Clinical trial NCT05153148
Conditions: Psoriatic Arthritis
Keywords: Placebo-Controlled Double-blind Multiple-dose study
Sponsor: Takeda
Start date: 2022-01-06; Completion date: 2023-06-02
Enrollment: 305 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to evaluate the efficacy, safety, and tolerability of NDI-034858 in participants with active Psoriatic Arthritis (PsA).

Detailed description:
This is a Phase 2b, Randomized, Multi-center, Double-Blind, Placebo-Controlled, Multiple Dose Study.

Randomization to one of the treatments with NDI-034858 Dose 1, 2, 3 or placebo once daily (QD) will be based on a 1:1:1:1 scheme.

The maximum study duration per participant is approximately 20 weeks, including up to 30 days for the screening period, a 12-week treatment period, and a 4-week safety follow-up period.

Efficacy will be assessed using the ACR20 composite measure (including tender and swollen joint count, patient assessment of PsA pain visual analog scale (VAS), patient global PsA assessment VAS, physician global PsA assessment, HAQ-DI, and hsCRP) as well as the additional components. Efficacy for psoriasis among participants who have ≥ 3% BSA) involvement on Day 1, will be measured using PASI, PGAs, and BSA.

Safety will be assessed by collecting AEs, recording vital signs, performing physical examinations, and evaluating clinical laboratory and ECGs results.

Blood samples will be collected to measure plasma concentrations of NDI-034858.

Arms: arm 1: Participants received placebo capsules, orally, QD for 12 weeks. arm 2: Participants received NDI-034858 low dose, capsules, orally, QD for 12 weeks. arm 3: Participants received NDI-034858 medium dose, capsules, orally, QD for 12 weeks. arm 4: Participants received NDI-034858 high dose, capsules, orally, QD for 12 weeks.
Interventions: intervention 1: NDI-034858 intervention 2: Placebo
Intervention descriptions: intervention 1: NDI-034858 oral capsule intervention 2: NDI-034858-matching oral placebo capsule

Protocol documents:
Prot_000.pdf: 
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A Phase 2b, Randomized, Multi-Center, Double-Blind, Placebo-Controlled, 
Multiple -Dose Study to evaluate the efficacy, safety, and tolerability of 
NDI-034858 in Subjects with active Psoriatic Arthritis
CLINICAL PROTOCOL 4858-202
EUdraCT Number: 2021-005888-52
IND Number: 158014
Sponsor:
Nimbus Lakshmi, Inc.
a fully owned subsidiary of Takeda Pharmaceuticals U.S.A., Inc.
95 Hayden Avenue
Lexington, MA, United States 02421
Telephone: +1 781-482-9222
Program Clinical Lead:
, MD Takeda Pharmaceuticals, Inc.
Telephone: 
Project Clinical Lead:
, PharmD, PhD
Takeda Pharmaceuticals, Inc.
Telephone:
Clinical Research 
Organization:
Parexel
433 Hackensack Ave #9
Hackensack, NJ  07601
201-342-6070
Version:
4.0, Amendment 3
Issue Date:
05 May 2023
Confidentiality Statement
This document is a confidential communication of Nimbus Lakshmi, Inc. Acceptance of this 
document constitutes the agreement by the recipient that no information contained herein will be 
published or disclosed without written authorization from Nimbus Lakshmi, Inc. Furthermore, 
the information is only meant for review and compliance by the recipient, his or her staff, and 
applicable institutional review committee and regulatory agencies to enable conduct of the study.
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3.4.1.
Primary Efficacy Endpoint..................................................................................44
3.4.2.
Secondary Efficacy Endpoints ............................................................................44
3.4.3.
Secondary Endpoints – Safety.............................................................................45
3.4.4.
Secondary Endpoints – Pharmacokinetics...........................................................45
3.4.5.
Exploratory Endpoints.........................................................................................45
4.
STUDY DESIGN ...................................................................................................................47
4.1.
Overall Design..........................................................................................................47
4.2.
Study Conduct During the Coronavirus Disease 2019 Pandemic............................48
4.3.
Scientific Rationale for Study Design......................................................................49
4.4.
Justification for Dose ...............................................................................................49
4.5.
End of Study Definitions..........................................................................................50
5.
STUDY POPULATION.........................................................................................................51
5.1.
Inclusion Criteria......................................................................................................51
5.2.
Exclusion Criteria.....................................................................................................53
5.3.
Screen Failures .........................................................................................................57
6.
TREATMENT........................................................................................................................58
6.1.
Study Treatment Administered ................................................................................58
6.2.
Preparation/Handling/Storage/Accountability .........................................................59
6.2.1.
Preparation/Storage/Handling .............................................................................59
6.2.2.
Accountability .....................................................................................................59
6.3.
Randomization .........................................................................................................59
6.3.1.
Blinding ...............................................................................................................60
6.3.2.
Study Treatment Compliance..............................................................................60
6.4.
Concomitant Therapy...............................................................................................61
6.4.1.
Permitted Therapies.............................................................................................61
6.4.1.1.
Emollients...............................................................................................61
6.4.2.
Prohibited Therapies or Procedures.....................................................................61
7.
DISCONTINUATION AND LOST TO FOLLOW-UP ........................................................64
7.1.
Discontinuation from Study Drug............................................................................64
7.2.
Discontinuation from Study .....................................................................................65
7.3.
Lost to Follow-Up ....................................................................................................66
7.4.
Study Termination....................................................................................................66
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8.
STUDY ASSESSMENTS AND PROCEDURES..................................................................67
8.1.
Screening Assessments ............................................................................................67
8.1.1.
Classification Criteria for Psoriatic Arthritis.......................................................67
8.1.2.
Chest X-ray..........................................................................................................67
8.1.3.
Tuberculosis Testing ...........................................................................................67
8.1.4.
Rheumatoid Factor ..............................................................................................67
8.1.5.
Anti-Cyclic Citrullinated Peptide........................................................................68
8.2.
Efficacy Assessments...............................................................................................68
8.2.1.
Primary Efficacy Endpoint - American College of Rheumatology 20................68
8.2.2.
Secondary Efficacy Endpoints ............................................................................68
8.2.2.1.
American College of Rheumatology 50/70............................................68
8.2.2.2.
Tender Joint Count 68 and Swollen Joint Count 66...............................68
8.2.2.3.
Patient Global Assessment of Psoriatic Arthritis ...................................69
8.2.2.4.
Patient Global Assessment of Psoriatic Arthritis Pain...........................69
8.2.2.5.
Physician Global Assessment of Psoriatic Arthritis...............................69
8.2.2.6.
Health Assessment Questionnaire – Disability Index............................69
8.2.2.7.
Dactylitis Count......................................................................................69
8.2.2.8.
Leed’s Enthesitis Index ..........................................................................69
8.2.2.9.
Physician Global Assessment of Psoriasis.............................................69
8.2.3.
Exploratory Efficacy Endpoints ..........................................................................70
8.2.3.1.
........................................70
8.2.3.2.
............................................................70
8.2.3.3.
......................................................70
8.2.3.4.
..........................................................70
8.2.3.5.
......................................................70
8.2.3.6.
.................................................................................70
8.2.3.7.
.......................................................................71
8.2.3.8.
.......................................................71
8.2.3.9.
.............................................................71
8.3.
Patient Reported Outcomes......................................................................................71
8.3.1.
..................................................................71
8.3.2.
..........................................71
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8.4.
Safety and Other Assessments .................................................................................71
8.4.1.
Vital Signs ...........................................................................................................71
8.4.2.
Physical Examination..........................................................................................72
8.4.3.
Targeted Physical Examination...........................................................................72
8.4.4.
Clinical Laboratory Tests ....................................................................................72
8.4.4.1.
Use of Local Laboratories......................................................................74
8.4.5.
Electrocardiogram ...............................................................................................74
8.4.6.
Plasma Concentrations of NDI-034858...............................................................75
8.4.7.
........................................................................75
8.5.
Adverse Events and Serious Adverse Events...........................................................75
8.5.1.
Definition of Adverse Event................................................................................75
8.5.2.
Definition of Serious Adverse Event...................................................................75
8.5.3.
Classification of an Adverse Event .....................................................................76
8.5.3.1.
Relationship to Study Drug....................................................................76
8.5.3.2.
Adverse Event Severity..........................................................................76
8.5.4.
Time Period and Frequency for Event Assessment and Follow-Up ...................77
8.5.5.
Adverse Event Reporting ....................................................................................78
8.5.6.
Serious Adverse Event Reporting .......................................................................78
8.5.7.
Adverse Events of Special Interest......................................................................78
8.5.7.1.
Immediate Reporting of AESIs..............................................................79
8.5.8.
Potential Drug Induced Liver Injury ...................................................................80
8.5.9.
Pregnancy Reporting ...........................................................................................81
8.5.10.
Overdose..............................................................................................................81
9.
STATISTICAL CONSIDERATIONS ...................................................................................82
9.1.
Statistical Hypotheses ..............................................................................................82
9.1.1.
Multiplicity Adjustment ......................................................................................82
9.2.
Analysis Sets ............................................................................................................82
9.3.
Statistical Analyses ..................................................................................................83
9.3.1.
General Considerations .......................................................................................83
9.3.2.
Efficacy Analyses................................................................................................83
9.3.3.
Study Drug Exposure and Compliance ...............................................................84
9.3.4.
Safety Analyses ...................................................................................................84
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9.3.4.1.
Adverse Events.......................................................................................84
9.3.4.2.
Electrocardiogram ..................................................................................85
9.3.4.3.
Vital Signs..............................................................................................86
9.3.4.4.
Safety Laboratory Tests .........................................................................86
9.3.4.5.
Physical Examination.............................................................................86
9.3.5.
Exploratory Analyses ..........................................................................................86
9.3.6.
Other Analyses ....................................................................................................86
9.3.6.1.
Pharmacokinetic Analyses .....................................................................87
9.3.7.
Planned Interim Analyses....................................................................................87
9.3.8.
Sample Size Determination.................................................................................87
10. REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS..............88
10.1.
Local Regulations/Declaration of Helsinki..............................................................88
10.2.
Ethical Review .........................................................................................................88
10.3.
Informed Consent Process........................................................................................88
10.4.
Study Discontinuation and Closure..........................................................................89
10.5.
Confidentiality and Privacy......................................................................................89
10.6.
Clinical Monitoring..................................................................................................90
10.7.
Quality Assurance and Quality Control ...................................................................90
10.8.
Data Handling and Record Keeping.........................................................................90
10.9.
Protocol Deviations..................................................................................................91
10.10.
Publication Policy ....................................................................................................91
11. REFERENCES .......................................................................................................................92
APPENDIX 1. PARTIAL LIST OF STRONG OR MODERATE INHIBITORS OF
CYP3A4.............................................................................................................................94
APPENDIX 2. CONTRACEPTION .............................................................................................95
APPENDIX 3. SELECT DMARDS HALF-LIFE.........................................................................97
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LIST OF TABLES
Table 1:
Schedule of Assessments............................................................................................31
Table 2:
Potential Risks of NDI-034858 ..................................................................................41
Table 3:
Study Drugs ................................................................................................................58
Table 4:
Prohibited Therapies or Procedures............................................................................62
Table 5:
Clinical Laboratory Testing........................................................................................73
Table 6:
Analysis Sets...............................................................................................................82
Table 7:
DMARDS Half-life ....................................................................................................97
LIST OF FIGURES
Figure 1:
Study Diagram............................................................................................................29
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PROTOCOL VERSION HISTORY
Version/Date: Version 1 / 06-Sep-2021
Rationale for amendment: Initial version
Main changes to the protocol: Not Applicable
Version/Date: Version 2, Amendment 1 / 27 Oct 2021
Rationale for amendment: Clarification of certain processes and correction of minor grammatical 
and typographical errors
Main changes to the protocol:

Subjects with SAEs or severe AEs may be discontinued from study drug regardless of
relationship to drug.

Added homeopathic medications to the concomitant medications recorded.

Clarified that erythrocyte sedimentation rates will be performed at the clinical sites, not
the central laboratory.

PGA 
 were described for clarity

Revised stopping rules for potential hepatic laboratory abnormalities

Global revisions for punctuation, formatting, grammatical and typographical errors
Version/Date: Version 3, Amendment 2 / 06 Apr 2022
Rationale for amendment: Inclusion of FDA requested changes. Clarification of certain processes 
and correction of typographical errors. See Summary of Changes document for comprehensive 
edits.
Main changes to the protocol:

Revised statistical analysis methods to include estimand of interest, clarifications for
definition of analysis data sets, use of the Mantel-Haenszel stratum-weighted test.

Clarified and defined study objectives and endpoints

Modified Inclusion Criteria 1 to remove upper age cap.

Referenced Appendix 2 in Inclusion Criteria 8 and 10. Appendix 2 provides local
contraception requirements that may apply

Clarified washout period for biologic agents in Exclusion Criteria 4 and 9. Added
Appendix 3 –DMARDS Half-life.

Noted Exclusion Criteria 37, the T-Spot.TB (TBT) test is an acceptable alternative to the
QFT test in regions where TBT is standard practice.
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
Added Exclusion Criteria 42 excluding subjects with severe hepatic impairment

Clarified in Section 6.1 that food intake is not restricted, subjects only need to fast at
visits requiring a fasting lipid panel

Added footnotes to SoA clarifying the timing of each visit is based on Day 1, allowance
for use of a T-Spot.TB test, and timing for AE collection based on Day 1 dosing time.

Update to Table 2 Potential Risks of NDI-034858, Potential risk of CPK elevation,
Summary of Data/Rationale for Risk to align with the current DSUR.

Added information to Section 6.1 defining the formulation of NDI-034858 used in this
study.
Version/Date: Version 4, Amendment 3 / 05 May 2023
Rationale for amendment: 
On February 08, 2023, Nimbus Lakshmi Inc. was acquired by Takeda Pharmaceuticals USA, 
Inc. (Takeda). 
Clarification of certain processes and correction of typographical errors. See Summary of 
Changes for comprehensive edits.
Main changes to the protocol:

Reflect that study sponsor, Nimbus Lakshmi Inc, is now a fully owned subsidiary of
Takeda.
o
Sponsor change of address
o
NDI-034858 is now also known as TAK-279

Stratification factor corrections for both prior treatment (“AND” to “OR”) and region
“(US&Germany/Eastern Europe)” to “(US/Germany)/(Eastern Europe)”
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STATEMENT OF COMPLIANCE
The study will be conducted in accordance with the protocol, International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP), and applicable local regulations. The 
principal investigator will assure that no planned deviation from, or changes to the protocol will 
take place without prior agreement from the sponsor and documented approval from the 
institutional review board (IRB), research ethics board (REB), and/or Independent Ethics 
Committee (IEC) except where necessary to eliminate an immediate hazard(s) to the study
subjects. All personnel involved in the conduct of this study have completed ICH GCP training.
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IRB/REB/IEC for review and approval. Approval of both the protocol and the 
consent form must be obtained before any subject is enrolled. Any amendment to the protocol 
will require review and approval by the IRB/REB/IEC before the changes are implemented to the 
study. All changes to the consent form will be IRB/REB/IEC approved.
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SIGNATURE PAGE
The signatures below constitute the approval of this protocol and provide the necessary 
assurances that this study will be conducted according to this protocol, applicable local 
regulations, and ICH GCP guidelines.
Electronic signatures of the following individuals are provided on the last page of this document.
MD, 
, Clinical Sciences
PharmD, PhD, 
. Clinical Sciences
, Statistics and Quantitative Sciences
 Pharmacovigilance
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PRINCIPAL/QUALIFIED INVESTIGATOR SIGNATURE PAGE
Investigator Name:
Signature:
Date:
(dd-Mon-yyyy)
Institution Name:
By my signature, I agree to personally supervise the conduct of this study at my study site and 
to ensure its conduct in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and in compliance with the protocol, informed consent, institutional 
review board/independent ethics committee procedures, instructions from sponsor’s
representatives, ICH GCP guidelines, and applicable local regulations governing the conduct 
of clinical studies.
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation 
Definition
AE
adverse event
ACR20/50/70
American College of Rheumatology 20/50/70
ADL
activities of daily living
AESI
adverse event of special interest
ALT
alanine aminotransferase
anti-CCP
Anti-cyclic citrullinated peptide antibodies
anti-HBc
antibody to hepatitis B core antigen
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUC%
percentage of the area under the concentration versus time curve
AUC0-inf
area under the plasma concentration versus time curve from time 0 to infinity
AUC0-last
area under the plasma concentration versus time curve from time 0 to the time of last 
measurable concentration
AUC0-tau
area under the plasma concentration versus time curve from time 0 to the end of the 
dosing period
β-hCG
β-human chorionic gonadotropin
BMI
body mass index
BSA
body surface area
CASPAR
Classification Criteria for Psoriatic Arthritis
Cmax
maximum observed concentration
COVID-19
Coronavirus Disease 2019
CPK
creatine phosphokinase
CRO
contract research organization
CRP
C-reactive protein
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
CYP3A
cytochrome P450 3A
DAPSA
Disease Activity Index for Psoriatic Arthritis
DDI
drug-drug interaction
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Abbreviation 
Definition
DMARD
disease-modifying anti-rheumatic drug
DTP
direct-to-patient
ECG
Electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EOS
end of study
EOT
end of treatment
ESR
erythrocyte sedimentation rate
ET
early termination
FAS
full analysis set
FDA
Food and Drug Administration
FIH
first in human
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl-transferase
gm
Gram
HAQ-DI
Health Assessment Questionnaire-Disability Index
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCT
Hematocrit
HCV
hepatitis C virus
Hgb
Hemoglobin
HIV
human immunodeficiency virus
hsCRP
high sensitivity C-reactive protein
IB
Investigator Brochure
IC50
half maximal inhibitory concentration
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
independent ethics committee
IL
Interleukin
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Abbreviation 
Definition
IND
Investigational New Drug
IFNγ
interferon gamma
IRB
institutional review board
ITT
intent-to-treat 
IWRS
Interactive Web Response System
JAK
Janus kinase
LEI
Leed’s Enthesitis Index
MAD
multiple ascending dose
MDA
Minimal Disease Activity
MH
Mantel-Haenzel
MTX
Methotrexate
N/A
not applicable
NMSC
non-melanoma skin cancer
NOAEL
no observable adverse effect level
NSAID
non-steroidal anti-inflammatory drug
PASI
Psoriasis Area and Severity Index
PASI-
50/75/90
50%/75%/90% improvement from baseline in Psoriasis Area and Severity Index
PBPK
physiologically based pharmacokinetic
PCR
polymerase chain reaction
PD
Pharmacodynamic
PGA
Physician Global Assessment
PK
pharmacokinetic 
PP
per-protocol 
PPD
purified protein derivative
PRN
as needed
PsA
psoriatic arthritis
PT
preferred term
PUVA
psoralen and ultraviolet A
QC
quality control
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Abbreviation 
Definition
QD
once daily
RA
rheumatoid arthritis
REB
research ethics board
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SDD
spray dried dispersion
SJC
swollen joint count
SOC
system organ class
sPGA
static Physician’s Global Assessment
STAT
signal transducers and activators of transcription
t1/2
terminal half-life
TB
tuberculosis
TBT
T-Spot.TB test
TEAE
treatment-emergent adverse event
TEAESI
Treatment-emergent adverse event of special interest
TESAE
treatment-emergent serious adverse events
Th
T helper
TJC
tender joint count
Tmax
time to maximum observed concentration
TNF
tumor necrosis factor
TNFi
tumor necrosis factor inhibitor
TPGS
d-α-tocopheryl polyethylene glycol 1000 succinate
TYK2
tyrosine kinase 2
ULN
upper limit of normal
UV
ultraviolet
VAS
visual analog scale
WOCBP
women of childbearing potential
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Name of Sponsor/Company: 
Nimbus Lakshmi, Inc.
Name of Investigational Product: 
NDI-034858 (TAK-279)
Name of Active Ingredient: 
NDI-034858 (TAK-279)
In order to be eligible to participate in this study, a subject must meet all of the following criteria, either at the 
screening and Day 1 visits or only at one of the specified visits (screening or Day 1) as noted in the criteria:
1.
Subject is male or female, aged ≥18 years, at the time of consent.
2.
Subject has PsA on the basis of the CASPAR with peripheral symptoms at the screening visit, as
assessed by the investigator.
3.
Subject has PsA symptoms for ≥ 6 months prior to screening, as assessed by the investigator.
4.
Subject has ≥ 3 tender joints and ≥ 3 swollen joints at screening and Day 1 visits, as assessed by the
investigator.
5.
Subject has at least one lesion of plaque psoriasis ≥2 cm in diameter, nail changes characteristic of
psoriasis, or a documented history of plaque psoriasis.
6.
Subject has active PsA despite previous standard doses of NSAIDs administered for ≥ 4 weeks, or
traditional DMARDs (including methotrexate and sulfasalazine) administered for ≥ 3 months, or TNFi
agents administered for ≥ 3 months, or subjects are intolerant to NSAIDs or DMARDs or TNFi agents,
as assessed by the investigator.
7.
If subject is on concurrent PsA treatments, they must be on stable doses as described below and for the
duration of the study:
a.
Methotrexate (MTX): subject must have received treatment for ≥ 3 months, with stable dose and
stable route of administration (not to exceed 25 mg MTX per week) for ≥ 4 weeks prior to
Day 1 until Week 16 (EOS); subjects on MTX should be taking folic acid supplementation
according to local standard of care to minimize the likelihood of MTX associated toxicity.
b.
Sulfasalazine: Maximum dose of 3 gm/day. Minimum duration of therapy 2 months and dose
stable for 4 weeks prior to Day 1.
c.
Other traditional DMARDs not listed may be considered on a case-by-case basis after
discussion with the medical monitor.
d.
Oral corticosteroids: the subject must be on a stable dose, not to exceed the equivalent of 10 mg
of prednisone per day, for ≥ 2 weeks prior to Day 1. If subject is not currently using oral
corticosteroids, must not have received for at least 2 weeks prior to Day 1.
e.
NSAIDs or paracetamol/acetaminophen: the subject must be on a stable dose for ≥2 weeks
prior to Day 1.  If not currently using NSAIDs, must not have received for at least 2 weeks prior
to Day 1.
8.
For female subjects of childbearing potential involved in any sexual intercourse that could lead to
pregnancy: the subject must agree to use a highly effective contraceptive method from screening until at
least 4 weeks after the last study drug administration. Highly effective contraceptive methods include
hormonal contraceptives (eg, combined oral contraceptive, patch, vaginal ring, injectable, or implant),
intrauterine devices or intrauterine systems, vasectomized partner(s) (provided vasectomy was
performed ≥4 months prior to screening), tubal ligation, or double barrier methods of contraception
(eg, male condom with cervical cap, male condom with diaphragm, and male condom with contraceptive
sponge) in conjunction with spermicide. See Appendix 2 for additional local requirements or restrictions
that may apply.
Note: Subjects must have been on a stable dose of hormonal contraceptives for at least 4 weeks before
Day 1.
Note: The above list of contraceptive methods does not apply to subjects who are abstinent for at least
4 weeks before Day 1 and will continue to be abstinent from penile-vaginal intercourse throughout the
study. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical
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Name of Sponsor/Company: 
Nimbus Lakshmi, Inc.
Name of Investigational Product: 
NDI-034858 (TAK-279)
Name of Active Ingredient: 
NDI-034858 (TAK-279)
study, and the preferred and usual lifestyle of the subject. Periodic abstinence (calendar, symptothermal, 
postovulation methods) is not acceptable.
Note: A female subject of nonchildbearing potential is defined as follows:
-
Female subject who has had surgical sterilization (hysterectomy, bilateral oophorectomy, or bilateral
salpingectomy)
-
Female subject who has had a cessation of menses for at least 12 months prior to the screening visit
without an alternative medical cause, and a follicle-stimulating hormone test confirming
nonchildbearing potential (refer to laboratory reference ranges for confirmatory levels).
9.
Female subjects of childbearing potential must have had a negative serum pregnancy test at screening
and negative urine pregnancy test at Day 1.
10. For male subjects involved in any sexual intercourse that could lead to pregnancy, subject must agree to
use one of the highly effective contraceptive methods listed in Inclusion Criterion 8, from Day 1 until at
least 12 weeks after the last study drug administration. If the female partner of a male subject uses any of
the hormonal contraceptive methods listed above, this contraceptive method should be used by the
female partner from at least 4 weeks before Day 1 until at least 12 weeks after the last study drug
administration. See Appendix 2 for additional local requirements or restrictions that may apply.
Note: Male subjects must refrain from donating sperm from Day 1 until at least 12 weeks after the last
study drug administration.
Note: No restrictions are required for a male subject who underwent a vasectomy at least 4 months prior
to screening and the procedure is documented. If vasectomy procedure is not documented or was
performed less than 4 months prior to screening, male subjects must follow the same contraception and
sperm donation requirements as for non-vasectomized subjects.
11. Subject has a body mass index (BMI) of >18 kg/m2, inclusive, (BMI = weight (kg)/[height (m)]2), and
total body weight >50 kg (110 lb).
12. Subject is willing to participate and is capable of giving informed consent. Note: Signed, dated, written
informed consent must be obtained prior to any study-related procedures.
13. Subjects must be willing to comply with all study procedures and must be available for the duration of
the study.
Exclusion Criteria:
A subject who meets any of the following criteria at the screening and/or Day 1 visits, as applicable, will be 
excluded from participation in this study:
1.
Subject has other disease(s) that might confound the evaluations of benefit of NDI-034858 therapy, including
but not limited to rheumatoid arthritis, axial spondyloarthritis (this does not include a primary diagnosis of
PsA with spondylitis), systemic lupus erythematosus, Lyme disease or fibromyalgia.
2.
Subject has a history of lack of response to any therapeutic agent targeting interleukin (IL)-12, IL-17, and/or
IL-23 (eg, ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, tildrakizumab, risankizumab)
at approved doses after at least 12 weeks of therapy, and/or received one of these therapies within 6 months
prior to baseline (Day 1).
3.
Subject has a history of lack of response to > 1 therapeutic agent targeting tumor necrosis factor.
4.
Subject has received infliximab, golimumab, adalimumab, or certolizumab pegol, or any biosimilar of these
agents, within 8 weeks or 5 half-lives (see Appendix 3), whichever is longer, prior to baseline (Day 1).
5.
Subject has received etanercept, or any biosimilar of etanercept, within 4 weeks prior to baseline (Day 1).
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Confidential
Name of Sponsor/Company: 
Nimbus Lakshmi, Inc.
Name of Investigational Product: 
NDI-034858 (TAK-279)
Name of Active Ingredient: 
NDI-034858 (TAK-279)
6.
Subject has received rituximab or any immune-cell-depleting therapy within 6 months prior to baseline
(Day 1).
7.
Subject has received any marketed or investigational biological agent, other than those specified in other
inclusion/exclusion criteria, within 12 weeks or 5 half-lives (whichever is longer, see Appendix 3) prior to
baseline (Day 1).
8.
Subject is currently receiving a non-biological investigational product or device or has received one within
4 weeks prior to baseline (Day 1).
9.
Subject has received apremilast or other non-biologic systemic treatment for PsA within 4 weeks prior to
baseline (Day 1), other than MTX, sulfasalazine, corticosteroids, NSAIDs, or paracetamol/acetaminophen,
which are allowed at stable doses as described in Inclusion Criterion 7. Subject has received leflunomide
within 95 days of baseline (Day 1) if no elimination procedure was followed or adhere to an elimination
procedure (eg, 11 days with cholestyramine or 30 days washout with activated charcoal as per local label).
For subjects not receiving MTX and sulfasalazine at Screening, MTX and sulfasalazine are excluded within
4 weeks prior to baseline (Day 1).
10. Subject has received intraarticular injection (including corticosteroids), intramuscular steroids, intralesional
steroids, or intravenous steroids within 4 weeks prior to baseline (Day 1). For subjects not receiving MTX
and sulfasalazine at screening, MTX and sulfasalazine are excluded within 4 weeks prior to baseline (Day 1).
11. Subject has received high potency opioid analgesics (eg, methadone, hydromorphone, or morphine) within
2 weeks prior to baseline (Day 1).
12. Subject has used any topical medication that could affect PsA or psoriasis (including corticosteroids,
retinoids, vitamin D analogues [such as calcipotriol], Janus kinase [JAK] inhibitors, or tar) within 2 weeks
prior to baseline (Day 1).
13. Subject has used any systemic treatment that could affect PsA or psoriasis (including oral retinoids,
immunosuppressive/immunomodulating medication, cyclosporine, oral JAK inhibitors, or apremilast) within
4 weeks prior to baseline (Day 1), unless otherwise excluded or allowed by protocol.
Note: Intranasal corticosteroids and inhaled corticosteroids are allowed. Eye and ear drops containing
corticosteroids are also allowed.
14. Subject has received any ultraviolet (UV)-B phototherapy (including tanning beds) or excimer laser within
4 weeks prior to baseline (Day 1).
15. Subject has had psoralen and ultraviolet A (PUVA) treatment within 4 weeks prior to baseline (Day 1).
16. Subject has received Chinese traditional medicine within 4 weeks prior to baseline (Day 1).
17. Subject has received any live-attenuated vaccine, including for Coronavirus Disease-19 (COVID-19), within
4 weeks prior to baseline (Day 1) or plans to receive a live-attenuated vaccine during the study and up to
4 weeks or 5 half-lives of the study drug, whichever is longer, after the last study drug administration.
Note: Non-live-attenuated vaccines or boosters for COVID-19 (eg, RNA-based vaccines, inactivated
adenovirus-based vaccines, protein-based vaccines) are allowed during the study. The study site should
follow local guidelines related to COVID-19.
18. Subject is currently being treated with strong or moderate cytochrome P450 3A (CYP3A4) inhibitors, such
as itraconazole or has received moderate or strong CYP3A4 inhibitors within 4 weeks prior to baseline
(Day 1).
19. Subject has consumed grapefruit or grapefruit juice within 1 week prior to baseline (Day 1).
Note: Consumption of grapefruit must be avoided during the treatment period and for at least 1 week after
last study drug administration.
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Name of Sponsor/Company: 
Nimbus Lakshmi, Inc.
Name of Investigational Product: 
NDI-034858 (TAK-279)
Name of Active Ingredient: 
NDI-034858 (TAK-279)
20. Subject has used tanning booths within 4 weeks prior to baseline (Day 1), has had excessive sun exposure, or
is not willing to minimize natural and artificial sunlight exposure during the study.
Note: Use of sunscreen products and protective apparel are recommended when sun exposure cannot be
avoided.
21. Subject is a female who is breastfeeding, pregnant, or who is planning to become pregnant during the study.
22. Subject has evidence of erythrodermic, pustular, predominantly guttate psoriasis, or drug-induced psoriasis.
23. Subject has a history of skin disease or presence of skin condition that, in the opinion of the investigator,
would interfere with the study assessments.
24. Subject has any clinically significant medical condition, evidence of an unstable clinical condition (eg,
cardiovascular, renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, immunologic, or local
active infection/infectious illness), psychiatric condition, or vital signs/physical/laboratory/ECG abnormality
that would, in the opinion of the investigator, put the subject at undue risk or interfere with interpretation of
study results.
25. Subject had a major surgery within 8 weeks prior to baseline (Day 1or has a major surgery planned during
the study.
26. Subject has a history of Class III or IV congestive heart failure as defined by New York Heart Association
Criteria.
27. Subject has an estimated creatinine clearance of < 40 mL/min based on the Cockcroft-Gault equation or a
history of renal failure as defined by the investigator

Cockcroft Gault equation:
Creatinine Clearance (estimated) / Conventional mL/min =
(140 - Age [years]) x Weight (kg) x Factor a) / (72 x serum creatinine [mg/dL])
Note: Factor a = 0.85 in females and 1.00 in males.
28. Subject was hospitalized in the 3 months prior to screening for asthma, has ever required intubation for
treatment of asthma, currently require oral corticosteroids for the treatment of asthma, or has required more
than one short-term (≤ 2 weeks) course of oral corticosteroids for asthma within 6 months prior to baseline
(Day 1).
29. Subject has a history of cancer or lymphoproliferative disease within 5 years prior to baseline (Day 1).
Subjects with successfully treated nonmetastatic cutaneous squamous cell or basal cell carcinoma and/or
localized carcinoma in situ of the cervix are not to be excluded.
30. Subject has a history of fever, inflammation, or systemic signs of illness suggestive of systemic or invasive
infection within 4 weeks prior to baseline (Day 1).
31. Subject has an active bacterial, viral, fungal, mycobacterial infection, or other infection (including
tuberculosis [TB] or atypical mycobacterial disease), or any major episode of infection that required
hospitalization or treatment with intravenous antibiotics within 12 weeks prior to baseline (Day 1), or oral
antibiotics within 4 weeks prior to baseline (Day 1).
32. Subject has a history of chronic or recurrent infectious disease, including but not limited to chronic renal
infection, chronic chest infection, recurrent urinary tract infection, fungal infection (with the exception of
superficial fungal infection of the nailbed), or infected skin wounds or ulcers.
33. Subject has a history of an infected joint prosthesis or has received antibiotics for a suspected infection of a
joint prosthesis, if that prosthesis has not been removed or replaced.
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Confidential
Name of Sponsor/Company: 
Nimbus Lakshmi, Inc.
Name of Investigational Product: 
NDI-034858 (TAK-279)
Name of Active Ingredient: 
NDI-034858 (TAK-279)
34. Subject has active herpes infection, including herpes simplex 1 and 2 and herpes zoster (demonstrated on
physical examination and/or medical history) within 8 weeks prior to Day 1.
35. Subject has a history of known or suspected congenital or acquired immunodeficiency state or condition that
would compromise the subject’s immune status in the opinion of the investigator (eg, history of splenectomy,
primary immunodeficiency).
36. Subject has positive results for hepatitis B surface antigens, antibodies to hepatitis B core antigens, hepatitis
C virus (HCV), or human immunodeficiency virus. Samples testing positive for HCV antibodies will require
polymerase chain reaction (PCR) qualitative testing for HCV RNA. Any HCV RNA PCR result that meets or
exceeds detection sensitivity is exclusionary.
37. Subject has clinical or laboratory evidence of active or latent TB infection at screening.
Note: Subjects will be evaluated for TB infection by QuantiFERON-TB Gold (or a purified protein
derivative [PPD] skin test, or equivalent, (or both if required per local guidelines) and chest X-ray. The PPD
skin test should be utilized only when a QuantiFERON-TB Gold Test is not possible for any reason (unless
local guidelines require both tests). Chest X-ray may be taken at screening or completed within 3 months
prior to the screening visit, with documentation showing no evidence of infection or malignancy as read by a
qualified physician.
Note: The T-Spot.TB test (TBT) is an acceptable alternative to the QFT test in regions where the TBT is
standard practice for tuberculosis screening. The medical monitor should be informed prior to using the TBT
in place of the QFT test. A negative TBT is required if the QFT test is not performed.
Note: Subjects with a history of active or latent TB will not be included in the study, unless documentation of
prior and complete anti-TB treatment, appropriate in duration and type according to current local country
guidelines, can be provided. Latent TB is defined as a positive QFT test or two successive indeterminate
QFT tests at screening.
38. Subject with any of the following laboratory values at the screening visit:
a)
Alanine aminotransferase or aspartate aminotransferase values ≥ 3 times the upper limit of normal
(ULN)
b)
Hemoglobin < 11.0 g/dL (< 110.0 g/L)
c)
White blood cell count < 3.5 x 109/L (< 3500/mm3)
d)
Absolute neutrophil count of < 1.8 x 109/L (< 1800/mm3)
e)
Absolute lymphocyte count of < 1.0 x 109/L (< 1000/mm3)
f)
Platelet count < 100 x 109/L (< 100,000/mm3)
g)
Total bilirubin ˃ 2 times the ULN
39. Subjects who have given > 50 ml of blood or plasma within 30 days of screening or > 500 mL of blood or
plasma within 56 days of screening (during a clinical study or at a blood bank donation).
40. Subject has a known or suspected allergy to NDI-034858 or any component of the investigational product, or
any other significant drug allergy (such as anaphylaxis or hepatotoxicity).
41. Subject has a known history of clinically significant drug or alcohol abuse in the last year prior to baseline
(Day 1).
42. Subject has known history of moderate to severe hepatic impairment, Class B or C, by Child-Pugh scoring
system.
Statistical methods:
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Name of Sponsor/Company: 
Nimbus Lakshmi, Inc.
Name of Investigational Product: 
NDI-034858 (TAK-279)
Name of Active Ingredient: 
NDI-034858 (TAK-279)
Categorical variables will be presented in tables as frequencies and percentages. Continuous variables will be 
summarized in tables including the number of subjects, mean, standard deviation, median, minimum, and 
maximum.
Further details regarding the efficacy and safety variable definitions, analyses strategy, statistical justification, 
and techniques for handling missing values (if applicable) will be detailed in a separate statistical analysis plan 
(SAP) that will be prepared before the database is locked and any analyses are undertaken. Any deviation(s) from 
the SAP will be described and justified in the final Clinical Study Report, as appropriate.
All statistical tests will be two-sided and will be performed with a significant level of 0.05, unless otherwise 
specified in the SAP. No adjustment to alpha will be made to account for multiple testing between treatment 
groups.
Study Drug Exposure and Compliance:
Exposure to study drug and study drug compliance will be summarized for each treatment group for the Safety 
Analysis Set.
Efficacy Analyses:
The primary endpoint can be translated as a responder analysis, where a subject will be classified as responder if 
they achieve ACR20 at Week 12. Comparison of the primary endpoint will be made between each dose group 
and the placebo group using a two-sided Mantel-Haenszel (MH) test of the risk difference in two proportions
stratified by the randomization stratification factors (prior treatment with biologics or non-traditional DMARDs
[yes/no], and region [(USA/Germany)/(Eastern Europe)]. The estimated MH risk difference will be summarized 
along with the two-sided 95% CI using MH stratum weights (Mantel, 1959) and the Sato variance estimator 
(Sato, 1989). The primary efficacy analysis will be performed on the full analysis set (FAS), while the
intent-to-treat and per protocol sets will be used as a supplementary analysis. Use of the FAS dataset as primary is 
to assess the clinical question of interest in the protocol to determine treatment effect for dosing and efficacy.
Estimands and additional sensitivity analyses will be described in the SAP.
A descriptive analysis will be performed in demographic subgroups including age, gender, race, and BMI to 
assess the consistency of the treatment effect. Additional subgroup analyses based on baseline disease 
characteristics and the randomization stratification factor will also be conducted and described in the SAP.
The secondary endpoints involving proportions of subjects will be analyzed using the same approach (MH test of
the difference) as described for the primary efficacy analysis and based on the FAS.
The continuous secondary endpoints involving change from baseline will be analyzed using a mixed model for 
repeated measures based on the FAS. The model will include fixed effects for treatment group, visit, and 
treatment group-by-visit interaction, with baseline score and the randomization stratification factor as covariates, 
and the change from baseline as the dependent variable. Additional details on sensitivity analyses and missing 
data imputation of the secondary endpoints will be provided in the SAP.
Safety Analyses:
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An unscheduled visit may be conducted for clinical reasons such as the appearance of new 
symptoms or an adverse event (AE); for laboratory testing pertaining to subject safety; to return 
study drug, particularly if there is an issue concerning loss of or damage to study drug; 
administrative reasons wherein the subject requests a visit for clarification of any study 
procedure; or other similar type of situation.
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Table 1:
Schedule of Assessments
Study Time Frame/
Visit
Screening Period
Treatment Perioda
Follow-
up
Screening
Day –30
to Day -1
Visit 1
Day --7b
Day 1
Visit 2
Week 1
Visit 3
Week 2
Visit 4
Week 4
Visit 5
Week 8
Visit 6
Week 12
EOT/ET
Visit 7
Week 16
EOS
Visit 8
Windows (days)
(±1)
(±1)
(±2)
(±2)
(±2)
(±3)
(±3)
(±4)
Informed consent
X
Demographics
X
Medical and surgical history
X
X
Inclusion and exclusion criteria
X
X
Pregnancy testc
X
X
X
X
X
X
X
X
Serology (HIV, HBV [HBsAg, 
antiHBc], HCV)
X
QuantiFERON-TB Gold testd
X
Chest X-raye
X
Rheumatoid factor and anti-CCP
X
Vital signsf
X
X
X
X
X
X
X
X
Complete physical examination
X
X
Targeted physical examinationg
X
X
X
X
X
X
Clinical laboratory tests 
(hematology, chemistry, UA, 
FSHh)
X
X
X
X
X
X
X
X
Fasting lipid panel
X
X
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Table 1:
Schedule of Assessments
Study Time Frame/
Visit
Screening Period
Treatment Perioda
Follow-
up
Screening
Day –30
to Day -1
Visit 1
Day --7b
Day 1
Visit 2
Week 1
Visit 3
Week 2
Visit 4
Week 4
Visit 5
Week 8
Visit 6
Week 12
EOT/ET
Visit 7
Week 16
EOS
Visit 8
Windows (days)
(±1)
(±1)
(±2)
(±2)
(±2)
(±3)
(±3)
(±4)
High sensitivity CRP and ESR
X
X
X
X
X
X
X
X
Electrocardiogrami
X
X
X
X
X
X
X
Tender and swollen joint counts 
(TJC 68, SJC 66)
X
X
X
X
X
X
X
X
CASPAR
X
Dactylitis
X
X
X
X
X
X
X
Patient global assessments of 
PsA, and PsA pain (VAS)
X
X
X
X
X
X
X
Physician global assessment of 
PsA (VAS)
X
X
X
X
X
X
X
HAQ-DI
X
X
X
X
X
X
X
LEI
X
X
X
X
X
X
X
PASI/ PGA of psoriasis/BSA
X
X
X
X
X
X
MDA
X
X
X
X
Randomization 
X
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Table 1:
Schedule of Assessments
Study Time Frame/
Visit
Screening Period
Treatment Perioda
Follow-
up
Screening
Day –30
to Day -1
Visit 1
Day --7b
Day 1
Visit 2
Week 1
Visit 3
Week 2
Visit 4
Week 4
Visit 5
Week 8
Visit 6
Week 12
EOT/ET
Visit 7
Week 16
EOS
Visit 8
Windows (days)
(±1)
(±1)
(±2)
(±2)
(±2)
(±3)
(±3)
(±4)
On-site study drug
administrationj
X
X
X
X
X
Dispense study drug
X
X
X
X
X
Collection of study drug
X
X
X
X
X
Subject dosing diary 
distribution/collection/ review
X
X
X
X
X
Xk
Blood samples for NDI-034858 
concentration
Xl
Xm
Xn
Xo
Concomitant medication
X
X
X
X
X
X
X
X
Adverse events evaluation
Xp
X
X
X
X
X
X
BSA = body surface area; CASPAR = Classification Criteria for Psoriatic Arthritis; CCP = cyclic citrullinated peptides; CRP = C-reactive protein; EOS = end of 
study; EOT = end of treatment; ESR = erythrocyte sedimentation rate; ET = early termination;
; 
FSH = follicle stimulating hormone; HAQ-DI = Health Assessment Questionnaire – Disability Index; HBsAg = Hepatitis B serum antigen; HBc = hepatitis B 
core; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; LEI = Leed’s Enthesitis Index; MDA = Minimal Disease 
Activity; PASI = Psoriasis Area Severity Index; PsA = psoriatic arthritis; PGA = Physician Global Assessment; 
; SJC 
= swollen joint count; TJC = tender joint count; UA = urinalysis; VAS – visual analog scale
Note:  Day 1 assessments will be used to confirm eligibility for the study. Subjects who do not meet continuing eligibility on Day 1 will not be allowed into the 
study.
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a Study Visit Weeks are scheduled based on Day 1. The Week 1 visit is 7 days ±2 days from Day 1; Week 2 is 14 days ±2 days from Day 1; Week 4 is 28 days 
±2 days from Day 1; Week 8 is 56 days ±3 days from Day 1; Week 12 is 84 days ±3 days from Day 1; and Week 16 is 112 days ±4 days from Day 1.
b Day -7 is not a subject visit and is only planned for randomization and to allow time for study drug shipment to the site.
c For female subjects of childbearing potential only, serum pregnancy test at screening, and urine pregnancy test at the other visits.
d A T-Spot.TB test may be used as an alternative to the QuantiFERON-TB Bold test as per Exclusion Criterion 37.
e Chest x-ray may be performed at screening or within 3 months prior to the screening visit, read and documented by a qualified physician as no evidence of 
infection or malignancy.
f Including height and weight. Height will be measured only at screening.
g Targeted examination includes: heart, lungs, abdomen, lower extremities, and lymph nodes.
h FSH to be performed at screening only, for females who have had a cessation of menses for ≥12 months prior to the screening visit without an alternative 
medical cause.
i In addition to the time points specified in the schedule of assessments, an ECG may be performed at any time during the study if in the opinion of the 
investigator it is clinically warranted.
j Study drugs will be taken at home QD for 12 weeks, except on visit days, when the study drugs will be administered on-site. No drug administration will occur 
on the day of Week 12 visit.
k Subject dosing diary will be collected and reviewed at Week 12 visit. Subject dosing diary will not be distributed at Week 12.
l Samples to be taken predose and 1 hour (±5 min) postdose on Day 1.
m Samples to be taken predose, 1 hour (±5 min) postdose, and 4 hours (± 10 min) postdose at Week 4.
n Samples to be taken predose at Week 8.
o Samples to be taken anytime at Week 12 (no study drug administration at this visit).
p Adverse event collection will begin after dosing on Day 1.
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2.
INTRODUCTION
2.1.
Background
2.1.1.
Psoriatic Arthritis
Psoriatic arthritis (PsA) is a chronic, systemic inflammatory disease that manifests as peripheral 
arthritis, axial disease, dactylitis, enthesitis, and skin and nail lesions (Mease et al. 2018). There 
is an estimated prevalence of 0.3 to 1% of the general population with psoriatic arthritis, with 
approximately 50% of subjects experiencing bone erosions within 2 years (Kavanaugh et al. 
2014). Psoriatic arthritis is present in up to 30% of psoriasis subjects (Ogdie et al. 2020) with 
disability from irreversible joint damage and deformities in many subjects (Mease et al. 2018). In 
addition, PsA is also associated with increased mortality (Duarte et al. 2012).
Psoriatic arthritis substantially impacts function, quality of life, and work productivity. If left 
untreated, the joint inflammation results in joint destruction and disability. The goals of 
treatment are to ameliorate the signs and symptoms of PsA, improve function, prevent structural 
damage, and enhance quality of life and productivity. The significant morbidities associated with 
PsA are typically treated with non-steroidal anti-inflammatory drugs (NSAIDs), traditional 
disease-modifying anti-rheumatic drugs ([DMARDs], e.g., methotrexate or sulfasalazine), and/or 
biologics such as tumor necrosis factor inhibitors (TNFi) or interleukin (IL)-12/23 or IL-17 
inhibitors. There are limited data supporting the use of traditional DMARDS for PsA and these 
may not prevent structural damage. The biologics require parenteral delivery which are 
inconvenient for subjects. In addition, despite these therapies, a low percentage of subjects 
achieve remission, many have variable efficacy regarding the multiple co-morbid manifestations 
of PsA or are intolerant to available therapies (Kavanaugh et al. 2014; Mease et al. 2018).Thus, 
there continues to be a significant unmet need for a safe and efficacious oral PsA therapy.
2.1.2.
NDI-034858
NDI-034858 (also known as TAK-279) is a small molecule allosteric inhibitor that binds to the 
JH2 pseudokinase domain of tyrosine kinase 2 (TYK2), leading to inhibition of the TYK2 
catalytic JH1 kinase domain and subsequent downstream signaling events. The allosteric 
interaction of NDI-034858 with the TYK2 JH2 domain results in highly selective inhibition of 
TYK2 kinase activity compared to the other homologous proteins in the Janus kinase (JAK) 
family of nonreceptor tyrosine kinases (JAK1, JAK2, and JAK3).
TYK2 catalyzes the phosphorylation of signal transducers and activators of transcription (STAT) 
proteins downstream of several cytokine receptors, including the IL-23 receptor, as well as the 
Type I interferon receptor and the IL-12 receptor (Watford et al. 2004). The activation of TYK2 
dependent receptors by their cytokine ligands results in the activation of STAT-dependent 
transcription and cellular functional responses specific for the receptors and cell types they are 
expressed on (Stark and Darnell 2012). The cytokine signaling pathways regulated by TYK2 
play key roles in several immune-mediated disorders. Most relevant for PsA pathogenesis, the 
cytokine IL-23 is central for the expansion and survival of T-helper (Th)17 cells and innate 
lymphoid cells, both of which have been shown to play key pathogenic roles in autoimmunity 
(Sutton et al. 2012). IL-23 stimulation drives the production of key proinflammatory cytokines 
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2.2.3.
Assessment of Risks and Benefits
NDI-034858 has undergone nonclinical and clinical development as described in the latest 
version of the IB. The collective nonclinical safety profile and safety results of the completed 
Phase 1 studies 4858-101 and 4858-102 have not resulted in identification of safety signals and 
suggest that NDI-034858 is generally safe and well tolerated. The potential risks associated with 
NDI-034858 can be monitored and mitigated, as outlined, by inclusion/exclusion criteria, 
monitoring of clinical laboratory tests and vital signs, treatment discontinuation criteria, and by 
exclusion of concomitant medications that may have clinically significant interaction with 
NDI-034848.
Efficacy data from the Phase 1 Study 4858-102 suggest the therapeutic potential of NDI-034858 
in moderate-to-severe plaque psoriasis. This is supported by Phase 2b and Phase 3 PsA and 
psoriasis studies from deucravacitinib, which validated blockade of TYK2 as a therapeutic 
approach for treatment of moderate-to-severe plaque psoriasis.
In summary, the collective nonclinical and clinical evidence supporting the inhibition of TYK2
as a therapeutic approach in PsA and the safety profile of NDI-034858 established to date in 
healthy volunteers and psoriasis subjects provide a strong scientific and clinical rationale for 
pursuing development of NDI-034858 in subjects with PsA. The benefit/risk for further 
development of NDI-034858 in PsA is therefore warranted.
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5.
STUDY POPULATION
5.1.
Inclusion Criteria
In order to be eligible to participate in this study, a subject must meet all of the following criteria, 
either at the screening and Day 1 visits or only at one of the specified visits (screening or Day 1) 
as noted in the criterion:
1.
Subject is male or female, aged ≥18 years, at the time of consent.
2.
Subject has PsA on the basis of the CASPAR with peripheral symptoms at the screening
visit, as assessed by the investigator.
3.
Subject has a history of PsA symptoms for ≥6 months prior to the screening visit, as
assessed by the investigator.
4.
Subject has ≥ 3 tender joints and ≥ 3 swollen joints at screening and Day 1 visits, as
assessed by the investigator.
5.
Subject has at least one lesion of plaque psoriasis ≥ 2 cm in diameter, nail changes
characteristic of psoriasis, or a documented history of plaque psoriasis.
6.
Subject has active PsA despite previous standard doses of NSAIDs administered for
≥4 weeks, or traditional DMARDs (including methotrexate and sulfasalazine)
administered for ≥ 3 months, or TNFi agents administered for ≥ 3 months, or subjects are
intolerant to NSAIDs or DMARDs or TNFi agents, as assessed by the investigator.
7.
If subject is on concurrent PsA treatments, they must be on stable doses as described
below and for the duration of the study:
a.
Methotrexate (MTX): subject has received treatment for ≥ 3 months, with stable
dose and stable route of administration (not to exceed 25 mg MTX per week) for
≥ 4 weeks prior to Day 1 until Week 16 (EOS); subjects on MTX should be taking
folic acid supplementation according to local standard of care to minimize the
likelihood of MTX associated toxicity.
b. Sulfasalazine: Maximum dose of 3 gm/day. Minimum duration of therapy
2 months and dose stable for 4 weeks prior to Day 1.
c.
Other traditional DMARDs not listed may be considered on a case-by-case basis
after discussion with the medical monitor
d. Oral corticosteroids: the subject must be on a stable dose, not to exceed the
equivalent of 10 mg of prednisone per day, for ≥ 2 weeks prior to Day 1. If
subject is not currently using oral corticosteroids, must not have received for at
least 2 weeks prior to Day 1.
a.
NSAIDs or paracetamol/acetaminophen: the subject must be on a stable dose for
≥ 2 weeks prior to Day 1.  If not currently using NSAIDs, must not have received
for at least 2 weeks prior to Day 1.
8.
For female subjects of childbearing potential involved in any sexual intercourse that
could lead to pregnancy: the subject must agree to us a highly effective contraceptive
method from screening until at least 4 weeks after the last study drug administration.
Highly effective contraceptive methods include hormonal contraceptives (eg, combined
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oral contraceptive, patch, vaginal ring, injectable, or implant), intrauterine devices or 
intrauterine systems, vasectomized partner(s) (provided vasectomy was performed 
≥4 months prior to screening), tubal ligation, or double barrier methods of contraception 
(eg, male condom with cervical cap, male condom with diaphragm, and male condom 
with contraceptive sponge) in conjunction with spermicide. See Appendix 2 for
additional local requirements or restrictions that may apply.
Note: Subjects must have been on a stable dose of hormonal contraceptives for at least 
4 weeks before Day 1.
Note: The above list of contraceptive methods does not apply to subjects who are 
abstinent for at least 4 weeks before Day 1 and will continue to be abstinent from 
penile-vaginal intercourse throughout the study. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the clinical study, and the preferred 
and usual lifestyle of the subject. Periodic abstinence (calendar, symptothermal, 
postovulation methods) is not acceptable.
Note: A female subject of nonchildbearing potential is defined as follows:

Female subject who has had surgical sterilization (hysterectomy, bilateral
oophorectomy, or bilateral salpingectomy)

Female subject who has had a cessation of menses for at least 12 months prior to
the screening visit without an alternative medical cause, and a follicle-stimulating
hormone (FSH) test confirming nonchildbearing potential (refer to laboratory
reference ranges for confirmatory levels).
9.
Female subjects of childbearing potential have had a negative serum pregnancy test at
screening and negative urine pregnancy test at Day 1.
10. For male subjects involved in any sexual intercourse that could lead to pregnancy, subject
must agree to use one of the highly effective contraceptive methods listed in Inclusion
Criterion 8, from Day 1 until at least 12 weeks after the last study drug administration. If
the female partner of a male subject uses any of the hormonal contraceptive methods
listed above, this contraceptive method should be used by the female partner from at least
4 weeks before Day 1 until at least 12 weeks after the last study drug administration. See
Appendix 2 for additional local requirements or restrictions that may apply.
Note: Male subjects must refrain from donating sperm from Day 1 until at least 12 weeks
after the last study drug administration.
Note: No restrictions are required for a male subject who underwent a vasectomy at least
4 months prior to screening and the procedure is documented. If vasectomy procedure is
not documented or was performed less than 4 months prior to screening, male subjects
must follow the same contraception and sperm donation requirements as for
nonvasectomized subjects.
11. Subject has a body mass index (BMI) of >18 kg/m2, inclusive, (BMI = weight
[kg]/[height (m)]2), and total body weight >50 kg (110 lb).
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12. Subject is willing to participate and is capable of giving informed consent. Note: Signed,
dated, written informed consent must be obtained prior to any study-related procedures.
13. Subjects must be willing to comply with all study procedures and must be available for
the duration of the study.
5.2.
Exclusion Criteria
A subject who meets any of the following criteria at the screening and/or Day 1 visits, as 
applicable, will be excluded from participation in this study:
1. Subject has other disease(s) that might confound the evaluations of benefit of
NDI-034858 therapy, including but not limited to rheumatoid arthritis (RA), axial
spondyloarthritis (this does not include a primary diagnosis of PsA with spondylitis),
systemic lupus erythematosus, Lyme disease, or fibromyalgia.
2. Subject has a history of lack of response to any therapeutic agent targeting IL-12, IL17,
and/or IL23 (eg, ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab,
tildrakizumab, risankizumab) at approved doses after at least 12 weeks of therapy, and/or
received one of these therapies within 6 months prior to baseline (Day 1).
3. Subject has a history of lack of response to > 1 therapeutic agent targeting TNF.
4. Subject has received infliximab, golimumab, adalimumab, or certolizumab pegol, or any
biosimilar of these agents, within 8 weeks or 5 half-lives (see Appendix 3), whichever is
longer, prior to baseline (Day 1).
5. Subject has received etanercept, or any biosimilar of etanercept, within 4 weeks prior to
baseline (Day 1).
6. Subject has received rituximab or any immune-cell-depleting therapy within 6 months
prior to baseline (Day 1).
7. Subject has received any marketed or investigational biological agent, other than those
specified in other inclusion/exclusion criteria, within 12 weeks or 5 half-lives (whichever
is longer, see Appendix 3) prior to baseline (Day 1).
8. Subject is currently receiving a non-biological investigational product or device or has
received one within 4 weeks prior to baseline (Day 1).
9. Subject has received apremilast or other non-biologic systemic treatment for PsA within
4 weeks prior to baseline (Day 1), other than MTX, sulfasalazine, corticosteroids,
NSAIDs, or paracetamol/acetaminophen, which are allowed at stable doses as described
in Inclusion Criterion 7. For subjects not receiving MTX and sulfasalazine at screening,
MTX and sulfasalazine are excluded within 4 weeks prior to baseline (Day 1). Subject
has received leflunomide within 95 days of baseline (Day 1) if no elimination procedure
was followed or adhere to an elimination procedure (eg, 11 days with cholestyramine or
30 days washout with activated charcoal as per local label). For subjects not receiving
MTX and sulfasalazine at Screening, MTX and sulfasalazine are excluded within
4 weeks prior to baseline (Day 1).
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10. Subject has received intraarticular injection (including corticosteroids), intramuscular
steroids, intralesional steroids, or intravenous steroids within 4 weeks prior to baseline
(Day 1). For subjects not receiving MTX and sulfasalazine at screening, MTX and
sulfasalazine are excluded within 4 weeks prior to baseline (Day 1). For subjects not
receiving MTX and sulfasalazine at screening, MTX and sulfasalazine are excluded
within 4 weeks prior to baseline (Day 1).
11. Subject has received high potency opioid analgesics (eg, methadone, hydromorphone, or
morphine) within 2 weeks prior to baseline (Day 1).
12. Subject has used any topical medication that could affect PsA or psoriasis (including
corticosteroids, retinoids, vitamin D analogues (such as calcipotriol), JAK inhibitors, or
tar) within 2 weeks prior to baseline (Day 1).
13. Subject has used any systemic treatment that could affect PsA or psoriasis (including oral
retinoids, immunosuppressive/immunomodulating medication, cyclosporine, oral JAK
inhibitors, or apremilast) within 4 weeks prior to baseline (Day 1), unless otherwise
excluded or allowed by protocol.
Note: Intranasal corticosteroids and inhaled corticosteroids are allowed. Eye and ear
drops containing corticosteroids are also allowed.
14. Subject has received any ultraviolet (UV)-B phototherapy (including tanning beds) or
excimer laser within 4 weeks prior to baseline (Day 1).
15. Subject has had psoralen and UV A (PUVA) treatment within 4 weeks prior to baseline
(Day 1).
16. Subject has received Chinese traditional medicine within 4 weeks prior to baseline
(Day 1)
17. Subject has received any live-attenuated vaccine, including for COVID-19, within
4 weeks prior to baseline (Day 1) or plans to receive a live-attenuated vaccine during the
study and up to 4 weeks or 5 half-lives of the study drug, whichever is longer, after the
last study drug administration.
Note: Non-live-attenuated vaccines or boosters for COVID-19 (eg, RNA-based vaccines,
inactivated adenovirus-based vaccines, protein-based vaccines) are allowed during the
study. The study site should follow local guidelines related to COVID-19.
18. Subject is currently being treated with strong or moderate cytochrome P450 3A
(CYP3A4) inhibitors, such as itraconazole or has received moderate or strong CYP3A4
inhibitors within 4 weeks prior to baseline (Day 1).
19. Subject has consumed grapefruit or grapefruit juice within 1 week prior to baseline
(Day 1).
Note: Consumption of grapefruit must be avoided during the treatment period and for at
least 1 week after last study drug administration.
20. Subject has used tanning booths within 4 weeks prior to baseline (Day 1), has had
excessive sun exposure, or is not willing to minimize natural and artificial sunlight
exposure during the study.
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Note: Use of sunscreen products and protective apparel are recommended when sun 
exposure cannot be avoided.
21. Subject is a female who is breastfeeding, pregnant, or who is planning to become
pregnant during the study.
22. Subject has evidence of erythrodermic, pustular, predominantly guttate psoriasis, or
drug -induced psoriasis.
23. Subject has a history of skin disease or presence of skin condition that, in the opinion of
the investigator, would interfere with the study assessments.
24. Subject has any clinically significant medical condition, evidence of an unstable clinical
condition (eg, cardiovascular, renal, hepatic, hematologic, gastrointestinal, endocrine,
pulmonary, immunologic, or local active infection/infectious illness), psychiatric
condition, or vital signs/physical/laboratory/ECG abnormality that would, in the opinion
of the investigator, put the subject at undue risk or interfere with interpretation of study
results.
25. Subject had a major surgery within 8 weeks prior to baseline (Day 1or has a major
surgery planned during the study.
26. Subject has a history of Class III or IV congestive heart failure as defined by New York
Heart Association Criteria.
27. Subject has an estimated creatinine clearance of < 40 mL/min based on the
Cockcroft-Gault equation or a history of renal failure as determined by the investigator

Cockcroft-Gault equation:
Creatinine Clearance (estimated) / Conventional mL/min =
(140 - Age [years]) x Weight (kg) x Factor a) / (72 x serum creatinine [mg/dL])
Note: Factor a = 0.85 in females and 1.00 in males.
28. Subject was hospitalized in the 3 months prior to screening for asthma, has ever required
intubation for treatment of asthma, currently require oral corticosteroids for the treatment
of asthma, or has required more than one short-term (≤2 weeks) course of oral
corticosteroids for asthma within 6 months prior to baseline (Day 1).
29. Subject has a history of cancer or lymphoproliferative disease within 5 years prior to
baseline (Day 1). Subjects with successfully treated nonmetastatic cutaneous squamous
cell or basal cell carcinoma and/or localized carcinoma in situ of the cervix are not to be
excluded.
30. Subject has a history of fever, inflammation, or systemic signs of illness suggestive of
systemic or invasive infection within 4 weeks prior to baseline (Day 1).
31. Subject has an active bacterial, viral, fungal, mycobacterial infection, or other infection
(including TB or atypical mycobacterial disease), or any major episode of infection that
required hospitalization or treatment with intravenous antibiotics within 12 weeks prior to
baseline (Day 1), or oral antibiotics within 4 weeks prior to baseline (Day 1).
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32. Subject has a history of chronic or recurrent infectious disease, including but not limited
to chronic renal infection, chronic chest infection, recurrent urinary tract infection, fungal
infection (with the exception of superficial fungal infection of the nailbed), or infected
skin wounds or ulcers.
33. Subject has a history of an infected joint prosthesis or has received antibiotics for a
suspected infection of a joint prosthesis, if that prosthesis has not been removed or
replaced.
34. Subject has active herpes infection, including herpes simplex 1 and 2 and herpes zoster
(demonstrated on physical examination and/or medical history) within 8 weeks prior to
Day 1.
35. Subject has a history of known or suspected congenital or acquired immunodeficiency
state or condition that would compromise the subject’s immune status in the opinion of
the investigator (eg, history of splenectomy, primary immunodeficiency).
36. Subject has positive results for hepatitis B surface antigens (HBsAg), antibodies to
hepatitis B core antigens (anti-HBc), hepatitis C virus (HCV), or human
immunodeficiency virus (HIV). Samples testing positive for HCV antibodies will require
polymerase chain reaction (PCR) qualitative testing for HCV RNA. Any HCV RNA PCR
result that meets or exceeds detection sensitivity is exclusionary.
37. Subject has clinical or laboratory evidence of active or latent TB infection at screening.
Note: Subjects will be evaluated for TB infection by QuantiFERON-TB Gold (or a
purified protein derivative [PPD] skin test or equivalent, or both if required per local
guidelines) and chest X-ray. The PPD skin test should be utilized only when a
QuantiFERON-TB Gold Test is not possible for any reason (unless local guidelines
require both tests). Chest X-ray may be taken at screening or completed within 3 months
prior to the screening visit, with documentation showing no evidence of infection or
malignancy as read by a qualified physician.
Note: The T-Spot.TB test (TBT) is an acceptable alternative to the QFT test in regions
where the TBT is standard practice for tuberculosis screening. The medical monitor
should be informed prior to using the TBT in place of the QFT test. A negative TBT is
required if the QFT test is not performed.
Note: Subjects with a history of active or latent TB will not be included in the study,
unless documentation of prior and complete anti-TB treatment, appropriate in duration
and type according to current local country guidelines, can be provided. Latent TB is
defined as a positive QFT test or two successive indeterminate QFT tests at screening.
38. Subject with any of the following laboratory values at the screening visit:

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values
≥3 times the upper limit of normal (ULN)

Hemoglobin < 11.0 g/dL (< 110.0 g/L)

White blood cell count < 3.5 x 109/L (< 3500/mm3)
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
Absolute neutrophil count of < 1.8 x 109/L (< 1800/mm3)

Absolute lymphocyte count of < 1.0 x 109/L (< 1000/mm3)

Platelet count < 100 x 109/L (< 100,000/mm3)

Total bilirubin ˃ 2 times the ULN
39. Subjects who have given > 50 ml of blood or plasma within 30 days of screening or
> 500 mL of blood or plasma within 56 days of screening (during a clinical study or at a
blood bank donation).
40. Subject has a known or suspected allergy to NDI-034858 or any component of the
investigational product, or any other significant drug allergy (such as anaphylaxis or
hepatotoxicity).
41. Subject has a known history of clinically significant drug or alcohol abuse in the last year
prior to baseline (Day 1).
42. Subject has known history of moderate to severe hepatic impairment, Class B or C, by
Child-Pugh scoring system.
5.3.
Screen Failures
Screen failures are defined as individuals who consent to participate in the clinical study but are 
not subsequently randomly assigned to the study treatment. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects, to meet the 
Consolidated Standards of Reporting Trials publishing requirements, and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
and eligibility criteria.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once, if deemed acceptable by the investigator. Rescreened subjects should be 
assigned a different screening number than the initial screening number. All screening 
procedures will be performed at the new screening visit except for chest X-ray if performed 
within 3 months of the new screening visit, including signature of a new consent form.
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Randomization will occur at the Day -7 visit. The randomization list will be generated using
validated software and will be stratified based on prior treatment with biologics or non-
traditional DMARDs (ie, yes/no), and region. The master randomization list will be kept secured 
until the study blind is broken at the end of study. This list will be uploaded into an Interactive 
Web Response System (IWRS). The investigator or designee will be able to acquire a 
randomization number for subjects by connecting to the IWRS. Of note, only eligible subjects 
(confirmed on Day 1) will receive the study drug.
6.3.1.
Blinding
This study will be double-blinded. At all times, treatment and randomization information will be 
kept confidential and will not be released to the investigator, the study staff, the contract research 
organization (CRO), or the sponsor’s study team until after the conclusion of the study.
Breaking the blind should be considered only when knowledge of the treatment assignment is 
deemed essential for the subject’s care. In such cases of a medical emergency, the investigator 
has the sole responsibility for determining if unblinding of a subject’s treatment assignment is 
warranted. Subject safety must always be the first consideration in making such a determination. 
If the investigator decides that unblinding is warranted, the investigator should make every effort 
to contact the medical monitor prior to unblinding a subject’s treatment assignment unless this 
could delay further management of the subject. If a subject’s treatment assignment is unblinded, 
the medical monitor and the sponsor must be notified within 24 hours after breaking the blind. 
The date and reason for breaking the blind must be documented in the source document and the 
eCRF.
In cases of accidental unblinding, the investigator should contact the medical monitor and ensure 
every attempt is made to preserve the blind. Any request to unblind a subject for nonemergency 
purposes must be discussed with the medical monitor prior to unblinding.
The subject for whom the blind has been broken for a safety-related reason will be permanently 
discontinued from the study drug. The primary reason for study drug discontinuation (the event 
or condition which led to the unblinding) will be recorded.
6.3.2.
Study Treatment Compliance
Study treatment compliance will be monitored at each visit. Adherence to treatment will be 
assessed by direct questioning, review of the subject’s dosing diary, and by maintaining adequate 
study drug dispensing and return records. 
Subjects who are significantly noncompliant with treatment will be counseled and could be 
discontinued from the study, at the discretion of the investigator, following consultation with the 
sponsor. Significant noncompliance is defined as missing 3 consecutive doses (ie, 3 days in a 
row) or missing a total of 10 doses.
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6.4.
Concomitant Therapy
All medications (including over-the-counter drugs, vitamins, herbal/natural drugs, homeopathic 
medications, and antacids) taken within 4 weeks prior to screening and throughout the study 
must be recorded. In addition, the last use of any prohibited medications before Day 1 must be 
recorded and fall within the timeframe described in the exclusion criteria.
Medication entries may be captured as generic or trade names. Trade names should be used for 
combination drugs. Entries should include as much as possible of the following information: the 
dose, unit, frequency of administration, route of administration, start date, end date, and 
indication. If the medication is stopped or the dosage is changed, these details must be recorded.
6.4.1.
Permitted Therapies
The following therapies are permitted:

Intranasal corticosteroids and inhaled corticosteroids are allowed. Eye and ear drops
containing corticosteroids are also allowed.

The use of oral corticosteroids and concomitant PsA treatments (ie, MTX and
sulfasalazine) are described in Section 5.1, number 7.

Use of sunscreen products and protective apparel are permitted when sun exposure
cannot be avoided. However, on the day of scheduled visits, subjects cannot apply
sunscreen products before their scheduled visit time.
6.4.1.1.
Emollients
Subjects can apply an emollient of their choice (except those containing salicylic acid) on their 
skin, including on psoriasis lesions. However, on the day of scheduled visits, subjects cannot 
apply emollient before their scheduled visit time.
Every effort should be made to keep the same emollient throughout the study for the same body 
region. However, the chosen emollient may differ depending on the body region (eg, body vs 
face emollient may be different). The commercial name of the selected emollient(s) will be 
recorded in the source document and the eCRF. No other products may be applied to the lesions 
during the study.
6.4.2.
Prohibited Therapies or Procedures
Prohibited medications that are not to be used from the defined washout periods before the first 
administration of study drug at the Day 1 visit through the last study visit are provided in 
Table 4.
Subjects who start prohibited medications (systemic and topical) or therapies that have been 
demonstrated to be effective for treatment of PsA or plaque psoriasis during the study may be 
discontinued from study drug. Investigators should contact the medical monitor as soon as 
possible when a prohibited medication is initiated, to discuss the appropriate steps. Subjects who 
start prohibited medications or therapies for other reasons during the study may be discontinued 
from study drug if an impact on efficacy assessment or safety of the subjects is expected.
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Table 4:
Prohibited Therapies or Procedures
Prohibited Medications, Products, And Procedures
Washout Period Prior To 
First Dose (Day 1)
DMARD Therapies
Therapeutic agent targeting IL-12, IL-17, and/or IL-23 (eg, ustekinumab, 
secukinumab, ixekizumab, brodalumab, guselkumab, tildrakizumab, 
risankizumab)
6 months
Rituximab or other immune-cell depleting agents
6 months
Therapeutic agent targeting TNF-α (eg, infliximab, golimumab, 
adalimumab, or certolizumab pegol) or any biosimilar of these agents
8 weeks
Leflunomide if no elimination procedure was followed.  Or if an 
elimination procedure is used then 11 days with cholestyramine or 30 
days washout with activated charcoal as per local label.
8 weeks
Apremilast or other non-biologic systemic treatment for PsA, other than 
MTX, sulfasalazine, corticosteroids, NSAIDs, or
paracetamol/acetaminophen, which are allowed at stable doses as 
described in inclusion criterion (Sutton et al. 2012)
4 weeks
Etanercept or any biosimilar of etanercept
4 weeks
Investigational Drugs or Vaccines
Any marketed or investigational biological agent (except those listed 
above)
12 weeks or 5 half-lives 
(whichever is longer)
Any live-attenuated vaccine, including for COVID-19 or plans or receive 
a live-attenuated vaccine
Note: Non-live-attenuated vaccines for COVID-19 (eg, RNA-based 
vaccines, inactivated adenovirus-based vaccines, protein-based vaccines) 
are allowed during the study. The study site should follow local 
guidelines related to COVID-19.
4 weeks or 5 half-lives 
(whichever is longer)
Non-biological investigational drug or device 
4 weeks
Steroids and Similar Therapies
Systemic treatment that could affect psoriasis or PsA (oral retinoids, 
immunosuppressive/immunomodulating medication, cyclosporine, oral 
JAK inhibitors, or apremilast)
Note: Intranasal corticosteroids and inhaled corticosteroids are allowed. 
Eye and ear drops containing corticosteroids are also allowed.
4 weeks
Intraarticular injection (including corticosteroids), intramuscular steroids, 
intralesional steroids, or intravenous steroids
4 weeks
Topical medication that could affect psoriasis (including corticosteroids, 
retinoids, vitamin D analogues [such as calcipotriol], JAK inhibitors, or 
tar)
2 weeks
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Table 4:
Prohibited Therapies or Procedures
Prohibited Medications, Products, And Procedures
Washout Period Prior To 
First Dose (Day 1)
Antibiotics/Antifungals/CYP3A4 inhibitors
Intravenous antibiotic treatment
12 weeks
Strong or moderate CYP3A4 inhibitors (such as itraconazole); see 
Appendix 1 for a list of prohibited medications in this class.
4 weeks
Oral antibiotic treatment
4 weeks
Grapefruit or grapefruit juice
Note: Consumption of grapefruit must be avoided during the treatment 
period and for at least 1 week after last dose administration.
1 week
All Other Prohibited Medications/Therapy
PUVA treatment, UV-B phototherapy (including tanning beds), or 
excimer laser, or tanning booths, has had excessive sun exposure, or is 
not willing to minimize natural and artificial sunlight exposure during the 
study
Note: Use of sunscreen products and protective apparel are recommended 
when sun exposure cannot be avoided.
4 weeks
Chinese traditional medicine
4 weeks
High potency opioid analgesics (eg, methadone, hydromorphone, or 
morphine)
2 weeks
COVID-19 = coronavirus Disease-2019; CYP3A4 = cytochrome P450 3A; IL = interleukin; JAK = Janus kinase; 
MTX = methotrexate; NSAIDs = nons-steroidal inflammatory drugs; PsA – psoriatic arthritis; 
PUVA = psoralen-ultraviolet-A; RNA = ribonucleic acid; TNF-α – tumor necrosis factor alpha; UV = ultraviolet.
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7.
DISCONTINUATION AND LOST TO FOLLOW-UP
7.1.
Discontinuation from Study Drug
Medical judgment should be applied to guide whether study drug discontinuation or careful 
monitoring may be the most appropriate course of action. If it is deemed by the investigator that 
it is in the best interest of the subject to discontinue further study drug, the medical monitor 
should be contacted as soon as possible for consultation. 
Subjects must be permanently discontinued from study drug for the following reasons:

Pregnancy of a female subject

The subject experiences a medical emergency that necessitates permanent
discontinuation and/or unblinding of the subject’s treatment assignment.

The subject is unwilling or unable to comply with the protocol.

At the discretion of the investigator for medical reasons or for noncompliance.

Subject experiences a Common Terminology Criteria for Adverse Events (CTCAE)
Grade ≥3 cytopenia (anemia, leukopenia, neutropenia, lymphopenia, and
thrombocytopenia; clinically significant or not) as defined in Section 8.5.7.

Subject initiates any of the following prohibited medications (Section 6.4.2):

Therapeutic agent targeting IL-12, IL-17, and/or IL-23 (eg, ustekinumab,
secukinumab, ixekizumab, brodalumab, guselkumab, tildrakizumab,
risankizumab)

Rituximab or other immune-cell depleting agents

Other marketed or investigational biological agent not listed above

Live-attenuated vaccine

Non-biological investigational drug or device

Intravenous antibiotic treatment

Systemic treatment that could affect psoriasis or PsA (including corticosteroids,
oral retinoids, immunosuppressive/immunomodulating medication, methotrexate,
cyclosporine, oral JAK inhibitors, or apremilast)
Subjects must at least be temporarily discontinued from study drug for the following reasons:

The subject has met study drug discontinuation criteria for abnormalities suggestive
of drug induced liver injury as described in Section 8.5.8.
If abnormalities suggestive of drug-induced liver injury as described in Section 8.5.8 are found to 
be related to study drug, the subject will be permanently discontinued from study drug.
Subjects may be discontinued from study drug for any of, but not limited to, the following
reasons:

Occurrence of an SAE (see Section 8.5.2).
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
Occurrence of a severe AE (see Section 8.5.3).

Initiation of a protocol prohibited therapy or procedure (Section 6.4.2) other than
those for which the subject must be permanently discontinued from study drug.
Study procedures should be continued to be evaluated for safety, PK, and other parameters even 
in the event of dosing discontinuation. The medical monitor should be contacted for consultation, 
including if it may be appropriate to exclude any of the planned procedures. In the event a 
decision is made to permanently discontinue dosing and all other interventions, please refer to 
the data to be collected at the ET visit of the Schedule of Assessments.
7.2.
Discontinuation from Study
Subjects have the right to withdraw from the study at any time for any reason without penalty. 
The investigator also has the right to withdraw subjects from the study if he or she feels it is in 
the best interest of the subject or if the subject is uncooperative or noncompliant.
Should a subject decide to withdraw, all efforts will be made to complete and report the 
observations as thoroughly as possible, particularly the examinations outlined in the ET visit.
The investigator or one of his or her staff members should contact the subject to determine as 
accurately as possible the primary reason for the withdrawal.
A complete final evaluation at the time of the subject’s withdrawal should be made with an 
explanation of why the subject is withdrawing from the study. If the reason for removal of a 
subject is an AE or an abnormal laboratory test result, the principal specific event or test will be 
recorded.
If a subject withdraws from the study, he or she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records.
Subjects who discontinue the study after the first dose will be asked, if they agree, to come for a 
last assessment (ET visit). Subjects who are discontinued for safety reasons may be asked to 
come for additional follow-up visits, at the investigator’s discretion, after the ET visit to ensure 
appropriate medical care and AE follow-up.
Subjects who discontinue will not be replaced.
Reasons for discontinuation from the study may include the following:

The investigator decides that the subject should be withdrawn. If this decision is made
because of an SAE, the study drug is to be discontinued for that subject immediately
and appropriate measures are to be taken. The investigator will notify the sponsor
immediately.

The subject, for any reason, requires treatment with another therapeutic agent that has
been demonstrated to be effective for treatment of the study indication.

The subject fails to comply with other protocol requirements.

The subject is unable to continue visits or the study site is closed due to COVID-19
pandemic restrictions.
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
The subject is withdrawn for any medical condition or circumstance that exposes the
subject to substantial risk and/or does not allow the subject to adhere to the
requirements of the protocol.

The subject is lost to follow-up. In this case, a reasonable attempt to contact the
subject and ascertain his or her status must be made, and these attempts must be
documented.

The subject becomes pregnant at any time during the study.

Other: the subject may withdraw from the study for any other reason, including
withdrawal of consent.

Study termination by the sponsor or regulatory authorities (refer to Section 7.4).
7.3.
Lost to Follow-Up
A subject will be considered lost to follow-up if he or she fails to return for scheduled visits and 
is unable to be contacted by the study site staff.
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit (unless this is required by the COVID-19 situation and virtual visits are scheduled instead):

The site will attempt to contact the subject and reschedule the missed visit. The site
will then counsel the subject on the importance of maintaining the assigned visit
schedule and ascertain if the subject wishes to or should continue in the study.

Before a subject is deemed lost to follow-up, the investigator or designee will make
every effort to regain contact with the subject (where possible, three telephone calls
and, if necessary, a certified letter to the subject’s last known mailing address or local
equivalent methods). These contact attempts should be documented in the subject’s
medical record or study file.

If all attempts to contact the subject fail, he or she will be considered to have
withdrawn from the study with a primary reason of lost to follow-up.
7.4.
Study Termination
The sponsor has the right to terminate the study for any reason and at any time. Reasons for 
terminating the study may include, but are not limited to, the incidence or severity of TEAEs in 
this or other studies indicating a potential health risk to subjects. In this case, all subjects will be 
discontinued from the study. The investigator will immediately, upon discontinuation of the 
study by the sponsor, in its entirety or at a clinical study site, inform both the subjects and the 
IRB/REB/IEC of the discontinuation, provide them with the reasons for the discontinuation and 
advise them in writing of any potential risks to the health of subjects or other persons. The study 
can also be terminated by IRB/REB/IEC and/or regulatory agency for any unforeseen reasons.
If more than one subject meets the criteria based on Hy’s Law (Section 8.5.8) and these are 
confirmed to be study-drug related after comprehensive safety review, the sponsor will terminate 
the trial.
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8.
STUDY ASSESSMENTS AND PROCEDURES
8.1.
Screening Assessments
8.1.1.
Classification Criteria for Psoriatic Arthritis
The CASPAR will be assessed at the Screening Visit only. The CASPAR consists of established 
inflammatory articular disease with at least 3 points from the following:
Feature
Points assigned
Current psoriasis
2
A history of psoriasis (in the absence of current psoriasis)
1
A family history of psoriasis (in the absence of current psoriasis and history of 
psoriasis)
1
Dactylitis
1
Juxta-articular new-bone formation
1
Rheumatoid factor negativity
1
Nail dystrophy
1
8.1.2.
Chest X-ray
Chest X-rays will be performed as a safety assessment during screening if specified in Table 1. 
Any evidence of TB will be reported. Chest X-ray may be taken at screening or completed 
within 3 months prior to the screening visit, with documentation showing no evidence of 
infection or malignancy as read by a qualified physician.
8.1.3.
Tuberculosis Testing
QuantiFERON-TB Gold or a PPD skin test or equivalent (or both if required per local 
guidelines) will be performed at screening. The PPD skin test should be utilized only when a 
QuantiFERON-TB Gold Test is not possible for any reason, unless local guidelines require both 
tests.
The T-Spot.TB test (TBT) performed by the site’s local laboratory, using the site laboratory 
supplies, is an acceptable alternative to the QFT test in regions where the TBT is standard 
practice for tuberculosis screening. The medical monitor should be informed prior to using the 
TBT in place of the QFT test. A negative TBT is required if the QFT test is not performed.
8.1.4.
Rheumatoid Factor
A blood sample will be taken to test for presence of rheumatoid factor (RF). An RF test can help 
with diagnosing immune disorders and estimate disease severity. This test will be used as part of 
the CASPAR. Subjects with RA are not eligible for the study.
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8.1.5.
Anti-Cyclic Citrullinated Peptide
A blood sample will be taken to test for presence of anti-cyclic citrullinated peptides (anti-CCP). 
The anti-CCP test is predictive of progression of disease, indicating more erosive disease or 
increases in joint involvement.
8.2.
Efficacy Assessments
Clinical evaluations of PsA will be performed by an experienced and qualified physician (board 
certified or equivalent) or other suitably qualified and experienced designee. To assure 
consistency and reduce variability, the same assessor, who is not involved in the study conduct 
or direct patient care should perform all clinical efficacy assessments on a given subject 
whenever possible.
8.2.1.
Primary Efficacy Endpoint - American College of Rheumatology 20
The ACR20 is a composite measure defined as both improvement of 20% in the number of 
tender (68) and number of swollen (66) joints, and a 20% improvement in three of the following 
five criteria: patient global assessment of psoriatic arthritis, physician global assessment of 
psoriatic arthritis, patient global assessment of psoriatic arthritis pain, disability history 
questionnaire (ie, HAQ-DI) and an acute phase reactant (ie, erythrocyte sedimentation rate [ESR] 
or hsCRP). For this primary endpoint, hsCRP will be used. The ACR-20 will be derived 
corresponding with collection of the listed assessments and timepoints as specified in Table 1.
8.2.2.
Secondary Efficacy Endpoints
8.2.2.1.
American College of Rheumatology 50/70
The ACR-50 and ACR-70 are a composite measure defined as both improvement of 50% or 
70%, respectively, in the number of tender (68) and number of swollen (66) joints, and a 50% or 
70%, respectively, improvement in three of the following five criteria: patient global assessment
of psoriatic arthritis, physician global assessment of psoriatic arthritis, patient global assessment 
of psoriatic arthritis pain, disability history questionnaire (ie, HAQ-DI) and an acute phase 
reactant (ie, hsCRP). For these endpoints, hsCRP will be used. The ACR-50 and ACR-70 will be 
derived corresponding with collection of the listed assessments and timepoints as specified in 
Table 1.
8.2.2.2.
Tender Joint Count 68 and Swollen Joint Count 66
The TJC 68 and SJC 66 (SJC minus hip joints, which cannot be assessed for swelling) are a total 
score of points assigned for presence of tenderness or swelling in the following:

Temporomandibular, sternoclavicular, acromioclavicular, shoulder, elbow, wrist, hip
(TJC only), knee, ankle, tarsus, typically assigned 2 points each

Metacarpophalangeal, finger proximal interphalangeal, metatarsophalangeal, toe
proximal interphalangeal, typically assigned 10 points each

Distal interphalangeal, typically assigned 8 points
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8.2.2.3.
Patient Global Assessment of Psoriatic Arthritis
Subjects will rate their assessment of their PsA using a VAS where 0 is ‘very good, no 
symptoms’ and 100 is ‘very poor, severe symptoms’.
8.2.2.4.
Patient Global Assessment of Psoriatic Arthritis Pain
Subjects will rate their assessment of their PsA pain using a VAS where 0 is ‘no pain’ and 100 is 
‘most severe pain’.
8.2.2.5.
Physician Global Assessment of Psoriatic Arthritis
The investigator or qualified sub-investigator will assess the patients’ overall disease status, 
taking into account signs, symptoms, and function, of all components of joint and skin which is 
affected at the time of the visit and will rate this overall status using a VAS scale where 0 is 
‘very good, asymptomatic, and no limitation of normal activities’ and 100 is ‘very poor, very 
severe symptoms which are intolerable, and inability to carry out all normal activities’.
8.2.2.6.
Health Assessment Questionnaire – Disability Index
The HAQ-DI will be assessed at the visits specified in Table 1. The HAQ-DI is comprised of 
eight domains: dressing, arising, eating, walking, hygiene, reach, grip, and activities. There are 
two or three questions per section. Scoring within each section is from 0 (without any difficulty) 
to 3 (unable to do). For each section the score given to that section is the worst score within the 
section (ie, if one question is scored 1 and another 2, then the score for the section is 2). In 
addition, if an aide or device is used or if help is required from another individual, then the 
minimum score for that section is 2. If the section score is already 2 or more then no 
modification is made. The eight scores of the eight sections are summed and divided by eight. 
The result is the DI or disability index. 
8.2.2.7.
Dactylitis Count
The dactylitis count consists of totaling the number of single digits in the hands and feet with 
tenderness.
8.2.2.8.
Leed’s Enthesitis Index
The LEI will be assessed at the visits specified in Table 1. The LEI is comprised of review of 
six bilateral sites: Achilles tendon insertions, medial femoral condyles, and lateral epicondyles of 
the humerus. Tenderness at each site is quantified on a dichotomous basis: 0 means nontender 
and 1 means tender.
8.2.2.9.
Physician Global Assessment of Psoriasis
The PGA will be assessed at the visits specified in Table 1. The PGA is measured using a 0 to 
4 scale with a 0 score meaning cleared and a 4 score meaning severe and a ≥ 2 grade 
improvement from baseline at a specified timepoint, specifically Week 12 in this study.
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8.4.2.
Physical Examination
The following sites/systems will at least be included in the complete physical examination,
which will be performed at the visits specified in Table 1:

General appearance

Dermatological (except plaque psoriasis)

Head, eyes, ears, nose, throat

Respiratory

Cardiovascular

Abdominal

Neurological

Musculoskeletal

Lymphatic
Information for all physical examinations must be included in the source document. Any 
significant change beginning after study drug administration on Day 1 will be reported as an AE 
in the source document and eCRF.
8.4.3.
Targeted Physical Examination
The following sites/systems will at least be included in the targeted physical examination that 
will be performed at the visits specified in Table 1:

General appearance

Dermatological (except plaque psoriasis)

Respiratory

Cardiovascular

Abdominal
If deemed appropriate by the investigator based on the subject’s condition, a complete physical 
examination as described in Section 8.4.2 can be performed instead of a targeted examination.
Information for all physical examinations must be included in the source document. Any 
significant change beginning after study drug administration on Day 1 will be reported as an AE 
in the source document and eCRF.
8.4.4.
Clinical Laboratory Tests
Laboratory tests will be performed at the visits specified in Table 1. The specific tests in these 
panels are listed in Table 5.
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Table 5:
Clinical Laboratory Testing
Laboratory 
Evaluation
Tests Included
Hematology
aPTT, HCT, Hgb, INR, MCH, MCHC, MCV, MPV, PLT, PT, RBC, WBC, 
and differentials (neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils relative and absolute)
Biochemistry
Albumin, alkaline phosphatase, ALT, AST, calcium, CPK, creatinine 
(enzymatic), GGT, glucose random, potassium, sodium, total bilirubin, direct 
bilirubin if total bilirubin > ULN, urea (BUN), uric acid
Fasting lipids
Cholesterol (total, LDL, and HDL), triglycerides (all fasting)
Urinalysis
Color, clarity, pH, specific gravity, bilirubin, glucose, ketones, leukocytes, 
nitrite, blood, protein, urobilinogen
Microscopic analysis (as required)
Urine pregnancy test
(conducted at the 
investigator site)
For WOCBP (at each visit, except screening)
Specialty evaluations
hsCRP, ESR, Rheumatoid factor, anti-CCP
Laboratory tests 
required at screening 
only
FSH levels for female subjects who have had a cessation of menses for at 
least 12 months prior to the screening visit without an alternative medical 
cause
β-hCG for WOCBP
Tuberculosis test (QuantiFERON-TB Gold)

Note: A T-Spot.TB test (TBT) may be used as an alternative to the
QuantiFERON-TB Gold test as per Exclusion Criterion 37. If the TBT is
used, the QuantiFERON-TB Gold test should not be performed.
Serology (HBV [HBsAg, anti-HBc], HCVa, HIV)
ALT = alanine aminotransferase; anti-HBc = antibody to hepatitis B core antigen = aPTT = activated partial 
thromboplastin time; AST = aspartate aminotransferase; β-hCG = β-human chorionic gonadotropin; BUN = blood
urea nitrogen; anti-CCP = cyclic citrullinated peptide antibodies; CPK = creatine phosphokinase; hsCRP = high 
sensitivity C-reactive Protein; ESR = erythrocyte sedimentation rate; FSH = follicle-stimulating hormone; 
GGT = gamma-glutamyl-transferase; HBsAg = hepatitis B surface antigens; HBV = hepatitis B virus; 
HCT = hematocrit; HCV = hepatitis C virus; HDL = high-density lipoprotein; Hgb = hemoglobin; HIV = human 
immunodeficiency virus; INR = international normalized ratio; LDH = lactate dehydrogenase; MCH = mean 
corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular 
volume; MPV = mean platelet volume; PCR = polymerase chain reaction, PLT = platelets; PT = prothrombin 
time; RBC = red blood cell (count); ULN = upper limit of normal; WBC = white blood cell (count); 
WOCBP = women of childbearing potential
a Samples testing positive for HCV antibodies will require PCR qualitative testing for HCV RNA. Any HCV 
RNA PCR result that meets or exceeds detection sensitivity is exclusionary.
In case of a screening laboratory value abnormality, the test can be repeated once within the 
original screening time window, if the investigator believes there is a reasonable possibility that 
the subject would be eligible if re-tested. The QuantiFERON-TB test can only be repeated once 
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if the result is indeterminate; tests with positive or negative results will not be repeated. The TBT 
may be used as an alternative to the QuantiFERON-TB test per Exclusion Criterion 37. The TBT
may be repeated once only if the result is borderline (equivocal); tests with positive or negative 
results will not be repeated.
Any clinically significant value will be reported as an AE beginning after study drug 
administration on Day 1. Any CTCAE Grade ≥3 cytopenia (anemia, leukopenia, neutropenia, 
lymphopenia, or thrombocytopenia; clinically significant or not) or CTCAE Grade ≥3 elevation 
of CPK (clinically significant or not) will be reported as an AE and AE of special interest (AESI, 
Section 8.5.7). Any CTCAE Grade ≥3 cytopenia (anemia, leukopenia, neutropenia, 
lymphopenia, or thrombocytopenia) will lead to permanent discontinuation of study drug 
(Section 7.1).
8.4.4.1.
Use of Local Laboratories
All protocol-specified laboratory tests (See Section 8.4.4) should be performed via the central 
laboratory except for ESR which is performed locally. The central laboratory will provide 
supplies for the ESR. The test will be performed, and results read at the local laboratory. For all
other tests, attempts should be made by the study site to perform the laboratory assessments via 
the central laboratory. In situations where the laboratory tests cannot be performed at the study 
site due to unexpected conditions, extreme difficulty, or other unforeseen situations, the 
protocol-specific laboratory examinations may be conducted through a local laboratory. If the 
TBT is used as an alternative to the QuantiFERON-TB Gold test as per Exclusion Criterion 37, it 
will be performed via a local laboratory. 
Please note: other use of local laboratories should be limited to testing for safety when visits to 
the site are not possible, such as quarantine or immobilization of the subject, and is not meant to 
be a replacement for the central laboratory.
Results determined by the investigator to be clinically significant laboratory abnormalities 
should be reported to the medical monitor ≤ 24hours of the investigator’s receipt. Follow-up 
safety monitoring will be conducted at the investigator’s discretion. Results determined by the 
investigator to be SAEs or AESIs, should be reported to the sponsor following the procedures 
described in Section 8.5.6, Section 8.5.7.
Unscheduled visits for laboratory testing should also be performed via the central laboratory and 
all efforts should be made to do so. In cases where this is not possible, the local laboratory may 
be used as above.
Results from local laboratories will be collected, recorded on the appropriate eCRF, and entered 
in the database.
8.4.5.
Electrocardiogram
Twelve-lead ECGs will be performed as a safety assessment at the visits specified in Table 1. 
Any clinically significant value beginning after study drug administration on Day 1 will be 
reported as an AE starting on Day 1.
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the other outcomes listed in the definition above. These should also usually be considered 
serious.
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse.
Scheduled hospitalizations or elective surgical procedures will not be considered SAEs. 
Prolongation of a scheduled hospitalization can be considered an SAE.
Laboratory abnormalities suggestive of drug-induced liver injury as described in Section 8.5.8
are to be considered SAEs/important medical events.
8.5.3.
Classification of an Adverse Event
8.5.3.1.
Relationship to Study Drug
The investigator will assess causal relationship between each reported AE or SAE, and the 
experimental drug. The investigator should take into account the subject’s medical history, most 
recent physical examination findings, and concomitant medications.
The following definitions will be used to determine the causality of an AE or SAE:

Not related: Temporal relationship of the onset of the AE or SAE, relative to the
experimental drug, is not reasonable, or another cause can explain the occurrence of
the AE.

Related: Temporal relationship of the onset of the AE or SAE, relative to the
experimental drug, is reasonable, follows a known response pattern to the drug, and
an alternative cause is unlikely.
8.5.3.2.
Adverse Event Severity
The severity of an AE or SAE is an estimate of the relative intensity of the event made by the 
investigator based on his or her clinical experience and familiarity with the literature. The 
following definitions from the National Cancer Institute CTCAE, Version 5.0, published 
27-Nov-2017 are to be used to rate the severity of an AE or SAE:

Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations
only; intervention not indicated.

Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age
appropriate instrumental activities of daily living (ADL)*.

Grade 3: Severe or medically significant but not immediately life-threatening;
hospitalization or prolongation of hospitalization indicated; disabling; limiting self
care ADL**.

Grade 4: Life-threatening consequences; urgent intervention indicated.

Grade 5: Death related to AE.
Note: A Semi-colon indicates ‘or’ within the description of the grade.
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*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the
telephone, managing money, etc.
**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking
medications, and not bedridden.
Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity. Adverse events characterized as intermittent 
require documentation of the start and stop of each incidence.
When changes in the severity of an AE occur more frequently than once a day, the maximum 
severity for the experience that day should be noted. If the severity category changes over a 
number of days, then those changes should be recorded separately (with distinct onset dates).
8.5.4.
Time Period and Frequency for Event Assessment and Follow-Up
The occurrence of an AE or SAE may come to the attention of study personnel during study 
visits and interviews of a study subject presenting for medical care, or upon review by a study 
monitor.
All AEs, including local and systemic reactions, will be captured on the appropriate eCRF. 
Information to be collected includes event description, date of onset, clinician’s assessment of 
severity, relationship to study drug (assessed only by those with the training and authority to 
make a diagnosis), and date of resolution/stabilization of the event. All AEs occurring while on 
study must be documented appropriately regardless of relationship.
Study site personnel will note the occurrence and nature of each subject’s medical condition(s) 
present prior to the administration of study drug on Day 1 in the appropriate section of the source 
document and eCRF. Starting on Day 1 after dosing with NDI-034858, site personnel will note 
any change in the condition(s) and the occurrence and nature of any AE.
Any medical condition that is present prior to dosing on Day 1 will be considered as part of 
medical history and not reported as an AE. However, if the study subject’s condition deteriorates 
after dosing on Day 1, it will be recorded as an AE.
Should a subject experience an AE at any time after dosing on Day 1 until the end of 
participation in the study, the event will be recorded as an AE in the source document and eCRF. 
Of note, any SAE related to the study participation (eg, screening procedure) will be recorded in 
the source document and eCRF from Day 1 until the end of participation in the study.
The investigator is responsible for appropriate medical care of subjects during the study. The 
investigator also remains responsible for following through with an appropriate health care 
option for all AEs that are ongoing at the end of the study. If an AE is ongoing at the end of 
study, the follow-up duration is left to the discretion of the investigator. Follow-up frequency 
will be performed at the discretion of the investigator. However, in case of an SAE, the subject 
should be followed until the event is resolved or stabilized as per the investigator’s judgment.
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8.5.5.
Adverse Event Reporting
Investigators are responsible for monitoring the safety of subjects who are participating in this 
study and for alerting the sponsor to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
8.5.6.
Serious Adverse Event Reporting
All SAEs, related to the experimental drug or not, occurring during the course of the study (from 
Day 1 after dosing, to last study visit) must be reported immediately without undue delay but not 
later than 24 hours of knowledge of the occurrence (this refers to any AE that meets one or more 
of the aforementioned serious criteria). When applicable, follow-up information should be 
reported in the same manner as the original SAE report.
All SAEs will be entered in the electronic data collection tool on the appropriate SAE electronic 
case report form (eCRF). If the electronic system is unavailable, a paper SAE report form should 
be completed and sent to Parexel Safety Services by email at NSISafety@parexel.com or fax to 
+1 781 434 5957. As soon as the electronic system is available, all SAE information should be
entered into the eCRF.
The sponsor will be responsible for reporting Suspected Unexpected Serious Adverse Reactions 
(SUSARs) for study drug NDI-034858 to ethics committees and regulatory authorities in 
accordance with current local requirements. The reference document for SUSAR reporting will 
be the most current version of the IB.
Any SAE occurring after the End of Study visit, and that is considered by the investigator to be 
causally related to study drug, must be reported to the sponsor according to SAE reporting 
procedures. The SAE reporting period for non-study related SAEs ends at the end of the follow-
up period.
8.5.7.
Adverse Events of Special Interest
The following are AESI:

CTCAE Grade ≥2 cytopenia (anemia, leukopenia, neutropenia, lymphopenia, or
thrombocytopenia; clinically significant or not) defined by the following ranges:

Hemoglobin < 10.0 g/dL (< 100.0 g/L).

White blood cell count < 3.0 x 109/L (< 3000/mm3).

Absolute neutrophil count of < 1.5 x 109/L (< 1500/mm3).

Absolute lymphocyte count of < 0.8 x 109/L (< 800/mm3).

Platelet count < 75 x 109/L (< 75000/mm3).

CTCAE Grade ≥3 elevation of CPK (clinically significant or not) defined as
CPK > 5x ULN

Major adverse cardiovascular events, defined as cardiovascular death, non-fatal
myocardial infarction, and non-fatal stroke
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
Thromboembolic events, defined as pulmonary embolism, deep vein thrombosis, and
other venous and arterial thromboembolic events (eg, non-cardiac, non-neurologic,
fatal and nonfatal)

Gastrointestinal perforation

Malignancies

All malignancies

Non-melanoma skin cancer (NMSC)

Malignancy excluding NMSC

Lymphoma

Infections

All infections

Serious infection

Opportunistic infection, excluding tuberculosis and herpes zoster

Herpes zoster

Active tuberculosis

Adverse events of abnormal liver function tests

Adverse events of renal dysfunction
Adverse events of special interest should be reported starting on Day 1 (first day of dosing) using 
the procedures detailed in Section 8.5.6. If an AESI does not meet any seriousness criteria, it 
must still be reported according to the SAEs reporting procedures for initial and follow-up 
reporting, and the AESI/overdose checkbox must be completed.
As per Section 7.1, the above mentioned CTCAE Grade ≥3 cytopenia requires permanent
discontinuation of study drug.
8.5.7.1.
Immediate Reporting of AESIs
Adverse events of special interest should be reported starting after dosing on Day 1 (day of first 
dose). The study site must formally notify the sponsor within 24 hours of knowledge of the 
occurrence.
Even if an AESI does not meet any seriousness criteria, it must still follow the SAEs reporting 
procedures for initial and follow-up reporting (Section 8.5.6); however, the AESI/overdose 
checkbox on the eCRF must be selected.
All AESIs must be reported to sponsor within 24 hours of knowledge of the occurrence 
regardless of the following:
1. Whether or not the subject has undergone study-related procedures
2. Whether or not the subject has received study drug
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3. The severity of the event
4. The relationship of the event to study drug
Refer to the Investigator Site File Study Contact List for complete contact information to report 
initial or follow-up information on an AESI.
8.5.8.
Potential Drug Induced Liver Injury
ALT or AST values ≥3 times the ULN will trigger the following actions and evaluations:

The medical monitor should be contacted immediately

Liver tests including ALT, AST, total bilirubin, and alkaline phosphatase will be
repeated from the original blood sample as soon as possible, and no longer than
72 hours after originally reported
The following combination of signs, symptoms, or laboratory values (based on the original 
values, not the repeat), require at least temporary discontinuation of the study medication while 
workup is ongoing:

Criteria based on Hy’s Law:

ALT or AST ≥ 3 times the ULN, or ≥ 3 times the baseline value if greater than the
ULN at baseline AND

total bilirubin > 2 times the ULN, or > 2 times the baseline value if greater than
the ULN at baseline, OR international normalized ratio > 1.5

in the presence of alkaline phosphatase < 2 times the ULN

ALT or AST ≥ 8 times the ULN, or ≥ 8 times the baseline value, if greater than the
ULN at baseline, regardless of other parameters

ALT or AST ≥3 times the ULN, or ≥ 3 times the baseline value, if greater than the
ULN at baseline with the appearance of fatigue, nausea, vomiting, right upper
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%)

Total bilirubin or direct bilirubin > 3 times the ULN, or > 3 times the baseline value,
if greater than the ULN at baseline
ALT or AST values ≥ 3 times the ULN but < 8 times the ULN without total bilirubin > 2 times 
the ULN or the presence of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (> 5%) do not require discontinuation of study drug while 
workup is ongoing. Nonetheless, a subject may have dosing held based on investigator’s medical 
judgement. If abnormalities suggestive of drug-induced liver injury as described in this section 
are confirmed and found to be related to study drug, the subject will be permanently discontinued 
from study drug and will be followed up with appropriate care until resolution.
The frequency of monitoring liver tests or relevant laboratory tests will be decided as part of the 
consultation between the investigator and medical monitor.
The medical monitor will work with the investigator to evaluate other possible causes of the 
observed liver test abnormalities. These other possible causes could include hepatitis (viral, 
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alcoholic, or autoimmune); hepatobiliary disorders; nonalcoholic steatohepatitis; cardiovascular 
causes; and other concomitant treatments (https://www.fda.gov/regulatory-information/search-
fda-guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation).
8.5.9.
Pregnancy Reporting
If a female subject becomes pregnant during the study and up to 4 weeks after the end of the 
study, or if a female partner of a male subject becomes pregnant during the study and up to 
12 weeks after the end of the study, the subject should inform the study site as soon as possible. 
Upon confirmation of the pregnancy, the female subject will be permanently discontinued from 
the study drug, if this occurs before the end of dosing period. The investigator must complete a 
study specific pregnancy form upon confirmation of a pregnancy and report it to the sponsor 
within 24 hours of confirmation of the pregnancy; the contact information is the same as for SAE 
reporting. All cases of pregnancy will be reported to the sponsor in a timely manner using the 
Pregnancy Form. Pregnancy is not itself an AE or SAE; however, maternal/fetal complications 
or abnormalities will be recorded as AEs or SAEs, as appropriate. The investigator will follow 
the pregnancy until completion or until pregnancy termination and, in the case of a live-born 
offspring, to 1 month of age in that infant. Congenital abnormalities and birth defects in the 
offspring of male or female subjects should be reported as an SAE if conception occurred during 
the study drug period or within 5 times the half-life or 12 weeks from their last dose of study 
drug, whichever is longer. The investigator will notify the pharmacovigilance unit of the 
outcome as a follow-up to the initial pregnancy form. All pregnancies should be reported to the 
sponsor and, when applicable, to the ethics committee.
8.5.10. 
Overdose
Study drug overdose is any accidental or intentional use of study drug in an amount higher than 
the dose indicated per protocol for a given subject. Study drug compliance (see Section 6.3.2) 
should be reviewed to detect potential instances of overdose (intentional or accidental).
Any study drug overdose during the study should be recorded on the source document and eCRF. 
In the event of overdose, the subject should be closely monitored for any potential AEs. All AEs 
associated with an overdose should be entered on the Adverse Event eCRF and reported using 
the procedures detailed in Section 8.5.6, Serious Adverse Events Reporting, even if the events do 
not meet seriousness criteria. If the AE associated with an overdose does not meet seriousness 
criteria, it must still be reported using the SAE reporting procedures but an AESI/overdose 
checkbox must be completed. The excess quantity and duration of the overdose should be 
recorded.
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9.
STATISTICAL CONSIDERATIONS
All statistical analyses will be performed using the latest available version of SAS® (SAS 
Institute Inc., Cary, North Carolina, United States).
The statistical analysis plan (SAP) will be finalized prior to database lock, and it will include a 
more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and secondary endpoints. The SAP supersedes any differences in the protocol.
9.1.
Statistical Hypotheses
This protocol is designed to evaluate the superiority of three doses (
 QD) 
of NDI-034858 to placebo for the treatment of rheumatological signs, symptoms and function in 
patients with active psoriatic arthritis.
For each dose within each endpoint, the null hypothesis is that there is no difference between
NDI-034858 and placebo, and the alternative hypothesis is that there is a difference between 
NDI-034858 and placebo.
9.1.1.
Multiplicity Adjustment
No multiplicity adjustment is planned in this study due to the non-pivotal nature of the study.
9.2.
Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Table 6:
Analysis Sets
Population (Analysis Set)
Description
Enrolled Population (EP)
All subjects who signed the informed consent
Intent-to-Treat (ITT)
Analysis Set
All randomized subjects. Subjects will be included into the analysis as 
randomized.
Full Analysis Set (FAS)
All randomized subjects who receive at least one dose of study drug.  
Subjects will be included into the analysis as randomized.
Per-Protocol (PP) Set
All FAS subjects who are compliant, as defined in Section 6.3.2, with 
study treatment and are without any major protocol deviations that could 
impact the primary endpoint.
Safety Analysis Set
All subjects who receive at least one dose of study drug. Subjects will be 
included into the analysis based on actual treatment received, regardless 
of the treatment randomized.
PK Analysis Set
All subjects in the Safety Analysis Set with at least one evaluable post-
dose PK assessment.
PK = pharmacokinetics
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The Full Analysis Set (FAS) will be used for all efficacy and baseline analyses. The Per Protocol 
(PP) Set will be determined prior to database lock and the PP and ITT Sets will be used as 
supplementary analyses of the primary endpoint. Additional analyses may be conducted on the 
PP set in order to evaluate the impact of major protocol deviations.
All safety analyses will be based on the Safety Analysis Set. All PK tabulations and statistical 
analyses will be based on the PK Analysis Set.
Other analysis sets, including a PD Analysis Set, may be defined in a separate analysis plan.
9.3.
Statistical Analyses
9.3.1.
General Considerations
Statistical analyses will include tabulations of summary data, inferential analyses, by-subject
listings, and figures.
All statistical tests will be two-sided and will be performed at the 5% level of significance, 
unless otherwise stated. Frequency counts (n and percentages) will be made for each qualitative 
variable. Descriptive statistics (n, mean, SD, median, minimum, and maximum) will be 
calculated for each quantitative variable, unless otherwise stated. All data will be summarized by 
treatment group.
The baseline value for analysis and reporting will be based on the last (non-missing) 
measurement before dosing on Day 1. If any safety measurements are repeated after dosing on 
Day 1, then the first (non-missing) value of any repeated measurements will be used in the 
descriptive statistics and in the calculation of changes from baseline.
9.3.2.
Efficacy Analyses
The primary endpoint can be translated as a responder analysis, where a subject will be classified 
as responder if they achieve ACR20 at Week 12. Comparison of the primary endpoint will be 
made between each dose group and the placebo group using a 2-sided Mantel-Haenszel (MH) 
test of the risk difference in two proportions stratified by the randomization stratification factors 
(prior treatment with biologics or non-traditional DMARDs [yes/no], and region
[(USA/Germany)/(Eastern Europe)]). The estimand MH risk difference will be summarized 
along with the two-sided 95% CI using MH stratum weights (Mantel and Haenszel 1959) and the 
Sato variance estimator (Sato 1989). The primary efficacy analysis will be performed on the 
FAS, while the ITT and PP sets will be used as a supplementary analysis. Use of the FAS dataset 
as primary is to assess the clinical question of interest in the protocol to determine treatment 
effect for dosing and efficacy. Handling of intercurrent events and missing data will be 
addressed in detail within the SAP. Estimands and additional sensitivity analyses will be 
described in the SAP.
A descriptive analysis will be performed in demographic subgroups including age, gender, race, 
and body mass index to assess the consistency of the treatment effect. Additional subgroup 
analyses based on baseline disease characteristics and the randomization stratification factor will 
also be conducted and described in the SAP.
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The secondary endpoints involving proportions of subjects will be analyzed using the same 
approach (MH test of the difference) as described for the primary efficacy analysis and based on 
the FAS.
The continuous secondary endpoints involving change from baseline will be analyzed using a 
mixed model for repeated measures based on the FAS. The model will include fixed effects for 
treatment group, visit, and treatment group-by-visit interaction, with baseline score and the 
randomization stratification factor as covariates, and the change from baseline as the dependent 
variable. Additional details on sensitivity analyses and missing data imputation of the secondary 
endpoints will be provided in the SAP.
9.3.3.
Study Drug Exposure and Compliance
Exposure to study drug and study drug compliance will be summarized for each treatment group 
for the Safety Analysis Set.
9.3.4.
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set. No inferential statistics will be 
performed for safety variables. Additional details will be provided in the SAP.
9.3.4.1.
Adverse Events
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 24.0 or higher and summarized by system organ class (SOC) and preferred term (PT). 
Collection of AEs will begin after dosing on Day 1. Analysis and reporting for AEs will be based 
on TEAEs. A TEAE is defined as an AE occurring (onset date/time) at the time of or after dosing 
on Day 1. Adverse events with missing start and/or end dates and/or times (if applicable) will be 
handled as described in the SAP.
All TEAEs will be listed for each subject. Separate listings will be presented for TEAEs, 
TESAEs, and TEAESIs. Each category will be presented for events leading to discontinuation of 
study drug and events leading so study discontinuation. All listings will be done by treatment 
group and subject, detailing verbatim, SOC, PT, start date, stop date (if resolved), intensity, 
seriousness, outcome, action taken with respect to study drug, and relationship to study drug. The 
AE onset will also be shown relative (in number of days) to the day of study drug administration.
An overview of all TEAEs will be presented by treatment group. The overview will include the 
following:

Number and percentage of subjects with TEAEs

Number and percentage of subjects with drug-related TEAEs

Number and percentage of subjects with TEAEs leading to discontinuation of study
drug

Number and percentage of subjects with TEAEs leading to study discontinuation

Number and percentage of subjects with TESAEs

Number and percentage of subjects with drug-related TESAEs
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
Number and percentage of subjects with TESAEs leading to discontinuation of study
drug

Number and percentage of subjects with TESAEs leading to study discontinuation

Number and percentage of subjects by intensity of TEAEs (CTCAE grades 1, 2, 3, 4,
5)

Number and percentage of subjects with TEAEs leading to death

Number and percentage of subjects with TEAESIs

Number and percentage of subjects with drug-related TEAESIs

Number and percentage of subjects with TEAESIs leading to discontinuation of study
drug

Number and percentage of subjects with TEAESIs leading to study discontinuation
Summaries of TEAEs by treatment group, SOC, and PT will be presented for the following:

All TEAEs

Drug-related TEAEs

TEAEs leading to discontinuation of study drug

TEAEs leading to study discontinuation

TESAEs

Drug -related TESAEs

TESAEs leading to discontinuation of study drug

TESAEs leading to study discontinuation

TEAEs by intensity (CTCAE grades 1, 2, 3, 4, 5)

TEAEs leading to death

TEAESIs, overall and by categories

Drug-related TEAESIs

TEAESIs leading to discontinuation of study drug

TEAESIs leading to study discontinuation
9.3.4.2.
Electrocardiogram
Electrocardiogram measurements will be listed by subject and timepoint including changes from 
baseline, any repeated/unscheduled measurements and the investigator’s assessment of clinically 
significant changes. Descriptive statistics (n, mean, SD, minimum, median, maximum) will be 
provided presented by treatment group and timepoint for both absolute values and changes from 
baseline. Clinically significant electrocardiogram measurements will also be summarized by 
treatment group.
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9.3.6.1.
Pharmacokinetic Analyses
Concentration data will be listed per subject and summarized descriptively per dose for each 
scheduled sampling time point.
9.3.7.
Planned Interim Analyses
No interim analysis is planned in this study.
9.3.8.
Sample Size Determination
A sample size of 65 per treatment group across all sites will have 83% power using a 
two-sided test for the difference in the two proportions, assuming a type I error rate of 0.05, a 
55% response rate for each NDI-034858 dose group as a proportion of ACR20 response, and a 
placebo ACR20 response rate of 30%. A total number of 260 subjects (65 per treatment group) 
are planned to be randomized into the study with a 1:1:1:1 allocation.
The sample size was calculated in nQuery 8.7 using a two-sample Z-Test (Chi-Square Test) 
pooled for difference of proportions.
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10.
REGULATORY, ETHICAL, AND STUDY OVERSIGHT
CONSIDERATIONS
10.1. 
Local Regulations/Declaration of Helsinki
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki and that are consistent with ICH Tripartite Guideline for GCP and 
the applicable laws and regulations of the country in which the research is conducted, whichever 
affords the greater protection to the individual.
10.2. 
Ethical Review 
It is the understanding of the sponsor that this protocol (and any amendments) as well as 
appropriate consent procedures, will be reviewed and approved by an IRB/REB/IEC. This board 
must operate in accordance with the current federal regulations. For sites with a local ethics 
committee, a letter or certification of approval will be sent by the investigator to the sponsor (or 
CRO) before initiation of the study and also whenever subsequent modifications to the protocol 
are made.
10.3. 
Informed Consent Process
An ICF describing in detail the study treatment, study procedures, and risks will be given to the 
subject, along with an assent form when required.
It is the responsibility of the investigator, or a person designated by the investigator (if 
acceptable by local regulation), to obtain written informed consent from each individual 
participating in this study, after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study.
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Consent forms will be 
IRB/REB/IEC approved, and the subject will be asked to read and review the document. The 
investigator will explain the research study to the subject and answer any questions that may 
arise. A verbal explanation will be provided in terms suited to the subject’s comprehension of the 
purposes, procedures, and potential risks of the study and of his or her rights as a research 
subject. Subjects will have the opportunity to carefully review the written consent form and ask 
questions prior to signing. The subjects should have the opportunity to discuss the study with 
their family or surrogates or think about it prior to agreeing to participate.
The subject will sign the informed consent document prior to any procedures being done 
specifically for the study. Subjects must be informed that participation is voluntary and that they 
may withdraw from the study at any time for any reason, without prejudice. A copy of the signed 
informed consent document will be given to the subjects for their records. The informed consent 
process will be conducted and documented in the source document (including the date), and the 
form signed, before the subject undergoes any study-specific procedures.
The rights and welfare of the subjects will be protected by emphasizing to them that the quality 
of their medical care will not be adversely affected if they decline to participate in this study.
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If new safety information results in significant changes in the risk/benefit assessment, or if any 
new information becomes available that may affect the willingness of a subject to continue to 
participate, the consent form should, if necessary, be reviewed and updated by the 
IRB/REB/IEC. All subjects (including those already being treated) should be informed of the 
new information, given a copy of the revised form, and asked to give their consent to continue in 
the study.
10.4.
Study Discontinuation and Closure
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study subjects, 
investigators, the sponsor, and regulatory authorities. If the study is prematurely terminated or 
suspended, the principal investigators will promptly inform study subjects and the IRB/REB/IEC
and will provide the reason(s) for the termination or suspension. Study subjects will be 
contacted, as applicable, and be informed of changes to study visit schedule.
Circumstances that may warrant termination or suspension of the study include, but are not 
limited to the following:

Determination of unexpected, significant, or unacceptable risk to subjects

Insufficient compliance to protocol requirements

Data that are not sufficiently complete or evaluable

Scientific or corporate reasons
The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed and satisfy the sponsor, IRB/REBIEC, Health Canada, European Medicines Agency, 
and/or FDA.
10.5. 
Confidentiality and Privacy
Subject confidentiality and privacy are strictly held in trust by the participating investigators, 
their staff, and the sponsor and their interventions. Confidentiality is extended to cover testing of 
biological samples in addition to the clinical information relating to subjects. Therefore, the 
study protocol, documentation, data, and all other information generated will be held in strict 
confidence.
The investigator must assure that the subjects’ anonymity will be maintained and that subjects’ 
identities are protected from unauthorized parties. On case report forms or other documents 
submitted to the sponsor, subjects should not be identified by their names, but by an 
identification code. The investigator should keep a subject log relating codes with the names of 
subjects. The investigator should maintain in strict confidence documents not for submission to 
Nimbus Lakshmi, Inc. (eg, subjects’ written consent forms).
All research activities will be conducted in a setting as private as possible.
The study monitor, other authorized representatives of the sponsor, and representatives of the 
IRB/REB/IEC, regulatory agencies, or pharmaceutical company supplying study drug may 
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inspect all documents and records required to be maintained by the investigator, including but 
not limited to, medical records (office, clinic, or hospital) and pharmacy records for the subjects 
in this study. The clinical study site will permit access to such records.
The study subject’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the applicable legal or regulatory requirements, the 
reviewing IRB/REB/IEC, institutional policies, or sponsor requirements.
10.6. 
Clinical Monitoring
Clinical site monitoring will be conducted to ensure that the rights and well-being of study 
subjects are protected; that the reported study data are accurate, complete, and verifiable; and 
that the conduct of the study is in compliance with the currently approved 
protocol/amendment(s), ICH GCP guidelines, and with applicable regulatory requirement(s). 
Details of clinical site monitoring will be documented in a Monitoring Plan.
Centralized monitoring, which consist of remote review of accumulating data from all sites, will 
be performed as detailed in the Centralized Monitoring Plan.
10.7. 
Quality Assurance and Quality Control
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation, and completion.
Quality control (QC) procedures will be implemented beginning with the data entry system, and 
data QC checks, which will be run on the database, will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
During the study, the sponsor or its representative will conduct monitoring visits at regular 
intervals. The monitoring visits will be conducted to ensure protocol adherence, quality of data, 
accuracy of entries on the eCRFs, study drug accountability, compliance with regulatory 
requirements, and continued adequacy of the study site and its facilities.
The site may be audited, monitored, or inspected by a quality assurance officer named by the 
sponsor, by the REB, IEC or IRB, and/or by the regulatory authorities. The investigator will be 
expected to cooperate with any audit and provide assistance and documentation (including 
source data) as requested. The study site will provide direct access to all study-related sites, 
source data/documents, and reports for the purpose of monitoring and auditing by the sponsor 
and inspection by local and regulatory authorities.
10.8. 
Data Handling and Record Keeping
Data collection is the responsibility of the clinical study staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported.
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
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be classified into two separate categories: investigator’s study files and subject clinical source 
documents.
The investigator must maintain source documents for each subject in the study. These source 
documents will consist of case and visit notes (clinical medical records) containing demographic 
and medical information and the results of any tests or assessments. All information on the 
eCRFs must be traceable to the source documents in the subject’s file. Data not requiring a 
written or electronic record will be defined before study start and will be recorded directly on the 
eCRFs, which will be documented as being the source data.
The records should be retained by the investigator according to ICH guidelines, local regulations, 
or as specified in the Clinical Trial Agreement, whichever retention period is longer.
Subject data will be entered by site personnel using Medidata RAVE electronic data capture 
(EDC), a web-based EDC and reporting system. This application will be set up for remote entry. 
Medidata is the developer and owner of RAVE EDC. The EDC software was fully validated and 
conforms to Title 21 of the Code of Federal Regulations, Part 11 requirements. Investigator site 
staff will not be given access to the EDC system until they have been fully trained. Designated 
investigator staff will enter the data required by the protocol into the eCRFs using this web-based 
application. Automatic validation programs check for data discrepancies in the eCRFs and, by 
generating appropriate error messages, allow modification or verification of the entered data by 
the investigator staff before confirming the data. The investigator must certify that the data are 
complete and accurate by applying an electronic signature to the eCRFs.
The data collected will be encoded and stored electronically in a database system. Validated data 
may subsequently be transferred to the sponsor.
10.9. 
Protocol Deviations
A protocol deviation is any noncompliance with the clinical study protocol requirements. The 
noncompliance may be either on the part of the subject, the investigator, or the study site staff. 
As a result of deviations, corrective actions are to be developed by the site and implemented 
promptly. The study monitor must ensure that a prompt action is taken to secure compliance. If a 
noncompliance that significantly affects or has the potential to significantly affect human subject 
protection or reliability of study results is discovered, a root cause analysis will be performed and 
appropriate corrective and preventive actions will be implemented.
Protocol deviations must be sent to the reviewing IRB/REB/IEC per their policies. The 
investigator is responsible for knowing and adhering to the reviewing IRB/REB/IEC 
requirements.
10.10. 
Publication Policy
The publication policy will be addressed in the Research and Financial Agreement, and all 
details outlined in the agreement will apply to this protocol. The study will be registered on 
ClinicalTrials.Gov prior to the first subject being dosed.
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Watford, W. T., Hissong, B. D., Bream, J. H., Kanno, Y., Muul, L. and O'Shea, J. J. 2004. 
Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol Rev,
202, 139-56.
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APPENDIX 2. CONTRACEPTION
LOCAL REQUIRMENTS: EU Member States
For Female Subjects
A female subject who does not meet either the definition of postmenopausal as defined in the 
Inclusion Criteria or who is not permanently surgically sterile is considered of childbearing 
potential and is required to use highly effective contraception from screening until at least 4 
weeks after the last study drug administration.
Highly effective contraceptive methods:

Combined estrogen and progestin containing hormonal contraceptives (eg, oral
contraceptive, patch, vaginal ring, injectable, or implant), or

Progestogen-only hormonal contraception (oral, injectable, implantable) associated
with inhibition of ovulation, or

Intrauterine devices or intrauterine systems, or

Vasectomized partner(s) (provided vasectomy was performed ≥4 months prior to
screening), or

Tubal ligation
Note: The above list of contraceptive methods does not apply to subjects who are abstinent for at 
least 4 weeks before Day 1 and will continue to be abstinent from penile-vaginal intercourse 
throughout the study. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical study, and the preferred and usual lifestyle of the subject. Periodic 
abstinence (calendar, symptothermal, postovulation methods) and withdrawal are not acceptable.
For Male Subjects
A male subject who is surgically sterile (vasectomy with medical assessment confirming surgical 
success) OR 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 
to use one of the highly effective contraceptive methods from Study Day 1 until at least 12 
weeks after the last study drug as follows:

Condom use and female partner(s) using at least one of the contraceptive measures as
defined in above 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. Periodic abstinence (calendar,
symptothermal, postovulation methods) and withdrawal are not acceptable.
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.
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It is important to note that contraception recommendations described are specifically intended to 
prevent pregnancy during exposure to the investigational study drug. Contraception 
recommendations related to use of concomitant therapies prescribed per standard of care should 
be based on the local label.
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APPENDIX 3. SELECT DMARDS HALF-LIFE
Table 7 lists those DMARDS that have a washout period based on half-life in the exclusion 
criteria.
Table 7:
DMARDS Half-life
DMARD
Half-life
Adalimumab (Humira 
(adalimumab) Injection for 
Subcutaneous Use 2019)
Mean terminal half-life is approximately 2 weeks, ranging from 10-
20 days across studies with doses 0.25 mg/kg to 10 mg/kg
Certolizumab (Cimzia 
(certolizumab pegol) for 
Injection for Subcutaneous Use 
2018)
Terminal elimination half-life is approximately 14 days for all doses 
tested
Golimumab (Simponi Aria® 
(golimumab) 2021)
Median terminal half-life is approximately 2 weeks for doses tested, 
0.1 mg/kg to 10 mg/kg
Infliximab (Infliximab 2021)
Half-life is 7.7 to 9.5 days for doses tested,
3 mg/kg, 5 mg/kg and 10 mg/kg
Leflunomide (Arava® 
(leflunomide) 2021)
Median half-life of 18-19 days for the active metabolite
(teriflunomide)
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SAP_001.pdf: 
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Parexel International
Nimbus Lakshmi, Inc.
4858-202
A PHASE 2B, RANDOMIZED, MULTI-CENTER, DOUBLE-BLIND, PLACEBO-
CONTROLLED, MULTIPLE DOSE STUDY TO EVALUATE THE EFFICACY, SAFETY, 
AND TOLERABILITY OF NDI-034858 IN SUBJECTS WITH ACTIVE PSORIATIC 
ARTHRITIS
Statistical Analysis Plan
Version v2.0
Parexel Project Number 264773
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................6
LIST OF FIGURES ...................................................................................................................6
REVISION HISTORY...............................................................................................................7
LIST OF ABBREVIATIONS....................................................................................................8
1.0
INTRODUCTION ........................................................................................................12
2.0
STUDY OBJECTIVES.................................................................................................13
2.1 Primary Objective(s).....................................................................................................13
2.2 Secondary Objective(s).................................................................................................13
2.3 Exploratory Objective(s)...............................................................................................13
3.0
INVESTIGATIONAL PLAN.......................................................................................14
3.1 Overall Study Design and Plan .....................................................................................14
3.2 Schedule of Assessments ..............................................................................................15
3.3 Endpoints ......................................................................................................................15
3.3.1 Primary Efficacy Endpoint and Estimand..............................................................15
3.3.1.1 Primary Efficacy Endpoint ..............................................................................15
3.3.1.2 Primary Estimand.............................................................................................15
3.3.2 Secondary Efficacy Endpoints...............................................................................15
3.3.2.1 Secondary Endpoints – Safety .........................................................................16
3.3.2.2 Secondary Endpoints – Pharmacokinetics.......................................................16
3.3.3 Exploratory Endpoints ...........................................................................................16
4.0
STATISTICAL METHODS.........................................................................................17
4.1 Data Quality Assurance.................................................................................................17
4.2 Definitions.....................................................................................................................17
4.3 General Presentation Considerations ............................................................................18
4.3.1 Analysis Window...................................................................................................19
4.3.2 Handling of Missing Data......................................................................................20
4.3.2.1 Partial dates and times .....................................................................................20
4.3.2.2 Partial Date of First Diagnosis of PsA.............................................................21
4.3.2.3 Missing Data for AEs.......................................................................................22
4.4 Software ........................................................................................................................22
4.5 Analysis Sets.................................................................................................................22
4.6 Study Subjects...............................................................................................................23
4.6.1 Disposition of Subjects ..........................................................................................23
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REVISION HISTORY
Version No.
Effective Date
Summary of Change(s)
1.0
14-Jul-2022
New document
2.0
01-Jul-2023

Updated the SAP per Study Protocol Version 4.0 (May 05,
2023)

Section 4.2: Clarifications and editorial changes

Section 4.3: Clarifications, editorial changes, update to the
analysis window

Section 4.5: Clarifications, editorial changes, adding
specificity to the criteria for the per protocol set

Section 4.6 to 4.11: Clarifications and editorial changes

Section 4.12: Clarifications, editorial changes, and
updates throughout the section, with significant updates to
the following:
o
Added the estimand framework in Section
4.12.1.2.
o
Updated the efficacy analysis and missing data
handling for secondary binary and continuous
endpoints in Section 4.12.1.3
o
Clarified derivation of primary endpoint in Section
4.12.2, added subsections for supplementary
analysis and sensitivity analysis
o
Clarified the derivation rules for TJC, SJC, HAQ-
DI, dactylitis in Section 4.12.3

Section 4.13: Clarifications, editorial changes, update and
adding analyses under clinical laboratory evaluation and
consideration for COVID

Section 4.14: Clarifications and editorial changes

Section 4.15: Clarifications, editorial changes, updates to
the derivations for selected exploratory endpoints

Section 4.17: Providing the changes in planned analysis
from protocol

Section 5: Updating reference

Section 
6:
Clarifications, 
editorial 
changes, 
and
incorporating updates
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1.0
INTRODUCTION
NDI-034858 (also known as TAK-279) is a small molecule allosteric inhibitor which leads to 
inhibition of the tyrosine kinase 2, therefore, has the potential to add value to the treatment 
algorithm of Psoriatic Arthritis (PsA), particularly considering the lack of highly efficacious oral 
agents. This study is a Phase 2b, randomized, multi-center, double-blind, placebo-controlled, 
multiple dose study designed to evaluate the efficacy, safety, and tolerability of NDI-034858 in 
subjects with active psoriatic arthritis.
On February 08, 2023, clinical study sponsor Nimbus Lakshmi, Inc became a directly owned 
subsidiary of Takeda Pharmaceuticals, U.S.A., Inc. 
The Statistical Analysis Plan (SAP) details the statistical methodology to be used in analyzing 
study data and outlines the statistical programming specifications for the tables, listings, and 
figures. It describes the variables, analysis populations, anticipated data manipulations and other 
details of the analyses not provided in the protocol.
The analyses described in this SAP are based upon the following study document:

Study Protocol, Version 4.0 (May 05, 2023)
The structure and content of the SAP are based upon the International Conference on 
Harmonisation (ICH) E3 – Guideline for Industry Structure and Content of Clinical Study Reports.
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4.0
STATISTICAL METHODS
4.1
Data Quality Assurance
All tables, figures and data listings to be included in the report will be independently checked for 
consistency, integrity and in accordance with standard Parexel procedures.
4.2
Definitions
Baseline value
Baseline values of laboratory and pharmacokinetic (PK) data is defined as the last non-missing 
value (including scheduled or unscheduled measurements) prior to the first dose of study drug or 
randomization if no study drug was given. Both day and time of assessment will be considered 
when defining baseline for laboratory and PK data. 
For all other endpoints, the baseline value is defined as the last non-missing value (including 
scheduled or unscheduled measurements) prior to or on the same day of the first dose of study 
drug. If multiple measurements occur at the same time, then the average of these measurements 
(for continuous data) or the worst among the measurements (for categorical data) should be 
considered as baseline.
Change from Baseline
Change from baseline is defined as post-baseline value minus baseline value.
Percent Change from Baseline
Percent change from baseline is defined as:
Percent change from Baseline = 100 ×
Postbaseline value value
Baseline value
%
Study Day 1
Study day 1 is defined as the date of first dose for treated subjects or the date of randomization for 
untreated randomized subjects.
Study Day
Study day of any event will be calculated relative to the date of first dose for treated subjects or 
the date of randomization for untreated randomized subjects.
If the event is prior to study day 1, then study day will be negative (prefixed with '-') and is 
calculated as:
Date of Event – Date of Day 1
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If event is on or after study day 1, then study day is calculated as:
Date of Event – Date of Day 1 + 1
Treatment-Emergent Adverse Events (TEAEs)
TEAEs are defined as any adverse events (AEs) occurring (onset date/time) at the time of or after 
study drug dosing until study end (inclusive of Week 16).
Partial dates will be imputed as described in Section 4.3.2.1. In the event a start or end date is 
partial, the imputed dates will be used to determine treatment-emergence. 
4.3
General Presentation Considerations
Continuous data will be summarized in terms of the mean, standard deviation (SD), median, 
minimum, maximum, 25th and 75th percentiles (Q1 and Q3), and number of observations. The 
minimum and maximum will be reported to the same number of decimal places as the raw data 
recorded in the database. The mean (arithmetic and geometric), median, Q1, and Q3 will be 
reported to one more decimal place, and SD (and the standard error [SE], if applicable) will be 
reported to two more decimal places, than the raw data recorded in the database. The geometric 
coefficient of variation (geoCV) will be reported as percentage to 1 decimal place. In general, the 
maximum number of decimal places reported shall be four for any summary statistic.
If the number of decimal places reported in the original raw data is varied, then use either the 
maximum raw number of reported decimal places or 3, whichever is the lowest, as a guide for the 
descriptive statistics.
For NDI-034858 plasma concentration, the geometric mean (geoMean) and corresponding 
coefficient of variation will be presented. The geoCV is calculated as below:
 =  !"#$
% −1
Where '()*
+ is the variance of the log-transformed data. 
If no subjects have data at a given time point, for example, then only n=0 will be presented. 
However, if 0<n<3, the n, minimum and maximum will be presented only. If n=3, n, mean, median, 
minimum, and maximum will be presented only. The other descriptive statistics will be left blank. 
Categorical data will be summarized in terms of the number of subjects providing data at the 
relevant time point (n), frequency counts and percent. Unless otherwise stated, the denominator 
for the percentage calculations will be based on the number of subjects in the respective analysis 
set.
Percentages will be presented to one decimal place except 100%. 100% will be presented as 100% 
instead of 100.0%.Percentages will not be presented for zero counts. If sample sizes are small, the 
data displays will show the percentages, but any textual report will describe frequencies only.
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When specified, a missing category shall be included only for categorical variables with missing 
data. The missing category will be omitted if there were no missing values for that variable.
Changes from baseline in categorical data will be summarized using shift tables where appropriate.
P-values greater than or equal to 0.001, in general, will be presented to three decimal places.  
P-values below 0.001 will be presented as “<0.001”. P-values greater than 0.999 will be presented 
as “>0.999”.
Confidence intervals (CI) will be presented to one more decimal place than the raw data. Unless 
specified otherwise, CIs will be calculated using the normal approximation. If there are less than 
5 events, the Clopper Pearson calculation will be used.
In the event that a subject was re-randomized (ie, subject 
 was initially 
randomized but never dosed and randomized again with a new randomization number and dosed), 
the new randomization number and the data associated with the re-randomization number will be 
used for statistical analyses.
4.3.1
Analysis Window
Subjects do not always adhere strictly to the visit timing stated in the protocol. The designation of
all visits, including unscheduled visits and early termination visit (for patients with premature 
study termination) will be assigned to the relevant analysis visit per the schedule of activities based 
on the following table by using the study days relevant to first dose of study drug. Accordingly, 
the study is divided into continuous and mutually exclusive analysis windows. 
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Table 4-1:
Analysis Visit Windows
Analysis Visit (Visit 
Number)
Target 
Day
Parameters and Allowed Window (in days)
Safety 
and 
efficacy 
Parameters*
PASI/ PhGA-
PsO/ BSA
ECG
Fasting 
Lipids
Baseline
1
≤1
≤1
≤1
≤1
Week 1 (Visit 3)
8
[2, 11]
[2, 11]
Week 2 (Visit 4)
15
[12, 22]
[2, 22]
[12, 22]
Week 4 (Visit 5)
29
[23, 43]
[23, 43]
[23, 43]
Week 8 (Visit 6)
57
[44, 71]
[44, 71]
[44, 71]
Week 12 (Visit 7)
85
[72, 99]
[72, 99]
[72, 99]
[72, 99]
Week 16 (Visit 8)
113
[100, EOS]
[100, EOS]
EOS=End of Study, PhGA = Physician Global Assessment.
* Safety endpoints include Vital Signs, Clinical Laboratory Tests, ESR, Physical Exam (Complete/Targeted); efficacy endpoints 
include TJC68, SJC66, Dactylitis, PGA-PsA, PGAAP, PhGA-PsA, HAQ-DI, LEI, MDA, and hsCRP. 
For repeated assessments collected within baseline window, see Section 4.2, Definitions.
For repeated assessments collected during post-baseline visits, if more than one assessment is 
available within the same analysis visit, the assessment with closest study day to the target study 
day will be reported for the analysis window. If two observations exist with the same distance to 
the target study day, then the last observation will be used. Analysis visit will be used for table 
summaries.
4.3.2
Handling of Missing Data
Every effort will be undertaken to avoid any missing or incomplete data, and missing data will not 
be imputed unless specified. If variables are imputed, the analysis dataset will contain a new 
variable with imputed value and the original variable will contain the original missing value.
Missing data handling related to efficacy endpoints is described in Section 4.12.1.3.
4.3.2.1
Partial dates and times
Inevitable partial dates will be imputed for start/end dates of AEs or prior/concomitant 
medications. 
Partial Start Dates for AE and prior/concomitant medications

If only day is missing, then it will be set to:
o
First day of the month that the event occurred, if month and year of the event start date 
is different than the month and year of the first dose date.
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o
The day of first dose date, if month and year of the event start date is the same as month
and year of the first dose date and month and year of the event end date is different.
o
The day of first dose date or day of event end date, whichever is earliest, if the month
and year of the event start and month and year of the first dose date and month and year 
of the event end date is the same.

If only month is missing, then it will be set to the earliest of the following:
o
January, as long as this date is after the first dose date
o
Month of the first dose date, if this date is the same day and year that the event occurred

If the day and month are both missing, then it will be set to following:
o
Month and day of the first dose date, if the year of first dose is same as the year of the 
start date and the (imputed) event stop date is after the date of first dose
o
January 1 of the year, if the year of first dose date in not same as the year of the start 
date or the date of the (imputed) event end is before the date of first dose

If dates are completely missing:
o
Use the date of first dose of study drug if the stop date is fully missing prior to any 
imputation per the rules below or not prior to the date of first dose of study drug
o
if the stop date is prior to the date of the first dose of study drug, then set the start date 
to the 1st of January of the year of the event stop date

If time is missing, time will be imputed as:
o
00:00 h if start date is not the same as the date of first dose of study drug
o
The time of first dose of study drug if the start date is the same as the date of first dose 
of study drug
Partial End Dates for AE and prior/concomitant medications

If only day is missing, then it will be set to the earliest of the last follow-up date, last day 
of the month, or the date of death.

If only month is missing, then it will be set to the earliest of the last follow-up date, 
December, or the date of death. 

If year is missing or event is ongoing, the end date will not be imputed.

If both month and day are missing, then use December 31st of that year.

If dates are completely missing, then use discharge date or data cut-off date. Discharge date 
refers to the date of the end of study visit for completed subjects or the date of 
discontinuation for subjects that were withdrawn. For any AEs with known start date after 
the date of discontinuation, the date of last contact will be used as the discharge date. For 
subjects still ongoing in the study at the time of the data cut-off, and for whom no discharge 
date is available, the date of the data cut-off will be used instead of the discharge date.

If time is missing and (imputed) end date is not missing, time will be imputed as 00:00 h 
If the imputed event end date is before the corresponding event start date, then the event end date 
will be set to the event start date.
4.3.2.2
Partial Date of First Diagnosis of PsA
Partial dates of the first diagnosis of PsA will be imputed as following:

If only the month and year are specified and the month and year of first dose are not the 
same as the month and year of the start date, then the 1st of the month will be used.
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
If only the month and year are specified and the month and year of first dose is the same 
as the month and year of the start date, then the date of first dosing will be used. 

If only the year is specified, and the year of first dose is not the same as the year of the start 
date, then January 1st of the year of the start date will be used.

If only the year is specified, and the year of first dose is the same as the year of the start 
date, then then start date will be set as missing and no imputation will be applied

If start date is completely unknown, then then start date will be set as missing and no 
imputation will be applied
4.3.2.3
Missing Data for AEs
In addition to the missing data handling rules for partial event dates, other missing AE data will 
be imputed for inclusion in the summary tables.
Any missing intensity will be queried for completion. If the intensity is still missing in the final 
data and the outcome of AE is death, then it will be deemed as Grade 5, and if the life-threatening 
is marked, then it will be deemed as Grade 4. Otherwise, the intensity still missing in the final data 
will be deemed as Grade 3.
Any missing causality will also be queried for completion, and any events that still have missing 
causality in the final data will be deemed as ‘Related’.
4.4
Software
All report outputs will be produced using SAS® version 9.4 or a later version in a secure and 
validated environment. 
4.5
Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Population 
(Analysis Set)
Description
All Subjects 
Screened
All subjects who signed the informed consent
Intent-to-Treat (ITT)
Analysis Set
All randomized subjects. Subjects will be included into the analysis as randomized.
Full Analysis Set 
(FAS)
All randomized subjects who receive at least one dose of study drug. Subjects will be 
included into the analysis as randomized.
Per-Protocol Set
(PPS)
All FAS subjects who are compliant with study treatment, and without any major 
protocol deviations that could impact the primary endpoint.
Safety Analysis Set
(SS)
All randomized subjects who receive at least one dose of study drug. Subjects will be 
included into the analysis based on actual treatment received, regardless of the treatment 
randomized.
PK Analysis Set
(PKS)
All subjects in the Safety Analysis Set with at least one evaluable post-dose PK 
assessment.
PK = pharmacokinetics
All subjects who signed the informed consent will be used to report disposition of subjects 
screened. A summary will be presented for the reasons for screen failure overall and for subjects 
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who were rescreened and failed again. The ITT set will be used to summarize the disposition and 
discontinuation reasons for randomized subjects. The FAS will be used for all efficacy and baseline 
analyses. The PPS will be determined prior to database lock and the ITT Set and PPS will be used 
in the context of sensitivity analyses of the primary endpoint. 
Protocol deviation and analysis set outputs will be produced. A Data Review Meeting will be 
arranged prior to the database lock/unblinding to identify analysis sets or data to be 
included/excluded from analysis including a review/confirmation of subjects with ICEs. Decisions 
made regarding the exclusion of subjects and/or subject data from analyses will be made prior to 
unblinding and will be documented in a data review report that will be approved by the Sponsor
prior to the analysis.
The PPS includes all subjects in the FAS who met the following criteria:
1. Subjects who had completed 12 weeks of treatment with valid efficacy endpoint 
assessment at baseline and Week 12
2. Treatment compliance ≥80%  
3. Without major protocol deviation that could impact the primary endpoint including but not 
limited to the following:
a.
Without violations of relevant inclusion/exclusion criteria
b. Without receiving prohibited concomitant medications that could impact the 
efficacy assessments before Week 12
All safety analyses will be based on the SS. 
All PK tabulations and statistical analyses will be based on the PKS.
The number and percentage of subjects in each analysis set by treatment group and overall will be 
summarized on ITT Set. By-subject listing of analysis population assignment will also be provided.
4.6
Study Subjects
4.6.1
Disposition of Subjects
A clear accounting of the disposition of all subjects who enter the study will be provided, from 
screening to study completion.
All subjects screened will be used to summarize below subject disposition:

Number and reasons for screen failure (collected on Screening Disposition eCRF).

Number of subjects screened by region, site, and overall, including first subject in date, last 
subject out date will be provided. Additionally, number of subjects by treatment group in
each analysis set (ITT, FAS, PPS, SS, PKS) will also be provided.
In addition, the following subject disposition will be summarized on ITT and FAS by treatment 
group and overall:

Number and percentage of subjects randomized

Number and percentage of subjects who received at least one dose of study drug

Number and percentage of subjects randomized but not treated who did not receive any 
study drug after randomization (only in ITT version).

Number of subjects who completed study drug
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
Number of subjects who completed the study but prematurely discontinued the study drug 

Number and percentage of subjects who prematurely discontinued from study drug and 
primary reason for discontinuation

Number of subjects who completed the study

Number and percentage of subjects who prematurely discontinued from study and primary 
reason for discontinuation
By-subject listings of disposition details will also be provided for all subjects screened, including 
the date of informed consent, the date and time of first and last dosing, and the date of premature 
termination and primary reason (if applicable).
4.6.2
Protocol Deviations
Protocol deviations (PDs) will be classified as “major” or “minor” on an ongoing basis by the 
clinical study team and sponsor.
Major PDs are defined as those deviations from the protocol likely to have an impact on the 
subject’s rights, safety, well-being, and/or the validity of the data for analysis. Minor PDs include 
all deviations from the protocol excluding the major PDs.  
The number and percentage of subjects with at least one major PD, and major PD categories, as 
well as at least one minor PD will be summarized by treatment and overall on the SS. By-subject 
listing of all PDs will also be provided.
4.7
Demographic and Other Baseline Characteristics
Demographics and other baseline characteristics as described below will be summarized on FAS
by treatment groups and overall. Additional demographic or baseline data may be added to the 
summary tables.

Age (years)

Age (<65 years, ≥65 years)

Age at initial disease diagnosis (<18, 18-39, ≥40 years)

Sex (Male, Female)

Race (American Indian or Alaska Native, Asian, Japanese descent, Black or African 
American, Native Hawaiian or Other Pacific Islander, White, Unknown, Not Available)

Race (White, Non-White)

Ethnicity

Weight (kg) 

Height (cm) 

Body Mass Index (kg/m2) 

Body Mass Index (kg/m2) (Normal [<25 kg/m2], Overweight [≥25 to <30 kg/m2], Obese 
[≥30 kg/m2])

Psoriatic arthritis subtype (collected in Diagnosis eCRF)

Duration of disease

Duration of disease (<Median, ≥Median)

Region (USA/Germany, Eastern Europe) [according to randomization stratum]

Region (USA/Germany, Eastern Europe) [according to eCRF]
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
In subjects taking steroids, daily dose at NDI-034858 initiation (Section 4.9): daily dose of 
steroid will be calculated by averaging the daily dose of all types of steroids the subjects
are taking after converting the dose to prednisone equivalent (see Appendix 6)

Baseline use of NSAIDs (under NSAID at the baseline visit) (Yes, No)

For baseline use of medications listed above, below calculation rules for weekly dose will 
be applied:

If Frequency = Daily, then weekly dose = Dose × 7 

If Frequency = Twice Daily, then weekly dose = Dose × 7 × 2

If Frequency = Three Times Daily, then weekly dose = Dose × 7 × 3

If Frequency = Four Times Daily, then weekly dose = Dose × 7 × 4

If Frequency = Every other Day, then weekly dose = Dose × 7 × 0.5

If Frequency = Once Weekly, then weekly dose = Dose

If Frequency = Twice Weekly, then weekly dose = Dose × 0.5

If Frequency = Monthly, then weekly dose = Dose × 0.25

If Frequency = Unknown, then weekly dose = missing

If Frequency = Other, then weekly dose will be calculated according to the detailed 
information collected (e.g., number of tablets taken for one week). If detailed information 
is not available, then weekly dose will be set as missing.

If Frequency = As Necessary, then weekly dose = missing
For daily dose calculation, apply the above calculation rules and divide by 7.
By-subject listing of demographic and other baseline characteristics as well as subgroups will also 
be provided for FAS.
4.8
Medical and Surgical History
Medical and surgical history at screening will be collected under Medical History form of the 
eCRF and will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 25.0 or later. Medical and surgical history will be summarized on the SS by treatment and 
overall by system organ class (SOC) and preferred term (PT). By-subject listing of medical and 
surgical history will also be provided.
4.9
Prior and Concomitant Medication
Prior medication is defined as any medications that started and stopped on or before the first dose 
of study drug. Concomitant medication is defined as any medications that started before the first 
dose of study drug and stops after the first dose of study drug, as well as any medications that 
started on or after the first dose of study drug. Baseline concomitant medication at study drug
initiation is defined as any medications being taken on the day or ongoing at the day of first study 
drug initiation.
Medication start and stop dates will be compared to the date of first dose of study drug to allow 
medications to be classified as either Prior or Concomitant. Medications starting after the study 
completion/withdrawal date will not be classified or summarized.
Incomplete start and end date of medications will be imputed as described in Section 4.3.2.1.
Medications will be coded using the World Health Organization Drug (WHO Drug) Global March 
2021 B3 or higher. Prior and concomitant medications will be summarized by Pharmacological 
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4.12
Efficacy Evaluation
4.12.1
Analysis and Data Conventions
Unless otherwise specified, all statistical tests will be 2-sided and performed at a significance level 
of 0.05. When applicable, 95% CIs will be presented. 
Selected efficacy endpoints will be calculated according to the algorithm specified in the respective 
section using response of individual component rather than results calculated by Medidata.
A by-subject listing for selected efficacy endpoints will be provided. 
4.12.1.1
Adjustments for Covariates
The binary efficacy analyses will be adjusted for the following randomization stratification factors:
1. Prior treatment with biologics or non-traditional DMARDs [Yes, No]
2. Region [USA/Germany (USA, Germany), Eastern Europe (Czech Republic, Poland)]
All continuous efficacy endpoints will be adjusted for baseline score and the randomization 
stratification factors (prior treatment with biologics or non-traditional DMARDs [Yes, No], and 
region [USA/Germany, Eastern Europe]).
Following the intent to treat principle, subjects will be analyzed with the strata to which they were 
randomized. A sensitivity analysis will be performed on the primary endpoint using the actual
stratification factors re-derived based on the data collected on the eCRF. A summary of 
mis-stratifications will be provided.
4.12.1.2
Estimands
Objectives
Estimands
[Primary] To assess the efficacy of NDI-
034858 (also known as TAK-279) orally 
administered QD at 
 
 for 12 weeks on the rheumatological 
signs, symptoms, and function in subjects 
with active PsA
The primary estimand will be based on a mixture of “composite 
strategy” and “treatment policy strategy” to assess the treatment effect 
of TAK-279 compared to placebo in subjects with active PsA.
Population: The target population consists of subjects with active 
PsA as defined by the protocol inclusion/exclusion criteria. The 
analysis population for the primary endpoint is FAS which includes 
all randomized subjects who receive at least one dose of study drug. 
Endpoint of interest: primary efficacy endpoint, assessed as the 
proportion of subjects achieving at least an ACR20 response at Week 
12.
Treatment of interest: TAK-279 
 QD, TAK-279 
 QD, or 
TAK-279 
 QD versus placebo.
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Objectives
Estimands
Strategy for addressing ICEs: The following events will be 
considered ICEs:

ICE1: Premature discontinuation of the study drug due to 
the lack of efficacy, AE, or any other reason prior to Week 
12.

ICE2: Death due to any cause prior to Week 12.

ICE3: Use of a prohibited medication as PsA treatment or of 
another treatment expected to have an effect on PsA clinical 
outcomes prior to the assessment of ACR20 at Week 12.

ICE4: Use of other prohibited medications (not PsA 
treatment or other treatments not expected to have a clinical 
effect on PsA clinical outcomes) prior to the assessment of 
ACR20 at Week 12.
The “composite strategy” will be implemented to handle ICE1, ICE2, 
and ICE3. Subjects with ICE1, ICE2, or ICE3 will be considered as 
non-responders (ie, treatment failure).
The “treatment policy strategy” will be implemented to handle ICE4. 
Subjects with ICE4 will be encouraged to be followed for efficacy 
and safety until EOS unless they have withdrawn consent for study 
participation for other reasons. The observed ACR20 will be 
considered regardless of the occurrence of the ICE following intent-
to-treat principle as this event reflects clinical practice. The subjects
who have nevertheless missing endpoint data at Week 12 will be 
imputed as non-responder (ie, treatment failure).
If there are subjects with multiple ICEs applying different strategies, 
the ICEs will be handled in the above order.
The subjects who have otherwise missing endpoint data at Week 12
will be imputed as non-responders (ie, treatment failure).
Population-level summary: Difference in the proportion of subjects 
achieving ACR20 response at Week 12 between each TAK-279 
treatment group and the placebo group. 
The supplementary estimand will be based on “treatment policy 
strategy” to assess the treatment effect of TAK-279 compared to 
placebo in subjects with active PsA.
Population, Endpoint of interest, and Treatments are the same as for 
the primary estimand of the primary efficacy endpoint.
Strategy for addressing ICEs. The following events will be considered 
ICEs:

ICE1: Premature discontinuation of the study drug due to 
the lack of efficacy, AE, or any other reason prior to Week 
12.

ICE2: Death due to any cause prior to Week 12.
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Objectives
Estimands

ICE3: Use of a prohibited medication as PsA treatment or of 
another treatment expected to have an effect on PsA clinical 
outcomes prior to the assessment of ACR20 at Week 12.

ICE4: Use of other prohibited medications (not PsA 
treatment or other treatments not expected to have a clinical 
effect on PsA clinical outcomes) prior to the assessment of 
ACR20 at Week 12.
The “treatment policy strategy” will be implemented to handle ICE1 
to ICE4. Subjects with ICEs will be encouraged to be followed for 
efficacy and safety until EOS unless they have withdrawn consent for 
study participation for other reasons. The observed ACR20 will be 
considered regardless of the occurrence of the ICEs following 
intent-to-treat principle as this event reflects clinical practice. The 
subjects who have nevertheless missing endpoint data at Week 12 will 
be imputed as non- responder (ie, treatment failure).
Population-level summary: Difference in the proportion of subjects 
achieving ACR20 response at Week 12 between each TAK-279 
treatment group and the placebo group.
[Secondary] 
To 
assess 
additional 
evaluations of efficacy of NDI-034858 
orally administered QD at 
 
 for 12 weeks in subjects with 
active PsA
The secondary estimands for binary secondary efficacy endpoints 
listed below will be based on a mixture of “composite strategy” and 
“treatment policy strategy” the same as to the primary estimand for 
primary efficacy endpoint to assess the treatment effect of TAK-279 
compared to placebo in subjects with active PsA.
Population: The target population consists of subjects with active PsA 
as defined by the protocol inclusion/exclusion criteria. The analysis 
population for the primary endpoint is FAS which includes all 
randomized subjects who received at least one dose of study drug. 
Endpoint of interest: the following binary secondary efficacy 
endpoints at Week 12.

ACR50 response at Week 12

ACR70 response at Week 12

MDA at Week 12

PASI-75 at Week 12 among subjects with ≥3% BSA psoriatic 
involvement at Day 1 

Physician Global Assessment of Psoriasis of 0 or 1 and at least a 
2 -point improvement from baseline at Week 12
Treatments, ICEs, ICE handling strategies, and population-level 
summaries are the same as for the primary estimand of primary 
efficacy endpoint. 
[Secondary] 
To 
assess 
additional 
evaluations of efficacy of NDI-034858 
orally administered QD at 
 
 for 12 weeks in subjects with 
active PsA
The secondary estimands
for continuous secondary efficacy 
endpoints will be based on “treatment policy strategy” to assess the 
treatment effect of TAK-279 compared to placebo in subjects with 
active PsA.
Population: The target population consists of subjects with active
PsA as defined by the protocol inclusion/exclusion criteria. The 
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Objectives
Estimands
analysis population for the primary endpoint is FAS which includes 
all randomized subjects who receive at least one dose of study drug. 
Endpoints of interest: the following continuous secondary efficacy 
endpoints at Week 12.

Change from baseline (Day 1) in tender joint count at 
Week 12

Change from baseline (Day 1) in swollen joint count at 
Week 12 

Change from baseline (Day 1) in Patient Global Assessment 
of Psoriatic Arthritis at Week 12 

Change from baseline (Day 1) in Patient Global Assessment 
of Psoriatic Arthritis pain at Week 12

Change from baseline (Day 1) in Physician Global 
Assessment of Psoriatic Arthritis at Week 12 

Change from baseline (Day 1) in HAQ-DI score at Week 12

Change from baseline (Day 1) in dactylitis count at Week 12, 
among subjects who have dactylitis at Day 1 

Change from baseline (Day 1) in LEI at Week 12, among 
subjects who have enthesitis at Day 1

Change from baseline (Day 1) in Disease Activity Index for 
DAPSA at Week 12
Treatment of interest: TAK-279 
 QD, TAK-279 
 QD, or 
TAK-279 
 QD versus placebo.
Strategy for addressing ICEs. The following events will be considered 
ICEs:

ICE1: Premature discontinuation of the study drug due to 
the lack of efficacy, AE, or any other reason prior to Week 
12.

ICE2: Death due to any cause prior to Week 12.

ICE3: Use of a prohibited medication as PsA treatment or of 
another treatment expected to have an effect on PsA clinical 
outcomes prior to the assessment of ACR20 at Week 12.

ICE4: Use of other prohibited medications (not PsA 
treatment or other treatments not expected to have a clinical 
effect on PsA clinical outcomes) prior to the assessment of 
ACR20 at Week 12.
The “treatment policy strategy” will be implemented to handle ICE1 
to ICE4. Subjects with ICEs will be encouraged to be followed for 
efficacy and safety until EOS unless they have withdrawn consent for 
study participation for other reasons. The observed data will be 
considered regardless of the occurrence of the ICEs following 
intent-to-treat principle as this event reflects clinical practice. 
Missing endpoint data despite effort to retain subjects after treatment 
discontinuation will be handled under the missing at random (MAR) 
assumption. 
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Objectives
Estimands
Population-level summary: Treatment difference in LS means at 
Week 12 between each TAK-279 treatment group and the placebo 
group.
ACR20: American College of Rheumatology 20% response; AE: adverse events; BSA: body surface area; Dudy 
APSA: Disease Activity Index for Psoriatic Arthritis; EOS: end of study; FAS: full analysis set; HAQ-DI: Health 
Activities Questionnaire – Disability Index; ICEs: intercurrent events; LEI: Leed’s Enthesitis Index; LS: least 
squares; MAR: missing at random; MDA: Minimal Disease Activity; PsA: psoriatic arthritis; 
 
; QD: once daily; SAP: statistical analysis plan.
4.12.1.3
Handling of Missing Data
The following approaches will be used to handle missing data for the efficacy endpoints taken into 
consideration the respective estimand framework and strategy to handle ICEs as specified in 
Section 4.12.1.2. If there are subjects with multiple ICEs applying the same strategies, the earliest 
onset of ICE will be used as the starting point for imputation.
Non-Responder Imputation (NRI) 
The NRI approach will categorize any subject who has a missing data to determine the binary 
endpoint status at a specific visit as non-responder (eg, treatment failure) for that visit. 
MMRM
For continuous efficacy endpoints, the efficacy data will be analyzed as observed via MMRM
assuming MAR.
Hybrid Imputation Method
For primary efficacy endpoint, ACR20 at Week 12, a supportive analysis will be performed to 
evaluate the robustness of missing data handling through a hybrid imputation method under 
different missing data mechanisms (Chen et al, 2021). The subjects who discontinued study drug 
prematurely due to lack of efficacy, due to AE or death, and subjects who received a prohibited
medication as PsA treatment prior to Week 12 will be imputed as non-responders via NRI under
MNAR; subjects who discontinued study drug prematurely due to other reason and subjects who 
have otherwise missing endpoint data to determine the status of ACR20 at Week 12 will be 
imputed via MI using a fully conditional specification (FCS) method under MAR.
For MI, each component of ACR20 will firstly be multiply imputed before deriving ACR20 to 
minimize the information loss. For example, missing data for TJC will be multiply imputed first 
before combining with other component data to derive ACR20 response. The MI will be conducted
by treatment group via FCS regression method. The missing baseline data, if any, will be imputed 
using randomization stratification factors. The missing data from each subsequent postbaseline 
visit will be imputed using all previous visits and the randomization stratification factors in a 
stepwise fashion. A hundred (100) imputation datasets will be generated. Once complete datasets
for each component of ACR20 are generated, ACR20 will be derived as specified in 
Section 4.12.2.
Combine the imputed ACR20 via NRI under MNAR and via MI under MAR to obtain a complete 
dataset containing all subjects in the analysis population. The comparison of each dose group to 
placebo using the Mantel-Haenszel (MH) test specified in Section 4.12.2.1 will be performed on 
the 100 datasets. An estimate for the difference in proportions and corresponding standard error 
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4.12.2
Primary Efficacy Analysis
4.12.2.1
Derivation of Primary Efficacy Endpoint 
The primary efficacy endpoint is a binary variable, where a subject will be classified as responder 
if they achieve ACR20 at Week 12. The ACR20 is a composite measure that needs to satisfy the 
following criteria:
1. Improvement of 20% in the number of tender joints (TJC68); 
And 
2. Improvement of 20% in the number of swollen joints (SJC66); 
And
3. A 20% improvement in at least three of the following five criteria:
o
PGA-PsA
o
PGAAP
o
PhGA-PsA
o
HAQ-DI
o
hsCRP
Given the limitation of Medidata eCOA system, three components of ACR20 (ie, TJC68, SJC66, 
HAQ-DI) will be re-derived based on the source data. 
While computing ACR20, missingness in individual component will affect the derivation
differently. The following algorithm should be followed: 
a.
If TJC68 ≥20% and SJC66 ≥20% and at least 3 of 5 components in criteria 3) has 
improvement ≥20%, then ACR20 will be considered as responder; 
b. If TJC68, SJC66, or at least 3 of the 5 components in criteria 3) has improvement <20%, 
then ACR20 will be considered as non-responder; 
c.
For all other cases, the ACR20 will be missing since insufficient data for determination. 
The following table illustrates examples for ACR response determination.
TJC68
SJC66
Component
ACR20
Scenario
1
2
3
4
5
a)
≥20%
≥20%
≥20%*
≥20%*
≥20%*
Responder
b)
≥20%
<20%
Regardless status of the components
Non-Responder
<20%
≥20%
Regardless status of the components
Non-Responder
<20%
<20%
Regardless status of the components
Non-Responder
.
<20%
Regardless status of the components
Non-Responder
<20%
.
Regardless status of the components
Non-Responder
≥20%
≥20%
<20%*
<20%*
<20%*
Non-Responder
.
.
<20%*
<20%*
<20%*
Non-Responder
c)
≥20%
.
Fewer than 3/5 components with <20%
Missing
.
≥20%
Fewer than 3/5 components with <20%
Missing
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TJC68
SJC66
Component
ACR20
Scenario
1
2
3
4
5
≥20%
≥20%
At least 3 of the 5 components in criteria 3) missing
Missing
≥20%
≥20%
≥20%
≥20%
<20%
<20%
.
Missing
.
.
≥20%
≥20%
≥20%
≥20%
≥20%
Missing 
*Components 1, 2, and 3 are used as an example in the table. The “at least 3 components” can be any combination
and can be more than 3 components. 
Note: scenarios in the table above are provided as examples and may not be all-inclusive of all possibilities. 
For any of the ACR20 components, if the baseline value equals 0 and the post-baseline value is 
greater than or equal to 0, then the percent improvement of that component will be treated as 0 for 
the purpose of ACR response calculations.
4.12.2.2
Main Analysis Approach
Comparison of the primary endpoint will be made between each dose group and the placebo group 
using a two-sided MH test of the difference in two proportions stratified by the randomization 
stratification factors (prior treatment with biologics or non-traditional DMARDs [Yes, No] and 
region [USA/Germany, Eastern Europe]). The estimated MH risk difference will be summarized 
along with the two-sided 95% CI using MH stratum weights (Mantel, 1959) and the Sato variance 
estimator (Sato, 1989).
The count and proportion of subjects with ACR20 response following primary estimand will be 
provided by study visit and treatment arm. A line plot showing the proportion of subjects with 
ACR20 response over time within each treatment group will be provided.
4.12.2.3
Supplementary Analysis
The primary efficacy endpoint will be analyzed following the supplementary estimand. The 
observed ACR20 will be analyzed regardless of the occurrence of the ICEs. The data that is 
nevertheless missing will be imputed as non-response via NRI. 
Comparison of the primary endpoint will be made between each dose group and the placebo group 
using the same method as used for the main analysis approach for the primary endpoint. 
The count and proportion of subjects with ACR20 response following supplementary estimand 
will be provided by study visit and treatment arm. A line plot showing the proportion of subjects 
with ACR20 response over time within each treatment group will be provided.
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4.12.2.4
Sensitivity Analysis
The following analyses will be performed for the primary efficacy endpoint to assess the 
robustness of the primary endpoint result. These analyses will be conducted using the FAS unless 
otherwise specified.
Type
Sensitivity Analysis
1
Repeat the primary endpoint analysis using ITT and PPS.
2
In the event that there is discrepancy between original randomization stratification factors assigned at the 
time of randomization in IRT system and the data collected in EDC, the stratification factors will be 
re-derived based on the EDC data subsequent to randomization. The primary efficacy analysis as described 
in Section 4.12.2.2 will be repeated on the FAS using the MH test adjusting for the re-derived stratification
factors.
3
Apply a hybrid imputation approach under different missing data mechanism to evaluate the impact of 
missing data handling in the primary endpoint analysis via NRI under MNAR and MI under MAR (see 
Section 4.12.1.3).
4
To evaluate the robustness of missing data handling, additional sensitivity analysis may be performed, such 
as tipping point analysis. 
5
Sensitivity analyses of the ACR20 response will be conducted using the TJC and SJC score calculated by
the alternative algorithms via a proportional extrapolation method (see Section 4.12.3.2.3) using FAS.
In addition, a multiple comparison procedure modelling (MCP-Mod) analysis may be conducted 
to support the dose selection for future trial/s. 
4.12.3
Secondary Efficacy Analysis
Secondary endpoints will be analyzed using the FAS unless otherwise specified.
4.12.3.1
Analysis Approach for Secondary Efficacy Endpoints
Secondary binary efficacy endpoints
The secondary binary efficacy endpoints at Week 12 will be analyzed using the secondary 
estimand framework as described in Section 4.12.1.2 (applying ICEs and missing data imputation).
The count and proportion of subjects achieving binary efficacy endpoints will be provided by study 
visit and treatment arm. For binary endpoints, a line plot showing the proportion of subjects 
achieving response by treatment group over time will be provided.
Comparison of each binary efficacy endpoint will be made between each dose group and the 
placebo group using the same method as described for the primary efficacy endpoint. The 
estimated MH risk difference will be summarized along with the two-sided 95% CI using MH 
stratum weights (Mantel, 1959) and the Sato variance estimator (Sato, 1989). Nominal p-values 
will be presented.
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Secondary continuous efficacy endpoints
For longitudinal continuous secondary efficacy endpoints, the changes from baseline will be 
analyzed as observed regardless of ICEs (ie, using treatment policy strategy) using the mixed 
model for repeated measures (MMRM) where the change from baseline will be the dependent 
variable, treatment group, visit, treatment-by-visit interaction and the randomization stratification 
factors (prior treatment with biologics or non-traditional DMARDs [Yes, No], and region 
[USA/Germany, Eastern Europe]) will be the fixed effects, and baseline score and will be included 
as a covariate. The parameter estimations will be based on the assumption of data being missing 
at random (MAR) and using the method of restrictive maximum likelihood (REML). The 
Kenward-Roger approximation (Kenward MG, 1997) will be used to estimate the denominator 
degrees of freedom. An unstructured (UN) covariance matrix will be used to model the 
within-subject correlation. If this model fails to converge, then covariance matrix in the order of 
compound symmetry (CS), autoregressive (1) [AR(1)], and Toeplitz (TOEP) will be used. 
The treatment effect measured by the continuous secondary efficacy endpoints at Week 12 
between each dose group and the placebo group will be estimated based on the least square (LS)
mean treatment difference at Week 12 obtained from the MMRM. The LS mean, the LS mean 
treatment difference, the associated 95% CI, and nominal p-value for each timepoint obtained from 
the MMRM will also be provided. A line plot showing the least square mean (SD) over time within 
each treatment group from MMRM will be provided.
4.12.3.2
Derivation of Secondary Endpoints
4.12.3.2.1
Proportion of subjects achieving ACR50 Response at Week 12
The ACR50 will be derived using the same derivation rules as for ACR20 except that the 
improvement of each of the seven components will be based on a 50% improvement instead of 
20%. 
4.12.3.2.2
Proportion of subjects achieving ACR70 response at Week 12
The ACR70 will be derived using the same derivation rules as for ACR20 except that the 
improvement of each of the seven components will be based on a 70% improvement instead of 
20%. 
4.12.3.2.3
Change from baseline in tender joint count (TJC) at Week 12 and change from 
baseline 
in 
swollen 
joint 
count 
(SJC) 
at 
Week 12
The tender joint count in 68 joints (TJC68) and swollen joint count in 66 joints (SJC66) are 
instruments measuring the peripheral arthritis activity. A total of 68 and 66 joints are assessed for 
tenderness and swollenness, respectively (note: the hips are assessed for tenderness but not for 
swelling). 
The following joints are included in the assessment: 

Temporomandibular, sternoclavicular, acromioclavicular, glenohumeral, elbow, wrist, hip 
(TJC only), knee, ankle, tarsus;

Metacarpophalangeal, finger proximal interphalangeal, finger distal interphalangeal,
metatarsophalangeal, toe proximal interphalangeal
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TJC68 is scored as a sum of the tender joints and SJC66 is scored as a sum of the swollen joints. 
When counting the number of joints with tenderness or swelling, the following scoring rules will 
be used:

Response as “Present” will be given a score of 1, 

Response as “Absent”, “Not Done”, or “Not Applicable”, or joints with missing response
will be given a score of 0. 

Any response other than “Present”, “Absent”, “Not Done”, or “Not Applicable” is 
considered as invalid response (eg, “Present, Not Done”, “Present, Not Applicable”,
“Absent, Not Done”, “Absent, Not applicable”) and will be given with a score of 0. 
The sum of the scores of all 68 or 66 joints will be used as the TJC68 or SJC66 scores, respectively,
for all analyses involving tender/swollen joint counts. Injected joints will be counted as both tender
and swollen from the date of injection up to the end of the study. If a subject had received any joint 
injection since last visit but without joint location specified, then 1 will be added to TJC68 and 
SJC66, respectively.
Note, given the limitation of the Medidata eCOA system, instead of using scores calculated by
Medidata, TJC68 and SJC66 scores used in all analyses will be re-derived based on the assessment 
of individual joints. In the event these scores are discrepant, the differences will be documented in 
the CSR narrative section. 
Acknowledging the data limitation, two sets of sensitivity analyses will be conducted using TJC68 
and SJC66 estimated by proportional extrapolation method, which has the advantage of providing 
meaningful imputation of the joints that are replaced, not assessed, or without valid responses. The 
sum of the scores of all joints will be divided by the number of joints with valid non-missing 
response, i.e., “Present” or “Absent”. This proportion will then be used to impute joint counts for 
the joints with missing score. 
=>68 = 68 × =ℎ =BCD EFGHI J >KLBM NKBℎ=LOILMM ("Present" or 1)
=ℎ =BCD EFGHI J >KLBM NKBℎLL-GKMMKL RMSLM
'>66 = 66 × =ℎ =BCD EFGHI J >KLBM NKBℎ'NDDKL ("Present" or 1)
=ℎ =BCD EFGHI J >KLBM NKBℎLL-GKMMKL RMSLM
Injected joints will be counted as both tender and swollen from the date of injection to the end of 
study. If a subject had received any joint injection since last visit but without joint location 
specified, 1 will be added to TJC68 and SJC66, respectively. When more than 50% of the joints 
have missing score, the TJC68 and SJC66 will be set as missing. 
The two sets of sensitivity analyses follow the same proportional extrapolation approach but differ 
in the way of handling invalid response. Separate scoring rules are described as follows:
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Scoring rules for sensitivity analysis #1

Response as “Present” will be given a score of 1.

Response as “Absent” will be given a score of 0.

Response as “Not Done”, “Not Applicable”, or missing will be set as missing. 

Invalid response (eg, “Present, Not Done”, “Present, Not Applicable”, “Absent, Not 
Done”, “Absent, Not applicable”) will be set as missing.
Scoring rules for sensitivity analysis #2

Response as “Present” will be given a score of 1

Response as “Absent” will be given a score of 0 

Response as “Not Done”, “Not Applicable”, or missing will be set as missing. 

Response containing “Present” (eg, “Present, Not Done” or “Present, Not Applicable” ) 
will be given a score of 1

Response containing “Absent” (eg, “Absent, Not Done”, “Absent, Not applicable”) will be 
given a score of 0
4.12.3.2.4
Change from baseline in Patient Global Assessment of Psoriatic Arthritis (PGA-PsA) 
at Week 12 and change from baseline in Patient Global Assessment of Psoriatic 
Arthritis Pain (PGAAP) at Week 12
In this study, PGA-PsA and PGAAP are scored using a Visual Analogue Scale (VAS) which is 
anchored on an unnumbered 100-mm horizontal line. The PGA-PsA VAS is anchored at the ends, 
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with 0 being “very good, no symptoms” and 100 being “very poor, severe symptoms”. The 
PGAAP VAS is anchored at the ends, with 0 is ‘no pain’ and 100 is ‘most severe pain’.
4.12.3.2.5
Change from baseline in Physician Global Assessment of Psoriatic Arthritis
(PhGA-PsA) at Week 12
The investigator or qualified sub-investigator will assess the subjects’ overall disease status, taking 
into account signs, symptoms, and function, of all components of joint and skin which is affected 
at the time of the visit and will rate this overall status using a VAS scale where 0 is ‘very good, 
asymptomatic, and no limitation of normal activities’ and 100 is ‘very poor, very severe symptoms 
which are intolerable, and inability to carry out all normal activities’.
4.12.3.2.6
Change from baseline in Health Activities Questionnaire – Disability Index score at 
Week 12
The HAQ-DI is comprised of eight domains: dressing, arising, eating, walking, hygiene, reach, 
grip, and activities. Each domain contains two or three questions scorings from 0 (without any 
difficulty) to 3 (unable to do). The worst score within each domain will be used as the domain 
score (i.e., if the score for one question is 1 and 2 for the other, then the worst score for the domain 
is 2). When an aide or device is used or help is required from another individual, the minimum 
score for that relevant domain is 2.
The HAQ-DI score is calculated by dividing the sum of the domain scores by the number of 
non-missing domains. If all questions within a given domain are unanswered, no score will be 
provided for that domain (this rule applies even if aids and devices are non-missing). If more than
2 domains are missing, score will be considered as missing. The HAQ-DI score ranges from 0 to 
3.0. A higher score indicates worse function and greater disability.
Given the limitation of the Medidata eCOA system, HAQ-DI score will be re-derived based on 
source data for analysis purpose. In the event the re-derived score and Medidata eCOA system 
calculated score are discrepant, the differences will be documented in the CSR narratives. 
4.12.3.2.7
Change from baseline in Dactylitis count at Week 12, among subjects who have 
dactylitis at Baseline
Dactylitis is defined as tenderness observed in any of the individual digit in the hands and feet. In 
the CRF, each individual digit is assessed for tenderness and four values are assigned: 0=“No 
tenderness”, 1=”Tender”, 2=”Tender and wince”, and 3=”Tender and withdraw”. Digit with values 
1, 2, and 3 will be considered as having tenderness. Dactylitis is present if the total number of 
digits with tenderness >=1, or absent if the total count is zero. 
The dactylitis score counts the total number of single digits in the hands and feet with tenderness.
A higher score indicates worse symptom of tenderness in the hands and feet. If a total score is ≥1, 
a subject is defined to have dactylitis. If a total score is 0, a subject is defined as not having 
dactylitis.
Given the limitation of the Medidata eCOA system, dactylitis score will be re-derived based on 
the source data for analysis purpose. In the event, the re-derived dactylitis score and Medidata 
eCOA system calculated score are discrepant, the differences will be documented in the CSR 
narratives. 
Analysis on dactylitis will be performed for all subjects in the FAS who have dactylitis at baseline.
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4.12.3.2.8
Change from baseline in Leed’s Enthesitis Index (LEI) at Week 12, among subjects 
who have enthesitis at Baseline
The LEI is comprised of review of six bilateral sites: Achilles tendon insertions (left and right), 
medial femoral condyles (left and right), and lateral epicondyles of the humerus (left and right). 
Tenderness at each site is quantified on a dichotomous basis: 0 means nontender and 1 means 
tender.
When assessments of 4 sites are missing, the LEI total score will be set to missing. If assessments 
of at least 3 sites are available, the total LEI score will be computed as a weighted score:
TUV = 6 × ∑
MXI
*
YZ[
∑
\V
*
YZ[
L refers to the number of total sites assessed and AI refers to the site with non-missing score.
The LEI total score ranges from 0 to 6, and a higher score indicates worse symptom of tenderness 
in the six bilateral sites. If LEI total score ≥ 1, a subject is defined to have enthesitis.
Analysis on LEI will be performed for all subjects in the FAS with baseline LEI score ≥1.
4.12.3.2.9
Proportion of subjects with Minimal Disease Activity (MDA) at Week 12
MDA is measured as whether a subject meet ≥5 of the 7 criteria (yes/no). The 7 criteria include:
1. TJC ≤1
2. SJC ≤1
3. PASI score ≤1 or BSA ≤3%
4. PGAAP, VAS score ≤15
5. PGA-PsA, VAS score ≤20
6. HAQ-DI ≤0.5
7. Tender enthesial points (LEI ≤1)
If any subject meets ≥5 of the 7 criteria, MDA is considered as “Yes”, whereas if any subject fails 
≥3 of the 7 criteria, MDA is considered as “No”. MDA will be set to “Missing” for any other 
scenarios.
4.12.3.2.10
Change from baseline in Disease Activity Index for Psoriatic Arthritis (DAPSA) at 
Week 12
The DAPSA score is a composite score calculated using TJC68, SJC66, PGA-PsA, PGAAP, and 
hsCRP level. 
The formula to calculate DAPSA composite score is as follows:
DAPSA = SJC66 + TJC68 + PGA-PsA/10 + PGAAP/10 + hsCRP
Where hs-CRP is expressed in mg/dL.
If any individual component score is missing, the DAPSA score will be set to missing.
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DAPSA values will also be categorized in the following disease activity categories:

DAPSA ≤4 for Remission 

DAPSA from >4 to ≤14 for Low Disease Activity

DAPSA from >14 to ≤28 for Medium Disease Activity 

DAPSA >28 for High Disease Activity
The count and percentage of DAPSA in each category will be summarized by visit, and treatment 
group.
4.12.3.2.11
Proportion of subjects achieving 75% improvement from baseline in psoriasis area 
severity index [(PASI)-75] among subjects with ≥3% BSA psoriatic involvement at 
baseline
The PASI is a composite score ranging from 0 to 72 and takes into account the degree of erythema, 
induration/infiltration, and desquamation (each scored from 0 to 4 separately) for each of four 
body regions, with adjustments for the percentage of BSA involved within each body region and 
for the proportion of the body region to the whole body.
PASI is a tool to measure the severity and extent of psoriasis involvement. To calculate PASI, the 
human body is divided into four regions: head and neck, upper extremities, trunk, and lower 
extremities, which account for 10%, 20%, 30%, and 40% of the total BSA, respectively. Within 
each region, the severity and the extent of the disease are evaluated separately. The severity is 
assessed using the intensity of erythema (redness), induration (thickness), and desquamation 
(scaling of the psoriasis). The intensity is rated on a scale of 0 to 4, with 0=no symptoms, 1=slight, 
2=moderate, 3=marked, and 4=very marked. The extent of the disease is measured by the 
percentage of the area affected by psoriasis within each region, and is expressed as 0-6, with 
0 = 0%, 1 = 1%-9%, 2 = 10%-29%, 3 = 30%-49%, 4 = 50%-69%, 5 = 70%-89%, and 6 = 90-100%. 
The following formula is used to calculate the PASI score:
PASI=10% × (Ie + Ii + Id) × Ah + 20% × ( Ie + Ii + Id) × Au + 30% × ( Ie + Ii + Id) × At + 40% × (Ie
+ Ii + Id) × Al
Where Ie = intensity of erythema, Ii = intensity of induration, Id = intensity of desquamation, 
Ah = percentage of psoriasis involvement in head and neck area, Au = percentage of psoriasis 
involvement in upper extremities, At = percentage of psoriasis involvement in trunk area, 
Al = percentage of psoriasis involvement in lower extremities. 
4.12.3.2.12
Proportion of subjects achieving a Physician Global Assessment of Psoriasis of 0 or 
1 and at least a 2-point improvement from baseline at Week 12
The PhGA-PsO is measured using a 0 to 4 scale with a 0 meaning clear or a 4 meaning severe. 
PhGA-PsO responder is defined as subjects 1) having PhGA-PsO score of 0 or 1 at any given visit;
and 2) having at least 2-point improvement from baseline. The proportion of subjects achieving 
PhGA-PsO response at Week 12 will be calculated and analyzed for subjects with a score of at 
least 2 at baseline.
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4.13
Safety Evaluation
4.13.1
Extent of Exposure
Duration of study drug exposure, cumulative dose (mg), and average daily dose (mg/day) will be 
summarized on SS by treatment and overall. 
Duration of study drug exposure (days) will be calculated as: Date of Last Dose – Date of First 
Dose + 1
Duration of study drug exposure including safety follow-up used for exposure adjusted incidence 
rate (EAIR) calculation will be calculated as: Date of EOS – Date of First Dose + 1
The cumulative dose taken by each subject during the treatment period will be determined using 
data collected in Study Drug Accountability eCRF and is defined as: Cumulative dose 
(mg) = [Total Amount Dispensed
- Total Amount Returned 
] × dose level 
(mg) / 2
Note: calculation of cumulative dose is only based on blister packets with complete data, i.e. both 
the number of 
dispensed and returned for the same packet should not be missing. 
Average daily dose will be calculated as below: Average daily dose= cumulative dose/Duration of 
study drug exposure.
In addition, the number and percentage of subjects will be summarized by the following study drug 
exposure duration (days) categories: 

1 day to ≤4 weeks (1 to ≤28 days)

4 weeks to ≤8 weeks (>28 to ≤56 days)

8 weeks to ≤12 weeks (>56 to ≤84 days)

>12 weeks (>84 days)
A by-patient listing of study drug exposure (including the start and end dates of study drug, 
duration of study drug exposure, cumulative dose, and average daily dose) will be provided on the 
SS. In addition, data collected from investigational product (IP) Administration-on site, IP 
Administration-at Home, and Patient Diary will be listed as well.
4.13.2
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 26.0 or higher. Intensity and causality of AE will be evaluated by the investigator. 
Intensity of AE will be graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE), version 5.0. Partial start and end date of the AE will be imputed as described in
Section 4.3.2.
Subjects with multiple incidences of events for a given PT and SOC will be counted only once. 
Similarly, if a subject experienced multiple incidents of events for a given PT and SOC, the worst 
intensity will be used in the summaries presenting intensity, and the worst causality to study drug 
will be used in the summaries presenting causality, respectively.
AE summaries will be sorted in decreasing frequency by SOC, and PT within SOC, in the overall 
SS, and then alphabetically for SOC, and PT within SOC if there are any ties in frequency. Analysis 
and reporting of AEs will be based on TEAEs. A TEAE is defined as an AE occurring (onset 
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date/time) at the time of or after dosing on Day 1. An overall summary of TEAEs will include the 
number and percentage of subjects with:

TEAEs

Drug-related TEAEs

TEAEs leading to discontinuation of study drug

TEAEs leading to study discontinuation

TESAEs

Drug-related TESAEs

TESAEs leading to discontinuation of study drug

TESAEs leading to study discontinuation

TEAEs by intensity (CTCAE grades 1, 2, 3, 4, 5)

TEAEs leading to death

TEAESIs

Drug-related TEAESIs

TEAESIs leading to discontinuation of study drug

TEAESIs leading to study discontinuation
Summaries of the following categories of TEAEs will be presented by treatment group, SOC, and 
PT:

All TEAEs

Drug-related TEAEs 

TEAEs leading to discontinuation of study drug

TEAEs leading to study discontinuation

TEAEs Grade 3 or higher

TESAEs 

Drug-related TESAEs

TESAEs leading to discontinuation of study drug

TESAEs leading to study discontinuation

TEAEs by intensity (CTCAE grades 1, 2, 3, 4, 5)

TEAEs leading to death
In order to assess the impact of AEs on geriatric subjects, tables for all TEAEs and Drug-related 
TEAEs will also be presented by age group (<65 years old and ≥65 years old), with associated 
listing for TEAEs for subjects ≥65 years old. Other age groups could be evaluated based on age 
distribution.
Summaries of the following events will be presented by treatment group and overall:

Potential Drug-induced Liver Injury (DILI) and Hy’s Law Summary

TEAEs by PT (descending order)

Drug-related TEAEs by PT (descending order)

Most frequent (≥5%) TEAEs by PT (descending order)

Most frequent (≥5%) drug-related TEAEs by PT (descending order)

Exposure Adjusted Incidence Rate (EAIRs) for TEAEs by SOC and PT
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Number and percentage of subjects who meet one or more of the following potential DILI criteria 
at any visit (including unscheduled visit) will be summarized by treatment group and overall:
1. Hy’s Law: ALT or AST of >3 times ULN (or ≥3 times the baseline value if greater than 
the ULN at baseline) AND total Bilirubin >2 times ULN (or >2 times the baseline value if 
greater than ULN at baseline, OR international normalized ratio >1.5) AND ALP <2 times 
the ULN.
In order to meet the above criteria, a subject must experience the elevation in bilirubin and 
ALT or AST at the same visit. For example, a subject who experiences a ≥2 × ULN 
elevation of bilirubin at one visit and a ≥3 × ULN elevation in ALT (or AST) at a 
subsequent visit has not fulfilled the potential Hy’s law criteria.
2. ALT or AST ≥8 times the ULN, or ≥8 times the baseline value, if greater than the ULN at 
baseline, regardless of other parameters
Note: ALT or AST ≥8 times the baseline value alone does not qualify the event to be 
classified as DILI. The baseline ALT/AST must be >ULN at the same time. 
Baseline ALT or 
AST
Postbaseline ALT or 
AST
ALT or AST ≥8 × ULN, or ≥8 × baseline value, if greater than the 
ULN at baseline, regardless of other parameters
Normal (≤1 
ULN)
≥8 × ULN
Yes
Normal (≤1 
ULN)
<8 × Baseline
No
Abnormal (>1 
ULN)
≥8 × Baseline
Yes
Abnormal (>1 
ULN)
≥8 × ULN but <8×
Baseline
No
Abnormal (>1 
ULN)
<8 × ULN 
No
3. Either ALT or AST ≥3 times the ULN, or ≥3 times the baseline value, if greater than the 
ULN at baseline and the appearance of fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, fever, rash, and/or eosinophilia (>5%)
Note: to be classified as DILI, both ALT/AST elevation and symptoms must be present at 
the same time. ALT/AST ≥3 times the baseline value alone does not qualify the event to 
be ALT/AST elevation. The baseline ALT/AST must be > ULN at the same time. 
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Baseline 
ALT or AST
Post-baseline 
ALT or AST
Selected 
AE Present
ALT or AST ≥3 times the ULN, or ≥ 3 times the baseline value, if 
greater than the ULN at baseline, and with the appearance of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (> 5%)
Normal (≤1 
ULN)
≥3 × ULN
Yes
Yes
Normal (≤1 
ULN)
≥3 × ULN
No
No
Normal (≤1 
ULN)
<3 × ULN
-
No
Abnormal 
(>1 ULN)
≥3× Baseline
Yes
Yes
Abnormal 
(>1 ULN)
≥3 ×
Baseline
No
No
Abnormal 
(>1 ULN)
≥3 × ULN 
but <3 ×
Baseline
-
No
Abnormal 
(>1 ULN)
<3 × ULN
-
No
4. Total bilirubin or direct bilirubin >3 times the ULN, or >3 times the baseline value, if 
greater than the ULN at baseline. 
Note: Total Bili or direction Bili >3 times the baseline value alone does not qualify the 
event to be classified as DILI. The baseline total BILI/direct BILI must be > ULN at the 
same time. In addition, postbaseline total bilirubin can only be compared with baseline 
total bilirubin and postbaseline direct bilirubin can only be compared with baseline direct 
bilirubin. 
Baseline Total Bilirubin or 
Direct Bilirubin
Post-baseline Total Bilirubin 
or Direct Bilirubin
Total bilirubin or direct bilirubin >3 times the 
ULN, or >3 times the baseline value
Normal (≤1 ULN)
>3 × ULN
Yes
Normal (≤1 ULN)
≤3 × ULN
No
Abnormal (>1 ULN)
>3 × Baseline
Yes
Abnormal (>1 ULN)
>3 × ULN but ≤3 × Baseline
No
Abnormal (>1 ULN)
≤3 × ULN
No
Exposure-adjusted incident rate (EAIR) is calculated as:
U\VR = The Number of Adverse Events
Total Exposure Time
× 100%
Where the total exposure time (person-year) sums the duration of study drug exposure (including 
safety follow up) from all subjects included in the SS. The total of the duration of study drug 
exposure in days will be converted into years by dividing it with 365.25. The duration of study 
drug exposure including safety follow-up = Date of EOS – Date of First Dose + 1. 
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By-subject listings of corresponding TEAE summary will also be provided including additional 
information such as action taken with study drug, other action taken, outcome, and pattern, etc.
4.13.3
Adverse Events of Special Interest
The following are AESIs from laboratory data:

CTCAE Grade ≥2 cytopenia (anemia, leukopenia, neutropenia, lymphopenia, or 
thrombocytopenia; clinically significant or not) defined by the following ranges: 
o
Hemoglobin <10.0 g/dL (<100.0 g/L).
o
White blood cell count <3.0 × 109/L (<3000/mm3).
o
Absolute neutrophil count of <1.5 × 109/L (<1500/mm3).
o
Absolute lymphocyte count of <0.8 × 109/L (<800/mm3).
o
Platelet count <75 × 109/L (<75,000/mm3).

CTCAE Grade ≥3 elevation of CPK (clinically significant or not) defined as 
CPK >5 × ULN
The following AEs are considered AESIs from adverse events data. These AESIs will initially be 
identified using search criteria below and will be adjudicated by Sponsor prior to the database lock.

Major adverse cardiovascular events (MACE), defined as cardiovascular death, non-fatal 
myocardial infarction, and non-fatal stroke
MACE will be identified using the following rules: 
o
Standardized MedDRA queries (SMQs): “myocardial infarction”, “Haemorrhagic 
central nervous system vascular conditions”, or “ischaemic central nervous system 
vascular condition”
o
Death

Thromboembolic events, defined as pulmonary embolism, deep vein thrombosis, and other 
venous and arterial thromboembolic events (e.g., non-cardiac, non-neurologic, fatal and 
nonfatal)
Thromboembolic events will be identified using the following 3 broad SMQs: “Embolic 
and thrombotic events, arterial”, “Embolic and thrombotic events, venous”, “Embolic and 
thrombotic events, vessel type unspecified and mixed arterial and venous”.

Gastrointestinal perforation
Gastrointestinal perforation will be identified using the PT “gastrointestinal perforation”.

Malignancies
o
All malignancies
o
Non-melanoma skin cancer (NMSC)
o
Malignancy excluding NMSC
o
Lymphoma
Malignancies will be identified using SOC “Neoplasms benign, malignant and unspecified 
(incl. cysts and polyps).

Infections
o
All infections
o
Serious infection
o
Opportunistic infection, excluding tuberculosis and herpes zoster
o
Herpes zoster
o
Active tuberculosis
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Infections will be identified using the SOC “Infections and Infestations”.

AEs of abnormal liver function tests
AEs of abnormal liver function tests will be identified using the high level group term 
“Hepatobiliary investigations”.

AEs of renal dysfunction
AEs of renal dysfunction will be identified using the SOC “renal and urinary disorders”.
Summaries of the TEAESIs will be presented by treatment group, SOC, and PT:

TEAESIs [overall and by specific categories defined above]

Drug-related TEAESIs

TEAESIs leading to discontinuation of study drug

TEAESIs leading to study discontinuation
By-subject listings of corresponding TEAESI summaries will also be provided including 
additional information such as action taken with study drug, other action taken, outcome, and 
pattern, etc.
4.13.4
Electrocardiogram
12-lead ECG interpretation will be summarized by treatment group.
A by-subject listing of 12-lead ECG will also be provided. 
4.13.5
Vital Signs
Descriptive summaries of actual values and changes from baseline at each visit will be summarized 
for temperature, systolic blood pressure, diastolic blood pressure, heart rate, and respiratory rate 
by treatment and overall. Clinically significant vital signs measurements meeting the criteria 
specified in Appendix 4 will also be summarized by treatment group.
A by-subject listing of vital sign parameters will also be provided. 
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4.13.6
Clinical Laboratory Evaluation
The following laboratory tests will be summarized by treatment and overall using standard 
international units:
Table 4-2:
Clinical Laboratory Parameters
Laboratory Evaluation
Tests Included
Hematology
aPTT, HCT, Hgb, INR, MCH, MCHC, MCV, MPV, PLT, PT, RBC, WBC, and 
differentials (neutrophils, lymphocytes, monocytes, eosinophils, and basophils 
relative and absolute)
Biochemistry
Albumin, alkaline phosphatase, ALT, AST, calcium, CPK, creatinine (enzymatic), 
GGT, glucose random, potassium, sodium, total bilirubin, direct bilirubin if total 
bilirubin > ULN, urea (BUN), uric acid
Fasting lipids
Cholesterol (total, LDL, and HDL), triglycerides (all fasting)
Urinalysis
Color, clarity, pH, specific gravity, bilirubin, glucose, ketones, leukocytes, nitrite, 
blood, protein, urobilinogen
Microscopic analysis (as required)
Urine pregnancy test 
(conducted at the 
investigator site)
For WOCBP (at each visit, except screening)
Specialty evaluations
hsCRP, ESR, Rheumatoid factor, anti-CCP
Laboratory tests required at 
screening only
FSH levels for female subjects who have had a cessation of menses for at least 
12 months prior to the screening visit without an alternative medical cause
β-hCG for WOCBP
Tuberculosis test (QuantiFERON-TB Gold)

Note: A T-Spot.TB test (TBT) may be used as an alternative to the 
QuantiFERON-TB Gold test as per Exclusion Criterion 37. If the TBT is 
used, the QuantiFERON-TB Gold test should not be performed.
Serology (HBV [HBsAg, anti-HBc], HCVa, HIV) 
ALT = alanine aminotransferase; anti-HBc = antibody to hepatitis B core antigen = aPTT = activated partial 
thromboplastin time; AST = aspartate aminotransferase; β-hCG = β-human chorionic gonadotropin; 
BUN = blood urea nitrogen; CPK = creatine phosphokinase; FSH = follicle-stimulating hormone; 
GGT = gamma-glutamyltransferase; HBsAg = hepatitis B surface antigens; HBV = hepatitis B virus; 
HCT = hematocrit; HCV = hepatitis C virus; HDL = high-density lipoprotein; Hgb = hemoglobin; HIV = human 
immunodeficiency virus; INR = international normalized ratio; LDH = lactate dehydrogenase; MCH = mean 
corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular 
volume; MPV = mean platelet volume; PCR = polymerase chain reaction, PLT = platelets; PT = prothrombin 
time; RBC = red blood cell (count); ULN = upper limit of normal; WBC = white blood cell (count); 
WOCBP = women of childbearing potential
aSamples testing positive for HCV antibodies will require PCR qualitative testing for HCV RNA. Any HCV 
RNA PCR result that meets or exceeds detection sensitivity is exclusionary.
Hematology, chemistry, and urine protein will be summarized using the SS. Continuous test results
and changes from baseline will be summarized at each visit by treatment and overall using 
descriptive statistics. Categorical test results will be summarized at each visit by treatment and 
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overall using frequencies and percentages. If a subject has both low and high out-of-normal 
post-baseline values, each low and high will be counted separately. 
All laboratory summaries will be based on observed values. For the purpose of summarizing the 
data, laboratory values below the lower limit of quantification (LLOQ) will be set to the midpoint 
between 0 and the LLOQ. If laboratory values are expressed as above a fixed value (ie, “>xx.xx”), 
then the numeric portion of the value will be used (ie, xx.xx).
The following summaries will be produced by treatment and overall on the SS:

A summary of the absolute values and changes from Baseline values in each laboratory 
variable (Hematology, Chemistry, Urine) by visit

Shift from baseline to each post-baseline visit for each laboratory parameter (Hematology, 
Chemistry, Urine Protein)

Shift from baseline to highest/lowest post-baseline range for select laboratory parameters 
(Hematology, Chemistry, Urinalysis). Highest post-baseline will be considered for the 
following laboratory variables: hematology (aPTT, INR, hematocrit, hemoglobin, 
platelets, white blood cell count, neutrophil count, lymphocyte count), chemistry (ALP, 
AST, ALT, bilirubin, CPK, creatinine, sodium, potassium, total cholesterol, LDL, 
triglycerides), and urinalysis (urine protein, leukocytes, erythrocytes). Lowest 
post-baseline will be considered for the following laboratory parameters: hematology 
(hematocrit, hemoglobin, platelets, white blood cell count, neutrophil count, lymphocyte 
count) and chemistry (albumin, sodium, potassium)

A summary of the number and percentage of subjects experiencing treatment-emergent 
markedly abnormal values by laboratory variable (Hematology, Chemistry and Urine 
protein). Markedly abnormal values are defined as those with a severity of Grade 3 and 
above based on the CTCAE criteria. Definitions of markedly abnormal values are given in 
Appendix 3.

A summary of the number and percentage of subjects by CTCAE grade (version 5.0) based 
on minimum/maximum post-Baseline value by laboratory variable (Hematology, 
Chemistry, Urine protein)

A summary of the number and percentage of subjects with CTCAE grade 2 or higher and 
at least 1 grade increase from baseline for selected lab parameters .
The selected lab abnormalities (neutropenia, lymphopenia, anemia, thrombocytopenia, white 
blood cell decreased, activated partial thromboplastin time prolonged, CPK elevation, ALT 
elevation, AST elevation, hypoalbuminemia, cholesterol elevation, triglyceride elevation, 
hypoglycemia, creatinine elevation, presence of urine protein, INR elevation, bilirubin elevation) 
and their associated CTCAE grade are described in Appendix 2.  
By-subject listings of laboratory parameters (Hematology, Chemistry, Urinalysis) will be provided
by study time point including changes from baseline. The abnormal values will be flagged with 
‘L’ for values below the lower limit of the clinical reference range and ‘H’ for values above the 
upper limit of the clinical reference range and included in the listings. 
A line plot for mean change from baseline of hematology labs, fasting lipids, hsCRP, and ESR 
will be presented by treatment group for the SS. A line plot for mean values over time will also be 
presented by treatment group for the following parameters: for lymphocytes, neutrophils, platelets, 
hemoglobin, total cholesterol, triglycerides, ALT, AST, and CPK.
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The results of pregnancy, serology, and TB will be listed for each subject.
4.13.7
Physical Examination
A complete physical examination will be conducted at Screening and Week 16 (End of Study)
visit, and includes:

General appearance

Dermatological (except plaque PSO)

Head, eyes, ears, nose, and throat (HEENT)

Respiratory

Cardiovascular

Abdominal

Neurological

Musculoskeletal

Lymphatic
A targeted physical examination will be performed at Weeks 1, 2, 4, 8, 12:

General appearance

Dermatological (except plaque PSO)

Respiratory

Cardiovascular

Abdominal
Abnormal findings of physical examinations will be summarized at each visit using frequencies 
and percentages by treatment and overall. A by-subject listing of all physical examination 
abnormalities including investigator determined clinical significance will also be provided.
4.13.8
Data and Safety Monitoring Board
No Data Safety Monitoring Board is planned.
4.13.9
Other Analysis Consideration 
Depending on the prevalence of coronavirus disease (COVID) infections and illness in regions 
where the study is conducted, additional analysis may be performed to evaluate the impact of 
COVID on the safety of all participating subjects, including but not limited to the following:

COVID related discontinuation

COVID related AEs, including preferred term that contains “COVID-19”, “SARS-CoV-2”, 
“SARS-CoV-2” and “Coronavirus”.

All SAEs in COVID infected subjects.

All protocol deviations related to COVID.

Data listing of all subjects affected by COVID-19 related study disruption, including 
subject ID, site ID, and description of how individual’s participation was altered.

Data listing of all subjects taking COVID-19 vaccine during the course of study, if data 
permits.
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12. SAS® Version 9.2 of the SAS System for Personal Computers. Copyright ©2002-2003. 
SAS Institute Inc. SAS and all other SAS Institute Inc. product or service names are 
registered trademarks or trademarks of SAS Institute Inc., Cary, NC, USA.
13. Chen J, Hunter S, Kisfalvi K, Lirio RA. A hybrid approach of handling missing data under 
different missing data mechanisms: VISIBLE 1 and VARSITY trials for ulcerative colitis.
Contemporary 
Clinical 
Trials. 
2021, 
100:106226. 
https://doi.org/10.1016/j.cct.2020.106226.
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6.5
Appendix 5: Statistical Methodology
Sample SAS Code for Mantel-Haenszel stratum weights and the Sato variance estimator:
proc freq data = data;
tables strata*trt01p*resp / commonriskdiff (test=mh cl=mh column=2);
run;
where strata variable has 4 levels (from the two stratification factors: prior treatment with biologics 
or non-traditional DMARDs [yes/no], and REGION [USA/Germany, Eastern Europe]), trt01p is 
planned treatment group, and resp is a responder outcome variable.
Sample SAS Code for MMRM:
proc mixed data = data;
class trt01p avisit usubjid dmards region;
model CHG = trt01p dmards region base avisit trt01p*avisit/ddfm=kr;
repeated avisit / subject= usubjid type=UN;
lsmeans trt01p*avisit / diff=all cl alpha=0.05;
run;
Sample SAS Code for Multiple Imputation of binary endpoint under MAR:
1) Generation of imputed data using proc mi
proc mi data = data out = outmi seed=25381 nimpute=100; 
      by trt01p; *trt01p includes all 4 treatment groups including placebo;
class dmards region;
var dmards region resp_wk1 resp_wk2 resp_wk4 resp_wk8 resp_wk12;
fcs nbiter=100
fcs reg(resp_wk1= dmards region); *trt01p includes all 4 treatment groups including 
placebo; 
fcs reg(resp_wk2= dmards region resp_wk1);
fcs reg(resp_wk4= dmards region resp_wk1 resp_wk2);
fcs reg(resp_wk8= dmards region resp_wk1 resp_wk2 resp_wk4);
fcs reg(resp_wk12=dmards region resp_wk1 resp_wk2 resp_wk4 resp_wk8 / details);
run;
2) Conduct analysis for each treatment group vs placebo using proc freq using each imputed 
dataset
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proc freq data = outmi;
by _imputation_;
tables strata*trt01p*resp / commonriskdiff (test=mh column=2);
ods output CommonPdiff= commonpdiff;
run;
3) Pooling the results from the imputed datasets using proc mianalyze:
proc mianalyze data= commonpdiff;
modeleffects riskdifference;
stderr;
run;
6.6
Appendix 6: Corticosteroid Dose Equivalents
Equivalent Dose
Steroid
1.2 mg
Betamethasone (long-acting)
1.5 mg
Dexamethasone (long-acting)
8 mg
Methylprednisolone (intermediate-acting)
8 mg
Triamcinolone (intermediate-acting)
10 mg
Prednisone (intermediate-acting)
10 mg
Prednisolone (intermediate-acting) 
40 mg
Hydrocortisone (short-acting)
50 mg
Cortisone (short-acting)
https://emedicine.medscape.com/article/2172042-overview
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6.7
Appendix 7: Algorithm for prohibited medications used for intercurrent events
Prohibited medications will be considered in 2 separate ICEs in the primary analysis. The method 
for identifying these medications will consider the following criteria and may consider clinical 
review.
Immunosuppressants (ATC3): any new concomitant mediation OR any increase in dose from 
prior medications (programmatic + clinical review)
This category will be coded on a case by case basis given the lack on specific ATC. 

Biologics: any new initiation of these would be treatment failure from the time of initiation.

Non-traditional DMARDs: any new initiation of these would be treatment failure from the 
time of initiation.

Traditional MTX and SSZ: dose increase from (baseline) prior medication dose level 
would classify for treatment failure.

Other traditional DMARDs (including hydroxychloroquine): dose increase from (baseline) 
prior medication dose level would classify for treatment failure.
Corticosteroids for systemic use, plain (ATC3): 
Treatment failure is considered:

If ROA oral: increase from stable baseline dose if prior medication (10 mg or less of 
prednisone equivalent) or add-on of new CS start within 14 days of Week 12 efficacy 
assessment (clinical review)

If ROA IV/IM: treatment failure from the time of initiation

If intraarticular corticosteroids: considered
in the derivation rule for TJC/SJC 
(Section 4.12.3.2.3)
Opioids (ATC3): Treatment failure is considered if new continuous treatment started within 7 
days of Week 12 Assessment (programmatic and clinical review)
Other analgesics and antipyretics (ATC3): Treatment failure is considered if any increase in 
dose compared to baseline OR add-on of daily continuous use for 7 days if not present at baseline 
within 7 days of Week 12 assessment OR one new dose given within 24 hours of Week 12 
assessment (programmatic and clinical review)
Anti-inflammatory and antirheumatic products, non-steroids (ATC3): Treatment failure is 
considered if any increase in dose compared to baseline (if prior) or add-on of daily continuous 
administration for 7 consecutive days within 7 days of Week 12 assessment (programmatic and 
clinical review)
Topical products for joint and muscular pain (ATC3): Treatment failure is considered if daily 
continuous administration for 7 days if not present at baseline within 7 days of Week 12 assessment 
(programmatic and clinical review)
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