph for Multiplicity Adjustment of Multiple Hypotheses .............110


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
23
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator.........................................137
Appendix B.
List of Protocol Signatories .................................................................139
Appendix C.
Study Activities...................................................................................140
Appendix D.
Potentially Clinically Significant (PCS) Laboratory Value...................147
Appendix E.
Protocol Amendment:  List of Changes ...............................................152


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
24
3.0
Introduction
Progressive Supranuclear Palsy
Progressive supranuclear palsy (PSP, also known as Steele-Richardson-Olszewski 
Syndrome) is a progressive neurodegenerative disorder, with an estimated annual 
incidence of 5 – 7 per 100,000.1  Within the United States (US), the disease affects 
approximately 20,000 individuals.  There is no apparent geographical, ethnic, gender, or 
racial disparity in PSP frequency.  PSP can initially present with clinical symptoms 
similar to other brain disorders, including idiopathic Parkinson's disease.  For this reason, 
correct diagnosis of PSP is sometimes delayed, often taking place 1 to 3 years after the 
initial onset of clinical symptoms.  Symptom onset is most often between the ages of 50 to 
70 years, and although the clinical course is variable, the typical survival from time of 
symptom onset is 5 to 9 years.2  Though some heterogeneity in clinical presentation 
exists, the most common and initially described PSP syndrome, now referred to as Steele-
Richardson-Olszewski Syndrome, presents with symptoms including prominent postural 
instability and axial rigidity leading to falls, supranuclear gaze palsy causing range of 
vision impairment, frontal-subcortical cognitive impairment, and dysphagia leading to 
aspiration.  The course of disease is progressive and uniformly fatal.3
Pathologically, PSP is characterized by the abnormal accumulation of 
hyperphosphorylated, insoluble aggregates of tau protein in neurons and glia in the 
brainstem, cerebellum, basal ganglia, and cerebral cortex.3  The degree and distribution of 
tau aggregation in PSP is strongly correlated with PSP symptomatology during life.4  The 
National Institute of Neurological Disorders and the Society for Progressive Supranuclear 
Palsy (NINDS-SPSP) research criteria which describe Steele-Richardson-Olszewski 
Syndrome are highly predictive of underlying PSP pathology.5  Neuronal loss in various 
regions of the brain accompanies neurofibrillary tangles (NFTs) that are composed of tau 
aggregates.  Multiple neurotransmitter abnormalities arise as well, including those 
affecting specific dopaminergic, cholinergic, GABAergic, and noradrenergic systems.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
25
There are no currently approved treatments for PSP.6  The negative outcomes of 
therapeutic efficacy studies in PSP preclude recommending an evidence-based standard 
therapy.7  In the absence of any effective disease modifying or neuroprotective therapies, 
PSP represents an urgent unmet medical need.
ABBV-8E12
ABBV-8E12 is a humanized monoclonal subclass of the IgG antibody (IgG4) against 
human microtubule-associated protein tau.  It is a recombinant glycoprotein produced in 
Chinese hamster ovary cells.  It targets soluble extracellular tau in the brain, which has 
been implicated in the development and spreading of tau pathology.  Neurofibrillary 
tangles, a characteristic pathologic feature in PSP and several other neurological disorders 
including corticobasal degeneration (CBD) and Alzheimer's disease (AD), 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 
neurodegenerative disorders associated with tau.
Preclinical Efficacy
In preclinical studies, the mouse version of the antibody (HJ8.5) was found to specifically 
block tau seeding activity from brain lysates of P301S transgenic mice in vitro.8  The 
P301S animal is a transgenic mouse model that carries a mutated human tau gene that 
leads to early onset frontotemporal dementia in humans.  In vivo, 3 months of treatment 
with HJ8.5 as a continuous intracerebroventricular infusion was associated with potent 
reductions in tau pathology, as evidenced by biochemical, histopathological, and 
functional/behavioral measures.  A similar study to assess the effects of peripherally 
(intraperitoneal, IP) administered HJ8.5, found that weekly IP injections of HJ8.5 was 
highly effective at reducing insoluble tau in the brain, reducing cortical and hippocampal 
atrophy, and improving sensorimotor function.9


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
26
Nonclinical Safety
ABBV-8E12 binds to human tau but not to tau protein from preclinical toxicology species 
(i.e., rhesus/cynomolgus monkey, canine, rabbit, rat or mouse).  Therefore, there is no 
pharmacologically relevant species in which to conduct toxicology studies to support 
safety of ABBV-8E12.  To assess toxicity in non-relevant species, a 4-week study in wild-
type mice was conducted at doses up to 250 mg/kg for 4 weeks via weekly intravenous 
(IV) injections.  There were no adverse effects at any dose level and the no observed 
adverse event level (NOAEL) was 250 mg/kg.  Based on predictions from the 2.5 and 7.5 
mg/kg groups in the single ascending dose (SAD) study, this is predicted to provide a 
margin of 1.4-fold over projected exposures at the highest dose of 4000 mg planned in 
this study.
A detailed discussion of the preclinical toxicology and pharmacology can be found in the 
Investigator's Brochure (IB).10
Clinical Experience
Prior to this study, treatment with ABBV-8E12 was initiated under an Expanded Access 
Investigational New Drug (IND) in the US for one patient with PSP, and subsequently 
treatment with ABBV-8E12 was initiated for one patient with CBD under a single named 
trial application in Germany.
The PSP patient received 20 monthly infusions (highest dose 25 mg/kg for the last 
7 infusions), then died from PSP complications unrelated to study drug.  The CBD patient 
received 3 monthly infusions (1 at 7.5 mg/kg, 2 at 15 mg/kg), but died due to suicide 
10 days after the second 15 mg/kg infusion.  The CBD patient had a strong history of 
suicidal ideation and premeditation that preceded compassionate treatment with 
ABBV-8E12.  No evidence of imaging abnormalities or other evidence of drug-related 
toxicity was detected in these 2 patients.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
27
Single Dose Study
The SAD study (Study C2N-8E12-WW-104) investigated 5 dose levels (2.5 mg/kg, 
7.5 mg/kg, 15 mg/kg, 25 mg/kg, and 50 mg/kg) in 30 patients with PSP (n = 23 on 
ABBV-8E12, n = 7 on placebo).  
Three serious adverse events (SAEs) were reported in this study.  In the 15 mg/kg dose 
group, 1 subject reported an SAE of a subdural hematoma resulting from a fall that was 
assessed as possibly related to study drug by the investigator.  The sponsor judged the 
SAE to be unlikely related to study drug, and likely related to the underlying PSP disease.  
In the 25 mg/kg dose group, 1 subject was hospitalized due to a severe increase in 
agitation, anxiety, and perseverative behavior; the subject was discontinued from the 
study after being unable to participate following the SAE.  The investigator and sponsor 
assessed that the worsening symptoms may represent progression of the patient's 
underlying disease, but that the study drug cannot be ruled out as a contributing factor, so 
the event was therefore assessed as possibly drug related.  In the 50 mg/kg dose group, 
1 subject was hospitalized for evaluation and treatment of hypertension.  This SAE was 
assessed by the investigator as moderate in severity, resolved without sequelae, and 
unrelated to study drug.
No subject experienced a systemic hypersensitivity reaction or injection site reaction, and 
there have been no clinically relevant patterns of adverse events (AEs) or abnormal 
laboratory findings observed.  Based on available anti-drug antibody (ADA) data in 
Study C2N-8E12-WW-104, no ADAs have been detected in post-dose samples on Day 14 
and Day 28.
The plasma pharmacokinetic data from Study C2N-8E12-WW-104 indicate dose-
proportional increases in area under the concentration time curve (AUC) from 2.5 to 
50 mg/kg.  The mean time to maximum plasma concentration (Tmax) ranged from 
0.3 hours to 4.6 hours, and half-life ranged from 27 to 37 days.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
28
Cerebrospinal fluid (CSF) concentrations increased with dose, and the CSF/plasma 
ABBV-8E12 ratio ranged from 0.181% to 0.385%.
3.1
Differences Statement
Study M15-562 Phase 2 study is the first randomized, placebo controlled clinical trial to 
evaluate efficacy, safety, tolerability, and pharmacokinetics (PK) of multiple doses of 
ABBV-8E12 in subjects with PSP.  The study features enhanced PK and safety 
assessments in Cohort 1, Cohort J1 and all subjects will be enrolled for an extended 
treatment period of up to 52 weeks.  The initial Phase 1 clinical study (Study C2N-8E12-
WW-104) is a randomized, double-blind, placebo controlled, SAD study in PSP patients 
at doses ranging from 2.5 mg/kg to 50 mg/kg and the results of the study indicate that 
ABBV-8E12 is generally well tolerated up to the highest tested dose of 50 mg/kg without 
notable treatment-related adverse effects or any clinically concerning safety findings.
3.2
Benefits and Risks
ABBV-8E12 was administered under protocol C2N-8E12-WW-104 to 23 subjects with 
PSP in single doses up to 50 mg/kg with no clinically concerning safety findings.  
In addition, 2 subjects received multiple doses of ABBV-8E12, one under an Expanded 
Access IND, protocol C2N-8E12-EA-001 (US) and the other under a single named trial 
application, C2N-8E12-DE-003 (Germany).  Treatment appeared well tolerated.  
One subject received 20 monthly doses up to 25 mg/kg and one subject received 
3 monthly doses up to 15 mg/kg.
ABBV-8E12 recognizes human tau and does not bind to tau from other species.  Off-
target toxicity of ABBV-8E12, up to 250 mg/kg/week, was assessed in a 4-week mouse 
toxicity study.  No adverse effects at any dose level were detected.  Evidence of efficacy 
demonstrated in preclinical studies and safety data from clinical studies obtained to date 
provide a strong rationale for continuing assessment of safety and efficacy in the current 
study.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
29
The benefit-risk profile will be further defined in this trial.
4.0
Study Objective
The primary objectives of this study are:
●
To assess the efficacy of ABBV-8E12 in slowing disease progression in 
subjects with progressive supranuclear palsy as measured by the PSP Rating 
Scale (PSPRS).
●
To assess the long term safety and tolerability of ABBV-8E12 for up to 
52 weeks in subjects with progressive supranuclear palsy.
The secondary objectives of this study are:
●
To assess the pharmacokinetics of multiple doses of ABBV-8E12 in subjects 
with progressive supranuclear palsy.
●
To assess the efficacy of ABBV-8E12 in slowing disease progression and 
functional impairment in subjects with progressive supranuclear palsy as 
measured by secondary endpoints.
●
To assess the efficacy of ABBV-8E12 in slowing regional and/or whole brain 
atrophy in subjects with progressive supranuclear palsy as measured by 
volumetric magnetic resonance imaging (MRI).
The exploratory objectives of this study are:
●
To assess the efficacy of ABBV-8E12 in slowing disease progression and 
functional impairment in subjects with progressive supranuclear palsy as 
measured by exploratory endpoints.
●
To assess the effect of ABBV-8E12 on CSF and plasma tau protein levels.
●
To assess the effect of ABBV-8E12 on potential CSF and plasma biomarkers 
of disease progression.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
30
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This Phase 2, randomized, double-blind, placebo-controlled, multiple dose, multicenter 
study will consist of a screening period of up to 8 weeks (56 days), a 52 week double-
blind treatment period, and a post-treatment follow-up period of approximately 20 weeks 
following last study drug administration (including those subjects who prematurely 
discontinue from treatment, decline to participate in or do not qualify for participation in a 
long term extension [LTE] study).  The study is planned to be conducted at approximately 
60 sites around the world.  Approximately 330 subjects will participate in the study.
At the end of the treatment period, eligible subjects who completed the 52 week treatment 
period may enter a separate LTE study for extended treatment.  All activities for the LTE 
study will be outlined in a separate extension study protocol.
Eligible subjects will be enrolled into the Treatment Period of the study on Day 1 and 
receive their first infusion of study drug.  During the first 4 weeks, subjects will have 
3 study drug infusions; the first on Day 1, the second at Day 15, and the third at Day 29; 
thereafter, subjects will return to the study site every 28 Days for their study drug 
infusion, blood collection, study procedures and assessments as outlined in the Study 
Activities Table (Appendix C).  This dosing schedule (with one additional dose delivered 
at Day 15) will enable rapid attainment of steady-state drug levels in plasma to maximize 
the likelihood of demonstrating a treatment effect.  Subjects will be observed on-site for at 
least 2 hours following each of the first 4 infusions of study drug and for at least 
30 minutes after the end of infusion of all doses thereafter.
Refer to Section 5.5.1 for details on infusion times.
Approximately 330 subjects with PSP matching the selection criteria described in 
Section 5.2, will be eligible to enter the study double-blind treatment period.  Eligible 
subjects will be randomized to one of the two ABBV-8E12 dose arms (2000 mg or 
4000 mg) or placebo in a 1:1:1 ratio.  Doses will be administered via IV infusion at Day 1, 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
31
Day 15, Day 29, and every 28 days thereafter through dose 14 at Week 48.  Refer to 
Section 5.5.1 for details on infusion times.
Safety and tolerability will be monitored throughout the study. 
The study will consist of 3 Cohorts (Table 1).
Table 1.
Description of Cohorts
Region
Cohort 1*
Cohort J1**
Cohort 2***
Global (not including 
Japan)
First 30 subjects 
enrolled#
NA
n = ~276
Japan
NA
First 9 subjects 
enrolled#
n = ~15
*
Cohort 1:  Augmented safety and PK assessments in the first 30 subjects enrolled into the global study from 
countries other than Japan.
**
Cohort J1:  Augmented safety and PK assessments in the first 9 subjects enrolled into the study from Japan.
*** Cohort 2:  All other subjects enrolled in the global study not participating in Cohort 1 or Cohort J1.
#
Augmented safety and pharmacokinetic assessments including additional study visits, more frequent neurological 
exams, vital signs, blood collections for safety labs, an additional lumbar puncture and MRI, and additional 
monitoring by the Data Monitoring Committee (DMC) will be performed in Cohort 1 and Cohort J1.
Eligible subjects will be enrolled into the Treatment Period of the study on Day 1 and 
receive their first infusion of study drug.  During the first 4 weeks, subjects will have 
3 study drug infusions; the first on Day 1, the second on Day 15, and the third on Day 29; 
thereafter, subjects will return to the study site every 28 Days for their study drug 
infusion, blood collection, study procedures and assessments as outlined in the Study 
Activities Table (Appendix C).  This dosing schedule (with one additional dose delivered 
at Day 15) will enable rapid attainment of steady-state drug levels in plasma to maximize 
the likelihood of demonstrating a treatment effect.  Subjects will be observed on-site for at 
least 2 hours following each of the first 4 infusions of study drug and for at least 
30 minutes after the end of infusion of all doses thereafter.  Subjects randomized in 
Cohort 1 and Cohort J1 will return to the study site on Day 5, Day 15, Day 89, Day 99, 
and Day 113 for collection of additional safety assessments and PK samples listed in 
Table 4 (Safety and PK Procedures for Cohort 1 and Cohort J1).


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
32
Subjects in Cohort J1 will be confined for a minimum of 24 hours following their 
first infusion.  For subjects expecting to be discharged on the second day (Day 2), the 
Investigator will assess safety to determine discharge.  Subjects will have another study 
visit 2 days after the first infusion (Day 3), either while in the hospital or as an outpatient 
to assess safety.  From their second to fourth infusion, Cohort J1 subjects will be observed 
on-site for at least 2 hours following each infusion of study drug.
Subjects in Cohort 2 will be observed on site for at least 2 hours following each of the 
first 4 infusions of study drug.  Following the 4th infusion, all subjects will be observed 
on-site for at least 30 minutes after the end of infusion of all doses (Table 2).
Investigators will monitor for AEs, including conditions associated with infusions in 
general, and infusion reactions.  Subjects experiencing AEs, including infusion reactions, 
may need to be observed for longer periods and undergo additional assessments at the 
Investigator's discretion.
Additionally, subjects enrolled in Cohort J1 (first 9 subjects) will be randomized at least 
2 days apart from each other.  During this 2-day interval the Investigator will assess for 
clinically relevant adverse events. In this context, the term "clinically relevant" adverse 
events refers to severe or life threatening adverse events potentially related to study drug, 
for example:  infusion-related allergic or hypersensitivity reactions, or neurologic AEs 
such as a seizure.  AbbVie will confirm that the Investigator has reviewed the safety of the 
most recently enrolled subject into Cohort J1, and will ensure the safety of the product 
prior to allowing the next subject to be randomized into Cohort J1.
In Japan, sites must contact AbbVie prior to randomizing any subject into Cohort J1 and 
AbbVie will notify sites when Cohort J1 is fully enrolled.  A DMC meeting will occur to 
review the safety of subjects enrolled in Cohort J1, and only after the DMC has 
recommended to continue enrollment into the study without modification, will Japanese 
subjects be enrolled into Cohort 2.  Henceforth, no further restriction to randomization 
will apply.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
33
Table 2.
Safety Observation Period Following Infusions
Cohort
Infusion 1
Infusions 2, 3, and 4
Infusion 5 and Onwards
Cohort 1*
Observed on-site for at 
least 2 hours
Observed on-site for at 
least 2 hours
Observed on site for at least 
30 minutes
Cohort J1
Confined for a minimum 
of 24 hours and safety 
confirmation 2 days post 
1st infusion
Observed on-site for at 
least 2 hours
Observed on site for at least 
30 minutes
Cohort 2
Observed on-site for at 
least 2 hours
Observed on-site for at 
least 2 hours
Observed on site for at least 
30 minutes
*
Cohort 1:  The first 30 subjects enrolled into the global study from countries other than Japan.
DMC Review of Interim Safety Data 
This study will utilize a DMC consisting of at least 2 external clinicians, at least 1 external 
statistician, and at least 1 external pharmacokineticist.  The DMC will review unblinded 
safety and efficacy data and make recommendations to the Sponsor based on the totality 
of available clinical data.  The DMC memberships, responsibilities and operating logistics 
will be documented in a charter that will be prepared prior to the first DMC review 
meeting.
In addition to blinded safety data monitoring by the Sponsor, the first three mandatory 
DMC reviews of unblinded safety data will take place after the 10th, 20th, and 30th subjects 
in Cohort 1 have received their second dose and results for the Day 15 Safety labs and the 
MRI performed within 2 weeks after their second dose are available.  The dataset 
reviewed will include all of the available safety and pharmacokinetic data in the study, 
including the data of any subjects from Cohort 2 who have received at least one dose of 
study drug. 
For Cohort J1, an additional mandatory DMC review will take place after the 9th subject 
enrolled in Japan has received their second dose and results for the Day 15 Safety labs and 
the MRI performed within 2 weeks after their second dose, are available.  Only after the 
DMC has recommended to continue enrollment into the study without modification, will 
Japanese subjects be enrolled into Cohort 2.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
34
Additional DMC reviews of available safety data will occur after a total of approximately 
80, 130, 180, 240, and 330 subjects are randomized and every 6 months thereafter until 
the study has completed.  Ad hoc meetings may occur as needed.
Doses may be decreased after the evaluation by the DMC of available safety, tolerability 
and PK data. 
Long-Term Extension Study:
If ABBV-8E12 is safe and well tolerated in the current study, a long-term extension study 
will be developed and implemented under a separate protocol. 
Post-Treatment Follow-Up:
All subjects who would not enter the separate long-term extension study for extended 
treatment (including subjects who prematurely discontinue from treatment, or would 
decline to participate in or would not qualify for the long-term extension study) will enter 
the Post-treatment Follow-up Period within this study.
A schematic of the study design is shown in Figure 1.  A table of sample size and dosing 
groups is provided in Table 3.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
35
Figure 1.
Study Schematic
Table 3.
Sample Size
Treatment Group
N = 330
Treatment Duration
Placebo
n = 110
IV infusion on Day 1, Day 15, Day 29, 
and then every 28 days for 52 weeks
(Total of 14 infusions)
ABBV-8E12 2000 mg
n = 110
ABBV-8E12 4000 mg
n = 110
Safety and PK procedures for Cohort 1 and Cohort J1 are presented in Table 4.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
36
Table 4.
Safety and PK Procedures for Cohort 1 and Cohort J1
Screening
Cohort 1 and Cohort J1, Doses 1 – 6
Visit 1
Visit 2
Dose 1
Dose 
2
Dose 
3
Dose 
4
Dose 
5
Dose 
6
Weeks of 
Study 
Drug 
Exposure
N/A
N/A
0
0
0
0
2
4
8
12
13
14
16
Days
–56 to –8
Days
–56 to –8
Day
1
Day 
2j,k
Day 
3j
Day
5
Day
15
Day
29
Day
57
Day 
85
Day 
89
Day 
99
Day 
113
Physical 
Exama
X
X
X
X
Neurolog-
ical Exam
X
X
X
X
X
X
X
X
X
X
Orthostatic 
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead 
ECG
X
Xb
Xc
Xb
Xd
Xd
Xb
Clinical 
Laboratory 
Tests
X
X
Xj
X
X
X
MRI
X
Xe
X
Lumbar 
Puncture/
CSF 
Sample 
Collection
X
Xf
PK Sample 
Collection
Xg
X
Xg
X
X
Xg
X
X
X
ADA 
Sample 
Collection
Xh
Xh
Xh
Xh
Xh
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
X
AE/
ConMed 
Review
X
X
X
X
X
X
X
X
X
X
X
X
X
24 hour 
confine-
menti
X
This table describes the frequency of safety and PK procedures for Cohort 1and Cohort J1 through Day 113.  Refer to 
Appendix C for complete list of required study procedures at each visit. 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
37
Table 4.
Safety and PK Procedures for Cohort 1 and Cohort J1 (Continued)
Visits on Days 5, 15, 89, and 99 must be scheduled within ± 2 days.  Visits on all other days may be scheduled within 
± 4 days.
a.
Additional symptom-driven physical exams can be performed as needed.
b.
Pre-dose and within 15 minutes after the end of the infusion and prior to the PK sample collection.
c.
Collection should be scheduled as close as possible to the corresponding time of the post infusion PK collection on 
Day.
d.
Pre-dose (just prior to the start of infusion).
e.
For subjects in Cohort 1 and Cohort J1, an MRI will be performed within 2 weeks following the second dose and 
results must be available prior to the next scheduled dose.
f.
The lumbar puncture will be performed approximately 14 days after the fifth dose.
g.
Prior to the start of the infusion (0 hour, no more than 30 minutes prior to the start of the infusion), immediately 
after the end of the infusion (within 15 minutes) and 1 and 2 hours after the end of the infusion.
h.
Prior to the start of the infusion (0 hour, no more than 30 minutes prior to the start of the infusion).
i.
A 24-hour confinement will be required following the first dose in Cohort J1.
j.
Cohort J1 subjects only.
k.
Cohort J1 Day 2 assessments will be performed only in subjects discharged on Day 2.
Detailed information regarding the regimens/treatments administered and assignment of 
the subjects to the treatments can be found in Section 5.5.1 and Section 5.5.3, 
respectively.
This study was designed to randomize approximately 330 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  Therefore, if the target number of subjects have been randomized, 
there is a possibility that additional subjects in screening will not be randomized.
5.2
Selection of Study Population
Subjects will undergo screening procedures within 8 weeks prior to initial study drug 
administration.  Adult male and female subjects who meet the inclusion criteria and who 
do not meet any of the exclusion criteria will be eligible for enrollment into the study.
Subjects who have signed informed consent and did not randomize because they did not 
complete the study-specific procedures during the Screening Period or did not meet all 
entry criteria will be considered Screen Failures.  The reason(s) for screen failure will be 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
38
recorded in the source documents and will be captured in the electronic case report form 
(eCRF).  Subjects who screen fail may be re-screened on a case-by-case basis after 
consulting the AbbVie Therapeutic Area Medical Director (TA MD) for approval.
Prior to enrolling a subject into Cohort J1, the Investigator/study staff must contact 
AbbVie to obtain approval.  AbbVie will notify sites when Cohort J1 has been fully 
enrolled and will also notify sites when enrollment into Cohort 2 for Japanese subjects 
may commence.
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 had the 
opportunity to have any questions answered.  The subject has voluntarily signed the 
Independent Ethics Committee (IEC)/Independent Review Board (IRB) approved 
Informed Consent, prior to the conduct of any study 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 have 
been signed by a person who has the legal right to act on behalf of the subject 
following national laws.  In Germany, where the subject's legally authorized 
representative (LAR) is not permitted to sign the IEC/IRB approved Informed 
Consent form on behalf of the subject, evaluation by an independent psychiatrist 
will be sought if the investigator who is evaluating the subject for inclusion in the 
study doubts the subject's cognitive ability to independently provide informed 
consent.
2.
Male or female subject with age 40 years or greater at the time of signed consent.
3.
Meets the following criteria for possible or probable PSP (Steele-Richardson-
Olszewski Syndrome):
●
gradually progressive disorder, with age at disease onset greater than or equal 
to 40 years


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
39
●
either or both of the following two items are met:  (Refer to Section 5.3.1.1, 
Neurological Examination, for a description of assessment techniques):
1. vertical supranuclear gaze palsy
2. slowing of vertical saccades AND postural instability with falls within the 
first 3 years of PSP symptoms
4.
Presence of PSP symptoms for less than 5 years.  For the purpose of this inclusion 
criterion, a PSP symptom will be defined as any neurological, cognitive or 
behavior symptom consistent with known symptoms of PSP, occurring newly and 
subsequently progressing during the clinical course in the absence of another 
identifiable cause.
5.
Subject is able to walk 5 steps with minimal assistance (stabilization of one arm or 
use of cane/walker).
6.
Subject has an identified, reliable, study partner (e.g., caregiver, family member, 
social worker, or friend), who has frequent contact with the subject (at least 
10 hours per week) and who can accompany the subject to study visits to provide 
information as to the subject's functional abilities.  The study partner has 
voluntarily signed the Independent Ethics Committee (IEC)/Institutional Review 
Board (IRB) approved Informed Consent, prior to the conduct of any study 
procedures.
7.
If female, the subject may not be pregnant or breastfeeding.
8.
If female and of non-childbearing potential, the subject must be either 
postmenopausal (defined as age ≥ 55 years with no menses for 12 or more months 
without an alternative medical cause) or permanently surgically sterile (bi-lateral 
oophorectomy, bilateral salpingectomy or hysterectomy).  If female and of 
childbearing potential, the subject must agree to practice at least one of the 
following methods of birth control throughout the study and for 20 weeks after 
study completion:
●
Total abstinence from intercourse;


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
40
●
Vasectomized partner(s);
●
Intrauterine device (IUD);
●
Using oral, injected,* or implanted* methods of hormonal contraceptives (oral, 
parenteral or transdermal) for at least 3 months prior to randomization and the 
partner should also use a barrier method (e.g., condom) with spermicidal* 
foam/gel/film/cream/suppository during this study and for 20 weeks after 
study completion.
9.
All female subjects of childbearing potential must have negative result of a serum 
pregnancy test performed at screening and a negative urine pregnancy test result is 
required prior to any radiological procedures.
10.
If male and sexually active with female partner(s) of childbearing potential, subject 
must agree, from Study Day 1 through 20 weeks after the last dose of study drug, 
to practice the protocol specified contraception (Refer to Section 5.2.4).
* Not approved in Japan.
Rationale for the Inclusion Criteria
1
In accordance with the harmonized Good Clinical Practice (GCP)
2 – 7
To select subject population appropriate for this study
8 – 10
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:
1.
Male or female subject weighing less than 44 kg (97 lbs.) at screening will be 
excluded.
2.
Mini-Mental State Examination (MMSE) score less than 15 at screening, or 
cognitive impairment that in the Investigator's opinion would preclude collection of 
outcome measures.  In Germany, for all subjects with an MMSE score of 24 or less 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
41
at the time of study entry, an evaluation by an independent psychiatrist will also be 
requested.  If, in the opinion of the independent psychiatrist, subject is unable to 
provide consent independently, the subject will not be enrolled in the study.
3.
Any contraindication or inability to tolerate brain MRIs (e.g., a pacemaker or any 
other implanted device or condition that would preclude proximity to a strong 
magnetic field).
4.
During enrollment of Cohort 1 and Cohort J1, any contraindication or inability to 
tolerate lumbar punctures (LP) (e.g., use of anticoagulant medications such as 
warfarin) are exclusionary.  During enrollment of Cohort 2, subjects who are not 
able to undergo LP may be admitted with permission of the AbbVie Medical 
Director, and these subjects will not be required to undergo LP during the study.
5.
Subject resides at a skilled nursing or dementia care facility, or admission to such a 
facility is planned during the study period.
6.
Evidence of any neurological disorder that could explain signs of PSP, including:
a.
Signs of idiopathic Parkinson's disease (e.g., severe asymmetric parkinsonian 
signs, clinically significant tremor at rest, or prominent and sustained response to 
levodopa therapy)
b. Signs of multiple system atrophy (MSA) (e.g., prominent early cerebellar limb 
ataxia or unexplained symptomatic autonomic dysfunction)
c.
Signs of Lewy body disease (e.g., hallucinations or delusions unrelated to 
dopaminergic therapy or other illness)
d. Probable Alzheimer's disease according to National Institute of Neurological and 
Communicative Disorders and Stroke and the Alzheimer's Disease and Related 
Disorders Association (NINCDS-ADRDA) criteria
e.
History of repeated strokes with stepwise progression of parkinsonian features
f.
History of major stroke
g. History of severe or repeated head injury
h. History of encephalitis


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
42
i.
History of neuroleptic use (with the exception of clozapine or quetiapine) for a 
prolonged period of time or within the past 6 months
j.
Oculogyric crises
k. Street-drug-related parkinsonism
l.
Known history of autosomal dominant PSP due to a microtubule associated 
protein tau (MAPT) mutation
m. Known history of an autosomal dominant mutation associated with frontotemporal 
lobar degeneration (FTLD) (e.g., an autosomal dominant mutation in C90RF72 or 
GRN)
n. Significant other neurological disease on MRI that could account for PSP 
symptoms
7.
Evidence of any clinically significant neurological disorder other than PSP, 
including but not limited to significant cerebrovascular abnormalities, vascular 
dementia, motor neuron disease or amyotrophic lateral sclerosis (ALS), 
Huntington's disease, normal pressure hydrocephalus, brain tumor, seizure 
disorder, multiple sclerosis, or known structural brain abnormalities.
8.
The subject has a history of or currently has schizophrenia, schizoaffective disorder 
or bipolar disorder according to Diagnostic and Statistical Manual of Mental 
Disorders, 5th Edition (DSM-V) or International Classification of Diseases 
(ICD)-10 criteria.
9.
In the opinion of the investigator, the subject has any clinically significant 
uncontrolled psychiatric illness.
10.
Subject has significant current suicidal ideation within one year prior to screening 
as evidenced by answering "yes" to questions 4 or 5 on the suicidal ideation portion 
of the Columbia-Suicide Severity Rating Scale (C-SSRS) completed at screening 
or a history of suicidal attempts within the last 2 years.
11.
Positive screen for drugs of abuse or marijuana at screening visit.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
43
12.
Current diagnosis or history of drug or alcohol abuse (by DSM-V criteria) within 
24 months prior to screening visit.
13.
Subject has had a significant illness or infection requiring medical intervention in 
the past 30 days.
14.
Subject has a positive test result for hepatitis B surface antigen (HbsAg) or 
hepatitis C virus antibody (HCV Ab), or a known history of Human 
Immunodeficiency Virus (HIV) infection.
15.
The subject has a history or evidence of a malignancy within the 2 years prior to 
the screening visit.  Subjects with some indolent malignancies (e.g., basal cell 
carcinoma or squamous cell carcinoma of the skin) may be permitted to enroll with 
the permission of the AbbVie Medical Director.
16.
Subject has had a myocardial infarction, advanced chronic heart failure, unstable 
angina, stroke, transient ischemic attack (TIA), clinically significant conduction 
abnormalities, or required intervention for any of these conditions (e.g., coronary 
artery bypass graft, percutaneous coronary intervention via cardiac catheterization, 
or thrombolytic therapy), within 1 year of screening.
17.
Any clinically significant hematological, autoimmune, endocrine, cardiovascular, 
neoplastic, renal, gastrointestinal, or other disorder that, in the Investigator's 
opinion, could interfere with the subject's participation in the study, place the 
subject at increased risk, or confound interpretation of study results.
18.
Subject has a planned major surgical procedure scheduled during the period when 
the subject would be participating in this study.  The subject may subsequently be 
considered for the study following full recuperation from the surgical procedure.
19.
History of serious adverse reaction to ABBV-8E12 or other monoclonal antibodies 
or biologics.
20.
Subject has received an investigational product (other than ABBV-8E12, also 
known as C2N 8E12) within a time period equal to 5 half-lives, if known, or within 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
44
6 weeks (for small molecules) or 6 months (for monoclonal antibodies or other 
biologics) prior to study drug administration.
21.
Subject is using any exclusionary medications as defined in Section 5.2.3.1.
22.
Subject has any history of prior receipt of active immunotherapy directed against 
tau.
23.
Current enrollment in another interventional clinical study involving a therapeutic 
agent.
24.
Male subject who is considering fathering a child or donating sperm during the 
study or for approximately 20 weeks after the last dose of study drug.
25.
Subject considered by the investigator, for any reason, an unsuitable candidate to 
receive ABBV-8E12 or unable or unlikely to comply with the dosing schedule or 
study evaluations.
Rationale for Exclusion Criteria
1, 2, 5 –
17, 22, 25
These criteria were selected to ensure the appropriate subject population
3, 4, 18, 23
To ensure the safety of the subjects
19 – 21
These products may interfere with the pharmacokinetics of the study drug
24
The effects of ABBV-8E12 on pregnancy are currently unknown
5.2.3
Prior and Concomitant Therapy
If a subject reports taking any over-the-counter or prescription medications, vitamins 
and/or herbal supplements, or if administration of any medication becomes necessary 
from 30 days prior to screening through the end of the study, the name of the medication, 
dosage information including dose, route and frequency, date(s) of administration 
including start and end dates, and reason for use must be recorded.  The AbbVie Medical 
Director must be notified if administration of any prohibited medication is reported during 
the study.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
45
All allowable concomitant medications must be at a stable dose for at least 30 days prior 
to the subject's screening visit, and it is anticipated that no change in dose will be required 
during the study treatment period.  All medications should remain at stable doses for the 
duration of the study unless a change in regimen is medically necessary.  All concomitant 
medications, including any change in dose must be recorded with the reason for use, dates 
of administration, dosages and frequency in the eCRF.
Permitted medications include the following:
●
Ramelteon, trazodone, amitriptyline and mirtazapine for sleep.
●
Selective benzodiazepines and gamma-aminobutyric acid (GABA) agonists, 
zolpidem, zaleplon, eszopiclone, alprazolam, clonazepam and lorazepam for 
sleep and anxiety.
●
Selective neuroleptics, clozapine or quetiapine for the treatment of psychotic 
symptoms.
●
Selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine 
reuptake inhibitors (SNRIs), buspirone, mirtazapine or trazodone for anxiety or 
depression.
●
Cholinesterase inhibitors (donepezil, rivastigmine, galantamine) or memantine 
for cognitive impairment.
●
Medications for Parkinsonian symptoms (including levodopa/carbidopa, 
dopamine agonists, monoamine oxidase inhibitors, Catechol-O-
Methyltransferase (COMT) inhibitors, or amantadine).
5.2.3.1
Prohibited Therapy
Unless approved by the Investigator in consultation with the Sponsor, subjects should not 
receive the following medications (not a comprehensive list) described in Table 5.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
46
Table 5.
Prohibited Medications
Anticoagulants (Exclusionary for Lumbar Puncture)
Examples
Vitamin K antagonists
Dabigatran
Enoxaparin sodium
Rivaroxaban
Apixaban
Heparin 
Neuroleptics*:  Prohibited within 30 days prior to screening and throughout the duration of the study
Examples
Chlorpromazine
Fluphenazine
Loxapine
Perphenazine
Thioridazine
Thiothixene
Trifluoperazine
Haloperidol
Benzodiazepines/Gamma-Aminobutyric Acid (GABA) agonists*:  Prohibited within 30 days prior to 
screening and throughout the duration of the study, such as:
Examples
Chlordiazepoxide
Diazepam
Midazolam
Flurazepam
Temazepam
Meprobamate
Triazolam
*
Excluding the selected compounds mentioned in Section 5.2.3.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
47
Additional recommendations are the following:
Drugs commonly known to cause excessive sedation, orthostatic hypotension or increased 
risk for falls should be avoided, if possible.
In general, dose changes or administration of additional medications with psychotropic 
effects (including opiates) on an as-needed (i.e., PRN) basis is prohibited.  In the 
exceptional case, low doses of anxiolytic/hypnotic agents, antipsychotic or opiate 
containing medications are permitted in the interest of patient safety or emergent 
symptom control; however, ongoing use of PRN medications should be discussed with the 
AbbVie Medical Director.  If a subject requires PRN use of a medication with 
psychotropic effects, subject efficacy scales must not be administered for at least 48 hours 
following the administration of the medication.  Depending on the time of dose 
administration, the next study visit should be rescheduled to assure an interval of at least 
48 hours between PRN medication administration and clinical or psychometric 
assessments.  Each case of PRN medication administration must be documented with the 
reason for use, dates of administration, and dosages in the eCRF.  Regularly scheduled 
medications administered to a subject on a daily basis should not be delayed, and 
administration times should not be altered due to cognitive assessments.
The AbbVie Medical Director should be contacted if there are any questions regarding 
concomitant and prior therapy(ies), or prohibited medications.
5.2.4
Contraception Recommendations and Pregnancy Testing
If female, subject must be either postmenopausal defined as:
●
Age > 55 years with no menses for 12 or more months without an alternative 
medical cause.
●
Age < 55 years with no menses for 12 or more months without an alternative 
medical cause AND a follicle-stimulating hormone (FSH) level > 40 IU/L.
OR


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
48
●
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy).
OR
●
Practicing at least one of the following methods of birth control, for at least 
3 months prior to randomization through at least 20 weeks after the last dose of 
study drug:
○
Combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal,* transdermal*) associated with the inhibition of 
ovulation, initiated at least 1 month prior to Study Day 1.
○
Progestogen-only hormonal contraception (oral, injectable,* implantable*) 
associated with inhibition of ovulation, initiated at least 1 month prior to 
Study Day 1.
○
Bilateral tubal occlusion/ligation.
○
Vasectomized partner(s) and is the sole sexual partner of the woman of 
childbearing potential (WOCBP) trial participant.
○
IUD.
○
Intrauterine hormone-releasing system (IUS).
○
Progestogen-only oral hormonal contraception, where inhibition of 
ovulation is not the primary mode of action, initiated at least 1 month prior 
to Study Day 1.
○
Male or female condom with or without spermicide.
○
Cap, diaphragm or sponge with spermicide.*
○
A combination of male condom with cap, diaphragm or sponge with 
spermicide* (double barrier method).
○
True abstinence:  Refraining from heterosexual intercourse when this is in 
line with the preferred and usual lifestyle of the subject (periodic 
abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation 
methods] and withdrawal are not acceptable).
* Not approved in Japan.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
49
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 
with female partner(s) of childbearing potential must agree from Study Day 1 through 
20 weeks after the last dose of study drug to practice contraception with:
●
Condom use
●
True abstinence:  Refraining from heterosexual intercourse – when this is in 
line with the preferred and usual lifestyle of the subject.  (Note:  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods 
by the female partner) and withdrawal are not acceptable).
●
Additionally, male subject agrees not to donate sperm from Study Day 1 
through 20 weeks after the last dose of study drug.
5.3
Efficacy, Pharmacokinetic, Biomarker, Pharmacogenetic 
and Safety Assessments/Variables 
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Appendix C.
5.3.1.1
Study Procedures
Identification of Study Partner
To be eligible for screening, each subject must have an identified, reliable, study partner 
(e.g., caregiver, family member, social worker, or friend), who has frequent contact with 
the subject (at least 10 hours per week) and who will accompany the subject to study 
visits to provide information as to the subject's functional abilities.  In the exceptional 
case the study partner is not available to accompany the subject to a visit he/she may 
provide the information regarding subject's functional abilities by telephone.  The 
designated study partner must be sufficiently familiar with the subject (as determined by 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
50
the investigator) to provide accurate data and be willing to be the study partner for the 
duration of the study.  The site investigator must consider the study partner to be able to 
perform all of these functions.  The site must obtain the name and contact information of 
the study partner and the source documents must record the study partner's consent to 
satisfy the responsibility of the study partner in this study.
Medical History
For all subjects, a complete medical history, including subject's history of PSP and any 
medications taken for symptoms related to PSP, will be obtained at screening.  In 
addition, history of alcohol and tobacco use will be obtained from each subject.  The 
medical history will be updated on Day 1.  The updated medical history on Day 1 will 
serve as the baseline for clinical assessment.
Ongoing concomitant medication (prescription or over-the-counter, including vitamins 
and herbal supplements) use and any medication stopped within 30 days prior to screening 
and any monoclonal antibodies or other biologics administered within 6 months prior to 
the study drug administration will also be recorded.
PSP Clinical Features32
A detailed assessment of PSP signs and symptoms present at Screening will be collected 
and include the following:
●
Ocular motor dysfunction
●
Postural instability
●
Akinesia
●
Cognitive dysfunction
Physical Examination
Physical examinations will be performed as indicated in the Schedule of Study Activities 
in Appendix C.  A symptom-directed physical examination will be performed when 
necessary.  The physical examination performed on Day 1 prior to the first dose will serve 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
51
as the baseline physical examination for clinical assessment.  Any significant physical 
examination findings after dosing will be recorded as adverse events.
Height will be measured at screening; the subject will not wear shoes.
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.
Vital Signs
Body temperature and measurements for orthostatic vital signs assessment will be 
obtained at the times indicated in the Schedule of Study Activities in Appendix C.  All 
systolic and diastolic blood pressure and pulse rate measurements are to be measured 
while the subject is supine (after 3 to 5 minutes) followed by measurements while 
standing (after 2 minutes).  Study staff should make efforts to measure with the same arm 
and method, including recording of the arm and method in the subject's source 
documentation.
The vital signs measurements just prior to dosing on Study Day 1 will serve as the 
baseline measurements for clinical assessment.
For visits in which both vital signs and blood sample(s) are collected, vital signs should be 
obtained prior to any blood collection.
Urine Screens for Drugs of Abuse
Urine specimens will be collected at times indicated in the Schedule of Study Activities in 
Appendix C to test for drugs of abuse by the central laboratory chosen for the study.  Any 
subject testing positive for cocaine metabolites, phencyclidine, opiates, barbiturates, 
benzodiazepines, marijuana metabolites, amphetamines, or methadone prior to 
randomization, will be excluded from the study, unless the detected drug has been 
appropriately prescribed by a physician.  Additional drug screens may be obtained at the 
discretion of the investigator.  With the exception of subjects who are regularly taking 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
52
opiates for pain control, any subjects testing positive during the study will be considered 
for premature discontinuation in consultation with the AbbVie Medical Director.
Hepatitis Screen
HbsAg and HCV Ab tests will be performed at screening.  The hepatitis test panel will be
performed by a certified laboratory.
Neurological Examination
A neurological examination will be performed at the times indicated in the Schedule of 
Study Activities Table in Appendix C.  The neurological exam performed on Day 1 will 
serve as the baseline for clinical assessment.  Symptoms identified during the screening 
period will not be recorded as adverse events; however, new symptoms or current 
symptoms that change in severity or frequency after the first day of study drug will be 
recorded as adverse events.
The neurological examination will assess:
●
Mental Status – assessment of orientation, speech, and memory
●
Cranial nerves – assessment of cranial nerves II-XII.  This will include an 
assessment of supranuclear gaze palsy and slowing of vertical saccades
○
Vertical supranuclear palsy will be established by neurological 
examination demonstrating a greater than 50% limitation of the range of 
voluntary gaze in the vertical plane, which is overcome by reflexive 
vestibular stimulation
○
Slowing of vertical saccades may be assessed by either of the two 
following methods:
●
Slowing of vertical saccades may be established by neurological 
examination of saccades toward a target held greater than 20 degrees 
from the position of primary gaze in the vertical plane.  Slowing of 
vertical saccades will be defined as present when ocular movement is 
slow enough for the examiner to see its progress, rather than just its 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
53
initial and final positions.  A delay in initiation of saccades is not 
considered slowing.
●
Slowing of vertical saccades may be established using quantitative 
measurements of saccades, such as infrared oculography of adequate 
spatial and temporal resolution to resolve multiple saccades.
●
Motor system – brief assessment of tone and strength, tremors
●
Sensory system – brief assessment of light touch and temperature sensation
●
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 (if clinically indicated and safe)
●
Station – assessment of posture and stability as defined by the following:
○
If clinically indicated and safe, postural instability may be assessed by 
determining the impairment of postural reflexes on neurological 
examination (i.e., retropulsion with or without unaided recovery after a 
backward pull) in the absence of any other medical cause to explain this 
impairment (e.g., primary sensory deficit, vestibular dysfunction, pontine 
infarction, cerebellar syndrome, prominent upper or lower motor neuron 
signs).
12-Lead Electrocardiogram (ECG)
A 12-lead resting ECG will be obtained as indicated in the Study Activities Table in 
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.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
54
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 
approximately 3 business days.
Local ECG Reading:
A qualified physician at the study site will interpret and document his/her global 
interpretation on the ECG tracing, based on the following conventions, as appropriate:
●
Normal ECG
●
Abnormal ECG – not clinically significant
●
Abnormal ECG – clinically significant
This physician will sign and date the ECG tracings.  Each ECG should be reviewed by the 
physician before the study drug administration to ensure the tracing is interpretable and no 
acute, medically serious condition is present.  The investigator's (or physician designee's) 
initial interpretation of the ECG will be the basis of any decisions related to the study 
conduct and treatment of the study subjects (e.g., eligibility at baseline, AE assessment, 
etc.).
Central ECG Reading:
Site personnel will transmit ECG data to an ECG central laboratory for central processing 
and reading by a qualified cardiologist (central reader) who, also blinded by study drug 
assignment, will independently review each ECG.  QT interval corrected for heart rate 
(QTc) will be determined using Fridericia's correction method (QTcF).  The central ECG 
laboratory's data will be entered into the database.  The central reader will also provide the 
interpretation of the ECG (i.e., "Normal" or "Abnormal").  The central ECG laboratory 
will send the ECG report to the site within approximately 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 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
55
(normal/abnormal) with the central ECG laboratory in case of relevant divergent 
assessments and reconcile as he/she determines is appropriate.
ECGs will be collected as single ECGs as follows:
Cohort 1 and Cohort J1 Subjects:
●
Screening
○
May be done at any time during the visit.
●
Day 1 (Dose 1)
○
Pre-dose (just prior to pre-infusion PK sample collection and the start of 
infusion) and within 15 minutes after the end of infusion prior to the PK 
sample collection
●
Day 5
○
Collection should be scheduled as close as possible to the corresponding 
time of the post infusion collection on Day 1. 
●
Day 15 (Dose 2)
○
Pre-dose (just prior to the start of infusion) and within 15 minutes after the 
end of infusion prior to the PK sample collection
●
Days 29 and 57 (Doses 3 and 4)
○
Pre-dose (just prior to the start of infusion)
●
Day 85 (Dose 5)
○
Pre-dose (just prior to the start of infusion) and within 15 minutes after the 
end of infusion (prior to the PK sample collection)
●
Weeks 24 and 36 (Doses 8 and 11)
○
Pre-dose (just prior to the start of infusion)
●
Week 52:  (Study Completion/Premature Discontinuation Visit)
○
May be done at any time during the visit.
●
Week 60:  (Post-Treatment Follow-up Visit)
○
May be done at any time during the visit.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
56
Cohort 2 Subjects:
●
Screening
○
May be done at any time during the visit.
●
Days 1, 29, 57, 85, and Weeks 24, and 36 (Doses 1, 3, 4, 5, 8, and 11)
○
Pre-dose (just prior to the start of infusion)
●
Week 52 (Study Completion/Premature Discontinuation Visit)
○
May be done at any time during the visit.
●
Week 60 (Post-Treatment Follow-up 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 6
at the time points designated in the Table 4 (Safety and PK Procedures for Cohort 1 and 
Cohort J1) and Study Activities Table (Appendix C).  
A certified laboratory will be utilized to process and provide results for the clinical 
laboratory tests.  Central Laboratory reference ranges will be provided 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.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
57
Table 6.
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)a
Mean corpuscular volume
(MCV)
Mean corpuscular hemoglobin
concentration (MCHC)
Prothrombin time (PT) 
Activated partial thromboplastin
time (aPTT)b
PT/INR (Prothrombin 
Time/International 
Normalized Ratio)b
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
Thyroid Stimulating Hormone 
(TSH)c
Thyroxine (T4)c
Vitamin B12 (cobalamin)c
Pregnancy testd
Specific gravity
Ketones
pH
Protein
Glucose
Blood
Urine pregnancy teste,f
Microscopic examination, if 
dipstick results are positive
CSF Basic Labsf
RBC, WBC with differential
Total Protein
Albumin
Glucose
Reference Tests if 
Vitamin B12 is Under the 
Lower Limit of Normal 
Range
Methylmalonic Acid (MMA)
Homocysteinec
Hepatitisc
HbsAg
HCV Ab
-Any positive HCV Ab test 
must be confirmed by a positive 
Hepatitis-C Viral RNA 
(polymerase chain reaction 
[PCR]) Qualitative test for 
HCV
a.
Platelet count results to be reviewed by investigator before the LP.
b.
Coagulation results to be reviewed by the investigator before the LP.
c.
Screening Visit only.
d.
For all females of child-bearing potential; a serum pregnancy test will be performed at the screening visit and 
Premature Discontinuation.
e.
For all females of child-bearing potential; a negative urine pregnancy test result is required prior to any radiological 
procedures.
f.
To be done at local laboratory.  If local laboratory is unable to perform, samples may be sent to the Central 
Laboratory for analyses of Total Protein, Albumin, and Glucose only.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
58
Abnormal Findings
For any laboratory test value outside the reference range that the investigator considers to 
be clinically significant:
●
The investigator will repeat the test to verify the out-of-range value.
●
The investigator will follow the out-of-range value to a satisfactory clinical 
resolution.
●
A laboratory test value that requires a subject to be discontinued from the 
study or requires a subject to receive treatment will be recorded as an adverse 
event.
For all laboratory abnormalities the investigator will determine if they indicate a new 
disease process, an exacerbation or worsening of an existing condition, or require further 
action to be taken and therefore need to be reported as adverse events.  Accordingly, for 
any values outside of the reference range, the Investigator will indicate on the report if the 
result is Clinically Significant (CS) or Not Clinically Significant (NCS).  If a laboratory 
abnormality meets criteria for a Potentially Clinically Significant (PCS) laboratory value, 
as defined in Appendix D, the investigator must either report an associated adverse event 
or document in source the reason(s) the finding was not considered an adverse event.
Any laboratory value that remains abnormal at Premature Discontinuation/End of Study 
and was judged to be clinically significant will be followed according to accepted medical 
standards until resolution of the abnormality.
Magnetic Resonance Imaging (MRI)
For all subjects, a Magnetic Resonance Imaging (MRI) of the brain will be obtained at 
time points indicated in the Study Activities Table (Appendix C) and interpreted by a 
radiologist or neurologist.  The subjects will be positioned supine on the MRI bed and 
their head will be positioned within a head coil with appropriate foam padding to decrease 
movement during the scan and to standardize the orientation of the head.  The subjects 
will then be positioned within the MRI scanner for imaging.  The screening MRI should 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
59
be completed after all other relevant screening procedures (except LP) have been 
completed and reviewed by the investigator.
The screening MRI assessment will be used to rule out the presence of any intracranial 
masses that might preclude the subject from undergoing a lumbar puncture, and exclude 
focal or diffuse processes that could indicate a clinically significant neurologic disorder 
other than PSP, including signal abnormalities on fluid attenuated inversion recovery 
(FLAIR) or T2 weighted images consistent with infectious, vascular, neoplastic or other 
degenerative processes.  The 3D T1 weighted sequences will also be acquired for 
volumetric analysis that will enable a quantitative assessment of whole brain volume and 
regional brain volume.
All or a subset of the following brain MRI imaging sequence types will be performed:
●
T1 weighted
●
Diffusion weighted imaging
●
T2 weighted FLAIR 
●
PD/T2 weighted
●
T2* weighted
●
Diffusion tensor imaging
The above listed imaging sequences may be adapted, sequences may be dropped or 
additional imaging sequences may be included based on feasibility.  The duration of each 
imaging session is not expected to exceed 60 minutes.  Details of the MRI procedures will 
be described in the MRI Procedures Manual provided by the Sponsor.  The 3D T1 
weighted sequences will also be acquired for volumetric analysis that will enable a 
quantitative assessment of whole brain volume and regional brain volume.
Scans at all protocol-required time points, including at screening, that are of poor quality 
(e.g., due to subject motion during the scan, inadequate coverage of the brain, improper 
positioning of the head, use of incorrect scan or geometry parameters or noisy image) as 
determined by the MRI technologist at the imaging center or reviewing radiologist or 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
60
Sponsor will be repeated at the earliest possible time but within 15 days of the protocol-
required time point to obtain a scan of good quality.
On-treatment MRIs will be performed at the time points indicated in the Study Activities 
Table (Appendix C).  The time window for the MRI procedure at each protocol-required 
time point is ±7 days.
Sedation is not recommended but is allowed.  Subjects who might need sedation should 
discuss this with the principal investigator prior to the imaging procedure.  If sedation is 
required it should occur after all scales and cognitive testing have been performed or, if 
this is not possible, at least 48 hours before the testing. 
The MRI technician is responsible for performing brain MRI scans at all protocol-
required time points.
Lumbar Puncture (LP)
For all subjects, LPs to collect cerebrospinal fluid (CSF) will be performed at time points 
indicated in the Study Activities Table (Appendix C).
Subjects in Cohort 1 and Cohort J1 will undergo a LP at the following time points:
●
Screening – To be done after all other entry criteria have been satisfied.
●
Day 99
●
Premature Discontinuation or Week 52 (Completion Visit/Premature 
Discontinuation) – if at least 3 months after the previous LP.
Subjects in Cohort 2 will undergo a LP at the following time points.
●
Screening – To be done after all other entry criteria have been satisfied.
●
Premature Discontinuation or Week 52 (Completion/Premature 
Discontinuation Visit) – if at least 3 months after the previous LP.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
61
A sample of CSF will be collected according to the Collection and Processing of CSF 
Samples manual provided to the study site by the Sponsor.  If sampling is not successful 
or is standard of care for the institution, other methods including CT/fluoro guided or 
ultrasound guided lumbar puncture can be used at the discretion of the local clinical site 
staff.  CSF clinical labs will be analyzed locally at the applicable clinical site after each 
lumbar puncture/CSF collection.  These measures include cell counts (red blood cell 
[RBC] and white blood cell [WBC] with differential), total protein, albumin, and glucose 
(Refer to Table 6 for Clinical Laboratory Tests).  If the local laboratory is unable to 
perform some of the CSF measurements, samples may be sent to the Central Laboratory 
for analyses of Total Protein, Albumin, and Glucose only.  Other CSF measurements 
(e.g., ABBV-8E12 concentration, tau and other exploratory biomarkers) will be analyzed 
by the applicable designated laboratory or at AbbVie.
Cohort 2 subjects who are not able to undergo a LP may be enrolled with permission of 
the AbbVie Medical Director without the requirement of a LP during the study.
Headaches may occur following withdrawal of CSF.  Subjects may be treated with the 
following:  IV hydration, IV caffeine administration, bed-rest and analgesics.  
Uncommonly a blood patch (injection of some of the subject's blood to patch the CSF 
leak) may be needed.  Potential but rare risks of lumbar puncture include infection, 
damage to nerves in the back, and bleeding into the CSF space.  The risk of these is much 
less than 1%.11  Institutional policy and investigator discretion should be followed to 
provide the appropriate post-lumbar puncture observation period, and to provide 
information to the patient on possible side effects and limitations on strenuous physical 
activity and driving.
Diagnostic Tools and Rating Scales
Prior to the start of the study, designated raters will be certified in the use of all scales 
used in this study.  The objective of this certification/training is to establish uniformity 
across sites in the administration, interpretation and scoring of these rating instruments.  
Raters who cannot participate in pre-study certification/training or raters who become 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
62
involved in the study after training at the investigator's meeting will not be permitted to 
perform any study-specified ratings until they have satisfactorily completed an 
individualized certification/training program designed by the central trainers, approved by 
AbbVie and supervised by the investigator or his/her designee.  It is the responsibility of 
the investigator to ensure that the raters at his/her site are appropriately trained and 
certified in the use of selected rating scales.  Every effort must be made by the 
investigative sites to ensure that each subject is rated by the same rater for each scale 
throughout their participation in the study.
AbbVie, in conjunction with the rater training vendor, will determine the minimum rater 
qualifications for each of the rating scales.  All raters must meet these qualifications prior 
to participation in the training process.  The qualifications of the raters will be verified 
through the training vendor.  Individual exceptions to these requirements must be 
approved by the Sponsor via the training vendor.
Administration of selected scales will be audio recorded (as permitted by local 
regulations) to allow for central review of the data and to ensure consistency and 
reliability.
Assessments will be performed at the times indicated in Table 7.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
63
Table 7.
Diagnostic Tools and Scale Order and Duration of Administration
Diagnostic 
Tools and 
Scalesa,b
Approx.
Duration 
(min.)
Patient 
(P)/ 
Study 
Partner 
(SP)
Screening 
Days –56 to –8
Week 0 
Day 1c
Week 8 
Day 57
Week 12 
Day 85
Week 20 
Day 141
Week 24 
Day 169
Week 32 
Day 225
Week 36 
Day 253
Week 48 
Day 337
Completion/ 
Premature 
Discontinuation 
Week 52
Visit 1
Visit 2
PSPRS
10
P and SP
1
1
1
1
1
1
CGI-S
40 – 60
P and SP
2
5
2
5
2
5
2
5
2
5
2
CGI-C
1
P and SP
6
3
6
3
6
3
6
3
SEADL
5 – 10
P
3
3
4
4
4
4
UPDRS 
Part II
10
P
4
4
5
5
5
5
RBANS
25
P
1
1
1
1
1
CTT 
(Parts 1 & 2)
5 – 10
P
2
2
2
2
2
Letter 
Fluency Test 
(wpm)
1
P
3
3
3
3
3
NNIPPS-
PPS*
30 – 45
P and SP
4
4
4
4
4
MMSEd
10 – 15
P
X
PGI-Ce
1 – 2
P
X
X
X
X
PSP-QoLe
30
P
X
X
X
X
X
X
EuroQoL-5D 
(EQ-5D)e
8
P
X
X
X
X
X
C-SSRSe,f
< 5
P
X
X
X
X
X
X
X
X
X
X
X


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
64
Table 7.
Diagnostic Tools and Scale Order and Duration of Administration (Continued)
CTT = Color Trails Test; WPM = words per minute
*
NNIPPS will not be administered in Japan.
a.
Numbering listed in the table provides a pre-defined order of administration that should occur during each visit.  
b.
Audio recordings/central review of the administration/assessment of selected scales may be conducted.  
c.
Assess prior to randomization and the first dose of study drug.
d.
MMSE will be administered during Screening to assess inclusion criteria only.
e.
Scale may be administered/assessed at any time during the visit with the exception of the scheduled infusion time.
f.
The C-SSRS will be done at each visit throughout the study (see Study Activities Table Appendix C for all time points).


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
65
The diagnostic tools and rating scales include the following:
PSP Rating Scale (PSPRS)12 (Primary Endpoint)
The 28-item PSPRS was initially constructed in 1992 by Golbe in consultation with 
numerous colleagues, and was developed over a 10-year period.  Content validity was 
established by interviewing patients who met the published diagnostic criteria for PSP, 
typically every 3 – 4 months.  Patient and study partner together were asked to assign a 
value to each PSP item.  When the patient did not concur with study partner observations, 
the interviewer encouraged discussion between the two parties and assigned a value to 
that particular item using clinical judgment.  Study data for patients were collected from 
baseline through study completion, or participant death.  Only the data of patients who 
presented with PSP symptoms and who subsequently developed PSP were included in the 
psychometric analysis.  All interviewed patients were taking medication for PSP-related 
symptoms.  However, the PSPRS has been widely used in clinical studies.7,13-15
The PSPRS contains 28 items comprised of 6 domains:  daily activities (7 items), 
mentation (4 items), bulbar (2 items), ocular motor (4 items), limb motor (6 items), and 
gait/midline (5 items).  Six items are graded 0 to 2 and 22 items are graded 0 to 4.  The 
PSPRS total score is the sum of item scores and ranges from 0 to 100.  It is administered 
to the subject and the Study Partner by a clinician and takes approximately 10 minutes to 
complete, as reported in Table 7.  
Schwab and England Activities of Daily Living Scale (SEADL)16 (Secondary Endpoint)
The SEADL scale will be used as a means of assessing the subject's ability to perform 
daily activities.  The Schwab England Activities of Daily Living (SEADL) scale was 
developed by Schwab and England in 1957 and consists of ten items intended to evaluate 
the daily life activities of a patient.  The SEADL is composed of two sections:  the first is 
a self-report questionnaire in which patients grade their own daily life activities, such as 
dressing, using the toilet, resting, eating, and social activities (subjective assessment), and 
the second is an assessment of motor functions, such as postural balance, speaking, 
rigidity, and tremors, conducted by a clinician (objective assessment).  It is a percentage 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
66
scale divided into deciles, and the results are reported between 0% (bedridden) and 100% 
(healthy).  It is administered to the subject by a clinician and takes approximately 
5 – 10 minutes to complete, as reported in Table 7.  
Unified Parkinson's Disease Rating Scale (UPDRS) (Secondary Endpoint)
The Unified Parkinson's Disease Rating Scale (UPDRS)17 is an Investigator-used rating 
tool to follow the longitudinal course of Parkinson's disease.  The UPDRS assessment will 
be performed by an approved, trained rater.  To be qualified by the Sponsor and the rater 
vendor, all raters must have participated in the Rater Training and have a current, valid 
Rater Certificate.
The UPDRS is made up of the following sections:
●
Part I – Mentation, Behavior, and Mood
●
*Part II – Activities of Daily Living
●
Part III – Motor Examination
●
Part IV – Complications of Therapy (including dyskinesias)
●
Part V – Modified Hoehn and Yahr Staging
*
Only Part II will be administered in this study.
It is administered to the subject by a clinician and takes approximately 10 minutes to 
complete, as reported in Table 7.  
Clinical Global Impression of Severity (CGI-S) and Clinical Global Impression of Change 
(CGI-C) (Secondary Endpoint)
The CGI-S is a clinician's rating of disease severity.  The CGI-S rates severity of illness 
on a 7-point scale, using a range of responses from 1 (normal) through to 7 (the most 
severely ill).  This rating is based upon observed and reported symptoms, behavior, and 
function in the past 7 days.  The CGI-C rates improvement by 7 categories:  very much 
improved, much improved, minimally improved, no change, minimally worse, much 
worse, very much worse.  These assessments are administered to the subject by a 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
67
clinician.  The CGI-S takes approximately 40 to 60 minutes to complete and the CGI-C 
takes approximately 1 minute to complete, as reported in Table 7.
PSP-Quality of Life (PSP-QoL)18 (Secondary Endpoint)
The PSP-QoL is a validated patient-reported outcome measure, specifically designed to 
assess the quality of life of patients with PSP.  There are 45 items and two subscales:  
physical and mental impact.  Items are scored from 0 (no problem) to 4 (extreme 
problems).  The total subscale sum scores are linearly converted into a 0 to 100 scale.  The 
PSP-QoL, with a 4-week time frame, can be completed by the patients or study partners.  
The PSP-QoL form includes a visual analog scale (VAS) about the patient's satisfaction 
with overall life.  It takes 30 minutes to complete.  The PSP-QoL was developed 
specifically for PSP and displays good psychometric properties.  A panel of experts in 
movement disorders determined that content validity was good.  Internal construct 
validity was verified through a moderate correlation between the two subscales.  
Convergent and discriminant validity was supported by correlations between the PSP-
QoL subscales and other measures (EuroQol-5D [EQ-5D] and the Hospital Anxiety and 
Depression Scale), with no differences by gender.  PSP-QoL is administered to the subject 
by a clinician and takes approximately 30 minutes to complete, as reported in Table 7.
Repeatable Battery for Assessment of Neuropsychological Status (RBANS)19
(Exploratory Endpoint)
The 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


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
68
5.
Delayed Memory – List Recall, List Recognition, Story Memory, and Figure 
Recall.
The RBANS has been shown to be effective at both detecting and characterizing dementia 
of different etiologies.  The RBANS has been translated into over 25 different languages, 
with extensive clinical validity data from a wide variety of geographic regions.  It is 
administered to the subject by a clinician and takes approximately 25 minutes to 
complete, as reported in Table 7.  
Color Trails Test (CTT) (Parts 1 and 2)20 (Exploratory Endpoint)
The Color Trails Test (CTT) (Parts 1 and 2) involves numbered circles that are printed 
with vivid pink or yellow backgrounds that are perceptible to color-blind individuals.  For 
Part 1, the respondent uses a pencil to rapidly connect circles numbered 1 – 25 in 
sequence.  For Part 2, the respondent rapidly connects numbered circles in sequence, but 
alternates between pink and yellow.  The length of time to complete each trial is recorded, 
along with qualitative features of performance indicative of brain dysfunction, such as 
near-misses, prompts, number sequence errors, and color sequence errors.  The clinician 
administering this test will need a stopwatch to record the length of time for the 
completion of each part.  It is administered to the subject by a clinician and takes 
approximately 5 – 10 minutes to complete, as reported in Table 7.  
Letter Fluency Test (LFT)21 (Exploratory Endpoint)
This is a phonemic fluency task, requiring subjects to generate as many words as they can 
that start with a given letter over a 60 second interval.  This study will employ two trials 
per administration, involving different letters.  The score is the total number of correct 
words generated over the two trials.  It will be administered to the subject by a clinician 
and will take approximately 1 minute for each of the two trials to complete, as reported in 
Table 7.  


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
69
Natural History and Neuroprotection in Parkinsons Plus Syndromes-Parkinson Plus Scale 
(NNIPPS-PPS)22 (Exploratory Endpoint)
The NNIPPS-PPS is a validated rating scale used to assess disease severity and 
progression in patients with PSP and MSA.  The NNIPPS-PPS contains 83 items, 
comprised of 11 domains:  functional disability (ADLs), mental function (cognition, 
mood, and behavior), motor disability (rigidity and bradykinesia), tremor, oculomotor 
function, cerebellar signs, pyramidal signs, dysautonomia, bulbar/pseudobulbar 
symptoms, myoclonus, and dystonia.  Responses are graded according to their severity.  It 
is administered by a clinician and takes approximately 30 – 45 minutes to complete, as 
reported in Table 7.   
The NNIPPS-PPS will not be administered in Japan.
Patient Global Impression of Change (PGI-C)23 (Exploratory Endpoint)
Subjects will evaluate the change in their PSP-related symptoms since initiation of study 
drug by choosing one of seven responses.  The PGI-C is a 7-point response scale.  The 
subject will be asked by the Investigator or qualified designee to rate their change in status 
using the following 7-point scale:
1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 
5 = Minimally worse, 6 = Much worse, 7 = Very much worse.
The responses of "Very much improved," "Much improved," "Minimally improved" and 
"No change" on the PGI-C will be used to define responders.  It is administered to the 
subject by a clinician and takes approximately 1 – 2 minutes to complete, as reported in 
Table 7.
EuroQuality of Life (EQ-5D)24 (Exploratory Endpoint)
The EQ-5D contains a health state descriptive part comprising five items, scored from 
1 (no problems or symptoms) to 3 (serious problems or symptoms); a question about 
change in health state in the preceding 12 months, and a VAS to evaluate current health 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
70
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, as reported in 
Table 7.
Mini-Mental State Exam (MMSE)25
The MMSE is a brief, 30-point questionnaire that provides a quantitative measure of 
cognitive status in adults and is widely used to screen for cognitive impairment and to 
estimate the severity of cognitive impairment at a given point in time.  The MMSE total 
score ranges from 0 to 30, with lower score indicating greater impairment.  The subject 
must have a score of greater than 15, inclusive, at screening to be eligible for study 
participation.  It is administered to the subject by a trained rater and takes approximately 
10 – 15 minutes to complete, as reported in Table 7.
Columbia-Suicide Severity Rating Scale (C-SSRS)26
The C-SSRS is a systematically administered instrument developed to track suicidal 
adverse events across a treatment study.  The instrument is designed to assess suicidal 
behavior and ideation, track and assess all suicidal events, as well as the lethality of 
attempts.  Additional features assessed include frequency, duration, controllability, reason 
for ideation, and deterrents.  The C-SSRS is considered a low-burden instrument as it 
takes less than 5 minutes to administer.  It is administered to the subject by a clinician and 
takes less than 5 minutes to complete, as reported in Table 7.
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 
clinical interview, will be evaluated immediately by the study physician.  The AbbVie 
Medical Director will also be informed.  Appropriate steps will be taken to protect the 
subject, including but not limited to possible discontinuation from the study and referral 
for appropriate psychiatric care.  Any such subject at screening or on Day 1 will also be 
excluded from the study.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
71
5.3.1.2
Collection and Handling of Biomarker and Pharmacogenetic 
Research Samples
Biomarker Samples
Blood and CSF samples will be collected as outlined in the Study Activities Table 
(Appendix C) and may be utilized to evaluate known and/or novel disease-related or drug-
related biomarkers.  The biomarker rationale will be discussed in the Biomarker Research 
Variables Section (Section 5.3.6.1).
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 PSP continues, but for 
no longer than 20 years from the end of the study, or per local requirement.
Blood samples (approximately 11 mL) will be collected prior to the start of the infusion 
(0 hour, no more than 30 minutes prior to the start of the infusion) at the time points 
indicated in the Study Activities Table (Appendix C).  Blood samples collected at 
Week 52 (Study Completion/Premature Discontinuation Visit) may be collected at any 
time during that visit.
CSF samples (18 – 20 mL) will be collected by lumbar puncture.
MAPT Pharmacogenetic Sample
One (required) 4 mL whole blood sample will be collected from each subject at study 
Day 1 for microtubule associated protein tau (MAPT) haplotype and progranulin (GRN) 
pharmacogenetic analysis.  This sample will not be used for any testing other than MAPT 
haplotyping and genetic analysis of GRN mutations.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
72
Optional Pharmacogenetic Exploratory Research Samples
Subjects will have the option to provide samples for exploratory research.  Subjects may 
still participate in the main study even if they decide not to participate in this optional 
exploratory research.
AbbVie (or people or companies working with AbbVie) will store the exploratory 
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 PSP and related conditions continues, but for no longer than 20 years after 
study completion.  The procedure for obtaining and documenting informed consent for 
exploratory research samples is discussed in Section 9.3.  Instructions for the preparation 
and shipment of the exploratory research samples will be provided in a laboratory manual.
Optional whole blood pharmacogenetic samples for Deoxyribonucleic Acid (DNA) and 
Ribonucleic acid (RNA) isolation will be collected from each subject who consents to 
provide samples for exploratory research.  Optional whole blood samples (6.5 mL) for 
DNA and RNA isolation will be collected at the following time points:
●
Day 1 (Dose 1)
●
Day 85 (Dose 5)
●
Week 36 (Dose 11)
●
Week 52:  (Completion/Premature Discontinuation Visit)
All pharmacogenetic samples (mandatory and optional) should be collected, processed, 
labeled and shipped as outlined in the study-specific laboratory manual, which will be 
provided separately.
5.3.1.3
Confinement
Subjects in Cohort J1 will be required to be confined for a minimum of 24 hours 
following their first dose.  The Investigator will assess the subject for safety prior to 
discharge to determine that the subject can be discharged.  If a subject is suspected of 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
73
having any abnormality during the medical examination prior to discharge, additional 
testing, including the extension of the confinement, will be considered.  
5.3.1.4
Meals and Dietary Requirements
There are no dietary requirements or restrictions for this study.
5.3.2
Drug and Anti-Drug Antibody Concentration Measurements 
5.3.2.1
Collection of Samples for Analysis
Specific instructions for collection of blood samples and subsequent preparation and 
storage of the serum samples for the pharmacokinetic assays of ABBV-8E12 will be 
provided by the central laboratory, the Sponsor, or its designee.
Blood Samples for ABBV-8E12 Assay
Blood samples, approximately 3 mL for ABBV-8E12 analysis will be collected by 
venipuncture as follows:
For Subjects Enrolled in Cohort 1 and Cohort J1 (*See Below for Allowable PK 
Windows)
●
Day 1 (Dose 1)
○
Prior to the start of the infusion (0 hour, no more than 30 minutes prior to 
the start of the infusion), immediately after the end of the infusion (within 
15 minutes) and 1 and 2 hours after the end of the infusion.
●
Day 5
○
Sample may be collected at any time during the visit.
●
Day 15 (Dose 2)
○
Prior to the start of the infusion (0 hour, no more than 30 minutes prior to 
the start of the infusion), immediately after the end of the infusion (within 
15 minutes) and 1 and 2 hours after the end of the infusion. 
●
Days 29 and 57 (Doses 3 and 4)
○
Sample may be collected at any time during the visit.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
74
●
Day 85 (Dose 5)
○
Prior to the start of the infusion (0 hour, no more than 30 minutes prior to 
the start of the infusion), immediately after the end of the infusion (within 
15 minutes) and 1 and 2 hours after the end of the infusion.
●
Days 89 and 99
○
Sample may be collected at any time during the visit.
●
Weeks 16, 24, and 36 (Doses 6, 8, and 11, respectively)
○
Prior to the start of the infusion (0 hour, no more than 30 minutes prior to 
the start of the infusion).
●
Week 52 (Study Completion/Premature Discontinuation Visit)
○
Sample may be collected anytime during the day.
●
Weeks 60 and 68 (Post-Treatment Follow-up Period)
○
Sample may be collected anytime during the day.
*Cohort 1 and Cohort J1 Allowable PK Windows
On Days 1, 15, and 85 and at Weeks 16, 24, and 36, the PK samples collected prior to 
infusion should be collected within 30 minutes of the start of infusion.  For 1-hour post-
dose samples (Days 1, 15, and 85), the allowable PK window is ± 6 minutes, and for 
2-hour post-dose samples (Days 1, 15, and 85), the allowable PK window is ± 12 minutes.  
The allowable window is ± 2 days for samples scheduled on Days 5, 89, and 99, and 
± 4 days for samples scheduled on other study days.  
For Subjects Enrolled in Cohort 2 (*See Below for Allowable PK Windows)
●
Days 1, 29, 85, and Weeks 24 and 36 (Doses 1, 3, 5, 8, and 11, respectively)
○
Prior to the start of the infusion (0 hour, no more than 30 minutes prior to 
the start of the infusion).
●
Day 15 (Dose 2)
○
Prior to the start of the infusion (0 hour, no more than 30 minutes prior to 
the start of the infusion), immediately after the end of the infusion (within 
15 minutes) and 1 and 2 hours after the end of the infusion. 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
75
●
Week 52:  (Study Completion/Premature Discontinuation Visit)
○
Sample may be collected anytime during the day.
●
Weeks 60 and 68 (Post-Treatment Follow-up Period)
○
Sample may be collected anytime during the day.
*Cohort 2 Allowable PK Windows
On Days 1, 15, 29, and 85 and at Weeks 24 and 36, the PK samples collected prior to 
infusion should be collected within 30 minutes of the start of infusion.  For 1-hour post-
dose sample (Day 15), the allowable PK window is ± 6 minutes, and for 2-hour post-dose 
samples (Day 15), the allowable PK window is ± 12 minutes.  For the samples scheduled 
for Weeks 52, 60, and 68, the allowable window is ± 4 days.
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.  The collection schedule for ADA will be the same for subjects who 
previously did or did not participate in the Single-Ascending Dose Study 
(Study C2N-8E12-WW-104).  The schedule for ABBV-8E12 ADA collection is as 
follows:
For Subjects Enrolled in Cohort 1 and Cohort J1 (*See Below for Allowable ADA 
Windows)
●
Days 1, 15, 29, 57, 85, and Weeks 16, 24, and 36 (Doses 1, 2, 3, 4, 5, 6, 8, 
and 11, respectively)
○
Prior to the start of the infusion (0 hour, no more than 30 minutes prior to 
the start of the infusion).
●
Days 89 and 99
○
Sample may be collected anytime during the day.
●
Week 52:  (Study Completion/Premature Discontinuation Visit)
○
Sample may be collected anytime during the day.
●
Weeks 60 and 68:  Post-Treatment Follow-up Period


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
76
○
Sample may be collected anytime during the day.
*Cohort 1 and Cohort J1 Allowable ADA Windows
On Days 1, 15, 29, 57, 85, and Weeks 16, 24, and 36, the ADA samples collected prior to 
infusion should be collected within 30 minutes of the start of infusion.  Blood samples 
may be collected within ± 2 days on Days 89, and 99, and ± 4 days on other study days.  
For Subjects Enrolled in Cohort 2 (*See Below for Allowable ADA Windows)
●
Days 1, 29, 85, and Weeks 24 and 36 (Doses 1, 3, 5, 8, and 11, respectively)
○
Prior to the start of the infusion (0 hour, no more than 30 minutes prior to 
the start of the infusion).
●
Week 52:  (Study Completion/Premature Discontinuation Visit)
○
Sample may be collected anytime during the day.
●
Weeks 60 and 68:  Post-Treatment Follow-up Period
○
Sample may be collected anytime during the day.
*Cohort 2 Allowable ADA Windows
On Days 1, 29, 85, and Weeks 24, and 36, the ADA samples collected prior to infusion 
should be collected within 30 minutes of the start of infusion.  Blood samples may be 
collected within ± 4 days on other study days.  
CSF Samples for ABBV-8E12 Assay
CSF samples will be collected as outlined in the Study Activities Table (Appendix C-
Assessment referred to as LP). 
The collection time and procedures of CSF samples can be found in the Lumbar Puncture 
section of Study Procedures Section (Section 5.3.1.1).  


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
77
As described in the Collection and Handling of Biomarker and Pharmacogenetic Research 
Samples Section (Section 5.3.1.2), CSF samples (18 – 20 mL) will be collected by lumbar 
puncture.
5.3.2.2
Measurement Methods
Analysis of Serum and CSF Samples
Serum concentrations and relative titers of ABBV-8E12 ADA will be determined using 
validated methods at the Bioanalysis Department at AbbVie.  CSF concentrations of 
ABBV-8E12 will be analyzed using qualified or validated methods.  Any additional 
analytes may be analyzed using non-validated methods either at AbbVie or by outside 
vendors or collaborators.  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 may be used for the analysis of neutralizing anti-drug 
antibodies.
5.3.3
Efficacy Variables
The primary efficacy variable will be the mean change from Baseline at Day 1 pre-dose to 
the Week 52 assessment in the PSP Rating Scale (PSPRS) total score to assess the effect 
of ABBV-8E12 in slowing disease progression. 
●
Secondary efficacy measures include the SEADL, UPDRS Part II, CGI-S, 
CGI-C, and PSP-QoL, and PSP Staging System and time to loss of ability to 
walk independently as measured by PSPRS item 26, as well as regional 
(midbrain, third ventricle, frontal lobes, superior cerebellar peduncle, 
brainstem) and whole brain atrophy as measured by volumetric MRI.
●
Exploratory efficacy variables include the RBANS, Color Trails Test (Parts 1 
and 2), Letter Fluency Test, NNIPPS-PPS, PGI-C, and EuroQoL-5D (EQ-5D).  
Exploratory quantitative MRI measures may additionally be evaluated; 
including diffusion tensor imaging (DTI), derived fractional anisotropy (FA) 
and diffusivity measures [radial diffusivity (RD), mean diffusivity (MD), and 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
78
axial diffusivity] to assess changes in pathophysiology and additional regions 
as measured by volumetric MRI.
Analysis of the secondary and exploratory efficacy variables obtained from these 
measures is detailed in Section 8.0.
5.3.4
Safety Variables
The following safety evaluations will be performed during the study:  adverse event 
monitoring (including infusion and allergic reactions), vital signs, physical examination, 
complete neurological exam, cognitive assessments, C-SSRS, laboratory abnormalities, 
ECG, MRI including FLAIR, and immunogenicity as determined by ADA responses in 
blood.
5.3.5
Pharmacokinetic Variables
Values for the following pharmacokinetic parameters will be estimated using non-
compartmental methods:  maximum observed serum concentration (Cmax), the time to 
Cmax (peak time, Tmax), the area under the concentration time curve (AUC) over the dosing 
interval after the first and the fifth doses in Cohort 1 and Cohort J1; and the observed 
serum concentration at the end of a dose interval (Ctrough, concentration prior to infusion 
on a day of dosing) in both Cohort 1, Cohort J1, and Cohort 2.
The concentration of ABBV-8E12 in CSF will be summarized after the fifth dose and 
after the final dose if administered at least 3 months after the previous LP for subjects in 
Cohort 1 and Cohort J1, and after final dose for subjects in Cohort 2.
A mixed-effect modeling approach will be used to estimate the population central value 
and the empirical Bayesian estimates of the individual values for ABBV-8E12 clearance 
(CL) and volume of distribution (V).
Additional parameters may be calculated if useful in the interpretation of the data.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
79
5.3.6
Biomarker and Pharmacogenetic Research Variables
5.3.6.1
Biomarker Research Variables
Blood and CSF samples will be collected to conduct research to investigate disease-
related and drug-related biomarkers.  The biomarkers to be analyzed may include, but are 
not limited to, the following:
●
CSF and plasma samples will be assayed for tau to demonstrate tau binding of 
ABBV-8E12 and for neurofilament to examine effects on neurodegeneration.
●
CSF or plasma samples may be analyzed for biochemical or macromolecular 
factors related to the pharmacodynamics and safety of ABBV-8E12.
Exploratory evaluations from blood and CSF samples 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.
The information learned from analyzing these data may be used to investigate factors 
impacting response to treatment, scientific questions related to PSP, support development 
of ABBV-8E12, or in the development of new therapies.  Furthermore, given the 
exploratory nature of these data the results may not be included in the study summary.
5.3.6.2
Pharmacogenetic Research Variables
MAPT H1/H2 haplotype status may be determined for each subject and analyzed as a 
factor contributing to the subject's response to study treatment.  The MAPT H1/H2 
haplotype results may be analyzed as part of a multi-study assessment of MAPT and 
response to ABBV-8E12 treatment.  Testing for GRN haploinsufficiency polymorphisms 
will also be conducted as patients with these mutations typically have low progranulin 
serum levels and are less likely to have tau brain pathology.  The results may also be used 
for the development of diagnostic tests related to ABBV-8E12, or other drugs in 
development for PSP or related conditions.  The MAPT haplotype and progranulin results 
may not be included in the study summary.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
80
Optional samples may be collected to conduct exploratory investigations into known and 
novel biomarkers.  The types of biomarkers to be analyzed may include, but are not 
limited to, nucleic acids, proteins, lipids or metabolites.  The samples may be analyzed as 
part of a multi-study assessment of factors influencing the subjects' response to the study 
drug (or drugs of the same or similar class) or the development and progression of the 
subjects' disease or related conditions.  The samples may also be used to develop new 
diagnostic tests, therapies, research methods or technologies.  The results from these 
analyses are exploratory in nature and may not be included with the study report.
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 adverse event or 
noncompliance with the protocol.
Severe allergic reactions or other adverse events that require the immediate interruption of 
ABBV-8E12 treatment will be taken into consideration by the AbbVie Medical Director 
for permanent discontinuation from further treatment and initiation of appropriate medical 
therapy and follow-up.
Any treatment-emergent, clinically significant, symptomatic neurological abnormalities 
and treatment-emergent MRI findings will be reported to the AbbVie Medical Director 
and subjects will be considered for discontinuation from treatment if clinically indicated.
Subjects at risk of suicide as indicated by answering yes to question 4 or 5 on the C-SSRS 
and/or determined by the investigator to be at risk of suicide, should be promptly referred 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
81
for appropriate follow-up care.  Subjects determined to be at ongoing risk of suicide 
should be discontinued from study participation.
If for any reason the subject becomes unable to continue treatment with ABBV-8E12, 
undergo protocol required procedures, or otherwise continue to participate in the study, 
discontinuation should be discussed with the AbbVie Medical Director.
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, MRI, LP, administration and completion of 
scales/questionnaires, C-SSRS and an assessment of adverse events and concomitant 
medications will be performed as soon as possible after discontinuation from the study 
(Refer to Study Activities Table, Appendix C).  Additional blood samples for drug 
measurement may be collected at the time of discontinuation from subjects who are 
discontinued due to adverse events; the clock time, time in relation to dose and date the 
sample was taken will be recorded.
If a subject is discontinued from the study with an ongoing adverse event or an unresolved 
laboratory result that is significantly outside of the reference range, the investigator will 
attempt to provide follow-up until a satisfactory clinical resolution of the laboratory result 
or adverse event is achieved.
In the event that a positive result is obtained on a pregnancy test for a subject or a subject 
reports becoming pregnant during the study, the administration of study drug to that 
subject must be discontinued immediately.  The investigator must report a pregnancy 
within 1 working day of the site being aware to one of the AbbVie representatives listed 
in Section 6.1.5 or Section 7.0.
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 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
82
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.
The DMC may evaluate the results of interim efficacy evaluation(s) and may make a 
recommendation to discontinue the entire study if the study is deemed to be futile.  The 
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 adjust the dose in one or both dose groups.
5.5
Treatments
5.5.1
Treatments Administered
For subjects randomized to the treatment arms, the solution contained in the study vial(s) 
of ABBV-8E12 will be diluted in the 0.9% Sodium Chloride Injection/Solution for 
Infusion.  Subject weight will be obtained prior to study drug administration to determine 
the appropriate infusion rate as shown in the table below.  Written instructions for the 
preparation of ABBV-8E12 solutions for infusion will be provided as a separate document 
from the protocol.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
83
Subject's Weight in kg/lbs.
Infusion Rate** 
*44 – 49 kg (97 – 109 lbs., inclusive) 
3.5 mL/min or 210 mL/hr
50 – 58 kg (110 – 128 lbs., inclusive) 
4.0 mL/min or 240 mL/hr
59 kg and over (129 lbs. and over)
4.7 mL/min or 282 mL/hr
*
Subjects weighing less than 44 kg (97 lbs.) will be excluded from enrollment (refer to exclusion criteria, 
Section 5.2.2, Exclusion Criterion 1).
**
Continue infusion until bag is empty.
Study continuation for subjects whose weight falls below 44 kg (97 lbs.) during the course 
of their participation will be discussed with the AbbVie Medical Director and adjustment 
of the infusion time or potential discontinuation from the study will be considered.
Study drug will be administered by IV infusion at each visit, in the morning if possible, as 
follows:
Study Drug
Formulation
Cohort 1/Cohort J1
IV infusions at Day 1, Day 15, and Day 29, then every 28 days for 
52 weeks (Total of 14 infusions)
Placebo (0.9% Sodium Chloride 
Injection/Solution for Infusion)
ABBV-8E12 2000 mg
ABBV-8E12 4000 mg
*Cohort 2
IV infusions at Day 1, Day 15, and Day 29, then every 28 days for 
52 weeks (Total of 14 infusions)
Placebo (0.9% Sodium Chloride 
Injection/Solution for Infusion)
ABBV-8E12 2000 mg
ABBV-8E12 4000 mg
(Visits on Days 5, 15, 89, and 99 must be scheduled within ±2 days.  Visits on all other days may be scheduled within 
±4 days).
*
Doses may be decreased after the evaluation by the DMC of available safety, tolerability and PK data.
The start and stop time of each study drug infusion will be recorded to the nearest minute.
5.5.2
Identity of Investigational Product
Information about the ABBV-8E12 and placebo products to be used in this study is 
presented in Table 8.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
84
Table 8.
Identity of Investigational Product
Investigational 
Product
Mode of 
Administration
Formulation
Strength
Manufacturer
ABBV-8E12
Infusion
Solution for infusion 
in a vial
300 mg/15 mL#
1000 mg/10 mL
AbbVie 
Deutschland 
GmbH & Co. KG, 
Ludwigshafen, 
Germany
Placebo
Infusion
0.9% Sodium 
Chloride 
Injection/Solution for 
Infusion, 500 mL
N/A
Various*
(See below)
#
Dosage formulation will not be used in Japan and Spain.
*
Can be sourced from approved marketed products from various commercial manufacturers depending on 
availability.
0.9% Sodium Chloride Injection/Solution for Infusion will be administered to those 
subjects not receiving active ABBV-8E12 and as a vehicle for administration of 
ABBV-8E12.  0.9% Sodium Chloride Injection/Solution for Infusion will be supplied 
with commercially available material in either bags or bottles, locally sourced by the sites.  
However, if mandated by local regulation, or in the case of exceptional circumstances 
when sites are unable to procure on their own, AbbVie may supply 0.9% Sodium Chloride 
Injection/Solution for Infusion if necessary.
5.5.2.1
Packaging and Labeling
ABBV-8E12 will be provided in a glass vial as solution for infusion.  One vial will be 
packaged per carton.  Each vial and carton will be labeled with the information necessary 
per country requirement.  Labels must remain affixed to the vial and carton.  All blank 
spaces on the label will be completed by the site staff prior to dispensing to the subjects.
The commercially sourced 0.9% Sodium Chloride Injection/Solution for Infusion will not 
be labeled as an Investigational Medicinal Product (IMP) prior to the handling by the 
unblinded pharmacist or qualified designee.  Instead, after addition of ABBV-8E12 to the 
0.9% Sodium Chloride Injection/Solution for Infusion to be administered in the active 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
85
arm, it will be labeled with a blinded dispensing label by the unblinded pharmacist or 
qualified designee as required.  0.9% Sodium Chloride Injection/Solution for Infusion 
without addition of ABBV-8E12, to be administered in the placebo arm, will be labeled 
with a blinded dispensing label by the unblinded pharmacist or qualified designee as well.  
Labels must remain affixed to the material.
If an IMP label on the 0.9% Sodium Chloride Injection/Solution for Infusion is mandated 
by local agencies, labels may be applied on the overwrap and will be removed by the 
unblinded pharmacist prior to administration.
5.5.2.2
Storage and Disposition of Study Drug
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.  Malfunctions or any 
temperature excursion must be reported to the Sponsor immediately using the AbbVie 
Temperature Excursion Management System (ATEMS).  Study medication should be 
quarantined and not dispensed until AbbVie (ATEMS) deems the medication as 
acceptable.
The investigational products are for investigational use only, and are to be used only 
within the context of this study.  The study drug supplied for this study must be 
maintained under adequate security and stored under conditions specified on the label 
until dispensed for subject use or returned to AbbVie.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
86
5.5.2.3
Preparation/Reconstitution of Dosage Form
The preparation of blinded doses will be performed by the unblinded pharmacist or 
qualified designee.  Placebo doses, consisting of 0.9% Sodium Chloride 
Injection/Solution for Infusion bags or bottles, will be essentially identical in volume to 
the active doses.  Written instructions for the preparation of ABBV-8E12 solutions for 
infusion will be outlined in the Pharmacy Manual.
5.5.3
Method of Assigning Subjects to Treatment Groups
Prior to enrolling subjects, each site will be provided with a user manual as well as a 
telephone number and user instructions for the Interactive Voice-Response/Interactive 
Web-Based (IVR/IWB) system.  Each user will receive a code number that will be used in 
combination with a personal identification number (PIN) to access the system by 
telephone and a unique username and confidential password to access the system through 
the internet.
As subjects are screened for the study, the IVR/IWB system will assign each subject a 
unique 5 digit subject number.  The first digit will be 1, the second and third digits will be 
the site number (01, 02, etc.) and the fourth and fifth digits will be assigned in ascending 
numerical order at each site.
At the Day 1 visit, each subject will be randomly assigned to a double-blind treatment 
group through the IVR/IWB system after the site verifies that the subject is eligible to 
participate in the study.  The first dose of study drug will be administered after 
randomization at the same visit.  The randomization schedule will be computer-generated 
before the start of the study by the Statistics Department, AbbVie.
5.5.4
Selection and Timing of Dose for Each Subject
Selection of the dose for this study is discussed in Section 5.6.4.  Each subject will be 
randomized to one of three dose groups as described in Section 5.5.1.  ABBV-8E12 will 
be administered via IV infusion; if possible this will be performed in the morning.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
87
AbbVie will inform all sites in Japan when Cohort J1 is open for enrollment in the
IVR/IWB system.  The IVR/IWB system will be programmed such that Subject 2 through 
Subject 9 may only be enrolled at least 48 hours after the prior subject was enrolled into 
Cohort J1.  This 48-hour pause is to allow adequate time for the Investigator to assess 
safety of the last subject and to allow AbbVie adequate time to review the safety of the 
subjects enrolled into Cohort J1.  Sites must contact AbbVie prior to enrolling any subject 
into Cohort J1 and AbbVie will notify sites when Cohort J1 is fully enrolled.
Cohort 2 in Japan will be opened in the IVR/IWB for enrollment only after Cohort J1 has 
been fully enrolled, following the DMC review of the Cohort J1 safety data, and after the 
DMC recommendation for the study to proceed without modifications, thus allowing 
AbbVie to commence enrolling Japanese subjects into Cohort 2.  AbbVie will notify all 
sites when Cohort 2 is open for enrollment in Japan.
5.5.5
Blinding
Subjects in the placebo group will be administered 0.9% Sodium Chloride 
Injection/Solution for Infusion that is essentially identical in volume to the ABBV-8E12 
solution.  Written instructions for preparation of ABBV-8E12 solutions for infusion and 
blinding procedures will be outlined in the Pharmacy Manual.  An unblinded pharmacist 
or qualified designee will be used for receiving and preparing of the blinded doses across 
the treatment groups.  The Investigator, study site personnel (except the unblinded 
pharmacist or qualified designee) and the subject will remain blinded to the treatment 
assignment throughout the course of the study.  The study Sponsor will remain blinded.
ABBV-8E12 and 0.9% Sodium Chloride Injection/Solution for Infusion (if applicable) 
will be delivered to the unblinded pharmacist or qualified designee in an open-label 
format.  The unblinded pharmacist or qualified designee will prepare the infusion of 
ABBV-8E12 or placebo (in a blinded manner) following the preparation instructions as 
appropriate based on the subject's assigned treatment group.  For blinding purposes, 
identical commercial 0.9% Sodium Chloride Injection/Solution for Infusion bag or bottle 
will be used in the placebo and ABBV-8E12 arms at each site.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
88
For investigational product monitoring, there will be an unblinded Clinical Research 
Associate (also referred to as a Pharmacy CRA) for verification of unblinded preparation 
documentation.  The unblinded Pharmacy CRA will be a separate individual than the 
blinded CRA to ensure blinding is maintained.  The unblinding procedure for the 
unblinded pharmacist/qualified designee and the unblinded Pharmacy CRA will be in a 
separate study-specific document.
The IVR system will be programmed with blind-breaker instructions.  The study blind for 
a subject may be broken, if, in the opinion of the investigator, it is in the subject's best 
interest to know the study drug assignment.
AbbVie must be notified before breaking the blind, unless identification of the study drug 
is required for a medical emergency, i.e., situation in which the knowledge or the specific 
blinded treatment will affect the immediate management of the subject's conditions 
(e.g., antidote is available).  AbbVie must then be notified within 24 hours of the blind 
being broken.  The date and reason that the blind was broken must be recorded in the 
source documentation and on the eCRF, as applicable.
Unblinding of Data for the Data Monitoring Committee (DMC)
In order to ensure that the DMC will be fully informed, the DMC will be unblinded in its 
assessment of safety and efficacy data.  The DMC will have full access to all data as 
needed for safety assessment.  SAS® data sets blinded with respect to treatment 
assignment will be sent to an external Statistical and Data Analysis Center (SDAC) and 
Exposure-Response Analysis Center (ERAC) by AbbVie.  The study randomization will
be sent to the SDAC and ERAC under separate cover.  The SDAC and ERAC will 
generate a Closed Report that includes unblinded information for DMC.  Review of the 
Closed Report will be limited to the DMC and, if necessary, an Internal Review 
Committee (IRC) from the Sponsor who may need to consult with the DMC in order to 
formulate a decision based on the DMC's recommendations.  Detailed communication 
plan between DMC and IRC will be specified in the DMC Charter.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
89
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 the Investigational 
Product accountability requirements will be provided as a separate document from the 
protocol.  Upon completion of the study, all original containers (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.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This study is designed to assess the efficacy, safety, and tolerability of ABBV-8E12 in 
subjects with PSP for up to 52 weeks.  The inclusion of placebo administration and the 
double blind nature of the study will provide unbiased assessments.  The parallel-group 
design with placebo control will provide a well-controlled unbiased assessment of the 
effect of ABBV-8E12 on clinical outcome measures and potential neuroimaging and CSF 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
90
biomarkers that are associated with PSP disease activity.  Toxicity management in the 
parallel group design is described in Section 6.1.7.
5.6.2
Appropriateness of Measurements
Standard pharmacokinetic, statistical, clinical, and laboratory procedures will be utilized 
in this study.
The PSPRS was developed to evaluate the severity and progression of PSP symptoms.
The PSPRS has been widely used in the scientific literature to evaluate PSP symptoms 
and has adequate reliability and validity.12  The SEADL, UPDRS Part II, RBANS, 
NNIPPS-PPS, and PSP-QoL are currently accepted and validated methods of evaluating 
subjects with PSP.  All safety assessments are standard measures used in pharmaceutical 
research.
On-treatment safety evaluations are scheduled at more frequent intervals for the subjects 
enrolled in Cohort 1 and Cohort J1 to promptly detect emerging safety signals.
5.6.3
Suitability of Subject Population
The research diagnostic criteria for possible and probable progressive supranuclear palsy 
developed by the National Institute of Neurological Disorders and the Society for 
Progressive Supranuclear Palsy (NINDS-SPSP) have been well validated and are highly 
predictive of underlying PSP pathology.5  The selection criteria are intended to identify 
subjects who have the potential to benefit from treatment would not be exposed to undue 
risk.  The selection of subjects who are otherwise in general good health is standard for 
pharmacokinetic studies, promotes compliance and reduces variability.
5.6.4
Selection of Doses in the Study
Cohort 1 and Cohort J1
Dose levels of 2000 mg and 4000 mg have been selected for Cohort 1 and Cohort J1 
based on available safety, tolerability and pharmacokinetic data from two patients with 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
91
tauopathies that received ABBV-8E12 under an expanded access IND (US; 20 monthly 
infusions; maximum dose of 25 mg/kg for the last 7 months) and a compassionate use 
trial application (Germany; 3 monthly infusions; maximum dose of 15 mg/kg for the last 
2 months) as well as preliminary safety, tolerability and pharmacokinetic data from the 
ongoing SAD study (Study C2N-8E12-WW-104) in patients with PSP, which is exploring 
the safety, tolerability, and pharmacokinetics of single doses of ABBV-8E12 ranging from 
2.5 mg/kg to 50 mg/kg.  In both compassionate-use protocols, the ABBV-8E12 infusions 
were well tolerated without any observed signs or symptoms of antibody-related toxicity.
Study C2N-8E12-WW-104 has been completed and ABBV-8E12 has been generally well
tolerated up to the highest tested dose of 50 mg/kg without notable treatment-related 
adverse effects or any clinically concerning safety findings.
The actual doses administered in the SAD study were based on the subject's body weight, 
and the range of actual doses at the 50 mg/kg group was 2625 mg to 4760 mg.  
The planned doses to be administered in this study are 2000 mg and 4000 mg, and these 
fixed-doses were determined based on an 80-kg person at the 2 highest doses administered 
in ongoing SAD study with patients with PSP (25 mg/kg and 50 mg/kg).  In the SAD 
study, mean body weight of the 23 patients with PSP who received ABBV-8E12 was 
74.8 kg, consistent with weights observed in previous studies7,27 in patients with PSP.
Based on modeling and simulations of all pharmacokinetic data in the SAD study, 
exposures following single dose of fixed-dose 4000 mg are expected to be comparable to 
the observed exposures at the 50 mg/kg group in the SAD study, and exposure variability 
following a fixed-dose regimen is predicted to be similar to a weight-based regimen.
In the 4-week preclinical mouse toxicology study, that assessed off-target toxicity of 
ABBV-8E12, the highest dose tested was 250 mg/kg and the corresponding Cmax and 
AUC0-168h were 3050 μg/mL and 298,000 hr•μg/mL (on Day 22) after 4 weeks of dosing.  
Assuming the pharmacokinetics of ABBV-8E12 is linear, the steady-state 
pharmacokinetic profiles were simulated at 2000 and 4000 mg following monthly 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
92
administration of ABBV-8E12 based on the available pharmacokinetic data in the 
ongoing SAD study in patients with PSP.  The predicted safety margin at the dose levels 
of 2000 and 4000 mg is approximately 3- and 1.4-fold, respectively, for both Cmax and 
AUC.  There is no pharmacologically relevant species in which to conduct toxicology 
studies to support safety of ABBV-8E12.
Overall, based on available safety and tolerability data and pharmacokinetic projections, it 
is expected that ABBV-8E12 should be well tolerated within the dose range to be 
administered in the planned Phase 2 study.  In order to minimize any potential risk 
associated with higher drug exposure following the administration of a fixed dose in an 
individual subject with low weight compared to the weight-based dosing regimen in 
Study C2N-8E12-WW-104 and/or the risk associated with higher drug exposure after 
multiple dosing, augmented safety, and pharmacokinetic monitoring in the initial cohorts 
of 39 subjects (Cohort 1 and Cohort J1) will be conducted in the Phase 2 study.  Subjects 
in Cohort 1 and Cohort J1 will have additional study visits, and more frequent 
neurological exams, vital signs, safety labs, and lumbar punctures.  Additionally, safety 
oversight will be provided by a Data Monitoring Committee.
Reductions in free CSF tau may be a target engagement marker that is associated with 
efficacy, as such, based on the pharmacokinetic data from the SAD study and the 
dissociation constant (kD) of ABBV-8E12 determined in vitro, 2000 mg and 4000 mg are 
predicted to lead to approximately 75% to 90% and 85% to 95% of tau in CSF being 
bound by the antibody, respectively, at predicted Ctrough and Cmax values.  Assuming 70% 
binding of tau by the 2000 mg dose, it is likely that lower doses would not provide 
sufficient binding to achieve near maximal efficacy and doses higher than 4000 mg of 
ABBV-8E12 would not lead to significantly higher percentage of tau binding and as such 
the 4000 mg dose has the greatest likelihood of being maximally effective.  Since PSP is a 
rare and rapidly progressing disorder with no currently approved treatments and there is a 
limited pool of potential study participants, there is a strong rationale to initially allocate 
subjects to doses that are likely to demonstrate maximum or near maximum efficacy.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
93
Cohort 2
Doses in Cohort 2 will not exceed the highest dose administered in Cohort 1 and 
Cohort J1, and dose-response and exposure-response relationships in CSF total and free 
tau levels (observed and change from baseline) will be evaluated to support dose selection 
in Cohort 2, if appropriate. 
Doses may be decreased after evaluation of the safety, tolerability, and available 
pharmacokinetic data by the DMC.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Section 6.1
through Section 6.1.6.  For product complaints, please refer to Section 6.2.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide an "Other" cause of the event.  For adverse events to be 
considered intermittent, the events must be of similar nature and severity.  Adverse 
events, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
94
All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, meet protocol specific criteria for potentially clinically significant 
(PCS) laboratory values defined in Appendix D and/or if the investigator considers them 
to be adverse events.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre-planned prior to study entry.  However, if the pre-
existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
95
6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event within 24 hours of the site being made aware of the serious adverse 
event:
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study subject.  
Disability is not intended to include experiences of relatively 
minor medical significance such as headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma
(e.g., sprained ankle).


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
96
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject and 
may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of subject, life-
threatening, hospitalization, prolongation of hospitalization, 
congenital anomaly, or persistent or significant 
disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.1.2
Adverse Event Severity
The investigator will use the following definitions to rate the severity of each adverse 
event:
Mild
The adverse event is transient and easily tolerated by the subject.
Moderate
The adverse event causes the subject discomfort and interrupts the 
subject's usual activities.
Severe
The adverse event causes considerable interference with the subject's 
usual activities and may be incapacitating or life-threatening.
6.1.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
97
Reasonable 
Possibility
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
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 serious 
adverse event.
6.1.4
Adverse Event Collection Period
All adverse events 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, serious adverse events and protocol-related nonserious adverse events 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.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
98
Figure 2.
Adverse Event Collection
6.1.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
electronic data capture (EDC) RAVE® system.  Serious adverse events that occur prior to 
the site having access to the RAVE® system or if RAVE is not operable can be emailed 
(this is the preferred route) or faxed to Clinical Pharmacovigilance within 24 hours of 
being made aware of the serious adverse event.
Email:  
FAX to:  
For safety concerns, contact the Neuroscience Safety Team at:
Neuroscience Safety Team
1 North Waukegan Road
North Chicago, IL 60064
Office:
Email:


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
99
For any subject safety concerns, please contact the physician listed below:
Primary AbbVie Medical Director:
Medical Director
Neuroscience Development
AbbVie Inc.
1 N Waukegan Road
North Chicago, IL 60064
Telephone Contact Information:  
Phone:
Cell:
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 Medical Director.
Phone:  
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 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.
Serious adverse events that meet the reporting criteria, as dictated by local regulations, 
will be reported to both responsible ethics committees 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 Harmonisation [ICH] Expedited 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
100
Reports or any additional reports required by local regulations) to the IEC/IRB of any 
changes that affect the conduct of the study and/or increase the risk to subjects.  Written 
documentation of the submission to the IEC/IRB should also be provided to AbbVie.
6.1.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  Subjects who become pregnant during the study must 
be discontinued from the study drug (Section 5.4.1).
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.
Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to AbbVie within 24 hours of the 
site becoming aware of the event.
6.1.7
Toxicity Management
For the purpose of medical management, all adverse events and laboratory abnormalities 
that occur during the study must be evaluated by the investigator.
A drug-related toxicity is an adverse event or laboratory value outside of the reference 
range that is judged by the investigator or AbbVie as a "reasonable possibility" of being 
related to the study drug (Section 6.1.3).  Toxicity is deemed "clinically significant" based 
on the medical judgment of the investigator.  The following guidelines should be used for 
study drug-related toxicity management.
Potential Drug-Related Toxicities
No potential drug related toxicities were identified from preclinical or clinical studies 
conducted to date.  Examples of safety concerns that could be hypothetically associated 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
101
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 the mouse version 
of ABBV-8E12 antibody bound to tau aggregates was detected in preclinical studies.28  
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, or rash.  ABBV-8E12 is lacking the 
Fragment Crystallizable (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 immune-safety profile.  
No infusion reactions have occurred in the single dose PSP clinical study or in the 
Expanded Access protocol (Studies C2N-8E12-EA-001 and C2N-8E12-DE-003).
Allergic Reactions Management
Subjects will be closely monitored for treatment-related adverse events, including allergic 
reactions, during the infusion.  For their first 4 ABBV-8E12 infusions, subjects should be 
monitored on site until 2 hours post-infusion.  For subsequent infusions, subjects should 
be monitored on site until at least 30 minutes after the end of infusion.  Subjects in 
Cohort J1 will be confined for a minimum of 24 hours following their first infusion.  The 
Investigator will assess safety 2 days after the first infusion, either while in hospital or as 
an outpatient.  From their second to fourth infusion, Cohort J1 subjects will be observed 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
102
on-site for at least 2 hours following each infusion of study drug.  Subjects in Cohort 2 
will be observed on-site for at least 2 hours following each of the first 4 infusions of study 
drug.  Following the 4th infusion, all subjects should be monitored on-site for at least 
30 minutes after the end of infusion. Longer observation periods and more frequent vital 
sign checks may be required in subjects who experience infusion reactions.  In general, 
Infusion reactions are more frequently observed during the first infusion and within 
24 hours from the start of administration, especially within the first 2 hours.29  Please refer 
to Table 2, Safety Observation Period Following Infusions, for a summary of the 
observation periods following infusions.
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, intravenous 
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 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.
6.1.7.1
Management of Adverse Events of the Nervous System
Subjects will be closely monitored for adverse events suggesting neurotoxicity.  A drug 
related adverse event is an adverse that is judged by the investigator or AbbVie to have a 
"reasonable possibility" of being related to the study drug.
Severe or life-threatening drug related adverse events of the nervous system will require 
discontinuation from further treatment with ABBV-8E12 and prompt notification of the 
AbbVie Medical Director.  Appropriate medical therapy will be initiated and subjects will 
be followed up until the resolution.
Clinically significant treatment-emergent neurological abnormalities or MRI findings will 
prompt notification of the AbbVie Medical Director; subjects will be considered for 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
103
discontinuation if clinically indicated, and may be permitted to continue in the study only 
after a management plan is discussed with the AbbVie Medical Director.
6.1.8
Collection of Data Regarding Known Complications of the 
Disease Under Study
Natural progression of PSP (including new or worsening neurological symptoms and 
signs) is expected in the subjects.  Disease progression will be assessed at pre-determined 
intervals throughout the treatment period by standardized criteria (such as the PSPRS, 
SEADL, UPDRS Part II, CGI-S, NNIPPS-PPS) and recorded on the corresponding case 
report form (CRF) pages for purposes or risk/benefit determinations.  Therefore, "disease 
progression" or other similar verbatim terms related to disease status SHOULD NOT be 
recorded on the AE CRF pages.  Similarly, since falls are a core component and defining 
feature of PSP (Steele-Richardson-Olszewski Syndrome), falls will not be recorded as 
AEs unless they lead to other injury or represent a change in frequency or character from 
pre-randomization falls.
Similarly, the slow progression of pre-existing disease-related signs and symptoms clearly 
associated with the disease during the treatment period will not be reported as AEs unless 
these signs and symptoms are judged by the Investigator to have become unusually severe 
or accelerated, or if the Investigator suspects the deterioration of disease-related signs and 
symptoms to be potentially related to the investigational drug.  If there is any uncertainty 
about the worsening of an AE being due solely to the disease under the treatment 
protocol, it should be reported as an AE or SAE as appropriate.
Discontinuation from this treatment protocol because of progression or deterioration of 
the disease should be recorded on the protocol Termination CRF page as discontinuation 
due to "disease progression" and NOT as discontinuation due to an AE.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
104
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product.
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product or packaging issues.
Any information available to help in the determination of causality to the events outlined 
directly above should be captured.
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 24 hours of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and documented in source as required by the Sponsor.  Product 
Complaints associated with adverse events will be reported in the study summary.  All 
other complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition.  In instances where a return is requested, every effort should be made by the 
investigator to return the product within 30 days.  If returns cannot be accommodated 
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.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
105
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 the 
appropriate Independent Ethics Committee (IEC)/Independent Review Board (IRB), 
regulatory authorities (as applicable), and the following AbbVie Clinical Monitor(s):
Primary Contact:
Study Project Manager
AbbVie
1 North Waukegan Road
North Chicago, IL 60064
Office:
Mobile:
Email:
Alternate Contact:
 
Study Management Associate 
AbbVie
1 North Waukegan Road
North Chicago, IL 60064
Mobile:
Email:
Clinical Project Manager
AbbVie
3-5-27, Mita, Minato-ku
Tokyo, Japan 108-6302
Office:
Fax:
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.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
106
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
General Considerations
Unless otherwise specified, when a total score of an efficacy or safety scale is calculated 
from a set of individual items, the total score will be considered missing if any of the 
individual items are missing.  When an average score is obtained from a set of individual 
items, it will be calculated from the non-missing items.
8.1.1
Analysis Data Sets
Intent-to-Treat Data Set
The intent-to-treat (ITT) data set will include all randomized subjects who take at least 
one dose of study drug.  The data from the ITT data set will be analyzed by the treatment 
group assigned at the time of randomization, even if the subject does not receive the 
correct treatment, is not compliant with the protocol or does not follow through with the 
study until completion.  All efficacy analyses will be conducted on the intent-to-treat data 
set unless otherwise specified.
Safety Data Set
The safety data set will include all randomized subjects who take at least one dose of 
study drug.  For this analysis data set, actual treatment received will be used instead of 
treatment assignment at the time of randomization.  All safety analyses will be conducted 
on the safety data set unless otherwise specified.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
107
8.1.2
Disposition, Demographics, and Other Baseline 
Characteristics
Subject Disposition
The number and percentage of subjects contributed by each country and site will be 
summarized for each treatment group and for all treatment groups combined for the safety 
data set.
The number and percentage of subjects who prematurely discontinue study drug will be 
summarized by treatment group and overall for the safety data set for the primary reason 
as well as for all reasons collected.  In the summary, the number and percentage of 
subjects who discontinue due to any reason as well as due to each specific primary reason 
will be presented.  Subjects may report multiple reasons for prematurely discontinuing 
study drug, but the primary reason for discontinuation will be indicated in the eCRF and 
used to infer treatment group difference in subject's disposition.  Two-sided Fisher's exact 
tests will be used to perform pairwise comparisons between each ABBV-8E12 dose group 
and placebo with respect to the proportion of subjects who discontinue for any reason and 
for each reason reported as primary.
Demographic and Other Baseline Characteristics
Demographics will be summarized for the intent-to-treat data set and the safety data set 
unless otherwise specified.  Treatment group differences will be evaluated using overall 
tests.  No pairwise comparisons between treatment groups will be performed unless the 
overall P value is ≤ 0.050.
For continuous demographic variables including age, weight, height, body mass index 
(BMI), descriptive statistics (number of subject with non-missing data, mean, standard 
deviation, median, and minimum and maximum) will be provided for each treatment 
group and for all treatment groups combined.  The overall treatment differences will be 
tested using one-way analysis of variance (ANOVA).


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
108
For categorical demographic variables including gender and race, the number and 
percentage of subjects in each category will be provided for each treatment group and for 
all treatment groups combined.  Fisher's exact test will be carried out to assess the overall 
comparability of treatment groups based on two-sided tests.
Efficacy and clinical measures at baseline (PSPRS total score, SEADL score, UPDRS 
Part II score, CGI-S score, CGI-C score, PSP-QoL subscale scores and VAS, RBANS 
score, Color Trails Test (Parts 1 and 2) scores, Letter fluency test score, NNIPPS-PPS 
total score, EQ-5D index score and VAS, and MMSE total score) will be summarized for 
the intent-to-treat data set only.  One-way ANOVA will be used to assess the overall 
comparability of treatment groups for all measurements.
Medical History
Medical history data, including subject's history of early PSP, will be summarized for the 
safety data set using body systems and conditions/diagnoses as captured on the eCRF and 
coded per Medical Dictionary for Regulatory Activities (MedDRA) guidelines.
Previous and Concomitant Medications
Previous and concomitant medications will be coded using the most recent World Health 
Organization (WHO) Drug dictionary, and will be summarized by treatment group for the 
safety data set.  No statistical testing will be performed.  A subject who reports two or 
more uses of medication that belong to the same category defined by WHO Drug will be 
counted only once for that WHO category.
8.1.3
Efficacy Analyses
All efficacy analyses will be conducted on the intent-to-treat data set unless otherwise 
specified.  Data collected more than 45 days after the last dose of the study drug will not 
be included in efficacy analyses.  Unless otherwise specified, for all efficacy analyses, 
"baseline" refers to the last non-missing observation prior to the first dose of study drug 
and "final" refers to the last non-missing observation after the first dose of study drug and 
no more than 45 days after the last dose of study drug administration.  Pairwise 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
109
comparisons between each ABBV-8E12 dose group and the placebo group will be 
performed with two-sided tests.  Hochberg procedure27 will be used for the efficacy 
analysis to handle multiplicity of comparisons between multiple ABBV-8E12 doses and 
placebo at the pre-specified significance level at the interim analysis.  For the final 
analysis, a graphic approach30 will be used to propagate alpha (α) among hypotheses 
testing and control overall family-wise error rate due to multiple comparisons for primary 
and key secondary efficacy endpoints for multiple ABBV-8E12 doses.  The overall α for 
the final analysis is 0.04998 after adjusting for interim futility analyses.  The α will be 
split equally between two dose groups to test the primary and key secondary endpoints at 
Week 52 within each dose level.  The order of efficacy endpoints to be tested will be the 
same within each dose level (Table 9).  The primary endpoint will be tested first followed 
by the secondary endpoints and α could be propagated between two doses and two 
families of hypotheses testing based on the graphic approach (Figure 3).  In the graph, the 
arrows specify the α transfer paths.  Once an endpoint is rejected (i.e., deemed significant) 
at its assigned significance level, its significance level will be transferred to subsequent 
endpoint(s) following the arrow(s).  The numbers on the arrows denote the weights for 
transferring and (possibly) splitting the significance level.  The overall type I error rate for 
this trial will be controlled at the two-sided 5% level.  The detailed hypotheses testing 
procedure and the details of analyses methods will be pre-specified in the Statistical 
Analysis Plan (SAP) which will be finalized and signed off before the first futility interim 
analysis of this trial.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
110
Table 9.
Hypotheses Testing Order in the Graphical Testing Approach
Efficacy 
Endpoints
Family
Ordered 
Efficacy Endpoints
Hypotheses
The High Dose 
(4000 mg) vs. 
Placebo
The Low Dose 
(2000 mg) vs. 
Placebo
Primary 
family
PSPRS total score change from baseline at Week 52
H11
H21
Secondary 
family
UPDRS Part II score change from baseline at Week 52
H12
H22
CGI-C score at Week 52
H13
H23
Volumetric MRI change from baseline at Week 52 –
Midbrain
H14
H24
SEADL score change from baseline at Week 52
H15
H25
Figure 3.
A Graph for Multiplicity Adjustment of Multiple Hypotheses


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
111
8.1.3.1
Primary Efficacy Analysis
The primary efficacy variable will be the change from baseline to Week 52 on the PSPRS 
total score.  The primary efficacy analysis will utilize a likelihood-based, mixed-effects 
model, repeated measures (MMRM) analysis of the change from baseline for each post-
baseline and compare each ABBV-8E12 dose group with the placebo group.  The model, 
which uses all observed data, will include fixed, categorical effects for treatment, site, 
visit, baseline score-by-visit interaction and treatment-by-visit interaction, with 
continuous fixed covariates for the corresponding baseline score.  The primary 
comparison will be the contrast between each ABBV-8E12 dose group and placebo at 
Week 52.  The treatment group differences at earlier visits will be assessed as secondary.  
An unstructured (co)variance structure will be used to model the within-subject errors.  
Satterthwaite's approximation will be used to estimate denominator degrees of freedom 
and the Type III sum-of-squares for the Least Square (LS) means will be used to estimate 
treatment group differences.
8.1.3.2
Secondary Efficacy Analysis
Secondary Efficacy Analysis of the Primary Efficacy Variable
The change from baseline to each post-baseline observation on the PSPRS total score will 
be summarized.  The change from baseline to final observation on the PSPRS total score 
will be analyzed by an analysis of covariance (ANCOVA) model with treatment and study 
site as the main effects and the baseline PSPRS total score as a covariate in the ITT data 
set.  Missing data could occur due to loss of follow-up or early termination during the 
treatment period in the trial.  To consider different missing data mechanisms, sensitivity 
analyses will be conducted on PSPRS total score after imputation of missing data.  
Detailed sensitivity statistical analysis plan will be described in the SAP.
Analyses for Secondary and Exploratory Efficacy Variables
The key secondary efficacy variables include: 
●
Unified Parkinson's Disease Rating Scale (UPDRS) Part II score


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
112
●
Clinical Global Impression of Change (CGI-C) score
●
Midbrain atrophy as measured by volumetric MRI
●
the Schwab and England Activities of Daily Living Scale (SEADL) score
Other secondary efficacy variables include:
●
Clinical Global Impression of Severity (CGI-S) 
●
PSP-Quality of Life (PSP-QoL) score
●
PSPRS domain scores
●
Regional (third ventricle, frontal lobes, superior cerebellar peduncle, 
brainstem) and whole brain atrophy as measured by volumetric MRI.
●
PSP Staging System (PSP-SS) (composite of dysphagia, gait, and sitting down 
items from PSPRS)
●
Time to loss of ability to walk independently as measured by PSPRS item 26
Exploratory efficacy variables include: 
●
Natural History and Neuroprotection in Parkinson Plus Syndromes-Parkinson 
Plus Scale (NNIPPS-PPS) total score (not conducted in Japan), 
●
Patient Global Impression of Change (PGI-C) score, 
●
Letter Fluency Test (LFT) score, 
●
Repeatable Battery for Assessment of Neuropsychological Status (RBANS) 
score, 
●
Color Trails Test (CTT) (Parts 1 and 2) score,  
●
EuroQoL-5D (EQ-5D) index score and Visual Analog Scale (VAS),
●
Exploratory quantitative MRI measures may additionally be evaluated, 
including diffusion tensor imaging (DTI) derived fractional anisotropy (FA) 
and diffusivity measures [radial diffusivity (RD), mean diffusivity (MD), and 
axial diffusivity] to assess changes in pathophysiology.
●
Additional brain regions that are not listed under secondary assessments may 
be measured by volumetric MRI.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
113
The change from baseline score on each secondary and exploratory efficacy variable if 
appropriate (with the exception of CGI-C and PGI-C scores) will be summarized and 
analyzed using the similar MMRM model described for the primary efficacy analysis.  
The analyses will be performed in the ITT data set.
CGI-C scores at each post-baseline visit will be analyzed using an MMRM model, 
including fixed, categorical effects for treatment, site, visit, and treatment-by-visit 
interaction, with continuous fixed covariates for baseline CGI-S.
PGI-C scores at each post-baseline visit will be analyzed using an MMRM model, 
including fixed, categorical effects for treatment, site, visit, and treatment-by-visit 
interaction.
8.1.4
Subgroup Analysis of PSPRS Total Score
To examine whether gender, age group, study site, country/region or other baseline 
variables have an impact on response to treatment, subgroup analyses on PSPRS total 
score will be conducted on change from baseline to last observations up to Week 52.  
Subgroup analyses will be performed using an ANCOVA model with the terms of 
treatment, site, subgroup variable, the treatment-by-subgroup variable interaction, and 
baseline score as a covariate.  The subgroup analysis for country/region will be performed 
using the same model but with the study site nested within country/region.  The 
hypothesis that consistent response to treatment across strata of a subgroup variable will 
be tested at the significance level of 0.100 by examining the P value of the treatment-by-
subgroup interaction term in the ANCOVA model specified above.  The statistical 
comparison of each ABBV-8E12 dose group with placebo within each subgroup stratum 
will be performed when the statistical significance of the treatment-by-subgroup 
interaction term is achieved at 0.100 level.  The subgroup analysis will be conducted in 
the ITT data set.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
114
8.1.5
Biomarker Analyses
An ANCOVA model will be used to evaluate CSF concentrations for total tau, free tau, 
and NFL for each scheduled time of evaluation during treatment.  Corresponding analyses 
on plasma measurements of total tau and NFL will be performed.  The observations will 
be classified by treatment and region, and the initial model will have an effect for the 
interaction of treatment and region.  The baseline value for total tau and free tau (last 
value before the first dose of study drug) will be the covariate in the case of total tau and 
free tau, but for the analysis on the ratio the covariate will be the baseline total tau 
concentration measurement.  If the test statistic on the interaction of treatment and region 
is not significant at level 0.050, the effect for interaction will be removed from the model.  
Within the framework of the analysis of covariance the means of the three treatments 
(with adjustment for baseline) will be estimated.  The hypothesis of no difference between 
the main effects of the higher ABBV-8E12 dose and placebo will be tested at significance 
level 0.05.  If this hypothesis is rejected, the hypothesis of no difference between the 
lower ABBV-8E12 dose and placebo will then be tested at significance level 0.050.  If the 
statistic on the interaction of treatment and region is significant at level 0.050, the tests for 
the comparison of the ABBV-8E12 dose levels to placebo will also be performed for each 
region within the framework of the final model.
If the probability distribution for a variable appears to have considerable non-symmetry 
(e.g., skewness coefficient > 1.00 in magnitude), a transformation will be sought that has 
an approximately normal distribution.  If a transformation is employed, estimates of 
central values on the original scale (back transformation of SAS least squares means) will 
be provided.  If the logarithmic transformation is used, the comparison of the treatments 
will be in terms of the ratio of central values.  
If data for other variables are reported, descriptive statistics will be provided and 
appropriate analyses performed.  The association between the variables referred to here as 
biomarkers and measures of clinical efficacy will be explored.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
115
8.1.6
Safety Analyses
All safety analyses will be performed on the safety data set unless otherwise specified.  
Comparisons between each ABBV-8E12 dose group and placebo will be performed with 
two-sided test at the significance level of 0.050, if applicable.  All safety assessments that 
are taken no more than 20 weeks after the last dose of study drug administration will be 
included in the safety evaluation of the Double-blind Treatment Period, and all safety 
assessments that are taken more than 20 weeks after the last dose of study drug will be 
included in the safety evaluation for the Post-treatment Follow-up Period.
Study Drug Exposure and Compliance
The number of doses on study drug will be summarized by treatment group and all 
treatment groups combined.  The number and percentage of subjects with at least 90% 
compliance with study drug dosing will be summarized by treatment group and all 
treatment groups combined.
Adverse Events
A treatment-emergent adverse event (TEAE) is defined as any adverse event that begins 
or worsens in severity on or after the first study drug dose date and no more than 
20 weeks after the last study drug dose date.
All other safety assessments that are taken no more than 20 weeks after the last dose of 
study drug will be included in the safety evaluation of the Double-blind Treatment Period, 
and all safety assessments that are taken more than 20 weeks after the last dose of study 
drug will be included in the safety evaluation for the Post-treatment Follow-up Period.
Unless otherwise specified, treatment group differences in continuous safety variables 
(e.g., change from baseline to final observation on laboratory tests) will be assessed using 
an ANOVA model with treatment as the main effect, and the treatment group differences 
in binary safety variables will be evaluated using Fisher's exact test.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
116
8.1.6.1
Analysis of Adverse Events
Adverse events will be coded using the most current version of the Medical Dictionary for 
Regulatory Activities (MedDRA).  The number and percentage of subjects who report 
TEAEs will be tabulated by MedDRA system organ class (SOC) and preferred term for 
each treatment group, overall ABBV-8E12 and all treatment groups combined.  Treatment 
group differences between each ABBV-8E12 dose group and the placebo group will be 
analyzed using Fisher's exact test.
The number and percent of subjects experiencing treatment-emergent SAEs (including 
deaths) and adverse events leading to premature discontinuation of study drug will be 
tabulated by MedDRA SOC and preferred term for each treatment group, overall 
ABBV-8E12 dose groups, and all treatment groups combined.  Treatment group 
differences between each ABBV-8E12 dose groups and placebo will be analyzed using 
Fisher's exact test.
8.1.6.2
Analysis of Laboratory Tests
Change from baseline to each double-blind visit value and to the minimum, maximum and 
final double-blind value will be presented for each continuous hematology, chemistry and 
urinalysis parameters.  Treatment differences between each ABBV-8E12 dose group and 
placebo in change from baseline to minimum, maximum and final clinical laboratory 
evaluation will be analyzed using one-way ANOVA with treatment as the main effect.
For each treatment group, shift tables will be generated showing the number and 
percentage of subjects with low, normal, high and missing values at baseline and final 
observation based on the reference ranges provided by each laboratory.
The number and percentage of subjects in each treatment group who have values meeting 
predefined criteria for potentially clinically significant values (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.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
117
8.1.6.3
Analysis of Vital Signs and Weight
Vital sign variables include pulse rate, systolic blood pressure, and diastolic blood 
pressure, body temperature, weight, and BMI.  Pulse rate and blood pressure variables 
will include measurement in the supine position, measurement in the standing position 
and the orthostatic change (from supine to standing).
Change from baseline to each double-blind visit value and to the minimum, maximum and 
final double-blind value will be presented for each vital sign and weight variable and 
analyzed using one-way ANOVA with treatment as the main effect.
The number and percentage of subjects in each treatment group who have values meeting 
predefined criteria for potentially clinically significant values (definitions will be provided 
in the Statistical Analysis Plan) 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.
8.1.6.4
Analysis of ECG Variables
ECG variables include heart rate, PR, QRS, QT, and QTcF intervals.  Change from 
baseline to final double-blind value will be presented for each ECG parameter and 
analyzed using one-way ANOVA with treatment as the main effect.
The number and percentage of subjects in each treatment group who have values meeting 
predefined criteria for potentially clinically significant values at any time after the 
first dose of study drug will be summarized.
8.1.6.5
Analysis of C-SSRS
Number and percentage of subjects in the following categories will be summarized for 
each treatment group by visit and for the entire study:
●
Answered 'Yes' to each C-SSRS item
●
Had suicidal ideation (defined as answering 'Yes' to one or more suicidal 
ideation items)


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
118
●
Had suicidal ideation only (defined as answering 'Yes' to one or more suicidal 
ideation items and answering 'No' to all suicidal behavior items)
●
Had suicidal behavior (defined as answering 'Yes' to one or more suicidal 
behavior items)
●
Had suicidal ideation or behavior (defined as answering 'Yes' to one or more 
suicidal ideation or behavior items)
8.1.7
Pharmacokinetics
8.1.7.1
Tabulations and Summary Statistics
For the combined data of Cohort 1 and Cohort J1, serum concentrations of ABBV-8E12 
and pharmacokinetic parameter values will be tabulated for each subject and each dose 
level, and summary statistics will be computed for each sampling time and each parameter 
by dose level.  Also, for the serum concentration data of all subjects (Cohort 1, Cohort J1, 
and Cohort 2), summary statistics will be provided for each scheduled time of sampling 
with breakdown by dose level.
CSF concentration data after the fifth dose (for subjects in Cohort 1 and Cohort J1) and 
the final dose will be tabulated and summarized by dose level.
8.1.7.2
Model and Tests
Unless stated otherwise, hypothesis tests will be performed at significance level 0.050.
Change in Concentration with Repeated Dosing
The concentration data of the planned pre-infusion sampling times of Cohort 2 (Days 15, 
29 and 85 plus Weeks 24 and 36) will be analyzed to investigate change in serum 
concentration over time.  The data of Cohort 1 and Cohort J1 will also be included in this 
analysis except for Day 29.  The logarithmic transformation will be used unless the data 
show that the logarithm has substantial non-symmetry (e.g., magnitude of skewness 
coefficient > 1.0) while untransformed concentration or another transformation has an 
approximately symmetric distribution.  A MMRM analysis will be performed.  The model 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
119
will have fixed effects for dose level, classification by time and the interaction of dose 
level and time.  The subjects will be viewed as a random sample, and an appropriate 
structure will be selected for the covariance matrix of the observations from a subject.  
The concentration central value (back transformation of the estimate of the mean of the 
transformed data) versus time curves for the two dose levels will be plotted on the same 
graph.  
Dose Proportionality
Analyses to address the issue of dose proportionality will be performed on the combined 
data of Cohort 1 and Cohort J1.  An analysis will be performed on each of dose 
normalized Cmax and dose-normalized AUC for each of the first dose interval (2 weeks in 
length) and the dose interval beginning at Day 85 (4 weeks in length).  An analysis will 
also be performed on dose-normalized Ctrough at Week 16.  The logarithmic transformation 
will be employed for Cmax and AUC and will likely be used for Ctrough.  An analysis of 
covariance (ANCOVA) will be performed for each exposure variable, with the greater 
emphasis on the dose interval that begins at Day 85.  Subjects will be classified by dose 
level and region, and the initial model will contain an effect for the interaction of dose 
level and region.  Body weight will be a covariate.  Other variables such as age and sex 
that might explain some of the variability among subjects will be considered for inclusion 
as covariates.  A necessary condition for such a variable to be included in the final model 
is that the regression coefficient be significant at level 0.100.  The dependence among 
explanatory variable candidates will also be considered when selecting the final model.  If 
the test statistic for interaction of dose level and region is not significant at level 0.100 for 
at least one of the three exposure variables for the dose interval beginning at Day 85, the 
effect for interaction will be removed from the model for all variables for both dose 
intervals.  For each of the two dose intervals for each variable, the hypothesis of no 
difference between the dose level main effects will be tested (a composite assessment 
across the regions) within the framework of the final model.  If the final model contains 
an effect for interaction of dose level and region and if the test statistic on interaction is 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
120
significant at level 0.100, the hypothesis of no difference between the dose levels will be 
tested for each region within the framework of the final model.
8.1.7.3
Missing Values and Model Violations
The possibility of bias from missing data of subjects who prematurely discontinue for 
reasons possibly related to study drug will be addressed.
In some cases of a missing individual concentration value, values of pharmacokinetic 
variables (Cmax, AUC, etc.) will be determined without replacing missing individual 
concentration values, but simply using the available data.  However, if a missing 
individual concentration value results in a value of a pharmacokinetic parameter that may 
be too low or too high to a meaningful degree, the value of the pharmacokinetic parameter 
will tentatively be considered missing.  In this case, a value for the missing individual 
concentration may be imputed so that an appropriate value of the pharmacokinetic 
parameter can be included in the analysis.  The imputed value will be obtained using 
appropriate methodology that takes into account the individual characteristics of the 
subject.  Also, if the concentration value at the beginning or end of the dose interval is 
missing, a value must be imputed in order for a value of AUC to be determined.
Transformation of variables in order to avoid a meaningful degree of non-normality in the 
probability distributions is discussed in Section 8.1.7.2.  If an adequate transformation is 
not found for a variable, then a non-parametric analysis may be performed.
8.1.7.4
Population Pharmacokinetic and Exposure-Response 
Analysis
Data from this study may be combined with data from other studies for the population 
pharmacokinetic and exposure-response analyses.  Population pharmacokinetic and 
exposure-response analyses of only data from this study may not be conducted.  The 
following general methodology will be used for the population pharmacokinetic and 
exposure-response analyses.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
121
Population pharmacokinetic analyses will be performed using the actual sampling time 
relative to dosing.  Pharmacokinetic models will be built using a non-linear mixed-effect 
modeling approach with the NONMEM software (version VII, or higher version).  The 
structure of the starting pharmacokinetic model will be based on the pharmacokinetic 
analysis of data from previous studies and Cohort 1 and Cohort J1 of this study.  Apparent 
CL and volume of distribution (V) of ABBV-8E12 will be the pharmacokinetic 
parameters of major interest in the NONMEM analyses.  If necessary, other parameters 
may be fixed if useful in the analysis.
The evaluation criteria described below will be used to examine the performance of 
different models.
The objective function of the best model is significantly smaller than the alternative 
model(s).
The observed and predicted concentrations from the preferred model are more randomly 
distributed across the line of unity (a straight line with zero intercept and a slope of one) 
than the alternative model(s).
Visual inspection of model fits, standard errors of model parameters and change in inter-
subject and intra-subject error.
Once an appropriate base pharmacokinetic model (including inter- and intra-subject error 
structure) is developed, empirical Bayesian estimates of individual model parameters will 
be calculated by the posterior conditional estimation technique using NONMEM.  The 
relationship between these conditional estimates of CL and V values and potentially
physiologically relevant or clinically meaningful covariates (such as subject age, sex, 
body weight, concomitant medications, laboratory markers of hepatic or renal function, 
etc.) will be explored using either stepwise forward selection method, or generalized 
additive method (GAM), or another suitable regression/smoothing method at a 
significance level of 0.050.  After identification of all relevant covariates, a stepwise 
backward elimination of covariates from the full model will be employed to evaluate the 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
122
significance (at P < 0.005, corresponding to a decrease in objective function > 7.88 for 
one degree of freedom) of each covariate in the full model.
Linear or non-linear relationships of primary pharmacokinetic parameters with various 
covariates will be explored.
Relationships between exposure and clinical observations (primary efficacy variable) will 
be explored with Cohort 1, Cohort J1, and Cohort 2 data combined.  Exposure-response 
relationships for secondary efficacy variables and/or some safety measures of interest may 
also be explored.  Initially, the time-course of placebo response will be modeled.  
Subsequently the relationship between exposure (e.g., population pharmacokinetic model 
predicted average concentrations or AUC or trough concentrations of the individual 
model-predicted pharmacokinetic profiles, or some other appropriate measure of 
exposure) and drug effect will be explored after accounting for the time-course of placebo 
response.  Several classes of models (e.g., linear, log-linear, exponential, Emax, sigmoid 
Emax, etc.) will be evaluated to characterize the exposure-response relationship based on 
the observed data.
Additional analyses will be performed if useful and appropriate.
The possibility of bias from missing data of subjects who prematurely discontinue due to 
an adverse event will be addressed.
8.1.8
Immunogenicity
The anti-drug antibody titers will be tabulated by dose level and summarized as 
appropriate.
Additional analyses will be performed if useful and appropriate.
8.1.9
Data Monitoring Committee (DMC)
This study will utilize a DMC consisting at least 2 external clinicians, at least 1 external 
statistician, and at least 1 external pharmacokineticist.  The DMC will review unblinded 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
123
safety and efficacy data and make recommendations to AbbVie based on the totality of 
available trial data.  An independent Statistical and Data Analysis Center (SDAC) and 
Exposure-Response Analysis Center (ERAC) will provide service to the DMC.  
Unblinded data will be kept by the SDAC and ERAC that will be conducting the analysis 
and preparing unblinded reports for the DMC and will not be released to the study team or 
study sites.  The DMC will provide recommendations about continuing, modifying, or 
stopping the trial for safety or efficacy reasons.  The DMC membership and 
responsibilities will be documented in the DMC charter.  After each DMC meeting, the 
chair of the DMC will communicate its recommendations to the designated AbbVie Point 
of Contact, as described in the DMC charter.  The AbbVie Representative will triage the 
recommendations to either the AbbVie Study Team if the recommendation can be 
implemented without unblinded data review or the AbbVie Internal Review Committee 
(IRC) if unblinded data review is required.  The AbbVie IRC will consist of a group of 
senior individuals representing, at a minimum, the Therapeutic Area (TA), 
Pharmacovigilance and Patient Safety (PPS), Regulatory Affairs (RA), Clinical 
Pharmacology and Pharmacometrics (CPPM), and Data and Statistical Sciences (DSS), 
who are not directly involved in the conduct of this clinical trial.  Members of IRC have 
technical depth to competently make decisions based on DMC recommendations to either 
(a) terminate the study or (b) implement significant unplanned protocol modifications.
8.1.10
Interim Analyses
Regular interim safety analyses and preplanned interim futility evaluation(s) will be 
performed in this study.  Assessment of safety and efficacy data at interim(s) will be 
performed by the DMC.
Safety Interim Analyses
The DMC will evaluate the available unblinded safety data and communicate their 
recommendations to the AbbVie Point of Contact.  The first three mandatory DMC 
reviews of unblinded safety data will take place after the 10th, 20th, and 30th subjects in 
Cohort 1 have been administered their second dose and results for the MRI scheduled at 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
124
approximately 2 weeks after their second dose are available.  An additional mandatory 
DMC review for Japanese subjects will take place after the 9th subject enrolled in Japan 
(Cohort J1) has been administered their second dose and results for the Day 15 Safety labs 
and MRI performed within 2 weeks after their second dose, are available for comparison 
with previous DMC review results as Cohort J1 patients' safety assessment.  The data set 
will consist of all of the available safety and pharmacokinetic data in the study, including 
the data of any subjects from Cohort 2 who have received at least one dose of study drug.  
Additional DMC reviews of available safety data will occur after a total of approximately 
80, 130, 180, 240, and 330 subjects are randomized and every 6 months thereafter until 
the study has completed.  Ad hoc meetings may occur as needed.
The DMC will communicate their recommendations to the AbbVie Contact (who is not 
involved in the conduct of the trial) regarding continuing, modifying or terminating the 
trial due to safety concerns in accordance with the DMC charter.  Details of safety interim 
analyses will be specified in the DMC Charter.
Futility Interim Analyses
Preplanned futility interim analyses may be performed.  The SDAC will be responsible 
for generating and providing unblinded statistical tables, figures, and listings to the DMC 
for the interim review for futility.  The DMC will communicate their recommendations to 
stop the trial for futility or to continue the study without modification to the AbbVie 
Contact who will share it with the IRC only.  The study will not be stopped because of 
positive results at the interim analyses and the α to be administratively spending at each 
interim analysis will be 0.00001.  DMC recommendations will not be communicated to 
the study team, study investigators, or any parties outside of the Sponsor.  To maintain the 
integrity of the trial, a specific data access plan with a strict firewall will be in place to 
protect the unblinded data and the details will be described in the DMC charter.
Details of futility interim analyses plan will be described in the DMC charter and the 
SAP.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
125
8.2
Determination of Sample Size
Approximately 330 PSP subjects (110 subjects/group) will be enrolled and randomized to 
two ABBV-8E12 dose groups and the placebo group with 1:1:1 randomization ratio.  This 
sample size has at least 90% power to detect an ABBV-8E12 effect size (vs. placebo) of 
0.56 for the high dose and 0.28 effect size for the low dose on the PSPRS total score 
changes from baseline at Week 52 using the Bonferroni method to control for multiplicity 
of multiple comparisons between two doses and placebo at the two-sided 5% significance 
level.  This sample size calculation was performed using East version 6.3.1 (Cytel).
In Japan, a total of 24 subjects (8 subjects/arm) randomized will have 80% probability to 
detect the consistent treatment effect among three regions (Japan, North America 
including US/Canada, and European countries including Australia assuming 7%, 54%, 
and 39% of the total 330 PSP subjects are randomized in three regions, respectively).  
This calculation is based on Method 231 and assumes that the significance level for 
comparison of each ABBV-8E12 dose vs. placebo is two-sided 2.5% and the dropout rate 
is 25% in all regions.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
126
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to International Council on 
Harmonisation (ICH) GCP.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki.  Responsibilities of the clinical 
investigator are specified in Appendix A.
9.3
Subject Information and Consent
Prior to the initiation of any screening or study-specific procedures, the investigator or 
his/her representative will explain the nature of the study to the subject, their study 
partner, and legally authorized representative (LAR) (if applicable), and answer all 
questions regarding this study.  
In Germany, if the investigator screening the subject has doubts about subject's cognitive 
capability, evaluation by an independent psychiatrist will be conducted to assess subject's 
ability to provide consent independently.  Additionally, for all subjects with an MMSE 
score of 24 or less at the time of study entry, an evaluation by an independent psychiatrist 
will also be requested.  If, in the opinion of the independent psychiatrist, subject is unable 
to provide consent independently, the subject will not be enrolled in the study.  
Each informed consent will be reviewed, signed and dated by the subject, the person who 
administered the informed consent, and any other signatories according to local 
requirements.  An informed consent statement will also be reviewed, signed and dated, by 
the subject's study partner prior to beginning any study related screening activities.  A 
copy of each informed consent will be given to the subject and their study partner and 
each original will be placed in the subject's medical record.  An entry must also be made 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
127
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.
If at any time during the study, a subject experiences diminished decision-making 
capacity, an informed consent must be obtained from an LAR.  In Germany, where the 
subject's LAR is not permitted to sign the IEC/IRB approved Informed Consent form on 
behalf of the subject, evaluation by an independent psychiatrist will be sought if the 
investigator who is evaluating the subject for inclusion in the study doubts the subject's 
cognitive ability to independently provide informed consent.
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 exploratory 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 exploratory 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 IEC/IRB, must be voluntarily signed and dated 
before samples are collected for pharmacogenetic exploratory research.  The nature of the 
testing should be explained and the subject given an opportunity to ask questions.  The 
informed consent must be signed before the samples are collected and any testing is 
performed.  If the subject does not consent to provide samples for pharmacogenetic 
exploratory research, it will not impact their participation in the study.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
128
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data, and records.  These may 
include hospital records, clinical and office charts, laboratory data/information, subject 
diaries or evaluation checklists, pharmacy dispensing and other records, recorded data 
from automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Source document data may be transcribed as required.  Data 
collected during this study must be recorded to the appropriate source document.
The investigator/institution will permit study-related monitoring, audits, IEC/IRB review, 
and regulatory inspection(s), providing direct access to source data documents.
10.2
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 electronic data capture (EDC) system called 
Rave® provided by the technology vendor Medidata Solutions Incorporated, NY, USA.  
The EDC system and the study-specific eCRFs will comply with Title 21 CFR Part 11.  
The documentation related to the validation of the EDC system is available through the 
vendor, Medidata, while the validation of the study-specific eCRFs will be conducted by 
AbbVie and will be maintained in the Trial Master File at AbbVie.
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
129
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.
11.0
Data Quality Assurance
Prior to enrolling any subject in the study, an initiation meeting will be held with AbbVie 
personnel, the investigator(s), and the study coordinators/project manager(s).  This 
meeting will include a detailed discussion and review of the protocol and essential 
documents, performance of study procedures, case report form completion and specimen 
collection methods.
The AbbVie monitor will monitor the study site throughout the study according to a 
monitoring plan.  Source document review will be made against entries in RAVE and a 
quality assurance check will be performed to ensure that the investigator is complying 
with the protocol and regulations.  During the study, an ongoing review of the data will be 
conducted by a physician or representative at AbbVie.  Computer logic will be run to 
identify inconsistent study data.  Any necessary corrections will be made to the database 
via the appropriate change process.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
130
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.
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 


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
131
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/director of 
the site in Japan and AbbVie.  Continuation of this study beyond this date must be 
mutually agreed upon in writing by both the investigator/director 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/director must retain any records related to the study according to local 
requirements.  If the investigator/director 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, 
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.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
132
14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for ABBV-8E12.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled Multiple Dose 
Study to Assess Efficacy, Safety, Tolerability, and Pharmacokinetics 
of ABBV-8E12 in Progressive Supranuclear Palsy
Protocol Date: 
13 December 2018
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
133
15.0
Reference List
1.
Golbe LI.  Progressive supranuclear palsy.  Semin Neurol.  2014;34(2):151-9.
2.
Houghton DJ, Litvan I.  Unraveling progressive supranuclear palsy:  from bedside 
back to the bench.  Parkinsonism Relat Disord.  2007;13 (Suppl 3):S341-6.
3.
Williams DR, Lees AJ.  Progressive supranuclear palsy:  clinicopathological 
concepts and diagnostic challenges.  Lancet Neurol.  2009;8(3):270-9.
4.
Schofield EC, Hodges JR, Bak TH, et al.  The relationship between clinical and 
pathological variables in Richardson's syndrome.  J Neurol.  2012;259(3):482-90.
5.
Litvan IY, Agid J, Jankovic C, et al.  Accuracy of clinical criteria for the diagnosis 
of progressive supranuclear palsy (Steele-Richardson-Olszewski Syndrome).  
Neurology.  1996;46(4):922-30.
6.
Stamelou MR, de Silva O, Arias-Carrión E, et al.  Rational therapeutic approaches 
to progressive supranuclear palsy.  Brain.  2010;133 (Pt 6):1578-90.
7.
Boxer AL, Lang AE, Grossman M, et al.  Davunetide in patients with progressive 
supranuclear palsy:  a randomised, double-blind, placebo-controlled phase 2/3 trial.  
Lancet Neurol.  2014;4422(14):1-10.
8.
Yanamandra KN, Kfoury H, Jiang TE, 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.
Yanamandra K, Jiang H, Mahan TE, et al.  Anti-tau antibody reduces insoluble tau 
and decreases brain atrophy.  Ann Clin Trans Neurol.  2015;2(3):278-88.
10.
AbbVie.  ABBV-8E12 Investigator's Brochure Edition 1.  25 March 2016; 
Addendum 1 to the Investigator's Brochure Edition 1.  August 2016.
11.
Duits FH, Martinez-Lage P, Paquet C, et al.  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.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
134
12.
Hall DA, Forjaz MJ, Golbe LI, et al.  Scales to assess clinical features of 
progressive supranuclear palsy:  MDS Task Force Report.  Movement Disorders 
Clinical Practice.  2015;2(2):127-34.
13.
Tolosa E, Litvan I, Hölglinger GU, et al.  A phase 2 trial of the GSK-3 inhibitor 
tideglusib in progressive supranuclear palsy.  Mov Disord.  (2014);29(4):470-8.
14.
Leclair-Visonneaua L, Rouauda T, Debily B, et al.  Randomized placebo-
controlled trial of sodium valproate in progressive supranuclear palsy.  Clinical 
Neurology and Neurosurgery.  146;(2016):35-9.
15.
Nuebling G, Hensler M, Paul S, et al.  PROSPERA:  a randomized, controlled trial 
evaluating rasagiline in progressive supranuclear palsy.  J Neurol.  (2016);1-10.
16.
Schwab RS, England AC.  Projection technique for evaluating surgery in 
Parkinson's disease.  In:  Gillingham FJ, Donaldson MC, eds.  Third synopsium on 
Parkinson's disease.  Edinburgh.  Livingston.  1969:152-7.
17.
Martinez-Martin P, Gil-Nagel A, Gracia LM, et al.  Unified Parkinson's disease 
rating scale characteristics and structure.  The Cooperative Multicentric Group.  
Mov Disord.  1994;9(1):76-83.
18.
Schrag A, Selai C, Quinn N, et al.  Measuring quality of life in progressive 
supranuclear palsy.  In:  Jenkinson C, Peters M, Bromberg M, eds.  Quality of Life 
Measurement in Neurodegenerative and Related Conditions.  Cambridge:  
Cambridge University Press.  2011;52-9.
19.
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.
20.
Uchiyama CL, Mitrushina MN, D'Elia LF, et al.  Frontal lobe functioning in 
geriatric and nongeriactric samples:  an argument for multimodal analyses.  Arch 
Clin Nueropsychol.  1994;9(3):215-27.
21.
Shao Z, Janse E, Visser K, et al.  What do verbal fluency tasks measure?  
Predictors of verbal fluency performance in older adults.  Front Psychol.  
2014;5:772.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
135
22.
Payan C, Viallet F, Landwehrmeyer B, et al.  Disease severity and progression in 
progressive supranuclear palsy and multiple system atrophy:  validation of the 
NNIPPS--Parkinson Plus Scale.  PLoS One.  2011;6(8):1-12.
23.
Guy W.  ECDEU Assessment Manual for Psychopharmacology.  Revised 
Rockville, MD, US Department of Health, Education, and Welfare, Public Health 
Service, Alcohol, Drug Abuse, and Mental Health Administration, NIMH 
Psychopharmacology Research Brand, Division of Extramural Research.
24.
EuroQol Group.  EuroQol - a new facility for the measurement of health-related 
quality of life.  Health Policy.  Elsevier Science.  1990;16(3):199-208.
25.
Folstein SE, Folstein SE, McHugh PR.  "Mini-mental state."  A practical method 
for grading the cognitive state of patients for the clinician.  J Psychiatry Res.  
1975;12(3):189-98.
26.
Columbia-Suicide Severity Rating Scale (C-SSRS) [homepage on the Internet].  
Columbia University Medical Center.  Available from:  
http//www.cssrs.columbia.edu/.
27.
Hochberg Y.  A sharper Bonferroni procedure for multiple tests of significance.  
Biometrika.  1988;75:800-2.
28.
Williams DR.  Tauopathies:  classification and clinical update on 
neurodegenerative diseases associated with microtubule-associated protein tau.  
J Intern Med J.  2006;36(10):652-60.
29.
Roselló S, Blasco I, García Fabregat L, et al.  Management of infusion reactions to 
systemic anticancer therapy:  ESMO Clinical Practice Guidelines.  Ann Oncol.  
2017;28 (Suppl_4):iv100-18.29.
30.
Bretz F, Maurer W, Brannath W, et al.  A graphical approach to sequentially 
rejective multiple test procedures.  Stat Med.  2009;28(4):586-604.
31.
Based on Method 2 of "Basic Principles on Global Clinical Trials" 
(YAKUSHOKUSHINSA Notification No. 0928010 dated on September 28, 2007, 
issued by Director of Evaluation and Licensing Division, Pharmaceutical and Food 
Safety Bureau, Ministry of Health Labour and Welfare).


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
136
32.
Hoglinger GU, Respondek G, Stamelou M, et al.  Clinical diagnosis of progressive 
supranuclear palsy:  The Movement Disorder Society Criteria.  Mov Disord.  
2017;32(6):853-64.  Available from:  doi: 10.1002/mds.26987.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
137
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.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
138
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 making any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
139
Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Clinical
Clinical
Statistics
Pharmacokinetics
Clinical
Bioanalysis


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
140
Appendix C.
Study Activities
Screeninga
Treatment Periodb
Dose 1
Dose 2
Dose 3
Dose 4
Dose 5
Dose 6
Dose 7
Weeks of Study Drug 
Exposure
Days –56 to –8
Week 
0
Week 
0
Week 
0
Week 
1
Week 
2
Week 
4
Week 
8
Week 
12
Week 
13
Week 
14
Week 
16
Week 
20
Activitiesc
Visit 
1
Visit 
2
Day 
1
Day
2u
Day
3
Day 5
Day 15
Day 29
Day 57
Day 85
Day 89
Day 99
Day 
113
Day 
141
Subject/Study Partner 
Informed Consentd
X
Medical Historye
X
X
X
Physical Examinatione,f
X
X
J1
J1
PSP Clinical Features
X
Orthostatic Vital 
Signse,g
X
X
X
J1
J1
C1/J1
X
X
X
X
C1/J1
C1/J1
X
X
Body Weight and 
Heighth 
X
X
X
X
X
X
X
X
X
Pregnancy Test 
(Females only) Urine 
(u) Serum (s)i
S
U
U
U
Urine Drug Screen
X
HbsAg, HCV Ab Tests
X
Neurological Exame
X
X
J1
J1
C1/J1
X
X
X
X
C1/J1
12-Lead ECGe,j
X
X
C1/J1
C1/J1
X
X
X
Clinical Laboratory 
Testse
X
X
J1
C1/J1
C1/J1
X
Brain MRIe,k,l
X
C1/J1
X


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
141
Screeninga
Treatment Periodb
Dose 1
Dose 2
Dose 3
Dose 4
Dose 5
Dose 6
Dose 7
Weeks of Study Drug 
Exposure
Days –56 to –8
Week 
0
Week 
0
Week 
0
Week 
1
Week 
2
Week 
4
Week 
8
Week 
12
Week 
13
Week 
14
Week 
16
Week 
20
Activitiesc
Visit 
1
Visit 
2
Day 
1
Day
2u
Day
3
Day 5
Day 15
Day 29
Day 57
Day 85
Day 89
Day 99
Day 
113
Day 
141
Lumbar Puncture 
(LP)/CSF 
Collectione,m,n
X
C1/J1
Pharmacogenetic 
MAPT Sample
X
Serum Plasma 
Biomarkers
X
C1/J1
Blood PK Sample
X
C1/J1
X
X
C1/J1
X
C1/J1
C1/J1
C1/J1
Optional Exploratory 
Pharmacogenetic DNA 
and RNA Sampleo
X
X
Serum Antibodies 
(ADA)
X
C1/J1
X
C1/J1
X
C1/J1
C1/J1
C1/J1
Randomizationp
X
Administer IV Study 
Drug
X
X
X
X
X
X
X
PSP Rating Scale 
(PSPRS)
1
1
1
CGI-S
2
5
2
5
2
5
CGI-C
6
3
6
SEADL
3
3
4


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
142
Screeninga
Treatment Periodb
Dose 1
Dose 2
Dose 3
Dose 4
Dose 5
Dose 6
Dose 7
Weeks of Study Drug 
Exposure
Days –56 to –8
Week 
0
Week 
0
Week 
0
Week 
1
Week 
2
Week 
4
Week 
8
Week 
12
Week 
13
Week 
14
Week 
16
Week 
20
Activitiesc
Visit 
1
Visit 
2
Day 
1
Day
2u
Day
3
Day 5
Day 15
Day 29
Day 57
Day 85
Day 89
Day 99
Day 
113
Day 
141
UPDRS Part II
4
4
5
RBANS
1
1
1
Color Trails Test (CTT)
Parts 1 & 2
2
2
2
Letter Fluency Test 
(LFT)
3
3
3
NNIPPS-PPS#
4
4
4
MMSEq
X
PGI-Cr
X
PSP-QoLr
X
X
X
Euro-QoL-5D (EQ-5D)r
X
X
X
C-SSRSr
X
X
X
C1/J1
X
X
X
X
C1/J1
C1/J1
X
X
Concomitant 
Medication
X
X
X
J1
J1
C1/J1
X
X
X
X
C1/J1
C1/J1
X
X
Adverse Event 
Assessments
X
X
X
J1
J1
C1/J1
X
X
X
X
C1/J1
C1/J1
X
X
24-hour confinementt
J1
Telephone Contactv
X


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
143
Treatment Periodb
Dose 8
Dose 9
Dose 10
Dose 11
Dose 12
Dose 13
Dose 14
Weeks of Study Drug Exposure
Week 24
Week 28
Week 32
Week 36
Week 40
Week 44
Week 48
Week 52
Week 60
Week 68
Activitiesc
Day 169
Day 197
Day 225
Day 253
Day 281
Day 309
Day 337
Completion/ 
Premature 
Discontinuation
Post-
Treatment 
Follow-Up
Post 
Treatment 
Follow-Up
Physical Examinationf
X
X
Orthostatic Vital Signsg
X
X
X
X
X
X
X
X
X
X
Body Weight
X
X
X
X
X
X
X
X
Pregnancy Test (Females only)  
Urine (u) Serum (s)i
U
U
S
Neurological Exam
X
X
X
X
12-Lead ECGj
X
X
X
X
Clinical Laboratory Tests
X
X
X
Administer IV Study Drug
X
X
X
X
X
X
X
Brain MRIk,l
X
X
Lumbar Puncture (LP)/CSF 
Collectionm,n
X
Serum Plasma Biomarkers
X
X
X
Optional Exploratory 
Pharmacogenetic DNA and RNA 
Sampleo
X
X
Blood PK Levels
X
X
X
X
X
Serum Antibodies (ADA)
X
X
X
X
X
PSP Rating Scale (PSPRS)
1
1
1
CGI-S
2
5
2
5
2


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
144
Treatment Periodb
Dose 8
Dose 9
Dose 10
Dose 11
Dose 12
Dose 13
Dose 14
Weeks of Study Drug Exposure
Week 24
Week 28
Week 32
Week 36
Week 40
Week 44
Week 48
Week 52
Week 60
Week 68
Activitiesc
Day 169
Day 197
Day 225
Day 253
Day 281
Day 309
Day 337
Completion/ 
Premature 
Discontinuation
Post-
Treatment 
Follow-Up
Post 
Treatment 
Follow-Up
CGI-C
3
6
3
6
3
SEADL
4
4
4
UPDRS Part II
5
5
5
RBANS
1
1
Color Trails Test (CTT)
Parts 1 & 2
2
2
Letter Fluency Test (LFT)
3
3
NNIPPS-PPS#
4
4
PGI-Cr
X
X
X
PSP-QoLr
X
X
X
Euro-QoL-5D (EQ-5D)r
X
X
C-SSRSr
X
X
X
X
X
X
X
X
X
X
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
Adverse Event Assessments
X
X
X
X
X
X
X
X
X
X
24-hour confinementt
Telephone Contactv
X
X
X


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
145
a.
All screening assessments are to be completed within –56 to –8 days prior to initial study drug administration (Day 1).  Refer to Table 7 for a pre-defined order of 
administration that should occur during each visit.  Screening visit assessments may be completed on a single date or multiple visit days.  Screening is complete when all 
screening assessments are complete or subject screen fails.  If screening assessments are completed on a single date, the scales for Screening Visit 1 (SV1) will be performed 
in the recommended order in this table, followed by the recommended order of scales for Screening Visit 2 (SV2).  Also, the CGI-S and the C-SSRS will only be performed 
once.
b.
Visits on Days 5, 15, 89, and 99 must be scheduled within ± 2 days.  Visits on all other days may be scheduled within ± 4 days.  The scheduled date for each study visit will 
be based on the number of days from the beginning of the treatment period on study Day 1, as indicated in the Study Activities table. 
c.
Audio recordings/central review of the administration/assessment of selected scales may be conducted.  
d.
Study-related assessments, procedures or activities may not occur prior to subject completing the signed informed consent process. If at any time during the study, a subject 
experiences diminished decision-making capacity, a legally authorized representative (LAR) is necessary when an informed consent must be obtained. 
e.
Update medical and/or neurological history with any findings prior to randomization.
f.
Additional symptom-driven physical examinations can be performed as needed.
g.
All systolic and diastolic blood pressure and pulse rate measurements are to be measured as part of an orthostatic assessment.  An attempt should be made to obtain all vital 
sign measurements at the same time of day and using the same arm.
h.
Height will be collected at the screening Visit 1 only.  On dosing days, weight will be collected prior to the start of the infusion.
i.
All females of child-bearing potential must have a negative serum pregnancy test performed at screening and Premature Discontinuation.  A negative urine pregnancy test 
result is required prior to any radiological procedures involving exposure to radiation.
j.
A detailed description for ECG parameters and schedule can be found in Section 5.3.1.1.
k.
Brain MRI scans will be without contrast and will include 3D T1 structural imaging, FLAIR, diffusion-weighted imaging, PD/T2, T2*, and diffusion tensor imaging including 
subcortical regions.  The additional MRI for subjects in Cohort 1 and Cohort J1 following Dose 2 will be performed within 2 weeks following the second dose and results 
must be available prior to the next scheduled dose.  The time window for the MRI procedure at each protocol-required time points is ± 7 days.
l.
If sedation is required it should occur after all scales and cognitive testing have been performed or, if this is not possible, at least 48 hours before the testing.
m.
Coagulation and complete blood cell (CBC) results must be reviewed by the investigator before the LP.  During Cohort 2, some subjects who are not able to undergo LP may 
be admitted with permission of the AbbVie Medical Director, and these subjects will not be required to undergo LP during the study.
n.
LP must be performed greater than 3 months from previous LP.
o.
Samples are optional.  Verify consent was obtained prior to sample collection.
p.
Randomization should be completed just prior to the first dose administration. 
q.
MMSE administered during Screening to assess inclusion criteria only.
r.
Scale may be administered/assessed at any time during the visit with the exception of during the scheduled time of infusion. 
s.
A detailed description for procedures involving adverse event assessments can be found in Section 6.1.1.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
146
t.
A 24-hour confinement will be required following the first dose in Cohort J1.
u.
Cohort J1 Day 2 assessments will be performed only in subjects discharged on Day 2.
v.
Only applicable to subjects who prematurely discontinue.  Verify consent was obtained prior to making contact.
#
The NNIPPS-PPS will not be administered in Japan.
Notes:
Activities labeled as "C1" and/or "J1"are to be completed for Cohort 1 and/or Cohort J1 only.
Unscheduled visits can be performed as clinically indicated.












ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
152
Appendix E.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes
Section 5.3.1.1  Study Procedures
Subsection PSP Clinical Features32
Add:  new subsection title and text
PSP Clinical Features32
A detailed assessment of PSP signs and symptoms present at Screening will be collected 
and include the following:
●
Ocular motor dysfunction
●
Postural instability
●
Akinesia
●
Cognitive dysfunction
Section 15.0  Reference List
Add:  new Reference 32
Hoglinger GU, Respondek G, Stamelou M, et al.  Clinical diagnosis of progressive 
supranuclear palsy:  The Movement Disorder Society Criteria.  Mov Disord.  
2017;32(6):853-64.  Available from:  doi: 10.1002/mds.26987.


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
153
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical
Clinical
Clinical
Statistics
Pharmacokinetics
Clinical
Bioanalysis
Has been changed to read:
Name
Title
Functional Area
Clinical
Clinical
Statistics
Pharmacokinetics
Clinical
Bioanalysis


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
154
Appendix C.  Study Activities
First table
Add:  new activity "PSP Clinical Features" and "Telephone Contactv"
Screeninga
Treatment Periodb
Dose 1
Dose 2
Dose 3
Dose 4
Dose 5
Dose 6
Dose 7
Weeks of Study Drug 
Exposure
Days –56 to –8
Week 
0
Week 
0
Week 
0
Week 
1
Week 
2
Week 
4
Week 
8
Week 
12
Week 
13
Week 
14
Week 
16
Week 
20
Activitiesc
Visit 
1
Visit 
2
Day 
1
Day
2u
Day
3
Day 5
Day 15
Day 29
Day 57
Day 85
Day 89
Day 99
Day 
113
Day 
141
PSP Clinical Features
X
Telephone Contactv
X
Appendix C.  Study Activities
Second table
Add:  new activity "Telephone Contactv"
Treatment Periodb
Dose 8
Dose 9
Dose 10
Dose 11
Dose 12
Dose 13
Dose 14
Weeks of Study Drug Exposure
Week 24
Week 28
Week 32
Week 36
Week 40
Week 44
Week 48
Week 52
Week 60
Week 68
Activitiesc
Day 169
Day 197
Day 225
Day 253
Day 281
Day 309
Day 337
Completion/ 
Premature 
Discontinuation
Post-
Treatment 
Follow-Up
Post 
Treatment 
Follow-Up
Telephone Contactv
X
X
X


ABBV-8E12
M15-562 Protocol Amendment 5
EudraCT 2016-001635-12
155
Appendix C.  Study Activities
Second table
Add:  new table note "v."
Only applicable to subjects who prematurely discontinue.  Verify consent was obtained 
prior to making contact.

SAP_001.pdf: 
ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
1
1.0
Title Page
Statistical Analysis Plan
Study M15-562
A Randomized, Double-Blind, Placebo-Controlled 
Multiple Dose Study to Assess Efficacy, Safety, 
Tolerability, and Pharmacokinetics of ABBV-8E12 in 
Progressive Supranuclear Palsy
Date:  23 Oct 2018
Version 1.0
NCT02985879


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
2
1.1
List of Abbreviations and Definition of Terms
Abbreviations
AD
Axial Diffusivity
ADA
Anti-Drug-Antibody
AE
Adverse Event
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
ANOVA
Analysis of Variance
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
Area Under the Concentration Time Curve
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CGI-C
Clinical Global Impression of Change
CGI-S
Clinical Global Impression of Severity
CL
Clearance
Cmax
Maximum Observed Serum Concentration
COMT
Catechol-O-Methyltransferase
CPK
Creatine Phosphokinase
CRF
Case Report Form
CSF
Cerebrospinal Fluid
CSR
Clinical Study Report
C-SSRS
Columbia-Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events 
Ctrough
Observed serum drug concentration at the end of a dose interval
CTT
Color Trails Test
DBP
Diastolic Blood Pressure
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
DTI
Diffusion Tensor Imaging
ECG
Electrocardiogram
eCRF
Electronic Case Report Form


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
3
EQ-5D
EuroQol-5D
ERAC
Exposure-Response Analysis Center
ES
Effective Size
FA
Fractional Anisotropy 
FLAIR
Fluid Attenuated Inversion Recovery
FWER
Family Wise Error Rate 
GABA
Gamma-Aminobutyric Acid
GEE
Generalized Estimation Equation
GGT
Gamma-Glutamyl Transpeptidase
HbsAg
Hepatitis B Surface Antigen
HR
Heart Rate
IA
Interim Analysis
ITT
Intent-to-Treat 
INR
International Normalized Ratio
LFT
Letter Fluency Test
LLN
Lower Limit of Normal
LP
Lumbar Puncture
LTE
Long-term Extension
LS
Least Square
MAPT
Microtubule Associated Protein Tau
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MCMC
Monte Carlo Markov Chain 
MD
Mean Diffusivity 
MMRM
Mixed-effect Model Repeated-Measures
MMSE
Mini-Mental State Examination
MRI
Magnetic Resonance Imaging
NFL
Neurofilament Light Protein
NNIPPS-PPS
Natural History and Neuroprotection in Parkinson Plus Syndromes-Parkinson 
Plus Scale
PCS
Potentially Clinically Significant
PGI-C
Patient Global Impression of Change
PK
Pharmacokinetic
PSP
Progressive Supranuclear Palsy
PSP-QoL
Progressive Supranuclear Palsy Health Related Quality of Life Scale


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
4
PSPRS
Progressive Supranuclear Palsy Rating Scale
PT
Prothrombin Time
PT/INR
Prothrombin Time/International Normalized Ratio
PTT
Partial Thromboplastin Time
PTs
Preferred Terms 
QRS
ECG QRS Complex
QT
Measure of the time between the start of the Q wave and the end of the T wave 
in the heart's electrical cycle
QTcF
QT corrected for heart rate using Fridericia's Method
RBANS
Repeatable Battery for Assessment of Neuropsychological Status
RBC
Red Blood Cell 
RD
Radial Diffusivity
RNA 
Ribonucleic Acid
SAE
Serious Adverse Event
SBP
Systolic Blood Pressure
SDAC
Statistical and Data Analysis Center
SEADL
Schwab and England Activities of Daily Living Scale
SOC
System Organ Class
TEAE
Treatment-emergent Adverse Event 
Tmax
Peak Time
ULN
Upper Limit of Normal
UPDRS
Unified Parkinson's Disease Rating Scale
VAS
Visual Analog Scale
WBC
White Blood Cell 
WHO
World Health Organization


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
5
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 ..................................................................5
3.0
Introduction...........................................................................8
4.0
Study Objectives, Design and Procedures............................8
4.1
Objectives .............................................................................................. 8
4.2
Study Design.......................................................................................... 9
4.3
Sample Size.......................................................................................... 22
4.4
Interim Analyses .................................................................................. 22
4.5
Efficacy Variables................................................................................ 24
4.6
Safety Variables ................................................................................... 25
4.7
Pharmacokinetic Variables ................................................................... 25
4.8
Biomarker and Pharmacogenetic Research Variables............................ 26
4.8.1
Biomarker Research Variables.............................................................. 26
4.8.2
Pharmacogenetic Research Variables.................................................... 26
5.0
Analysis Populations ...........................................................27
5.1
Analysis Datasets ................................................................................. 27
5.2
Variables Used for Stratification of Randomization .............................. 27
6.0
Analysis Conventions ..........................................................28
6.1
Statistical Significance ......................................................................... 28
6.2
Visit Definitions................................................................................... 28
7.0
Demographics, Baseline Characteristics, Subject 
History, and Previous/Concomitant Medications..............34
7.1
Demographic and Baseline Characteristics ........................................... 34
7.2
Medical History.................................................................................... 36
7.3
Previous and Concomitant Medications ................................................ 37
8.0
Subject Disposition..............................................................38
9.0
Study Drug Exposure and Compliance..............................38
10.0
Efficacy Analysis .................................................................39
10.1
General Considerations......................................................................... 39
10.2
Primary Analysis of Primary Efficacy Endpoint ................................... 39


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
6
10.3
Secondary Efficacy Analyses ............................................................... 40
10.3.1
Analysis of Secondary Efficacy Variables ............................................ 40
10.3.2
Analysis of Exploratory Efficacy Variables .......................................... 43
10.4
Additional Efficacy Analysis................................................................ 44
10.4.1
Listing of Randomized Subjects Not Included in the Primary 
Efficacy Analysis ................................................................................. 44
10.4.2
Combination of Sites with Fewer Than 2 Subjects per Treatment 
Group................................................................................................... 45
10.5
Handling of Missing Data for Efficacy Assessments and 
Sensitivity Analysis of the Primary Efficacy Endpoint.......................... 46
10.5.1
Sensitivity analysis accounting for missing data ................................... 48
10.6
Handling of Multiplicity....................................................................... 50
10.7
Efficacy Subgroup Analysis ................................................................. 52
11.0
Safety Analysis.....................................................................53
11.1
General Considerations......................................................................... 53
11.2
Analysis of Adverse Events.................................................................. 53
11.2.1
Adverse Event Overview...................................................................... 53
11.2.2
Adverse Event Incidence ...................................................................... 54
11.2.3
Listing of Adverse Events..................................................................... 55
11.3
Analysis of Laboratory Tests................................................................ 56
11.3.1
Analysis of Mean Changes for Laboratory Tests................................... 56
11.3.2
Shifts Between Normal and Abnormal for Laboratory Tests................. 57
11.3.3
Potentially Clinically Significant Laboratory Values ............................ 57
11.4
Analysis of Vital Signs and Weight ...................................................... 58
11.4.1
Vital Sign and Weight Mean Changes .................................................. 58
11.4.2
Potentially Clinically Significant Vital Sign and Weight Values ........... 59
11.5
Analysis of Electrocardiogram (ECG) Variables................................... 59
11.5.1
ECG Mean Changes ............................................................................. 59
11.5.2
Potentially Clinically Significant ECG Values...................................... 60
11.6
Analysis for Other Safety Variables...................................................... 60
11.6.1
Columbia-Suicide Severity Rating Scale (C-SSRS) .............................. 60
11.6.2
Analysis of CSF Safety Parameters....................................................... 60
11.6.3
Summary of MRI Safety Evaluations.................................................... 61


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
7
12.0
Pharmacokinetic Analysis...................................................61
12.1
Determination of Values of Pharmacokinetic Parameters...................... 61
12.2
Tabulations and Summary Statistics ..................................................... 63
12.3
Model and Tests ................................................................................... 63
12.4
Missing Values and Model Violations .................................................. 65
13.0
Analysis of Biomarker Research Variables .......................67
14.0
Summary of Changes ..........................................................69
15.0
Reference List......................................................................69
List of Tables
Table 1.
Safety and PK Procedures for Cohort 1 and Cohort J1.......................... 12
Table 2.
Study Activities.................................................................................... 14
Table 3.
Hypotheses Testing Order in The Graphical Testing Approach............. 51
List of Figures
Figure 1.
Study Schematic................................................................................... 11
Figure 2.
A graph for multiplicity adjustment of multiple hypotheses .................. 52
List of Appendices
Appendix A.
Potentially Clinically Significant (PCS) Laboratory Value.................... 70
Appendix B.
Criteria for Potentially Clinically Significant Vital Sign and 
Weight Values...................................................................................... 71
Appendix C.
Criteria for Potentially Clinically Significant ECG Values.................... 72


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
8
3.0
Introduction
This analysis plan describes the statistical analyses to be completed by AbbVie Pipeline 
Statistics and Programming for ABBV-8E12 Study Protocol M15-562, that incorporates 
the original protocol and three amendments (original Protocol, Amendment 1, 
Amendment 2, Amendment 2.01 [US only], Amendment 2.02 [Germany only], 
Amendment 3, Amendment 3.01 [Germany Only], Amendment 3.02 [Japan Only], 
Amendment 2.01.01 [US only], Amendment 4).
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, if performed, will be conducted separately and are not included in this SAP.
Analyses will be performed using SAS version 9.3 or higher (SAS Institute Inc., 
Cary, NC 27513) under the UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objectives of this study are:
●
To assess the efficacy of ABBV-8E12 in slowing disease progression in 
subjects with progressive supranuclear palsy as measured by the PSP Rating 
Scale (PSPRS).
●
To assess the long term safety and tolerability of ABBV-8E12 for up to 
52 weeks in subjects with progressive supranuclear palsy.
The secondary objectives of this study are:
●
To assess the pharmacokinetics of multiple doses of ABBV-8E12 in subjects 
with progressive supranuclear palsy.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
9
●
To assess the efficacy of ABBV-8E12 in slowing disease progression and 
functional impairment in subjects with progressive supranuclear palsy as 
measured by secondary endpoints.
●
To assess the efficacy of ABBV-8E12 in slowing regional and/or whole brain 
atrophy in subjects with progressive supranuclear palsy as measured by 
volumetric magnetic resonance imaging (MRI).
The exploratory objectives of this study are:
●
To assess the efficacy of ABBV-8E12 in slowing disease progression and 
functional impairment in subjects with progressive supranuclear palsy as 
measured by exploratory endpoints.
●
To assess the effect of ABBV-8E12 on cerebrospinal fluid (CSF) free/total tau 
protein levels.
●
To assess the effect of ABBV-8E12 on potential CSF biomarkers of disease 
progression.
4.2
Study Design
This Phase 2, randomized, double-blind, placebo-controlled, multiple dose, multicenter 
study will consist of a screening period of up to 8 weeks (56 days), a 52 week double-
blind treatment period, and a post-treatment follow-up period of approximately 20 weeks 
following last study drug administration (including those subjects who prematurely 
discontinue from treatment, decline to participate in or do not qualify for participation in a 
long term extension [LTE] study).  The study is planned to be conducted at approximately 
60 sites in the US and outside of the US.  Approximately 330 subjects who are at least 
40 years of age with PSP will be eligible to participate in the study according to the 
selection criteria.
Upon completion of screening and baseline procedures, eligible subjects will be 
randomized to one of the two ABBV-8E12 dose arms (2000 mg or 4000 mg) or placebo 
in a 1:1:1 ratio.  Subjects will enter the Treatment Period of the study on Day 1 and 
receive their first infusion of study drug.  During the first 4 weeks, subjects will have 


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
10
3 study drug infusions; the first on Day 1, the second on Day 15, and then on Day 29; 
thereafter, subjects will return to the study site every 28 Days for their the schedules for 
study drug infusion, blood collection, study procedures and assessments as outlined in the 
Study Activities Table (Table 1 and Table 2).  This dosing schedule (with one additional 
dose delivered on Day 15) is intended to enable subjects to reach steady-state levels of 
ABBV-8E12 in plasma as soon as reasonably possible in order to maximize the potential 
benefit to subjects during the treatment period.  This study will utilize a Data Monitoring 
Committee (DMC) consisting of 4 external clinicians, 1 external statistician and 1 external 
pharmacokineticist.  The DMC will review unblinded safety and efficacy data and make 
recommendations to the Sponsor based on the totality of available clinical data.  The 
DMC memberships, responsibilities and operating logistics will be documented in a 
charter that will be prepared prior to the first DMC review meeting.
The first 30 subjects enrolled into the study in countries not including Japan will be 
represented as Cohort 1 in this protocol while the first 9 Japanese subjects enrolled into 
the study will compose Cohort J1.  Subjects enrolled subsequent to Cohort 1 and 
Cohort J1 will be represented as Cohort 2.  Augmented safety and pharmacokinetic 
monitoring including additional study visits, more frequent neurological exams, vital 
signs, blood collections for safety labs, an additional lumbar puncture and MRI, and 
additional monitoring by the DMC will be performed in Cohorts 1 and J1.
A schematic of the study design is shown below in Figure 1.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
11
Figure 1.
Study Schematic


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
12
Table 1.
Safety and PK Procedures for Cohort 1 and Cohort J1
Screening
Cohort 1 and Cohort J1, Doses 1 – 5
Visit 1
Visit 2
Dose 1
Dose 2
Dose 3
Dose 4
Dose 5
Dose 6
Weeks of Study Drug 
Exposure
N/A
N/A
0
0
0
0
2
4
8
12
13
14
16
Days –56 
to –8
Days –56 
to –8
Day 1
Day 2j,k
Day 3j
Day 5
Day 15
Day 29
Day 57
Day 85
Day 89
Day 99
Day 113
Physical Exama
X
X
X
X
Neurological Exam
X
X
X
X
X
X
X
X
X
X
Orthostatic Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
Xb
Xc
Xb
Xd
Xd
Xb
Clinical Laboratory Tests
X
X
Xj
X
X
X
MRI
X
Xe
X
Lumbar Puncture/
CSF Sample Collection
X
Xf
PK Sample Collection
Xg
X
Xg
X
X
Xg
X
X
X
ADA Sample Collection
Xh
Xh
Xh
Xh
Xh
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
X
AE/
ConMed Review
X
X
X
X
X
X
X
X
X
X
X
X
X
24 hour confinementi
X
a.
Additional symptom-driven physical exams can be performed as needed.
b.
Pre-dose and within 15 minutes after the end of the infusion and prior to the PK sample collection.
c.
Collection should be scheduled as close as possible to the corresponding time of the post infusion PK collection on Day.
d.
Pre-dose (just prior to the start of infusion).


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
13
Table 1.
Safety and PK Procedures for Cohort 1 and Cohort J1 (Continued)
e.
For subjects in Cohort 1 and Cohort J1, an MRI will be performed within 2 weeks following the second dose and results must be available prior to the next scheduled dose.
f.
The lumbar puncture will be performed approximately 14 days after the fifth dose.
g.
Prior to the start of the infusion (0 hour, no more than 30 minutes prior to the start of the infusion), immediately after the end of the infusion (within 15 minutes) and 1 and 
2 hours after the end of the infusion.
h.
Prior to the start of the infusion (0 hour, no more than 30 minutes prior to the start of the infusion).
i.
A 24-hour confinement will be required following the first dose in Cohort J1.
j.
Cohort J1 subjects only.
k.
Cohort J1 Day 2 assessments will be performed only in subjects discharged on Day 2.
Note:
Visits on Days 5, 15, 89, and 99 must be scheduled within ± 2 days.  Visits on all other days may be scheduled within ± 4 days.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
14
Table 2.
Study Activities
Screeninga
Treatment Periodb
Dose 1
Dose 2
Dose 3
Dose 4
Dose 5
Dose 6
Dose 7
Weeks of Study 
Drug Exposure
Days –56 to –8
Week 0
Week 0
Week 0
Week 1
Week 2
Week 4
Week 8
Week 12
Week 13
Week 14
Week 16
Week 20
Activitiesc
Visit 1
Visit 2
Day 1
Day 2u
Day 3
Day 5
Day 15
Day 29
Day 57
Day 85
Day 89
Day 99
Day 113
Day 141
Subject/Study 
Partner Informed 
Consentd
X
Medical Historye
X
X
X
Physical 
Examinatione,f
X
X
J1
J1
Orthostatic Vital 
Signse,g
X
X
X
J1
J1
C1/J1
X
X
X
X
C1/J1
C1/J1
X
X
Body Weight and 
Heighth
X
X
X
X
X
X
X
X
X
Pregnancy Test
(Females only) 
Urine (u) 
Serum (s)i
S
U
U
U
Urine Drug 
Screen
X
HbsAg, HCV Ab 
Tests
X
Neurological 
Exame
X
X
J1
J1
C1/J1
X
X
X
X
C1/J1
12-Lead ECGe,j
X
X
C1/J1
C1/J1
X
X
X


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
15
Table 2.
Study Activities (Continued)
Screeninga
Treatment Periodb
Dose 1
Dose 2
Dose 3
Dose 4
Dose 5
Dose 6
Dose 7
Weeks of Study 
Drug Exposure
Days –56 to –8
Week 0
Week 0
Week 0
Week 1
Week 2
Week 4
Week 8
Week 12
Week 13
Week 14
Week 16
Week 20
Activitiesc
Visit 1
Visit 2
Day 1
Day 2u
Day 3
Day 5
Day 15
Day 29
Day 57
Day 85
Day 89
Day 99
Day 113
Day 141
Clinical 
Laboratory Testse
X
X
J1
C1/J1
C1/J1
X
Brain MRIe,k,l
X
C1/J1
X
Lumbar Puncture 
(LP)/CSF 
Collectione,m,n
X
C1/J1
Pharmacogenetic 
MAPT Sample
X
Serum Plasma 
Biomarkers
X
C1/J1
Blood PK Sample
X
C1/J1
X
X
C1/J1
X
C1/J1
C1/J1
C1/J1
Optional 
Exploratory 
Pharmacogenetic 
DNA and RNA 
Sampleo
X
X
Serum Antibodies 
(ADA)
X
C1/J1
X
C1/J1
X
C1/J1
C1/J1
C1/J1
Randomizationp
X
Administer IV 
Study Drug
X
X
X
X
X
X
X


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
16
Table 2.
Study Activities (Continued)
Screeninga
Treatment Periodb
Dose 1
Dose 2
Dose 3
Dose 4
Dose 5
Dose 6
Dose 7
Weeks of Study 
Drug Exposure
Days –56 to –8
Week 0
Week 0
Week 0
Week 1
Week 2
Week 4
Week 8
Week 12
Week 13
Week 14
Week 16
Week 20
Activitiesc
Visit 1
Visit 2
Day 1
Day 2u
Day 3
Day 5
Day 15
Day 29
Day 57
Day 85
Day 89
Day 99
Day 113
Day 141
PSP Rating Scale 
(PSPRS)
1
1
1
CGI-S
2
5
2
5
2
5
CGI-C
6
3
6
SEADL
3
3
4
UPDRS Part II
4
4
5
RBANS
1
1
1
Color Trails Test 
(CTT)
Parts 1 & 2
2
2
2
Letter Fluency 
Test (LFT)
3
3
3
NNIPPS-PPS#
4
4
4
MMSEq
X
PGI-Cr
X
PSP-QoLr
X
X
X
Euro-QoL-5D 
(EQ-5D)r
X
X
X
C-SSRSr
X
X
X
C1/J1
X
X
X
X
C1/J1
C1/J1
X
X


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
17
Table 2.
Study Activities (Continued)
Screeninga
Treatment Periodb
Dose 1
Dose 2
Dose 3
Dose 4
Dose 5
Dose 6
Dose 7
Weeks of Study 
Drug Exposure
Days –56 to –8
Week 0
Week 0
Week 0
Week 1
Week 2
Week 4
Week 8
Week 12
Week 13
Week 14
Week 16
Week 20
Activitiesc
Visit 1
Visit 2
Day 1
Day 2u
Day 3
Day 5
Day 15
Day 29
Day 57
Day 85
Day 89
Day 99
Day 113
Day 141
Concomitant 
Medication
X
X
X
J1
J1
C1/J1
X
X
X
X
C1/J1
C1/J1
X
X
Adverse Event 
Assessments
X
X
X
J1
J1
C1/J1
X
X
X
X
C1/J1
C1/J1
X
X
24-hour 
confinementt
J1


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
18
Table 2.
Study Activities (Continued)
Treatment Periodb
Dose 8
Dose 9
Dose 10
Dose 11
Dose 12
Dose 13
Dose 14
Weeks of Study Drug Exposure
Week 24
Week 28
Week 32
Week 36
Week 40
Week 44
Week 48
Week 52
Week 60
Week 68
Activitiesc
Day 169
Day 197
Day 225
Day 253
Day 281
Day 309
Day 337
Completion/ 
Premature 
Discontinuation
Post-
Treatment 
Follow-Up
Post 
Treatment 
Follow-Up
Physical Examinationf
X
X
Orthostatic Vital Signsg
X
X
X
X
X
X
X
X
X
X
Body Weight
X
X
X
X
X
X
X
X
Pregnancy Test (Females only) 
Urine (u) Serum (s)i
U
U
S
Neurological Exam
X
X
X
X
12-Lead ECGj
X
X
X
X
Clinical Laboratory Tests
X
X
X
Administer IV Study Drug
X
X
X
X
X
X
X
Brain MRIk,l
X
X
Lumbar Puncture (LP)/CSF 
Collectionm,n
X
Serum Plasma Biomarkers
X
X
X
Optional Exploratory 
Pharmacogenetic DNA and RNA 
Sampleo
X
X
Blood PK Levels
X
X
X
X
X
Serum Antibodies (ADA)
X
X
X
X
X


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
19
Table 2.
Study Activities (Continued)
Treatment Periodb
Dose 8
Dose 9
Dose 10
Dose 11
Dose 12
Dose 13
Dose 14
Weeks of Study Drug Exposure
Week 24
Week 28
Week 32
Week 36
Week 40
Week 44
Week 48
Week 52
Week 60
Week 68
Activitiesc
Day 169
Day 197
Day 225
Day 253
Day 281
Day 309
Day 337
Completion/ 
Premature 
Discontinuation
Post-
Treatment 
Follow-Up
Post 
Treatment 
Follow-Up
PSP Rating Scale (PSPRS)
1
1
1
CGI-S
2
5
2
5
2
CGI-C
3
6
3
6
3
SEADL
4
4
4
UPDRS Part II
5
5
5
RBANS
1
1
Color Trails Test (CTT)
Parts 1 & 2
2
2
Letter Fluency Test (LFT)
3
3
NNIPPS-PPS#
4
4
PGI-Cr
X
X
X
PSP-QoLr
X
X
X
Euro-QoL-5D (EQ-5D)r
X
X
C-SSRSr
X
X
X
X
X
X
X
X
X
X
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
Adverse Event Assessments
X
X
X
X
X
X
X
X
X
X
24-hour confinementt


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
20
Table 2.
Study Activities (Continued)
a.
All screening assessments are to be completed within –56 to –8 days prior to initial study drug administration (Day 1).  Refer to Table 7 in the protocol for a pre-defined order 
of administration that should occur during each visit.  Screening visit assessments may be completed on a single date or multiple visit days.  Screening is complete when all 
screening assessments are complete or subject screen fails.  If screening assessments are completed on a single date, the scales for Screening Visit 1 (SV1) will be performed 
in the recommended order in this table, followed by the recommended order of scales for Screening Visit 2 (SV2).  Also, the CGI-S and the C-SSRS will only be performed 
once.
b.
Visits on Days 5, 15, 89, and 99 must be scheduled within ± 2 days.  Visits on all other days may be scheduled within ± 4 days.  The scheduled date for each study visit will 
be based on the number of days from the beginning of the treatment period on study Day 1, as indicated in the Study Activities table. 
c.
Audio recordings/central review of the administration/assessment of selected scales may be conducted.  
d.
Study-related assessments, procedures or activities may not occur prior to subject completing the signed informed consent process.  If at any time during the study, a subject 
experiences diminished decision-making capacity, a legally authorized representative (LAR) is necessary when an informed consent must be obtained. 
e.
Update medical and/or neurological history with any findings prior to randomization.
f.
Additional symptom-driven physical examinations can be performed as needed.
g.
All systolic and diastolic blood pressure and pulse rate measurements are to be measured as part of an orthostatic assessment.  An attempt should be made to obtain all vital 
sign measurements at the same time of day and using the same arm.
h.
Height will be collected at the screening Visit 1 only.  On dosing days, weight will be collected prior to the start of the infusion.
i.
All females of child-bearing potential must have a negative serum pregnancy test performed at screening and Premature Discontinuation.  A negative urine pregnancy test 
result is required prior to any radiological procedures involving exposure to radiation.
j.
A detailed description for ECG parameters and schedule can be found in Section 5.3.1.1 in the protocol.
k.
Brain MRI scans will be without contrast and will include 3D T1 structural imaging, FLAIR, diffusion-weighted imaging, PD/T2, T2*, and diffusion tensor imaging including 
subcortical regions.  The additional MRI for subjects in Cohort 1 and Cohort J1 following Dose 2 will be performed within 2 weeks following the second dose and results 
must be available prior to the next scheduled dose.  The time window for the MRI procedure at each protocol-required time points is ± 7 days.
l.
If sedation is required it should occur after all scales and cognitive testing have been performed or, if this is not possible, at least 48 hours before the testing.
m.
Coagulation and complete blood cell (CBC) results must be reviewed by the investigator before the LP.  During Cohort 2, some subjects who are not able to undergo LP may 
be admitted with permission of the AbbVie Medical Director, and these subjects will not be required to undergo LP during the study.
n.
LP must be performed greater than 3 months from previous LP.
o.
Samples are optional.  Verify consent was obtained prior to sample collection.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
21
Table 2.
Study Activities (Continued)
p.
Randomization should be completed just prior to the first dose administration. 
q.
MMSE administered during Screening to assess inclusion criteria only.
r.
Scale may be administered/assessed at any time during the visit with the exception of during the scheduled time of infusion. 
s.
A detailed description for procedures involving adverse event assessments can be found in Section 6.1.1 in the protocol.
t.
A 24-hour confinement will be required following the first dose in Cohort J1.
u.
Cohort J1 Day 2 assessments will be performed only in subjects discharged on Day 2.
#
The NNIPPS-PPS will not be administered in Japan.
Note:
Activities labeled as "C1" and/or "J1" are to be completed for Cohort 1 and/or Cohort J1 only.  Unscheduled visits can be performed as clinically indicated.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
22
4.3
Sample Size
Approximately 330 PSP subjects (110 subjects/group) will be enrolled and randomized 
into two ABBV-8E12 dose groups and the placebo group with 1:1:1 randomization ratio.  
This sample size has ~90% power to detect an ABBV-8E12 effect size (vs. placebo) of 
0.56 for the high dose and 0.28 effect size for the low dose on the PSPRS total score 
changes from baseline at Week 52 using the Bonferroni method to control for multiplicity 
due to multiple comparisons between two doses and placebo at the two-sided 5% 
significant level.  A no data rate of 25% at Week 52 is assumed in this sample size 
calculation using East version 6.3.1 (Cytel). 
In Japan, a total of 24 subjects (8 subjects/arm) randomized will have 80% probability to 
detect the consistent treatment effect among three regions (Japan, North America 
including US/Canada, and European countries including Australia assuming 7%, 54%, 
and 39% of the total 330 PSP subjects are randomized in three regions, respectively). 
This calculation is based on Method 21 and assumes that the significance level for 
comparison of each ABBV-8E12 dose vs. placebo is two-sided 2.5% and the dropout rate 
is 25% in all regions.
4.4
Interim Analyses
Regular interim safety analyses and two preplanned interim futility analyses will be 
performed in this study.  Assessment of safety and efficacy data at interims will be 
performed by the DMC.  An independent statistical and data analysis center (SDAC) will 
be responsible for generating and providing unblinded statistical tables, figures, and 
listings to the DMC for the interim review.  An independent exposure-response analysis 
center (ERAC) will provide exposure-response analysis services to the DMC.  To 
maintain the integrity of the trial, a specific data access plan with a strict firewall will be 
in place to protect the unblinded data and the details will be described in the DMC charter.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
23
Safety Interim Analyses
The DMC will evaluate the available unblinded safety data and communicate their 
recommendations to the AbbVie Contact.  In addition to blinded safety data monitoring 
by the Sponsor, the first three mandatory DMC reviews of unblinded safety data will take 
place after the 10th, 20th, and 30th subjects in Cohort 1 have been administered their second 
dose and results for the MRI scheduled at approximately 2 weeks after their second dose 
are available.  For Cohort J1, an additional mandatory DMC review will take place after 
the 9th subject enrolled in Japan has received their second dose and results for the Day 15 
safety labs and the MRI performed within 2 weeks after their second dose, are available.  
Only after the DMC recommends continuing enrollment into the study without 
modification, will Japanese subjects be enrolled into Cohort 2.  The dataset will consist of 
all of the available safety and pharmacokinetic data in the study, including the data of any 
subjects from Cohort 2 who have received at least one dose of study drug.  Additional 
DMC reviews of available safety data will occur after a total of approximately 80, 130, 
and 180, 240, and 330 subjects are randomized and every 6 months thereafter until the 
study has completed.
The DMC will communicate their recommendations to the AbbVie Contact (who is not 
involved in the conduct of the trial) regarding continuing, modifying or terminating the 
trial due to safety concerns in accordance with the DMC charter.  More details of safety 
interim analyses will be specified in the DMC Charter.
Futility Interim Analyses
Two pre-planned interim efficacy analyses for futility will be performed.  The DMC will 
communicate their recommendations to AbbVie Contact who will share recommendations 
to the Sponsor.  The DMC will make recommendation to the Sponsor to stop the trial for 
futility or to continue the study without modification.  The study will not be stopped 
because of positive results at the interim futility analyses and administrative α spending at 
each interim analysis will be 0.00001.  Futility interim analyses will be conducted on 
PSPRS total score changes from baseline.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
24
Mixed Model Repeated Measure (MMRM) analysis on PSPRS total score change from 
the baseline up to Week 52 using observed data will be conducted in the futility interim 
analyses.
Rules for Interim Futility Analyses
A simulation study was conducted to determine the timing and decision making 
thresholds for futility interim analyses (see details of the simulation report in the DMC 
Charter). 
The timing of futility interim analysis was determined based on the need to have sufficient 
information available to make a decision with reasonable confidence.  Two futility interim 
analyses are planned for this trial.  The first futility interim is planned to occur when 
approximately 60 subjects (20 subjects/group) have completed 52 Week visit; the second 
futility interim is planned to occur when approximately 120 subjects (40 subjects/group) 
have completed 52 Week visit (see projected timing on Table 1 in simulation report in the 
DMC Charter).
At both futility interim analyses, if observed effect sizes at Week 52 for both doses are 
below the threshold, the DMC will make the recommendation to terminate the study due 
to futility.
Details of interim futility analyses plan will be described in the DMC charter for this 
study.
4.5
Efficacy Variables
The primary efficacy variable will be the change from baseline to the Week 52 assessment 
in the PSP Rating Scale (PSPRS) total score to assess the effect of ABBV-8E12 in 
slowing disease progression. 
Secondary efficacy variables include the changes from baseline of Unified Parkinson's 
Disease Rating Scale (UPDRS) Part II score, Clinical Global Impression of Severity and 


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
25
Change (CGI-S, CGI-C) score, the Schwab and England Activities of Daily Living Scale 
(SEADL) score, PSP-Quality of Life (PSP-QoL) total score, PSP Staging System and 
time to loss of ability to walk independently as measured by PSPRS item 26, PSPRS 
domain scores, and regional (midbrain, frontal lobes, and third ventricle) and whole brain 
atrophy as measured by volumetric MRI.
Exploratory efficacy variables include the Natural History and Neuroprotection in 
Parkinson Plus Syndromes-Parkinson Plus Scale (NNIPPS-PPS) total score and 
dimensional scores, Patient Global Impression of Change (PGI-C) score, Letter Fluency 
Test (LFT) score, Repeatable Battery for Assessment of Neuropsychological Status 
(RBANS) total scale score and subtest scores, Color Trails Test (CTT) (Parts 1 and 2) 
completion time, EuroQoL-5D (EQ-5D) summary index score.  Exploratory quantitative 
MRI measures may additionally be evaluated; including diffusion tensor imaging (DTI) 
derived fractional anisotropy (FA) and diffusivity measures [radial diffusivity (RD), mean 
diffusivity (MD), and axial diffusivity (AD)] to assess changes in microstructural 
integrity.
4.6
Safety Variables
The following safety variables will be analyzed for the study:  adverse event (including 
infusion and allergic reactions), vital signs, C-SSRS, laboratory tests, ECG, and MRI 
safety evaluations. 
4.7
Pharmacokinetic Variables
Values for the following pharmacokinetic parameters will be determined using non-
compartmental methods:  maximum observed serum concentration (Cmax), the time to 
Cmax (peak time, Tmax), the area under the concentration time curve (AUC) over the dosing 
interval after the first and the fifth doses in Cohort 1 and Cohort J1; and the observed 
serum concentration at the end of a dose interval (Ctrough) in all subjects.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
26
4.8
Biomarker and Pharmacogenetic Research Variables
4.8.1
Biomarker Research Variables
Blood and CSF samples will be collected to conduct research to investigate disease-
related and drug-related biomarkers.  The biomarkers to be analyzed may include, but are 
not limited to, the following:
●
CSF and serum/plasma samples will be assayed for free/total tau to 
demonstrate tau binding of ABBV-8E12.
●
CSF or serum/plasma samples may be analyzed for biochemical or 
macromolecular factors (e.g., NFL) related to the pharmacodynamics and 
safety of ABBV-8E12.
Exploratory evaluations from samples 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.  Analysis of these exploratory biomarkers will be described in a separate 
biomarker document. 
The information learned from analyzing these data may be used to investigate factors 
impacting response to treatment, scientific questions related to PSP, support development 
of ABBV-8E12, or in the development of new therapies.  Furthermore, given the 
exploratory nature of these data the results may not be included in the clinical study report 
(CSR).
4.8.2
Pharmacogenetic Research Variables
MAPT haplotype status may be determined for each subject and analyzed as a factor 
contributing to the subject's response to study treatment.  The MAPT haplotype results 
may be analyzed as part of a multi-study assessment of MAPT and response to 
ABBV-8E12 treatment.  The results may also be used for the development of diagnostic 
tests related to ABBV-8E12, or other drugs in development for PSP or related conditions.  
The MAPT haplotype results may not be included in the CSR.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
27
Optional pharmacogenetic samples may be collected to conduct exploratory investigations 
into known and novel biomarkers.  The types of biomarkers to be analyzed may include, 
but are not limited to, nucleic acids, proteins, lipids or metabolites.  The samples may be 
analyzed as part of a multi-study assessment of factors influencing the subjects' response 
to the study drug (or drugs of the same or similar class) or the development and 
progression of the subjects' disease or related conditions.  The samples may also be used 
to develop new diagnostic tests, therapies, research methods or technologies.  The results 
from these analyses are exploratory in nature and may not be included in the CSR.
5.0
Analysis Populations
5.1
Analysis Datasets
Intent-to-Treat (ITT) Dataset
The intent-to-treat (ITT) dataset will include all randomized subjects who receive any 
dose of study drug infusion.  The data from the ITT dataset will be analyzed by the 
treatment group assigned at the time of randomization, even if the subject does not receive 
the correct treatment, is not compliant with the protocol or does not follow through with 
the study until completion.  All efficacy analyses will be conducted on the intent-to-treat 
dataset unless otherwise specified.
Safety Dataset
The safety dataset will include all randomized subjects who received at least one dose of 
study drug infusion.  For this analysis dataset, actual treatment received instead of 
treatment assignment at the time of randomization will be used.  All safety analyses will 
be conducted on the safety dataset unless otherwise specified.
5.2
Variables Used for Stratification of Randomization
Subject randomization is stratified by study site except for Japanese subjects who are 
randomly assigned to three groups with 1:1:1 ratio within Japan.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
28
6.0
Analysis Conventions
6.1
Statistical Significance
Unless otherwise specified, statistical tests will be two-sided for efficacy and safety 
analyses.  The null hypotheses for efficacy will be rejected at the pre-specified 
significance level with the overall Type I family wise error rate (FWER) to be controlled 
at the two-sided 5% level (including type I error rate spent in interim analyses).  P values 
will be rounded to five decimal points for primary and key secondary variables included 
in the FWER control and rounded to three decimal points for other analyses before 
assessing statistical significance.  Multiplicity adjustment will be carried out to control the 
overall FWER rate in this study.  
6.2
Visit Definitions
Definition of Rx Day (Days Relative to the First Dose of Study Drug)
Rx Day is calculated for each time point as the number of days between the day of the 
first dose of study drug and the specific time point.  For dates before the first dose date of 
study drug, Rx day = date of time point – first dose date; for dates on or after the first dose 
date of study drug, Rx day = date of time point – first dose date + 1.  Thus, Rx Day is a 
negative value when the time point of interest is prior to the first study drug dose day;
Rx Day is a positive value when 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.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
29
Definition of Baseline and Final Observation
Unless otherwise specified, for all efficacy analyses and for all safety analyses of the 
double-blind Treatment Period, "baseline" shall refer to the last non-missing observation 
prior to the first dose of study drug and "final" for the double-blind Treatment Period shall 
refer to the last non-missing observation no more than 45 days after the last dose of the 
study drug for both efficacy variables and safety variables.  The "final" for the post-
treatment follow-up period for safety variables shall refer to the last non-missing 
observation greater than 45 days but no more than 20 weeks after the last dose of study 
drug.
Randomization and study drug administration are the last activities of the Day 1 Visit 
after the site completes other study procedures and verifies that the subject is eligible to 
participate in the study.  From the definition of "baseline," it is clear that a baseline for a 
specific measurement is the last non-missing observation taken up to and on the Day 1 
Visit (the Randomization Visit).  At the computation level, the value of "baseline" for an 
efficacy or safety assessment is determined using the Rx Day associated with the visit.  
Namely, baseline value is determined by taking the last non-missing observation obtained 
before the time of first dosing on Rx Day 1.  If an SAE occurs on the first dosing day, the 
event will be reported as a post baseline event and the related safety assessments will be 
considered post-baseline data as well.
Definition of Analysis Windows
To perform longitudinal data analysis, observations that are obtained after the first day of 
study drug administration will be assigned to an analysis "week" associated with the Rx 
Days that are corresponding to the observations.  Unless otherwise specified, efficacy 
observations and safety observations no more than 45 days after the last dose of study 
drug will be included in analyses for the double-blinded 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 


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
30
each schedule visit (Rx Days X through Y) include both Rx Days X and Y.  The nominal 
day for each scheduled visit is defined in "Activities" row in Table 2.
For measurements that are planned to be collected during double-blind treatment period at 
Weeks 12, 24, 36, and 52, i.e., PSPRS, SEADL, PGI-C, PSP-QoL and UPDRS Part II, 
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 210
●
Week 36
Rx Days 211 through 308
●
Week 52
Rx Days > 308
For measurements that are planned to be collected during double-blind treatment period at 
Weeks 8, 20, 32, and 48, i.e., RBANS, Color Trails Test (Parts 1 & 2), letter fluency, 
EQ-5D, and NNIPPS-PPS, observations will be mapped to an analysis "week" according 
to the following windows defined by Rx day.
●
Week 8
Rx Days 2 through 98
●
Week 20
Rx Days 99 through 182
●
Week 32
Rx Days 183 through 280
●
Week 48
Rx Days > 280
For measurements that are planned to be collected during double-blind treatment period at 
Weeks 8, 12, 20, 24, 32, 36, 48 and 52, i.e., CGI-S and CGI-C, observations will be 
mapped to an analysis "week" according to the following windows defined by Rx day.
●
Week 8
Rx Days 2 through 70
●
Week 12
Rx Days 71 through 112
●
Week 20
Rx Days 113 through 154
●
Week 24
Rx Days 155 through 196
●
Week 32
Rx Days 197 through 238


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
31
●
Week 36
Rx Days 239 through 294
●
Week 48
Rx Days 295 through 350
●
Week 52
Rx Days > 350
For measurements that are planned to be collected during double-blind treatment period at 
Weeks 1, 2, 4, 8, 12, 13, 14, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52, i.e., vital sign and 
C-SSRS observations will be mapped to an analysis "week" according to the following 
windows defined by Rx day.  The first 30 randomized subjects represent Cohort 1 and the 
rest randomized subjects represent Cohort 2.
●
Week 1
Rx Days 2 through 10 (Cohort 1 and Cohort J1 only)
●
Week 2
Rx Days 11 through 22 (Cohort 1 and Cohort J1 subjects)
Rx Days 2 through 22 (Cohort 2 subjects)
●
Week 4
Rx Days 23 through 42
●
Week 8
Rx Days 43 through 70
●
Week 12
Rx Days 71 through 87 (Cohort 1 and Cohort J1 subjects)
Rx Days 71 through 98 (Cohort 2 subjects)
●
Week 13
Rx Days 88 through 94 (Cohort 1 and Cohort J1 only)
●
Week 14
Rx Days 95 through 105 (Cohort 1 and Cohort J1 only)
●
Week 16
Rx Days 106 through 126 (Cohort 1 and Cohort J1 subjects)
Rx Days 99 through 126 (Cohort 2 subjects)
●
Week 20
Rx Days 127 through 154
●
Week 24
Rx Days 155 through 182
●
Week 28
Rx Days 183 through 210
●
Week 32
Rx Days 211 through 238
●
Week 36
Rx Days 239 through 266
●
Week 40
Rx Days 267 through 294
●
Week 44
Rx Days 295 through 322
●
Week 48
Rx Days 323 through 350
●
Week 52
Rx Days > 350


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
32
For measurements that are planned to be collected during double-blind treatment period at 
Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52, i.e., body weight observations 
will be mapped to an analysis "week" according to the following windows defined by 
Rx day.
●
Week 2
Rx Days 11 through 21
●
Week 4
Rx Days 22 through 42
●
Week 8
Rx Days 43 through 70
●
Week 12
Rx Days 71 through 98
●
Week 16
Rx Days 99 through 126
●
Week 20
Rx Days 127 through 154
●
Week 24
Rx Days 155 through 182
●
Week 28
Rx Days 183 through 210
●
Week 32
Rx Days 211 through 238
●
Week 36
Rx Days 239 through 266
●
Week 40
Rx Days 267 through 294
●
Week 44
Rx Days 295 through 322
●
Week 48
Rx Days 323 through 350
●
Week 52
Rx Days > 350
For measurements that are planned to be collected during double-blind treatment period at 
Weeks 2, 4, 8, 12, 24, 48, and 52, i.e., clinical laboratory tests will be mapped to an 
analysis "week" according to the following windows defined by Rx day.
●
Week 2
Rx Day 2 through 21 ( Cohort J1 only)
●
Week 4
Rx Day 22 through 42 (Cohort J1 only)
Rx Day 2 through 42 (Cohort 1 only)
●
Week 8
Rx Day 43 through 70 (Cohort 1 and Cohort J1 only)
●
Week 12
Rx Days 71 through 126 (Cohort 1 and Cohort J1 subjects)
Rx Days 2 through 126 (Cohort 2 subjects)


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
33
●
Week 24
Rx Days 127 through 252
●
Week 48
Rx Days 253 through 350
●
Week 52
Rx Days > 350
For measurements that are planned to be collected during double-blind treatment period at 
Weeks 1, 2, 4, 8, 12, 24, 36 and 52, i.e., ECG observations will be mapped to an analysis 
"week" according to the following windows defined by Rx day.
●
Week 1
Rx Days 2 through 10 (Cohort 1 and Cohort J1 only)
●
Week 2
Rx Days 11 through 21 (Cohort 1 and Cohort J1 only)
●
Week 4
Rx Days 22 through 42 (Cohort 1 and Cohort J1 subjects)
Rx Days 2 through 42 (Cohort 2 subjects)
●
Week 8
Rx Days 43 through 70
●
Week 12
Rx Days 71 through 126
●
Week 24
Rx Days 127 through 210
●
Week 36
Rx Days 211 through 308
●
Week 52
Rx Days > 308
For measurements that are planned to be collected during double-blind treatment period at 
Weeks 2, 12, 24, and 52, i.e., brain volumetric MRI observations will be mapped to an 
analysis "week" according to the following windows defined by Rx day.
●
Week 2
Rx Days 2 through 49 (Cohort 1 and Cohort J1 only)
●
Week 12
Rx Days 50 through 126 (Cohort 1 and Cohort J1 subjects)
Rx Days 2 through 126 (Cohort 2 subjects)
●
Week 24
Rx Days 127 through 266
●
Week 52
Rx Days > 266
For vital sign measurements and C-SSRS assessments that are planned to be collected 
during post-treatment follow-up period on Weeks 60 and 68, observations will be mapped 
to an analysis "week" according to the following windows defined by RxEnd day.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
34
●
Post-Treatment Week 12 RxEnd Days 46 through 112
●
Post-Treatment Week 20 RxEnd Days > 112
For ECG measurements that are planned to be collected during post-treatment follow-up 
period at Weeks 60, observations will be mapped to an analysis "week" according to the 
following windows defined by RxEnd day.
●
Post-Treatment Week 12 RxEnd Days > 45
If more than 1 observation is included in a visit time window, the observation that is 
closed to the nominal day of the visit will be used in the analysis.  If two observations 
have the same distance to the nominal day of the visit, the last non-missing observation 
will be used in analyses.  If more than 1 observation occurs on the same day, the average 
will be calculated and used in analyses.
7.0
Demographics, Baseline Characteristics, Subject 
History, and Previous/Concomitant Medications
7.1
Demographic and Baseline Characteristics
The following demographic and baseline characteristics will be summarized for each 
treatment group, for the combination of both ABBV-8E12 dose groups ("ABBV-8E12 
Overall") and for the combination of all treatment groups ("Total Subjects") for the safety 
dataset.  
●
Gender (male/female)
●
Race (white, black, American Indian/Alaska native, Native Hawaiian or other 
Pacific Islander, Asian, Other, Multi-Race)
●
Ethnicity (Hispanic or Latino)
●
Age (years)
●
Age group (≤ 65, > 65)
●
Weight for all subjects (kg)
●
Weight for all male subjects (kg)


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
35
●
Weight for all female subjects (kg)
●
Height (cm)
●
Body mass index (BMI, kg/m2)
●
Body mass index category (BMI, kg/m2) (≤ 25, > 25)
Alcohol and tobacco uses will be summarized for each treatment group, ABBV-8E12 
Overall and Total Subjects for the safety dataset.  For alcohol use, the number and 
percentage of subjects who are drinkers, ex-drinkers and non-drinkers (defined as those 
who have never been a drinker) will be presented.  For the tobacco use, the number and 
percentage of users, ex-users and non-users (defined as those who have never been a user) 
will be presented.  A subject reporting multiple use categories for the different types of 
tobacco (cigarette, pipe, cigar and chewing tobacco) will be counted in the tobacco user 
category.
The following baseline efficacy variables will be summarized for each treatment group, 
ABBV-8E12 Overall and Total Subjects for the intent-to-treat dataset.
●
PSPRS total and domain scores
●
SEADL score
●
UPDRS Part II score
●
RBANS scale score
●
Color trails test (Parts 1 and 2) completion time
●
Letter Fluency Test score
●
NNIPPS-PPS total and dimension scores
●
CGI-S score
●
PSP-QoL total and subscale core and Visual Analog Scale (VAS) scores
●
EQ-5D index score and VAS score
Categorical variables will be summarized by the number and percentage of subjects in 
each category.  No comparisons of treatment groups will be performed for alcohol and 
nicotine uses.  Continuous variables will be summarized with descriptive statistics 


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
36
(number of non-missing observations, mean, standard deviation, median, minimum and 
maximum).  No comparisons between treatment groups will be performed.
7.2
Medical History
The conditions/diagnoses recorded in medical/surgery history eCRF will be coded using 
the most current version of the Medical Dictionary for Regulatory Activities (MedDRA).  
Data will be summarized and presented using system organ classes (SOCs) and preferred 
terms (PTs).  The SOC will be presented in alphabetical order and the PTs will be 
presented in alphabetical order within each SOC.  The number and percentage of subjects 
with any condition/diagnosis and condition/diagnosis in a particular SOC and PT will be 
summarized for each treatment group, ABBV-8E12 Overall and Total Subjects for the 
safety dataset.  Subjects reporting more than one PT within a SOC will be counted only 
once for that SOC.  No comparison among treatment groups will be performed.
The following progressive supranuclear palsy disease history variables will be 
summarized for each treatment group, ABBV-8E12 Overall and Total Subjects for the 
safety dataset.
●
Age at onset of symptoms of PSP (years)
●
Age when first diagnosed as having PSP (years)
●
Years since onset of PSP symptoms (Date of Day 1 – Date of onset)
●
Years since PSP diagnosis (Date of Day 1 – Date of diagnosis)
●
Family history of PSP (None, biological mother, biological father, full sibling, 
biological child)
Categorical variables will be summarized with the number and percentage of subjects in 
each category.  Continuous variables will be summarized with descriptive statistics 
(number of non-missing observations, mean, standard deviation, median, minimum and 
maximum).  No comparisons of treatment groups will be performed.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
37
7.3
Previous and Concomitant Medications
Previous medications are defined as all medications with a start date before the first study 
drug administration date.  Concomitant medications are defined as all medications, other 
than study drug, taken during the treatment period (i.e., from the first day of study drug 
administration through 45 days after the last day of study drug administration).  Previous 
and concomitant medications will be coded using the World Health Organization (WHO) 
dictionary and will be summarized by generic name and Anatomical Therapeutic 
Chemical (ATC) classification system level 3.  The number and percentage of subjects 
who take at least 1 medication and who take at least 1 dose of each specific medication in 
the following categories will be summarized for each treatment group, ABBV-8E12 
Overall.
●
Previous medications for PSP (CMCAT = "PROGRESSIVE 
SUPRANUCLEAR PALSY MEDICATIONS") will be summarized by the 
following categories:
○
Antipsychotic medication
○
Antidepressants
○
Medications for Parkinsonian symptoms (including levodopa/carbidopa, 
dopamine agonists, monoamine oxidase inhibitors, COMT inhibitors, and 
amantadine).
○
Anti-dementia drugs (CMCLAS3 = ANTI-DEMENTIA DRUGS): 
cholinesterase inhibitors (donepezil, rivastigmine, galantamine) or 
memantine for cognitive impairment.
○
Selective benzodiazepines and gamma-aminobutyric acid (GABA) 
agonists (zolpidem, zaleplon, eszopiclone, alprazolam, clonazepam and 
lorazepam for sleep and anxiety).
○
Other medications
●
Other previous medications
●
Concomitant medications for PSP (CMCAT = "PROGRESSIVE 
SUPRANUCLEAR PALSY MEDICATIONS") will be summarized by the 
same categories as previous medications for PSP.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
38
●
Other concomitant medications
No comparisons of treatment groups will be performed.
8.0
Subject Disposition
The number of subjects who are screened will be summarized and screen failures will be 
summarized in Total Subjects and by each reason for screen failure.
For subjects who are randomized in the study, the number and percentage of subjects in 
each randomization disposition category (prematurely discontinued and completed) will 
be summarized for each treatment group, ABBV-8E12 Overall and Total Subjects.
The number and percentage of subjects who prematurely discontinued study drug or 
prematurely discontinued from the study will be summarized by reason (primary or any 
reason) for each treatment group, ABBV-8E12 Overall and Total Subjects.  The treatment 
group differences in the percentage of subjects who discontinued for any reason as well as 
for each specific reason as the primary will be assessed using Fisher's exact test.
In addition, the following additional summaries will be presented for all randomized 
subjects:
●
The number and percentage of subjects who are enrolled at each site.
●
The number and percentage of subjects who prematurely discontinued at each 
site.
9.0
Study Drug Exposure and Compliance
Summaries of study drug exposure and compliance will be prepared for the safety dataset.
Study drug exposure will be summarized for each treatment group, ABBV-8E12 Overall, 
and Total Subjects.  Duration of exposure is calculated as the last study drug 
administration date minus the first study drug administration date + 30.  Total subject 


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
39
years of exposure is calculated by summing the duration of exposure across all subjects 
and dividing this sum by 365 (1 year will be considered to be 365 days).  The number and 
percentage of subjects who have taken a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 
14 doses of study drug will be summarized.  No comparisons of treatment groups will be 
performed for this summary.  In addition, duration of exposure will be summarized with 
descriptive statistics (number of non-missing observations, mean, standard deviation, 
median, minimum and maximum duration and total subject years).
At each scheduled dosing visit, the investigator will document whether the subject has 
received the entire infusion 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, 
ABBV-8E12 Overall and Total Subjects.  
10.0
Efficacy Analysis
10.1
General Considerations
All efficacy analyses will be conducted on the intent-to-treat dataset unless otherwise 
specified.  Data collected more than 45 days after the last dose of the study drug will not 
be included in efficacy analyses.
10.2
Primary Analysis of Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline to Week 52 visit on the PSPRS 
total score.  The primary analysis population will be subjects in the ITT dataset and the 
primary analysis will be a likelihood-based, mixed-effects model, repeated measures 
(MMRM) analysis of the change from baseline to each post-baseline assessment up to and 
including Week 52.  The model will include fixed, categorical effects for treatment, site, 
visit, baseline score-by-visit and treatment-by-visit interactions, with continuous fixed 


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
40
covariates for baseline score.  The primary comparison will be the contrast between each 
ABBV-8E12 dose group and placebo group at Week 52.  Contrasts between each 
ABBV-8E12 dose group and placebo at Weeks 12, 24, and 36 and overall across the 
treatment period will be obtained and will be considered as secondary.  An unstructured 
(co)variance structure will be used to model the within-patient errors.  If this analysis fails 
to converge, compound symmetry (co)variance structures will be tested.  The same 
(co)variance structure will also be used for all MMRM analyses for secondary efficacy 
variables.  Satterthwaite's approximation will be used to estimate denominator degrees of 
freedom.
The following statistics will be presented on the statistical table of MMRM analysis for 
change from baseline to each visit (Weeks 12, 24, 36, and 52):  descriptive statistics 
(number of non-missing observations, mean, standard deviation, minimum and maximum) 
for each treatment group.  LS mean and standard error within group will be presented for 
each treatment group.  LS mean, standard error, 95% confidence interval and two-sided 
nominal P value of treatment difference comparing each ABBV-8E12 dose group with 
placebo will also be presented for each post-baseline visit.  The LS mean, standard error, 
95% confidence interval and two-sided nominal P value of treatment difference 
comparing each ABBV-8E12 dose group with placebo across the treatment period will be 
included in the output as well.  
In addition, a histogram will be generated to describe the proportion of subjects in each 
PSPRS response category for each treatment group.  The 1-point interval response 
categories are defined based on PSPRS total score change from the baseline to final 
starting from the minimum to the maximum of the change score (e.g., …; –5 < to ≤ –4;
–4 < to ≤ –3; –3 < to ≤ –2; –2 < to ≤ –1; –1 < to ≤ 0; 0 < to ≤ 1; 1 < to ≤ 2; 2 < to ≤ 3; 
….).
10.3
Secondary Efficacy Analyses
10.3.1
Analysis of Secondary Efficacy Variables
The secondary efficacy variables include change from baseline in the following score:


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
41
●
Unified Parkinson's Disease Rating Scale (UPDRS) Part II score
●
Clinical Global Impression of Change (CGI-C) score (the score itself indicate 
change)
●
Midbrain atrophy measured by volumetric MRI change from baseline
●
Schwab and England Activities of Daily Living Scale (SEADL) score
●
Clinical Global Impression of Severity (CGI-S) score
●
PSP Quality of Life (PSP-QoL) total, subscales and VAS scores
●
PSPRS domain scores
●
Regional atrophy measured by volumetric MRI – third ventricle, frontal lobes, 
superior cerebellar peduncle, brainstem, whole brain 
●
PSP Staging System (PSP-SS) (composite of dysphagia and gait items from 
PSPRS) score
●
Time to loss of ability to walk independently as measured by PSPRS item 26, 
which is the Rx day of the first time when the post-baseline item 26 score is 
3 or 4.
UPDRS Part II score, CGI-C score, SEADL score and the midbrain atrophy measured by 
volumetric MRI are key secondary efficacy variables, and the Week 52 contrasts for these 
variables for ABBV-8E12 doses vs placebo will be included in the multiplicity adjustment 
for the overall FWER control.  Volumetric MRI atrophy variables (third ventricle, frontal 
lobes, superior cerebellar peduncle, brainstem, whole brain), PSP-QoL total score and 
subscale and VAS scores, PSPRS domain scores, CGI-S score, PSP-SS score and time to 
loss of ability to walk analysis (measured by PSPRS item 26) will not be included in the 
multiplicity adjustment for the overall FWER control.  The MMRM method used for the 
primary efficacy analysis will be applied to analyze the change from the baseline to each 
post-baseline assessment up to and including Week 52 for all secondary variables except 
time to loss of ability to walk independently as measured by PSPRS item 26.  The model 
will include fixed, categorical effects for treatment, site, visit, baseline score-by-visit and 
treatment-by-visit interaction, with continuous fixed covariate for baseline score and the 
baseline score-by-visit interaction in the model.  The comparison will be the contrast 
between each ABBV-8E12 dose group and placebo group at each post-baseline visit.  For 


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
42
CGI-C analysis, the dependent variable is the CGI-C score itself, baseline CGI-S score 
will be used in the MMRM model as a covariate and no baseline score-by-visit interaction 
in the model.  For the volumetric MRI variables, the model will have a second covariate, a 
measure of head size (i.e., estimated pseudo total intracranial volume).
The following statistics will be presented on the statistical table of MMRM analysis for 
change from baseline to each post-baseline visit:  descriptive statistics (number of non-
missing observations, mean, standard deviation, minimum, and maximum) for each 
treatment group.  LS mean and standard error within group will be presented for each 
treatment group.  LS mean, standard error, 95% confidence interval and two-sided 
P values of treatment difference comparing each ABBV-8E12 dose group with placebo 
will also be presented for each post-baseline visit.  The overall LS mean, standard error, 
95% confidence interval and two-sided raw P values of treatment difference comparing 
each ABBV-8E12 dose group with placebo across the treatment period will be included in 
the output as well.
Responder analysis will be conducted for CGI-C variable.  The responses of "Very much 
improved," "Much improved," "Minimally improved" and "No change" on the CGI-C will 
be defined as responders.  Repeated measure analysis of responders over time on CGI-C 
responder status will be conducted using a generalized estimation equation (GEE) model 
with a logit link function to compare the probability of being a responder between each 
ABBV-8E12 dose and placebo.  The model will include fixed, categorical effects for 
treatment, site, visit and treatment-by-visit interaction in the model using exchangeable 
working correlation structure.  The odds ratio and corresponding 95% confidence interval 
will be provided for each ABBV-8E12 dose vs placebo at each visit.  This responder 
analysis will not be included in multiplicity adjustment for FWER.
The time to loss of ability to walk independently as measured by PSPRS item 26 will be 
analyzed using log-rank test to compare median time to loss of ability to walk between 
placebo and ABBV-8E12 arms. 


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
43
If both doses are statistically significant on the primary endpoint (PSPRS total score 
change from baseline at Week 52) after multiplicity adjustment, the contrast between 
pooled two ABBV-8E12 doses vs. placebo will also be obtained from the MMRM or 
GEE models for the primary and all secondary efficacy variables.  
10.3.2
Analysis of Exploratory Efficacy Variables
The exploratory efficacy variables include the following:
●
Natural History and Neuroprotection in Parkinson Plus Syndromes-Parkinson 
Plus Scale (NNIPPS-PPS) total score and dimensional scores
●
Patient Global Impression of Change (PGI-C) score
●
Letter Fluency Test (words per minute) score
●
Repeatable Battery for Assessment of Neuropsychological Status (RBANS) 
total scale score and subtest scores
●
Color Trails Test (Parts 1 and 2) completion time
●
EuroQuality of Life (EQ-5D-3L) summary index score and VAS score
●
Exploratory quantitative MRI measures including diffusion tensor imaging 
(DTI) derived fractional anisotropy (FA) and diffusivity measures [radial 
diffusivity (RD), mean diffusivity (MD), and axial diffusivity (AD)]  
The MMRM method used for the primary efficacy analysis will be applied to analyze the 
change from the baseline to each post-baseline assessment up to the last visit of these 
exploratory variables with the exception of PGI-C for which the dependent variable is the 
PGI-C score itself.  The model will include fixed, categorical effects for treatment, site, 
visit and treatment-by-visit interaction, with continuous fixed covariate for baseline score 
and the baseline score-by-visit interaction in the model.  There is no baseline score and 
baseline score-by-visit interaction in the MMRM model for PGI-C analysis.  The 
comparison will be the contrast between each ABBV-8E12 dose group and placebo group 
at each post-baseline visit.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
44
The following statistics will be presented on the statistical table of MMRM analysis for 
change from baseline to each post-baseline visit:  descriptive statistics (number of non-
missing observations, mean, standard deviation, minimum and maximum) for each 
treatment group.  LS mean and standard error within group will be presented for each 
treatment group.  LS mean, standard error, 95% confidence interval and two-sided 
norminal P values of treatment difference comparing each ABBV-8E12 dose group with 
placebo will also be presented for each post-baseline visit.  No multiplicity adjustment 
will be conducted for multiple comparisons of exploratory efficacy variables.
Responder analysis will be conducted for PGI-C variable.  The responses of "Very much 
improved," "Much improved," "Minimally improved" and "No change" on the PGI-C will 
be defined as responders.  Repeated measure analysis of responders over time on PGI-C 
responder status will be conducted using a GEE model with a logit link function to 
compare probability of being a responder between each ABBV-8E12 dose and placebo.  
The model will include fixed, categorical effects for treatment, site, visit and treatment-
by-visit interaction using an exchangeable working correlation structure in the model.  
The odds ratio and corresponding 95% confidence interval will be provided for each dose 
group at each visit.  This responder analysis will not be included in multiplicity 
adjustment for FWER.
10.4
Additional Efficacy Analysis
10.4.1
Listing of Randomized Subjects Not Included in the Primary 
Efficacy Analysis
A listing of the randomized subjects that were not included in the primary efficacy 
analysis will be prepared.  The listing will include the reason(s) the subject was not 
included (did not receive study drug, had no baseline observation and/or had no post-
baseline observation no more than 45 days after the last dose of study drug).


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
45
10.4.2
Combination of Sites with Fewer Than 2 Subjects per 
Treatment Group
When "site" is included as a factor in a statistical model for the interim or final analyses, 
Japan is considered as one site because randomization is stratified by country for Japan.  
In countries other than Japan, sites that do not have at least 2 subjects per treatment group 
for the ITT dataset will be combined within each country as follows.
1.
Divide the sites into 2 groups with Group 1 including all sites that have at least 
2 subjects per treatment group and Group 2 including all remaining sites.  Sort each 
group in ascending order by total sample size and investigator number.
2.
Starting at the top of the Group 2 list (i.e., the first site with the smallest sample 
size), combine the minimum number of sites required to achieve a pseudo-site that 
has at least 2 subjects per treatment group.  Continue this process until all Group 2 
sites have been grouped into pseudo-sites.
3.
If there is a site (or sites) left after Step 2, combine this site (or sites) with the last 
pseudo-site that is created.  For the situation where there is no previous pseudo-site 
exists, combine this site (or sites) with the first site on the sorted Group 1 list.
The naming of the pseudo-sites will be given by xxx99901, xxx99902, etc., where xxx is 
the country code.
The combined pseudo-sites will be used in all statistical models that include the "Site" as 
a factor.  However, the original site identification will be used in all summaries of subject 
disposition or discontinuation by Study Site and in all data listings.  In the summaries of 
the number and percentage of subjects contributed by each site in each treatment group 
for the ITT dataset, the name of pseudo-sites will also be displayed.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
46
10.5
Handling of Missing Data for Efficacy Assessments and 
Sensitivity Analysis of the Primary Efficacy Endpoint
Missing Items for a Rating Scale
Unless otherwise specified, when a total or domain score of an efficacy measure is 
calculated from a set of individual items, the total or domain score will be considered 
missing if any of the individual items are missing.  When an average score is obtained 
from a set of individual items, it will be calculated from the non-missing items.  Missing 
items will be imputed specifically for the following scales:
●
UPDRS Part II:  if no more than 15% of items are missing for an assessment, 
i.e., if 1 item has missing answer, the missing item will be imputed using the 
mean of non-missing items' scores for the assessment.  If 2 or more items are 
missing for an assessment, the items' score will not be imputed and UPDRS 
Part II score is missing.  
●
NNIPPS-PPS:
○
Total score:  if no more than 15% of all items are missing for an 
assessment, i.e., if less than or equal to 12 items are missing, each item 
score is imputed using the mean value of the same item from subjects of 
the same treatment group whose data are not missing for the item at the 
same visit.  NNIPPS-PPS total score will be calculated based on this 
imputation but dimensional scores will not be calculated from this 
imputation.  If more than 12 items of NNIPPS-PPS for an assessment for a 
subject are missing, then those items will not be imputed and the NNIPPS-
PPS total score will be missing.  Dimensional scores without any missing 
items will not be missing.
○
Dimensional score:  if no more than 15% items for a dimension is missing, 
then each item score is imputed using the mean value of the same item 
from subjects of the same treatment group whose data are not missing for 
the item at the same visit.  If more than 15% of all items for the dimension 
are missing, then those items will not be imputed and the dimensional 
score will be missing.  After the imputation of this step, dimensional scores 


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
47
will be calculated and used in dimensional score analysis, total score will 
not be calculated based on this imputation.
●
PSP-QoL
○
Missing VAS score will not be imputed. 
○
Total score:  If no more than 15% of the 45 items, i.e., less than or equal to 
6 items are missing for an assessment, each item score is imputed using the 
mean value of the same item from subjects of the same treatment group 
whose data are not missing for the item at the same visit.  If more than 
6 items of PSP-QoL for an assessment for a subject are missing, then those 
items will not be imputed and the PSP-QoL total score will be missing.  
After the imputation in this step, subscale scores won't be calculated and 
only the total score will be added up and used in total score analysis.
○
Subscale score:  if no more than 15% of all items are missing in a subscale, 
each item score is imputed using the mean value of the same item from 
subjects of the same treatment group whose data are not missing for the 
item at the same visit.  If more than 15% of all items for a subscale are 
missing, then those items will not be imputed and the subscale score will 
be missing.  After the imputation of this step, subscale scores will be 
calculated and used in subscale score analysis, the total score will not be 
calculated based on this imputation.
Missing Visit Data
Before conducting any imputation of missing visit data, patterns of missing data for the 
primary endpoint PSPRS total score changes in placebo and two ABBV-8E12 arms will 
be assessed.  Observed mean changes from baseline in PSPRS total score will be 
summarized over time for different missing patterns of longitudinal data (discontinued 
after Week 12 assessment, discontinued after Week 24 assessment, discontinued after 
Week 36 assessment, completer).  Number and percentage of subjects for each missing 
pattern will be summarized as well.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
48
10.5.1
Sensitivity analysis accounting for missing data
To evaluate robustness of the primary efficacy results on PSPRS total score changes from 
baseline, sensitivity analysis of PSPRS total score changes will be conducted using a 
multiple imputation (MI) assuming monotonic missing in this study.  Sensitivity analysis 
will be conducted only if at least one ABBV-8E12 dose is statistically significant different 
from the placebo with multiplicity adjustment in the primary efficacy endpoint analysis.
Sensitivity analyses using MI will be conducted in the following three steps:
1.
Using Monte Carlo Markov Chain (MCMC) methodology from PROC MI to 
impute the intermittent missing data to achieve a monotone missing pattern by 
treatment group; 
2.
Impute missing data to create 20 complete datasets including observed completers 
and imputed data for PSPRS total score changes from baseline using the MI 
method;
3.
Analyze each imputed dataset generated in Step 1 with the same analysis model for 
the primary efficacy analysis of the primary endpoint and keep analysis results for 
each imputed dataset;
4.
Combine analysis results across imputed datasets.
The multiple imputation (MI) method will be used to impute missing data at various visits 
overtime.  The MI method will be applied separately for each ABBV-8E12 dose arm and 
placebo arm.  Multivariate regression models will be used to impute PSPRS total score 
missing data for different visits.  To impute missing values for PSPRS total score for 
Visit X, variables included in the impute model are baseline PSPRS total score, PSPRS 
total score before discontinuation at Visit X, investigator site.  A mean vector and 
variance covariance matrix based on all available cases will be used for the imputation.  If 
the monotonic missing pattern is not satisfied, the MCMC method will be used to create 
monotonic missing pattern by filling missing values between visits where data are 
observed.  Imputed PSPRS total score needs satisfy the range requirement for the scale 


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
49
(0 to 100).  The MI will be implemented using PROC MI in SAS 9.4.  In Step 3, SAS 
PROC MIANALYZE procedure will be used to combine MMRM analysis results based 
on 20 imputed datasets.
The following analysis results will be presented for the sensitivity analysis with multiple 
imputations:  LS mean difference between ABBV-8E12 doses and placebo, standard 
error, 95% confidence interval of LS mean difference at Week 52 based on imputed data 
including observed data and p-values comparing ABBV-8E12 doses against placebo.  
Parameters based on imputed dataset will be combined estimation across 20 imputed 
datasets using Rubin's rules.
Tipping-point sensitivity analysis using multiple imputations to impute missing data will 
also be performed to evaluate robustness of primary analysis results for PSPRS total score 
changes from baseline if missing data deviate from the missing at random (MAR) 
assumption.  A total of 20 imputed datasets will be generated using MI for each shift 
parameter.  The shift parameter k indicates the percentage of treatment group difference 
(Δ) between ABBV-8E12 and placebo for PSPRS total score change obtained in the 
primary MMRM analysis that is not maintained for the MI sensitivity analysis.  For each 
k, the imputation will be carried out by subtracting k*Δ from imputed missing data for 
those treated subjects in ABBV-8E12 groups after dropout.  The imputation will be 
conducted with corresponding visit specific k*Δ for missing data after dropout.  The 
values of k range from 0% to 100% or higher in 10% increments.  The first value of k that 
reverses the study conclusion is considered the tipping point.  The treatment group 
differences and associated p-values from tipping point analysis for each value of k will be 
presented. 
The tipping point analysis will be conducted in the following steps: 
1.
Using Monte Carlo Markov Chain (MCMC) methodology from SAS PROC MI by 
treatment group to impute the intermittent missing data to a monotone missing 
pattern; 


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
50
2.
Using a standard multiple imputation approach from SAS PROC MI to impute data 
from monotone missing data; 
3.
For subjects who have missing data in the ABBV-8E12 groups, a shift which is 
equal to k*Δ will be subtracted for imputed values in Step 2 after the dropout, with 
k described in the above.  For subjects in the placebo group, no shift will be 
performed for missing data after dropout;
4.
Using MMRM model for the primary efficacy endpoint analysis to analyze the 
observed data along with the imputed data from Step 3 for PSPRS total score 
change from baseline; 
5.
Obtaining the overall results using PROC MIANALYZE for each shift parameter k 
using Rubin's rules.
The following analysis results will be presented by the shift parameter k for the tipping 
point analysis:  LS mean difference between ABBV-8E12 doses and placebo, standard 
error, 95% confidence interval of LS mean difference at Week 52 based on imputed data 
including observed data and p-values comparing ABBV-8E12 doses against placebo.  
10.6
Handling of Multiplicity
Pairwise comparisons between each ABBV-8E12 dose group and the placebo group will 
be performed with two-sided tests.  Hochberg procedure2 will be used for the efficacy 
analysis to handle multiplicity of comparisons between multiple ABBV-8E12 doses and 
placebo at the pre-specified significance level at the interim analysis (α = 0.00001 at each 
futility interim analysis), which is described in the DMC Charter. 
For the final analysis, a graphic approach3 will be used to control overall family wise error 
rate due to multiple comparisons for primary and key secondary efficacy endpoints for 
multiple ABBV-8E12 doses.  The overall α for the final analysis is 0.04998 after 
accounting for α spending at interim futility analyses.  This α will be split equally between 
two dose groups to test the efficacy endpoints in the primary and key secondary families 
within each dose level at Week 52.  The order of efficacy endpoints to be tested is PSPRS 


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
51
total score change at Week 52, UPDRS-II score change at Week 52, CGI-C score at 
Week 52, midbrain atrophy measured by volumetric MRI change from baseline at 
Week 52, SEADL score change at Week 52 (Table 3).  The primary endpoint will be 
tested first followed by the secondary endpoints and α could be propagated between 
two doses and two families of hypotheses testing based on the graphic approach 
(Figure 2).  In the graph, the arrows specify the α transfer paths.  Once an endpoint is 
rejected (i.e., deemed significant) at its assigned significance level, its significance level 
will be transferred to subsequent endpoint(s) following the arrow(s).  If more than 
one arrow originates from an endpoint, the significance level for this endpoint (once 
rejected) will be split between multiple subsequent endpoints following the arrows.  The 
numbers on the arrows denote the weights for transferring and (possibly) splitting 
significance levels.  Specifically, the weight 1 denotes 100% transfer of significance level.  
The number underneath of each hypothesis is the original weight for α splitting assigned 
to the hypothesis.  The overall type I error rate for this trial will be controlled at the 
two-sided 5% level.  Nominal P values and multiplicity adjusted P values for all variables 
listed in Table 3 will be presented in a table.
Table 3.
Hypotheses Testing Order in The Graphical Testing Approach
Efficacy 
Endpoints
Family
Ordered
Efficacy Endpoints
Hypotheses
The High Dose 
(4000 mg) vs. 
Placebo
The Low Dose 
(2000 mg) vs. 
Placebo
Primary family
PSPRS total score change from 
baseline at Week 52
H11
H21
Secondary family
UPDRS Part II score change from 
baseline at Week 52
H12
H22
CGI-C score at Week 52
H13
H23
Midbrain atrophy measured by 
volumetric MRI change from 
baseline at Week 52
H14
H24
SEADL score change from 
baseline at Week 52
H15
H25


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
52
Figure 2.
A graph for multiplicity adjustment of multiple hypotheses
               High Dose (α/2 = 0.02499)                                 Low Dose (α/2 = 0.02499)
10.7
Efficacy Subgroup Analysis
To examine whether gender, age group (≤ 65 vs > 65 year old), disease severity 
(≤vs > median of PSPRS baseline total score which is rounded to the closest multiple of 
5.  E.g., if the median is 38.5 then the median cut off will be 40.), and geographical region 
(North America including US and Canada, European countries plus Australia, and Japan) 
have an impact on response to treatment, subgroup analyses on PSPRS total score will be 
conducted on change from baseline to final.  Subgroup analyses will be performed using 
an ANCOVA model with the terms of treatment, subgroup variable, site (site nested 
within a region will be used for subgroup analysis by geographical region), the treatment-
by-subgroup variable interaction, and baseline score as a covariate.  The hypothesis that 
consistent response to treatment across strata of a subgroup variable will be tested at the 


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
53
significance level of 0.100 by examining the P value of the treatment-by-subgroup 
interaction term in the ANCOVA model specified above.  The statistical comparison of 
each ABBV-8E12 dose group with placebo within each subgroup stratum will be 
performed when the statistical significance of the treatment-by-subgroup interaction term 
is achieved at 0.100 level.  The subgroup analysis will be conducted on the ITT dataset.
11.0
Safety Analysis
11.1
General Considerations
All safety analyses will be performed on the safety dataset.  Treatment group differences 
in safety parameters are evaluated using two-sided test at the significance level of 0.050.  
When statistical tests are performed, the comparisons will be between each ABBV-8E12 
dose and placebo.  With the exception of adverse events, all safety assessments that are 
taken no more than 45 days after the last dose of study drug will be included in the safety 
evaluation of the Double-blind Treatment Period.  All safety assessments that are taken 
more than 45 days but no more than 20 weeks after the last dose of study drug will be 
included in the safety evaluation for the Post-Treatment Follow-Up Period.
11.2
Analysis of Adverse Events
All adverse events will be coded using the most current version of the Medical Dictionary 
for Regulatory Activities (MedDRA).  A treatment-emergent adverse event (TEAE) is 
defined as any adverse event that begins or worsens in severity on or after the first study 
drug dose date and no more than 20 weeks after the last study drug dose date.  Analysis of 
adverse events will also be conducted by geographical region (North America including 
US and Canada, European countries plus Australia, and Japan).
11.2.1
Adverse Event Overview
The number and percentage of subjects experiencing one or more adverse events in the 
following adverse event categories will be summarized for each treatment group, 
ABBV-8E12 Overall.  No comparisons of treatment groups will be performed.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
54
●
Any TEAE
●
Any TEAE that was rated as having reasonable possibility of being related to 
study drug by the investigator 
●
Any severe TEAE
●
Any serious TEAE
●
Any TEAE that led to discontinuation of study drug
●
Any fatal TEAE
●
All deaths
11.2.2
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 alphabetical order within 
each system organ class.  Subjects reporting more than one adverse event for a given 
MedDRA PT will be counted only once for that term.  Subjects reporting more than 
one adverse event within a SOC will be counted only once for the SOC total.  Subjects 
reporting more than one adverse event will be counted only once in the overall adverse 
event total.
The number and percentage of subjects experiencing one or more TEAEs will be 
summarized by PT for each treatment group, ABBV-8E12 Overall.  The PTs will be 
presented by decreasing frequency in ABBV-8E12 Overall.  
The number and percentage of subjects experiencing one or more adverse events in the 
following adverse event categories will be summarized by primary SOC and PT for each 
treatment group, ABBV-8E12 Overall.  
●
Any TEAE
●
Any serious TEAE
●
Any TEAE that led to discontinuation of study drug


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
55
●
Any TEAE assessed by the investigator to have Reasonable Possibility of 
Being Related to study drug
The number of subjects experiencing one or more TEAEs will also be summarized by 
maximum severity category (mild, moderate, severe and unknown) and primary SOC and 
PT for each treatment group, ABBV-8E12 Overall.  Subjects reporting more than 
one TEAE for a given PT will be counted only once for that term in the most severe 
category 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.  No 
comparisons of treatment groups will be performed.
The number of subjects experiencing one or more TEAEs will also be summarized by 
maximum relationship category (Reasonable Possibility of Being Related, No Reasonable 
Possibility of Being Related and Unknown), as assessed by the investigator, and primary 
SOC and PT for each treatment group, ABBV-8E12 Overall.  Subjects reporting more 
than one TEAE for a given PT will be counted only once for that term in the most related 
category reported.  If a subject has an adverse event with unknown relationship, then the 
subject will be counted in the relationship category of "unknown," 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."  No comparisons between 
treatment groups will be performed.
11.2.3
Listing of Adverse Events
The following additional summaries of adverse events will be prepared.
●
List of subject numbers associated with each PT for all TEAEs


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
56
●
List of subject numbers associated with each PT for all TEAEs assessed by the 
investigator as having Reasonable Possibility of Being Related. 
●
Listing of all serious adverse events
●
Listing of all adverse events that led to discontinuation of study drug
●
Listing of all fatal adverse events
●
Listing of all deaths
11.3
Analysis of Laboratory Tests
The laboratory tests are described in the following table.
Hematology
Clinical Chemistry
Urinalysis
Hematocrit
Hemoglobin
Red blood cell (RBC) count
White blood cell (WBC) count
Neutrophils
Bands (if detected)
Lymphocytes
Monocytes
Basophils (if detected)
Eosinophils (if detected)
Platelet count (estimate not 
acceptable)
Mean corpuscular volume 
(MCV) 
Mean corpuscular hemoglobin 
concentration (MCHC)
Prothrombin time (PT)
Activated partial thromboplastin 
time (aPTT)
PT/INR (Prothrombin 
Time/International 
Normalized Ratio)
Blood urea nitrogen (BUN)
Creatinine
Total bilirubin
Albumin
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphate
Uric acid
Cholesterol
Total protein
Glucose
Triglycerides
Bicarbonate/Carbon Dioxide 
(CO2) Chloride
Specific gravity 
pH
11.3.1
Analysis of Mean Changes for Laboratory Tests
Analyses of mean change from baseline to each double-blind visit value and to the 
minimum, maximum and final double-blind value will be presented for each continuous 


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
57
hematology, chemistry and urinalysis variable.  Analyses of mean change from final 
double-blind value to final post-treatment value will also be presented for each continuous 
hematology, chemistry, urinalysis, and vital sign variables.
For each mean change analysis, the mean and median change will be presented for each 
treatment group.  The mean change for each ABBV-8E12 dose group will also be 
compared to the mean change for the placebo group using an ANOVA with treatment as 
the factor.  P values and 95% confidence intervals will be calculated based on pairwise 
contrasts within the ANOVA.
11.3.2
Shifts Between Normal and Abnormal for Laboratory Tests
Laboratory observations will be categorized as normal, low, or high relative to the 
reference (normal) range associated with the laboratory that performed the assay.  For 
each hematology, chemistry and urinalysis variable with a reference range, shift tables 
will be prepared for shifts from baseline to lowest, highest and final value during the 
entire study for each treatment group and ABBV-8E12 Overall.  No comparisons of 
treatment groups will be performed.  Shift tables will also be prepared by geographical 
region.  The tables will present: 
●
The numbers and percentages of subjects with low or normal observations at 
baseline who have a high observation at any post-baseline visit 
●
The numbers and percentages of subjects with normal or high observations at 
baseline who have a low observations at any post-baseline visit
●
The numbers and percentages of subjects with low or normal observations at 
baseline who have a high observation at the final visit 
●
The numbers and percentages of subjects with normal or high observations at 
baseline who have a low observations at the final visit
11.3.3
Potentially Clinically Significant Laboratory Values
Criteria for potentially clinically significant (PCS) values have been predefined for 
selected laboratory variables as outlined in Appendix A.  For each variable, a summary of 


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
58
the number and percentage of subjects in each treatment group who have at least 
one double-blind observation that meets the PCS criteria and is more extreme than their 
baseline value will be provided.  A listing will also be prepared that will include, for each 
variable, all observations for each subject that met the PCS criteria for that variable at any 
time during the study.  PCS analysis for laboratory values will also be prepared by 
geographical region.  No comparisons of treatment groups will be performed.
11.4
Analysis of Vital Signs and Weight
Vital sign variables include:  diastolic blood pressure (DBP), systolic blood pressure 
(SBP) and pulse rate at supine and standing positions, orthostatic diastolic blood pressure, 
orthostatic systolic blood pressure, orthostatic pulse rate, and body temperature.  The 
calculations of orthostatic vital sign values are:
●
Orthostatic SBP (mmHg) = Standing SBP – Supine SBP
●
Orthostatic DBP (mmHg) = Standing DBP – Supine DBP
●
Orthostatic Pulse Rate (bpm) = Standing Pulse Rate – Supine Pulse Rate.
Weight variables include weight and BMI.
11.4.1
Vital Sign and Weight Mean Changes
Diastolic blood pressure, systolic blood pressure and pulse will be analyzed separately for 
each position of measurement.  Analyses of mean change from baseline to each double-
blind visit value and to the minimum, maximum and final double-blind value will be 
presented for each vital sign and weight variable.  Analyses of mean change from final 
double-blind value to each post-treatment visit will also be presented for vital sign 
variable.
For each mean change analysis, the mean and median change will be presented for each 
treatment group.  The mean change for each ABBV-8E12 dose group will also be 
compared to the mean change for the placebo group using an ANOVA with treatment as 


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
59
the factor.  P values and 95% confidence intervals will be calculated based on pairwise 
contrasts within the ANOVA.
11.4.2
Potentially Clinically Significant Vital Sign and Weight 
Values
Criteria for potentially clinically significant values have been predefined for selected vital 
sign and weight variables as outlined in Appendix B.  For each variable, a summary of the 
number and percentage of subjects in each treatment group who have at least one double 
blind observation that meets the PCS criteria and is more extreme than their baseline 
value will be provided.  A listing will also be prepared that will include, for each variable, 
all observations for each subject that met the PCS criteria for that variable at any time 
during the study.  PCS analysis for vital sign and weight will also be conducted by 
geographical region.  No comparisons of treatment groups will be performed.
11.5
Analysis of Electrocardiogram (ECG) Variables
Electrocardiogram (ECG) variables include:  heart rate (HR), PR interval, QRS interval, 
uncorrected QT interval, and QT interval corrected for heart rate using Fridericia's 
formula (QTcF).
11.5.1
ECG Mean Changes
Analyses of mean change from baseline to each double-blind visit value and to the 
minimum, maximum and final double-blind value will be presented for each ECG 
variable.  Analyses of mean change from final double-blind value to final post-treatment 
value will also be presented for each ECG variable.
For each mean change analysis, the mean and median change will be presented for each 
treatment group.  The mean change for each ABBV-8E12 dose group will also be 
compared to the mean change for the placebo group using an ANOVA with treatment as 
the factor.  P values and 95% confidence intervals will be calculated based on pairwise 
contrasts within the ANOVA.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
60
11.5.2
Potentially Clinically Significant ECG Values
Criteria for potentially clinically significant values have been predefined for selected ECG 
variables as outlined in Appendix C.  For each variable, a summary of the number and 
percentage of subjects in each treatment group who have at least one double-blind 
observation that meets the PCS criteria and is more extreme than their baseline value will 
be provided.  Listings will also be prepared to include all observations for each variable 
for each subject that met the PCS criteria for that variable at any time during the study.  
PCS analysis for ECG values will also be conducted by geographical region.  No 
comparisons of treatment groups will be performed.
11.6
Analysis for Other Safety Variables
11.6.1
Columbia-Suicide Severity Rating Scale (C-SSRS)
Number and percentage of subjects in the following categories will be summarized for 
each treatment group and ABBV-8E12 Overall by visit and for the entire study:
●
Answered 'Yes' to each C-SSRS item
●
Had suicidal ideation (defined as answering 'Yes' to one or more suicidal 
ideation items)
●
Had suicidal ideation only (defined as answering 'Yes' to one or more suicidal 
ideation items and answering 'No' to all suicidal behavior items)
●
Had suicidal behavior (defined as answering 'Yes' to one or more suicidal 
behavior items)
●
Had suicidal ideation or behavior (defined as answering 'Yes' to one or more 
suicidal ideation or behavior items)
11.6.2
Analysis of CSF Safety Parameters
CSF safety variables include RBC and WBC with differential, total protein, albumin, 
glucose and IgG.  Analyses of mean change from baseline to Week 14 (Cohort 1 subjects 
only) and mean change from baseline to final double-blind value will be presented for 
each CSF safety variable.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
61
For each mean change analysis, the mean and median change will be presented for each 
treatment group.  The mean change for each ABBV-8E12 dose group will also be 
compared to the mean change for the placebo group using an ANOVA with treatment as 
the factor.  P values and 95% confidence intervals will be calculated based on pairwise 
contrasts within the ANOVA.
11.6.3
Summary of MRI Safety Evaluations 
MRI safety evaluations will be summarized and compared between each ABBV-8E12 
dose and placebo based on MRI evaluations in the double blinded period.  The summaries 
include the number and percentage of subjects pertaining cerebral edema, micro- and 
macro-haemorrhages, white matter hyperintensities (ARWMC score) across visits; 
number and percentage of subjects with presence and increasing severity of cerebral 
edema; number and percentage of subjects with new micro- and macro-haemorrhage 
lesions; number and percentage of subject with white matter hyperintensities change 
(ARWMC score) from previous time point.  Descriptive statistics (mean, median, 
minimum, maximum) of number of new micro- and macro-hemorrhages or new lesions, 
as well as changes in ARWMC score in the double-blinded period will be presented.
12.0
Pharmacokinetic Analysis
12.1
Determination of Values of Pharmacokinetic Parameters
Cmax for a dose interval will be the maximum observed concentration after the beginning 
of infusion of the dose and before the beginning of infusion of the next dose.  Tmax will be 
the time of Cmax relative to the beginning of infusion.  The values of Cmax and Tmax will be 
considered missing if there is no measurement from a sample obtained before 3 hours 
after the end of infusion. 
AUC for a dose interval will be obtained using straight lines between adjacent 
concentrations for times before 4 hours after the end of infusion.  An exponential curve 
will be used between the last time point of measurement before 4 hours after the end of 
infusion and the first time point of measurement after 4 hours after the end of infusion, 


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
62
and an exponential curve will be used between adjacent time points of measurement in the 
dose interval that come after this.  Actual times relative to the beginning of infusion will 
be used in the calculation of AUC.
The scheduled length of the first and fifth dose intervals is 336 hours and 672 hours, 
respectively.  If the actual length of a dose interval differs from the scheduled length by 
more than an hour, a value for the ABBV-8E12 concentration at the scheduled end of the 
dosing interval (336 hours or 672 hours after the start of infusion of the dose at the 
beginning of the dose interval) will be imputed.  In this case, the AUC will be calculated 
using the imputed value at the scheduled end of the dosing interval.  The imputed value 
will be obtained from interpolation with, or extrapolation of, the exponential curve 
defined by the last two concentration measurements in the dosing interval.
For the first dose interval, the concentration at the beginning of infusion of the dose will 
be assumed to be 0 even if the scheduled pre-dose blood sample is mistakenly obtained 
after the beginning of infusion.  For the fifth dose interval, the concentration of the pre-
dose sample will be used as the concentration at the beginning of infusion of the dose 
provided that the blood sample is obtained in the 30 minute interval before the beginning 
of infusion.  If the blood sample is obtained earlier than 30 minutes before the beginning 
of infusion, for the calculation of AUC the concentration at the beginning of infusion will 
be the Cobs X e–βt, where Cobs is the reported measurement for the pre-dose concentration, 
β is the rate constant determined from the exponential curve defined by the last 
two concentrations in the fifth dose interval and t the length of the time interval between 
the pre-dose blood sample and the beginning of infusion.  If the pre-dose sample for the 
fifth dose interval is mistakenly obtained after the beginning of infusion of the dose, a 
value for the concentration at the beginning of the dose interval (beginning of infusion) 
must be imputed unless the sample was obtained within a very few minutes of the 
beginning of infusion (< 15 minutes).  The data of other subjects in the same treatment 
group who have values for the concentrations at the beginning of the fifth dose interval, 
the beginning of the fourth dose interval and the end of the fifth dose interval may be used 
to obtain a linear regression model for the concentration at the beginning of the fifth dose 


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
63
interval, with the concentrations at the beginning of the fourth dose interval and the end of 
the fifth dose interval as explanatory (predictor) variables.  The missing value may be 
replaced by the predicted value from the regression model.
12.2
Tabulations and Summary Statistics
For the data of Cohort 1, serum concentrations of ABBV-8E12 and pharmacokinetic 
parameter values will be tabulated for each subject and each dose level, and summary 
statistics will be computed for each sampling time and each parameter by dose level.  
Also, for the serum concentration data of all subjects (Cohort 1 and Cohort 2), summary 
statistics will be provided for each scheduled time of sampling with breakdown by dose 
level.
CSF concentration data after the fifth dose (for subjects in Cohort 1) and the final dose 
will be tabulated and summarized by dose level.
Summary statistics will consist of:  number of observations (n), mean, standard deviation, 
coefficient of variation as a percentage (quotient of standard deviation and mean, 
multiplied by 100), minimum, median and maximum.  In addition, the geometric mean 
will be given for Cmax and AUC.
12.3
Model and Tests
Unless stated otherwise, hypothesis tests will be performed at significance level 0.050.
Change in Concentration with Repeated Dosing
The concentration data of the planned pre-infusion sampling times of Cohort 2 (Days 15, 
29 and 85 plus Weeks 24 and 36) will be analyzed to investigate change in serum 
concentration over time.  The data of Cohort 1 and Cohort J1 will also be included in this 
analysis except for Day 29.  The logarithmic transformation will be used unless the data 
show that the logarithm has substantial non-symmetry (e.g., magnitude of skewness 
coefficient > 1.0) while untransformed concentration or another transformation has an 
approximately symmetric distribution.  A MMRM analysis will be performed.  The model 


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
64
will have fixed effects for dose level, geographical region (as identified in Section 10.7), 
classification by time, interaction of dose level and time and the interaction or region and 
time.  The subjects will be viewed as a random sample, and an appropriate structure will 
be selected for the covariance matrix of the observations from a subject.  If the statistic on 
the interaction of region and time is not significant at level 0.050, that term will be 
removed from the model.  The concentration central value estimate versus time curves for 
the two dose levels will be plotted on the same graph, with the estimate of the central 
value for a dose level at a given time being the back transformation of the SAS least 
squares mean for the transformed data.
Dose Proportionality
Analyses to address the issue of dose proportionality will be performed on the combined 
data of Cohort 1 and Cohort J1.  An analysis will be performed on each of dose 
normalized Cmax and dose-normalized AUC for each of the first dose interval (2 weeks in 
length) and the dose interval beginning at Day 85 (4 weeks in length).  An analysis will 
also be performed on dose-normalized Ctrough at Week 16.  The logarithmic transformation 
will be employed for Cmax and AUC and will likely be used for Ctrough.  An analysis of 
covariance (ANCOVA) will be performed for each exposure variable, with the greater 
emphasis on the dose interval that begins at Day 85.  Subjects will be classified by dose 
level and geographical region, and body weight will be a covariate.  The initial model will 
include a term for the interaction of dose level and region, but this term will be removed 
from the model if the statistic for it is not significant at level 0.050.  Other variables such 
as age and sex that might explain some of the variability among subjects will be 
considered.  A necessary condition for such a variable to be included in the final model is 
that the regression coefficient be significant at level 0.100.  The dependence among 
explanatory variable candidates will also be considered when selecting the final model.  
Within the framework of the final model, the hypothesis of no difference between the 
means of the two doses (main effects for the two doses) will be tested.  If the statistic on 
the interaction of dose level and region is significant at level 0.050, the test will be 
performed for each region separately within the framework of the final model.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
65
Comparison of the Geographical Regions with Respect to Drug Exposure Variables
The data set for this analysis will be the same as that for the analysis to address the issue 
of dose proportionality.  Because Cohort 1 and Cohort J1 have no data from Canada, 
European countries or Australia, the analysis provides a comparison of the Japan region to 
the North America region (US).  The model will be the same as the final model for the 
analysis on dose proportionality with the one exception that body weight will not be 
included as a covariate.  Assuming that the logarithmic transformation is employed, the 
estimates of the central values for the four combinations of region and dose level (on the 
original scale and without dose normalization) will be provided by exponentiation of the 
corresponding SAS least squares means, followed by multiplication of the respective dose 
levels.  
Within the framework of the final model, the hypothesis of no difference between the 
means of the two regions (main effects for the two regions) will be tested.  The estimate 
of the ratio of the central values (a composite value for the two dose levels) of the 
two regions will be provided by exponentiation of the difference of the SAS least squares 
means for the two regions.  If the statistic on the interaction of dose level and region is 
significant at level 0.050, the test will be performed for each dose level separately within 
the framework of the final model, and the corresponding estimate of the ratio of region 
central values provided by exponentiation of the difference of least squares means for the 
two regions for the given dose level.
12.4
Missing Values and Model Violations
The possibility of bias from missing data of subjects who prematurely discontinue for 
reasons possibly related to study drug will be addressed.  If it is concluded that there may 
be a bias of meaningful magnitude as a result of premature discontinuation, a value may 
be imputed for the missing pharmacokinetic parameter or missing concentrations.  
Sensitivity analyses might be carried out with the missing value replaced over a range of 
values. 


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
66
In some cases of a missing individual concentration value, values of pharmacokinetic 
variables (Cmax, AUC, etc.) will be determined without replacing missing individual 
concentration values, but simply using the available data.  However, if a missing 
individual concentration value results in a value of a pharmacokinetic parameter that may 
be too low or too high to a meaningful degree, the value of the pharmacokinetic parameter 
will tentatively be considered missing.  In this case, a value for the missing individual 
concentration may be imputed so that an appropriate value of the pharmacokinetic 
parameter can be included in the analysis.  The imputed value will be obtained using 
appropriate methodology that takes into account the individual characteristics of the 
subject.  Also, if the concentration value at the beginning or end of the dose interval is 
missing, a value must be imputed in order for a value of AUC to be determined.  
An imputed value will be obtained using appropriate methodology that takes into account 
the individual characteristics of the subject.  The dataset from which the value is imputed 
will be restricted to that of subjects whose data could be considered a random sample 
from the probability distribution applicable to the subject with the missing data.  
Ordinarily, the dataset from which the imputed value is obtained would be that of the 
treatment group to which the subject with the missing value is a member, or some 
appropriate subset of the treatment group, using only subjects who do not have missing 
values of their own that would make them unsuitable for the purpose.
Transformation of variables in order to avoid a meaningful degree of non-normality in the 
probability distributions is discussed in Section 12.3.  The primary purpose of a 
transformation will be to have a random variable with an approximately symmetric 
probability distribution, but an approximately symmetric distribution with apparently very 
heavy tails (e.g., kurtosis coefficient, as defined in the SAS Procedure Univariate, 
exceeding 9) would also be of concern.  If an adequate transformation is not found for a 
variable, then a non-parametric analysis may be performed.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
67
13.0
Analysis of Biomarker Research Variables
Descriptive statistics will be provided for each variable by treatment and scheduled time 
of measurement.  The statistics will consist of:  number of observations (n), mean, 
standard deviation, coefficient of variation as a percentage (quotient of standard deviation 
and mean, multiplied by 100), minimum, median and maximum.  If the logarithmic 
transformation is employed for the analysis of a variable, the geometric mean will also be 
reported.
An ANCOVA model will be used to evaluate CSF concentrations for total tau, free tau 
and the ratio of free tau concentration to total tau concentration for each scheduled time of 
evaluation during treatment.  A corresponding analysis will be performed on plasma total 
tau concentration and on other plasma tau variables for which data are reported.  The 
observations will be classified by treatment and geographical region (as identified in 
Section 10.7).  The initial model will have a term for the interaction of treatment and 
region.  The baseline value for total tau and free tau (last value before the first dose of 
study drug) will be the covariate in the case of total tau and free tau, but for the analysis 
on the ratio the covariate will be the baseline total tau concentration measurement.  The 
term for the interaction of treatment and region will be removed if the statistic for this 
term is not significant at level 0.050.  Within the framework of the analysis of covariance 
model, the hypothesis of no difference between main effects of the higher ABBV-8E12 
dose and placebo will be tested at significance level 0.05.  If this hypothesis is rejected, 
the hypothesis of no difference between the lower ABBV-8E12 dose and placebo will 
then be tested at significance level 0.050.  The SAS least squares means corresponding to 
the treatment main effects (a composite estimate for the three regions) will be provided.  
If the term for the interaction of treatment and region is retained in the final model, the 
testing procedure described for the main treatment effects will be carried out for each 
region, and the SAS least squares means will be provided for all the combinations of 
region and treatment.
For the analysis of a tau concentration variable, the conditions on the time that a sample is 
obtained in order for a measurement to be included in an analysis for a planned time are 


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
68
given in the table below.  If a measurement qualifies for more than one of the times, it will 
be used only for the time that is nearest the actual time of the sample (in terms of 
Rx Day).
Scheduled Time
Conditions on Time of Blood or CSF Sample
Week 12 (Cohort 1 
and Cohort J1 only)
Rx Day 71 – 99, after at least four doses, between 21 and 
35 days after the last previous dose 
Week 14 (Cohort 1 
and Cohort J1 only)
Rx Day 85 – 113, after at least four doses, between 7 and 
21 days after the last previous dose
Week 24
Rx Day 141 – 197, after at least six doses, between 21 and 
35 days after the last previous dose
Week 28
Rx Day 169 – 225, after at least seven doses, between 21 and 
35 days after the last previous dose
Week 48
Rx Day 281 or later, after at least 10 doses, 21 to 35 days 
after the last previous dose administered 
Week 52
Rx Day 281 or later, after at least 11 doses, 21 to 35 days 
after the last previous dose administered
If the probability distribution for a variable appears to have considerable non-symmetry 
(e.g., skewness coefficient > 1.00 in magnitude), a transformation will be sought that has 
an approximately normal distribution.  If a transformation is employed, estimates of 
central values on the original scale (back transformation of SAS least squares means) will 
be provided in place of the SAS least squares means referred to above.  If the logarithmic 
transformation is used, the comparison of the treatments will be in terms of the ratio of 
central values.  
If data are reported for CSF NFL concentration, serum or plasma NFL concentration, 
other continuous variables, or count variables that can be appropriately analyzed as a 
continuous variable (perhaps after transformation), then descriptive statistics will be 
provided and an analysis like that described for the tau concentration variables will be 
performed.  If data for other types of variables are reported, appropriate descriptive 
statistics and analyses will be provided.  


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
69
The association between the variables referred to here as biomarkers and measures of 
clinical efficacy will be explored.
14.0
Summary of Changes
There are some changes in the planned analyses from the protocol (original protocol, 
protocol Amendment 1, Amendment 2, Amendment 3, Amendment 4) to Statistical 
Analysis Plan version 1.0.  The multiplicity adjustment method using Dunnet's test at 
interim analyses have changed to using Hochberg procedure in Amendment 3 and in the 
current SAP.  Detailed multiplicity adjustment method is added in protocol Amendment 3 
and is reflected in Section 10.6 for multiplicity method change in the SAP.  The sample 
size increase from 180 (in protocols prior to Amendment 3) to 330 (Amendment 3) and 
including Japan in Study M15-562 are reflected in the current SAP.  These changes are 
reflected in Section 4.3.  Analysis of the primary efficacy variables and safety variables 
analysis by geographical region are included in Section 10.7 and Section 11.0 of the 
current SAP, respectively.
15.0
Reference List
1.
"Basic Principles on Global Clinical Trials" (YAKUSHOKUSHINSA Notification 
No. 0928010 dated on September 28, 2007, issued by Director of Evaluation and 
Licensing Division, Pharmaceutical and Food Safety Bureau, Ministry of Health 
Labour and Welfare).
2.
Hochberg Y.  A sharper Bonferroni procedure for multiple tests of significance.  
Biometrika.  1988;75(4):800-2.
3.
Bretz F, Maurer W, Brannath W, et al.  A graphical approach to sequentially 
rejective multiple test procedures.  Stat Med.  2009;28(4):586-604.
4.
Westfall PH, Krishen A.  Optimally weighted, fixed-sequence, and gatekeeping 
multiple testing procedures.  J Stat Plan Infer.  2001;99:25-40.


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
70
Appendix A.
Potentially Clinically Significant (PCS) Laboratory Value
Clinical Laboratory Tests
Very Low (VL)
Very High (VH)
Hematology
Activated partial thromboplastin time
NA
> ULN
Hemoglobin  
< 100 g/L (6.2 mmol/L)
> 40 g/L above ULN
Prothrombin Intl. Normalized Ratio  
NA
> ULN
Leukocytes
< 2 × 109/L
> 100 × 109/L
Lymphocyte
< 0.5 × 109/L
> 20 × 109/L
Neutrophil
< 1 × 109/L
NA
Platelets
< 75 × 109/L
NA
Chemistry
Bilirubin
NA
> 1.5 × ULN
Cholesterol
NA
> 12.92 mmol/L (500 mg/dL)
Creatinine
NA
> 1.5 × ULN
Calcium (corrected serum)
< 1.75 mmol/L (7.0 mg/dL)
> 3.1 mmol/L (12.5 mg/dL)
Glucose (fasting)
< 2.2 mmol/L (40 mg/dL)
> 13.9 mmol/L (250 mg/dL)
Potassium
< 3.0 mmol/L
> 6.0 mmol/L
Triglycerides
NA
> 5.7 mmol/L (500 mg/dL)
Urate
NA
> 590 umol/L (10 mg/dL)
Albumin
< 20 g/L
NA
Sodium
< 130 mmol/L
> 155 mmol/L
Phosphate
< 0.6 mmol/L (2.0 mg/dL)
NA
Enzymes
Alanine aminotransferase (ALT)
NA
> 3 × ULN
Alkaline phosphatase
NA
> 2.5 × ULN
Aspartate aminotransferase (AST)
NA
> 3 × ULN
NA = not applicable; ULN = upper limit normal
Note:
Adapted from the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published:  
May 28, 2009 (v4.03:  June 14, 2010).


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
71
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
Orthostatic SBP (Hypotension) 
(mmHg)
Decrease of ≥ 30 in SBP (supine 
to standing)
NA
Orthostatic DBP (Hypotension) 
(mmHg)
Decrease of ≥ 20 in DBP (supine 
to standing)
NA
Orthostatic pulse (bpm) 
NA
Increase ≥ 30 bpm
(supine to standing)
Weight (kg)
Decreased ≥ 7% from baseline
Increased ≥ 7% from baseline


ABBV-8E12
M15-562 – Statistical Analysis Plan
Version 1.0 – 23 Oct 2018
72
Appendix C.
Criteria for Potentially Clinically Significant ECG Values
ECG Parameters
Significant Values
QTcF Interval (msec)
> 499
QTcF Interval Increased from Baseline (msec)
> 60