Clinical trial NCT02925117
Conditions: Atopic Dermatitis
Keywords: ABT-494 Atopic Dermatitis
Sponsor: AbbVie
Start date: 2016-10-25; Completion date: 2019-01-31
Enrollment: 167 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study was to evaluate the safety and efficacy of multiple doses of upadacitinib monotherapy versus placebo in the treatment of adults with moderate to severe atopic dermatitis (AD).

Detailed description:
The study was to include a 16-week double-blind treatment period (Period 1) and a 72-week double-blind treatment period (Period 2) for a total of 88 weeks of treatment. Participants who met eligibility criteria were to be randomized in a 1:1:1:1 ratio to one of the four treatment groups. Participants who completed Period 1 were re-randomized at Week 16 into a 72-week double-blind, placebo-controlled treatment period (Period 2) in a 1:1 ratio:

* Group 1: Upadacitinib 7.5 mg once daily (QD) (Day 1 to Week 16) → upadacitinib 7.5 mg QD or placebo (Week 16 - and thereafter)
* Group 2: Upadacitinib 15 mg QD (Day 1 to Week 16) → upadacitinib 15 mg QD or placebo (Week 16 and thereafter)
* Group 3: Upadacitinib 30 mg QD (Day 1 to Week 16) → upadacitinib 30 mg QD or placebo (Week 16 - and thereafter)
* Group 4: Matching placebo (Day 1 to Week 16) → upadacitinib 30 mg QD or placebo (Week 16 and thereafter)

In Period 1, discontinuation from study drug was mandatory for any participant with an Eczema Area and Severity Index (EASI) score worsening of 25% or more compared with their Baseline EASI score at any 2 consecutive scheduled study visits from Week 4 to Week 12.

In Period 2, blinded rescue therapy with upadacitinib 30 mg QD was provided after the first instance of a \< EASI 50 response starting at the Week 20 visit (4 weeks after re-randomization into Period 2) for the remainder of the study.

Arms: arm 1: Participants randomized to receive placebo once daily (QD) for 16 weeks in Period 1. At Week 16 participants were re-randomized to receive 30 mg upadacitinib or placebo once a day for 72 weeks in Period 2. arm 2: Participants randomized to receive upadacitinib 7.5 mg QD for 16 weeks in Period 1. At Week 16 participants were re-randomized to receive 7.5 mg upadacitinib or placebo QD for 72 weeks in Period 2. arm 3: Participants randomized to receive upadacitinib 15 mg QD for 16 weeks in Period 1. At Week 16 participants were re-randomized to receive 15 mg upadacitinib or placebo QD for 72 weeks in Period 2. arm 4: Participants randomized to receive upadacitinib 30 mg QD for 16 weeks in Period 1. At Week 16 participants were re-randomized to receive 30 mg upadacitinib or placebo QD for 72 weeks in Period 2.
Interventions: intervention 1: Upadacitinib intervention 2: Placebo
Intervention descriptions: intervention 1: Tablet for oral use intervention 2: Tablet

Protocol documents:
Prot_000.pdf: 
ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
1
1.0
Title Page
Clinical Study Protocol M16-048
A Phase 2b Multicenter, Randomized, 
Placebo-Controlled, Double-Blind Dose-Ranging 
Study to Evaluate ABT-494 (Upadacitinib) in Adult 
Subjects with Moderate to Severe Atopic Dermatitis
Incorporating Amendments 1, 2, 3, 3.01 (VHP 
Countries:  Belgium, Finland, Germany, Ireland and 
Spain Only), 4 and 5
AbbVie Investigational
  Product:
ABT-494 (upadacitinib)
Date:
30 August 2017
Development Phase:
2b
Study Design:
This is a Phase 2b Multicenter, Randomized, Placebo-Controlled, 
Double-Blind Dose-Ranging Study
EudraCT Number:
2016-002451-21
Investigators:
Multicenter Trial (Investigator information is on file at AbbVie)
Sponsor*:
AbbVie Inc.*
Dept. R477, Bldg. AP31-3
1 North Waukegan Road
North Chicago, IL 60064 USA
Sponsor/Emergency 
  Contact:
* 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.
NCT02925117


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
2
1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions 
Protocol 
Date
Original
24 June 2016
Amendment 1
25 July 2016
Amendment 2
18 October 2016
Amendment 3
16 December 2016
Amendment 3.01
08 March 2017
Amendment 4
07 June 2017
The purpose of this amendment is to:
●
Update Section 6.1.1.3, Adverse Events of Special Interest.
Rationale:  Updated list of AEs of special interest to be consistent with the 
current AbbVie list of AEs of special interest.
●
Update Section 8.1.6.2.1, Treatment-Emergent Adverse Events (TEAE).
Rationale:  Updated list of AEs of special interest to be consistent with the 
current AbbVie list of AEs of special interest.
An itemized list of all changes made to this protocol under this amendment can be found 
in Appendix Q.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
3
1.2
Synopsis
AbbVie Inc.
Protocol Number:  M16-048
Name of Study Drug:  ABT-494 (upadacitinib)
Phase of Development:  2b
Name of Active Ingredient:  ABT-494 (upadacitinib)
Date of Protocol Synopsis:  30 August 2017
Protocol Title:  A Phase 2b Multicenter, Randomized, Placebo-Controlled, Double-Blind Dose-Ranging 
Study to Evaluate ABT-494 (Upadacitinib) in Adult Subjects with Moderate to Severe Atopic Dermatitis
Objective:  
To evaluate the safety and efficacy of multiple doses of ABT-494 (upadacitinib) monotherapy versus 
placebo in the treatment of adults with moderate to severe atopic dermatitis.
Investigators:  Multicenter
Study Sites:  Approximately 45
Study Population:  
Adult female and male subjects who are ≥ 18 and ≤ 75 years of age with moderate to severe atopic 
dermatitis defined by a baseline Eczema Area and Severity Index (EASI) of ≥ 16, affected Body Surface 
Area (BSA) of ≥ 10% and Investigator's Global Assessment (IGA) of ≥ 3.
Number of Subjects to be Enrolled:  Approximately 160 subjects (40 subjects per treatment group)
Methodology:  
This is an 88-week Phase 2b, randomized, double-blind, parallel-group, placebo-controlled multicenter 
study to evaluate the safety and efficacy of ABT-494 (upadacitinib) in adult subjects with moderate to 
severe atopic dermatitis.  In Period 1, subjects will be randomized in a 1:1:1:1 ratio to one of four 
treatment groups:  (1) ABT-494 7.5 mg, (2) ABT-494 15 mg, (3) ABT-494 30 mg, (4) matching placebo, 
once daily for 16 weeks.  The primary endpoint analysis will be performed at Week 16.  Randomization 
will be stratified by geographic region (US/PR/Canada, EU/AUS, and Japan).  Enrollment in Japan will 
be capped at 10% of subjects (4 subjects per group).
Group 1:  ABT-494 7.5 mg QD for 16 weeks
Group 2:  ABT-494 15 mg QD for 16 weeks
Group 3:  ABT-494 30 mg QD for 16 weeks
Group 4:  Matching Placebo for 16 weeks
The analysis of the double-blind 16-week period of the study (Period 1), including the primary endpoint 
analysis, will be conducted after all subjects have either completed the Period 1 or discontinued from the 
study; and the data regarding Period 1 have been cleaned and an interim database lock is performed.  This 
efficacy analysis is the only and final analysis of the double-blind Period 1, thus no adjustment of 
alpha-level is needed.  In addition, there will be an interim analysis after all subjects have either reached 
Week 32 or discontinued from the study; and the data is cleaned.
In Period 1, discontinuation from study drug will be mandatory for any subject with an EASI score 
worsening of 25% or more compared with their Baseline EASI score at any 2 consecutive scheduled 
study visits from Week 4 to Week 12.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
4
Methodology (Continued):
Subjects who complete Period 1 will be re-randomized at Week 16 within their original treatment group 
assignments to either ABT-494 (upadacitinib) or placebo into a 72-week double-blind, placebo controlled 
treatment period (Period 2) in a 1:1 ratio as shown in Figure 1 (study design).  Randomization will be 
stratified by geographic region and EASI 75 response at Week 16.  At the Week 16 visit, all subjects will 
be re-randomized as follows into Period 2:
!
Subjects from Group 1 in Period 1:  ABT-494 7.5 mg QD or matching placebo for 24 weeks 
!
Subjects from Group 2 in Period 1:  ABT-494 15 mg QD or matching placebo for 24 weeks
!
Subjects from Group 3 in Period 1:  ABT-494 30 mg QD or matching placebo for 24 weeks
!
Subjects from Group 4 in Period 1:  ABT-494 30 mg QD or matching placebo for 24 weeks
For subjects re-randomized to placebo, ABT-494 7.5 mg QD or ABT-494 15 mg QD in Period 2, blinded 
rescue therapy with ABT-494 30 mg QD will be provided after the first instance of a < EASI 50 response 
starting at the Week 20 visit (4 weeks after re-randomization into Period 2).  These subjects will continue 
on ABT-494 30 mg QD for the remainder of the study.  These subjects will continue on ABT-494 30 mg 
QD for the remainder of the study. 
During Period 2, concomitant class III – IV, medium potency topical corticosteroid treatment will be 
permitted at the Week 24 visit and thereafter in subjects after a second instance of < EASI 50 response in 
any two Period 2 study visits beginning from Week 20 (see Section 5.2.3.4 for a list or permitted 
treatments).  For subjects who receive topical corticosteroid rescue therapy, an additional visit will be 
required 4 weeks later.  Discontinuation from study drug will be mandatory for subjects with < EASI 50 
response compared with their Baseline EASI score 4 weeks following rescue with topical corticosteroids 
or at any visit thereafter.
In order to minimize missing data for efficacy and safety assessments, subjects who prematurely 
discontinue study drug treatment should continue to be followed for all regularly scheduled visits, unless 
they have decided to discontinue the study participation entirely (withdrawal of informed consent).
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
1.
Adult male or female, ≥ 18 and ≤ 75 years old at Screening.
2.
Atopic dermatitis with a diagnosis confirmed by a dermatologist (according to the Hanifin and Rajka 
criteria); and also onset of symptoms at least 1 year prior to baseline.
3.
Moderate to severe atopic dermatitis defined by an EASI ≥ 16, BSA ≥ 10% and an IGA score ≥ 3 at 
the Baseline visit.
4.
Documented history (within 1 year prior to the screening visit) of inadequate response to treatment 
with topical corticosteroids (TCS), or topical calcineurin inhibitors (TCI), or for whom topical 
treatments are otherwise medically inadvisable (e.g., because of important side effects or safety 
risks).
5.
Twice daily use of an additive-free, bland emollient for at least 7 days prior to Baseline.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
5
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion:  
1.
Prior exposure to any systemic or topical JAK inhibitor (including but not limited to tofacitinib, 
baricitinib, ruxolitinib, and filgotinib).
2.
Treatment with topical corticosteroids (TCS), topical calcineurin inhibitors (TCI), prescription 
moisturizers or moisturizers containing additives such as ceramide, hyaluronic acid, urea, or filaggrin 
within 10 days prior to the Baseline visit.
3.
Prior exposure to dupilumab. 
4.
Prior exposure to any investigational systemic treatment within 30 days or 5 half-lives (whichever is 
longer) of the Baseline visit or is currently enrolled in another clinical study.
5.
Treatment with omalizumab within 3 months prior to the Baseline visit.
6.
Prior exposure to systemic therapy for atopic dermatitis, including but not limited to corticosteroids, 
methotrexate, cyclosporine, azathioprine, phosphodiesterase type 4 (PDE4)-inhibitors and 
mycophenolate mofetil within 4 weeks prior to the Baseline visit.
7.
Subject with other active skin diseases or skin infections (bacterial, fungal, or viral) requiring 
systemic treatment within 4 weeks of the Baseline visit or would interfere with the appropriate 
assessment of atopic dermatitis lesions.
8.
Phototherapy treatment, tanning booth, or extended sun exposure that could affect disease severity or 
interfere with disease assessments within 4 weeks prior to the Baseline visit and during the study.
Investigational Product:
ABT-494 (upadacitinib)
Doses:
ABT-494 7.5 mg QD
ABT-494 15 mg QD
ABT-494 30 mg QD
Mode of Administration:
Oral
Reference Therapy:
Matching placebo
Dose:
N/A
Mode of Administration:
Oral
Duration of Treatment:  88 weeks
Criteria for Evaluation:
Efficacy:
Primary Endpoint:
Mean percent (%) change from Baseline (Day 1) in EASI score at Week 16.
Secondary Endpoints:
!
Proportion of subjects achieving an EASI 75 response, defined as at least a 75% reduction in 
EASI score, at Week 16 relative to the Baseline (Day 1)
!
Proportion of subjects achieving an Investigator Global Assessment (IGA) of 0 or 1 at Week 16
!
Percent change from Baseline to Weeks 2, 8 and 16 in pruritus numerical rating scale (NRS)
!
Percent change in EASI score from Baseline at Week 8
!
Percent change in SCORAD score from Baseline at Weeks 8 and 16


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
6
Criteria for Evaluation (Continued):
Efficacy (Continued):
Secondary Endpoints:
!
Proportion of subjects achieving EASI 50/75/90 response at Weeks 8 and 16
!
Proportion of subjects achieving SCORAD 50/75/90 response at Weeks 8 and 16
!
Proportion of subjects with Dermatology Life Quality Index (DLQI) = "0" or "1" at Weeks 8 and 
16
!
Change from Baseline in DLQI at Weeks 8 and 16
!
Change and percent change from Week 16 (re-randomization) in EASI score at all Period 2 
visits
!
Time to loss of EASI 50 response relative to Baseline among those who were re-randomized as 
EASI 75 responders at Week 16
!
Summary of EASI 75 at all visits in Period 2 among those who were re-randomized as EASI 75 
non-responders at Week 16
Exploratory Endpoints:
!
Time to EASI 50/75/90 and IGA "0" or "1" response in Period 1
!
Proportion of subjects achieving EASI 50/75/90/100 response at all visits
!
Proportion of subjects achieving SCORAD 50/75/90 response at all visits
!
Change from Baseline to Week 16 in Patient Oriented Eczema Measure (POEM)
!
Change from Baseline to Week 16 in Medical Outcomes Study (MOS) Sleep Scale
!
Change from Baseline to Week 16 in in Asthma Symptoms Questionnaire
!
Change from Baseline to Week 16 in Daytime Nasal Symptom Questionnaire
!
Change from Baseline in total sleep time per night (TST min), Sleep Efficiency (%), Wake After 
Sleep Onset (WASO), number of scratching events per hour, mean activity during rest (sleep) 
periods as measured by actigraphy.
Primary and secondary variables will also be evaluated at all scheduled visits through Week 88.
Exploratory Research Variables and Validation Studies (Optional):
Prognostic, predictive, surrogate and pharmacodynamics biomarkers signatures may be evaluated.  To 
this end, blood and skin biopsies samples will be collected at various time points.  Assessments will 
include but may not be limited to nucleic acids, proteins, metabolites, or lipids.
Selected sites will be asked to perform a complete investigation of biomarkers.  For such sites, these 
assessments (blood samples and skin biopsy collections) will be made mandatory as part of the main 
study.  There will be a specific Informed Consent Form (ICF) for subjects in these selected sites.
Pharmacokinetic:
Blood samples for assay of ABT-494 (upadacitinib) will be collected at each visit beginning at Week 2.  
Blood samples at Week 2 and 4 visits will be collected prior to dosing if possible.  For all other visits, 
blood samples will be collected at any time during the visit.
Safety:
Safety evaluations include adverse event (AE) monitoring, physical examinations, vital sign 
measurements, electrocardiogram, and clinical laboratory testing (hematology, chemistry, and urinalysis).


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
7
Statistical Methods:
Efficacy:
Efficacy analyses will be carried out in the Intent-to-treat population, which includes all randomized 
subjects.  All statistical tests will be conducted at two-sided alpha level of 0.05 unless otherwise 
specified.  Pairwise comparison of each ABT-494 (upadacitinib) treatment group versus placebo will be 
performed.  
Categorical variables will be analyzed using the Cochran-Mantel-Haenszel test adjusting for stratification 
factors.
Continuous variables will be analyzed using the analysis of covariance (ANCOVA) model with treatment 
group and stratification factors as fixed effects, and the corresponding baseline value as covariates.
Time to event variables will be analyzed using Kaplan-Meier methodology.
Multiple imputation and last observation carried forward (LOCF), and as-observed approaches will be 
utilized for continuous endpoints.  Non-responder Imputation will be the primary approach to impute 
missing values for the categorical endpoints.
A total of 160 subjects will be randomized to three treatment groups and placebo in a ratio of 1:1:1:1.  
The sample size for this study is based on the percent change in EASI from baseline at Week 16.  
Assuming a percent change in EASI from baseline at Week 16 of 35, 45, 60, and 70 in the placebo, 
7.5 mg, 15 mg, and 30 mg arms with a standard deviation of 40 and a maximum efficacy of 80, a sample 
size of 40 subjects per treatment group is sufficient to test for the presence of a dose response signal, to 
select the best dose response model for the observed data out of a pre-specified set of candidate models, 
and to estimate target doses of interest (e.g., the minimum effective dose, MED) using MCP-Mod 
(Multiple comparison procedure and modeling) approach.  This approach provides 99% average power to 
detect a dose effect at 5% level of significance (one-sided) with the linear, Emax, exponential, logistic and 
sigEmax models pre-specified as likely candidates to characterize the dose-response for ABT-494 for the 
percent change in EASI. 
A sample of size 40 per group provides 97% power to detect a significant difference between 30 mg QD 
and placebo, and 78% power to detect a significant difference between 15 mg QD and placebo at 
two-sided level of significance of 5.0%.
Pharmacokinetic:
A non-linear mixed-effects modeling approach will be used to estimate the population central values and 
the empirical Bayesian estimates of the individual values for ABT-494 (upadacitinib) oral clearance 
(CL/F) and volume of distribution (V/F).  Additional parameters may be estimated if useful in the 
interpretation of the data.
Safety:
Safety analyses will be carried out using the safety population, for both periods, which includes all 
subjects who receive at least one dose of study medication and is based on treatments actually received.  
Safety will be assessed by AEs, physical examination, laboratory assessments, ECG, and vital sign 
results.  Frequency tables and lists of subjects with treatment-emergent AEs (TEAEs) by the Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term will be presented.  
AEs will further be analyzed by severity and relationship to study drug as assessed by the investigator.  
Summaries will include percentage of patients and events per 100 patient-years.  The changes from 
baseline in vital signs and clinical laboratory values will be analyzed in a descriptive manner.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
8
1.3
List of Abbreviations and Definition of Terms
Abbreviations
AE
Adverse Event
AD
Atopic Dermatitis
ADerm-IS
Atopic Dermatitis Impact Scale
ADerm-SS
Atopic Dermatitis Symptom Scale
ADL
Activities of Daily Living
ALT
Alanine Aminotransferase
ANA
Antinuclear Antibody
ANC
Absolute neutrophil count
ANOVA
Analysis of variance
ANT
Absolute Lymphocyte Count
AST
Aspartate Aminotransferase
BCG
Bacille Calmette- Guerin
bHCG
Beta Human Chorionic Gonadotropin
BL
Baseline Visit
BSA
Body Surface Area
BUN
Blood urea nitrogen
CBC
Complete Blood Count
CCP
Cyclic Citrullinated Peptide
CPK
Creatine Phosphokinase
CYP3A
Cytochrome P450 3A
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CXR
Chest X-Ray
DLQI
Dermatology Life Quality Index
DNA
Deoxyribonucleic acid
DO
Doctor of Osteopathy
EASI
Eczema Area and Severity Index
ECG
Electrocardiogram
EDC
Electronic Data Capture
ePRO
Electronic Patient Recorded Outcome
FDA
US Food and Drug Administration


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
9
F/U
Follow-up
FSH
Follicle-Stimulating Hormone
GCP
Good Clinical Practice
GFR
Estimated Glomerular Filtration Rate
HBV
Hepatitis B
HBsAg
Hepatitis B Surface Antigen
HBsAb
Hepatitis B Surface Antibody
HCV
Hepatitis C
HCV Ab
Hepatitis C virus antibody
HDL-C
High-Density Lipoprotein Cholesterol
HIV
Human Immunodeficiency Virus
HsCRP
High Sensitive C Reactive Protein
ICH
International Conference on Harmonization
DMC
Data Monitoring Committee
IEC
Independent Ethics Committee
IGA
Investigators Global Assessment
IGRA
Interferon-Gamma Released Assay
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
JAK
Janus Activated Kinase
LDL-C
Low-Density Lipoprotein Cholesterol
LOCF
Last Observation Carried Forward
MDRD
Modification of diet in renal disease
MD
Medical Doctor
MedDRA
Medical Dictionary for Regulatory Activities
MOS
Medical Outcomes Study
NCI
National Cancer Institute
NK
Natural Killer
NKT
Natural Killer T
NMSC
Non-Melanoma Skin Cancer
NRS
Numerical Rating Scale


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
10
NYHA
New York Heart Association
PA
Physician Assistant
PBMC
Peripheral Blood Mononuclear Cell
PCR
Polymerase Chain Reaction
PD
Premature Discontinuation
PDE4 
Phosphodiesterase Type 4
PGIS
Patient Global Impression of Severity
PK
Pharmacokinetic
POEM
Patient Oriented Eczema Measure
PPD
Purified Protein Derivate
PRO
Patient Reported Outcome
PUVA
Photochemotherapy
QD
Once Daily
QTc
QT interval corrected for heart rate
QTcF
Friedericia's correction formula 
RAVE
EDC System from Medidata
RNA
Ribonucleic acid
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCORAD
Scoring Atopic Dermatitis
SUSAR
Suspected Unexpected Serious Adverse Reaction
TEAE
Treatment Emergent Adverse Event
TB
Tuberculosis
TCI
Topical Calcineurin Inhibitors
TCS
Topical Corticosteroids
ULN
Upper Limit of Normal
UVA
Ultraviolet A
UVB
Ultraviolet B
WBC
White Blood Count
Wk
Week


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
11
2.0
Table of Contents
1.0
Title Page ...............................................................................1
1.1
Protocol Amendment:  Summary of Changes ......................................... 2
1.2
Synopsis................................................................................................. 3
1.3
List of Abbreviations and Definition of Terms........................................ 8
2.0
Table of Contents ................................................................ 11
3.0
Introduction......................................................................... 16
3.1
Differences Statement .......................................................................... 18
3.2
Benefits and Risks................................................................................ 18
4.0
Study Objective ................................................................... 19
5.0
Investigational Plan.............................................................20
5.1
Overall Study Design and Plan:  Description ........................................ 20
5.2
Selection of Study Population............................................................... 26
5.2.1
Inclusion Criteria.................................................................................. 26
5.2.2
Exclusion Criteria................................................................................. 28
5.2.3
Prior and Concomitant Therapy............................................................ 31
5.2.3.1
Prior Therapy ....................................................................................... 32
5.2.3.2
Permitted Background and Concomitant Therapy................................. 33
5.2.3.3
Prohibited Therapy............................................................................... 33
5.2.3.4
Rescue Therapy.................................................................................... 37
5.2.4
Contraception Recommendations ......................................................... 38
5.3
Efficacy, Pharmacokinetic, Specific Cellular Pharmacodynamic 
Changes, Exploratory Research and Validation Studies, and 
Safety Assessments/Variables............................................................... 41
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ............... 41
5.3.1.1
Study Procedures.................................................................................. 50
5.3.1.2
Collection and Handling of Optional and Mandatory Samples for 
Exploratory Research and Validation Studies ....................................... 67
5.3.1.2.1
Samples for Exploratory Research Variables and Validation 
Studies ................................................................................................. 67
5.3.2
Drug Concentration Measurements....................................................... 69
5.3.2.1
Collection of Samples for Analysis....................................................... 69


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
12
5.3.2.2
Measurement Method........................................................................... 70
5.3.3
Efficacy Variables................................................................................ 70
5.3.3.1
Primary Variable .................................................................................. 70
5.3.3.2
Secondary Variables............................................................................. 70
5.3.3.3
Exploratory Variables........................................................................... 71
5.3.4
Safety Variables ................................................................................... 72
5.3.5
Pharmacokinetic Variables ................................................................... 72
5.3.6
Exploratory Research Variables and Validation Studies........................ 72
5.4
Removal of Subjects from Therapy or Assessment ............................... 73
5.4.1
Discontinuation of Individual Subjects ................................................. 73
5.4.2
Discontinuation of Entire Study............................................................ 76
5.5
Treatments ........................................................................................... 76
5.5.1
Treatments Administered...................................................................... 76
5.5.2
Identity of Investigational Product........................................................ 76
5.5.2.1
Packaging and Labeling........................................................................ 76
5.5.2.2
Storage and Disposition of Study Drug................................................. 77
5.5.3
Method of Assigning Subjects to Treatment Groups ............................. 77
5.5.4
Selection and Timing of Dose for Each Subject .................................... 78
5.5.5
Blinding ............................................................................................... 80
5.5.5.1
Blinding of Data for Data Monitoring Committee (DMC) .................... 81
5.5.6
Treatment Compliance ......................................................................... 81
5.5.7
Drug Accountability ............................................................................. 81
5.6
Discussion and Justification of Study Design........................................ 82
5.6.1
Discussion of Study Design and Choice of Control Groups .................. 82
5.6.2
Appropriateness of Measurements........................................................ 83
5.6.3
Suitability of Subject Population .......................................................... 83
5.6.4
Selection of Doses in the Study ............................................................ 83
6.0
Complaints........................................................................... 84
6.1
Medical Complaints ............................................................................. 84
6.1.1
Definitions ........................................................................................... 85
6.1.1.1
Adverse Event...................................................................................... 85
6.1.1.2
Serious Adverse Events........................................................................ 86
6.1.1.3
Adverse Events of Special Interest........................................................ 87


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
13
6.1.2
Adverse Event Severity ........................................................................ 88
6.1.3
Relationship to Study Drug................................................................... 88
6.1.4
Adverse Event Collection Period.......................................................... 89
6.1.5
Serious Adverse Event.......................................................................... 91
6.1.6
Pregnancy............................................................................................. 92
6.1.7
Toxicity Management........................................................................... 93
6.1.8
Data Monitoring Committee................................................................. 97
6.1.9
Cardiovascular Adjudication Committee .............................................. 97
6.2
Product Complaint................................................................................ 97
6.2.1
Definition............................................................................................. 97
6.2.2
Reporting ............................................................................................. 98
7.0
Protocol Deviations ............................................................. 98
8.0
Statistical Methods and Determination of Sample 
Size ....................................................................................... 99
8.1
Statistical and Analytical Plans............................................................. 99
8.1.1
Analysis Populations ...........................................................................100
8.1.2
Planned Methods of Statistical Analysis ..............................................101
8.1.3
Subject Accountability, Disposition and Study Drug Exposure............101
8.1.3.1
Subject Accountability ........................................................................101
8.1.3.2
Subject Disposition..............................................................................101
8.1.3.3
Study Drug Exposure and Compliance ................................................101
8.1.4
Demographics and Baseline Characteristics.........................................102
8.1.5
Statistical Analyses of Efficacy ...........................................................102
8.1.5.1
Primary Analysis of Efficacy...............................................................103
8.1.5.2
Secondary Analysis of Efficacy...........................................................105
8.1.6
Safety Analysis....................................................................................105
8.1.6.1
General Considerations........................................................................105
8.1.6.2
Analysis of Adverse Events.................................................................106
8.1.6.2.1
Treatment-Emergent Adverse Events (TEAE) .....................................106
8.1.6.2.2
Serious Adverse Events and Death ......................................................107
8.1.6.3
Analysis of Laboratory, Vital Sign, and ECG Data ..............................107
8.1.7
Interim Analysis..................................................................................108
8.1.8
Pharmacokinetic and Exposure-Response Analyses.............................108


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
14
8.1.9
Statistical Analysis of Biomarker Data ................................................110
8.2
Determination of Sample Size .............................................................111
8.3
Randomization Methods......................................................................112
9.0
Ethics.................................................................................. 112
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ........................................................................................112
9.2
Ethical Conduct of the Study...............................................................113
9.3
Subject Information and Consent.........................................................113
9.3.1
Informed Consent Form and Explanatory Material ..............................115
9.3.2
Revision of the Consent Form and Explanatory Material .....................115
10.0
Source Documents and Case Report Form 
Completion ........................................................................ 115
10.1
Source Documents...............................................................................115
10.2
Case Report Forms..............................................................................116
11.0
Data Quality Assurance .................................................... 118
12.0
Use of Information ............................................................ 119
13.0
Completion of the Study ................................................... 120
14.0
Investigator's Agreement.................................................. 121
15.0
Reference List.................................................................... 122
List of Tables
Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and 
Inducers................................................................................................ 37
Table 2.
Study Activities.................................................................................... 42
Table 3.
Study Activities – Optional and Mandatory Samples for 
Exploratory Research and Validation Studies ....................................... 48
Table 4.
Clinical Laboratory Tests ..................................................................... 61
Table 5.
Identity of Investigational Product........................................................ 76
Table 6.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values ................................................................................ 95


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
15
List of Figures
Figure 1.
Study Design........................................................................................ 23
Figure 2.
Criteria for HBV DNA PCR Qualitative Testing .................................. 64
Figure 3.
Adverse Event Collection..................................................................... 90
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator.........................................124
Appendix B.
List of Protocol Signatories .................................................................126
Appendix C.
TB Risk Assessment Form Example....................................................127
Appendix D.
Investigator's Global Assessment Example ..........................................128
Appendix E.
Eczema Area and Severity Index (EASI) Scoring Example..................129
Appendix F.
SCORing Atopic Dermatitis (SCORAD) Example ..............................131
Appendix G.
Dermatology Life Quality Index (DLQI) Example...............................133
Appendix H.
Pruritus (Itch) Numerical Rating Scale (NRS) Example.......................135
Appendix I.
Medical Outcomes Study (MOS) Sleep Scale-Revised Example..........136
Appendix J.
Patient Oriented Eczema Measure (POEM) Example...........................138
Appendix K.
Asthma Symptoms Questionnaire Example .........................................140
Appendix L.
Daytime Nasal Symptoms Questionnaire Example ..............................141
Appendix M.
Atopic Dermatitis Symptom Scale (ADerm-SS) Questionnaire 
Example ..............................................................................................142
Appendix N.
Atopic Dermatitis Impact Scale (ADerm-IS) Questionnaire 
Example ..............................................................................................145
Appendix O.
Patient Global Impression of Severity (PGIS) Questionnaire 
Example ..............................................................................................147
Appendix P.
Local Canada Requirements ................................................................148
Appendix Q.
Protocol Amendment:  List of Changes ...............................................151


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
16
3.0
Introduction
Atopic Dermatitis
Atopic Dermatitis (AD; also known as atopic eczema) is an inflammatory, pruritic, 
chronic or chronically relapsing skin disease.  Common clinical characteristics include 
erythema, edema, xerosis, erosions/excoriations, oozing and crusting, and lichenification, 
but these vary by patient age and chronicity of lesions.  Pruritus is a hallmark of the 
condition that is responsible for much of the disease burden borne by patients and their 
families.1  Sleep disturbance is commonly associated with AD and stems in large part 
from the significant itch associated with the disease.2,3
AD is also associated with multiple other comorbid conditions, including a higher 
prevalence of other atopic diseases such as rhinitis, food allergies and asthma with the 
severity of eczema directly related to the severity of these comorbidities.4
The diagnosis of AD is made clinically and is based on historical features, morphology 
and distribution of skin lesions, and associated clinical signs.  Several criteria have been 
developed by various groups to aid in classification.  One of the earliest and most 
recognized sets of diagnostic criteria is the 1980 Hanifin and Rajka criteria5 which require 
that 3 of 4 major criteria and 3 of 23 minor criteria be met.
AD is one of the most common skin diseases which affects up to 20% of children and 1 –
3% of adults worldwide.6  In approximately 70% of cases, the onset of AD starts in 
children under 5 years of age7 and while the majority of affected individuals have 
resolution of disease by adulthood, it persists in about 10% to 30% of cases.8  In addition, 
a smaller percentage of patients first develop symptoms of AD as adults.9
JAK Inhibition
Evidence suggests that inhibition of Janus kinase (JAK)-mediated pathways may be a 
promising approach for the treatment of patients with moderate to severe AD.10  AbbVie 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
17
is developing a small molecule inhibitor of JAK, ABT-494 (upadacitinib), that may 
address the current needs.
The JAK family is composed of 4 family members:  JAK1, 2, 3, and Tyrosine kinase 2 
(Tyk2).  These cytoplasmic tyrosine kinases are associated with membrane cytokine 
receptors such as common gamma-chain receptors and the glycoprotein 130 
transmembrane proteins.11  Activation of JAK pathways initiates expression of survival 
factors, cytokines, chemokines, and other molecules that facilitate leukocyte cellular 
trafficking and cell proliferation which contribute to inflammatory and autoimmune 
disorders.
Hence, the JAK family has evoked considerable interest in the area of inflammatory 
diseases leading to the development of JAK inhibitors with different selectivity profiles 
against JAK1, JAK2, JAK3, and Tyk2, of which tofacitinib has showed initial indication 
of efficacy in individuals with AD.12,13  Although tofacitinib, a non-selective JAK 
inhibitor, has demonstrated efficacy in both rheumatoid arthritis and plaque psoriasis, 
questions regarding the safety profile remain for both indications, including serious 
infections, herpes zoster reactivation, malignancies, and hematologic adverse events 
(AEs).
The second generation of JAK inhibitors, with different selectivity profiles against JAK1, 
JAK2, JAK3, and Tyk2, are in development.14  ABT-494 (upadacitinib) is a novel 
selective JAK1 inhibitor currently being developed for RA, UC and CD.  In an in vitro 
setting, ABT-494 potently inhibits JAK1 activity, but to a lesser degree, inhibits the other 
isoforms, JAK2 and JAK3.  The enhanced selectivity of ABT-494 against JAK1 may 
offer an improved benefit-risk profile in patients with moderate to severe AD.
The clinical hypothesis is that ABT-494 (upadacitinib) should be effective in targeting 
Th2-mediated inflammation and itch associated with AD by interfering with 
JAK1-mediated signaling pathways that are central to its pathophysiology (TSLP, IL31, 
IL-4 and IL13 all signal through JAK1)15,16 without causing excessive anemia due to its 
reduced activity against JAK2, which is essential for erythropoietin signaling.  ABT-494 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
18
is also less potent against JAK3, an important component of lymphocyte activation and 
function.  As such, treatment with ABT-494, a selective JAK1 inhibitor with reduced 
JAK3 inhibition, could result in a decreased risk for infection (including viral 
reactivation) and/or malignancy compared to a pan JAK inhibitor or less selective JAK 
inhibitors.
ABT-494 Pharmacokinetics
After administration of ABT-494 (upadacitinib) once-daily tablet formulation, ABT-494 
maximum plasma concentration was achieved within 2 to 4 hours and its terminal 
elimination half-life was 9 to 14 hours.  ABT-494 displayed no significant accumulation 
in plasma with multiple dosing.  Food has no clinically meaningful effect on ABT-494 
exposure from the once-daily formulation; therefore, ABT-494 can be administered 
without regard to meals.  
In vitro studies suggest that ABT-494 is not an inhibitor of cytochrome P450 (CYP) 1A2, 
2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 at concentrations exceeding those relevant clinically.  
ABT-494 increased mRNA expression for CYP3A4 and CYP2B6 in vitro in a 
concentration-dependent manner.  However, physiologically-based pharmacokinetic 
modeling suggests that ABT-494 does not affect plasma concentrations of concomitant 
medications that are substrates for CYP3A or CYP2B6 at the relevant clinical doses.
3.1
Differences Statement
This Phase 2 study differs from other ABT-494 (upadacitinib) studies as it is the first to 
evaluate the safety and efficacy of multiple dosages of ABT-494 versus placebo in the 
treatment of moderate to severe AD.
3.2
Benefits and Risks
Treatment of AD in adult patients depends on the extent and severity of disease.  Topical 
agents alone are commonly used for mild to moderate cases.  The most commonly used 
topical agents are corticosteroids, calcineurin inhibitor agents and moisturizers.  When 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
19
topical therapies are insufficient for treating the signs and symptoms of AD, systemic 
therapy or phototherapy are generally added to topical agents.17
Treatment guidelines developed by the American Academy of Dermatology recommend 
the use of systemic immunomodulatory agents for patients in whom optimized topical 
regimens and/or phototherapy do not adequately control the signs and symptoms of 
disease.  These guidelines recognize that insufficient data exist to firmly recommend 
optimal dosing, duration of therapy, and precise monitoring protocols for any systemic 
immunomodulating medication.18  Importantly, in addition to the lack of well-controlled 
efficacy data supporting their use in moderate to severe AD, the duration of use of many 
traditional systemic immunomodulatory agents are limited due to cumulative toxicity.  
This significant unmet need has also been independently detected by a recent systematic 
review of systemic treatments for moderate to severe AD that concluded that, although 
12 different interventions for moderate to severe AD have been studied in 34 RCTs, 
strong recommendations are only possible for the short-term use of cyclosporin A.19
At this time there is no FDA-approved systemic treatment and only one EMA-approved 
systemic treatment (cyclosporin A) for AD.  Thus, there is a high unmet need for a 
significant number of patients with an inadequate response to topical agents. 
ABT-494 (upadacitinib) is a novel selective orally available JAK1 inhibitor with the 
potential to decrease Th2-mediated skin inflammation and itch mediated by JAK1 
signaling in AD, while having minimal inhibitory effects on JAK2 and JAK3.  This could 
potentially minimize some of the reported safety concerns with non-selective JAK 
inhibition which are thought to be mediated by inhibition of JAK2 and JAK3 signaling 
pathways.
4.0
Study Objective
To evaluate the safety and efficacy of multiple doses of ABT-494 (upadacitinib) 
monotherapy versus placebo in the treatment of adults with moderate to severe AD.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
20
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is an 88-week Phase 2b, randomized, double-blind, parallel-group, placebo-
controlled multicenter study to evaluate the safety and efficacy of ABT-494 (upadacitinib) 
in adult subjects with moderate to severe AD.
The study was designed to enroll approximately 160 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 has been enrolled, there 
is a possibility that additional subjects in screening will not be enrolled.
The duration of the study will be up to 88 weeks and will include a 35-day maximum 
screening period, a 16-week double-blind treatment period (Period 1) and a 72-week 
double-blind treatment period (Period 2).  In addition, a 30-day follow-up visit (or phone 
call if a visit is not possible) should occur to determine the status of any ongoing 
AEs/SAEs or the occurrence of any new AEs/SAEs.  
In Period 1, subjects will be randomized in a 1:1:1:1 ratio to one of four treatment groups:  
(1) ABT-494 7.5 mg, (2) ABT-494 15 mg, (3) ABT-494 30 mg, (4) matching placebo, 
once daily for 16 weeks.  The primary endpoint analysis will be performed at Week 16.  
Randomization will be stratified by geographic region (US/PR/Canada, EU/AUS, and 
Japan).  Enrollment in Japan will be capped at 10% of subjects (approximately 4 subjects 
per group).
Group 1:  ABT-494 7.5 mg QD for 16 weeks
Group 2:  ABT-494 15 mg QD for 16 weeks
Group 3:  ABT-494 30 mg QD for 16 weeks
Group 4:  Matching Placebo for 16 weeks
The analysis of the double-blind 16-week period of the study (Period 1), including the 
primary endpoint analysis, will be conducted after all subjects have either completed the 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
21
Period 1 or discontinued from the study; and the data regarding Period 1 have been 
cleaned and an interim database lock is performed. This efficacy analysis is the only and 
final analysis of the double-blind period, thus no adjustment of alpha-level is needed.  In 
addition, there will be an interim analysis after all subjects have either reached Week 32 
or discontinued from the study; and the data is cleaned.
In Period 1, discontinuation from study drug will be mandatory for any subject with an 
EASI score worsening of 25% or more compared with their Baseline EASI score at any 
2 consecutive scheduled study visits from Week 4 to Week 12.
Subjects who complete Period 1 will be re-randomized at Week 16 within their original 
treatment group assignment to either ABT-494 (upadacitinib) or placebo into a 72-week 
double-blind, placebo controlled treatment period (Period 2) in a 1:1 ratio as shown in 
Figure 1 (study design).  Randomization will be stratified by geographic region and EASI 
75 response at Week 16.  At the Week 16 visit, all subjects will be re-randomized as 
follows into Period 2:
●
Subjects from Group 1 in Period 1:  ABT-494 7.5 mg QD or matching placebo 
for 24 weeks 
●
Subjects from Group 2 in Period 1:  ABT-494 15 mg QD or matching placebo 
for 24 weeks
●
Subjects from Group 3 in Period 1:  ABT-494 30 mg QD or matching placebo 
for 24 weeks
●
Subjects from Group 4 in Period 1:  ABT-494 30 mg QD or matching placebo 
for 24 weeks
For subjects re-randomized to placebo, ABT-494 7.5 mg QD or ABT-494 15 mg QD in 
Period 2, blinded rescue therapy with ABT-494 30 mg QD will be provided after the 
first instance of a < EASI 50 response starting at the Week 20 visit (4 weeks after 
re-randomization into Period 2).  These subjects will continue on ABT-494 30 mg QD for 
the remainder of the study.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
22
During Period 2, concomitant class III – IV, medium potency topical corticosteroid 
treatment will be permitted at the Week 24 visit and thereafter in subjects after a 
second instance of < EASI 50 response in any two Period 2 study visits beginning from 
Week 20 (see Section 5.2.3.4 for permitted treatments).  For subjects who receive topical 
corticosteroid rescue therapy, an additional visit will be required 4 weeks later.  
Discontinuation from study drug will be mandatory for subjects with < EASI 50 response 
compared with their Baseline EASI score 4 weeks following rescue with topical 
corticosteroids or at any visit thereafter.
In order to minimize missing data for efficacy and safety assessments, subjects who 
prematurely discontinue study drug treatment should continue to be followed for all 
regularly scheduled visits, unless they have decided to discontinue the study participation 
entirely (withdrawal of informed consent).
A schematic of the overall study design is shown in Figure 1.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
23
Figure 1.
Study Design


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
24
Screening Period
Within 35 days prior to the Baseline Visit, subjects will receive a full explanation of the 
study design and study procedures, provide a written informed consent, and undergo the 
screening procedures outlined in Table 2.  Lab values can be re-tested once during the 
screening period.
Beginning at the Screening Visit, twice daily use of an additive-free, bland emollient is 
required for at least 7 days prior to Baseline and during the study. 
Subjects that initially screen fail for the study are permitted to re-screen once following 
re-consent.  For additional re-screening, AbbVie Therapeutic Area Medical/Scientific 
Director approval is required.  These cases must be brought to the attention of the AbbVie 
Therapeutic Area Scientific Director who will discuss with the AbbVie Medical Director 
as needed and provide a recommendation.
All screening procedures with the possible exceptions noted below will be repeated during 
re-screening.  The subject must meet all the inclusion and none of the exclusion criteria at 
the time of re-screening in order to qualify for the study.  There is no minimum period of 
time a subject must wait to re-screen for the study.  If the subject had a complete initial 
screening evaluation including the assessment of an Interferon-Gamma Release Assay 
(IGRA; QuantiFERON Tuberculosis [TB] Gold In Tube test) or a purified protein 
derivative (PPD) test (or equivalent), or chest x-ray and electrocardiogram (ECG), these 
tests will not be required to be repeated for re-screening provided the conditions noted in 
Section 5.2 are met and no more than 90 days have passed.
Period 1:  16-Week Treatment Period
Period 1 will begin at the Baseline Visit (Day 1) and will end at the Week 16 Visit.  At the 
Baseline Visit, subjects who meet all the inclusion criteria and none of the exclusion 
criteria described in Section 5.2.1 and Section 5.2.2 will be enrolled into the study and 
randomized to double-blind treatment.  During Period 1 of the study, subjects will visit 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
25
the study site at Baseline, Weeks 2, 4, 8, 12, and 16.  A ± 3 day window is permitted 
around scheduled study visits.  Subjects will start on their respective dose at Baseline.  
Twice daily use of an additive-free, bland emollient is required throughout Period 1.
Period 2:  72-Week Treatment Period
Period 2 will begin after the Week 16 Visit and will end at the Week 88 Visit.  At the 
Week 16 Visit, subjects will be re-randomized as described in Section 5.1.  During 
Period 2 of the study, subjects will visit the study site at Weeks 20, 24, 32, 40, 52, 64, 76, 
and 88.  A ± 5 day window is permitted around scheduled study visits.  Subjects will start 
on their assigned treatment at the Week 16 visit.
The last dose of study drug is taken the day prior to the Week 88 visit.
Twice daily use of an additive-free, bland emollient is required throughout Period 2.
Discontinuation of Study Drug and Continuation of Study Participation
Subjects may discontinue study drug treatment, but may choose to continue to participate 
in the study (refer to Section 5.4.1 for additional details).  Subjects who prematurely 
discontinue study drug should complete a Premature Discontinuation Visit (PD visit) as 
soon as possible, preferably within 2 weeks.  Afterwards, subjects should follow the 
regular visit schedule as outlined in Table 2 and adhere to all study procedures except for 
dispensing study drug, PK sample collection, and blood and skin biopsy sample collection 
for optional exploratory research and validation studies.  In addition, all future rescue and 
efficacy-driven discontinuation criteria no longer apply.
In Period 1, discontinuation from study drug will be mandatory for any subject with an 
EASI score worsening of 25% or more compared with their Baseline EASI score at any 
2 consecutive scheduled study visits from Week 4 to Week 12.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
26
In Period 2, discontinuation from study drug will be mandatory for subjects with 
< EASI 50 response compared with their Baseline EASI score 4 weeks following rescue 
with topical corticosteroids or at any visit thereafter.
Premature Discontinuation of Study (Withdrawal of Informed Consent) 
Subjects may withdraw from the study completely (withdrawal of informed consent) for 
any reason at any time (refer to Section 5.4.2 for additional details).  If a subject 
prematurely discontinues study participation (withdrawal of informed consent), the 
procedures outlined for the Premature Discontinuation visit (PD visit) should be 
completed as soon as possible, preferably within 2 weeks of study drug discontinuation.  
In addition, if the subject is willing, a 30-day follow-up visit (or phone call if a visit is not 
possible) may occur to determine the status of any ongoing AEs/SAEs or the occurrence 
of any new AEs/SAEs.
Follow-Up Period
Subjects who prematurely discontinue the study or complete the study will have a 
follow-up visit (or phone call if a visit is not possible) approximately 30 days after the last 
administration of study drug to obtain information on any new or ongoing AEs, and to 
collect vital signs and clinical laboratory tests.
5.2
Selection of Study Population
It is anticipated that approximately 160 adult subjects with moderate to severe atopic 
dermatitis will be randomized at approximately 45 study centers globally.
A subject may be enrolled in this study provided that he/she has met all of the inclusion 
criteria and none of the exclusion criteria specified in this protocol.
5.2.1
Inclusion Criteria
1.
Adult male or female, ≥ 18 and ≤ 75 years old at Screening.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
27
2.
Atopic dermatitis with a diagnosis confirmed by a dermatologist (according to the 
Hanifin and Rajka criteria); and also onset of symptoms at least 1 year prior to 
baseline.
3.
Moderate to severe AD defined by an EASI ≥ 16, BSA ≥ 10% and an IGA score 
≥3 at the Baseline visit.
4.
Documented history (within 1 year prior to the screening visit) of inadequate 
response to treatment with topical corticosteroids (TCS), or topical calcineurin 
inhibitors (TCI), or for whom topical treatments are otherwise medically 
inadvisable (e.g., because of important side effects or safety risks).
5.
Twice daily use of an additive-free, bland emollient for at least 7 days prior to 
Baseline.
6.
A negative serum pregnancy test for all female subjects at the Screening Visit and a 
negative urine pregnancy test for all female subjects of childbearing potential at the 
Baseline Visit prior to administration of first dose of study drug.  Note:  subjects 
with borderline pregnancy test at Screening must have a serum pregnancy test 
≥3 days later to document continued lack of a positive result.
7.
If female, subject must be postmenopausal OR permanently surgically sterile OR 
for Women of Childbearing Potential practicing at least one protocol specified 
method of birth control (Section 5.2.4), that is effective from the Baseline visit 
through at least 30 days after the last dose of study drug.  
If male and subject is sexually active with a female partner(s) of childbearing 
potential, he must practice the protocol specified contraception from the Baseline 
visit through at least 30 days after last dose of study drug (Section 5.2.4).
Additional local requirements may apply.  Refer to Appendix P for local 
requirements in Canada.
8.
Subjects must voluntarily sign and date an informed consent, approved by an 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to 
the initiation of any screening or study-specific procedures.  For subjects in Japan 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
28
only:  if a subject is under 20 years of age, then the subject and their parent or legal 
guardian must voluntarily sign and date an informed consent.
Rationale for Inclusion Criteria
1 – 5
To select the appropriate subject population
6 – 7
The impact of ABT-494 on pregnancy and reproduction is unknown
8
In accordance with harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
1.
Prior exposure to any systemic or topical JAK inhibitor (including but not limited 
to tofacitinib, baricitinib, ruxolitinib, and filgotinib).
2.
Treatment with topical corticosteroids (TCS), topical calcineurin inhibitors (TCI), 
prescription moisturizers or moisturizers containing additives such as ceramide, 
hyaluronic acid, urea, or filaggrin within 10 days prior to the Baseline visit.
3.
Prior exposure to dupilumab. 
4.
Prior exposure to any investigational systemic treatment within 30 days or 
5 half-lives (whichever is longer) of the Baseline visit or is currently enrolled in 
another clinical study.
5.
Treatment with omalizumab within 3 months prior to the Baseline visit.
6.
Prior exposure to systemic therapy for AD, including but not limited to 
corticosteroids, methotrexate, cyclosporine, azathioprine, phosphodiesterase type 4 
(PDE4)-inhibitors and mycophenolate mofetil within 4 weeks prior to the Baseline 
visit.
7.
Use of traditional Chinese medicine within 4 weeks prior to the Baseline visit.
8.
Subject with other active skin diseases or skin infections (bacterial, fungal, or viral) 
requiring systemic treatment within 4 weeks of the Baseline visit or would interfere 
with the appropriate assessment of AD lesions. 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
29
9.
Phototherapy treatment, tanning booth, or extended sun exposure that could affect 
disease severity or interfere with disease assessments within 4 weeks prior to the 
Baseline visit and during the study.
10.
Current or past history of infection including: 
●
History of recurrent or disseminated (even a single episode) herpes zoster; 
●
History of disseminated (even a single episode) herpes simplex;
●
History of known invasive infection (e.g., listeriosis and histoplasmosis); 
●
Known immunodeficiency syndrome;
●
Subject has active TB or meets TB exclusionary parameters (refer to 
Section 5.3.1.1 for specific requirements for TB testing);
●
Non-skin related active infection(s) requiring treatment with parenteral anti-
infectives within 30 days, or oral anti-infectives within 14 days prior to the 
Baseline Visit.
●
Chronic recurring infection and/or active invasive infection (e.g., listeriosis 
and histoplasmosis) and viral infection that based on the investigator's clinical 
assessment makes the subject an unsuitable candidate for the study;
●
Active HBV, HCV, or HIV defined as:
○
HBV:  hepatitis B surface antigen (HBs Ag) positive (+) or detected 
sensitivity on the HBV deoxyribonucleic acid (DNA) polymerase chain 
reaction (PCR) qualitative test for hepatitis B core antibody (HBc Ab) 
positive subjects (and for Hepatitis B surface antibody positive [+] subjects 
in Japan only);
○
HCV:  HCV ribonucleic acid (RNA) detectable in any subject with anti-
HCV antibody (HCV Ab).
○
HIV: confirmed positive anti-HIV antibody (HIV Ab) test.
11.
Underlying medical diseases or problems including but not limited to the 
following: 
●
Clinically relevant or significant ECG abnormalities, including ECG with QT 
interval corrected for heart rate (QTc) using Friedericia's correction formula 
(QTcF) > 500 msec.;


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
30
●
History of moderate to severe congestive heart failure (New York Heart 
Association class III or IV), recent (within past 6 months) cerebrovascular 
accident, myocardial infarction, or coronary stenting, or uncontrolled 
hypertension as defined by a confirmed systolic blood pressure > 160 mmHg 
or diastolic blood pressure > 100 mmHg;
●
Subject has been a previous recipient of an organ transplant;
●
History of gastrointestinal perforation, diverticulitis or significantly increased 
risk for GI perforation per investigator judgment;
●
Conditions that could interfere with drug absorption including but not limited 
to short bowel syndrome; 
●
History of any malignancy except for successfully treated NMSC or localized 
carcinoma in situ of the cervix;
●
History of clinically significant medical conditions or any other reason which 
in the opinion of the investigator would interfere with the subject's 
participation in this study or would make the subject an unsuitable candidate to 
receive study drug or would put the subject at risk by participating in the 
protocol; or permanently wheelchair-bound or bedridden or very poor 
functional status which prevents the ability to perform self-care.
12.
Systemic use of known strong cytochrome P450 (CYP) 3A inhibitors or strong 
CYP3A inducers from Screening through the end of the study (refer to Table 1 for 
examples of commonly used strong CYP3A inhibitors and inducers).
13.
Receipt of any live vaccine within 4 weeks (8 weeks in Japan) prior to the Baseline 
Visit, or expected need of live vaccination during study participation including at 
least 4 weeks after the last dose of study drug. 
14.
History of an allergic reaction or significant sensitivity to constituents of the study 
drugs and/or other products in the same class.
15.
History of clinically significant (per Investigator's judgment) drug or alcohol abuse 
within the last 6 months preceding the Baseline Visit.
16.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant 
during the study or for approximately 30 days after the last dose of study drug.  


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
31
17.
Male subject who is considering fathering a child or donating sperm during the 
study or for approximately 30 days after the last dose of study drug.
18.
Laboratory values meeting the following criteria within the Screening period prior 
to the first dose of study drug (Baseline Visit):
●
Serum aspartate transaminase (AST) > 2 × ULN;
●
Serum alanine transaminase (ALT) > 2 × ULN;
●
Estimated glomerular filtration rate (GFR) by simplified 4-variable 
Modification of Diet in Renal Disease (MDRD) formula 
< 40 mL/min/1.73 m2;
●
Total white blood cell count (WBC) < 2,500/μL;
●
Absolute neutrophil count (ANC) < 1,500/μL;
●
Platelet count < 100,000/μL;
●
Absolute lymphocyte count < 800/μL; 
●
Hemoglobin < 10 g/dL.
19.
Consideration by the Investigator, for any reason, that the subject is an unsuitable 
candidate to receive ABT-494 (upadacitinib) or participate in this study.
20.
For subjects in Japan only:  Positive result of beta-D-glucan (screening for 
pneumocystis jiroveci infection).
Rationale for Exclusion Criteria
1 – 7, 9
To select the appropriate subject population
8, 10 – 15, 18 – 20
To ensure safety of the subjects throughout the study
16, 17
ABT-494 is teratogenic in both rats and rabbits.  The impact of 
ABT-494 on pregnancies is unknown
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements including folic acid) that the subject is receiving 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
32
within 28 days prior to Screening, or receives during the study, must be recorded along 
with the reason for use, date(s) of administration including start and end dates, and dosage 
information including dose, route, and frequency on the appropriate electronic case report 
form (eCRF).  
Vaccines recommended by local guidelines should be considered.  If the investigator 
chooses to administer a vaccine, this should be completed before first dose of study drug 
with appropriate precautions and time interval.  It is recommended that subjects be up to 
date for recommended vaccines that are inactivated, toxoid or biosynthetic vaccines, such 
as injectable flu vaccine, pneumococcal, and pertussis (Tdap).  It is recommended that the 
live herpes zoster vaccine be considered for administration at least 4 weeks (8 weeks in 
Japan) before the first dose of study drug in subjects greater than 50 years of age (per 
label).  If the herpes zoster vaccine is to be administered pre-existing immunity should be 
confirmed antibody testing at or prior to screening and prior to administration of the 
herpes zoster vaccine. If screening varicella antibody testing is negative the herpes zoster 
vaccine should not be administered.  See Section 5.2.3.3 for a list of commonly used live 
vaccines.
If there are any questions regarding concomitant or prior therapies the AbbVie 
Therapeutic Area Scientific Director should be contacted who will then discuss with the 
AbbVie Medical Director and provide a recommendation.
5.2.3.1
Prior Therapy
Any systemic treatments for AD since initial diagnosis (as determined through medical 
history records or through subject or parent or legal representative interview) and any 
prescribed treatments for AD prior to study entry will be recorded on the eCRF.  For 
subjects previously treated with systemic agents, the duration of therapy, maximum dose, 
and reason(s) for termination of treatment with should be documented.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
33
5.2.3.2
Permitted Background and Concomitant Therapy
Beginning at the Screening Visit, twice daily use of an additive-free, bland emollient is 
required for at least 7 days prior to Baseline and during the study.
Oral antibiotics for up to 2 weeks for AD-associated superficial skin infections are 
allowed and will be captured as concomitant therapy.
5.2.3.3
Prohibited Therapy
Non-Biologic Systemic Therapies
JAK Inhibitors
Prior and concomitant oral and topical exposure to any other JAK inhibitors besides the 
investigational drug, ABT-494 (including but not limited to ruxolitinib, tofacitinib, 
baricitinib, and filgotinib) is not allowed.
Other Non-Biologic Systemic Therapy
Systemic therapy for the treatment of AD is not allowed during the study, including but 
not limited to: 
●
methotrexate, 
●
cyclosporine, 
●
azathioprine, 
●
PDE4-Inhibitors, 
●
mycophenolate mofetil.
Corticosteroids
Oral, parenteral, and intralesional corticosteroids are NOT allowed during the study.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
34
Biologic Therapies
All prior and concomitant targeted biologic therapies are prohibited during the study.  
Examples of targeted biologic therapies include but are not limited to the following:
●
Zolair (omalizumab);
●
Dupilumab;
●
Adalimumab;
●
Etanercept;
●
Infliximab;
●
Abatacept;
●
Anakinra;
●
Rituximab;
●
Natalizumab;
●
Efalizumab;
●
Tocilizumab;
●
Golimumab;
●
Certolizumab;
●
Ustekinumab;
●
Belimumab;
●
Secukinumab;
●
Denosumab
Phototherapy, Tanning Booth, and Extended Sun Exposure
UVB or UVA phototherapy including PUVA for at least 4 weeks prior to the Baseline 
visit and during the study.
Tanning booth use or extended sun exposure that could affect disease severity or interfere 
with disease assessments for at least 4 weeks prior to the Baseline visit and during the 
study.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
35
Topical Therapy
No topical treatments for AD, including but not limited to calcineurin inhibitors, 
corticosteroids, prescription moisturizers or moisturizers containing additives such as 
ceramide, hyaluronic acid, urea, or filaggrin, should be started during the course of the 
study; except for rescue treatment allowed in Period 2 (see Section 5.2.3.4).
Investigational Drugs
Subjects who have been treated with any investigational drug within 30 days or 
five half-lives of the drug (whichever is longer) prior to the first dose of study drug are 
excluded from participation in this study.  Investigational drugs are also prohibited during 
the study.
Vaccines
Although not mandated by the protocol, vaccines recommended by local guidelines 
should be considered.  If the subject and investigator choose to administer live vaccines, 
these vaccinations must be completed per local label or at least 4 weeks (8 weeks in 
Japan), whichever is longer, before the first dose of study drug with appropriate 
precautions.  Live vaccines are NOT allowed during study participation and including up 
to 4 weeks after the last dose of study drug.  Examples of live vaccines include, but are 
not limited to, the following:
●
Monovalent live influenza A (H1N1) (intranasal);
●
Seasonal trivalent live influenza (intranasal);
●
Herpes zoster;
●
Rotavirus;
●
Varicella (chicken pox);
●
Measles-mumps-rubella or measles mumps rubella varicella;
●
Oral polio vaccine;
●
Smallpox;
●
Yellow fever;


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
36
●
Bacille Calmette-Guérin (BCG);
●
Typhoid.
Examples of common vaccines that are inactivated, toxoid or biosynthetic, include but are 
not limited to:  injectable influenza vaccine, pneumococcal and, pertussis ((Tdap) 
vaccines).
Cannabis
Concomitant use of medicinal and recreational cannabis is prohibited during the study.  
Strong CYP3A Inhibitors or Inducers
Systemic use of known strong CYP3A inhibitors or strong CYP3A inducers is excluded 
from the Screening Visit through the end of the study.  The most common strong CYP3A 
inhibitors and inducers are listed in Table 1.
Traditional Chinese Medicine
Traditional Chinese medicine is not permitted during the study, and subjects must have 
discontinued all traditional Chinese medicines at least 4 weeks prior to the first dose of 
study drug.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
37
Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and 
Inducers
Strong CYP3A Inhibitors 
Strong CYP3A Inducers
Boceprevir
Avasimibe
Clarithromycin
Carbamazepine
Conivaptan
Phenytoin
Grapefruit (fruit or juice)
Rifampin
Indinavir
St. John's Wort
Itraconazole
Ketoconazole
Lopinavir/Ritonavir
Mibefradil
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Voriconazole
5.2.3.4
Rescue Therapy
For subjects re-randomized to placebo, ABT-494 7.5 mg QD or ABT-494 15 mg QD in 
Period 2, blinded rescue therapy with ABT-494 30 mg QD will be provided after the 
first instance of a < EASI 50 response starting at the Week 20 visit (4 weeks after 
re-randomization into Period 2).  These subjects will continue on ABT-494 30 mg QD for 
the remainder of the study. 
During Period 2, concomitant class III – IV, medium potency topical corticosteroid 
treatment will be permitted at the Week 24 visit and thereafter in subjects after a second 
instance of < EASI 50 response in any two Period 2 study visits beginning from Week 20.  
For subjects who receive topical corticosteroid rescue therapy, an additional visit will be 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
38
required 4 weeks after receiving topical corticosteroid rescue therapy.  Discontinuation 
from study drug will be mandatory for subjects with < EASI 50 response compared with 
their Baseline EASI score 4 weeks following rescue with topical corticosteroids or at any 
visit thereafter.  
Topical treatment allowed is limited to up to twice daily triamcinolone acetonide 0.1% 
cream or up to once daily mometasone furoate 0.1% cream.  Use of a topical 
corticosteroid treatment should be recorded on the appropriate concomitant medication 
eCRF.
5.2.4
Contraception Recommendations 
Contraception Recommendation for Females
A woman who is postmenopausal or permanently surgically sterile (bilateral 
oophorectomy, bilateral salpingectomy or hysterectomy) is not considered to be a woman 
of childbearing potential and is not required to follow contraception recommendations.
Postmenopausal is defined as:
●
Age ≥ 55 years with no menses for 12 or more months without an alternative 
medical cause; or 
●
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.
If the female subject is < 55 years of age:
AND has had no menses for ≥ 12 months AND has no history of permanent surgical 
sterilization (defined above), FSH should be tested at Screening.
●
If FSH is not tested, it is assumed that the subject is of childbearing potential 
and protocol-specified contraception is required.
●
If the FSH is tested and the result is consistent with post-menopausal status, 
contraception is not required.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
39
●
If the FSH is tested and the result is consistent with pre-menopausal status, 
contraception is required, and a serum pregnancy test must be performed (see 
Section 5.3.1.1 pregnancy test).
For a female subject at any age:
●
Female subjects with menses within the past 12 months are of childbearing 
potential and FSH is therefore not required but contraception is required.
●
Female subject who are surgically sterile (defined above) are not of 
childbearing potential and therefore no FSH testing or contraception is 
required.
A woman who does not meet the definition of postmenopausal or permanently surgically 
sterile is considered of childbearing potential and is required to practice at least one of the 
following highly effective methods of birth control that is effective from Study Day 1 (or 
earlier) through at least 30 days 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 30 days prior to Baseline Visit.
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 30 days prior to 
Baseline Visit. 
●
Bilateral tubal occlusion/ligation (Japan only:  bilateral tubal ligation only).
●
Vasectomized partner(s) provided the vasectomized partner has received 
medical confirmation of the surgical success and is the sole sexual partner of 
the women of childbearing potential trial participant.
●
Intrauterine device (IUD). 
●
Intrauterine hormone-releasing system (IUS).
●
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).


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
40
If required per local practices, male or female condom with or without spermicide OR 
cap, diaphragm or sponge with spermicide should be used in addition to one of the birth 
control methods listed above (excluding true abstinence). 
Additional local requirements may apply.  Refer to Appendix P for local requirements in 
Canada.
Contraception Recommendation for Males
For a male subject who has a female partner who is postmenopausal or permanently 
sterile, no contraception is required.
A male subject who is sexually active with female partner(s) of childbearing potential 
must agree from Study Day 1 through 30 days after the last dose of study drug to practice 
contraception with:
●
Condom use and female partner(s) using at least one of the contraceptive 
measures (as defined in the protocol for female study subjects of childbearing 
potential). 
OR
●
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] 
and withdrawal are not acceptable).
Additionally, male subjects must agree not to donate sperm from the Baseline Visit 
through 30 days after the last dose of study drug. 
Male subjects are responsible for informing his partner(s) of the risk of becoming 
pregnant and for reporting any pregnancy to the study doctor.  If a pregnancy occurs, a 
partner authorization form requesting pregnancy outcome information will be requested 
from the pregnant partner.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
41
It is important to note that contraception recommendations described above are 
specifically intended to prevent pregnancy during exposure to the investigational 
therapies. 
Additional local requirements may apply.  Refer to Appendix P for local requirements in 
Canada.
5.3
Efficacy, Pharmacokinetic, Specific Cellular 
Pharmacodynamic Changes, Exploratory Research and 
Validation Studies, 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 Table 2.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
42
Table 2.
Study Activities
Activity
Screening
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk
16
Wk 
20
Wk 
24
Wk 
32
Wk
40 
Every 
12 Weeksx
or PDa
4 Weeks 
Post 
Topical 
Rescue 
Visity
30-Day 
F/U 
Visita
D –35 to D –1
D1b
D15
D29
D57
D85
D113
D141
D169
D225
D281 D365 – D617
Informed consentc
X
Inclusion/exclusion criteria
X
X
EASI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BSA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IGA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SCORAD
X
X
X
X
X
X
X
X
X
X
X
X
X
Alcohol and nicotine use
X
Patient questionnairesd DLQI 
X
X
X
X
X
Patient questionnairesd Daily Pruritus 
NRS, PGIS, ADerm-SS, and ADerm-IS
X
X
X
X
X
X
X
X
X
X
X
X
Xd
Patient questionnairesd MOS Sleep 
Scale POEM
X
X
X
X
X
Xd
X
Patient questionnairesd,e Asthma 
Symptoms and Daytime Nasal 
Symptoms
X
X
X
X
Actigraphy Device Download
X
X
X
X
X
X
Medical/surgical historyf
X
X


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
43
Table 2.
Study Activities (Continued)
Activity
Screening
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk
16
Wk 
20
Wk 
24
Wk 
32
Wk
40 
Every 
12 Weeksx
or PDa
4 Weeks 
Post 
Topical 
Rescue 
Visity
30-Day 
F/U 
Visita
D –35 to D –1
D1b
D15
D29
D57
D85
D113
D141
D169
D225
D281 D365 – D617
AE assessmentg
Only SAEs and 
Protocol-
related 
nonserious AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior/concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Latent TB risk factor questionnaireh
X
Central lab QuantiFERON-TB Gold test 
(or local PPD skin test)h
X
Chest x-rayi
X
12-lead ECGj
X
X
Height (screening only) and weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signsk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examl
X
X
X
X
X
X
Serum pregnancy test at central labm
X
X
Xm
Pregnancy testn,o
X
X
X
X
X
X
X
X
X
X
X
X
X
Lab Tests 
hsCRPp
Blood chemistryq
Hematology (CBC) 
Urinalysisr
X
X
X
X
X
X
X
X
X
X
X
X
X
X


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
44
Table 2.
Study Activities (Continued)
Activity
Screening
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk
16
Wk 
20
Wk 
24
Wk 
32
Wk
40 
Every 
12 Weeksx
or PDa
4 Weeks 
Post 
Topical 
Rescue 
Visity
30-Day 
F/U 
Visita
D –35 to D –1
D1b
D15
D29
D57
D85
D113
D141
D169
D225
D281 D365 – D617
HIVt/HBV/HCV screenings
X
Xs
Xs
Blood samples for ABT-494 PK assay
Xu
Xu
Xv
Xv
Xv
Xv
Xv
Xv
Xv
Xv
Blood samples for TBNK 
immunophenotyping
X
X
X
X
Blood samples for exploratory research 
and validation studies (optional for 
some sites – see table for optional 
samples below)w
X
X
X
X
X
Skin biopsies for exploratory research 
and validation studies (optional for 
some sites – see Table 3 for optional 
samples below)w
X
X
X
Study Drug Dispensing/Administration
X
X
X
X
X
X
X
X
X
Xz
Dispense hand-held ePRO (includes 
subject diary) and actigraphy device
X
Subject Diary Review
X
X
X
X
X
X
X
X
X


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
45
Table 2.
Study Activities (Continued)
ADerm-IS = Atopic Dermatitis Impact Scale; ADerm-SS = Atopic Dermatitis Symptom Scale; BL = Baseline Visit; BSA = body surface area; CBC = complete blood count; 
D = Day; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; ECG = electrocardiogram; F/U = Follow-Up; HBV = hepatitis B virus; 
HCV = hepatitis C virus; HIV = human immunodeficiency virus; hsCRP = high-sensitivity C reactive protein; IGA = Investigator's Global Assessment; MOS = Medical Outcomes 
Study; NRS = Numerical Rating Scale (for pruritus); PD = Premature Discontinuation; PGIS = Patient Global Impression of Severity; PK = pharmacokinetics; POEM = Patient 
Oriented Eczema Measure; PPD = purified protein derivative; PtGA = Patient's Global Assessment; SAE = serious adverse event; SCORAD = Scoring atopic dermatitis; 
TB = tuberculosis; Wk = Week
a.
This visit is 30 days (± 3 days) after last dose of study drug.  For those subjects who prematurely discontinue the study, if the subject is willing, a 30-day follow-up visit (or 
phone call if a visit is not possible) may occur to determine the status of any ongoing AEs/SAEs or the occurrence of any new AEs/SAEsy.  If a subject is discontinued from 
study drug, the procedures outlined for the Premature Discontinuation visit (PD visit) should be completed as soon as possible, preferably within 2 weeks of study drug 
discontinuation.
b.
The Baseline visit procedures will serve as the reference for all subsequent visits with the exception of the ECG which will be obtained at Screening only and used as the 
baseline reference.
c.
Obtain prior to performing any study-related procedures. 
d.
Prior to other procedures; except for the questionnaires on the electronic hand-held device given to subjects to take home at Screening: daily Pruritus NRS, 
 
ADerm-SS and ADerm-IS Hand-held device usage stops at the Week 40 visit.  Starting at the Week 52 visit, the questionnaires on the hand-held device (Pruritus NRS, 
ADerm-SS and ADerm-IS) will be given on the tablet during site visits.  The MOS Sleep Scale questionnaire will stop at the Week 40 visit.  The PGIS, POEM and DLQI 
questionnaires will be given on the tablet at site visits throughout the study.
e.
Asthma Symptoms and Daytime Nasal Symptoms questionnaires are collected only for subjects with symptoms of asthma or rhinitis, respectively, at Screening and stop at the 
Week 40 visit.
f.
Also note herpes zoster and hepatitis B vaccination status in medical history.
g.
Collect SAEs and protocol-related nonserious AEs that occur after a subject signs the informed consent, prior to the first dose of study drug.
h.
Refer to Section 5.3.1.1 Study Procedures TB Testing for specific requirements for TB testing and TB prophylaxis.
i.
The screening chest x-ray will not be required if a subject had a previous normal chest-x-ray within 90 days of Screening, provided that all source documentation is available 
at the site.
j.
For subjects with a normal ECG taken within 90 days of Screening, a repeat ECG at Screening will not be required, provided all source documentation is available.
k.
Blood pressure, pulse rate, body temperature, and respiratory rate should be performed before blood draws are performed.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
46
Table 2.
Study Activities (Continued)
l.
A full physical exam is required at the visits indicated.  A symptom-directed physical exam may be performed when necessary.
m.
For all females, collect serum for pregnancy test at screening and the Week 88 or PD visit.  If serum pregnancy test comes back indeterminate or positive, a repeat test is 
necessary (pregnancy is an exclusion criterion); see Section 5.3.1.1 and Section 6.1.6 for details.
n.
Urine pregnancy test will be performed locally at every visit for all women of childbearing potential.  If urine pregnancy test (which is performed at the site) is negative, begin 
or continue dosing.  If urine pregnancy test is positive, withhold dosing and perform a serum pregnancy test.  Pregnant subjects must discontinue from the study.
o.
If time between visits is longer than 1 month, then collect the results of the monthly at home urine pregnancy test between scheduled visits (see Section 5.3.1.1).  If a urine 
pregnancy test is positive, the subject must stop dosing, come in to the clinic and have blood drawn for a serum pregnancy test that will be analyzed at the central laboratory.  
A pregnant or breastfeeding female will not be eligible for participation or continuation in this study.  The monthly at home tests between scheduled on-site visits are to occur 
at Weeks 28 and 36; unless an on-site visit is necessary due to rescue therapy with topical corticosteroids per Section 5.2.3.4.
p.
hsCRP results will remain blinded to the Sponsor, Investigator, study site personnel, and subject for all visits except Screening.  Investigators should refrain from locally and 
periodically testing hsCRP and serum amyloid A.  Investigators should also refrain from locally testing procalcitonin except for safety evaluations of signs and symptoms of 
infection or adverse events.
q.
Minimum 8-hour fast.  If a subject is not able to fast when necessary, due to unforeseen circumstances, the non-fasting status will be recorded in study source documentation.
r.
A urine dipstick macroscopic urinalysis will be completed by the central laboratory at all required visits.  A microscopic analysis will be performed in the event the dipstick 
results show leukocytes, nitrite, protein, ketones, or blood greater than negative or glucose greater than normal.
s.
For Japan only:  for subjects with HBs Ab+ and/or HBc Ab+ at Screening, the HBV-DNA PCR test should be performed again at Week 12 and Week 24.  In cases where the 
recurrence of HBV-DNA is observed, the subject should be discontinued from the study drug.  Retesting at Week 12 and Week 24 is not necessary for subjects that have a 
history of HBV vaccine and are HBs Ab+.
t.
HIV testing will be performed at Screening.  The Investigator must discuss any local reporting requirements to local health agencies with the subject.  The site will report 
confirmed positive results to their health agency per local regulations, if necessary.  If the result is confirmed as positive, then the Investigator will discuss with the subject 
potential implications to the subject's health and next steps.  If a subject has a confirmed positive result, the Investigator must discuss with the subject the potential 
implications to the subject's health and subject should receive or be referred for clinical care promptly.  This testing is to be done at the central lab.  A subject will not be 
eligible for study participation if test results indicate a positive HIV infection.  AbbVie will not receive results from the testing and will not be made aware of any positive 
result.
u.
At Week 2 and Week 4 visits, PK samples should be collected prior to dosing and the subjects should take the study drug dose at the clinic after collecting the PK blood 
sample.  However, if the subject normally takes the study drug dose at a time that is after the time of the scheduled study visit, the subject should follow the regular dosing 
schedule and the PK sample will be collected at any time during the visit.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
47
Table 2.
Study Activities (Continued)
v.
PK samples will be collected at any time during the visit.  Subject should follow the regular dosing schedule.
w.
Samples only collected if subject provides written consent.  Subjects should be in fasting condition (8 hours, except for water) prior to samples collection.  For selected sites, 
these assessments (blood samples and skin biopsies collection) will be made mandatory as part of the main study.
x.
Visits are every 12 weeks from the Week 40 visit to the Week 88 visit (Wk 52, Wk 64, Wk 76, and Wk 88).
y.
A visit will be required 4 weeks after receiving topical rescue therapy.  After this visit, patients will continue to follow the standard protocol visit schedule, as applicable from 
that date (Wk 32, Wk 40, Wk 52, Wk 64, Wk 76, and Wk 88).
z.
Study Drug Dispensing stops at the Week 76 visit.
Note 1:
Visit window is ± 3 days for Period 1 (Weeks 2, 4, 8, 12 and 16) and ± 5 days for Period 2 (Weeks 20, 24, 32, 40, 52, 64, 76 and 88) and a visit 4 weeks following 
topical rescue if applicable.  Any of the procedures may be performed at an unscheduled visit at the discretion of the investigator.  Subjects who choose to 
discontinue study drug treatment, but continue to participate in the study, should complete a Premature Discontinuation Visit (PD Visit) as soon as possible, 
preferably within 2 weeks.  Afterwards, subjects should follow the regular visit schedule and adhere to all study procedures except for dispensing study drug, 
PK sample collection, and blood and skin sample collection for exploratory research and validation studies.  In addition, all future rescue and efficacy-driven 
discontinuation criteria no longer apply.
Note 2:
Twice daily use of an additive-free, bland emollient is required for at least 7 days prior to Baseline and during the study.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
48
Table 3.
Study Activities – Optional and Mandatory Samples for Exploratory Research and Validation Studies
Activity
Screening
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
32
Wk 
40
Every 
12 Weeks 
or PDa
4 Weeks 
Post 
Topical 
Rescue 
Visit
30-
Day 
F/U 
Visit
D –30 to 
D –1
D1
D15
D29
D57
D85
D113
D141
D169
D225
D281 
D365 –
D617
Pharmacogenetic samplesa
X
Epigenetic samplesa
X
X
X
X
X
Transcriptomic and epigenetic samplesa
X
X
X
X
X
Plasma samples for analyses including, but 
not limited to, proteomic and targeted 
protein investigationsa
X
X
X
X
X
Serum samples for analyses including, but 
not limited to, proteomic and targeted 
protein investigationsa
X
X
X
X
X
Sample for PBMC assaysa
X
X
X
Skin Biopsies for analyses including, but 
not limited to, epigenetics, 
transcriptomics, proteomics, 
immunohistochemistry` and targeted 
investigationsa,b
X
X
X
BL = Baseline Visit; D = Day; F/U = Follow-Up; PBMC = Peripheral Blood Mononuclear Cell; PD = Premature Discontinuation; Wk = Week
a.
Based on the value of the different technologies, samples may also be used to assess other biomarker signatures, including but not limited to metabolomics, lipidomics, and 
other approaches.  Samples may be used for assay of study drugs if needed.
b.
Subjects may still participate in the optional exploratory research/validation studies if they decide not to participate in this optional collection of biopsies.  In selected sites all 
samples in Table 3, including biopsies, will be made mandatory as part of the main study.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
49
Table 3.
Study Activities – Optional and Mandatory Samples for Exploratory Research and Validation Studies 
(Continued)
Note 1:
Collections to be performed only if subject provides separate written consent to collect the exploratory research/validation studies samples; if the consent is not 
signed, no samples can be collected.  It is preferred that the subject has fasted (8 hours, except for water) prior to sample collection, however it is not required.  
It must be recorded whether the subject has fasted or not at the time of collection.
Note 2:
Selected sites will be asked to perform a complete investigation of biomarkers.  For such sites, all samples in Table 3 will be made mandatory as part of the 
main study.  There will be a specific ICF for subjects in these selected sites.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
50
5.3.1.1
Study Procedures
The study procedures outlined in Table 2 are discussed in detail in this section, with the 
exception of exploratory research and validation studies (discussed in Section 5.3.1.2), 
drug concentration measurements (discussed in Section 5.3.2), the collection of prior and 
concomitant medication information (discussed in Section 5.2.3), and the collection of AE 
information (discussed in Section 6.1.1).  All study data will be recorded in source 
documents and on the appropriate eCRFs.
Informed Consent
At the Screening visit, the subject will sign and date a study specific, IEC/IRB approved, 
informed consent form before any study procedures are performed or any medications are 
withheld from the subject in order to participate in this study.  Separate written consent 
will be required for each subject in order to participate in the optional exploratory 
research and validation studies.  Details regarding how informed consent will be obtained 
and documented are provided in Section 9.3.
Inclusion/Exclusion Criteria
Subjects will be evaluated to ensure they meet all inclusion criteria and have none of the 
exclusion criteria at both Screening and Baseline Visits.
Medical and Surgical History
A complete non-AD medical and surgical history, including history of alcohol and 
nicotine use, will be taken from each subject at the Screening visit.  
Additionally, a list of each subject's specific AD related medical and surgical history 
should be recorded at Screening.  History of clinical herpes zoster, herpes zoster 
vaccination, and hepatitis B vaccination status will be recorded as part of the medical 
history.  An updated medical history will be obtained prior to study drug administration at 
Baseline/Day 1, to ensure the subject is still eligible for enrollment. 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
51
A detailed medical history with respect to TB risk factors will be documented in the study 
source documentation.  This information will include BCG vaccination, cohabitation with 
individuals who have had TB, and travel to, residence in, or work in TB endemic 
locations.
Atopic Dermatitis Investigator Evaluations
Body Surface Area (BSA)
A qualified investigator should select the subject's right or left hand as the measuring 
device.  For purposes of clinical estimation, the total surface of the palm plus five digits 
will be assumed to be approximately equivalent to 1%.  Measurement of the total area of 
involvement by the physician is aided by imagining if scattered plaques were moved so 
that they were next to each other and then estimating the total area involved.  The site 
should make every attempt to have the same qualified Investigator or designee perform all 
BSA assessments on a given subject throughout the study and are to be performed as 
specified in Table 2.
Eczema Area and Severity Index (EASI)
A qualified investigator will perform the EASI assessment (Appendix E).  The site should 
make every attempt to have the same qualified Investigator or designee perform all EASI 
assessments on a given subject throughout the study, following the schedule in Table 2.
Investigator's Global Assessment for Atopic Dermatitis (IGA)
A qualified investigator will perform the IGA assessment (Appendix D).  The site should 
make every attempt to have the same qualified Investigator or designee perform all IGA 
assessments on a given subject throughout the study and are to be performed as specified 
in Table 2.
SCORing Atopic Dermatitis (SCORAD)
A qualified investigator will perform the SCORAD assessment (Appendix F).  The site 
should make every attempt to have the same qualified Investigator or designee perform all 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
52
SCORAD assessments on a given subject throughout the study and are to be performed as 
specified in Table 2; via an electronic tablet device provided to sites.
Patient Questionnaires
Subjects will complete the following questionnaires as specified in Table 2:
●
Dermatology Life Quality Index (DLQI) (Appendix G)
●
Daily Pruritus (itch) Numerical Rating Scale (NRS) (Appendix H)
●
Medical Outcomes Study (MOS) Sleep Scale (Appendix I)
●
Patient Oriented Eczema Measure (POEM) (Appendix J)
●
Asthma Symptoms Questionnaire (only for subjects with asthma symptoms) 
(Appendix K)
●
Daytime Nasal Symptoms Questionnaire (only for subjects with rhinitis 
symptoms) (Appendix L)
●
Atopic Dermatitis Symptom Scale (ADerm-SS) (Appendix M)
●
Atopic Dermatitis Impact Scale (ADerm-IS) (Appendix N)
●
Patient Global Impression of Severity (PGIS) (Appendix O)
All patient-reported outcomes (PROs) are collected electronically (discussed in 
Section 10.2).
The subject should complete the questionnaires before site personnel perform any clinical
assessments and before any interaction with clinical site personnel has occurred to avoid 
biasing the subject's response; except for the questionnaires on the electronic hand-held 
device (daily Pruritus NRS, 
 ADerm-SS and ADerm-IS).  
Hand-held device usage stops at the Week 40 visit.  Starting at the Week 52 visit, the 
questionnaires on the hand-held device (Pruritus NRS, ADerm-SS and ADerm-IS) will be 
given on the tablet during site visits.  The MOS Sleep Scale questionnaire will stop at the 
Week 40 visit.  The PGIS, POEM and DLQI questionnaires will be given on the tablet 
throughout the study as specified in Table 2.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
53
Asthma Symptoms and Daytime Nasal Symptoms questionnaires are collected only for 
subjects with symptoms of asthma or rhinitis, respectively, at Screening and stop at the 
Week 40 visit.
TB Testing
The TB screening tests are diagnostic test results to be interpreted in the context of the 
subject's epidemiology, history, exam findings, etc., and it is the responsibility of the 
Investigator to determine if a subject has previous, active, or latent TB.
All subjects will be assessed for evidence of increased risk for TB by a risk assessment 
form (Appendix C) and tested for TB infection by QuantiFERON-TB Gold Test.  The 
PPD Skin Test should be utilized only when a QuantiFERON-TB Gold Test is not 
possible for any reason (unless both tests are required per local guidelines).  The site staff 
will complete the TB risk assessment form and enter the data into an appropriate eCRF.
●
Preferred Method:  QuantiFERON-TB Gold Test will be analyzed by the 
central laboratory (QuantiFERON test is preferred over PPD skin test).
●
If QuantiFERON-TB Gold Test is NOT possible (or if both an Interferon-
Gamma Release Assays [IGRA] and PPD Skin Test are required per local 
guidelines): the PPD Skin Test (also known as a TB Skin Test) will be 
performed according to standard clinical practice.  The TB Skin Test should be 
read by a licensed healthcare professional between 48 and 72 hours after 
administration.  A subject who does not return within 72 hours will need to be 
rescheduled for another skin test.  The reaction will be measured in millimeters 
(mm) of induration and induration ≥ 5 mm for AD subjects is considered a 
positive reaction.  The absence of induration will be recorded as "0 mm" not 
"negative."  Subjects who have had an ulcerating reaction to the TB Skin Test 
in the past should not be re-exposed and should not be tested by a PPD skin 
test.
If a subject had a negative QuantiFERON-TB Gold (or PPD) test (or IGRA equivalent 
such as T-SPOT TB test) within 90 days prior to Screening and source documentation is 
available, the test does not need to be repeated, provided nothing has changed in the 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
54
subject's medical history to warrant a repeat test.  These cases must be brought to the 
attention of the AbbVie Therapeutic Area Scientific Director who will discuss with the 
AbbVie Medical Director and provide a recommendation.  The results of the TB test(s) 
will be retained at the site as the original source documentation.
In the event both a PPD test and a QuantiFERON-TB Gold test are performed, the result 
of the QuantiFERON-TB Gold test will supersede the result of the PPD test, unless 
otherwise required by local guidelines.  If the QuantiFERON-TB Gold test is 
indeterminate, the site should repeat the test with another blood sample.  If the second 
QuantiFERON-TB Gold test is also indeterminate, the subject is considered to be positive.
Subjects with a negative QuantiFERON®-TB Gold test (OR negative PPD TB skin test) 
and chest x-ray (CXR) not suggestive of active TB or prior TB exposure may be enrolled.  
Any positive TB screen after the subject has started the study, should be reported as an 
adverse event of latent TB (in the absence of an adverse event of active TB).
If the subject has evidence of a latent TB infection (QuantiFERON®-TB Gold test or the 
PPD test positive and the subject has a CXR not suggestive of active TB), prophylactic 
treatment must be initiated at least 2 weeks prior to administration of study drug (or per 
local guidelines, whichever is longer).  The prophylaxis needs to be completed; however, 
the full course of prophylaxis does not need to be completed prior to the first dose of 
study drug.  If the Investigator deems that it is necessary, consultation with a TB expert 
could be considered.
Of note:  Rifampicin is not allowed for TB prophylaxis.
Subjects with a prior history of latent TB that have documented completion of a full 
course of anti-TB therapy within 1 year prior to first study drug administration will be 
allowed to enter the study provided nothing has changed in the subject's medical history to 
warrant repeat treatment.
Subjects with a documented completion of a full course of anti-TB therapy greater than 
1 year prior to first study drug administration may be allowed to enter the study only after 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
55
consultation with the AbbVie Therapeutic Area Scientific Director who will discuss with 
the AbbVie Medical Director and provide a recommendation.
Newly initiated prophylactic treatment should be captured on the concomitant 
medications page in the eCRF and in the source documents.  Prior therapy should be 
captured in the eCRF.
Chest X-Ray (CXR)
A CXR (posterior-anterior and lateral views) is required for all subjects at Screening to 
rule out the presence of TB or other clinically relevant findings.  The CXR will not be 
required if the subject had a previous normal CXR (posterior-anterior and lateral views) 
within 90 days of Screening, provided all source documentation is available at the site as 
outlined below and provided nothing has changed in the subject's medical history to 
warrant a repeat test.  
Subjects can have a repeat CXR at any time during the study as warranted, based on the 
opinion of the Investigator.
Only qualified personnel must perform an assessment of the CXR.  The Principal 
Investigator will indicate the clinical significance of any findings and will sign and date 
the report.  In the assessment of the CXR, the Principal Investigator or their delegate must 
indicate the presence or absence of (1) calcified granulomas, (2) pleural 
scarring/thickening, and (3) signs of active TB.  If the CXR demonstrates changes 
suggestive of previous TB (e.g., calcified nodule, fibrotic scar, apical or basilar pleural 
thickening) or other findings that are clinically significant, the Investigator must contact 
the AbbVie Therapeutic Area Scientific Director who will discuss with the AbbVie 
Medical Director before enrolling the subject.
12-Lead ECG
A resting 12-lead ECG will be performed at the designated study visits as specified in 
Table 2.  A qualified physician will interpret the clinical significance of any abnormal 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
56
finding, sign, and date each ECG.  ECG with QT interval corrected for heart rate using 
Friedericia's correction formula (QTcF) should be reported (or calculated) and 
documented in the source documents and later transcribed on to the appropriate eCRF if 
QTcF prolongation is observed.  In these cases, the baseline QTcF will need to be entered 
into the appropriate eCRF for comparison as well.  In addition, any clinically significant 
findings will be documented in the source documents and later transcribed on to the 
appropriate eCRF.  Each signed original ECG will be monitored by the responsible site 
monitor and kept with subject's source documents onsite.
For subjects with a normal ECG taken within 90 days of Screening, a repeat ECG at 
Screening will not be required, provided source documentation is available.  If there are 
other findings that are clinically significant, the Investigator must bring this to the 
attention of the AbbVie Therapeutic Area Scientific Director who will discuss with the 
AbbVie Medical Director and provide a recommendation before the subject can be 
enrolled.
Subjects can have a repeat ECG at any time during the study as warranted, based on the 
opinion of the Investigator.
Height and Weight
Height will be measured at the Screening Visit only (with shoes off).  Body weight will be 
measured at all scheduled visits, as specified in Table 2.  All measurements will be 
recorded in metric units where applicable.
Vital Signs
Vital sign determinations of systolic and diastolic blood pressure in sitting position, pulse 
rate (counted for at least 30 seconds after 5 minutes in sitting position), respiratory rate, 
and body temperature will be obtained at visits specified in Table 2.  Blood pressure, 
pulse rate, body temperature, and respiratory rate should be measured before blood draws 
are performed.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
57
Physical Examination
A complete physical examination will be performed at the designated study visits as 
specified in Table 2.  The physical examination at the Baseline Visit will serve as the 
baseline physical examination for the entire study.  Physical examination abnormalities 
noted by the Investigator at Baseline prior to the first dose of study drug will be recorded 
in the subject's medical history; abnormalities noted after the first dose of study drug will 
be evaluated and documented by the Investigator as to whether or not the abnormality is 
an AE (see Section 6.1.1 for AE definition).  All findings, whether related to an AE or 
part of each subject's medical history, will be captured on the appropriate eCRF page.
At any time, a symptom-directed physical examination can be performed as deemed 
necessary by the Investigator.
Pregnancy Test
A serum pregnancy test will be performed for all female subjects of child bearing 
potential at the Screening Visit and the Week 88 or PD visit.  The serum pregnancy test 
will be sent to and performed by the central laboratory.  If the serum pregnancy test is 
positive the subject is considered a screen failure.  If the serum pregnancy test is 
indeterminate, it should be repeated ≥ 3 days later to determine eligibility.  If the repeat 
serum pregnancy test is:
●
Positive, the subject is considered a screen failure;
●
Negative, the subject can be enrolled into the trial;
●
Still borderline ≥ 3 days later, this will be considered documentation of 
continued lack of a positive result and the subject can be enrolled into the 
study in the absence of clinical suspicion of pregnancy and other pathological 
causes of borderline results.
A urine pregnancy test will be performed for all female subjects of childbearing potential 
at the Baseline Visit prior to the first dose of study drug and at all subsequent visits.  More 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
58
frequent pregnancy tests will be performed throughout the study if required per 
local/country requirements.
●
If the baseline urine pregnancy test performed at the site is negative, then 
dosing with study drug may begin.  If the baseline urine pregnancy test 
performed at the site is positive, dosing with study drug must be withheld and 
a serum pregnancy test is required.  The serum pregnancy test will be sent to 
and performed by the central laboratory.  If the serum pregnancy test is 
positive, study drug must be withheld and the subject must be discontinued 
from the study.  In the event a pregnancy test comes back borderline, a repeat 
test is required.
●
If a urine pregnancy test post baseline is positive, study drug needs to be 
temporarily discontinued and a serum pregnancy test is required.  The serum 
pregnancy test will be sent to and performed by the central laboratory.  If the 
serum pregnancy test is positive, study drug must be permanently 
discontinued.
In Period 2, for women of childbearing potential, a urine pregnancy test will be performed 
at all visits and monthly at home between scheduled study visits (at Weeks 28 and 36 at 
home, unless an on-site visit is necessary due to rescue therapy with topical 
corticosteroids per Section 5.2.3.4).  The results of the monthly at home tests will be 
communicated to the site.  If a urine pregnancy test is positive, the subject must stop 
dosing, come in to the clinic and have blood drawn for a serum pregnancy test that will be 
analyzed at the central laboratory. 
At each visit, the study staff should review the pregnancy avoidance recommendations 
with each subject of childbearing potential and male subjects with a partner of 
childbearing potential, and document this discussion in the subject's source records.
A pregnant or breastfeeding female will not be eligible for participation or continuation in 
this study.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
59
Clinical Laboratory Tests
Blood and urine samples will be obtained for clinical laboratory tests listed in Table 4.  
Samples will be obtained at the designated study visits in Table 2.
Unscheduled clinical labs may be obtained at any time during the study if deemed 
appropriate per Investigator's discretion.  A certified central laboratory will be utilized to 
process and provide results for the clinical laboratory tests.  All abnormal laboratory tests 
that are considered clinically significant by the investigator will be followed to a 
satisfactory resolution.
The central laboratory chosen for this study will provide instructions regarding the 
collection, processing, and shipping of these samples.
Blood draws should be performed after all clinical assessments and questionnaires and 
vital sign determinations have been completed; but before any study drug administration 
during a visit. 
For clinic visits where samples for serum chemistry and/or advanced lipid panel tests are 
collected, subjects should be fasting (a minimum 8-hour fast) whenever possible.  If a 
subject is not able to fast when necessary, due to unforeseen circumstances, the non-
fasting status will be recorded in study source documentation.
Urine samples will be obtained for urinalysis testing at visits specified in Table 2.  The 
central laboratory will be responsible for performing a macroscopic urinalysis (urine 
dipstick) on the collected urine specimens.  Specified abnormal macroscopic urinalyses 
defined as leukocytes, nitrite, protein, ketones, or blood greater than negative, or glucose 
greater than normal will be followed up with a microscopic analysis at the central 
laboratory.
For any laboratory test value outside the reference range that the investigator considers to 
be clinically significant the Investigator should apply the standard of care for medical 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
60
evaluation and treatment per local guidelines (see Section 6.1.7 for toxicity management 
guidelines):
●
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 drug or 
requires a subject to receive treatment will be recorded as an AE.  The central laboratory 
chosen for this study will provide instructions regarding the collection, processing and 
shipping of these samples.  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.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
61
Table 4.
Clinical Laboratory Tests
Hematology
Clinical Chemistrya
Urinalysisb
Other Laboratory Tests
Hematocrit
Hemoglobin
RBC count
WBC count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubin
INR (reflex only)c
Albumin
Aspartate aminotransferase 
(AST)
Alanine aminotransferase 
(ALT)
Alkaline phosphatase
CPK
Sodium
Potassium
Bicarbonate/CO2
Chloride 
Calcium
Inorganic phosphate
Uric acid
Total protein
Glucose 
Cholesterol
LDL-C
HDL-C
Triglycerides
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Urobilinogen
Bilirubin
Leukocytes
Nitrites
Microscopic 
examination, 
if needed
Central Lab Tests:
Serum Pregnancy (bHCG) 
testd
HBsAge
HBsAbe
HBcAbe
HBV DNA PCR reflex onlye
HCV Abe
HCV RNA reflex onlye
HIV Abi
QuantiFERON-TB Gold
High sensitivity CRP
(hs-CRP)f
FSHig
Local Lab Tests:
Urine pregnancy testh
ALT = alanine aminotransferase; AST = aspartate aminotransferase; bHCG = beta human chorionic gonadotropin; 
BUN = blood urea nitrogen; CPK = creatine phosphokinase; DNA = deoxyribonucleic acid; FSH = Follicle-Stimulating 
Hormone; HBc Ab = hepatitis B core antibody; HBs Ab = hepatitis B surface antibody; HBs Ag = hepatitis B surface 
antigen; HBV = hepatitis B virus; HCV Ab = hepatitis C virus antibody; HDL-C = high-density lipoprotein cholesterol; 
HIV = human immunodeficiency virus; hsCRP = high sensitivity C-reactive protein; INR = international normalized 
ratio; LDL-C = low-density lipoprotein cholesterol; PCR = polymerase chain reaction; pH = RBC = red blood cell; 
RNA = ribonucleic acid; TB = tuberculosis; WBC = white blood cell
a.
Minimum 8-hour fast.  If a subject is not able to fast when necessary, due to unforeseen circumstances, the non-
fasting status will be recorded in study source documentation.
b.
A urine dipstick macroscopic urinalysis will be completed by the central laboratory at all required visits.  A 
microscopic analysis will be performed in the event the dipstick results show leukocytes, nitrite, protein, ketones, 
or blood greater than negative or glucose greater than normal.
c.
INR will only be measured if ALT and/or AST > 3 × ULN.
d.
A serum pregnancy test will be performed for all female subjects at the Screening Visit and if postbaseline urine 
pregnancy test turns positive.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
62
Table 4.
Clinical Laboratory Tests (Continued)
e.
At Screening only.  For Japan only:  for subjects with HBs Ab+ and/or HBc Ab+ at Screening, the HBV-DNA 
PCR test should be performed again at Week 12 and Week 24.  In cases where the recurrence of HBV-DNA is 
observed, the subject should be discontinued from the study drug.  Retesting at Week 12 and Week 24 is not 
necessary with subjects that have a history of HBV vaccine and are HBs Ab+.
f.
The hs-CRP results starting from Baseline (Day 1) will not be reported to the Sponsor, Investigator, study site 
personnel, and the subject.  For safety evaluations of signs and symptoms of infection and management of adverse 
events, the investigator may locally test procalcitonin.  Results of tests such as hsCRP, serum amyloid A and 
procalcitonin may be blunted in subjects taking a JAK inhibitor, thereby limiting the clinical utility of these tests in 
the setting of a possible safety assessment or adverse event management.  Any hsCRP, CRP, serial serum amyloid 
A, or serial procalcitonin local tests reported to the investigator will be recorded as protocol deviations.
g.
At screening for female subjects < 55 years old.
h.
A urine pregnancy test will be performed for all female subjects at the Baseline Visit prior to the first dose of study 
drug and all subsequent visits.  If the baseline urine pregnancy test performed at the site is negative, then dosing 
with study drug may begin.  If the baseline urine pregnancy test performed at the site is positive, dosing with study 
drug must be withheld and a serum pregnancy test is required.  The serum pregnancy test will be sent to and 
performed by the central laboratory.  If the serum pregnancy test is positive, study drug must be withheld and the 
subject must be discontinued from the study.  In the event a pregnancy test comes back borderline, a repeat test is 
required.  If a urine pregnancy test postbaseline is positive, study drug needs to be temporarily discontinued and a 
serum pregnancy test is required.  The serum pregnancy test will be sent to and performed by the central 
laboratory.  If the serum pregnancy test is positive, study drug must be permanently discontinued.
i.
Anti-HIV Ab will be performed at Screening.  The Investigator must discuss any local reporting requirements to 
local health agencies with the subject.  The site will report confirmed positive results to their health agency per 
local regulations, if necessary.  If a subject has a confirmed positive result, the Investigator must discuss with the 
subject the potential implications to the subject's health and subject should receive or be referred for clinical care 
promptly.  This testing is to be done at the central lab.  A subject will not be eligible for study participation if test 
results indicate a positive HIV infection.  AbbVie will not receive results from the testing and will not be made 
aware of any positive result.  
Hepatitis Screen:
All subjects will be tested for the presence of HBV and HCV at Screening.
Hepatitis B:
Subjects will be tested for the presence of HBV at screening using the following tests:
HBs Ag
HBc Ab/anti-HBc
HBs Ab/anti-HBs (Hepatitis B surface antibody)


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
63
A positive result for HBs Ag will be exclusionary.
A negative result for HBs Ag will be tested (automatic reflex testing) for core antibodies 
(HBc Ab) and surface antibodies (HBs Ab).
●
A negative test result for HBc Ab does not require HBV DNA PCR qualitative 
testing and the subject may be enrolled (Figure 2, Scenarios A and B).  For a 
subject who has had a HBV vaccination (should document in the medical 
history), a positive test result for HBs Ab is expected and the subject may be 
enrolled (Figure 2, Scenario B).*
●
A positive test result for HBc Ab requires HBV DNA PCR testing (automatic 
reflex testing) (Figure 2), (Scenarios C and D).
○
A positive result for HBV DNA or a result that exceeds detection 
sensitivity will be exclusionary.
○
A subject with a negative result for HBV DNA testing may be enrolled.
○
For Japan only:  for subjects with HBs Ab+ and/or HBc Ab+ at Screening, 
the HBV-DNA PCR test should be performed again at Week 12 and 
Week 24.  In cases where the recurrence of HBV-DNA is observed, the 
subject should be discontinued from the study drug.  Retesting at Week 12 
and Week 24 is not necessary with subjects that have a history of HBV 
vaccine and are HBs Ab+.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
64
Figure 2.
Criteria for HBV DNA PCR Qualitative Testing
*
For subjects who have had a HBV vaccination (should document in the medical history), a positive test result for 
HBs Ab is expected and these subjects may be enrolled.
Hepatitis C:
All subjects will be tested for the presence of Hepatitis C Virus antibodies (HCV Ab) at 
Screening.  Samples positive for HCV Ab require PCR qualitative testing for HCV RNA.  
Any HCV RNA PCR result that meets or exceeds detection sensitivity will be 
exclusionary.  Subjects with a history of treated HCV infection may be allowed to enroll 
if documentation of effective treatment is available and no evidence of HCV is detected 
by HCV RNA PCR.
TBNK Assessment By Immunophenotyping
Blood samples will be collected at the Baseline, Week 8, Week 16, and Week 20, visits 
and will be utilized to assess effects of JAK inhibition on certain leukocyte subsets, 
including T (CD4+ and CD8+) cells, B (CD19+) cells, natural killer (NK) cells, and 
natural killer-T (NKT) cells.  Instructions for the preparation and shipment of the samples 
will be provided in the laboratory manual.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
65
HIV
Subjects with HIV infection are excluded from study participation.  HIV testing will be 
performed at Screening.  This testing is to be done at the central lab.  The Investigator 
must discuss any local reporting requirements to local health agencies with the subject.  
The site will report confirmed positive results to their health agency per local regulations, 
if necessary.  If a subject has a confirmed positive result, the Investigator must discuss 
with the subject the potential implications to the subject's health and subject should 
receive or be referred for clinical care promptly.  A subject will not be eligible for study 
participation if the test results indicate a positive HIV infection.  AbbVie will not receive 
results from the testing and will not be made aware of any positive result.
Randomization/Drug Assignment
All Screening laboratory results must be reviewed, signed, and dated by the Principal 
Investigator or Sub-investigator prior to the Baseline Visit.  Subjects will not be enrolled 
into the study if laboratory or other Screening result abnormalities are deemed clinically 
significant by the Principal Investigator or Sub-investigator.
Subjects will be eligible for randomization if they continue to meet all of the selection 
criteria (Section 5.2) at Baseline and are willing to continue in the study.
In Period 1, at the Baseline visit, subjects will be randomized in a 1:1.1:1 ratio using 
interactive response technology (IRT) to receive double-blind study drug in one of the 
following treatment groups:
●
Group 1:  ABT-494 7.5 mg QD for 16 weeks 
●
Group 2:  ABT-494 15 mg QD for 16 weeks 
●
Group 3:  ABT-494 30 mg QD for 16 weeks 
●
Group 4:  Matching Placebo for 16 weeks  


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
66
Randomization will be stratified by geographic region (US/PR/Canada, EU/AUS, and 
Japan).  Enrollment in Japan will be capped at 10% of subjects (approximately 4 subjects 
per group).
In Period 2, at the Week 16 visit, all subjects will be re-randomized in a 1:1 ratio using 
interactive response technology (IRT) to receive double-blind study drug in one of the 
following treatment groups:
●
Subjects from Group 1 in Period 1:  ABT-494 7.5 mg QD or matching placebo 
for 24 weeks 
●
Subjects from Group 2 in Period 1:  ABT-494 15 mg QD or matching placebo 
for 24 weeks
●
Subjects from Group 3 in Period 1:  ABT-494 30 mg QD or matching placebo 
for 24 weeks
●
Subjects from Group 4 in Period 1:  ABT-494 30 mg QD or matching placebo 
for 24 weeks
During Period 2, starting at the Week 20 visit, subjects re-randomized to placebo, 
ABT-494 7.5 mg QD or ABT-494 15 mg QD will be reassigned in a blinded manner to 
ABT-494 30 mg QD if at any visit their response is < EASI 50.  These subjects will 
continue on ABT-494 30 mg QD for the remainder of the study. 
See Section 5.5.3 for details.
Study Drug Dispensing, Dosing, and Compliance
Study drug and Dosing Diary will be dispensed to subjects beginning at Baseline (Day 1) 
and as specified in Table 2.  The first dose of study drug will be administered after all 
other Baseline (Day 1) procedures are completed.  Subjects will maintain an electronic 
dosing diary for all study medication administered outside of the study visit, (e.g., at 
home) to capture dosing dates and times.  At all visits, except Baseline, Week 2, 4-week 
follow-up visit after topical corticosteroid rescue in Period 2, and the 30-day follow-up 
visit, the site personnel will review the electronic diary data, returned study drug kits, and 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
67
empty study drug packaging to verify compliance. Electronic diary data stops at the 
Week 40 visit.
(Refer to Section 5.5 for additional information.)
Actigraphy Device
During the Screening Visit, subjects will be dispensed two actigraphy devices and will be 
trained on how and when to wear the devices by site staff.  Subjects will be instructed to 
wear two actigraphy watch-type devices (one on each wrist) at bedtime daily during their 
whole daily rest (sleep) period (see Section 10.2 for more detail).  Data will be collected 
from the day of the Screening visit through the Week 16 visit (see Table 2 for visits 
requiring data download).
5.3.1.2
Collection and Handling of Optional and Mandatory 
Samples for Exploratory Research and Validation Studies
5.3.1.2.1
Samples for Exploratory Research Variables and Validation 
Studies
Subjects will have the option to provide samples for exploratory research and validation 
studies.  Subjects may still participate in the main study even if they decide not to 
participate in this optional exploratory research/validation study.
Exploratory research can help to improve our understanding of how individuals respond 
to drugs and our ability to predict which subjects would benefit from receiving specific 
therapies.  In addition, exploratory research may help to improve our understanding of 
how to diagnose and assess/monitor AD by assessing associations between disease 
characteristics, outcomes data, and biomarkers of interest.
Validation studies, including those related to the development of potential in-vitro 
diagnostic tests, may be carried out retrospectively in order to assess associations between 
events of interest (i.e., efficacy and/or safety events) and candidate biomarkers.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
68
For Japan only:  research on DNA and RNA exploratory research samples will be 
restricted to treatment response of pharmacokinetics, efficacy, tolerability, and safety.
AbbVie (or people or companies working with AbbVie) will store the exploratory 
research/validation studies samples in a secure storage space with adequate measures to 
protect confidentiality.  The samples will be retained while research on ABT-494 (or 
drugs of this class) or AD and related conditions continues, but for no longer than 
20 years after study completion.
All subjects are preferred to have been fasting for a minimum of 8 hours prior to sample 
collection.  If a subject is not able to fast when necessary, due to unforeseen 
circumstances, the non-fasting status will be recorded in study source documentation.  
The following samples will be collected according to Table 3 for each subject who 
consents to provide samples for exploratory research/validation studies:
●
DNA samples for pharmacogenetic or epigenetic analyses;
●
RNA samples for transcriptomic and/or epigenetic analyses;
●
Serum and plasma samples for systemic analyses, including but not limited to 
proteomic and metabolomics (these samples may be used for assay of study 
drugs if needed);
●
Blood samples for peripheral blood mononuclear cell (PBMC) investigations;
●
Skin biopsies for pathological and biological investigations, including, but not 
limited to transcriptomics, proteomic profiling, immunohistochemistry (IHC), 
and targeted investigations, e.g., identification of specific analytes, and target 
identification.
The procedures for obtaining and documenting informed consent are discussed in 
Section 9.3.
Samples will be shipped to AbbVie or a designated laboratory for RNA/DNA extraction, 
if applicable, and/or analyses or long-term storage.  Instructions for the preparation and 
shipment of the samples will be provided in the laboratory manual.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
69
Skin Biopsy samples for investigations that include, but are not limited to, 
epigenetics, transcriptomics, proteomics, IHC and targeted investigations.
For subjects who consent, 2 skin biopsies should be collected at the Baseline and Week 16 
visits (one lesional and one non-lesional from the same general area at each visit) and 
one lesional skin biopsy at the Week 4 visit.  Skin biopsies should be between 4.5 and 
5 millimeters.  Non-lesional skin biopsies should be at least 1.5 centimeters away from the 
lesional biopsied area and in the same general area.  The procedure for obtaining and 
documenting informed consent is discussed in Section 9.3.
Samples will be shipped to AbbVie or a designated laboratory for extraction, if applicable 
and/or analyses and/or long-term storage.  Instructions for the preparation and shipment of 
the samples will be provided in a laboratory manual.
Mandatory Exploratory Research/Validation Studies Samples Collection From 
Selected Sites
Selected sites will be asked to perform a complete investigation of biomarkers.  For such 
sites, these assessments (blood sample and skin biopsy collections) will be made 
mandatory as part of the main study.  There will be a specific ICF for subjects in these 
selected sites.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood samples (plasma) for pharmacokinetic (PK) assay of ABT-494 (upadacitinib) and 
possibly other medications will be collected as follows:
●
At Weeks 2 and 4 prior to dosing;
●
At Weeks 8, 12, 16, 20, 24, 32, 40, 52, 64, 76 and 88/PD at any time during 
the visit.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
70
On Week 2 and Week 4 visit days, if possible, subjects should take the study drug dose at 
the clinic after collecting the PK blood sample, except if the subjects regularly take the 
study drug dose at night.  Those subjects who regularly take the study drug dose at night 
should continue to take study drug according to their normal schedule.  For all other 
visits, subjects can take the study drug dose on visit days at their regular schedule and not 
necessarily at the clinic.
For all PK samples, the date and accurate time of the PK sample collection will be 
recorded on the lab requisition form.  The date and accurate time of the PK sample 
collection and the last two study drug doses will be recorded on the eCRF to the nearest 
minute.
Refer to the study specific laboratory manual for detailed instructions on sample 
collection, processing, and shipment.
5.3.2.2
Measurement Method
Plasma concentrations of ABT-494 (upadacitinib) will be determined by the Drug 
Analysis Department at AbbVie using a validated liquid chromatography/mass 
spectrometry method.
5.3.3
Efficacy Variables
5.3.3.1
Primary Variable
The primary endpoint is the mean percent (%) change from Baseline (Day 1) in EASI 
score at Week 16.
5.3.3.2
Secondary Variables
●
Proportion of subjects achieving an EASI 75 response, defined as at least a 
75% reduction in EASI score, at Week 16 relative to the Baseline (Day 1)
●
Proportion of subjects achieving an Investigator Global Assessment (IGA) of 
"0" or "1" at Week 16


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
71
●
Percent change from Baseline to Weeks 2, 8 and 16 in pruritus numerical 
rating scale (NRS)
●
Percent change in EASI score from Baseline at Week 8
●
Percent change in SCORAD score from Baseline at Weeks 8 and 16
●
Proportion of subjects achieving EASI 50/75/90 response at Weeks 8 and 16
●
Proportion of subjects achieving SCORAD 50/75/90 response at Weeks 8 and 
16
●
Proportion of subjects with Dermatology Life Quality Index (DLQI) = "0" or 
"1" at Weeks 8 and 16
●
Change from Baseline in DLQI at Weeks 8 and 16
●
Change and percent change from Week 16 (re-randomization) in EASI score at 
all Period 2 visits
●
Time to loss of EASI 50 response relative to Baseline among those who were 
re-randomized as EASI 75 responders at Week 16
●
Summary of EASI 75 at all visits in Period 2 among those who were re-
randomized as  EASI 75 non-responders at Week 16
5.3.3.3
Exploratory Variables
●
Time to EASI 50/75/90 and IGA "0" or "1" response in Period 1
●
Proportion of subjects achieving EASI 50/75/90/100 response at all visits
●
Proportion of subjects achieving SCORAD 50/75/90 response at all visits
●
Change from Baseline to Week 16 in Patient Oriented Eczema Measure
(POEM)
●
Change from Baseline to Week 16 in Medical Outcomes Study (MOS) Sleep 
Scale
●
Change from Baseline to Week 16 in Asthma Symptoms Questionnaire
●
Change from Baseline to Week 16 in Daytime Nasal Symptoms Questionnaire
●
Change from Baseline in total sleep time per night (TST min), Sleep 
Efficiency (%), Wake After Sleep Onset (WASO), number of scratching 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
72
events per hour, mean activity during rest (sleep) periods as measured by 
actigraphy.
Primary and secondary variables will also be evaluated at all scheduled visits through 
Week 88.
5.3.4
Safety Variables
Safety evaluations include AE monitoring, physical examinations, vital sign 
measurements, ECG, and clinical laboratory testing (hematology, chemistry, and 
urinalysis).
5.3.5
Pharmacokinetic Variables
Plasma ABT-494 (upadacitinib) concentrations will be measured at the times indicated in 
Table 2.  A non-linear mixed-effects modeling approach will be used to estimate the 
population central values and the empirical Bayesian estimates of the individual values for 
ABT-494 oral clearance (CL/F) and volume of distribution (V/F).  Additional parameters 
may be estimated if useful in the interpretation of the data.
5.3.6
Exploratory Research Variables and Validation Studies
Optional and mandatory (at selected sites only) 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.
For Japan only:  research on DNA and RNA exploratory research samples will be 
restricted to treatment response of pharmacokinetics, efficacy, tolerability, and safety.
Biomarker assessments may be used to assess and generate prognostic, predictive, 
pharmacodynamic, or surrogate biomarker signatures.  These assessments may be 
explored in the context of AD or related conditions and/or ABT-494 or drugs of similar 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
73
classes.  The results from these analyses are exploratory in nature and may not be 
included with the clinical study report (CSR).
The samples may also be used to develop new therapies, research methods or 
technologies.  In addition, samples from this study may be stored for future use.  Samples 
may then be used to validate putative biomarker signatures obtained from a prospective 
study, leading to the development of diagnostic tests.
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
A subject may withdraw from the study at any time and for any reason.  The Investigator 
may discontinue any subject's participation for any reason, including an AE, safety 
concerns, or failure to comply with the protocol.  See Section 6.1.7 for toxicity 
management criteria.
Subjects will be withdrawn from the study immediately if any of the following occur:
●
Clinically significant abnormal laboratory results or AEs, which rule out 
continuation of the study drug, as determined by the Investigator and the 
AbbVie Therapeutic Area Medical/Scientific Director.  
●
Serious infections (e.g., sepsis) which cannot be adequately controlled within 
2 weeks by anti-infective treatment or would put the subject at risk for
continued participation in the trial as determined by the Investigator in 
consultation with the AbbVie Therapeutic Area Medical/Scientific Director.  
●
The Investigator believes it is in the best interest of the subject.
●
The subject requests withdrawal from the study.
●
Inclusion or exclusion criteria violation was noted after the subject started 
study drug, when continuation of the study drug would place the subject at risk 
as determined by the AbbVie Therapeutic Area Medical/Scientific Director.  
●
Introduction of prohibited medications or dosages when continuation of the 
study drug would place the subject at risk, as determined by the AbbVie 
Therapeutic Area Medical/Scientific Director.  


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
74
●
Subject is non-compliant with TB prophylaxis (if applicable) or develops 
active TB at any time during the study.
●
The subject becomes pregnant while on study drug.
●
Malignancy, except for localized NMSC or carcinoma in-situ of the cervix.
●
Subject is significantly non-compliant with study procedures which would put 
the subject at risk for continued participation in the trial in consultation with 
the AbbVie Therapeutic Area Medical/Scientific Director.  
●
Subject develops a gastrointestinal perforation.
●
Subjects with disease progression or not responding to treatment are to be 
withdrawn from the trial based on investigator's discretion.
●
In Period 1, discontinuation from study drug will be mandatory for any subject 
with an EASI score worsening of 25% or more compared with their Baseline 
EASI score at any 2 consecutive study visits from Week 4 to Week 12.
●
In Period 2, discontinuation from study drug will be mandatory for subjects 
with < EASI 50 response compared with their Baseline EASI score 4 weeks 
following rescue with topical corticosteroids or at any visit thereafter.
Discontinuation of Study Drug and Continuation of Study Participation
In order to minimize missing data for efficacy and safety assessments, subjects who 
prematurely discontinue study drug treatment complete a Premature Discontinuation Visit 
(PD visit) as soon as possible, preferably within 2 weeks.  Afterwards, subjects should 
continue to be followed for all regularly scheduled visits as outlined in Table 2 on 
standard of care, unless they have decided to discontinue the study participation entirely 
(withdrawal of informed consent).  Subjects should be advised on the continued scientific 
importance of their data even if they discontinue treatment with study drug early. 
Subjects that choose to participate in the study after discontinuation of study drug 
treatment should follow the regular visit schedule as outlined in Table 2; and adhere to all 
study procedures except for dispensing study drug, PK and exploratory research sample 
collection.  In addition, all future rescue and efficacy-driven discontinuation criteria no 
longer apply.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
75
Premature Discontinuation of Study (Withdrawal of Informed Consent) 
If a subject prematurely discontinues study participation (withdrawal of informed 
consent), the procedures outlined for the PD Visit should be completed as soon as 
possible, preferably within 2 weeks of the last dose of study drug, and preferably prior to 
the initiation of another therapy.  In addition, if subject is willing, a 30-day follow-up on-
site visit (or phone call if a visit is not possible) after the last dose of study drug may be 
completed to determine the status of any ongoing AEs/SAEs, the occurrence of any new 
AEs/SAEs, and medications used to treat AEs/SAEs. 
All attempts must be made to determine the date of the last study drug dose and the 
primary reason for discontinuation of study drug or study participation.  The information 
will be recorded on the appropriate eCRF page.  However, these procedures should not 
interfere with the initiation of any new treatments or therapeutic modalities that the 
Investigator feels are necessary to treat the subject's condition.  Following discontinuation 
of the study drug, the subject will be treated in accordance with the Investigator's best 
clinical judgment.
Follow-Up Period
A follow-up visit (or phone call if a visit is not possible) should occur for all subjects 
approximately 30 days after the last dose of study drug to determine the status of any 
ongoing AEs/SAEs or the occurrence of any new AEs/SAEs.
For subjects to be considered lost to follow-up, reasonable attempts must be made to 
obtain information on the final status of the subject.  At a minimum, two phone calls must 
be made and one certified letter must be sent and documented in the subject's source 
documentation.
Subjects who discontinue the study or study drug prematurely after randomization will not 
be replaced.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
76
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
Study drug will be taken orally once daily beginning on Day 1 (Baseline).  Subjects will 
be instructed to take one daily dose at approximately the same time each day.  The study 
drug can be taken with or without food.
5.5.2
Identity of Investigational Product
The individual study drug information is presented in Table 5.
Table 5.
Identity of Investigational Product
Investigational Product
Mode of 
Administration
Formulation
Strength
Manufacturer
ABT-494 (upadacitinib)
oral
tablet
7.5 mg 
15 mg 
30 mg
AbbVie
Matching placebo 
oral
tablet
NA
AbbVie
5.5.2.1
Packaging and Labeling
ABT-494 (upadacitinib) and matching placebo will be packaged in bottles with quantities 
sufficient to accommodate study design.  Each bottle (kit) label will contain a unique kit 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
77
number.  This kit number is assigned to a subject via IRT and encodes the appropriate 
study drug to be dispensed at the subject's corresponding study visit.  Each kit will be 
labeled as required per country requirements.  Labels must remain affixed to the bottles 
(kits).  All blank spaces on the label will be completed by the site staff prior to dispensing 
to the subjects.
5.5.2.2
Storage and Disposition of Study Drug
ABT-494 (upadacitinib) must be stored at controlled room temperature (15° to 25°C/59° 
to 77°F).  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 the conditions specified on the label 
until dispensed for subject use or destroyed on site as appropriate.
Emollients
A commercially available skin moisturizer will be provided to subjects to maintain skin 
hydration.  Emollients for subject use will be provided by AbbVie to study sites on a 
regular basis.  See local product information for further instructions regarding 
recommended storage conditions and packaging configuration.
5.5.3
Method of Assigning Subjects to Treatment Groups
All subjects will be randomized using IRT.  Before the study is initiated, IRT directions 
will be provided to each site.
All subjects will be assigned a unique identification number by the IRT at the Screening 
Visit.  Subjects who meet the inclusion and none of the exclusion criteria defined in 
Section 5.2.1 and Section 5.2.2 will be randomized by IRT in in 1:1:1:1 ratio to one of 
four treatment groups:  (1) ABT-494 7.5 mg, (2) ABT-494 15 mg, (3) ABT-494 30 mg or 
(4) matching placebo, once daily for 16 weeks in a double-blinded manner.  The 
randomization will be stratified by geographic region (US/PR/Canada, EU/AUS, and 
Japan).  The IRT will assign a randomization number that will encode the subject's 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
78
treatment group assignment according to the randomization schedule generated by the 
Statistics Department at AbbVie.
Subjects who complete Period 1 will be re-randomized at Week 16 within their original 
treatment group assignments to either ABT-494 or placebo into a 72-week double-blind, 
placebo controlled treatment period (Period 2) in a 1:1 ratio as shown in Figure 1 (study 
design).  Randomization will be stratified by geographic region and EASI 75 response at 
Week 16.  In Period 2, at the Week 16 visit, all subjects will be re-randomized as follows:
●
Subjects from Group 1 in Period 1:  ABT-494 7.5 mg QD or matching placebo 
for 24 weeks 
●
Subjects from Group 2 in Period 1:  ABT-494 15 mg QD or matching placebo 
for 24 weeks
●
Subjects from Group 3 in Period 1:  ABT-494 30 mg QD or matching placebo 
for 24 weeks
●
Subjects from Group 4 in Period 1:  ABT-494 30 mg QD or matching placebo 
for 24 weeks
During Period 2, starting at the Week 20 visit, subjects re-randomized to placebo, 
ABT-494 7.5 mg QD or ABT-494 15mg QD will be reassigned in a blinded manner to 
ABT-494 30 mg QD if at any visit their response is < EASI 50.  These subjects will 
continue on ABT-494 30 mg QD for the remainder of the study. 
IRT will provide the appropriate study drug kit number(s) to dispense to each subject.  
Study drug will be administered at the study visits as summarized in Section 5.3.1.1.  
Returned study drug must not be re-dispensed to any subject.
5.5.4
Selection and Timing of Dose for Each Subject
Subjects should take study drug as outlined in Section 5.5.1.
On dosing days that occur on study visit days, subjects should follow the regular dosing 
schedule (refer to Section 5.3.2.1 regarding Week 2 and Week 4 visits).


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
79
Each subject's dosing schedule should be closely monitored by the site at each study visit 
by careful review of the subject's dosing diary.  This will ensure that all subjects enrolled 
into the study maintain their original dosing schedule beginning with the first dose of 
study drug (Baseline/Day 1).
In Period 1, subjects will be randomized in a 1:1:1:1 ratio to one of four treatment groups:  
(1) ABT-494 7.5 mg, (2) ABT-494 15 mg, (3) ABT-494 30 mg or (4) matching placebo, 
once daily.  Subjects who complete Period 1 will be re-randomized at Week 16 into the 
72-week double-blind, placebo controlled treatment period (Period 2) in a 1:1 ratio as 
follows:
●
Subjects from Group 1 in Period 1:  ABT-494 7.5 mg QD or matching placebo 
for 24 weeks 
●
Subjects from Group 2 in Period 1:  ABT-494 15 mg QD or matching placebo 
for 24 weeks
●
Subjects from Group 3 in Period 1:  ABT-494 30 mg QD or matching placebo 
for 24 weeks
●
Subjects from Group 4 in Period 1:  ABT-494 30 mg QD or matching placebo 
for 24 weeks
During Period 2, starting at the Week 20 visit, subjects re-randomized to placebo, 
ABT-494 7.5 mg QD or ABT-494 15 mg QD will be reassigned in a blinded manner to 
ABT-494 30 mg QD if at any visit their response is < EASI 50.  These subjects will 
continue on ABT-494 30 mg QD for the remainder of the study.
●
If a subject should forget to take their ABT-494 (or matching placebo) dose at 
their regularly scheduled dosing time, they should take the forgotten dose as 
soon as they remember the dose was missed as long as it is at least 10 hours 
before their next scheduled dose.  If a subject only remembers the missed dose 
within 10 hours before next scheduled dose, the subject should skip the missed 
dose and take the next dose at the scheduled time.
●
If the subject experiences a study drug interruption > 14 consecutive days in 
Period 1 or > 21 consecutive days in Period 2 (other than for reasons listed in 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
80
Section 6.1.7), they should notify their study site physician, and the subject 
should be discontinued from the study drug.
Before the study is initiated, directions for system use of the IRT will be provided to each 
site.
5.5.5
Blinding
Study sites and subjects will remain blinded for the duration of the study.  To maintain 
integrity of the trial and avoid introduction of bias, the study team will only have access to 
unblinded subject level data for AEs of special interests and SAEs for regulatory 
submissions.  In order to maintain the blind, the ABT-494 (upadacitinib) tablets and 
placebo tablets provided for the study will be identical in appearance.  The IRT will 
provide access to unblinded subject treatment information in the case of medical 
emergency.
In the event of a medical situation that requires unblinding of the study drug assignment, 
the Investigator is requested to contact the AbbVie Therapeutic Area Scientific Director 
who will discuss with the AbbVie Medical Director and provide a recommendation prior 
to breaking the blind.  However, if an urgent therapeutic intervention is necessary which 
warrants breaking the blind prior to contacting the Therapeutic Area Scientific Director, 
the Investigator can directly access the IRT system to break the blind without AbbVie 
notification or agreement.  Unblinding is available in the IRT system via the Unblind 
Subject transaction, which is available only to the Investigator.  If the IRT system is 
unavailable, unblinding may occur by contacting EndPoint technical support via either 
phone (preferred) or email (support@endpointclinical.com).  For country-specific phone 
numbers, please see the following website:  http://www.endpointclinical.com/helpdesk/.
In the event that the blind is broken before notification to the AbbVie Therapeutic Area 
Scientific Director, we request that the AbbVie Therapeutic Area Scientific Director be 
notified within 24 hours of the blind being broken.  The date and reason that the blind was 
broken must be conveyed to AbbVie Laboratories and recorded on the appropriate eCRF.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
81
5.5.5.1
Blinding of Data for Data Monitoring Committee (DMC)
An external Data Monitoring Committee (DMC) comprised of persons independent of 
AbbVie and with relevant expertise in their field will review unblinded safety data from 
the ongoing study.  If necessary to ensure subject safety, the DMC will also be given 
access to efficacy data.  The primary responsibility of the DMC will be to protect the 
safety of the subjects participating in this study.
A separate DMC charter will be prepared outside of the protocol and will describe the 
roles and responsibilities of the DMC members, frequency of data reviews, and relevant
safety data to be assessed.
Communications from the DMC to the Study Teams will not contain information that 
could potentially unblind the team to subject treatment assignments.
5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense 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.
Subject dosing will be recorded on a subject dosing diary.  Subjects will be instructed to 
return all drug containers (even if empty) to the study site personnel at each clinic visit.  
The study site personnel will document compliance in the study source documents.
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 and by registering the arrival of drug through the 
IRT.  The original Proof of Receipt Note and the IRT confirmation sheet will be kept in 
the site files as a record of what was received.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
82
In addition, an IRT will be used to document investigational product accountability 
including but not limited to date received, the lot number, kit number(s), date dispensed, 
subject number, and the identification of the person dispensing the drug.
All empty/used study drug packaging will be inventoried by the site and verified by the 
site monitor.  Empty/used study drug packaging should be returned by the subject at each 
visit for accountability and compliance purposes and new packaging issued as necessary.  
Empty/used packaging will be retained (unless prohibited by local law) until the site 
monitor is on site to confirm the returned study drug.  Site monitor(s) and site staff will 
complete study drug accountability via IRT, source documents, subject dosing diaries, and 
by visually inspecting the packaging whenever possible.  After drug accountability has 
been completed, used packaging and unused study drug will be destroyed on site 
according to local procedures or regulations or returned to the destruction depot by the 
site monitor (for those sites that do not meet AbbVie's documentation requirements for 
on-site destruction).  The use of a third party vendor for drug destruction must be pre-
approved by AbbVie.  For sites performing on-site drug destruction or using a third party 
vendor for drug destruction, a copy of the destruction methodology and date of 
destruction should be maintained at the site's facility.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
ABT-494 (upadacitinib) is a potent JAK1 selective inhibitor.  The proposed study is a 
88-week, randomized, double-blind, placebo-controlled study to compare multiple doses 
of ABT-494 versus placebo in moderate to severe AD adult patients that are candidates 
for systemic therapy.  In order to assess the potential of ABT-494 to benefit patients with 
AD, patients with moderate to severe disease (baseline EASI ≥ 16, BSA of ≥ 10% and an 
IGA score ≥ 3) will be enrolled and the mean percent change from Baseline in EASI score 
for different doses of ABT-494, compared to placebo will be assessed.  The 16-week 
therapy (Period 1) is generally accepted as the timeframe during which an effective 
treatment would be expected to produce clinical benefit in AD.  The 72-week double-


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
83
blind treatment period (Period 2) is to evaluate more long-term safety and efficacy of 
repeated administration of ABT-494 and to evaluate potential loss of response in AD 
subjects who have completed Period 1.
Placebo has been selected as the appropriate control group since, as discussed in 
Section 3.2, there is a lack of approved systemic therapies for moderate to severe AD, 
especially for long-term use.
5.6.2
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All
primary and secondary efficacy measurements in this study are standard for assessing 
disease activity in adult subjects with AD.  Other than the biomarker analyses which are 
exploratory, all clinical and laboratory procedures in this study are standard and generally 
accepted.
5.6.3
Suitability of Subject Population
This study will enroll adult female and male subjects who are at least of 18 years of age 
and are no more than 75 years of age at the time of the Screening visit; and have been 
diagnosed with moderate to severe AD.  The study population selected in this study 
reflects the standard population for AD trials with new interventions.
5.6.4
Selection of Doses in the Study
This study is designed to evaluate the safety and efficacy and to define the dose- and 
exposure-response relationships of ABT-494 (upadacitinib) in subjects with moderate to 
severe AD.  Doses in this study are selected based on efficacy and safety results from 
two Phase 2 studies in patients with rheumatoid arthritis (RA).  In the Phase 2 studies in 
RA, all the evaluated doses of ABT-494 immediate release capsule formulation (3 mg 
BID, 6 mg BID, 12 mg BID, 18 mg BID, and 24 mg QD) were generally well-tolerated 
and without unexpected safety signals.  The Phase 2 dose-response and exposure response 
results in RA show that the 6 mg BID dose of the immediate release formulation 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
84
approaches the plateau of efficacy in RA, and increasing the dose to 12 mg BID appears 
to result in some incremental efficacy benefit.  
In order to enhance patients' compliance and to provide a more convenient dosing 
regimen than BID administration, AbbVie developed a once-daily tablet formulation 
which will be used in the current study.
The 15 mg and 30 mg QD doses of the once-daily formulation used in this study achieve 
equivalent daily area under the plasma concentration-time curve, and comparable 
maximum and minimum plasma concentration during a day to the 6 mg BID and 12 mg 
BID immediate release doses, respectively.  Evaluating the 7.5 mg QD dose aims to 
ensure that the minimally efficacious dose is characterized.
The maximum dose for this study will not exceed 30 mg per day for 88 weeks to limit 
potential drug-related toxicity.
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 AEs, please refer to Section 6.1 through 
Section 6.1.1.  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 AEs on 
a routine basis throughout the study.  The investigator will assess and record any AE in 
detail including the date of onset, event diagnosis (if known) or sign/symptom, severity, 
time course (end date, ongoing, intermittent), relationship of the AE to study drug, and 
any action(s) taken.  For serious AEs considered as having "no reasonable possibility" of 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
85
being associated with study drug, the investigator will provide an Other cause of the 
event.  For AEs to be considered intermittent, the events must be of similar nature and 
severity.  AEs, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded.
All AEs will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a 
causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an AE.  Worsening in 
severity of a reported AE should be reported as a new AE.  Laboratory abnormalities and 
changes in vital signs are considered to be adverse events only if they result in 
discontinuation from the study, necessitate therapeutic medical intervention, meets 
protocol specific criteria (see Section 6.1.7 regarding toxicity management) and/or if the 
investigator considers them to be AEs.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
AE if the surgery/procedure is being performed for a 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 AE.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
86
Expected manifestations of AD (i.e., itching, excoriations, oozing, crusting, erythema, 
etc.) should not be reported as AEs unless considered to be a worsening of the underlying 
disease. 
6.1.1.2
Serious Adverse Events
If an AE meets any of the following criteria, it is to be reported to AbbVie as a serious 
adverse event (SAE) within 24 hours of the site being made aware of the SAE.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes 
with the activities of daily living of a study subject.  Disability 
is not intended to include experiences of relatively minor 
medical significance such as headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g., sprained 
ankle).


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
87
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity).  
Additionally, any elective or spontaneous abortion or stillbirth 
is considered an important medical event.  Examples of such 
events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse.
For SAEs with the outcome of death, the date and cause of death will be recorded on the 
appropriate case report form.
6.1.1.3
Adverse Events of Special Interest
The following AEs of special interest will be monitored during the study (see detailed 
toxicity management in Section 6.1.7):
●
Serious infections
●
Opportunistic infections
●
Malignancy
●
Hepatic Disorder
●
Gastrointestinal perforations
●
Anemia
●
Neutropenia
●
Herpes Zoster
●
Creatine Phosphokinase (CPK Elevation)
●
Decreased lymphocyte counts
●
Renal Dysfunction
●
Tuberculosis


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
88
●
Adjudicated cardiovascular events
●
Cardiac Arrhythmias
6.1.2
Adverse Event Severity
The investigator will use the following definitions to rate the severity of each AE:
When criteria are available, events should be graded as described in the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), which can 
be accessed at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc.
If no grading criteria are provided for the reported event, then the event should be graded 
as mild, moderate, or severe per the investigator's judgment. 
Mild
Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated
Moderate
Minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL)
Severe
Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL
6.1.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the AE to 
the use of study drug:
Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is sufficient evidence (information) to suggest a 
causal relationship.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
89
No Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is insufficient evidence (information) to suggest a 
causal relationship
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an Other cause of event must be provided by the investigator for the serious 
adverse event.
6.1.4
Adverse Event Collection Period
All AEs reported from the time of study drug administration until 30 days, following 
discontinuation of study drug administration have elapsed, whether solicited or 
spontaneously reported by the subject.  AEs will be collected from the time of study drug 
administration until completion of this study.  In addition, SAEs and protocol-related 
non-SAEs will be collected from the time the subject signed the study-specific informed 
consent.
AE information will be collected as shown in Figure 3.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
90
Figure 3.
Adverse Event Collection
Additionally, in order to assist the adjudication process, additional information on any 
potential MACE will be collected, if applicable.
In the case of any of the following reported events, an appropriate supplemental MACE 
eCRF should be completed:
●
Cardiac events;
●
Myocardial infarction or unstable angina;
●
Heart failure;
●
Cerebral vascular accident and transient ischemic attack;
●
Cardiovascular procedures (SAE Supplemental Procedure eCRF).
In the case of certain AEs, the corresponding supplemental AE eCRF should be 
completed:
●
Hepatic;
●
Renal;
●
Herpes Zoster Infection;
●
CPK increases considered by the investigator to be an AE.
SAEs and
Protocol-Related 
Nonserious AEs
Consent
Signed
Study Drug 
Start
Study Drug 
Stopped
30 Days After 
Study Drug 
Stopped
SAEs and Nonserious AEs
Elicited and/or Spontaneously Reported


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
91
6.1.5
Serious Adverse Event
In the event of a SAE, whether associated with study drug or not, the Investigator will 
notify Clinical Pharmacovigilance within 24 hours of the site being made aware of the 
SAE by entering the SAE data into the electronic data capture (EDC) RAVE® system.  
SAE 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 SAE.
Email:  
FAX to
For safety concerns, contact the Immunology Safety Team at:
Immunology Safety Team
1 North Waukegan Road
North Chicago, IL 60064
Phone:
Email:
For any subject safety concerns, please contact the AbbVie Therapeutic Area Scientific 
Director listed below; who will discuss with the AbbVie Medical Director as needed.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
92
In emergency situations involving study subjects when the primary Therapeutic Area 
Scientific Director is not available by phone, please contact the 24-hour AbbVie Medical 
Escalation Hotline where your call will be re-directed to a designated backup AbbVie 
Therapeutic Area Medical Director:
Phone:  
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure for ABT-494 
(upadacitinib).
In Japan, the principal investigator will provide documentation of all SAEs to the Director 
of the investigative site and the Sponsor.
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 (Section 5.4.1).
Information regarding a pregnancy occurrence in a study subject or the partner of an 
enrolled subject and the outcome of the pregnancy will be collected.  Pregnancies in study 
female subjects and female partners of male subjects will be collected from the date of the 
first dose through 30 days following the last dose of study drug.
Pregnancy in a study subject is not considered an AE.  However, the medical outcome of 
an elective or spontaneous abortion, stillbirth or congenital anomaly is considered a SAE 
and must be reported to AbbVie within 24 hours of the site becoming aware of the event.
Subjects and their partners should avoid pregnancy throughout the course of the study, 
starting with the Screening Visit through 30 days after the last study drug administration 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
93
for female subjects and through 30 days after the last study drug administration for male 
subjects.  Male subjects should refrain from donating sperm for up to 30 days post last 
dose of study drug.  Results of a positive pregnancy test or confirmation of a pregnancy 
will be assessed starting with the Screening Visit through the final study visit.  In the 
event of pregnancy occurring in the partner of an enrolled subject, written informed 
consent for release of medical information from the partner must be obtained prior to the 
collection of any pregnancy-specific information and the pregnancy will be followed to 
outcome.
6.1.7
Toxicity Management
The toxicity management of the AEs including AEs of special interest consists of safety 
monitoring (review of AEs on an ongoing basis, and periodical/ad hoc review of safety 
issues by a safety data monitoring committee), interruption of study drug dosing with 
appropriate clinical management if applicable, and discontinuation of the subjects from 
the study drug.  The management of specific AEs and laboratory parameters is described 
below.
For subjects who discontinued study drug but continued study participation and are on 
standard of care therapies, these toxicity management requirements do not apply 
(including alerts from the central lab) and any intolerability to standard of care therapies 
should be managed by the prescribing physician.
Serious Infections:  Subjects should be closely monitored for the development of signs 
and symptoms of infection during and after treatment with study drug.  Study drug should 
be interrupted if a subject develops a serious infection or an opportunistic infection.  A 
subject who develops a new infection during treatment with study drug should undergo 
prompt diagnostic testing appropriate for an immunocompromised subject.  As 
appropriate, antimicrobial therapy should be initiated, and the subject should be closely 
monitored.  Re-challenge with study drug may occur once the infection has been 
successfully treated.  If study drug has been interrupted for more than 14 consecutive days 
in Period 1 or more than 21 consecutive days in Period 2, the subject must be 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
94
discontinued from the study drug.  Subjects who develop active TB must be discontinued 
from the study drug.
Serious Gastrointestinal Events:  Subjects presenting with the onset of signs or 
symptoms of a serious gastrointestinal event should be evaluated promptly for early
identification of gastrointestinal perforation.  If the diagnosis of gastrointestinal 
perforation is confirmed, the subject must be discontinued from the study drug.
Cardiovascular Events (MACE):  Subjects presenting with potential cardiovascular 
events should be carefully monitored.  These events will be reviewed and adjudicated by 
an independent Cardiovascular Adjudication Committee in a blinded manner.
Malignancy:  Subjects who develop malignancy other than NMSC or carcinoma in-situ 
of the cervix must be discontinued from the study drug.  Information including 
histopathological results should be queried for the confirmation of the diagnosis.
ECG Abnormality:  Subjects must be discontinued from study drug for an ECG change 
considered clinically significant OR a confirmed absolute QTcF value > 500 msec.
Management of Select Laboratory Abnormalities:  For any given confirmed laboratory 
abnormality (confirmation by repeat testing with a new sample), the Investigator should 
assess the subject, apply the standard of care for medical evaluation and treatment 
following any local guidelines.  Specific toxicity management guidelines for abnormal 
laboratory values are described in Table 6 and may require an appropriate supplemental 
eCRF be completed.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
95
Table 6.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values
Laboratory Parameter
Toxicity Management Guideline
Hemoglobin
!
If hemoglobin < 8 g/dL interrupt study drug dosing and confirm by 
repeat testing with new sample
!
If hemoglobin decreases ≥ 3.0 g/dL from baseline, without an 
alternative etiology, interrupt study drug dosing and confirm by repeat 
testing with new sample.
!
If hemoglobin decreases ≥ 3.0 g/dL from baseline and an alternative 
etiology is known, the subject may remain on study drug at the 
investigator's discretion.
!
If confirmed, continue to withhold study drug until hemoglobin value 
returns to normal reference range or its baseline value.
Absolute neutrophil count 
(ANC)
!
If confirmed < 1000/μL by repeat testing with new sample, interrupt 
study drug dosing until ANC value returns to normal reference range 
or its baseline value.
!
Discontinue study drug if confirmed < 500/μL by repeat testing with 
new sample.
Absolute lymphocyte 
counts (ALC)
!
If confirmed < 500/μL by repeat testing with new sample, interrupt 
study drug dosing until ALC returns to normal reference range or its 
baseline value.
Total white blood cell 
count 
!
If confirmed < 2000/μL by repeat testing with new sample, interrupt 
study drug dosing until white blood cell count returns to normal 
reference range or its baseline value.
Platelet count 
!
If confirmed < 50,000/μL by repeat testing with new sample, interrupt 
study drug dosing until platelet count returns to normal reference 
range or its baseline value.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
96
Table 6.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values (Continued)
Laboratory Parameter
Toxicity Management Guideline
AST or ALT
!
Discontinue study drug if confirmed ALT or AST > 3 × ULN by 
repeat testing with new sample and either total bilirubin > 2 × ULN or 
international normalized ratio > 1.5
o
INR will only be measured in subjects with ALT or AST 
> 3 × ULN by the central lab by reflex testing and confirmation is 
not needed for consideration in toxicity management criteria.
!
Discontinue study drug if confirmed ALT or AST > 3 × ULN by 
repeat testing with new sample along with appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (> 5%).
!
Discontinue study drug if confirmed ALT or AST > 8 × ULN by 
repeat testing with new sample.
!
Discontinue study drug if confirmed ALT or AST > 5 × ULN by 
repeat testing with new sample for more than 2 weeks.
For all of the above ALT or AST elevation scenarios, complete 
supplemental hepatic eCRF.
Serum Creatinine
!
If serum creatinine is > 1.5 × the baseline value and > ULN, repeat the 
test for serum creatinine (with subject in an euvolemic state) to 
confirm the results.  If the results of the repeat testing still meet this 
criterion then interrupt study drug and re-start study drug once serum 
creatinine returns to ≤ 1.5 × baseline value and > ULN.
!
If confirmed serum creatinine ≥ 2.0 mg/dL, interrupt study drug and 
re-start study drug once serum creatinine returns to normal reference 
range or its baseline value. 
For the above serum creatinine elevation scenarios, complete supplemental 
renal eCRF.
Creatine Phosphokinase
!
If any confirmed CPK value ≥ 4 × ULN (if symptomatic or 
asymptomatic), complete supplemental CPK eCRF.
!
If confirmed CPK ≥ 4 × ULN accompanied by symptoms suggestive 
of myositis or rhabdomyolysis, interrupt study drug, complete 
supplemental CPK eCRF, and contact the AbbVie Therapeutic Area 
Scientific Director who will discuss with the AbbVie Medical 
Director.
For allowed study drug interruption, the following rules apply:
●
For ABT-494/placebo (daily dosing):  


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
97
○
Allow study drug interruption up to ≤ 14 consecutive days for AEs and 
emergency surgery during Period 1.
○
In Period 2 (after Week 16), study drug interruption due to AEs/surgery is 
allowed ≤ 21 consecutive days.
●
Elective surgery during Period 1 (up to Week 16) is not allowed.  Elective 
surgery during Period 2 only up to the Week 40 visit is discouraged and needs 
to be discussed with the AbbVie Therapeutic Area Scientific Director who will 
discuss with the AbbVie Medical Director.  If the subject undergoes elective 
surgery, the study drug should be interrupted 1 week prior to the planned 
surgery.  If the subject must undergo emergency surgery, the study drug should 
be interrupted at the time of the surgery.  After emergency surgery, allow 
reintroduction of study drug once the physician has examined the surgical site 
and determined that it has healed and there is no sign of infection.
6.1.8
Data Monitoring Committee
An external DMC will review unblinded safety data.  See Section 5.5.5.1 for details.
6.1.9
Cardiovascular Adjudication Committee
An independent committee of physician experts in cardiovascular adjudication will be 
utilized to assess potential cardiovascular AEs in a blinded manner as defined by the 
Cardiovascular Adjudication Committee charter.
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 or to the medical device component(s).
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.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
98
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 AEs will be reported in the study summary.  All other 
complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition.  In instances where a return is requested, every effort should be made by the 
investigator to return the product within 30 days.  If returns cannot be accommodated 
within 30 days, the site will need to provide justification and an estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
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 occurs (or is identified) 
after a subject has been enrolled, the principal investigator is responsible for notifying 
Independent Ethics Committee (IEC)/Independent Review Board (IRB) regulatory 
authorities (as applicable), and  the following AbbVie Clinical Monitor(s):


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
99
Primary Contact:
Alternate Contact:
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.
Examples of protocol deviations include the following:
●
Subject entered into the study even though she/he did not satisfy entry criteria;
●
Subject who developed withdrawal criteria during the study and was not 
withdrawn; 
●
Subject who received wrong treatment or incorrect dose;
●
Subject who received excluded or prohibited concomitant treatment.
In Japan, the Investigator will record all protocol deviations in the appropriate medical 
records at site.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
The objectives of the statistical analyses are to evaluate the safety and efficacy of multiple 
doses of ABT-494 (upadacitinib) versus placebo, and assess the dose-response 
relationships among the three ABT-494 treatment groups and placebo group.  Pairwise 
comparison of each ABT-494 treatment group versus placebo will be performed for all 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
100
primary and secondary endpoints in Period 1.  Descriptive summaries will be provided for 
all treatment groups in Period 2.
Complete and specific details of the statistical analysis will be described and fully 
documented in the Statistical Analysis Plan (SAP).  The SAP will be finalized prior to the 
database lock and blind break.  The statistical analyses will be performed using a 
Statistical Analysis System (SAS) (SAS Institute Inc., Cary, NC, USA).
8.1.1
Analysis Populations
The Intent-to-Treat (ITT) Subject Population, including all randomized subjects, will be 
used for the efficacy analyses.  ITT populations will be defined for Period 1 and Period 2.  
The ITT Population in Period 1 is defined as all subjects who are randomized at Day 1.  
The ITT Population in Period 2 is defined as all subjects who are re-randomized at the 
entry of Period 2.
A Per-protocol Population will be defined if deemed necessary to exclude subjects with 
major protocol violations.  The criteria for excluding subjects from the Per-protocol 
Population will be defined in the SAP and subjects to be excluded from the Per-protocol 
Population will be finalized before database lock and blind break.  The Per-protocol 
Population, if defined, will be used to analyze the primary efficacy endpoint and key 
secondary efficacy endpoints.
The Safety Population, including all randomized subjects who receive at least one dose of 
study drug, will be used for the safety analysis.  Safety populations will be defined for 
Period 1 and Period 2.  The Safety Population in Period 1 is defined as all subjects who 
are randomized and receive at least one dose of study drug in Period 1.  The Safety 
Population in Period 2 is defined as all subjects who are re-randomized at the entry of 
Period 2 and receive at least one dose of study drug in Period 2.
For efficacy analysis, subjects will be included in the treatment group to which they are 
randomized, regardless of which treatment the subjects actually received.  The Safety will 
be analyzed by treatment group as treated. 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
101
8.1.2
Planned Methods of Statistical Analysis
Unless otherwise specified, all statistical tests will be two-sided significance level of 0.05.  
A test will be deemed significant if the P value rounded to three decimal places is less 
than or equal to 0.050 unless otherwise specified.  Descriptive statistics will be provided 
including the number of observations, mean, median, standard deviation, minimum, and 
maximum for continuous variables, and counts and percentages for discrete variables.
8.1.3
Subject Accountability, Disposition and Study Drug 
Exposure
8.1.3.1
Subject Accountability
The following information will be summarized by site and by treatment group, as well as 
overall:  number of subjects randomized, the number of subjects who received at least 
one dose of study drug, the number of subjects who completed the study, and the number 
of subjects who prematurely discontinued.
8.1.3.2
Subject Disposition
The number and percentage of subjects who are randomized, received at least one dose of 
study drug, prematurely discontinued, and completed the study will be summarized by 
treatment group and overall.  Reasons for premature discontinuation of study drug will be 
summarized for all randomized subjects by treatment group and overall, with frequencies 
and percentages by reason for discontinuation.
8.1.3.3
Study Drug Exposure and Compliance
Exposure to study drug will be summarized for the Safety Populations in Period 1 and 
Period 2.  The exposure to study drug (days) will be summarized with the mean, standard 
deviation, median, and range for each treatment group.  The exposure to study drug is 
defined as the difference between the dates of the first and last doses of the study drug 
plus 1 day.  Study drug compliance will also be summarized for each treatment group.  
The compliance is defined as the number of tablets taken (i.e., the difference between the 
number of tablets dispensed and the number of tablets returned) during the subject's 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
102
participation in the study divided by the number of tablets a subject is supposed to take 
each day times the length of time that the subject was in the Treatment Phase of the study.
8.1.4
Demographics and Baseline Characteristics
Demographics and Baseline characteristics of the study subjects will be summarized for 
each arm of the study using descriptive statistics.  
Summary statistics for continuous variables will include the number of observations, 
mean, standard deviation, median, and range for each treatment group, and will be 
compared among treatment groups using analysis of variance (ANOVA).  For other 
categorical or discrete variables, frequencies and percentages will be computed in each 
category for each treatment group, as well as for all subjects combined, and will be 
compared among treatment groups using chi-square test or Fisher's exact test (if 25% of 
the cells have expected counts less than 5).
8.1.5
Statistical Analyses of Efficacy
The efficacy analysis will be conducted in the ITT Population, and Per-protocol 
Population if defined, in each Period.  Visit windows and the data handling conventions 
for summarizing efficacy results will be defined in the Statistical Analysis Plan.  Missing 
data will be imputed using the following methods for the efficacy analyses in the ITT 
Populations:
●
Non-Responder Imputation (NRI):  the NRI analysis will categorize any 
subject who has missing value at a specific visit as non-responder for that visit.  
In NRI analysis, subjects who prematurely discontinue study drug will be 
considered non-responders on or after discontinuation date.  NRI will be the 
primary approach for binary endpoints.
●
Last Observation Carried Forward (LOCF):  The LOCF analyses will use the 
completed evaluation from the previous visit to impute missing data at later 
visits.  Baseline value will not be carried forward.  LOCF will be the primary 
approach in the analysis of continuous variable, and the secondary approach in 
the analysis of categorical variables.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
103
●
As-observed (OC):  The OC analysis will not impute values for missing 
evaluations, and thus a subject who did not have an evaluation on a scheduled 
visit will be excluded from the as observed analysis for that visit.  As-observed 
analysis will be the secondary approach in the analysis of continuous variables.
●
Multiple Imputation (MI):  The MI analysis imputes missing data multiple 
times under appropriate random variation and thus generates multiple imputed 
"pseudo-complete" datasets.  Results will be aggregated across the multiple 
imputed datasets, overcoming drawbacks of the single imputation methods.  
MI will be performed for the primary efficacy variable and the proportion of 
subjects achieving IGA of "clear" or "almost clear" and EASI 75 at Week 16.
Efficacy parameters for the subjects who are rescued with 30 mg ABT-494 or topical 
corticosteroids in Period 2, and subjects who discontinued study drug due to EASI score 
worsening during Period 1 will be imputed from the point of rescue using non-responder 
imputation for categorical variables or LOCF for the continuous variables.
8.1.5.1
Primary Analysis of Efficacy
Primary efficacy endpoint is the percent change in EASI from baseline at Week 16.  The 
comparisons between an ABT-494 (upadacitinib) treatment groups and placebo on 
primary efficacy endpoints will be performed using MCPMod approach.
The primary analysis will be carried out in the ITT Population and the Per-protocol 
Population, if defined.
LOCF will be used as primary approach for missing values.  Sensitivity analyses using
Multiple Imputation will be performed for the primary efficacy endpoint, EASI 75, and 
IGA 0 or 1.
Primary efficacy endpoint will also be analyzed using an appropriate model and terms 
included in the model for baseline characteristics.  Due to likely small numbers, 
investigational site effects will not be fitted in the model.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
104
The dose-response relationships among the three ABT-494 treatment groups and placebo 
group will be characterized for the primary endpoint at Week 16 using MCPMod 
approach.  The following models will be considered:  linear, Emax, exponential, logistic 
and sigEmax.  The MCPMod approach for trial analysis stage consists of two main steps:  
MCP and Mod step.  The MCP step focuses on establishing evidence for a drug effect 
across the doses, i.e., detecting a statistically significant dose response signal for the 
clinical endpoint and patient population investigated in the study.  This step will typically 
be performed using an efficient test for trend, adjusting for the fact that multiple candidate 
dose response models are being considered.  If a statistically significant dose response 
signal has been established, one proceeds with determining a reference set of significant 
dose response models by discarding the non-significant models from the initial candidate 
set.
The MCP step in MCPMod approach will typically be performed using an efficient test 
for trend, adjusting for the fact that multiple candidate dose response models are being 
considered.
The fitted curve for response function will be shown graphically with confidence intervals 
for each dose.  Estimates of the treatment differences in response function and the 
associated 90% and 95% confidence intervals (CIs) for each active dose against placebo 
will be calculated from the model. 
These results will be back-transformed to provide point estimates of the treatment 
difference in the primary efficacy endpoint and the associated 90% and 95% confidence 
intervals.  The validity of the given dose-response model will be tested.  Should any of the 
assumptions of the proposed analysis procedures not be met, alternative procedures will 
be implemented and fully documented.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
105
8.1.5.2
Secondary Analysis of Efficacy
For binary endpoints, frequencies and percentages will be reported for each treatment 
group.  Pairwise comparison of each ABT-494 group and placebo will be performed using 
the Cochran Mantel-Haenszel test adjusting for stratification factors.
For continuous endpoints, the mean, standard deviation, median, and range will be 
reported for each treatment group.  Pairwise comparisons for each of the ABT-494 
treatment groups and the placebo group will be carried out using the analysis of 
covariance (ANCOVA) model with treatment group as the fixed factor, and the 
corresponding baseline value and the stratification factors as the covariates.
Time to event variables will be analyzed by stratified log-rank test adjusting for 
stratification factors.  
Proportion of subjects achieving EASI 75 at Week 16 and proportion of subjects 
achieving IGA of "clear" or "almost clear" at Week 16 will also be analyzed by 
demographic subgroups including age, gender, weight, body mass index, race and 
geographical region.  Additional subgroup analysis based on baseline characteristics may 
be conducted.
8.1.6
Safety Analysis
8.1.6.1
General Considerations
Safety analyses will be carried out using the Safety Population, in each period, and is 
based on treatments actually received.  Safety will be assessed by AEs, physical 
examination, laboratory assessments, ECG, and vital signs.  Frequency tables and lists of 
subjects with treatment-emergent AEs by preferred term as in the Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary, by system organ class, by severity, and by 
relationship to the study drug as assessed by the Investigator will be provided.  The 
changes from baseline in vital signs, physical examination results, and clinical laboratory 
values will be analyzed in a descriptive manner.  Shift of laboratory values from baseline 
to defined time points will be tabulated.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
106
Missing safety data will not be imputed.
8.1.6.2
Analysis of Adverse Events
8.1.6.2.1
Treatment-Emergent Adverse Events (TEAE)
AEs will be coded using MedDRA.  A TEAE is defined as an AE that began or worsened 
in severity after initiation of study drug.
AEs starting more than 30 days following the last dose of study drug will not be included 
in summaries of TEAEs.
As a general safety summary, the number and percentage of subjects experiencing TEAEs 
will be summarized for each treatment group for the following AE categories:
●
All AEs;
●
All severe AEs;
●
All reasonably possibly related AEs;
●
All SAEs;
●
Frequent AEs (reported in 5% of subjects or more in any treatment group);
●
Frequent reasonably possibly related AEs (reported in 5% of subjects or more 
in any treatment group);
●
Discontinuations due to AEs;
●
Death.
TEAEs will also be summarized separately for the period when subjects receive ABT-494 
monotherapy, the period when subjects receive concomitant mometasone furoate, and the 
period when subjects receive concomitant triamcinolone acetonide.
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
107
TEAEs will be summarized and presented by system organ classes (SOCs) and preferred 
terms (PTs) using MedDRA.  The SOCs will be presented in alphabetical order, and the 
PTs will be presented in alphabetical order within each SOC.
TEAE will also be summarized by maximum severity and by maximum relationship.
●
The AEs of special interest (including but not limited to serious infections, 
opportunistic infections, malignancy, hepatic disorder, gastrointestinal 
perforations, anemia, neutropenia, herpes zoster, creatine phosphokinase (CPK 
elevation), decreased lymphocyte counts, renal dysfunction, tuberculosis, 
adjudicated cardiovascular events, cardiac arrhythmias) will be summarized.  
Event rate (per 100 patient years) for AEs of special interest will also be 
summarized for the combined safety analysis of Period 1 and Period 2.
All AEs leading to discontinuation will be presented in listing format.  A listing by 
treatment group of TEAEs grouped by SOC and MedDRA preferred term with subject 
identification numbers will be generated.
8.1.6.2.2
Serious Adverse Events and Death
All treatment-emergent SAEs and AEs leading to death will also be presented in listing 
format.  In addition, SAEs will be summarized by SOC and MedDRA PT.
8.1.6.3
Analysis of Laboratory, Vital Sign, and ECG Data
Changes from baseline by visit, and changes from baseline to minimum value, maximum 
value, and final values in continuous laboratory data, and vital signs will be summarized 
by treatment group. 
The laboratory data will be categorized as low, normal, or high based on the normal 
ranges of the laboratory used in this study.  The shift tables will tabulate the number and 
percentage of subjects with baseline values below/within/above the normal range versus 
minimum/maximum/final values below/within/above the normal range.  Shift tables for 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
108
liver elevations from baseline to post baseline maximum value will be summarized for 
each treatment group.
Listings will be provided for potentially clinically significant laboratory values and vital 
signs.
Analysis details will be specified in the SAP.
8.1.7
Interim Analysis
The analysis of the double-blind 16-week period of the study (Period 1), including the 
primary endpoint analysis, will be conducted after all subjects have either completed the 
Period 1 or discontinued from the study; and the data regarding Period 1 have been 
cleaned and an interim database lock is performed.  This efficacy analysis is the only and 
final analysis of the double-blind Period 1, thus no adjustment of alpha-level is needed.  
In addition, there will be an interim analysis after all subjects have either reached 
Week 32 or discontinued from the study; and the data is cleaned.
8.1.8
Pharmacokinetic and Exposure-Response Analyses
Individual ABT-494 (upadacitinib) plasma concentrations at each study visit will be 
tabulated and summarized with appropriate statistical methods.
Data from this study may be combined with data from other studies for the population 
pharmacokinetic and exposure-response analyses.  Population pharmacokinetic and 
exposure-response analyses of only data from this study may not be conducted.  The 
following general methodology will be used for the population pharmacokinetic and 
exposure-response analyses.
Population PK analyses will be performed using the actual sampling time relative to 
dosing.  PK models will be built using a non-linear mixed-effects modeling approach with 
NONMEM software (Version 7, or a higher version). The structure of the starting PK 
model will be based on the PK analysis of data from previous studies.  The CL/F and V/F 
of ABT-494 will be the PK parameters of major interest in the analyses.  If necessary, 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
109
other parameters, including the parameters describing absorption characteristics, may be 
fixed if useful in the analysis.
The evaluation criteria described below will be used to examine the performance of 
different models.
1.
The objective function of the best model is significantly smaller than the alternative 
model(s).
2.
The observed and predicted concentrations from the preferred model are more 
randomly distributed across the line of unity (a straight line with zero intercept and 
a slope of one) than the alternative model(s).
3.
Visual inspection of model fits, standard errors of model parameters and change in 
inter-subject and intra-subject error.
Once an appropriate base PK model (including inter- and intra-subject error structure) is 
developed, empirical Bayesian estimates of individual model parameters will be 
calculated by the posterior conditional estimation technique using NONMEM.  The 
relationship between these conditional estimates CL/F and V/F values with only 
potentially physiologically relevant or clinically meaningful covariates (such as subject 
age, sex, body weight, concomitant medications, laboratory markers of hepatic of renal 
function, etc.) will be explored using stepwise forward selection method, or another 
suitable regression/smoothing method at a significance level of 0.05.  After identification 
of all relevant covariates, a stepwise backward elimination of covariates from the full 
model will be employed to evaluate the significance (at P < 0.005, corresponding to a 
decrease in objective function > 7.88 for one degree of freedom) of each covariate in the 
full model.
Linear or non-linear relationships of primary PK parameters with various covariates will 
be explored.  


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
110
Relationships between ABT-494 exposure and clinical observations (primary efficacy 
variable) will be explored.  Exposure-response relationships for secondary efficacy 
variables and/or some safety measures of interest may also be explored.  The relationship 
between exposure (e.g., population PK model predicted average concentrations, area 
under the curve, trough concentrations, the individual model-predicted PK profiles, or 
some other appropriate measure of exposure) and drug effect will be explored.  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 observed data.  
Results of the PK and exposure-response analyses may be summarized in a separate report 
prior to regulatory filing of ABT-494 (upadacitinib) for the treatment of RA, rather than in 
the CSR.
Additional analyses will be performed if useful and appropriate.
8.1.9
Statistical Analysis of Biomarker Data
Summary statistics for the in vivo pharmacodynamic biomarkers (NK, NKT, B cells, and 
T cells) at baseline and post-treatment time points (Weeks 8 and 16 or PD), in addition to 
change from baseline at each time will be provided; this will include mean, standard 
deviation, median, quartiles, and range for each group.  The pharmacodynamic effect of 
each biomarker between the placebo and ABT-494 (upadacitinib) treatment groups will be 
evaluated via a non-linear mixed-effects modeling approach with Change from baseline of 
the biomarker as response variable, Treatment, Time, and Treatment × Time interaction as 
fixed-effects, the corresponding baseline biomarker score as a covariate, and "subjects 
nested within the treatment group" as a random-effect.  Other baseline variables such as 
age, weight, etc., may be considered as appropriate.  For biomarkers identified to have 
significant overall treatment effect via the non-linear mixed-effects modeling analysis, 
dose-response models with the biomarker as a continuous response will be explored.  In 
addition to the above analyses of biomarkers individually, the effect of certain 
combination of biomarkers on the treatment groups may be explored.  If the optional 
exploratory research/validation studies variables, including an additional panel of 
prognostic, predictive, surrogate and pharmacodynamic biomarkers are evaluated, then 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
111
those data may be analyzed as follows.  The association of biomarkers to the efficacy and 
safety endpoints may be explored for each biomarker one at a time, and also for 
combinations of biomarkers via some multivariate predictive modeling algorithms.  
Optimal multivariate combinations of biomarkers that associate with efficacy endpoints, 
subject response/non-response (with respect to appropriate clinical endpoints), and also 
with safety endpoints may be explored via a variety of statistical predictive modeling 
algorithms.  Also cut-points for individual biomarkers and optimal combinations of 
biomarkers that differentiate the subject response with respect to efficacy/safety endpoints 
may be explored.  The significance of these multivariate combinations of biomarkers may 
be assessed via at least 20 iterations of 5-fold cross-validation.
Analyses will be performed for each of IL-6 induced STAT3 phosphorylation, 
IL-7-induced STAT5 phosphorylation and GMCSF induced STAT5 phosphoylation as 
measured in a whole blood ex vivo assay.  Descriptive statistics will be provided by dose 
level (with placebo considered a dose level) for the measure of phosphorylation at each 
scheduled time point of evaluation.  Descriptive statistics will also be provided for the 
percent inhibition of phosphorylation for each of the post dose times of evaluation, with 
the pre-dose measurement from the first day of the ABT-494 regimen as the baseline 
value.  For each day of serial measurements, a repeated measures analysis will be 
performed on the measure of phosphorylation.  Alternatively, the analysis may be 
performed on the percent inhibition of phosphorylation.  In either case the baseline 
measurement of phosphorylation will be a covariate.  If the responses have a probability 
distribution that is meaningfully non-symmetric, a transformation will be sought to 
produce an approximately symmetric distribution.  Also, if percent inhibition is analyzed 
and if the variances for the various dose levels appear to differ so that incorrect 
conclusions may be reached, a transformation may be employed to achieve more nearly 
equal variances.
8.2
Determination of Sample Size
Approximately 160 subjects will be randomized to three treatment groups and placebo in 
a ratio of 1:1:1:1.  The sample size for this study is based on the percent change in EASI 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
112
from baseline at Week 16.  Assuming a percent change in EASI from baseline at Week 16 
of 35, 45, 60, and 70 in the placebo, 7.5 mg, 15 mg, and 30 mg arms with a standard 
deviation 40 and a maximum efficacy of 80, a sample size of 40 subjects per treatment 
group is sufficient to test for the presence of a dose response signal, to select the best dose 
response model for the observed data out of a pre-specified set of candidate models, and 
to estimate target doses of interest (e.g., the minimum effective dose, MED) using MCP-
Mod (Multiple comparison procedure and modeling) approach.  This approach provides 
99% average power to detect a dose effect at 5% level of significance (one-sided) with the 
linear, Emax, exponential, logistic and sigEmax models pre-specified as likely candidates to 
characterize the dose-response for ABT-494 for the percent change in EASI. 
A sample of size 40 per group provides 97% power to detect a significant difference 
between 30 mg QD and placebo, and 78% power to detect a significant difference 
between 15 mg QD and placebo at two-sided level of significance of 5.0%.
8.3
Randomization Methods
Subjects will be randomly assigned in a 1:1:1:1 ratio to one of the four treatment groups 
per the study design diagram Figure 1 in Period 1.  Randomization will be stratified by 
geographic region (US/PR/Canada, EU/AUS, and Japan).
Subjects who complete Period 1 will be randomized at Week 16 to the 72-week double-
blind treatment period (Period 2) in a 1:1 ratio within the treatment group in Period 1.  
Randomization will be stratified by geographic region (US/PR/Canada, EU/AUS, and 
Japan) and EASI 75 response at Week 16.
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 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
113
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to ICH GCP.
Any SAEs 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., ICH Expedited Reports, and 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.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (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
The investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 
the informed consent form will be given to the subject and the original will be placed in 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
114
the subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
In the event a subject withdraws consent to participate from the study, stored biomarker 
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 
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.
The skin biopsies and samples for exploratory research/validation studies will only be 
collected if the subject has voluntarily signed and dated the separate written consents for 
skin biopsies and exploratory research/validation studies, approved by an IRB/IEC, after 
the nature of the testing has been explained and the subject has had an opportunity to ask 
questions.  The separate written consents must be signed before the skin biopsies and 
exploratory research/validation studies samples are collected and testing is performed.  If 
the subject does not consent to the exploratory skin biopsies and research/validation 
studies, it will not impact the subject's participation in the study.
Selected sites will be asked to perform a complete investigation of biomarkers.  For such 
sites, these assessments (blood sample and skin biopsy collections) will be made 
mandatory as part of the main study.  There will be a specific ICF for subjects in these 
selected sites.
In the event a subject withdraws from the main study, optional exploratory research 
samples will continue to be stored and analyzed unless the subject specifically withdraws 
consent for the optional samples.  If consent is withdrawn for the optional sampling, the 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
115
subject must inform their study doctor, and once AbbVie is informed, the optional 
samples will be destroyed.  However, if the subject withdraws his/her consent and the 
samples have already been tested, those results will still remain as part of the overall 
research data.
9.3.1
Informed Consent Form and Explanatory Material
In Japan, the principal investigator will prepare the consent form and explanatory material 
required to obtain subject's consent to participate in the study with the cooperation of the 
sponsor and will revise these documents as required.  The prepared or revised consent 
forms and explanatory material will be submitted to the sponsor. Approval of the IRB 
will be obtained prior to use in the study.
9.3.2
Revision of the Consent Form and Explanatory Material
In Japan, when important new information related to the subject's consent becomes 
available, the principal investigator will revise the consent form and explanatory material 
based on the information without delay and will obtain the approval of the IRB prior to 
use in the study.  The investigator will provide the information, without delay, to each 
subject already participating in the study, and will confirm the intention of each subject to 
continue the study or not.  The investigator shall also provide a further explanation using 
the revised form and explanatory material and shall obtain written consent from each 
subject of their own free will to continue participating in the study.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
116
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.
The investigator(s)/institution(s) 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
Case report forms (CRF) 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 electronic case report forms (eCRFs) will comply with Title 21 CFR 
Part 11.  The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the study-specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
117
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.
Electronic Patient Reported Data:
Patient reported data must be completed for each subject screened/enrolled in this study.  
Some of these data are being collected with an Electronic Patient Reported Outcome 
(ePRO) system called Trialmax, provided by the technology vendor CRF Health of 
Plymouth Meeting, PA, USA.  The ePRO system is in compliance with Title 21 CFR 
Part 11.  The documentation related to the system validation of the ePRO system is 
available through the vendor, CRF Health, while the user acceptance testing of the 
study-specific PRO design will be conducted and maintained at AbbVie.
The subject will be entering the data on an electronic device; these data will be uploaded 
to a server.  The data on the server will be considered source, and maintained and 
managed by CRF Health.
The ePRO data of DLQI, MOS-R, POEM, PGIS, Asthma Symptoms, and Daytime Nasal 
Symptoms Questionnaires will be collected electronically via an onsite tablet device into 
which the patient will directly enter the required pieces of information at visits specified 
in Table 2.  The electronic tablet device will be programmed to allow data entry for only 
the visits specified in the protocol and will not allow for patients to complete more than 
one of the same assessments at any one visit.  The daily pruritus NRS, 
 
ADerm-SS, and 
 ADerm-IS ePROs will be collected from patients 
electronically every evening via a handheld device provided to the subject at Screening.  
Hand-held device usage stops at the Week 40 visit. The handheld electronic device will 
be programmed to allow data entry once per day.  All data entered on the devices will be 
immediately stored to the devices itself and automatically uploaded to a central server 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
118
administrated by CRF Health.  The Investigator and delegated staff will be able to access 
all uploaded patient entered data via a password protected website, up until the generation, 
receipt and confirmation of the study archive.
Internet access to the ePRO data will be provided by CRF Health for the duration of the 
study.  This access will be available for the duration of the study to the site investigator, as 
well as delegated personnel.  Such access will be removed from investigator sites 
following the receipt of the study archive.  Data from the ePRO 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 ePRO data.  It will be possible for the investigator to make 
paper print-outs from that media.
Electronic Actigraphy Data:
Patient data on sleep activity and scratching events must be collected for each subject 
screened/enrolled in this study.  Some of these data are being collected with an electronic 
actigraphy wearable watch device called Geneactiv Scratching Device, provided by the 
technology vendor Philips of Andover, MA, USA.  The actigraphy system is in 
compliance with Title 21 CFR Part 11.  The documentation related to the system 
validation of the actigraphy system is available through the vendor, Philips.
All data collected on the devices will be manually uploaded by site staff during the study 
visits outlined in Table 2 to a central server administrated by Philips.  The data on the 
server will be considered source; and maintained and managed by Philips.
Detailed instructions for the actigraphy devices and data uploading will be provided in the 
Philips custom instruction manual for this study.
11.0
Data Quality Assurance
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
119
12.0
Use of Information
All information concerning ABT-494 (upadacitinib) 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 ABT-494.  
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/validation studies that may be using optional and mandatory exploratory 
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 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
120
subject identifiers.  Individual results will not be reported to anyone not directly involved 
in this research other than for regulatory purposes.  Aggregate data from optional and 
mandatory exploratory research/validation studies from this study may be provided to 
investigators and used in scientific publications or presented at medical conventions.  
Optional and mandatory exploratory research/validation studies data will be published or 
presented only in a way that does not identify any individual subject.
13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The investigator must retain any records related to the study according to local 
requirements.  If the investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
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 Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
121
14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for ABT-494 
(upadacitinib).
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
A Phase 2b Multicenter, Randomized, Placebo-Controlled, Double-
Blind Dose-Ranging Study to Evaluate ABT-494 (Upadacitinib) in 
Adult Subjects with Moderate to Severe Atopic Dermatitis
Protocol Date:
30 August 2017
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
122
15.0
Reference List
1.
Williams HC.  Clinical practice.  Atopic dermatitis.  N Engl J Med.  
2005;352(22):2314-24. 
2.
Chamlin SL, Mattson CL, Frieden IJ, et al.  The price of pruritus:  sleep 
disturbance and cosleeping in atopic dermatitis.  Arch Pediatr Adolesc Med.  
2005;159(8):745-50.
3.
Hanifin JM, Reed ML; Eczema Prevalence and Impact Working Group.  A 
population-based survey of eczema prevalence in the United States.  Dermatitis.  
2007;18(2):82-91.
4.
Silverberg JI, Simpson EL.  Association between severe eczema in children and 
multiple comorbid conditions and increased healthcare utilization.  Pediatr Allergy 
Immunol.  2013;24(5):476-86.
5.
Hanifin JM, Rajka G.  Diagnostic features of atopic dermatitis.  Acta Derm 
Venereol.  1980;92:44-7.
6.
Williams HC, ed.  Atopic Dermatitis.  The Epidemiology, Causes and Prevention 
of Atopic Eczema.  Cambridge University Press, Cambridge, UK, 2000.
7.
Williams HC, Wüthrich B.  The natural history of atopic dermatitis.  In:  Williams 
HC, ed.  Atopic dermatitis:  the epidemiology, causes, and prevention of atopic 
eczema.  Cambridge, United Kingdom:  Cambridge University Press, 2000:41-59. 
8.
Ellis CN, Mancini AJ, Paller AS, et al.  Understanding and managing atopic 
dermatitis in adult patients.  Semin Cutan Med Surg.  2012;31 (3 Suppl):S18-22.
9.
Bannister MJ, Freeman S.  Adult-onset atopic dermatitis.  Australas J Dermatol.  
2000;41(4):225-8.
10.
Bao L, Zhang H, Chan LS.  The involvement of the JAK-STAT signaling pathway 
in chronic inflammatory skin disease atopic dermatitis.  JAKSTAT.  
2013;2(3):e24137.
11.
Murray PJ.  The JAK-STAT signaling pathway:  input and output integration.  J 
Immunol.  2007;178(5):2623-9.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
123
12.
Levy LL, Urban J, King BA.  Treatment of recalcitrant atopic dermatitis with the 
oral Janus kinase inhibitor tofacitinib citrate.  J Am Acad Dermatol.  
2015;73(3):395-9.
13.
Bissonnette R, et al.  Efficacy and safety of topical janus kinase inhibitor tofacitinib 
in the treatment of atopic dermatitis:  results of a phase 2a randomized clinical trial.  
World Congress of Dermatology, Vancouver, 2015.
14.
Hsu L, Armstrong AW.  JAK inhibitors:  treatment efficacy and safety profile in 
patients with psoriasis.  J Immunol Res.  2014;2014:283617.  
15.
Chu CC1, Di Meglio P, Nestle FO.  Harnessing dendritic cells in inflammatory 
skin diseases.  Semin Immunol.  2011;23(1):28-41.
16.
Nobbe S, Dziunycz P, Mühleisen B, et al.  IL-31 expression by inflammatory cells 
is preferentially elevated in atopic dermatitis.  Acta Derm Venereol.  
2012;92(1):24-8.
17.
Eichenfield LF, Tom WL, Berger TG, et al.  Guidelines of care for the 
management of atopic dermatitis:  section 2.  Management and treatment of atopic 
dermatitis with topical therapies.  J Am Acad Dermatol.  2014;71(1):116-32.
18.
Sidbury R, Davis DM, Cohen DE, et al.  Guidelines of care for the management of 
atopic dermatitis:  section 3.  Management and treatment with phototherapy and 
systemic agents.  J Am Acad Dermatol.  2014;71(2):327-49.
19.
Roekevisch E, Spuls PI, Kuester D, et al.  Efficacy and safety of systemic 
treatments for moderate-to-severe atopic dermatitis:  a systematic review.  J 
Allergy Clin Immunol.  2014;133(2):429-38.
20.
Severity scoring of atopic dermatitis:  the SCORAD index.  Consensus Report of 
the European Task Force on Atopic Dermatitis.  Dermatology.  1993;186(1):23-31.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
124
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.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
125
9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
126
Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Clinical Development, Immunology
Clinical Development, Immunology
Clinical Development, Immunology
Pharmacovigilance and Patient Safety
Data and Statistical Sciences
Clinical Pharmacokinetics
Clinical Operations


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
127
Appendix C.
TB Risk Assessment Form Example
1.
Have you or an immediate family member or other close contact ever been 
diagnosed or treated for tuberculosis?
2.
Have you lived in or had prolonged travels to countries in the following regions:
●
Africa
●
Eastern Europe
●
Asia
●
Latin America
●
Caribbean Islands
●
Russia
3.
Have you lived or worked in a prison, homeless shelter/refugee camp, immigration 
center, health care worker in a hospital or nursing home?
4.
Have you, or an immediate family member, had any of the following problems for 
the past 3 weeks or longer:
●
Chronic Cough
●
Chest pain, or pain with breathing or coughing
●
Blood-Streaked Sputum (coughing up blood)
●
Unexplained Weight Loss
●
Fever
●
Fatigue/Tiredness
●
Night Sweats
●
Shortness of Breath
From:
http://www mayoclinic.org/diseases-conditions/tuberculosis/symptoms-causes/dxc-20188557
http://www.in.gov/fssa/files/Tuberculosis_Questionnaire.pdf


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
128
Appendix D.
Investigator's Global Assessment Example
Score
Short Description
Detailed Description
0
Clear
No inflammatory signs of atopic dermatitis
1
Almost Clear
Just perceptible erythema and just perceptible 
papulation/infiltration
2
Mild
Mild erythema and mild papulation/infiltration
3
Moderate
Moderate erythema and moderate 
papulation/infiltration
4
Severe
Severe erythema and severe papulation/infiltration 
with or without oozing/crusting


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
129
Appendix E.
Eczema Area and Severity Index (EASI) Scoring Example
An EASI score is a tool used to measure the extent (area) and severity of atopic eczema 
(Eczema Area and Severity Index).  EASI score does not include a grade for dryness or 
scaling.
Assignments for the following body regions are as follows: 
●
Head and Neck
●
Trunk:  include with the lower extremities
●
Upper limbs 
●
Lower limbs
Area Score
Area score is recorded for each of the four regions of the body.  The area score is the 
percentage of skin affected by eczema.
Area score Percentage of skin affected by eczema in each region:
●
0 = no eczema in this region
●
1 = 1% – 9%
●
2 = 10% – 29% 
●
3 = 30% – 49% 
●
4 = 50% – 69% 
●
5 = 70% – 89% 
●
6 = 90% – 100%:  the entire region is affected by eczema
Severity Score
Severity score is recorded for each of the four regions of the body.  The severity score is 
the sum of the intensity scores for four signs.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
130
The four signs are: 
1.
Redness (erythema, inflammation)
2.
Thickness (induration, papulation, swelling – acute eczema)
3.
Scratching (excoriation) 
4.
Lichenification (lined skin, prurigo nodules – chronic eczema)
The average intensity of each sign in each body region is assessed as:  none (0), mild (1), 
moderate (2) and severe (3).
Score Intensity of redness, thickness/swelling, scratching, lichenification:
0 = None, absent 
1 = Mild 
2 = Moderate 
3 = Severe
For each region, record the intensity for each of four signs and calculate the severity 
score.
Severity score = redness intensity + thickness intensity + scratching intensity + 
lichenification intensity
For each region, multiply the severity score by the area score and by a multiplier.
●
Head and neck:  severity score × area score × 0.1
●
Trunk:  severity score × area score × 0.3
●
Upper limbs:  severity score × area score × 0.2
●
Lower limbs:  severity score × area score × 0.4
Add up the total scores for each region to determine the final EASI score.  The minimum 
EASI score is 0 and the maximum EASI score is 72.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
131
Appendix F.
SCORing Atopic Dermatitis (SCORAD) Example
The SCORAD is a tool used in clinical research and clinical practice that was developed 
to standardize the evaluation of the extent and severity of AD.20
Body Area Affected:
The extent of AD is assessed as a percentage of each defined body area.  To help in 
determining this extent, the sites affected by eczema are shaded on a drawing of a body.  
The rule of 9 is used to calculate the affected area (A) as a percentage of the whole body:
●
Head and neck 9%
●
Upper limbs 9% each
●
Lower limbs 18% each
●
Anterior trunk 18%
●
Back 18%
●
Genitals 1%
The score for each area is added up.  The total area is 'A,' which has a possible maximum 
of 100%.
Symptom Severity:
A representative area of eczema is selected.  In this area, the intensity of each of the 
following 6 specific symptoms is assessed as none (0), mild (1), moderate (2) or severe 
(3).
●
Redness
●
Swelling
●
Oozing/crusting
●
Scratch marks
●
Skin thickening (lichenification)
●
Dryness (this is assessed in an area where there is no inflammation)


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
132
The scores for these 6 specific symptoms should be added, for a maximum of 18 total 
points, assigned as "B" in the overall SCORAD calculation.
Subjective Symptoms:
Subjective assessment of itch and sleeplessness is recorded for each symptom by the 
subject on a visual analogue scale (VAS), where 0 is no itch (or sleeplessness) and 10 is 
the worst imaginable itch (or sleeplessness), with a maximum possible score of 20.  This 
parameter is assigned as "C" in the overall SCORAD calculation.
(10 cm in length)
SCORAD Calculation:
The SCORAD is calculated as:  A/5 + 7B/2 + C. 


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
133
Appendix G.
Dermatology Life Quality Index (DLQI) Example


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
134




ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
136
Appendix I.
Medical Outcomes Study (MOS) Sleep Scale-Revised Example


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
137


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
138
Appendix J.
Patient Oriented Eczema Measure (POEM) Example


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
139


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
140
Appendix K.
Asthma Symptoms Questionnaire Example


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
141
Appendix L.
Daytime Nasal Symptoms Questionnaire Example


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
142
Appendix M.
Atopic Dermatitis Symptom Scale (ADerm-SS) Questionnaire 
Example


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
143


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
144


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
145
Appendix N.
Atopic Dermatitis Impact Scale (ADerm-IS) Questionnaire 
Example


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
146


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
147
Appendix O.
Patient Global Impression of Severity (PGIS) Questionnaire 
Example


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
148
Appendix P.
Local Canada Requirements
Section 5.2.1, Inclusion Criteria
10.
If female of childbearing potential, must be practicing at least two reliable 
methods of contraception (one highly effective method combined with one 
effective method, refer to Section 5.2.4), that are effective from Study Day 1 
through at least 30 days after the last dose of study drug.
11.
If male, and subject is sexually active with the female partner(s) of childbearing 
potential, he must agree, from Study Day 1 through 30 days after the last dose of 
study drug, to practice the protocol-specified contraception (refer to Section 5.2.4).
Section 5.2.4, Contraception Recommendations
Contraception Recommendation for Females
A woman who is postmenopausal or permanently surgically sterile (bilateral 
oophorectomy, bilateral salpingectomy or hysterectomy) is not considered to be a woman 
of childbearing potential and is not required to follow contraception recommendations.  
Postmenopausal is defined as:
●
Age ≥ 55 years with no menses for 12 or more months without an alternative 
medical cause; or
●
Age < 55 years with no menses for 12 or more months without an alternative 
medical cause AND an FSH level > 40 mIU/L.
A woman who does not meet the definition of postmenopausal or permanently surgically 
sterile is considered of childbearing potential and is required to use two forms of 
contraception.  This includes one form of highly effective contraception and one effective 
method of contraception.  That is effective from Study Day 1 (or earlier) through at least 
30 days after the last dose of oral study drug.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
149
●
Highly effective methods:
○
Hormonal contraceptives started at least 2 months prior to randomization 
(e.g., combined [estrogen and progestogen containing] [oral contraceptives, 
patch, vaginal ring, injectables, and implants); 
○
Intrauterine device (IUD) or intrauterine system (IUS); 
○
Vasectomy and tubal ligation.
●
Effective methods:
○
Barrier methods of contraception (e.g., male condom, female condom, 
cervical cap, diaphragm, contraceptive sponge)
○
Note: The proper use of diaphragm or cervical cap includes use of 
spermicide and is considered one barrier method. The cervical cap and 
contraceptive sponge are less effective in parous women. The use of 
spermicide alone is not considered a suitable barrier method for 
contraception.  When used consistently and correctly, "double barrier" 
methods of contraception (e.g., male condom with diaphragm, male 
condom with cervical cap) can be used as an effective alternative to the 
highly effective contraception methods described above.  Male and female 
condoms should not be used together as they can tear or become damaged.
Contraception Recommendation for Males
For a male subject who has a female partner who is postmenopausal or permanently 
sterile, no contraception is required.
A male subject who is sexually active with female partner(s) of childbearing potential 
must agree from Study Day 1 through 30 days after the last dose of oral study drug to 
practice contraception with:
●
Condom use and female partner(s) using at least one of the highly effective 
contraceptive methods (as defined in the protocol for female study subjects of 
childbearing potential).


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
150
Additionally, male subjects must agree not to donate sperm from Study Day 1 through 
30 days after the last dose of oral study drug.
Male subjects are responsible for informing his partner(s) of the risk of becoming 
pregnant and for reporting any pregnancy to the study doctor.  If a pregnancy occurs, a 
partner authorization form requesting pregnancy outcome information will be requested 
from the pregnant partner.


ABT-494
M16-048 Protocol Amendment 5
EudraCT 2016-002451-21
151
Appendix Q.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes:
Section 6.1.1.3  Adverse Events of Special Interest
Add:  new tenth bullet
Decreased lymphocyte counts
Section 8.1.6.2.1  Treatment-Emergent Adverse Events (TEAE)
Eighth paragraph previously read:
The AEs of special interest (including but not limited to serious infections, opportunistic 
infections, malignancy, hepatic disorder, gastrointestinal perforations, anemia, 
neutropenia, herpes zoster, creatine phosphokinase (CPK elevation), renal dysfunction, 
tuberculosis, adjudicated cardiovascular events, cardiac arrhythmias) will be summarized.  
Event rate (per 100 patient years) for AEs of special interest will also be summarized for 
the combined safety analysis of Period 1 and Period 2.
Has been changed to read:
●
The AEs of special interest (including but not limited to serious infections, 
opportunistic infections, malignancy, hepatic disorder, gastrointestinal 
perforations, anemia, neutropenia, herpes zoster, creatine phosphokinase (CPK 
elevation), decreased lymphocyte counts, renal dysfunction, tuberculosis, 
adjudicated cardiovascular events, cardiac arrhythmias) will be summarized.  
Event rate (per 100 patient years) for AEs of special interest will also be 
summarized for the combined safety analysis of Period 1 and Period 2.

SAP_001.pdf: 
Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
1.0
Title Page
Statistical Analysis Plan
Study M16-048
Phase 2b
A Phase 2b Multicenter, Randomized, Placebo 
Controlled, Double-Blind Dose-Ranging Study to 
Evaluate ABT-494 (Upadacitinib) in Adult Subjects 
with Moderate to Severe Atopic Dermatitis
Date:  23 Aug 2017
Version 1.0
1
NCT02925117


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................6
4.0
Study Objectives, Design and Procedures............................6
4.1
Objectives .............................................................................................. 6
4.2
Design Diagram ..................................................................................... 6
4.3
Sample Size............................................................................................ 9
4.4
Interim Analysis ................................................................................... 10
5.0
Analysis Populations ........................................................... 10
5.1
Analysis Populations ............................................................................ 10
5.2
Variables Used for Stratification of Randomization .............................. 12
6.0
Analysis Windows ............................................................... 12
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications..............20
7.1
Demographic and Baseline Characteristics ........................................... 20
7.2
Medical History.................................................................................... 22
7.3
Previous Treatment and Concomitant Medications ............................... 22
7.4
Protocol Deviations .............................................................................. 23
8.0
Patient Disposition............................................................... 23
9.0
Study Drug Exposure and Compliance..............................24
9.1
Study Drug Exposure ........................................................................... 24
9.2
Compliance .......................................................................................... 25
10.0
Efficacy Analysis ................................................................. 25
10.1
General Considerations......................................................................... 25
10.1.1
Analysis of Binary Variables................................................................ 26
10.1.2
Analysis of Continuous Variables......................................................... 26
10.1.3
Analysis of Time to Event Variables .................................................... 26
10.1.4
Analysis of Dose Response................................................................... 27
10.1.5
Missing Data Imputation ...................................................................... 28
10.2
Analysis of Daily Efficacy Measurements ............................................ 30
10.3
Primary Efficacy Analysis.................................................................... 31
2


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
10.4
Secondary Efficacy Analyses ............................................................... 31
10.5
Exploratory Variables........................................................................... 32
10.6
Handling of Multiplicity....................................................................... 34
10.7
Efficacy Subgroup Analysis ................................................................. 34
11.0
Safety Analysis.....................................................................35
11.1
General Considerations......................................................................... 35
11.2
Analysis of Adverse Events.................................................................. 35
11.2.1
Treatment-Emergent Adverse Events.................................................... 36
11.2.1.1
Adverse Event Overview...................................................................... 36
11.2.1.2
Adverse Events by System Organ Class and Preferred Term ................ 37
11.2.1.3
Adverse Events by Maximum Severity................................................. 37
11.2.1.4
Adverse Events by Maximum Relationship .......................................... 37
11.2.1.5
Frequent (≥ 5%) Adverse Events and Reasonably Possibly 
Related Adverse Events by System Organ Class and Preferred 
Term .................................................................................................... 38
11.2.1.6
Adverse Events of Special Interests...................................................... 38
11.2.1.7
Adverse Events by 100 Patient Years ................................................... 40
11.2.2
Serious Adverse Events (Including Deaths) and Adverse Events 
Leading to Study Drug Discontinuation................................................ 40
11.2.3
Listing of Adverse Events..................................................................... 40
11.3
Analysis of Laboratory Data................................................................. 41
11.3.1
Variables and Criteria Defining Abnormality........................................ 41
11.3.2
Statistical Methods ............................................................................... 42
11.3.2.1
Analysis for Continuous Laboratory Data............................................. 42
11.3.2.2
Shift Table Analyses............................................................................. 43
11.3.2.3
Potentially Clinically Significant Laboratory Values ............................ 43
11.3.2.4
Liver Function Tests............................................................................. 43
11.4
Analysis of Vital Signs and Weight ...................................................... 44
11.4.1
Variables and Criteria Defining Abnormality........................................ 44
11.4.2
Statistical Methods ............................................................................... 45
11.5
Analysis of ECG Parameters ................................................................ 45
12.0
Summary of Changes .......................................................... 46
3


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
12.1
Summary of Changes Between the Latest Version of Protocol and 
the Current SAP ................................................................................... 46
12.2
Summary of Changes Between the Previous Version and the 
Current Version of the SAP .................................................................. 46
13.0
References............................................................................ 47
List of Tables
Table 1.
Notations for Treatment Groups ........................................................... 12
Table 2.
Analysis Windows for EASI, SCORAD, IGA, BSA, PGIS, 
Laboratory Parameters, and Vital Sign Variables (Period 1) ................. 15
Table 3.
Analysis Windows for Pruritus NRS, ADerm-SS, ADerm-IS, and 
Actigraphy (Period 1)........................................................................... 16
Table 4.
Analysis Windows for DLQI, MOS, and POEM (Period 1).................. 16
Table 5.
Analysis Windows for Asthma Symptoms Questionnaire and 
Daytime Nasal Symptoms Questionnaire (Period 1) ............................. 17
Table 6.
Analysis Windows for Blood Sample Parameters* (Period 1)............... 17
Table 7.
Analysis Windows for EASI, SCORAD, IGA, BSA, PGIS, 
Laboratory Parameters and Vital Sign Variables (Period 2) .................. 17
Table 8.
Analysis Windows for Daily Pruritus NRS, ADerm-SS, and 
ADerm-IS (Period 2)............................................................................ 18
Table 9.
Analysis Windows for DLQI (Period 2)................................................ 19
Table 10.
Analysis Windows for MOS, and POEM (Period 2) ............................. 19
Table 11.
Analysis Windows for Asthma Symptoms Questionnaire and 
Daytime Nasal Symptoms Questionnaire (Period 2) ............................. 19
Table 12.
Analysis Windows for Blood Sample Parameters* (Period 2)............... 19
Table 13.
Candidate Models................................................................................. 28
Table 14.
Subgroup Analysis ............................................................................... 35
Table 15.
AESI for Upadacitinib with SMQs/CMQs Searches ............................. 39
Table 16.
List of Laboratory Variables................................................................. 41
Table 17.
Definitions of Potentially Clinically Significant Chemistry and 
Hematology Variables Based on CTCAE Grades ................................. 42
Table 18.
Definition of Potentially Clinically Significant Vital Signs 
Variables.............................................................................................. 45
4


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
List of Figures
Figure 1.
Study Design Schematic......................................................................... 9
List of Appendices
Appendix A.
SCORAD Scoring Algorithm ............................................................... 48
Appendix B.
Patient Reported Outcome Scoring ....................................................... 51
5


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analysis to be completed by 
the AbbVie Data and Statistical Science Department for Upadacitinib study 
Protocol M16-048 dated 07 June 2017, which incorporates four amendments (original 
protocol:  24 June 2016; Amendment 1:  25 July 2016; Amendment 2:  18 October 2016; 
Amendment 3:  16 December 2016; Amendment 4:  07 June 2017).  It provides details to 
further elaborate statistical methods as outlined in the protocol and describes analysis 
conventions to guide the statistical programming work.
This is the first version of the SAP for Protocol M16-048.
Unless noted otherwise, all analyses will be performed using SAS version 9.2 or later 
(SAS Institute Inc., Cary, NC  27513) under the UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objective of this study is to evaluate the efficacy of multiple doses of 
upadacitinib compared with placebo in the treatment of adults with moderate to severe 
atopic dermatitis (AD).  The secondary objectives of this study are to evaluate the safety 
of upadacitinib compared with placebo as measured by adverse events (AEs), laboratory 
data, vital signs and Electrocardiogram (ECG).
4.2
Design Diagram
This is an 88-week Phase 2b, randomized, double-blind, parallel-group, placebo-
controlled multicenter study of safety and efficacy of upadacitinib in adult subjects with 
moderate to severe AD.
The duration of the study will be up to 88 weeks and will include a 35-day maximum 
screening period, a 16-week double-blind treatment period (Period 1) and a 72-week 
double-blind treatment period (Period 2).  In addition, a 30-day follow-up visit (or phone 
6


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
call if a visit is not possible) should occur to determine the status of any ongoing AEs or 
serious adverse events (SAEs), or the occurrence of any new AEs/SAEs.
Period 1:  A 16-week double-blind, placebo-controlled treatment period during which 
subjects will be randomized in a 1:1:1:1 ratio to one of four treatment groups:
●
Group 1:  upadacitinib 7.5 mg once daily (QD) for 16 weeks
●
Group 2:  upadacitinib 15 mg QD for 16 weeks
●
Group 3:  upadacitinib 30 mg QD for 16 weeks
●
Group 4:  Matching Placebo for 16 weeks
Randomization will be stratified by geographic region (US/PR/Canada, EU/AUS, and 
Japan).  Enrollment in Japan will be capped at 10% of subjects (4 subjects per group).
In Period 1, discontinuation from study drug will be mandatory for any subject with an 
Eczema Area and Severity Index (EASI) score worsening of 25% or more compared with 
their baseline EASI score at any 2 consecutive scheduled study visits from Week 4 to 
Week 12.
Period 2:  a 72-week double-blind, placebo controlled treatment period during which 
subjects who complete Period 1 will be re-randomized at Week 16 within their original 
treatment group assignments to either upadacitinib or placebo into a 72-week 
double-blind, placebo controlled treatment period in a 1:1 ratio as shown in Figure 1
(study design).  Randomization will be stratified by geographic region and the 
improvement of EASI score by at least 75% (EASI 75 response) at Week 16.  At the 
Week 16 visit, all subjects will be re-randomized as follows into Period 2:
●
Group 1 in Period 1:  upadacitinib 7.5 mg QD or matching placebo for 
72 weeks
●
Group 2 in Period 1:  upadacitinib 15 mg QD or matching placebo for 
72 weeks
●
Group 3 in Period 1:  upadacitinib 30 mg QD or matching placebo for 
72 weeks
7


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
●
Group 4 in Period 1:  upadacitinib 30 mg QD or matching placebo for 
72 weeks
Starting at the Week 20 visit (4 weeks after re-randomization into Period 2), rescue 
therapy with upadacitinib 30 mg QD will be provided to subjects who have a first instance 
of an EASI score improvement of less than 50% (i.e., < EASI 50 response), when 
compared against the Baseline.  These subjects will continue on upadacitinib 30 mg QD 
for the remainder of the study.
During Period 2, concomitant class III – IV, medium potency topical corticosteroid 
treatment will be permitted at the Week 24 visit and thereafter in subjects after a 
second instance of < EASI 50 response in any two Period 2 study visits beginning from 
Week 20 (see Protocol Section 5.2.3.4 for permitted treatments).  For subjects who 
receive topical corticosteroid rescue therapy, a visit will be required 4 weeks after 
receiving the rescue therapy.  Discontinuation from study drug will be mandatory for 
subjects with < EASI 50 response compared with their baseline EASI score 4 weeks 
following rescue with topical corticosteroids or at any visit thereafter.
In order to minimize missing data for efficacy and safety assessments, subjects who 
prematurely discontinue study drug should continue to be followed for all regularly 
scheduled visits, unless they have decided to discontinue the study participation entirely 
(withdrawal of informed consent).
A schematic of the overall study design is shown in Figure 1.
8


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
Figure 1.
Study Design Schematic
4.3
Sample Size
Approximately 160 subjects will be randomized to the four treatment groups in a ratio of 
1:1:1:1.  The sample size for this study is based on the percent change in EASI from 
baseline at Week 16.  Assuming a percent change in EASI from baseline at Week 16 of 
35, 45, 60, and 70 in the placebo, 7.5 mg, 15 mg, and 30 mg arms with a standard 
deviation 40 and a maximum efficacy of 80, a sample size of 40 subjects per treatment 
group is sufficient to test for the presence of a dose response signal, to select the best dose 
response model for the observed data out of a pre-specified set of candidate models, and 
to estimate target doses of interest (e.g., the minimum effective dose, MED) via modeling 
9


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
using the MCP-Mod (Multiple comparison procedure and modeling) approach.  This 
approach provides 99% average power to detect a dose effect at the 5% level of 
significance (one-sided) with the linear, Emax, exponential, logistic and sigEmax models 
pre-specified as likely candidates to characterize the dose-response for upadacitinib for 
the percent change in EASI.
A sample of size 40 per group provides 97% power to detect a significant difference 
between 30 mg QD and placebo, and 78% power to detect a significant difference 
between 15 mg QD and placebo at the two-sided level of significance of 5.0%.
4.4
Interim Analysis
The analysis of safety and efficacy data for the first double blind period will be conducted 
after all subjects have either completed Period 1 or discontinued from the study.  This 
efficacy analysis is the only and final analysis of Period 1, thus no adjustment of alpha-
level is needed.  In addition, there will be an interim analysis after all subjects have either 
reached Week 32 or discontinued from the study.
An external Data Monitoring Committee (DMC) comprised of persons independent of 
AbbVie and with relevant expertise in their field will review unblinded safety data from 
the ongoing study.  If necessary the DMC will also be given access to efficacy data upon 
request.  A DMC charter was prepared to describe the roles and responsibilities of the 
DMC members, frequency of data reviews, and relevant safety data to be assessed.
Communications from the DMC to the Study Teams will not contain information that 
could potentially unblind the team to subject treatment assignments.
5.0
Analysis Populations
5.1
Analysis Populations
Intent-to-Treat (ITT) Population
An ITT population will be defined for each period and be used for the efficacy analyses.
10


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
●
The ITT Population in Period 1 (ITT_1) is defined as all subjects who are 
randomized at Day 1.
●
The ITT Population in Period 2 (ITT_2) is defined as all subjects who are re-
randomized at the entry of Period 2.
For efficacy analyses, subjects included in the ITT populations will be analyzed as 
randomized.  If a subject is randomized or re-randomized in the wrong strata, the subject 
will be analyzed according to the actual strata that subject belongs to.
Safety Population
A Safety population will be defined for each period and be used for safety analyses.
●
The Safety Population in Period 1 (Safety_1) is defined as all subjects who are 
randomized and receive at least one dose of study drug in Period 1.
●
The Safety Population in Period 2 (Safety_2) is defined as all subjects who are 
re-randomized at the entry of Period 2 and receive at least one dose of study 
drug in Period 2.
For the Safety populations, subjects are assigned to a treatment group based on the "as 
treated" treatment group.  In the case where the subject received more than one treatment, 
the "as treated" is determined by the dosage that a patient received the most during a 
period.
11


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
Table 1.
Notations for Treatment Groups
Population
Treatment Code
Definition
ITT_1 and 
Safety 1
UPA 7.5 MG
Upadacitinib 7.5 mg.
UPA 15 MG
Upadacitinib 15 mg.
UPA 30 MG
Upadacitinib 30 mg.
PBO
Placebo
ITT_2 and 
Safety 2
UPA 7.5 MG/UPA 7.5 MG
Upadacitinib 7.5 mg in Period 1 and upadacitinib 
7.5 mg in Period 2
UPA 7.5 MG/PBO
Upadacitinib 7.5 mg in Period 1 and placebo in 
Period 2
UPA 15 MG/UPA 15 MG
Upadacitinib 15 mg in Period 1 and upadacitinib 
15 mg in Period 2
UPA 15 MG/PBO
Upadacitinib 15 mg in Period 1 and placebo in 
Period 2
UPA 30 MG/UPA 30 MG
Upadacitinib 30 mg in Period 1 and upadacitinib 
30 mg in Period 2
UPA 30 MG/PBO
Upadacitinib 30 mg in Period 1 and placebo in 
Period 2
PBO/UPA 30 MG
Placebo in Period 1 and upadacitinib 30 mg in 
Period 2
PBO/PBO
Placebo in Period 1 and placebo in Period 2
5.2
Variables Used for Stratification of Randomization
For Period 1, the randomization will be stratified by geographic region (US/PR/Canada, 
EU/AUS, and Japan); for Period 2, the re-randomization will be stratified by geographic 
region and EASI 75 response at Week 16.
6.0
Analysis Windows
Definition of Baseline
Baseline refers to the last non-missing observation prior to the first dose of study drug.  
For randomized but not treated subjects, the baseline value will be the last non-missing 
measurement recorded prior to the randomization.
12


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
Zero or Missing Baseline Values when Calculating Percent Change from Baseline
When baseline value is missing for a subject, percent change from baseline cannot be 
calculated and therefore percent change values will be set to missing in these situations.  
When the baseline value is 0, the percent change will be set to missing, except when the 
post baseline value is also 0, in which case the percent change will be set to 0.
Definition of Final Observation for Safety Analysis
Period 1:  The final observation is defined as the last non-missing observation collected
●
within 30 days following the last dose of study drug in Period 1 for subjects 
who discontinued from the study drug without having any dose of study drug 
in Period 2,
●
on or before the day of the first dose of study drug in Period 2 for subjects who 
had at least one dose of the study drug in Period 2.
Laboratory and vital sign evaluations performed on the day of the first dose of study drug 
in Period 2 will be included in the analysis for Period 1.  AEs with onset on the date of the 
first dose of Period 2 will be attributed to Period 1.
Period 2:  The final Observation in each period is defined as the last non-missing 
observation collected within 30 days following the last dose of study drug in the 
respective period.
Definition of Rx Days (Days Relative to the First Dose of Study Drug)
Rx days are calculated for each time point relative to the date of first dose of study drug.  
They are defined as the number of days between the day of the first dose of study drug 
and the specific time point.  Rx days are negative values when the time point of interest is 
prior to the first study drug dose day.  Rx days are positive values when the time point of 
interest is on or after the first study drug dose day.  The day of the first dose of study drug 
is defined as Rx Day 1, while the day prior to the first study drug dose is defined as Rx 
Day –1 (there is no Rx Day 0).
13


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
For analysis in Period 1 (P1 Rx Day) and Period 2 (P2 Rx Day), the Rx Day is calculated 
relative to the first dose of study drug in Period 1 and Period 2, respectively.
For subjects randomized but not dosed, Rx Days are calculated relative to the 
randomization.
Definition of Analysis Windows
All time points and corresponding time windows in Periods 1 and 2 are defined based on 
P1 Rx Days P1 and P2 Rx Day, respectively.
Analysis time windows are constructed using the following algorithm:
●
Determine the nominal Rx Day for each scheduled visit (e.g., Week 4 [4 weeks 
after baseline visit] equals P1 Rx Day 29).
●
In order to include all post baseline data, the first post-baseline interval starts 
on the first day after the first dose of study drug (P1 or P2 Rx Day 2).
●
Determine the window around a specific nominal Rx Day by adding or 
subtracting half of the interval between adjacent visits (e.g., days between 
Week 2 and Week 4 is 14).  The threshold between adjacent visits is 
determined by splitting the interval evenly between the visits.  If the resulting 
split is between Rx days, then the threshold is determined as the midpoint 
between the adjacent visits.  If the resulting split is on an Rx day, then the 
threshold is determined as being between that Rx day and the Rx day prior to it 
(e.g., the split between Week 2 and Week 4 would be between P1 Rx Days 22 
and 23).
●
If more than one assessment is included in a time window, the assessment 
closest to the nominal day will be used.  If there are two observations 
equidistant to the nominal day, the one after the nominal day will be used in 
analyses.  If more than one assessment is included on the same day, then the 
worst assessment on that day will be used in analyses, except otherwise 
specified.
14


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
For subjects randomized but not dosed, Rx Day calculated relative to Randomization in 
each period.
For the efficacy variables, vital signs, and laboratory values, visit windows are defined as 
follows.
Table 2.
Analysis Windows for EASI, SCORAD, IGA, BSA, PGIS, 
Laboratory Parameters, and Vital Sign Variables (Period 1)
Scheduled Week
Nominal Day
P1 Rx Day Interval
Baseline
1
≤ 1
Week 2
15
2 – 22
Week 4
29
23 – 43
Week 8
57
44 – 71
Week 12
85
72 – 99
Week 16
113
100 – 126a
a.
Minimum of the upper bound and the day of the first dose in Period 2.
15


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
Table 3.
Analysis Windows for Pruritus NRS, ADerm-SS, ADerm-IS, and 
Actigraphy (Period 1)
Scheduled Week
Nominal Day
P1 Rx Day Interval
Baseline
–1
< 1a
Week 1
8
2 – 11
Week 2
15
12 – 18
Week 3
22
19 – 25
Week 4
29
26 – 32
Week 5
36
33 – 39
Week 6
43
40 – 46
Week 7
50
47 –53
Week 8
57
54 – 60
Week 9
64
61 – 67
Week 10
71
68 – 74
Week 11
78
75 – 81
Week 12
85
82 – 88
Week 13
92
89 – 95
Week 14
99
96 – 102
Week 15
106
103 – 109
Week 16
113
110 – 116b
a.
ADerm-IS 
 
assessments collected on or before Day 1 will be used as baseline (P1 Rx Day Interval:  ≤ 1).
b.
Minimum of the upper bound and the day of the first dose in Period 2 for efficacy analyses.
Table 4.
Analysis Windows for DLQI, MOS, and POEM (Period 1)
Scheduled Week
Nominal Day
P1 Rx Day Interval
Baseline
1
≤ 1
Week 4
29
2 – 71
Week 16
113
72 – 154a
a.
Minimum of the upper bound and the day of the first dose in Period 2.
16
CCI


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
Table 5.
Analysis Windows for Asthma Symptoms Questionnaire and 
Daytime Nasal Symptoms Questionnaire (Period 1)
Scheduled Week
Nominal Day
P1 Rx Day Interval
Baseline
1
≤ 1
Week 16
113
2 – 224a
a.
Minimum of the upper bound and the day of the first dose in Period 2.
Table 6.
Analysis Windows for Blood Sample Parameters* (Period 1)
Scheduled Week
Nominal Day
P1 Rx Day Interval
Baseline
1
≤ 1
Week 8
57
2 – 85
Week 16
113
86 – 140a
*
Including T (CD4+ and CD8+) cells, B (CD19+) cells, natural killer (NK) cells, and natural killer-T (NKT) cells.
a.
Minimum of the upper bound and the day of the first dose in Period 2.
Table 7.
Analysis Windows for EASI, SCORAD, IGA, BSA, PGIS, 
Laboratory Parameters and Vital Sign Variables (Period 2)
Scheduled Week
Nominal Day
P2 Rx Day Interval
Entry of Period 2 (Week 16)
1
≤ 1
Week 20
29
2 – 43
Week 24
57
44 – 85
Week 32
113
86 – 141
Week 40
169
156 – 211
Week 52
253
212 – 295
Week 64
337
296 – 379
Week 76
421
378 – 463
Week 88
505
464 – 546
17


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
Table 8.
Analysis Windows for Daily Pruritus NRS, ADerm-SS, and
ADerm-IS (Period 2)
Scheduled Week
Nominal Day
P2 Rx Day Interval
Entry of Period 2 (Week 16)
1
< 1a
Week 17
8
2 – 11
Week 18
15
12 – 18
Week 19
22
19 – 25
Week 20
29
26 – 32
Week 21
36
33 – 39
Week 22
43
40 – 46
Week 23
50
47 – 53
Week 24
57
54 – 60
Week 25
64
61 – 67
Week 26
71
68 – 74
Week 27
78
75 – 81
Week 28
85
82 – 88
Week 29
92
89 – 95
Week 30
99
96 – 102
Week 31
106
103 – 109
Week 32
113
110 – 116
Week 33
120
117 – 123
Week 34
127
124 – 130
Week 35
134
131 – 137
Week 36
141
138 – 144
Week 37
148
145 – 151
Week 38
155
152 – 158
Week 39
162
159 – 165
Week 40
169
166 – 211
Week 52
253
212 – 295
Week 64
337
296 – 379
Week 76
421
380 – 463
Week 88
505
464 – 546
a.
ADerm-IS
 
assessments collected on or before Day 1 of Period 2 will be used as entry of Period 2 (P2 Rx Day Interval:  ≤ 1).
18
CCI


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
Table 9.
Analysis Windows for DLQI (Period 2)
Scheduled Week
Nominal Day
P2 Rx Day Interval
Entry of Period 2 (Week 16)
1
≤ 1
Week 40
169
2 – 211
Week 52
253
212 – 295
Week 64
337
296 – 379
Week 76
421
378 – 463
Week 88
505
464 – 546
Table 10.
Analysis Windows for MOS, and POEM (Period 2)
Scheduled Week
Nominal Day
P2 Rx Day Interval
Entry of Period 2 (Week 16)
1
≤ 1
Week 24
57
2 – 113
Week 40
169
114 – 211
Week 52
253
212 – 295
Week 64
337
296 – 379
Week 76
421
378 – 463
Week 88
505
464 – 546
Table 11.
Analysis Windows for Asthma Symptoms Questionnaire and 
Daytime Nasal Symptoms Questionnaire (Period 2)
Scheduled Week
Nominal Day
P2 Rx Day Interval
Entry of Period 2 (Week 16)
1
≤ 1
Week 40
169
2 – 336
Table 12.
Analysis Windows for Blood Sample Parameters* (Period 2)
Scheduled Week
Nominal Day
P2 Rx Day Interval
Entry of Period 2 (Week 16)
1
≤ 1
Week 20
29
2 – 56
*
Including T (CD4+ and CD8+) cells, B (CD19+) cells, natural killer (NK) cells, and natural killer-T (NKT) cells.
19


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
Dealing with Multiple Measurements Collected on the Same Day
For efficacy related analyses, if there are multiple measurements for a particular 
parameter collected on the same day for the same subject, the most conservative 
measurement indicating the worst disease status will be used in the analyses.
For safety related analyses, if there are multiple measurements made for a particular 
laboratory or vital sign parameter on the same day for the same subject without the actual 
times, the average of the values will be used in the mean change analyses.  For summaries 
and listings for shift from baseline on the minimum, maximum, final, and potentially 
significant values, all collected values within the defined treatment-emergent window will 
be used.
Definition of Missing Data Imputation
No global imputation is taking place at the database level.  Efficacy related imputations 
are outlined in Section 10.1.5.  There is no imputation for missing values in the safety 
analyses.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications
7.1
Demographic and Baseline Characteristics
Demographics and Baseline characteristics will be summarized for each arm and for 
overall of the ITT populations.  Continuous variables will be summarized with the number 
of non-missing observations by mean, standard deviation, first quartile, median, 
third quartile, minimum and maximum values.  Categorical data will be summarized using 
frequencies and percentages.
The following demographic and baseline parameters will be summarized.
Subject Demographics
●
Sex (Male, Female)
20


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
●
Age (years), defined as the number of years from year of birth to year of 
first dose of study drug
●
Age categories (< 40 years, 40 – 65 years, ≥ 65 years)
●
Race (White, Black, American Indian/Alaska Native, Native Hawaiian or 
Other Pacific Islander, Asian, Other)
●
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
●
Body weight (kg)
●
Height (cm)
●
BMI (kg/m2)
●
BMI category (< 25, ≥ 25 – < 30, ≥ 30 – < 40, ≥ 40)
●
Geographic Region (US/PR/Canada, EU/AUS, Japan)
Tobacco/Nicotine and Alcohol Use
●
Tobacco/Nicotine Use (unknown, never, current, former)
●
Alcohol Use (unknown, never, current, former)
Baseline Characteristics
●
EASI overall score and body region scores
●
Investigators Global Assessment (IGA)
●
Body Surface Area (BSA) in percentage
●
Scoring Atopic Dermatitis (SCORAD)
●
Dermatology Life Quality Index (DLQI)
●
Daily pruritus Numerical Rating Scale (NRS)
●
Patient Global Impression of Severity (PGIS)
●
Atopic Dermatitis Symptom Scale (ADerm-SS)
●
Atopic Dermatitis Impact Scale (ADerm-IS)
●
Medical Outcomes Study (MOS) Sleep Scale
●
Patient Oriented Eczema Measure (POEM)
●
Asthma Symptoms and Daytime Nasal Scores (subjects with symptoms)
21


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
●
Actigraphy data:  total sleep time per night (TST min), Sleep Efficiency (%), 
Wake After Sleep Onset (WASO), number of scratching events per hour, mean 
activity during rest (sleep)
●
Disease duration since diagnosis (years)
●
Disease duration since symptoms started (years)
●
Duration between symptoms and diagnosis (years)
●
Prior Atopic Dermatitis Treatment
●
Electrocardiogram (ECG), containing categories including normal, abnormal –
not clinically significant, abnormal – clinically significant, unable to evaluate, 
and details of the abnormality when applicable.
●
TB Status:  Tuberculin PPD skin test result, QuantiFERON-TB Gold test result
!
Chest x-ray
○
Normal, Abnormal
○
Calcified granulomas (Absent, Present)
○
Pleural scarring (Absent, Present)
○
Pleural thickening (Absent, Present)
7.2
Medical History
For the ITT_1 population, the medical history data will be summarized and presented 
using body systems and conditions/diagnoses as captured on the CRF.  The body systems 
will be presented in alphabetical order and the conditions/diagnoses will be presented in 
alphabetical order within each body system.  The number and percentage of subjects with 
a particular condition/diagnosis will be summarized for each treatment group.  Subjects 
reporting more than one condition/diagnosis within a body system will be counted only 
once for that body system.  If no subject reported information for a specific body system, 
then that category will not be displayed in the summary table.
7.3
Previous Treatment and Concomitant Medications
Prior and concomitant medications will be summarized by generic name.  A prior 
medication is defined as any medication taken prior to the first dose of study drug.  A 
22


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
concomitant medication is defined as any medication that started prior to the first dose of 
study drug and continued to be taken after the first dose of study drug or any medication 
that started after the first dose of study drug, but not after the last dose of study drug.  The 
number and percentage of subjects who had taken medications will be summarized by 
generic drug name assigned by the World Health Organization (WHO) for both prior and 
concomitant medications.
7.4
Protocol Deviations
Number and percentage of subjects who reported at least one of the following protocol 
deviation categories will be provided.
●
Subject entered into the study even though she/he did not satisfy entry criteria
●
Subject who developed withdrawal criteria during the study and was not 
withdrawn
●
Subject who received wrong treatment or incorrect dose
●
Subject who received excluded or prohibited concomitant treatment
8.0
Patient Disposition
The number of subjects for each of the following categories will be summarized, for 
overall and for each treatment group in the ITT_1 Population:
●
Number of subjects randomized to Period 1
●
Number of subjects treated in Period 1
●
Number of subjects who completed Period 1
●
Number of subjects who discontinued study drug during Period 1
●
Number of subjects who prematurely discontinued from Period 1
The number of subjects for each of the following categories will be summarized, for 
overall and for each treatment group in the ITT_2 Population:
●
Number of subjects re-randomized to Period 2
23


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
●
Number of subjects treated in Period 2
●
Number of subjects who completed Period 2
●
Number of subjects who discontinued study drug during Part Period 2
●
Number of subjects who prematurely discontinued from Period 2
In addition, the reasons (primary and all reason) for premature discontinuation of study 
drug and discontinuation from the study will be summarized with frequencies and 
percentages.
9.0
Study Drug Exposure and Compliance
9.1
Study Drug Exposure
Summary of study drug exposure and study drug compliance will be provided for each 
treatment arm for ITT_1 and ITT_2.
Study drug exposure (days) will be summarized using the sample size, mean, standard 
deviation, minimum, median and maximum for each treatment part.  Study drug exposure 
will be summarized as follows:
Period 1:
For subjects who did not continue into Period 2:
●
Date of last dose of study drug in Period 1 – Date of first dose of study drug in 
Period 1 + 1.
For subjects who continued into Period 2:  the minimum of
●
Date of first dose of study drug in Period 2 – Date of first dose of study drug in 
Period 1.
●
Date of last dose of study drug in Period 1 – Date of first dose of study drug in 
Period 1 + 1.
24


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
Period 2:
●
Date of last dose of study drug in Period 2– Date of first dose of study drug in 
Period 2 + 1.
●
For interim analysis at Week 32, minimum of the above and (cutoff date – Date 
of first dose of study drug in Period 2 + 1).
Additional summaries of upadacitinib exposures by dose level will also be performed 
including exposure to each dose level across periods.
9.2
Compliance
Treatment compliance (TC) will summarized for each treatment group in each period.  
The treatment compliance is defined as the number of tablets actually taken by the subject 
divided by the number of tablets planned to be taken by the subject during the double-
blind treatment period of the study.  Of note, the compliance in Period 2 will be 
summarized up to the date prior to the first dose of rescue.  Based on a daily dose of 
one tablet for the study drug, TC will be calculated using the following formula:
%
100
drug
study 
blinded
of
dose
last 
first to
from
days
of
number 
 taken
 tablets
of
number 
∀
#
TC
10.0
Efficacy Analysis
10.1
General Considerations
Efficacy analyses will be carried out in ITT_1 and ITT_2, respectively for Periods 1 
and 2.  Pairwise comparisons of each upadacitinib treatment group versus placebo will be 
performed in Period 1.  Descriptive summaries will be provided for all treatment groups in 
Period 2.
25


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
10.1.1
Analysis of Binary Variables
For binary variables, frequencies and percentages will be reported for each treatment 
group.  Pairwise comparison of each upadacitinib group and placebo will be performed 
using the Cochran Mantel-Haenszel test adjusting for stratification factors.  If there is a 
stratum for a treatment group that has no subject in it, a value of 0.1 will be added to all 
cells in the corresponding table in order to prevent dividing by 0, as suggested in 
Greenland and Robins (1985).1  Point estimates and 95% CIs for the difference in 
proportions between each of upadacitinib treatment groups and placebo will be provided.  
Construction of CIs for the common risk difference will be based on the Mantel-Haenszel 
estimate adjusting for stratification factors.
10.1.2
Analysis of Continuous Variables
For continuous variables, the model based mean and standard error will be provided.  The 
Baseline and visit means will also be presented for each treatment group.  The treatment 
groups will be compared using the analysis of covariance (ANCOVA) model with 
treatment group and stratification factors as fixed effects, and the corresponding baseline 
value as covariates.  Point estimates and 95% CIs of mean change from baseline within 
treatment groups, and between each upadacitinib treatment group and placebo will be 
provided.
10.1.3
Analysis of Time to Event Variables
For the time to event endpoints, the time to event will be calculated as:
●
Time to first event (as observed) = [date of first event in Period 1] – [date of 
first study drug in Period 1] + 1;
●
If a subject never attains an event in Period 1, then that subject's time to 
first achievement will be censored at the last visit where the variable was 
measured in Period 1.
26


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
Time to EASI 50/75/90 response and IGA "0" or "1" response will be evaluated for 
Period 1. Time to loss of EASI 50 response among those who were re-randomized as 
EASI 75 responders at Week 16 will be evaluated for Period 2.
Time to event variables will be analyzed by stratified log-rank test adjusting for 
stratification factors.
10.1.4
Analysis of Dose Response
The dose-response relationship among the 3 upadacitinib dose groups and the placebo 
group will be characterized for the primary efficacy endpoint percent change from 
Baseline in EASI score at Week 16 and two secondary endpoints of EASI 75 and IGA 0/1 
at Week 16 using the Multiple Comparison Procedure – Modeling (MCP-Mod)2,3 method.  
The response based on the LOCF imputation will be used, and ADDPLAN DF software 
will be used to perform the MCP-Mod analyses.
A set of six pre-specified standardized candidate dose-response models, as described in 
Table 13 will be utilized to examine the dose-response relationship.  For each endpoint 
separately, a statistically significant dose response relationship will be declared if at least 
one model is identified by the MCP-Mod method to be statistically significant at the level 
α = 0.05 one-sided.  The fitted dose-response curves will be presented graphically for all 
statistically significant models along with confidence bands.  The MED will be identified 
for each statistically significant model based on the pre-specified clinical meaningful 
target of a 20% target difference from placebo.  The weighted MED across all significant 
models will be calculated, with weights being the inverse of model AIC.
27


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
Table 13.
Candidate Models
10.1.5
Missing Data Imputation
Missing data will be imputed using the following methods for the efficacy analyses:
●
Non-Responder Imputation (NRI):  the NRI analysis will categorize any 
subject who does not have evaluation during a specific visit window as a non-
responder for that visit.  The exception is when the subject is a responder both 
before and after a specific visit window, in which case the subject will be 
categorized as a responder for the visit.  Only observations within the same 
analysis period will be used.  The NRI will be the primary approach in the 
analyses of categorical variables.
28


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
●
Last Observation Carried Forward (LOCF):  The LOCF analyses will carry 
forward the most recent previous non-missing value (last completed 
non-missing value, for composite endpoint) to impute missing data at later 
visits in the same period.  Baseline efficacy evaluations will not be carried
forward.  LOCF will be the primary approach in the analyses of continuous 
variables, and the secondary approach in the analysis of categorical variables.
●
As-Observed Cases (OC):  The as-observed analysis will not impute values for 
missing evaluations, and thus a subject who does not have an evaluation on a 
scheduled visit will be excluded from the as-observed analysis for that visit.  
As-observed analysis will be the secondary approach in the analysis of 
continuous variables.
●
Multiple Imputation (MI):  The MI approach will be used for sensitivity 
analyses on the Week 16 endpoints of EASI percent change from Baseline, 
EASI 75, and the Investigator Global Assessment (IGA) response of 0 (clear) 
or 1 (almost clear).  If MI is not applicable due to the nature of the data 
(e.g., MCMC algorithm does not converge), logistic regression or mixed effect 
model repeat measurement (MMRM) methods will be applied as the 
sensitivity approach, whichever applicable.
The Multiple Imputation analysis will be carried out in three steps.
●
Imputation of missing data.  The imputation will be generated for each efficacy 
endpoint measurement.  The variables to be included in the imputation model 
are:  Baseline EASI (or IGA), treatment group, and measurements at each visit 
up to the end of the analysis period.  For each endpoint, 20 'complete' datasets 
will be generated using SAS PROC MI.  The imputed post-baseline 
measurements will be rounded to the same precision as the observed data 
before the determination of responder status (e.g., EASI 75 and EASI 
percentage change from Baseline).
●
Analysis of imputed data sets.  Using the corresponding statistical methods for 
the categorical and continuous endpoints, the imputed endpoints from Step 2 
will be analyzed using each of the 20 datasets.
29


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
●
Synthesis of imputation and analysis results.  SAS PROC MIANALYZE will 
be used to generate the final inferences of the risk difference between 
treatment groups.
Of note, subjects who take rescue upadacitinib 30 mg or take rescue topical treatment in 
Period 2 will have their efficacy assessments taken from the date after the first dose of 
rescue excluded from the analyses, as the result, the subjects will be considered as non-
responders in the NRI approach, and have their last observations on or prior to the date of 
rescue carried forward, and be removed from the OC approach.
10.2
Analysis of Daily Efficacy Measurements
For daily efficacy 
 
 
 
For Period 1 or the entry value for Period 2, the rolling weekly average score is calculated 
starting from the first day when a measurement was available to the last day with a 
measurement, Let Pm-6, Pm-5,…, Pm-1, Pm be the daily total scores from day m – 6 to day m, 
and Nm be the number of days with non-missing pain scores from day m – 6 to day m, then 
the rolling weekly average for Day m is:
If the values from four or more days of the seven-day period are missing, then the rolling 
weekly average of Day m will be set to missing.  If more than one assessment is included 
on the same day, the assessment associated with the worst condition on that day will be 
chosen as the daily score.
m
m
m
i
i
N
P
∃
%
#
6
30
CCI


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
Analysis value for a given visit will be selected from rolling averages based on analysis 
window conventions, after dropping the rolling averages from Day 1 – 6 for Actigraphy, 
and Day 1 – 7 for other assessments, in each period.
For the visits where the questionnaire is completed at the site, scores from single clinic 
visits will be used as the analysis value.
10.3
Primary Efficacy Analysis
The primary efficacy variable is the percent (%) change from Baseline in EASI score at 
Week 16.  The analysis of the primary efficacy variable will be carried out in ITT_1 with 
the LOCF missing data imputation.  The dose-response relationship will be evaluated by 
MCP-Mod method.
10.4
Secondary Efficacy Analyses
The secondary efficacy variables include:
●
Proportion of subjects achieving an EASI 75 response, defined as at least a 
75% reduction in EASI score, at Week 16 relative to Baseline
●
Proportion of subjects achieving an IGA 0 or 1 response at Week 16
●
Percent change from Baseline in pruritus numerical rating scale (NRS) by 
week
●
Percent change in EASI score from Baseline at Week 8
●
Percent change in SCORAD score from Baseline at Weeks 8 and 16
●
Proportion of subjects achieving EASI 50/75/90 response at Weeks 8 and 16
●
Proportion of subjects achieving SCORAD 50/75/90 response at Weeks 8 
and 16
●
Change from Baseline in BSA at Week 16
●
Percent change from re-randomization in EASI score in Period 2
●
Time to loss of EASI 50 response among those who were re-randomized as 
EASI 75 responders at Week 16
31


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
●
Summary of EASI 75 at all visits in Period 2 among those who were 
re-randomized as EASI 75 non-responders at Week 16
●
Proportion of subjects  with reduction of ≥ 4 from Baseline in pruritus NRS 
among subjects with a baseline of ≥ 4
10.5
Exploratory Variables
The following endpoints will be analyzed at all visits or weeks that the assessments are 
collected, except for daily assessments where results based on a rolling average by week 
will be presented.
●
Time to EASI 50/75/90 and IGA "0" or "1" response in Period 1.
●
Proportion of subjects achieving EASI 50/75/90/100 response.
●
Proportion of subjects achieving SCORAD 50/75/90 response.
●
Change from Baseline in POEM at Weeks 4, 16, 24 and 40.
●
Change from Baseline at Weeks 4, 16, 24 and 40 in MOS Sleep Scale (Sleep 
Disturbance Score, Snoring Score, Short of Breath Score, Sleep Adequacy 
Score, Sleep Somnolence Score, Sleep Problems Index 1 Score, Sleep 
Problems Index 2 Score, Optimal Sleep Score, and Sleep Quantity Score).
●
Change from Baseline at Weeks 16 and 40 in Asthma Symptoms 
Questionnaire.
●
Change from Baseline at Weeks 16 and 40 in Daytime Nasal Symptoms 
Questionnaire.
●
Change from Baseline in total sleep time per night (TST min), Sleep 
Efficiency (%), Wake After Sleep Onset (WASO), number of scratching 
events per hour, mean activity during rest (sleep) periods as measured by 
actigraphy, by week until Week 40 and by visit thereafter.
●
Change from Baseline in ADERM-SS and ADERM-IS by week until Week 40 
and by visit thereafter.
●
Change from Baseline in PGIS.
●
Proportion of subjects with a DLQI 0 or 1 response.
32


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
●
Change from Baseline in DLQI.
●
Change from re-randomization in EASI score in Period 2.
Primary and secondary variables will also be evaluated at all scheduled visits.
The efficacy of rescue will be summarized for subjects who received the rescue 
medication.
Due to collection issues in DLQI Question 7, the corresponding secondary endpoints have 
been changed to exploratory variables and the answers to Question 7 will be removed 
from the analyses.  Of note, correction to the DLQI ePRO device has been corrected while 
the study is ongoing.  Additional analyses based on correct DLQI data may be performed.
The EASI overall score, IGA and pruritus NRS score will be summarized at Baseline and 
Week 16 for subjects from Japan, with the percentage changes in EASI and pruritus NRS 
from baseline to Week 16.
In addition to the overall EASI score, body region EASI scores will be analyzed.  The 
analysis will include all the four body component scores for head/neck, trunk, upper and 
lower extremities.  Body component EASI scores are determined by multiplying the total 
of erythema, edema/papulation, excoriation, and lichenification scores within each body 
region by the area score.
EASI body region score = (erythema score + edema/papulation score + excoriation score 
+ lichenification score)*area score
In addition, the SCORAD affected areas of head/neck and genitals will be analyzed along 
with the overall score.
Information on the scoring and missing value handling the SCORAD and Patient 
Reported Outcomes (PROS) is presented in Appendix A and Appendix B.  The types of 
PROS include POEM, MOS, pruritus NRS, PGIS, ADerm-SS, ADerm-IS, Asthma 
33


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
Symptoms Questionnaire, Daytime Nasal Symptom Questionnaire and ActiGraphy 
measurements.
MCP-Mod will also be performed for proportion of subjects achieving EASI 75 and 
achieving IGA 0 or 1 at Week 16.
10.6
Handling of Multiplicity
Multiplicity adjustments are not performed in this Phase 2b study.
10.7
Efficacy Subgroup Analysis
To evaluate the impact of baseline characteristics, subgroup analyses will be performed at 
Week 16 for the primary efficacy variable, percent change in EASI from baseline, and 
two of the secondary efficacy variables, proportion of subjects achieving EASI 75 and 
proportion of subjects achieving IGA of 0 or 1.  The subgroups are defined by each of the 
demographic factors on age, gender, body mass index (BMI), race, weight and 
geographical region as shown in Table 14 below.  Additional subgroup analysis based on 
baseline characteristics may be conducted.
If any of the resulting subgroups has fewer than 5 subjects, the subgroup analyses for that 
variable will not be presented.
34


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
Table 14.
Subgroup Analysis
Subgroup Factor
Categories
Age
< 40 years old
≥ 40 – < 65 years
≥ 65 years old
Sex
Male
Female
BMI
< 25
≥ 25 – < 30
≥ 30 – < 40
≥ 40
Race
White
Asian
Other
Weight
< median
≥ median
Geographic region
US/PR/Canada
EU/AUS
Japan
11.0
Safety Analysis
11.1
General Considerations
Safety analyses will include adverse events, laboratory, and vital sign measurements.  
Safety summaries will be provided using the safety population in each period.  
Comparison between each upadacitinib group and placebo group will be performed for 
change from baseline laboratory and vital sign parameters in the Safety_1 Population, 
using one-way ANOVA.
Missing safety data will not be imputed.
11.2
Analysis of Adverse Events
Treatment-emergent adverse events (TEAEs) will be summarized in each period.
35


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
Pre-treatment adverse event and protocol-defined non SAE will be presented in a data 
listing.  TEAEs will also be summarized separately for the time period when subjects 
receive upadacitinib monotherapy of each dose level across Period 1 and Period 2, the 
time period when subjects receive concomitant mometasone furoate, and the time period 
when subjects receive concomitant triamcinolone acetonide.
11.2.1
Treatment-Emergent Adverse Events
A treatment-emergent Adverse Event (TEAE) is defined as an adverse event with an onset 
or worsening date that is on or after the first dose of study drug, and no more than 30 days 
after the last dose of study drug.
AEs where the onset date is the same as the study drug start date are assumed to be 
treatment-emergent.  If an incomplete onset date was collected for an adverse event, the 
event will be assumed to be treatment-emergent unless there is other evidence that 
confirms that the event was not treatment-emergent (e.g., the event end date was prior to
the study drug start date).
TEAEs for the safety population in each period are defined as an event with a start date on 
or after the date of first study drug dose in each period and up to 30 days after the last 
dose of study drug in the analysis period, or prior to the date of first dose in the 
subsequent period for subjects who entered in to the subsequent period.
Adverse event data will be coded using the Medical Dictionary for Drug Regulatory 
Activities (MedDRA) version 20.0 or most up to date version.
11.2.1.1
Adverse Event Overview
The number and percentage of subjects experiencing TEAEs will be summarized for each 
treatment group for the following AE categories.
●
Any TEAE
●
Any treatment-emergent serious adverse events (TESAE)
●
Any TEAE leading to discontinuations of study drug
36


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
●
Any severe TEAE
●
Any reasonably possibly related TEAE
●
Any reasonably possibly related TESAE
●
Any TEAE leading to death
●
TEAEs of Special Interest
●
Any Death
11.2.1.2
Adverse Events by System Organ Class and Preferred Term
TEAEs will be summarized and presented by system organ class (SOC) and preferred 
terms (PT).  The SOCs will be presented in alphabetical order, and the PTs will be 
presented in alphabetical order within each SOC.
A subject who reports more than 1 AE in different SOCs will be counted only once in the 
overall total.  A subject who reports 2 or more different PTs within the same SOC, will be 
counted only once in the SOC total.  A subject who reports more than 1 AE with the same 
PT will be counted only once for that PT using the most extreme incidence.
11.2.1.3
Adverse Events by Maximum Severity
TEAEs will be summarized by maximum severity.  If a subject has an AE with an 
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 that if the subject has another occurrence of the same AE with the most 
extreme severity (severe).  In this case, the subject will be counted under the severe 
category.
11.2.1.4
Adverse Events by Maximum Relationship
TEAEs will be summarized by maximum relationship to study drug, as assessed by the 
investigator.  If a subject has an AE with an 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 if the 
37


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
subject has another occurrence of the same AE with a relationship assessment of 
reasonable possibility in which case, the subject will be counted under reasonable 
possibility category.
11.2.1.5
Frequent (≥ 5%) Adverse Events and Reasonably Possibly 
Related Adverse Events by System Organ Class and 
Preferred Term
TEAEs and reasonably possibly related AEs occurring for more than 5% of the subjects in 
any treatment groups will be summarized by MedDRA PT in decreasing frequency 
separately.
11.2.1.6
Adverse Events of Special Interests
The AESI categories will be identified by the following search criteria per Standard 
MedDRA Queries (SMQs)/Company MedDRA Queries (CMQs) specified in Table 15.
38


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
Table 15.
AESI for Upadacitinib with SMQs/CMQs Searches
AESI
Type of 
MedDRA 
Query
Broad 
or 
Narrow 
Search
SMQ/CMQ Search Criteria
Serious Infections
CMQ
"Infections" – Subset for SAEs
Opportunistic Infection
CMQ
"Opportunistic Infection" 
Malignancy
SMQ
Narrow
"Malignancies" 
Non-Melanoma Skin 
Cancer (NMSC)
SMQ
Broad
Skin Malignant tumours (Broad SMQ) removing 
Melanoma CMQ
Malignancy excluding 
NMSC
Malignancy Narrow SMQ and removing NMSC 
output
Lymphoma
SMQ
"Malignant Lymphomas"
Hepatic Disorder
SMQ
Narrow
"Drug Related Hepatic Disorders" 
Gastrointestinal 
Perforations
SMQ
Narrow
"Gastrointestinal Perforation" 
Anemia
CMQ
"Non-Hemolytic and Non-Aplastic Anemias" 
Neutropenia
CMQ
"Hematological Toxicity – Neutropenia"
Lymphopenia
CMQ
"Hematological Toxicity – Lymphopenia 
(Veliparib Product Specific)"
Herpes Zoster
CMQ
"Herpes Zoster"
Rhabdomyolysis/myopathy
SMQ
Narrow
"Rhabdomyolysis/Myopathy"
Creatine Phosphokinase 
(CPK Elevation)
PT
Search only for the PT of "Blood creatine 
phosphokinase increased"
Renal Dysfunction
SMQ
Narrow
"Acute Renal ,Failure"
Tuberculosis
CMQ
"Tuberculosis"
Adjudicated cardiovascular 
eventsa
Output 
from CAC
Cardiac Arrhythmias
SMQ
Narrow
"Torsade de pointes/QT Prolongation"
"Tachyarrhythmias"
a.
Reviewed and adjudicated by an independent Cardiovascular Adjudication Committee in a blinded manner.
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.
39


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
11.2.1.7
Adverse Events by 100 Patient Years
TEAEs will be summarized by event rate per 100 subject years, defined as
100 * (Number of TEAEs)/(Total Patient Years)
where total patient years is defined as the sum of the study drug exposure (defined in 
Section 9.1) of all subjects normalized by 365.25, and rounded to 1 decimal place.  Event 
rate (per 100 patient years) for AEs of special interest will also be summarized for the 
combined safety analysis of Period 1 and Period 2.
11.2.2
Serious Adverse Events (Including Deaths) and Adverse 
Events Leading to Study Drug Discontinuation
All TESAEs, deaths, and TEAEs leading to discontinuation of study drug will be 
summarized.  The number and percentage of subjects experiencing SAEs (including 
deaths) and adverse events leading to discontinuation of study drug will be tabulated by 
SOC and PT for each treatment group.
11.2.3
Listing of Adverse Events
The following additional summaries will be provided for treatment-emergent adverse 
events, unless otherwise specified.
●
List of subject numbers associated with each PT for TEAEs.
●
List of subject numbers associated with each PT for TEAEs assessed by the 
investigator as reasonable possibility of being related to study drug.
●
Listing of pretreatment AEs.
●
Listing of TESAEs.
●
Listing of TEAEs that led to discontinuation of study drug.
●
Listing of all deaths.
●
Listing of treatment-emergent AESIs.
40


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
11.3
Analysis of Laboratory Data
For the assessments of laboratory data, values observed more than 30 days after the last 
dose of study drug will be excluded.
All laboratory parameters to be collected in this study are listed in Table 16 below.  
Laboratory parameters will be reported using the standard international (SI) units.
Table 16.
List of Laboratory Variables
Hematology
Chemistry
Urinalysis
White Blood Cell (WBC) Count
Red Blood Cell (RBC) Count
Hemoglobin
Hematocrit
Platelets count
Neutrophils 
Basophils 
Eosinophils 
Lymphocytes
Monocytes  
Reticulocytes*
Bands
Total Bilirubin
Alkaline Phosphatase (ALP)
Serum glutamic oxaloacetic 
transaminase (SGOT/AST)
Serum glutamic pyruvic 
transaminase (SGPT/ALT)
Total Protein
Albumin
Glucose
Triglycerides
Blood Urea Nitrogen (BUN)
Creatinine
Uric acid
Sodium
Potassium
Calcium
Inorganic Phosphorus
Creatine Phosphokinase (CPK)
Chloride
Bicarbonate
Cholesterol
LDL cholesterol
HDL cholesterol
Specific Gravity
pH
Protein*
Glucose*
Ketones*
Blood*
Nitrite*
Microscopic Examination*
Other
hsCRP
HBs Ab*
HBc Ab*
Hbs Ag*
HBV DNA PCR reflex only*
HCV Ab*
HCV RNA reflex only*
QuantiFERON-TB Gold*
*
The parameters will only be presented in data listing.
11.3.1
Variables and Criteria Defining Abnormality
Criteria for Potentially Clinically Significant chemistry and hematology variables are 
listed in Table 17 below.
41


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
Table 17.
Definitions of Potentially Clinically Significant Chemistry and 
Hematology Variables Based on CTCAE Grades
Test
Grade 1
Grade 2
Grade 3
Grade 4
SGPT/ALT
> ULN – 3.0 × ULN
> 3.0 – 5.0 × ULN
> 5.0 – 20.0 × ULN
> 20.0 × ULN
SGOT/AST
> ULN – 3.0 × ULN
> 3.0 – 5.0 × ULN
> 5.0 – 20.0 × ULN
> 20.0 × ULN
ALP
> ULN – 2.5 × ULN
> 2.5 – 5.0 × ULN
> 5.0 – 20.0 × ULN
> 20.0 × ULN
TBL
> ULN – 1.5 × ULN
> 1.5 – 3.0 × ULN
> 3.0 – 10.0 × ULN
> 10.0 × ULN
Creatinine increased  
> ULN – 1.5 × ULN
> 1.5 – 3.0 × ULN
> 3.0 – 6.0 × ULN
> 6.0 × ULN
CPK increased 
> ULN – 2.5 × ULN
> 2.5 – 5.0 × ULN
> 5.0 – 10.0 × ULN
> 10.0 × ULN
Hemoglobin decreased
< LLN – 100.0 g/L
< 100.0 – 80.0 g/L
< 80.0 g/L
N/A
Neutrophil count 
decreased 
< LLN – 1.5 × 109/L
< 1.5 – 1.0 × 109/L
< 1.0 – 0.5 × 109/L
< 0.5 × 109/L
WBC decreased 
< LLN – 3.0 × 109/L
< 3.0 – 2.0 × 109/L
< 2.0 – 1.0 × 109/L
< 1.0 × 109/L
Lymphocyte count 
decreased
< LLN – 0.8 × 109/L
< 0.8 – 0.5 × 109/L
< 0.5 – 0.2 × 109/L
< 0.2 × 109/L
Definitions of Potential Hy's Law Cases
According to FDA's Guidance for Industry "Drug-Induced Liver Injury:  Premarketing 
clinical evaluation (July 2009), when aminotransferase (AT) abnormalities indicating 
hepatocellular injury are accompanied by evidence of impaired hepatic function (bilirubin 
elevation > 2 × ULN), in the absence of evidence of biliary obstruction (i.e., significant 
elevation of ALP) or some other explanation of the injury (e.g., viral hepatitis, alcohol 
hepatitis), the combined finding (i.e., Hy's Law cases) represents a signal of a potential for 
the drug to cause severe DILI.
11.3.2
Statistical Methods
11.3.2.1
Analysis for Continuous Laboratory Data
Mean changes from baseline in all continuous laboratory parameters in each visit in 
Period 1 will be summarized with the number of observations, mean, standard deviation 
and median.  The treatment comparison between groups will be using a one-way 
ANOVA.  Percent change from baseline for selected lab parameters will also be 
summarized.  Summaries for the baseline and final value will be presented for subjects 
42


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
who have both baseline and post-baseline values.  Categorical data will be summarized 
using frequencies and percentages.
11.3.2.2
Shift Table Analyses
Baseline and post-baseline laboratory observations will be categorized as Grade 1, 
Grade 2, Grade 3, and Grade 4 according to National Cancer Institute Common Toxicity 
Criteria (NCI CTC) AE version 4.03 grades (publish date:  June 14, 2010) (See definition 
in Table 17).  Shift tables for changes from Baseline according to the NCI CTC toxicity 
grade will be provided for each hematology, clinical chemistry and urinalysis parameter.
11.3.2.3
Potentially Clinically Significant Laboratory Values
Criteria for identify Potentially Clinically Significant laboratory values are listed in the 
table above.  Of note, a post-baseline value has to be more extreme than baseline value to 
be considered.
Frequencies and percentages of subjects with post Baseline lab values that are Grade 3 or 
above according to the CTC toxicity criteria, will be summarized.  A listing of the 
subjects with laboratory values that are CTC toxicity Grade 3 or above will be provided.  
For each of these subjects, the whole course of the respective parameter will be listed.
11.3.2.4
Liver Function Tests
Additional summaries will be presented for liver function tests including ALT or SGPT, 
AST or SGOT, alkaline phosphatase, and total bilirubin.  Each laboratory value will be 
categorized as follows:
●
< 1.5 × ULN
●
≥ 1.5 × ULN – < 3.0 × ULN
●
≥ 3.0 × ULN – < 5.0 × ULN
●
≥ 5.0 × ULN – < 10.0 × ULN
●
≥ 10.0 × ULN – < 20.0 × ULN
●
≥ 20.0 × ULN
43


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
For the purpose of assessing for potential Hy's law cases, the frequencies and percentages 
of subjects with post baseline liver specific function test values that meet the following 
criteria of potential clinical interest should be presented:
●
ALT ≥ 3 × ULN
●
ALT ≥ 5 × ULN
●
ALT ≥ 10 × ULN
●
ALT ≥ 20 × ULN
●
AST ≥ 3 × ULN
●
AST ≥ 5 × ULN 
●
AST ≥ 10 × ULN 
●
AST ≥ 20 × ULN
●
TBL ≥ 2 × ULN
●
Alkaline phosphatase ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 2 × ULN
11.4
Analysis of Vital Signs and Weight
11.4.1
Variables and Criteria Defining Abnormality
Definition of Potentially Clinically Significant vital signs variables based on Criteria are 
listed in Table 18 below.
44


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
Table 18.
Definition of Potentially Clinically Significant Vital Signs Variables
Vital Sign
Category
Criteria for Potential Clinically Significant Vital Signs
Systolic blood pressure
Low
Value ≤ 90 mmHg and decrease ≥ 20 mmHg from Baseline
High
Value ≥ 160 mmHg and increase ≥ 20 mmHg from Baseline
Diastolic blood pressure
Low
Value ≤ 50 mmHg and decrease ≥ 15 mmHg from Baseline
High
Value ≥ 105 mmHg and increase ≥ 15 mmHg from Baseline
Pulse
Low
Value ≤ 50 bpm and decrease ≥ 15 bpm from Baseline
High
Value ≥ 120 bpm and increase ≥ 15 bpm from Baseline
Respiratory Rate
Low
< 10 rpm
High
> 24 rpm
Body temperature
High
> 39.0°C (102.3°F)
Weight
High
> 7% increase from baseline
Low
> 7% decrease from baseline
11.4.2
Statistical Methods
Changes from Baseline to post-baseline visits will be summarized with the baseline mean, 
the visit mean, change from baseline mean, standard deviation, and median.  An ANOVA 
model with only treatment as a factor, not controlling for baseline, will be used to test 
statistical significance for the change from baseline mean, and present confidence 
intervals for the difference between each of the upadacitinib treatment group and placebo 
in Period 1.  The number and percentage of subjects meeting the criteria for potentially 
clinically significant vital sign values will be summarized.
Vital sign results satisfying the criteria for potentially clinically significant vital sign 
findings will be identified in a listing.  Of note, a post-baseline value has to be more 
extreme than baseline value to be considered.
11.5
Analysis of ECG Parameters
ECG is collected at baseline visit, and Week 16.  ECG findings will be summarized by 
treatment group for each parameter and visit.  Summaries will include n (%) of patients in 
following categories:
45


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
●
Normal
●
Abnormal – Not Clinically Significant
●
Abnormal – Clinically Significant
●
Unable To Evaluate
●
Missing
12.0
Summary of Changes
12.1
Summary of Changes Between the Latest Version of 
Protocol and the Current SAP
The protocol planned statistical tests for baseline variables were removed sine it is not 
meaningful to conduct hypothesis test of randomization.
In the protocol, five models were proposed to be considered for MCP-Mod:  linear, Emax, 
exponential, logistic and sigEmax.  In the SAP, quadratic model was added as an additional 
candidate model.
In the protocol, DLQI is a secondary endpoint.  Due to collection issues in DLQI 
Question 7, the corresponding secondary endpoints have been changed to exploratory 
variables and the answers to Question 7 will be removed from the analyses.  Of note, 
correction to the DLQI ePRO device has been implemented while the study is ongoing.  
Additional analyses based on correct DLQI data may be performed.
Proportion of subjects achieving an improvement of 4 or more points from Baseline in 
pruritus NRS among subjects with a baseline of at least 4 was added as a secondary 
endpoint.
12.2
Summary of Changes Between the Previous Version and the 
Current Version of the SAP
Not applicable.  This is the first version of SAP.
46


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
13.0
References
1.
Greenland S, Robins M.  Estimation of a common effect parameter from sparse 
follow-up data.  Biometrics.  1985;41(1):55-68.
2.
Pinheiro J, Bornkamp B, Bretz F.  Design and analysis of dose-finding studies 
combining multiple comparisons and modeling procedures.  J Biopharm Stat.  
2006;16(5):639-56.
3.
Bretz F, Pinheiro J, Branson M.  Combining multiple comparisons and modeling 
techniques in dose-response studies.  Biometrics.  2005;61(3):738-48.
47


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
Appendix A.
SCORAD Scoring Algorithm
48


1
Appendix A.
SCORAD Scoring Algorithm
Table of Contents
0.0
Questionnaire..............................................................................................................................1
1.0
Scoring Algorithm ........................................................................................................................2
2.0
Missing Value Handling................................................................................................................2
3.0
Efficacy Variables.........................................................................................................................2
4.0
Reference ....................................................................................................................................2
0.0
Questionnaire
Body Area Affected:
The extent of AD is assessed as a percentage of each defined body area.  To help in 
determining this extent, the sites affected by eczema are shaded on a drawing of a body.  The 
rule of 9 is used to calculate the affected area (A) as a percentage of the whole body:
●
Head and neck 9%
●
Upper limbs 9% each
●
Lower limbs 18% each
●
Anterior trunk 18%
●
Back 18%
●
Genitals 1%
The score for each area is added up.  The total area is 'A,' which has a possible maximum of 
100%.
Symptom Severity:
A representative area of eczema is selected.  In this area, the intensity of each of the 
following 6 specific symptoms is assessed as none (0), mild (1), moderate (2) or severe (3).
●
Redness
●
Swelling
●
Oozing/crusting
●
Scratch marks
49


2
●
Skin thickening (lichenification)
●
Dryness (this is assessed in an area where there is no inflammation)
The scores for these 6 specific symptoms should be added, for a maximum of 18 total points, 
assigned as "B" in the overall SCORAD calculation.
Subjective Symptoms:
Subjective assessment of itch and sleeplessness is recorded for each symptom by the subject on a 
visual analogue scale (VAS), where 0 is no itch (or sleeplessness) and 10 is the worst imaginable 
itch (or sleeplessness), with a maximum possible score of 20.  This parameter is assigned as "C" 
in the overall SCORAD calculation.
(10 cm in length)
1.0
Scoring Algorithm
The SCORAD is calculated as:  A/5 + 7B/2 + C. 
A-Total affected area
B-Symptom severity
C- Subjective assessment of itch and sleeplessness.
2.0
Missing Value Handling
If any of the components is missing, then the overall score will be treated as missing.
3.0
Efficacy Variables
!
Changes from Baseline for the overall SCORAD score and the affected area scores of 
head/neck and genitals 
!
Achievement on pre-specified percentages of improvement, SCORAD 50/75/90 .
4.0
Reference
Dermatology in 1993; 186(1): 23-31 Consensus Report of the European Task Force on Atopic 
Dermatitis.
50


Upadacitinib
M16-048 – Statistical Analysis Plan
Version 1.0 – 23 Aug 2017
Appendix B.
Patient Reported Outcome Scoring
51


1
Appendix B.
Patient Reported Outcome Scoring
Table of Contents
1.0
Patient Oriented Eczema Measure (POEM) .................................................................................. 3
1.1
Questionnaire ..........................................................................................................................3
1.2
Scoring Algorithm.....................................................................................................................4
1.3
Missing Value Handling ............................................................................................................4
1.4
Efficacy Variables .....................................................................................................................4
1.5
References...............................................................................................................................4
2.0
Medical Outcomes Study (MOS)...................................................................................................6
2.1
Questionnaire ..........................................................................................................................6
2.2
Scoring Algorithm.....................................................................................................................7
2.3
Efficacy Variables .....................................................................................................................8
3.0
Pruritus Numerical Rating Scale (NRS)..........................................................................................9
3.1
Questionnaire ..........................................................................................................................9
3.2
Scoring Algorithm.....................................................................................................................9
3.3
Missing Value Handling ............................................................................................................9
3.4
Efficacy Variable.......................................................................................................................9
4.0
Patient Global Impression of Severity (PGIS) .............................................................................. 10
4.1
Questionnaire ........................................................................................................................ 10
4.2
Scoring Algorithm................................................................................................................... 10
4.3
Missing Value Handling ..........................................................................................................10
4.4
Efficacy Variable..................................................................................................................... 10
5.0
Atopic Dermatitis Symptom Scale (ADerm-SS)............................................................................ 11
5.1
Questionnaire ........................................................................................................................ 11
5.2
Scoring Algorithm................................................................................................................... 13
5.3
Missing Value Handling ..........................................................................................................13
5.4
Efficacy Variable..................................................................................................................... 13
6.0
Atopic Dermatitis Impact Scale (ADerm-IS)................................................................................. 14
6.1
Questionnaire ........................................................................................................................ 14
6.2
Scoring Algorithm................................................................................................................... 15
52


2
6.3
Missing Value Handling ..........................................................................................................15
6.4
Efficacy Variable..................................................................................................................... 15
7.0
Asthma Symptoms Questionnaire.............................................................................................. 16
7.1
Questionnaire ........................................................................................................................ 16
7.2
Scoring Algorithm................................................................................................................... 17
7.3
Missing Value Handling ..........................................................................................................17
7.4
Efficacy Variables ................................................................................................................... 17
8.0
Daytime Nasal Symptom Questionnaire..................................................................................... 18
8.1
Questionnaire ........................................................................................................................ 18
8.2
Scoring Algorithm...................................................................................................................19
8.3
Missing Value Handling ..........................................................................................................19
8.4
Efficacy Variables ...................................................................................................................19
9.0
ActiGraphy Measurements ........................................................................................................20
10.0
Dermatology Life Quality Index (DLQI) ....................................................................................... 21
10.1
Questionnaire ........................................................................................................................ 21
10.2
Scoring Algorithm................................................................................................................... 22
10.3
Missing Value Handling ..........................................................................................................22
10.4
Efficacy Variables ................................................................................................................... 24
10.5
Adjustment Accommodating Device Error in this Study .......................................................... 24
10.6
References:............................................................................................................................ 24
53


3
1.0
Patient Oriented Eczema Measure (POEM)
1.1
Questionnaire
54


4
1.2
Scoring Algorithm
Each of the seven questions carries equal weight and the responses are scored from 0 to 4 as 
detailed below:
!
0 = no days
!
1 = 1-2 days
!
2 = 3-4 days
!
3 = 5-6 days
!
4 = Every day
Then take the sum of seven responses.
1.3
Missing Value Handling
If one question is left unanswered or scored “unable to answer” this is scored 0 and the 
scores are summed and expressed as usual out of a maximum of 28. If more than one 
question is left unanswered or scored “unable to answer” the questionnaire is not scored. If 
two or more response options are selected for a single question, the response option with the 
highest score should be recorded. 
1.4
Efficacy Variables
!
The sum of the seven questions will be analyzed by change from Baseline.
1.5
References
1. The Patient-Oriented Eczema Measure: development and initial validation of a new tool 
for measuring atopic eczema severity from the patients' perspective. Charman C, Venn A, 
Williams HC. Arch Dermatol. 2004;140:1513-1519 
2. Translating Patient-Oriented Eczema Measure (POEM) scores into clinical practice by 
suggesting severity strata derived using anchor-based methods. Charman CR, Venn AJ, 
Ravenscroft JC, Williams HC. Br J Dermatol. 2013; 169(6): 1326–1332.
3. The Patient-Oriented Eczema Measure in young children: responsiveness and minimal 
clinically important difference.  Gaunt DM, Metcalfe C, Ridd M. Allergy 2016
4. EASI, (objective) SCORAD and POEM for atopic eczema: responsiveness and minimal 
clinically important difference. Schram ME, Spuls PI, Leeflang MM, Lindeboom R, Bos 
JD, Schmitt J. Allergy 2012 Jan; 67(1):99-106.
55


5
5. POEM a core instrument to measure symptoms in clinical trials: a HOME 
statement.Spuls PI, Gerbens LA, Simpson E, Apfelbacher CJ, Chalmers JR, Thomas KS, 
Prinsen CA, von Kobyletzki LB, Singh JA, Williams HC, Schmitt J; HOME initiative 
collaborators .Br J Dermatol. 2016.
56


6
2.0
Medical Outcomes Study (MOS)
2.1
Questionnaire
57


7
2.2
Scoring Algorithm
The 12-item MOS Sleep yields scores on six subscales, each consisting of one to 
four items  
The subscales are:
!
Sleep Disturbance. This four-item subscale addresses sleep initiation problems, as 
reported via the usual length of time to fall asleep and the frequency of trouble falling 
asleep, and sleep maintenance problems, as indicated by the frequency of 
experiencing sleep that was not “quiet” and the frequency of being awakened with 
trouble falling back to sleep.
o
Q#, 1, 3e, 3a, 3f
!
Sleep Quantity. This single-item subscale represents the average number of hours the 
respondent sleeps each night.
o
Q: 2
o
Sleep Adequacy. This two-item subscale asks about the frequency of awakening fresh 
and rested in the morning and the frequency of getting the amount of sleep needed.
o
Q: 3b
o Somnolence. Previously referred to as “Sleep Somnolence,” this three-item subscale 
measures how frequently during the day the respondent feels drowsy, takes naps, and 
has trouble staying awake.
o
Q: 3d, 3i, 3g
58


8
!
Shortness of Breath or Headache. This single-item subscale asks about the frequency 
of awakening during the night with shortness of breath or with a headache.Q: 3c
!
Snoring. This single-item subscale addresses the frequency of snoring during sleep.
o
Q: 3h
The sub-scores and overall score are calculated by the external vender OPTUM, and thus no 
missing value algorithm is available in this document.
2.3
Efficacy Variables
!
The six sub-scores and the overall score will be analyzed by change from Baseline.
59




10
4.0
Patient Global Impression of Severity (PGIS)
4.1
4.2
Scoring Algorithm
PGIS is collected at site visits.
4.3
Missing Value Handling
Missing values will not be imputed for PGIS.
4.4
Efficacy Variable
PGIS will be analyzed by change from Baseline.
61
CCI
CCI


11
5.0
Atopic Dermatitis Symptom Scale (ADerm-SS)
5.1
62
CCI
CCI


12
63
CCI


13
5.2
Scoring Algorithm
5.3
Missing Value Handling
Missing values will not be imputed for ADerm-SS. If any of Items
 is missing then the 
 Score will be treated as missing.
5.4
Efficacy Variable
!
For each of Items
 changes from Baseline will be analyzed using the rolling 
 average. 
!
The 
Score will be analyzed by change from Baseline.
64
CCI
CCI
CCI
CCI
CCI
CCI


14
6.0
Atopic Dermatitis Impact Scale (ADerm-IS)
6.1
65
CCI
CCI


15
6.2
Scoring Algorithm
6.3
Missing Value Handling
Missing values will not be imputed for ADerm-IS. If any of Items 
 is missing then the 
 Score- will be treated as missing.
6.4
Efficacy Variable
!
For each of Items 
, changes from Baseline will be analyzed using the rolling 
 average. 
!
The 
 Score is analyzed by change from Baseline.
66
CCI
CCI
CCI
CCI
CC
I
CCI
CCI


16
7.0
Asthma Symptoms Questionnaire
7.1
67
CCI
CCI


17
7.2
Scoring Algorithm
7.3
Missing Value Handling
The missing values of individual items will not be imputed. If response 
 
 is selected 
, remaining items automatically become void. 
 
 No missing value imputation is 
performed for individual Items
7.4
Efficacy Variables
!
Items
 will be analyzed by frequency and percentage of response categories. 
!
Item  and the summary score
 will be analyzed by change from 
Baseline. The analysis will be performed only for subjects who had a response
at baseline.
68
CCI
CCI
CCI
CCI
CCI
CCI
CCI
C
C
CCI
CCI
CCI


18
8.0
Daytime Nasal Symptom Questionnaire
8.1
69
CCI
CCI


19
8.2
Scoring Algorithm
8.3
Missing Value Handling
If any of the responses is missing then corresponding summary score will be treated as 
missing.
8.4
Efficacy Variables
!
 will be analyzed by frequency and percentage of response 
categories. 
!
 Symptoms and 
 Scores will be analyzed by 
change from Baseline.
 
70
CCI
CCI
CCI
CCI
CCI
CCI


20
9.0
ActiGraphy Measurements
Patient data on sleep activity and scratching events are collected daily with an electronic actigraphy 
device called Geneactiv Scratching Device. The measurements of interest downloaded from the 
device are total sleep time per night (TST min, in minutes), Sleep Efficiency (%), Wake After Sleep 
Onset (WASO, in minutes), and mean activity during rest (sleep), The parameter of interest related to 
scratching is events per hour. These five parameters will be analyzed by change from Baseline using 
the rolling weekly average. 
71


21
10.0
Dermatology Life Quality Index (DLQI)
10.1
Questionnaire
DLQI is a simple 10-item questionnaire used to assess the handicap experienced by patients with 
various chronic skin diseases.
DERMATOLOGY LIFE QUALITY INDEX     
DLQI
Hospital No:
Date:
  Score:
Name:
Diagnosis:
Address:
The aim of this questionnaire is to measure how much your skin problem has affected your 
life OVER THE LAST WEEK.  Please tick one box for each question.
1
.
Over the last week, how itchy, sore, painful
or stinging has your skin been?
Very much
A lot
A little
Not at all




1.
Over the last week, how embarrassed or 
self conscious have you been because of 
your skin?
Very much
A lot
A little
Not at all




2.
Over the last week, how much has your skin 
interfered with you going shopping or 
looking after your home or garden?
Very much
A lot
A little
Not at all




Not relevant 
3.
Over the last week, how much has your skin 
influenced the clothes you wear?
Very much
A lot
A little
Not at all




Not relevant 
4.
Over the last week, how much has your skin 
affected any social or leisure activities?
Very much
A lot
A little
Not at all




Not relevant 
6
.
Over the last week, how much has your skin 
made it difficult for you to do any sport?
Very much
A lot
A little
Not at all




Not relevant 
7
a
Over the last week, has your skin prevented 
you from working or studying?
yes
no


Not relevant 
72


22
7
b
If "No", over the last week how much has 
your skin been a problem at work or 
studying?
A lot
A little
Not at all 



8
.
Over the last week, how much has your skin 
created problems with your partner or any of 
your close friends or relatives? 
Very much
A lot
A little
Not at all




Not relevant 
9
.
Over the last week, how much has your skin 
caused any sexual difficulties?
Very much
A lot
A little
Not at all




Not relevant 
1
0
.
Over the last week, how much of a problem 
has the treatment for your skin been, for 
example by making your home messy, or by 
taking up time?
Very much
A lot
A little
Not at all




Not relevant 
10.2
Scoring Algorithm
The DLQI measures six aspects of impaired dermatologic quality of life (Symptoms and feelings, 
Daily activities, Leisure, Work and School, Personal relationships, Treatment) and scores range from 
0-30, with higher scores indicating more impaired quality of life. 
Table 1. Scoring of DLQI questions
The scoring of each question is as follows:
Very much
A lot
A little
Not at all
Not relevant
Question unanswered
Question 7: "prevented work or studying" 
scored 3
scored 2
scored 1
scored 0
scored 0
scored 0
scored 3
The DLQI is calculated by summing the score of the 10 questions resulting in a maximum of 
30 and a minimum of 0. The higher the score, the more quality of life is impaired. The DLQI 
can also be expressed as a percentage of the maximum possible score of 30
10.3
Missing Value Handling
For DLQI, missing values in individual questions are handled as follows.
73


23
!
One Question unanswered this is scored 0 and the scores are summed and expressed as usual out 
of a maximum of 30.
!
Two or more questions left unanswered – do not score questionnaire.
!
If two or more response options (adjacent or non-adjacent) are checked for any question, the 
response option with the highest score will be entered into the database.
!
If one item is missing from a two-item subscale that subscale should not be scored.
!
If there is a response between two tick boxes, the lower of the two score options should be 
recorded. If there are responses between more than two tick boxes, the lowest of all the score 
options should be recorded.
!
Question 7 is always counted as one question (for Abbott data management purposes only, the 
responses are coded in two sub-questions 7A and 7B.
o
When question 7A is “yes” then the score = 3 and question 7B is ignored.           
o
When question 7A is “no”:
            the score=2 if question 7B is “a lot”
            the score=1 if question 7B is “a little”
the score=0 if 7B is “not at all” 
the score=missing if 7B is not checked
o
When question 7A is “not relevant” and 7B is not checked, the score=0.
If 7B is checked:
            the score=2 if question 7B is “a lot”
            the score=1 if question 7B is “a little”
            the score=0 if question 7B is “not at all”
o
When question 7A is missing:
            the score=2 if question 7B is “a lot”.
            the score=1 if question 7B is “a little”.
            the score=0 if question 7B is “not at all” or “not relevant”.
            the score=missing if 7B is not scored.
o
When question 7A is “no” and “not relevant”, enter “not relevant” for question 7A.
74


24
10.4
Efficacy Variables
!
Proportion of subjects with a DLQI 0 or 1 response. 
!
Change from Baseline in total DLQI score.
10.5
Adjustment Accommodating Device Error in this Study
During Period 1 of the study, there was an error in the device that Question 7.b) was 
displayed to a subject only when the subject answered “Yes” to Question 7.c). The error was 
corrected in August, with the baseline measurements being affected for all subjects, and the 
Period 1 post-baseline measurements being impacted for almost all subjects. In order to 
mitigate the bias caused by the device error, Items 7. a) and b) are excluded in calculating the 
total DLQI score for the Period 1 visits of all subjects.  
10.6
References:
1. Wales College of Medicine, Department of Dermatology. Website: 
http://www.dermatology.org.uk/index.asp. Date accessed: May 20, 2008
2. Finlay A Y, Khan G K. Dermatology Life Quality Index(DLQI): A simple practical 
measure for routine clinical use. Clinical and Experimental Dermatology.1994;19:210-216
3. Shikiar R, Willian MK, Okun MM, Thompson CS, Revicki DA.  The Validity and 
Responsiveness of Three Quality of Life Measures in the Assessment of Psoriasis Patients: 
Results of a Phase II Study.  Health Qual Life Outcomes.  2006;4:71(27 September 2006).  
Open access available at www.hqlo.com. 
4. Shikiar R, Bresnahan BW, Stone SP, Thompson C, Koo J, Revicki DA. Validity and 
reliability of patient reported outcomes used in Psoriasis: results from two randomized 
clinical trials. Health Qual Life Outcomes 2003, 1:53.
5. Willian MK, Chmiel J, Chen N. Dermatology Life Quality Index (DLQI) Scoring 
Convention (Abbott Internal Document). February 16, 2007.
75