Clinical trial NCT03724916
Conditions: Systemic Lupus Erythematosus Lupus Erythematosus, Systemic
Keywords: Drug therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2018-11-26; Completion date: 2021-11-04
Enrollment: 23 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to evaluate the safety and tolerability of TAK-079 in comparison with matching placebo, administered once every 3 weeks over a 12-week dosing period in participants with active SLE who are receiving stable background therapy for SLE.

Detailed description:
TAK-079 is being tested in a study population with moderate to severe SLE. This study will evaluate the safety and biologic activity of TAK-079 or matching placebo in combination with stable SLE background therapy.

The study will enroll approximately 24 participants across 3 sequentially enrolling cohorts. Each cohort will enroll 8 participants, where 6 participants will be assigned to TAK-079 injection, and 2 participants will be assigned to Placebo. Participants will receive TAK-079 or matching placebo in combination with principal investigator directed background therapy for SLE.

This multi-center trial will be conducted in the United States. Participants will make multiple visits to the clinic, and will be followed up for the safety assessment for the additional 12 weeks up to Week 24 after receiving their last dose of study drug. Based on the clinical assessments, participants may complete or may advance to long-term safety follow up period for an additional 12-week safety monitoring period up to Week 36.

Arms: arm 1: TAK-079 placebo-matching injection, subcutaneously, once every 3 weeks in combination with principal investigator-directed background therapy for SLE for up to 12 weeks. Placebo data will be pooled across all the dose levels. arm 2: TAK-079 45 mg injection subcutaneously, once every 3 weeks in combination with principal investigator-directed background therapy for SLE for up to 12 weeks. arm 3: TAK-079 90 mg injection subcutaneously, once every 3 weeks in combination with principal investigator-directed background therapy for SLE for up to 12 weeks. arm 4: TAK-079 135 mg injection subcutaneously, once every 3 weeks in combination with principal investigator-directed background therapy for SLE for up to 12 weeks.
Interventions: intervention 1: TAK-079 intervention 2: TAK-079 Placebo
Intervention descriptions: intervention 1: TAK-079 subcutaneous injection. intervention 2: TAK-079 placebo-matching subcutaneous injection.

Protocol documents:
Prot_000.pdf: 


TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 1b Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of TAK-079 
in Combination With Standard Background Therapy in Patients With Moderate to Severe 
Systemic Lupus Erythematosus
Study Identifier:
TAK-079-2001
Compound:
TAK-079
Date:
19 February 2019
Version/Amendment 
Number:
01
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TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................7
Protocol Amendment 01 Summary of Changes ........................................................10
1.1
2.0
STUDY SCHEMATIC..................................................................................................12
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................14
4.0
INTRODUCTION.........................................................................................................20
4.1
Background .............................................................................................................20
Rationale for Proposed Study...................................................................................21
4.2
Rationale for Study Design, Dose, and Endpoints ....................................................22
4.3
4.3.1
Rationale of Study Design...........................................................................22
4.3.2
Rationale for Selected Patient Population ....................................................22
4.3.3
Rationale for Dose ......................................................................................23
4.3.4
Rationale for Endpoints...............................................................................24
Benefit-Risk Profile .................................................................................................24
4.4
Benefits and Risks Conclusions ...............................................................................26
4.5
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................27
Objectives................................................................................................................27
5.1
5.1.1
Primary Objective .......................................................................................27
5.1.2
Secondary Objective ...................................................................................27
5.1.3
Exploratory Objectives................................................................................27
Endpoints.................................................................................................................27
5.2
5.2.1
Primary Endpoint ........................................................................................27
5.2.2
Secondary Endpoints...................................................................................27
5.2.3
Exploratory Endpoints.................................................................................27
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................29
Study Design ...........................................................................................................29
6.1
Study Drug ..............................................................................................................29
6.2
6.2.1
Premedication .............................................................................................30
6.2.2
Post-dose Medications.................................................................................30
6.2.3
TAK-079 and Matching Placebo Administration.........................................31
6.2.4
Rescue Therapy...........................................................................................31
Study Stopping Rules...............................................................................................32
6.3
6.3.1
Assessment and Criteria for Terminating Patient Dosing .............................32
6.3.2
Assessment and Criteria for Terminating Cohort Advancement...................35
Precautions and Restrictions ....................................................................................35
6.4
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6.4.1
Pregnancy and Lactation .............................................................................35
6.4.2
Drug Interactions ........................................................................................35
6.4.3
Interference with Serological Testing ..........................................................35
Management of Events of Clinical Interest...............................................................36
6.5
6.5.1
Hypersensitivity Reactions: Infusion and Injection Site Reactions ...............36
6.5.2
Cytokine Release Syndrome........................................................................38
6.5.3
Hematologic Effects....................................................................................39
6.5.4
Infections ....................................................................................................40
6.5.5
Antidrug Antibody Interactions ...................................................................40
6.5.6
Overdose.....................................................................................................40
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ..............41
Inclusion Criteria .....................................................................................................41
7.1
Exclusion Criteria ....................................................................................................42
7.2
Excluded and Dose-Limited Medications.................................................................45
7.3
Criteria for Discontinuation or Withdrawal of a Patient............................................46
7.4
Procedures for Discontinuation or Withdrawal of a Patient ......................................46
7.5
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................47
Clinical Study Drug .................................................................................................47
8.1
8.1.1
Clinical Study Drug Labeling......................................................................47
8.1.2
Clinical Study Drug Inventory, and Storage ................................................47
8.1.3
Clinical Study Drug Blinding ......................................................................48
8.1.4
Randomization Code Creation and Storage .................................................48
8.1.5
Clinical Trial Blind Maintenance/Unblinding Procedure .............................49
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs ........................49
9.0
STUDY PROCEDURES ...............................................................................................51
Administrative Procedures.......................................................................................51
9.1
9.1.1
Informed Consent Procedure.......................................................................51
9.1.2
Assignment of Randomization Numbers .....................................................51
9.1.3
Study Drug Assignment ..............................................................................51
Clinical Procedures and Assessments.......................................................................51
9.2
9.2.1
Inclusion and Exclusion ..............................................................................51
9.2.2
Medical History and Demography...............................................................51
9.2.3
Concomitant Medications and Procedures...................................................52
9.2.4
Physical Examination..................................................................................52
9.2.5
Vital Signs ..................................................................................................52
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9.2.6
12-Lead Electrocardiogram.........................................................................53
9.2.7
AE Monitoring............................................................................................53
9.2.8
Laboratory Procedures and Assessments .....................................................53
9.2.9
Pregnancy Test............................................................................................55
Pharmacokinetic, and Pharmacodynamic Samples .................................56
9.3
9.3.1
Pharmacokinetic Measurements ..................................................................56
9.3.2
Immunogenicity Samples and assessments ..................................................56
9.3.3
56
9.3.4
57
End-of-Study Assessments.......................................................................................57
9.4
10.0
ADVERSE EVENTS ....................................................................................................59
Pretreatment Events.................................................................................................59
10.1
Definitions and Elements of AEs .............................................................................59
10.2
10.2.1
SAEs...........................................................................................................61
10.2.2
AEs of Clinical Interest ...............................................................................62
10.2.3
Assigning Severity/Intensity of Adverse Events ..........................................62
10.2.4
Assigning Causality of Adverse Events .......................................................63
10.2.5
Collection and Reporting of AEs, SAEs, and AEs of Clinical Interest .........63
10.2.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities ..................................................................................................65
Drug Safety Monitoring Board.................................................................................65
10.3
11.0
STATISTICAL METHODS ..........................................................................................66
Statistical and Analytical Plans ................................................................................66
11.1
11.1.1
Analysis Sets...............................................................................................66
11.1.2
Analysis of Demography and Other Baseline Characteristics.......................66
11.1.3
Immunogenicity Analysis............................................................................67
11.1.4
Pharmacokinetic Analysis ...........................................................................67
11.1.5
Pharmacodynamic Analysis ........................................................................67
11.1.6
Safety Analysis ...........................................................................................67
Interim Analysis and Criteria for Early Termination ................................................68
11.2
Determination of Sample Size..................................................................................68
11.3
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................69
Study Site Monitoring Visits....................................................................................69
12.1
Protocol Deviations..................................................................................................69
12.2
Quality Assurance Audits and Regulatory Agency Inspections ................................69
12.3
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................70
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IRB and/or IEC Approval ........................................................................................70
13.1
Subject Information, Informed Consent, and Subject Authorization .........................71
13.2
Subject Confidentiality ............................................................................................72
13.3
Publication, Disclosure, and Clinical Trial Registration Policy.................................72
13.4
13.4.1
Publication and Disclosure ..........................................................................72
13.4.2
Clinical Trial Registration ...........................................................................73
13.4.3
Clinical Trial Results Disclosure .................................................................73
Insurance and Compensation for Injury....................................................................73
13.5
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................74
Administrative Information......................................................................................74
14.1
14.1.1
Study Contact Information ..........................................................................74
14.1.2
Investigator Agreement ...............................................................................75
14.1.3
Study-Related Responsibilities....................................................................76
15.0
LIST OF ABBREVIATIONS........................................................................................77
16.0
DATA HANDLING AND RECORDKEEPING............................................................79
CRFs (Electronic and Paper)....................................................................................79
16.1
Record Retention .....................................................................................................79
16.2
17.0
REFERENCES..............................................................................................................81
18.0
APPENDICES...............................................................................................................83
LIST OF IN-TEXT TABLES
Table 3.a
Schedule of Study Events: Dosing Period...........................................................14
Table 3.b
Schedule of Study Events: Safety Follow-up and Long-term Safety Follow-up 
Periods...............................................................................................................17
Table 3.c
Pharmacokinetic, CD38, TBNK Samples, and ECG Times by Visit ...................18
Table 6.a
TAK-079 Dosing by Study Cohort .....................................................................30
Table 6.b
Summary of Dosing Criteria ..............................................................................33
Table 7.a
Excluded Medications........................................................................................45
Table 7.b
Dose-Limited Concomitant Medications ............................................................45
Table 9.a
Clinical Chemistry and Hematology Assessments ..............................................54
Table 9.b
Clinical Urinalysis Assessments.........................................................................55
Table 9.c
End-of-Study Clinical Parameters ......................................................................58
Table 10.a
General List of Takeda Medically Significant AEs.............................................62
Table 10.b
AE Definitions for Severity/Intensity by Category .............................................62
Table 10.c
AE Definitions for Causality ..............................................................................63
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LIST OF IN-TEXT FIGURES
Figure 2.a
TAK-079-2001 Study Cohort Reviews...............................................................12
Figure 2.b
TAK-079-2001 Study Schematic........................................................................13
LIST OF APPENDICES
Appendix A
Pregnancy and Contraception.............................................................................83
Appendix B
Clinical Signs and Symptoms of Cytokine Release Syndrome............................87
Appendix C
Grading System for Cytokine Release Syndrome ...............................................88
Appendix D
Responsibilities of the Investigator.....................................................................89
Appendix E
Investigator Consent to the Use of Personal Information ....................................91
Appendix F
Elements of the Subject’s Informed Consent ......................................................92
Appendix G
Dose Modeling of TAK-079 ..............................................................................95
Appendix H
Detailed Description of Amendment to Text ......................................................99
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1.0
STUDY SUMMARY 
Name of Sponsor:
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of 
Takeda Pharmaceutical Company Limited
Compound:
TAK-079
Study Identifier: TAK-079-2001
Phase: 1b
Protocol Title: A Phase 1b Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of TAK-079 in 
Combination With Standard Background Therapy in Patients With Moderate to Severe Systemic Lupus 
Erythematosus
Background:
Systemic lupus erythematosus (SLE) is a heterogenous autoimmune disease characterized by dysregulation of T and B 
lineage cells, as well as other components of the innate immune system. A hallmark of the disease is the production of 
pathogenic autoantibodies to double-stranded DNA (dsDNA), phospholipids, blood cells, and other targets. Tissue 
damage in SLE is caused primarily by these pathogenic autoantibodies through immune complex deposition with Fc-
and complement-mediated inflammation, as well as through direct antibody-target interactions.
The therapeutic agents that are used for treatment of SLE have demonstrated limited success in targeting autoantibody 
production. Short-lived plasmablasts (PB), plasma cells (ie, terminally differentiated B cells), and long-lived plasma 
cells produce the characteristic pathogenic autoantibodies and are therefore critically involved in SLE pathogenesis. 
CD38 is a type II glycoprotein that is highly and uniformly expressed on antibody-producing PBs and plasma cells, 
making it a potential target for treatment of SLE. TAK-079 is a fully human IgG1 mAb that binds with high affinity to 
CD38. The available nonclinical and clinical data demonstrate an acceptable safety profile and encouraging 
pharmacodynamic (PD) effects in reducing target cells expressing CD38. Therefore, TAK-079 is proposed to be 
investigated for potential treatment of adult patients with moderate to severe SLE.
Trial Design:
This multicenter, phase 1b study is designed to further elucidate the proof of mechanism and potential biologic activity 
of TAK-079 in a study population with moderate to severe SLE. The study design allows for the evaluation of the 
safety and biologic activity of TAK-079 or matching placebo in combination with stable SLE background therapy.
Sequentially enrolling, dose-escalating cohorts will allow for the evaluation of TAK-079 dosing in a step-wise, 
double-blinded design, thereby providing for both an intracohort and cross-cohort analysis of active TAK-079 and 
matching placebo. The dosing regimen will consist of a single subcutaneous (SC) injection, of either TAK-079 or 
matching placebo, to be administered every 21 days (ie, 3 weeks) over the course of a 12-week dosing period, for a 
maximum 4 study doses, in combination with a stable principal investigator–directed background therapy for SLE. 
After the 12-week dosing period, patients will continue on study for a 12-week postdose safety follow-up period, 
allowing for continued observation and assessment of safety and sustainability of biologic activity. Patients whose 
protocol-defined safety parameters do not return to adequate protocol-defined rebound levels by the end of the safety 
follow-up period will progress to a long-term follow-up period for continued monitoring. These continued safety 
observation periods provide optimal oversight and assessment of any ongoing study-related sequela.
Takeda clinicians/designees will provide ongoing safety oversight and surveillance throughout the study dosing 
period. As such, TAK-079 clinicians/designee will receive and trend all reported adverse events (AEs) and serious 
adverse events (SAEs), and a blinded review of all safety data will be conducted periodically throughout the study. 
Based on the outcomes of the Takeda safety reviews and in accordance with predefined criteria, decisions about the 
dosing regimen for current cohorts will be implemented.
As such, before each study dose, principal investigators will provide the medical monitor with a summary of 
assessment outcomes associated with the dosing criteria for review and approval. In instances where clinical 
parameters do not meet dosing criteria, study dosing will be temporarily withheld until parameters meet 
protocol-defined dosing levels. 
An assessment of safety trends and potential risks associated within and across dosing cohorts will be conducted near 
the completion of each cohort. Based on these findings, and in alignment with protocol-defined dose determination 
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and cohort dose-escalation stoppage criteria, the study may: (1) advance enrollment to the next cohort at the next 
protocol-defined dose level, (2) advance enrollment in the next cohort at a reduced intermediate dose level, (3) expand 
enrollment at the current dose level, or (4) enact early termination of the study.
Study Primary Objective:
The primary objective of this study is to evaluate the safety and tolerability of TAK-079 in comparison with matching 
placebo, administered once every 3 weeks over a 12-week dosing period in patients with active SLE who are receiving 
stable background therapy for SLE.
Secondary Objectives:
The secondary objective of this study is to assess the pharmacokinetics (PK), PD, and immunogenicity of TAK-079 
administration over a 12-week dosing period.
Study Subject Population: The study population is limited to patients with SLE who exhibit moderate to severe 
disease with persistent disease activity, who have not responded adequately to standard SLE background therapy 
treatment, and have not recently had an acute flare that was moderate to severe in nature. 
Planned Number of Subjects: 24 subjects
Planned Number of Sites: 20 sites
Dose Levels by 3 Sequentially Enrolling Cohorts
Cohort A: (n = 6) TAK-079 dosed 45 mg
Cohort B: (n = 6) TAK-079 dosed 90 mg
Cohort C: (n = 6) TAK-079 dosed 135 mg
Each cohort will enroll an additional 2 patients 
randomized to matching placebo
Route of Administration:
Subcutaneous injection
Duration of Treatment:
Dosing period: 12 weeks
Planned Trial Duration:
Total study participation: 24 to 36 weeks (approximately 6 
to 9 months) 
Total study duration: 18 to 24 months
Main Criteria for Inclusion:
To be eligible for study participation, patients must: 
Be aged 18 to 75 years at the time of signing the study informed consent.
1.
Meet either the 2012 Systemic Lupus International Collaborating Clinics criteria or the American College of 
2.
Rheumatology criteria for SLE diagnosis.
Have a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score ≥6.
3.
Be positive for anti-dsDNA antibodies and/or antiextractable nuclear antigens antibodies.
4.
Main Criteria for Exclusion:
The following criteria will deem the patient ineligible for study participation:
An opportunistic infection ≤12 weeks before initial study dosing or is currently undergoing treatment for a 
1.
chronic opportunistic infection, such as tuberculosis, pneumocystis pneumonia, cytomegalovirus, herpes simplex 
virus, herpes zoster, or atypical mycobacteria.
An acute or chronic infection requiring hospitalization ≤30 days before the screening visit and/or administration 
2.
of parenteral (intravenous [IV] or intramuscular) antibacterial, antiviral, antifungal, or antiparasitic agents ≤30 
days before the screening visit. 
Drug-induced SLE and any other rheumatologic or autoimmune disease (excluding secondary Sjögren syndrome, 
3.
and mixed connective tissue disease).
Active neuropsychiatric SLE (eg, new or worsening impaired level of consciousness; psychosis; delirium or 
4.
confusional state; grand mal seizure [including status epilepticus]; aseptic meningitis, ascending or transverse 
myelitis; chorea, cerebellar, ataxia, or demyelinating syndromes) that has required therapeutic 
intervention ≤60 days before initial study dosing. 
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Protocol-defined active glomerulonephritis with concurrent acute renal flare or with documented acute renal flare 
5.
in the previous 3 months that has required lupus nephritis induction therapy.
A positive hepatitis B surface antigen or hepatitis C antibody, or HIV antibody/antigen.
6.
Concurrent medical condition that, in the opinion of the investigator, could confound interpretation of results or 
7.
affect the patient’s ability to fully participate in the study.
Laboratory test values outside of the limits for the tests specifically defined in the protocol. 
8.
Concomitant medications that do not meet the protocol criteria (with regard to excluded and dose-limited 
9.
medications).
Main Criteria for Evaluation and Analyses:
The primary endpoints of this study will evaluate the safety and tolerability of TAK-079 to include the incidence, type, 
and grade of AEs, as well as the percentage of patients with ≥1 AE leading to study treatment discontinuation.
The secondary endpoints will be assessed through evaluation of the following parameters: 
PK evaluations of TAK-079.
1.
PD evaluations of TAK-079.
2.
Assessment of immunogenicity of TAK-079.
3.
Statistical Considerations:
The safety analysis set will consist of all patients who are enrolled and received at least 1 dose of study drug. All 
pretreatment events (PTEs) and treatment-emergent adverse events (TEAEs) will be coded by system of organ class 
and preferred term using the Medical Dictionary for Regulatory Activities. TEAEs with an onset occurring during the 
dosing period and safety follow-up periods will be listed and included in the summary tables. Summary tables will 
include TEAEs and drug-related AEs, the relationship of AEs to study drug (related vs not-related), grade, and 
severity of AEs. AEs leading to study drug discontinuation and SAEs will be listed. 
Sample Size Justification: 
This study is not statistically powered for any hypothesis testing. The sample size for each study cohort are considered 
to be sufficient to fulfill the study objectives of the evaluation of safety, tolerability, and pharmacokinetics of each 
cohort.
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Protocol Amendment 01 Summary of Changes 
1.1
Rationale for Amendment 01
This document describes the changes to the protocol incorporating Amendment 01. The primary 
reason for the amendment is to adjust T-cell laboratory levels for dosing criteria to better take into 
consideration the clinical setting for patients with SLE on background therapy, the patient’s 
baseline value, and the quantification of important changes from baseline as safety endpoints. 
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only. 
For specific descriptions of the text changes and where the changes are located see Appendix H. 
Changes in Amendment 01
Clarification that the assessment of systemic lupus erythematosus antibodies (Ab) is expected 
1.
at baseline.
Clarification that no dosing criteria assessments are to be conducted as part of screening.
2.
Removal of redundant RNA sampling schedule in Table 3.a.
3.
Addition of a one-day window (+/- 1 day) for visits: HV7, HV8 and HV9, has been added for 
4.
consistency with other visits.
Removal of details for urine sample collection.
5.
Clarification of T-cell safety parameters as they pertain to dosing criteria. This clarification 
6.
takes into consideration the natural history of SLE on background therapy, the patient’s T-cell 
baseline values, as well as changes from baseline that would warrant the continuation or 
holding of a dose of TAK-079.
Changes to dosing criteria in the event of infusion related reaction, to better align actions with 
7.
the appropriate grading criteria. Grade 2 or higher reactions still require dose discontinuation.
Clarification of dosing criteria in the event of hypersensitivity-related events, to better align 
8.
with the CTCAE criteria for allergic reactions, as originally intended. Any symptom of an 
anaphylactic reaction continues to require TAK-079 discontinuation.
Clarification that Common Terminology Criteria for Adverse Events version 4.03 must be 
9.
used in the study.
Clarification of excluded and dose limited concomitant medications.
10.
The addition of a protocol subsection to provide clarification regarding potential interference 
11.
with serological testing.
Clarifications made regarding the management of hypersensitivity reactions to better align 
12.
with the CTCAE criteria for allergic reactions, as originally intended.
Removal of any reference to an unblinded pharmacist.
13.
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Clarification that ECGs are to be read locally, to include readings of triplicate 
14.
electrocardiograms for safety assessments. Otherwise, triplicate ECGs will be submitted for 
subsequent central reading at a future time.
Clarification of Coombs testing to be analyzed by local labs; with further clarification that all 
15.
other laboratory tests, unless otherwise noted, should be submitted for central analysis.
Adjustments to pregnancy test methodology during screening and just prior to the first dose of 
16.
TAK-079, though 2 negative pregnancy tests are still needed prior to dosing. Details about the 
duration of continued contraception after the last dose of study medication have been added.
Removal of British Isles Lupus Assessment Group assessments and all associated trainings 
17.
and site/study activities.
Clarification that the statistical analysis plan will be prepared before database lock.
18.
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2.0
STUDY SCHEMATIC
Figure 2.a
TAK-079-2001 Study Cohort Reviews
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Figure 2.b
TAK-079-2001 Study Schematic
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4.0
INTRODUCTION
4.1
Background
Systemic lupus erythematosus (SLE) is a serious condition that has defied efforts to develop 
effective therapies, leaving a significant unmet medical need for patients with moderate to severe 
disease. During the past several decades, more than 30 promising, strategically targeted biologics 
have entered early development for the treatment of lupus; however, only belimumab has 
successfully completed a phase 3 program to obtain regulatory approvals worldwide [1]. These 
failures, which may be partially attributed to heterogeneity in the pathophysiology of SLE, 
indicate the need for the development of more effective targeted therapeutics. 
SLE is a heterogenous autoimmune disease characterized by dysregulation of 
T and B lineage cells, as well as other components of the innate immune system. A hallmark of the 
disease is the production of pathogenic autoantibodies to double-stranded DNA (dsDNA), 
phospholipids, blood cells, and other targets. Tissue damage in SLE is caused primarily by these 
pathogenic autoantibodies through immune complex deposition with Fc- and 
complement-mediated inflammation, as well as through direct antibody-target interactions [2]. 
Virtually any organ or system in the body can be affected by SLE [3,4].
The clinical course of SLE is episodic, with flares of disease activity that lead to increased 
disability and organ damage over time. For moderate to severe cases, the current standard of care 
includes off-label therapies, including immunosuppressants (azathioprine, cyclophosphamide, and 
mycophenolate mofetil), high-dose steroids, and intravenous (IV) immunoglobulin for cytopenia.
The therapeutic agents that are used for treatment of SLE have demonstrated limited success in 
targeting autoantibody production. Short-lived plasmablasts (PB), plasma cells (ie, terminally 
differentiated B cells), and long-lived plasma cells produce the characteristic pathogenic 
autoantibodies and are therefore critically involved in SLE pathogenesis. 
Studies have shown an increased number of PBs in the blood of patients with active SLE [3]. 
Rituximab (anti-CD20) and belimumab (anti-BLys) target B cells, interrupting the release of 
newly generated PBs from memory B cells that are depleted by the drugs and thereby reducing 
autoantibody production to some degree [4]. However, PBs and long-lived plasma cells are not 
susceptible to these therapies [5-7]. Similarly, the available broadly acting immunosuppressant 
agents (eg, azathioprine, cyclophosphamide, and mycophenolate mofetil) and high-dose steroids 
do not specifically target plasma cells and PBs, and their utility is further limited because of 
tolerability issues. 
CD38 is a type II glycoprotein that is highly and uniformly expressed on antibody-producing PBs 
and plasma cells [8], making it a potential target for treatment of SLE. In an ex vivo study of CD38 
expression on various immune cells in peripheral blood mononuclear cells from patients with SLE, 
the highest CD38 expression was observed on plasma cells and PBs, followed by natural killer 
(NK) cells, plasmacytoid dendritic cells, a regulatory T cell subpopulation, and naïve T cells [9]. 
The significantly higher CD38 expression on PCs and PBs compared with other immune cells 
suggests the potential for selectively depleting these cells with an anti-CD38 antibody. Consistent 
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with this hypothesis, daratumumab, a commercially available CD38 antibody licensed for 
treatment of multiple myeloma, effectively depleted plasma cells and PBs in peripheral blood 
mononuclear cells from patients with SLE in a dose-dependent manner in vitro [9]. 
Other studies have confirmed that the levels of CD38-expressing PBs are increased in patients 
with SLE. A study that transcriptionally profiled blood samples from 158 pediatric SLE patients 
identified 13 distinct signatures (ie, phenotypes) of lupus, out of which the PB signature with 
elevated expression of CD38 and increased levels of anti-dsDNA, antibodies was most strongly 
positively correlated with disease activity [10]. These findings were supported by a study of 
immunophenotyping of 143 patients with SLE [11] and are consistent with previous studies in 
patients with SLE treated with rituximab that showed a positive correlation between disease 
progression and the level of CD38-expressing PBs that are not susceptible to the anti-CD20 
antibody [12]. 
Thus, the level of unmet need in SLE remains high, and therapies with novel mechanisms of action 
are needed to provide improved efficacy in reducing disease activity, to help decrease use of 
corticosteroids, and to improve quality of life for patients with SLE. Specifically, targeted 
therapies that deplete PBs and plasma cells could be of important therapeutic benefit for patients 
with SLE. 
Rationale for Proposed Study
4.2
TAK-079 is, a fully human IgG1 monoclonal antibody (mAb) that binds with high affinity to 
CD38. The available nonclinical and clinical data demonstrate an acceptable safety profile and 
encouraging pharmacodynamic (PD) effects in reducing target cells expressing CD38. Therefore, 
TAK-079 is being proposed as a potential treatment for moderate to severe SLE in adult patients.
Preclinical studies showed that TAK-079 depletes the CD38-expressing target cells by means of 
antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity 
(TAK-079-10012). In in vitro experiments, the addition to TAK-079 to blood or bone marrow 
samples taken from patients with lupus was shown to deplete 80% of plasma cell populations, 
including short-lived plasma cells (CD19+ plasma cells) and long-lived plasma cells (CD19-
plasma cells). Additionally, the number of cells producing autoantigen-specific antibodies was 
dramatically reduced, including VH4-34 9G4+ antibodies (70% reduction), anti-Ro antibody 
(70% reduction), and anti-dsDNA antibody (80% reduction) [13].
In vivo, the efficiency of depletion of each cell type correlated with the levels of CD38 expression 
and exposure of TAK-079 in healthy cynomolgus monkeys (TAK-079-10015, TAK-079-10018, 
TAK-079-10019). Furthermore, TAK-079 demonstrated anti-inflammatory and 
disease-modifying activity in a monkey model of collagen-induced arthritis (CIA) that mirrors 
clinical aspects of human rheumatoid arthritis (RA) (TAK-079-10032). TAK-079 treatment 
prevented or reduced joint inflammation and subsequent joint, bone, and cartilage damage with 
efficacy comparable to high-dose dexamethasone but with better tolerability (as measured by 
changes in body weight). This efficacy correlated with the reduction of B, NK, and T cells in 
peripheral blood. 
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To date, TAK-079 has been evaluated in a single escalating-dose study of healthy subjects (n = 74; 
TAK-079-101). In that study, TAK-079 administration resulted in dose-dependent, reversible 
reduction of blood cell subsets that express CD38, including NK cells, PBs, B cells, and T cells. 
TAK-079 was well tolerated, with no unexpected and unwanted clinical or hematologic effects 
identified.
In conclusion, the available nonclinical and clinical data demonstrate an acceptable safety profile, 
and encouraging PD effects in reducing target cells expressing CD38. These findings suggest that 
TAK-079 may have the potential to address the unmet needs of SLE.
The primary objective of the TAK-079 SLE development program is to investigate the utility of 
TAK-079 as a disease-modifying therapy in SLE. This phase 1b double-blind, placebo-controlled, 
multicenter study will evaluate the safety, tolerability, pharmacokinetics (PK), and PD of 
TAK-079 in patients with moderate to severe SLE by comparing active TAK-079 with matching 
placebo in combination with standard background therapy for SLE. 
Rationale for Study Design, Dose, and Endpoints
4.3
4.3.1
Rationale of Study Design 
This phase 1b study is designed to further understand the proof of mechanism and potential 
biologic activity of TAK-079 in a study population with specific, measurable clinical 
manifestations of SLE. The study design allows for patients to continue their SLE background 
therapy, managed under the care of their physician, while evaluating the benefit-risk of TAK-079 
as an investigational add-on therapy.
Sequentially enrolling the double-blind cohorts allows for the evaluation of TAK-079 dosing in a 
step-wise, double-blinded design, thereby providing for both an intracohort and cross-cohort 
analysis of active TAK-079 and matching placebo (see Figure 2.a).
Takeda clinicians conduct reviews of adverse events (AEs), serious adverse events (SAEs), and 
related clinical parameters to ensure consistency with an acceptable benefit-risk ratio throughout 
the study. At the patient level, safety and tolerability are closely monitored for each patient at the 
completion of each dose and before the next subsequent dose to ensure clinical dosing criteria are 
met before each subsequent administration of TAK-079 or matching placebo. Further, safety is 
assessed at the end of treatment in each cohort, which allows for decisions regarding enrollment in 
subsequent cohorts. A 12-week post-dose safety follow-up period allows for continued 
observation and assessment of safety and sustainability of biologic activity. Patients whose safety 
parameters do not return to adequate protocol-defined rebound levels by the end of the safety 
follow-up period may progress to a long-term follow-up period for continued monitoring (Table 
3.b, Table 6.b). These continued safety observation periods provide optimal oversight and 
assessment of any ongoing study-related sequela.
4.3.2
Rationale for Selected Patient Population
As outlined in inclusion criteria (Section 7.1), the study population is limited to patients with SLE 
who exhibit moderate to severe disease with persistent disease activity and who have not
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responded adequately to standard SLE background therapy treatment but have not recently had an 
acute flare that was moderate to severe in nature. All patients must be positive for anti-dsDNA 
antibodies and/or antiextractable nuclear antigens (anti-ENA) antibodies. 
Based on findings from the first-in-human (FIH) study (TAK-079-101), most subjects will have 
detectable expression of CD38. The level of CD38 expression (quantified in molecules of 
equivalent soluble fluorochrome [MESF]) on PB cells was evaluated from samples obtained at 
screening in the TAK-079-101 study in healthy subjects. A total of 129 evaluable subjects were 
analyzed for expression of CD38, of whom 100% had detectable levels of CD38. The level of 
CD38 expression in these healthy subjects ranged approximately 5-fold from 693,474 MESF units 
to 3,531,222 MESF units, with a mean of 1,747,840 MESF units. The lowest CD38 expression 
was approximately 7-fold higher than background, indicating that healthy subjects express high 
levels of CD38 on the surface of peripheral blood PBs (Supplemental Study Report, Baseline 
CD38 Expression in Healthy Subjects from the TAK-079-101 Study, is available on request).
4.3.3
Rationale for Dose 
The study dosing regimen consists of a single subcutaneous (SC) injection of either TAK-079 or 
matching placebo, administered every 21 days (ie, 3 weeks) over the course of a 12-week dosing 
period for a maximum of 4 study doses, in combination with a principal investigator–directed 
background therapy for SLE.
The selection of doses and the frequency of administration of TAK-079 are based on a 
comprehensive review and analysis of data derived from the following: (1) dosing of healthy 
subjects with TAK-079 (Study TAK-079-101); (2) nonclinical repeat TAK-079 dosing studies 
(TAK-079-10015, TAK-079-1018, and TAK-079-10019) in cynomolgus monkeys; and (3) data 
derived from repeat dosing of daratumumab (Darzalex), a related anti-CD38 cytolytic antibody 
that is licensed for treatment in multiple myeloma [11]. 
The starting dose of 45 mg for the initial dosing cohort (ie, Cohort A) is selected based on the 
favorable safety profile and PD target effect (ie, a sustained reduction of PBs) observed after a 0.6 
mg/kg dose was administered to healthy subjects (Study TAK-079-101). A single SC dose of 0.6 
mg/kg TAK-079 reduced the level of PBs in peripheral blood >90% and NK cells >80% without 
comparable reductions in monocytes and B and T cells. Levels of PBs and NK cells recovered to 
50% of baseline levels 21 days after administration, on average. At this dose, there were no SAEs, 
on-study deaths, or AEs that led to study discontinuation. No remarkable findings for laboratory 
tests, electrocardiogram (ECGs), vital signs, or physical examinations were reported that were 
related to TAK-079 administration. Two subsequent dosing cohorts are planned at doses of 90 mg 
(2-fold increase from the first dose cohort) and 135 mg (a 50% increase from the previous cohort). 
Because patients with lupus generally exhibit higher levels of PBs expressing CD38 than those 
seen in healthy study subjects, higher doses may be needed to achieve comparable PD effects; 
subjects should be carefully monitored to maintain a balance of benefit-risk (refer to the 
dose-modeling overview shown in Figure 4, provided in Appendix G).
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criteria). Preliminary data show antimyeloma activity with minimal toxicity at a dose of 45 mg 
after 4 weekly doses.
The expected potential benefits of TAK-079 in patients with SLE are based on the observed 
non-clinical and clinical PD effects, as described in detail in the investigator’s brochure. Quite 
relevant to this study, the therapeutic efficacy of TAK-079 was demonstrated in a monkey 
collagen-induced arthritis model, which mirrors clinical aspects of human RA. TAK-079 
treatment reduced joint inflammation and subsequent joint, bone, and cartilage damage. It had 
comparable efficacy to the steroid dexamethasone, as evidenced by reduction of arthritis scores 
and faster reduction of C-reactive protein levels. This efficacy correlated with the reduction of B, 
NK, and T cells in peripheral blood. Furthermore, TAK-079 was better tolerated than 
dexamethasone; no weight loss was observed in animals treated with TAK-079, in contrast to 
those treated with dexamethasone (TAK-079-10032).
In the FIH study (TAK-079-101), a single dose of TAK-079 IV or SC treatment resulted in the 
transient, dose-dependent, reversible reduction of blood cell subsets that express CD38, including 
NK cells, PBs, B cells, and T cells. Although the duration of PB depletion was relatively 
short-lived (up to 15 days in SC cohorts) after a single administration at low doses, this study 
demonstrated that PBs are particularly sensitive to TAK-079 as would be expected, based on the 
target of this mAb and the high expression of CD38 on PBs.
In conclusion, considering the efficacy signals following administration of TAK-079 in a monkey 
collagen-induced arthritis model, and the promising PD effects following TAK-079 administration 
observed in both in vitro and in vivo studies, as well as in the FIH study in healthy subjects, further 
investigation of TAK-079 as a potential treatment for SLE is warranted. Patients with SLE have a 
PB (CD38-expressing) phenotype, therefore an agent such as TAK-079 that specifically targets 
CD38-expressing cells may have potential benefit for patients with SLE.
Possible AEs are based on the intrinsic pharmacology of TAK-079, reports from other biologic 
agents, the nonclinical data to date, and the limited data from Study TAK-079-101 in healthy 
human subjects. Risks of TAK-079 may include, but are not limited to, the following: ISRs, CRS, 
changes in hematologic parameters, and infections. Patients will be monitored closely for these 
and other potential side effects in accordance to the assessments and procedures outlined in this 
protocol (see Sections 6.4, 6.5, and 9.0). Further details on TAK-079 risks can be found in the 
TAK-079 Investigator’s Brochure.
In the FIH trial (Study TAK-079-101), single doses of TAK-079 ranging from 0.0003 to 0.06 
mg/kg given by IV infusion and 0.03 to 0.6 mg/kg given by SC injection were well tolerated. AEs 
were mild to moderate in intensity, with most AEs being mild. There were no SAEs or deaths 
reported in the study, and no AEs led to either study or visit discontinuation. No remarkable 
findings for laboratory tests, ECGs, vital signs, or physical examinations were reported that were 
related to TAK-079 treatment (TAK-079-101 CSR).
Mild, transient CRS was observed in subjects who were administered higher TAK-079 doses, 
mostly in the 2 cohorts receiving higher intravenous doses. Common symptoms included fever, 
headache, dizziness, and orthostatic hypotension. Incidences of CRS coincided with moderate 
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cytokine increases and occurred in the same cohorts that significant and rapid lymphocyte 
depletion occurred, suggesting that the symptoms associated with CRS could have been caused by 
lymphocyte depletion rather than activation. These data are consistent with findings from 
nonclinical studies that showed that TAK-079 is a cell-depleting antibody and did not elicit 
cytokine release from viable leukocytes. Relative to the intravenously dosed study groups, the 
subcutaneously dosed study groups had fewer subjects who experienced CRS, and there were 
minimal cytokine level increases despite subjects receiving TAK-079 at doses 10-fold higher than 
the intravenously dosed study groups. This could be the result of differences in the kinetics of the 
drug. However, SC administration effectively depleted PB for a longer duration than seen with IV 
administration, suggesting SC administration is a suitable route of administration for future 
clinical development. In addition, only mild, transient ISRs were observed after SC injections, 
most of which resolved within 7 days. The ISRs have an inverse dose-effect relationship, as 5 out 
of 6 subjects administered the lowest SC dose had ISRs, whereas only one subject had a mild ISR 
in each of the 2 highest dose cohorts.
Benefits and Risks Conclusions
4.5
Because of the limited clinical exposure of TAK-079, the overall clinical benefits and risks of 
TAK-079 have not been fully determined.
Risks of TAK-079 may include, but are not limited to, the following: ISRs, CRS, hypersensitivity 
reactions, changes in hematologic parameters, and infections. These AEs are based on the intrinsic 
pharmacology of TAK-079, reports from other biologic agents, the nonclinical data to date, and 
the limited data from Study TAK-079-101 in healthy human subjects. Patients will be monitored 
closely for these AEs in clinical studies with TAK-079.
Potential benefits of TAK-079 in patients with SLE are based on nonclinical and clinical PD 
effects. Patients with SLE have a PB (CD38-expressing) phenotype; therefore, an agent such as 
TAK 079 that specifically targets CD38-expressing cells may have potential benefit for patients 
with SLE.
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6.0
STUDY DESIGN AND DESCRIPTION
This phase 1b double-blind, placebo-controlled, multicenter study will evaluate the safety, PK, 
and PD of TAK-079 in a study population receiving standard principal investigator–directed 
background therapy for moderate to severe SLE. 
Study Design 
6.1
The study will compare active TAK-079 with matching placebo in combination with a background 
SLE standard treatment, across 3 sequentially enrolling cohorts in a double-blinded study design. 
A 3:1 randomization, within each cohort, will assign each patient to: (1) TAK-079 administered as 
a single SC injection every 3 weeks for 12 weeks (total of 4 doses); or, (2) matching placebo given 
in same route and schedule (see Figure 2.a). Each cohort will enroll 8 patients; 6 patients will be 
randomized to TAK-079 dosing and 2 patients to TAK-079 matching placebo. After each dosing 
day, patients will return for postdose assessments as outlined in Table 3.a and Table 3.b.
Following completion of the 12-week dosing period, patients will return for an additional 12-week 
safety follow-up period, completing safety visits every 4 weeks and ending this postdosing study 
period with a safety visit on Week 24. Based on clinical assessments at this visit, patients may 
complete the study or may advance to the long-term safety follow-up period, for an additional 
on-study 12-week safety monitoring period (based on end-of-study criteria outlined in Table 9.c), 
during which time the end of study parameters not met and deemed by the principal investigator as 
study related, will continue to be assessed and followed as outlined in Section 9.4. 
Study Drug
6.2
Study drug is to be administered only to eligible patients under the supervision of the principal 
investigator or identified subinvestigator(s). Patients will be dosed TAK-079 or matching placebo 
in accordance to their assigned study cohort every 3 weeks, as outlined in Table 6.a. All 
protocol-specific criteria for administration of study drug must be met and documented before 
drug administration (see Table 6.b. During the study, dosing of TAK-079 may be temporarily held 
or discontinued, based on the dosing criteria outlined in Table 6.b or in accordance to the principal 
investigator’s judgment. Dosing of TAK-079 may not otherwise be reduced or escalated for any 
given patient (study dosing by cohort, will be assessed and sequentially increased, as outlined in 
Figure 2.a). 
Concomitant medication, to include acceptable criteria for principal investigator-directed SLE 
background medications, are provided in Section 9.2.3. Rescue therapy information is outlined in 
Section 6.2.4.
In accordance with timings and criteria outlined in Section 6.3.1 key safety data will be reviewed 
and evaluated by Takeda clinicians/designees, who will review the safety of all treated patients and 
make decisions regarding dose escalation. In addition, changes to the dose-escalation scheme or 
dose schedule (dosing interval) may be considered. All decisions will be documented in writing. 
Any decision to modify the dose-escalation scheme and schedule (with the exception of testing 
intermediate dose levels, or expanding a dose level) will be communicated to institutional review 
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boards (IRBs). The investigators will also be informed in writing of the more conservative 
approach. The protocol will be considered for amendment accordingly. 
Table 6.a
TAK-079 Dosing by Study Cohort
Study Dosing Arms
Cohort
TAK-079 a
Matching Placebo a
Patients
(n)
Dose
(mg)
Patients
(n)
Dose
(mg)
Cohort A 
6
45
2
NA
Cohort B
6
90
2
NA
Cohort C 
6
135
2
NA
Abbreviations: NA, not applicable.
a Patients will receive TAK-079 or matching placebo through SC administration every 21 days (ie, 3 weeks) over the 
course of 12 weeks, for 4 total doses.
6.2.1
Premedication
On each dosing day, 1 to 3 hours before TAK-079 administration, patients are to be premedicated 
with a regimen consistent with, but not limited to, the following:
Antipyretic: oral acetaminophen (650 to 1000 mg).
1.
Antihistamine: oral or IV diphenhydramine (25 to 50 mg, or equivalent).
2.
The clinical site is responsible for sourcing premedications outlined in the protocol.
6.2.2
Post-dose Medications
Patients may receive low-dose methylprednisolone (<20 mg) for the prevention of delayed 
injection-related reaction, as clinically indicated, and under the discretion of the principal 
investigator.
NOTE: Patients with a higher risk of respiratory complications (eg, patients with a history of 
chronic obstructive pulmonary disease [COPD] and patients with asthma) may be administered the 
following, after each study dose (at the investigator’s discretion):
a) An antihistamine (diphenhydramine or equivalent) on the first and second days after study 
dosing.
b) A short-acting β2-adrenergic receptor agonist, such as salbutamol (albuterol) aerosol.
c) Control medications for lung disease, such as the following: 
–
Inhaled corticosteroids with or without long-acting β2 adrenergic receptor agonists for 
patients with asthma. 
–
Long-acting bronchodilators, such as tiotropium or salmeterol with or without inhaled 
corticosteroids, for patients with COPD.
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The clinical site is responsible for sourcing treatments administered pre- or post-TAK-079 
injection, as outlined in the protocol.
Based on emerging data, the Takeda physician/designee may enhance treatments administered 
pre- or post-TAK-079 injection to ensure patient safety.
6.2.3
TAK-079 and Matching Placebo Administration
The strength of the TAK-079 drug product for SC use in this study is 100 mg TAK-079 in 1 mL 
(100 mg/mL). 
After patients have received premedication treatment, the TAK-079 dose or matching placebo will 
be administered with a syringe as SC injections up to a maximum volume of 2 mL, such that the 
full schedule dose has been administered. The time and anatomical site of SC injection must be 
recorded for each dose, with the site of injection rotated for each dose (injection sites of the 
abdomen, thighs, arms, and upper buttock area are acceptable). Refer to the pharmacy manual for 
detailed instructions regarding preparation of TAK-079 and matching placebo dose. 
6.2.4
Rescue Therapy
Rescue therapy is defined as additional dosing of concomitant medications in accordance with 
institutional practices or the physician’s best medical judgment to control and manage underlying 
SLE conditions. Protocol-restricted and dose-limited concomitant medications are outlined in 
Table 7.a and Table 7.b (Note: Concomitant dosing of cyclophosphamide is restricted during study 
enrollment).
Patients should remain on their stable dose of immunosuppressive and corticosteroid therapies 
throughout the study (as aligned with protocol requirements in Table 7.a and Table 7.b). 

Decreases in the dose of immunosuppressants, due to toxicity, are allowed at the discretion of 
the investigator. 

Increasing, adding, or changing background immunosuppressive, or adding a medication not 
otherwise within protocol limits, as deemed necessary by the principal investigator to treat 
manifestations of SLE, must result in discontinuation of the patient from study dosing and 
advancement to safety follow-up; these patients will be categorized as study nonresponders.
NOTE: Patients who require an increase in corticosteroid dose above 0.5 mg/kg/d (or 40 mg/d of 
prednisone) or equivalent, for control of SLE activity, or management of a new SLE flare during 
the study, are to be discontinued from study drug. The prednisone dosage or equivalent may be 
increased to a dose that is less than or equal to 0.5 mg/kg/d or 40 mg/d, whichever is lower. 
However, dosing should be tapered to the preflare level or 20 mg/d, whichever is greater, within 4 
weeks or less. If tapering is not possible AND a higher dose is needed to treat SLE manifestations, 
the patient must be discontinued from study drug and advanced to safety follow-up, and be 
designated a study nonresponder. 
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Study Stopping Rules
6.3
Takeda clinicians/designee will provide ongoing safety oversight and surveillance throughout the 
study dosing period and safety follow-up periods. As such, TAK-079 clinicians are to receive and 
trend all reported SAEs and conduct a review of all safety data periodically throughout the study. 
Based on outcomes of the Takeda safety reviews and in accordance with predefined criteria, 
decisions about the dosing regimen are to be made and implemented.
6.3.1
Assessment and Criteria for Terminating Patient Dosing
Before each study dose, principal investigators provide the medical monitor (MM) with a 
summary of assessment outcomes associated with the dosing criteria, for review and approval. In 
instances where clinical parameters do not meet dosing criteria, study dosing must be temporarily 
withheld until parameters meet dosing levels or discontinued, as outlined in Table 6.b. As such, 
patients should return for re-evaluation of dosing criteria every 3 weeks until completion of Week 
12 of the dosing period, at which time the patient begins the safety follow-up period.
In addition, study drug must be permanently discontinued, and patients must advance to the safety 
follow-up period of the study, if any of the following is experienced: 

An AE or other medical condition in which the principal investigator deems it is not in the best 
interest of the patient to continue study dosing. 

The patient chooses to withdrawal from study dosing.

The patient has a confirmed pregnancy.
NOTE: If two or more patients discontinue study drug dosing based on the dose discontinuation 
criteria in Table 6.b, the Takeda clinician/designee will review available safety data, to determine 
if adjustments to the treatment plan should be made. In such instances, discontinued patients will 
need to be unblinded to assess relatedness to the study drug. The unblinding process is outlined in 
Section 8.1.5.
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Table 6.b
Summary of Dosing Criteria
Safety Parameter
Dosing Criteria
Continue Dosing
Dose Hold a
Dose Discontinuation b
Laboratory Investigations
Neutrophils
ANC ≥1500/mm3
Total neutrophils ≥Grade 2 c
ANC <1500/mm3
Platelets
Thrombocytopenia ≤Grade 2
Platelets ≥50,000/mm3
Thrombocytopenia ≥Grade 3 c
Platelets <50,000/mm3
T cells
T cells ≥500 cells/uL 
NOTE: Dosing may continue in 
instances of T cells < 500 cells/uL 
if CD3+ cell count is ≥70% of the 
baseline level
CD3+ cells count <500 cells/uL and
is < 70% of baseline CD3+ cell 
count level.
Hgb
≥8 g/dL
<8 g/dL
IgG, IgA, IgM levels
>50% LLN
≤50% LLN 
Events of Clinical Interest
TAK-079–related infusion reaction (to include systemic 
signs and symptoms related to CRS d)
NOTE: IRR is classified in accordance to the NCI 
CTCAE criteria, version 4.03. CRS is classified in 
accordance to the parameters outlined in Appendix B
and Appendix C.
≤Grade 1 with symptomatic 
treatment allowed in accordance 
with Appendix C.
NOTE: Dosing may resume after 
symptoms have resolved f. 
≥Grade 2 IRR 
or CRS f leading to moderate clinical 
symptoms based on a global assessment of 
symptoms
Hypersensitivity (allergic reaction or anaphylaxis) e
≤Grade 2
In accordance with NCI CTCAE, 
version 4.03 grading for allergic 
reactions which respond promptly 
to symptomatic measures
≥Grade 3 c
In accordance with NCI CTCAE (version 
4.03) grading for allergic reaction
or any signs or symptoms of an anaphylactic 
reaction [14]
Systemic infection
Grade 2 c 
Hold dosing until the infection is 
resolved
≥Grade 3c
or infections requiring hospitalization 
Abbreviations: ANC, absolute neutrophil count; CRS, cytokine release syndrome; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; Hgb, 
hemoglobin; IRR, infusion-related reaction; LLN, lower limit of normal. 
a Patients whose clinical parameters meet dose-hold criteria, will not receive their next scheduled cohort dose (ie, TAK-079 or matching placebo), and instead return for the next 
scheduled dose-criteria assessment for reassessment and evaluation of the subsequent dosing.
b Patients whose clinical parameters meet dose discontinuation criteria are to be permanently discontinued from study dosing (ie, TAK-079 or matching placebo); patients are to then 
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advance to the safety follow-up period of the study, completing all associated assessments, while continuing to receive standard background therapy for SLE, in accordance to 
principal investigator’s discretion and local institutional practices.
c Laboratory grading, allergic reactions, and infection grading is based on NCI CTCAE v4.03.
d Afull cytokine panel is to be obtained for any suspected events, at any grade, of CRS; refer to Section 6.5.2 for further information and suggested management of CRS. 
e See Section 6.5.1 for further information regarding study-related hypersensitivity reactions. 
f See Appendix B and Appendix C for further details on the grading and clinical signs and symptoms of CRS.
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6.3.2
Assessment and Criteria for Terminating Cohort Advancement
A cohort analysis, assessing for safety trends and potential risks associated within and across 
dosing cohorts will be conducted near the completion of each cohort. The Takeda 
clinicians/designee will take into consideration all SAEs and AEs of severe intensity medically 
considered related to study drug in dose escalation decisions. Analysis for each cohort will be 
initiated at the time the seventh patient within each study cohort completes all follow-up 
assessments and procedures associated with their second study dose. Decisions regarding cohort 
advancement will be made once the cohort completes full enrollment, incorporating full 
assessment of safety parameters of all patients in the cohort. 
Based on these findings, and in alignment with protocol-defined dose hold and dose 
discontinuation criteria, the study may: (1) advance enrollment to the next cohort at the next 
protocol-defined dose level, (2) advance enrollment in the next cohort at a reduced intermediate 
dose level, (3) expand enrollment at the current dose level, or (4) enact early termination of the 
study.
Precautions and Restrictions
6.4
Patients should be closely monitored both before and for at least 4 hours after each dose, with 
additional assessment and observations as necessary based on the principal investigator’s best 
medical judgment, and as warranted by exhibited clinical signs or symptoms at each study clinic 
visit. Postdose monitoring should include vital sign assessments as outlined in Section 9.2.5, and 
additional postdose medications for those with a history of asthma or COPD, as outlined in 
Section 6.2.2.
6.4.1
Pregnancy and Lactation
TAK-079 has not been administered to women who are pregnant or lactating. Dedicated fertility 
and embryo-fetal development toxicology studies have not been conducted with TAK-079. 
However, there were no TAK-079–related changes in organ weights or microscopic findings noted 
in the male and female reproductive tract of monkeys following administration for up to 13 weeks. 
Women of child-bearing potential may be enrolled in clinical trials with appropriate precautions to 
prevent pregnancy (additional details in Section 9.2.9).
TAK-079 should not be administered to women who are pregnant or breastfeeding.
6.4.2
Drug Interactions
Nonclinical drug interaction studies have not been conducted with TAK-079. However, as a fully 
human IgG1 mAb, the risk of drug-drug interactions is low.
6.4.3
Interference with Serological Testing
Anti-CD38 monoclonal antibodies have been reported to bind to CD38 on red blood cells 
(RBCs) and results in a positive indirect coombs test, which may persist for up to 6 months. The 
determination of a patient’s ABO and Rh blood type are not impacted, but the RBC binding may 
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mask detection of antibodies to minor antigens in the patient’s serum [14,15]. It is possible 
TAK-079 may affect the results of these blood tests, this is being evaluated. Until those tests are 
known, it is recommended that baseline type and serological screening be established before 
starting TAK-079. Patients should keep these results in case future transfusions are needed. Blood 
transfusion centers should also be informed of this interference with serological testing as 
necessary. 
Management of Events of Clinical Interest
6.5
6.5.1
Hypersensitivity Reactions: Infusion and Injection Site Reactions
Since infusion reactions and other antibody-mediated hypersensitivity reactions have been 
reported with other biologic agents, similar AEs may be seen with TAK-079. Infusion reactions 
are potentially dose-limiting AEs, not uncommonly associated with IV administration of biologic 
agents, but are less frequently associated with SC injection of these therapies [16-19].
Symptoms of hypersensitivity may range from mild skin rash to more severe reactions, wheezing, 
hypotension, poor perfusion, respiratory arrest, and rarely death. Nonanaphylactic clinical 
hypersensitivity typically occurs within the first hour; however, delayed responses have been 
reported in literature. Symptoms of anaphylaxis, a potentially life-threatening condition, range 
from swelling, angioedema, bronchospasm, respiratory distress, and shock [20]. Hypersensitivity 
reactions in the literature often occur within a few hours following drug intake. Based on outcomes 
from studies with daratumumab, patients with pre-existing COPD or asthma may be at particular 
risk for such respiratory complications as bronchospasm should an infusion reaction event occur. 
Therefore, patients whose forced expiratory volume in 1 second (FEV1) is <50% of predicted 
normal will be excluded from study participation (see Section 7.2) [21]. Eligible patients with a 
history of COPD may require additional postdose medications to manage respiratory 
complications (see Section 6.2.2) [18].
To date, subjects administered TAK-079 have not exhibited anaphylactic symptoms. In the 
clinical study of healthy subjects (TAK-079-101), an infusion-related reaction (IRR) was defined 
as a treatment-emergent adverse event (TEAE) occurring within 2 hours of the start of an infusion; 
there were no IRRs in this study as no allergic or cytokine release reactions were observed within 
this time period.
In this study:

Patients with a history of severe allergic or anaphylactic reactions to recombinant proteins or 
excipients used in the TAK-079 formulation are not eligible for this study and therefore will 
not be exposed to TAK-079. 

Premedication before each study dose, to prevent infusion reactions, is mandatory for all 
patients (as described in Section 6.2.1); postdose medication can be administered at the 
investigator’s discretion.
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
Patients who are treated with TAK-079 will be carefully monitored in the clinic for 4 hours 
after dosing, and any AE will be managed in accordance with available guidelines or 
institutional standards of care [22,23]. 
NOTE: Additional blood pressure (BP) measure should be assessed at any time the patient 
complains of symptoms consistent with an infusion reaction. If the patient experiences 
hypotension (with or without symptoms), intensive blood pressure monitoring according to local 
practice should be instituted. The patient should not be released from the site until blood pressure 
has returned to Grade 1 or baseline for at least 1 hour.
6.5.1.1
Management Recommendations for Hypersensitivity Reactions
Patients in clinical trials receiving TAK-079 are to be carefully monitored for signs and symptoms 
of ISRs, with appropriate medical management of these events. Depending on the severity of the 
reaction, management may include discontinuation of SC administration of TAK-079 and/or the 
administration of appropriate medical therapy.
Recommendations for the management of hypersensitivity reactions [22], are as follows:
Grade 1 
a) Study Management:

If the full dose of TAK-079 has not yet been administered, hold dosing until 
symptoms resolve, at which time the remainder of TAK-079 dose may be 
administered. 
b) Patient Support: 

Monitor closely until resolution of symptoms.
Grade 2
a) Study Management:

If the full dose of TAK-079 has not yet been administered, hold dosing until 
symptoms resolve, at which time the remainder of TAK-079 dose may be 
administered.
b) Patient Support: 

Administer appropriate symptomatic and prophylactic medical care; 
consider post-injection medications as outlined in Section 6.2.2.

For allergic reaction, provide symptomatic treatment (e.g. antihistimines, 
nonsteroidal anti-inflammatory drugs, narcotics, epinephrine) as medically 
appropriate and consider post-infection medications (as per Section 6.2.2).
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Grade 3 or Greater (symptomatic bronchospasm with or without urticaria, angioedema, 
hypotension). 
a) Study Management: 

Patients are to discontinue study dosing and advance to the safety follow-up 
period of the study.
b) Patient Support: 

Provide symptomatic treatment, including epinephrine, until symptoms 
resolve. 

Consider hospitalization as appropriate.
Local injection site abnormalities have not been observed in monkey and rat nonclinical studies 
after SC and/or IV administration of TAK-079. In the clinical study of healthy subjects 
(TAK-079-101), mild injection site AEs were reported; most were Grade 1 and included primarily 
erythema or tenderness. All injection reactions resolved within a few days.
6.5.2
Cytokine Release Syndrome
CRS represents an important infusion reaction often associated with the use of monoclonal 
antibodies used in anti-inflammatory and antitumor therapies. Onset of CRS may occur early in 
therapy, often after the first infusion of the drug due to a high level of activation of the immune 
system and engagement and proliferation of T cells that can result in increased cytokine release. 
Nonclinical studies have shown that TAK-079 has no agonist activity, suggesting that TAK-079 is 
unlikely to cause cytokine release due to cell activation. There were no TAK-079–related 
increases in cytokines at 0.1 mg/kg. At ≥0.3 mg/kg, dose-related increases (up to 29.5-fold for any 
individual monkey) in tumor necrosis factor alpha (TNF-α) were observed 30 minutes after the 
first dose of TAK-079. These increases were considered small compared with elevations observed 
during a cytokine storm event, were not accompanied by changes in other cytokines, and did not 
translate into clinical manifestation of an IRR. Increases in serum TNF-α may be related to 
TAK-079–mediated lyses of CD38+ lymphocytes.
In the FIH study, conducted in healthy subjects, rarely observed symptoms consistent with mild 
CRS were reported, particularly at higher doses; dose adjustment or interruption was not required.
The CRS hallmark is fever. CRS also presents with rash, urticaria, headache, chills, fatigue, 
nausea, and/or vomiting. [16,17]. Severe CRS is characterized by severe dyspnea, often 
accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and 
angioedema. The acute respiratory failure may be accompanied by such events as pulmonary 
interstitial infiltration or edema visible on a chest x-ray. The syndrome frequently manifests within 
1 or 2 hours of initiating the first infusion. Patients with a history of pulmonary insufficiency or 
those with pulmonary tumor infiltration may be at greater risk of poor outcome and should be 
treated with increased caution [16]. On the basis of outcomes from studies of the anti-CD38 mAb 
daratumumab, patients with pre-existing COPD or asthma may be at particular risk for respiratory 
complications, such as bronchospasm, should an infusion reaction or CRS event occur [21]. 
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Therefore, if the patient’s FEV1 is <50% of predicted normal, they will be excluded from study 
participation (see Section 7.2). Eligible patients with a history of COPD may require additional 
postinfusion medications to manage respiratory complications [18](see Section 6.2.2)
6.5.2.1
Management Recommendations for CRS
Premedication before each study dose, to prevent infusion reaction, is mandatory for all patients as 
described in Section 6.2.1. Poststudy dosing medication, to be administered at the investigator’s 
discretion, is described in Section 6.2.2. 
Immediate clinical assessment and management of symptoms is key to symptom management. In 
the anti-CD38 literature, IRRs are almost always reported with the first dose [18,24], therefore 
especially for the first dose, patients will be monitored in the clinic for at least 4 hours after dosing. 
Medical symptomatic treatment according to guidelines or institutional standard of care is 
recommended [17]. Before discharge from the clinic, all patients will receive information about 
possible signs and symptoms of anaphylactic reactions and CRS to monitor at home. Further, 
patients should receive information about what to do if emergency care is needed (see Appendix B
and Appendix C tables for further details on clinical signs and symptoms associated with CRS and 
the CRS grading system [17]).
If a patient is exhibiting signs or symptoms possibly assessed as a CRS by the investigator, a blood 
draw should be performed for central evaluation that could include, but not limited to, immune 
markers and cytokine markers. Additional guidance for study management and patient support for 
CRS, by grade is as follows: 
Grade 1 (defined as fever, constitutional symptoms) 
a) Study Management: Hold study dosing until symptoms resolve; resume dose of 
TAK-079 at same dose level after symptom resolution.
b) Patient Support: Provide vigilant supportive symptomatic treatment, which may include 
antipyretics, analgesics, and antihistamines (see Appendix C).
Grade 2 (defined as hypotension, hypoxia, organ toxicity) 
a) Study Management: Discontinue study dosing and advance to safety follow-up period.
b) Patient Support: Provide vigilant supportive symptomatic treatment, which may include 
antipyretics, analgesics, antihistamines, with or without tocilizumab. 
Grade 3 (defined as hypotension, hypoxia, and severe organ toxicity) 
a) Study Management: Discontinue study dosing and advance to safety follow-up period.
b) Patient Support: Provide vigilant supportive care, including but not limited to 
tocilizumab, antipyretics, analgesics, and antihistamines, as medically indicated [17]. 
6.5.3
Hematologic Effects
Reductions in platelets, lymphocytes, and red blood cells (RBCs) occurred in nonclinical studies in 
some animals administered doses of TAK-079 higher than the no-observed-adverse-effect level 
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(NOAEL) of 0.3 mg/kg. In the FIH study, no decreases were seen in RBCs or platelets, despite 
observations of reductions in these cell counts in monkey toxicology studies after repeated dosing 
at higher dose levels (≥ 1 mg/kg). 
Patients will be monitored closely, including testing of hematology parameters throughout this 
clinical study as described in Section 9.2.8 and Table 9.a and outlined in Table 3.a and Table 3.b. 
In instances where clinical parameters do not meet dosing criteria, study dosing must be 
temporarily or permanently withheld as outlined in Table 6.b. Medical interventions may be 
administered according to institutional guidelines. 
6.5.4
Infections
In a Good Laboratory Practice (GLP)-compliant 13-week toxicology study, bacterial and/or viral 
infection, secondary to immune suppression, was observed in cynomolgus monkeys at IV doses of 
3, 30, and 80 mg/kg administered once every 2 weeks. The NOAEL dose of 0.3 mg/kg, 
administered IV once every week, was not associated with infections. In the FIH study, mild 
infections, specifically nasopharyngitis, was reported. 
Patients will be monitored for any signs and symptoms of infections throughout this clinical study 
(see Table 3.a, Table 3.b, and Table 6.b). In instances where clinical parameters do not meet 
dosing criteria, study dosing must be temporarily or permanently withheld as outlined in Table 6.b.
Management of infections according to standard medical care is recommended.
6.5.5
Antidrug Antibody Interactions
Antidrug antibody (ADA) responses were detected in most monkeys in the single-dose PK studies 
and the 4-week (non-GLP) and 13-week (GLP) toxicology studies. Stronger positive ADA 
responses were generally associated with lower serum concentrations of TAK-079, and this was 
especially notable in the 13-week repeat-dose toxicity studies and at lower doses. In the 
single-dose healthy subject study (TAK-079-101), 5 of 54 TAK-079–treated subjects were 
positive for ADA (3 subjects with transient ADA and 2 subjects with persistent ADA). Of these, 
one subject was treated in the 0.06 mg IV cohort and the remaining 4 subjects were treated with 
0.03 mg/kg (2 subjects), 0.1 mg/kg (1 subject), or 0.6 mg/kg (1 subject) SC TAK-079. 
Immunogenicity was not associated with clinically significant AEs, even in the 2 subjects with 
persistent immunogenicity.
6.5.6
Overdose
As outlined in Section 10.2, an overdose is defined as a known deliberate or accidental 
administration of investigational drug, to or by the study subject, at a dose above that which was 
assigned to that individual subject (ie, patient) according to the study protocol. 
To date, there is no experience with overdose. If an overdose does occur, as defined in 
Section 10.2, close monitoring and supportive treatment, as medically required, are recommended. 
Events of overdose, with or without an associated adverse event, should be promptly reported to 
the study MM and will be entered into the electronic case report forms (eCRFs) as an AE.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
The study population is limited to patients diagnosed with SLE who meet all eligibility criteria 
outlined in Sections 7.1 and 7.2.
Inclusion Criteria 
7.1
Patients eligible for enrollment in the study must meet the following criteria: 
The patient understands and agrees to study participation by providing a signed and dated 
1.
written informed consent form (ICF) and any required privacy authorization before the 
initiation of any study procedures (as applicable, the patient’s legally acceptable representative 
may provide written ICF in accordance to local and regional regulatory requirements) and, in 
the opinion of the investigator, is capable of complying with protocol requirements.
The patient is aged 18 to 75 years, at the time of signing the study ICF.
2.
The patient been diagnosed with SLE as defined by either the 2012 Systemic Lupus 
3.
International Collaborating Clinics or the American College of Rheumatology diagnostic 
criteria. 
The patient has a SLEDAI-2K score ≥6. 
4.
The patient is positive for anti-dsDNA antibodies and/or anti-ENA antibodies. 
5.
The patient is receiving current concomitant medication that is consistent with medication 
6.
restrictions and limitations outlined in Table 7.a and Table 7.b and, in the best medical 
judgment of the principal investigator, the patient is considered likely to be able to maintain 
dosages consistent with protocol limitations throughout the study dosing period, unless 
precluded by toxicity or the need for protocol-defined rescue therapy.
The patient meets and/or agrees to the following birth control requirements:
7.
a) Men:

Sterile, or if nonsterile, agrees to (1) remain abstinent or (2) use an appropriate method of 
contraception, including a condom with spermicide, from study drug administration on the 
first day of the first dose until 90 days or 5 half-lives of study drug, whichever is longer, 
after the last dose of study drug administration (see Appendix A). No restrictions are 
required for a vasectomized male patient provided the patient is at least 1 year postbilateral 
vasectomy procedure before study drug administration on first day of the first dose. A male 
patient whose vasectomy procedure was performed less than 4 months before study drug 
administration on the first day of the first dose must follow the same restrictions as a 
nonvasectomized man. Appropriate documentation of surgical procedure should be 
provided.

Agrees to not donate sperm from study drug administration on the first day of the first dose,
until 90 days or 5 half-lives of study drug, whichever is longer, after the last dose of study 
drug administration (see Appendix A)
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b) Women: 

Women of child-bearing potential: 
–
Female patients who are of child-bearing potential must agree to remain abstinent or use 
double barrier contraception, consisting of protocol-defined, medically acceptable 
methods (eg, implants, injectables, oral contraceptives, intrauterine devices). 
Contraception must be used from the time of signing the ICF through 90 days or 
5 half-lives of study drug, whichever is longer, after the last dose of study drug 
administration (see Appendix A).

Women with no child-bearing potential will be defined as meeting at least one of the 
following criteria:
–
Postmenopausal (defined as 12 months of spontaneous amenorrhea in women with 
serum follicle-stimulating hormone [FSH] levels >40 mIU/mL). Appropriate 
documentation of FSH levels is required.
–
Surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate 
documentation of surgical procedure.
–
Had a tubal ligation with appropriate documentation of surgical procedure.
–
Has a congenital condition resulting in no uterus.
Exclusion Criteria
7.2
Patients meeting any of the following criteria are not eligible for study enrollment:
1. The patient has participated in another investigational study within 4 weeks or 5 half-lives of 
study drug, whichever is the longer, before the screening visit (the 4-week window is derived 
from the date of the last study procedure, and/or AE related to the study procedure in the 
previous study, to the screening visit of the current study).
2. The patient has a positive pregnancy test.
3. The patient is currently lactating/nursing or plans to nurse during the study (to include during 
the 12-week safety follow-up period of the study).
4. The patient has a history of chronic alcohol or drug abuse ≤12 months before the screening 
visit.
5. The patient has a history of a malignant disease (except for successfully treated basal cell 
carcinoma, squamous cell carcinoma, or cervical carcinoma in situ) ≤5 years before the 
screening visit.
6. Patients has COPD or asthma with a FEV1 <50% of predicted normal. 
Note: FEV1 testing is required for patients suspected of having COPD or asthma.
7. The patient has had a major surgery and/or donated or lost ≥1 unit of blood (approximately 
500 mL) in ≤4 weeks before the screening visit.
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8. The patient had an opportunistic infection ≤12 weeks before initial study dosing or is currently 
undergoing treatment for a chronic opportunistic infection, such as tuberculosis (TB), 
pneumocystis pneumonia, cytomegalovirus, herpes simplex virus, herpes zoster, or atypical 
mycobacteria.
9. The patient currently has, or recently had, an acute or chronic infection requiring one or more 
of the following interventions: 
–
Hospitalization ≤30 days before the screening visit.
–
Administered parenteral (IV or intramuscular) antibacterial, antiviral, antifungal, or 
antiparasitic agents ≤30 days before the screening visit.
10. The patient has a positive T-cell interferon-γ release assay (TIGRA) (resulted through Quanti 
FERON TB Gold test or T-Spot/Elispot) at the screening visit (to be analyzed by local 
laboratory), noting the following: 
a) A purified protein derivative (PPD) skin test may be used as a replacement, if TIGRA 
testing is not available.
b) Patients with an indeterminate TIGRA result must meet the following criteria: 
–
Negative PPD skin test (defined as <5 mm induration).
–
Low risk of acquiring TB (eg, avoids close contact with TB positive individual[s]), 
and/or chest x-ray ≤6 months before the screening visit that is consistent with no 
evidence of latent or active TB).
11. The patient has drug-induced SLE or any other rheumatologic or autoimmune disease 
(excluding secondary Sjögren syndrome or mixed connective tissue disease).
12. The patient required therapeutic intervention ≤60 days before initial study dosing for active 
neuropsychiatric SLE, as demonstrated by, but not limited to, the following: 
a) New or worsening impaired level of consciousness.
b) Psychosis.
c) Delirium or confusional state.
d) Grand mal seizure (including status epilepticus).
e) Aseptic meningitis.
f)
Ascending or transverse myelitis.
g) Chorea, cerebellar ataxia, or demyelinating syndromes.
13. The patient has an active glomerulonephritis (ie, a concurrent acute renal flare or documented 
acute renal flare in the previous 3 months that required lupus nephritis induction therapy) that 
meets at least one of the following criteria: 
a) Proteinuria (protein >3000 mg/24 hr).
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b) Urine protein-to-creatinine ratio of >300 mg/mmol.
c) An estimated glomerular filtration rate (GFR) <30 mL/min/1.73m2 (as calculated by the 
Modification of Diet in Renal Disease [MDRD] formula [see Section 9.2.8.2]).
14. The patient has at least one of the following laboratory test values:
a) Alanine aminotransferase or aspartate aminotransferase >3 times the upper limit of normal 
(ULN).
b) Total bilirubin >1.5 times ULN (Note: Patients with a confirmed diagnosis of Gilbert 
syndrome that is documented in the patient’s medical record are not excluded based on this 
criterion).
c) Platelets <75,000/mm3.
d) Neutrophils <1500/mm3.
e) Hemoglobin <8 g/dL.
f)
IgG less than lower limit of normal (LLN).
15. The patient has a positive test result for hepatitis B surface antigen or hepatitis C antibody, or 
HIV antibody/antigen, at screening. 
16. The patient has a concurrent medical condition that, in the opinion of the investigator, could 
confound interpretation of results or affect the patient’s ability to fully participate in the study.
17. The patient has a history of severe allergic or anaphylactic reactions to recombinant proteins or 
excipients used in the TAK-079 formulation.
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Excluded and Dose-Limited Medications
7.3
Excluded and dose-limited concomitant medications are provided in Table 7.a and Table 7.b.
Table 7.a
Excluded Medications
Category or Agent
Exclusion Criteria
(Exclusion Criteria Must Be Upheld Throughout Study Participation, in 
Addition to the Timepoints Indicated Below) a
Belimumab, abatacept, or 
tocilizumab
≤3 months before the screening visit
Cyclophosphamide
Restricted from ≤12 weeks before initiation of on-study dosing
Immunosuppressant 
regimen
To include calcineurin-inhibitors (eg, systemic cyclosporine and tacrolimus), 
leflunomide, to be excluded throughout study participation. Must be discontinued at 
least 3 months before screening visit.
Live vaccines
All vaccines: Maintain restrictions as follows and throughout study participation, 
until 12 weeks following the last dose of study dosing
Live vaccines: 90 days before initial dosing on study Day 1
Inactivated vaccines: 30 days before initial dosing on study Day 1 
Rituximab or other cell 
depleting biological agents
≤6 months before the screening visit 
Alemtuzumab 
No previous or concurrent dosing while on study
Abbreviation: AE, adverse event. 
a Exceptions to excluded medications may be allowed for treatment of adverse events, after discussion and agreement 
between the sponsor and principal investigator.
Table 7.b
Dose-Limited Concomitant Medications
Medications
Dosing Criteria
(Criteria Are to Be Maintained From Screening to Completion of Study 
Dosing Phase)
Immunosuppressants a

Generally, agents must be dosed for at least 12 weeks before screening, with 
stable dosing for at least 8 weeks before the first dose of TAK-079 or matching 
placebo.

Regimens consisting of < 2 agents while on study (not applicable to topical 
agents; see dose restrictions outlined in Table 7.a). 

Azathioprine
1 to 2 mg/kg/d

Mycophenolate mofetil
1 to 2 g/d

Methotrexate
7.5 to 25 mg/wk.
Corticosteroid a
Stable dosing equivalent to ≤20 mg/day of oral prednisone maintained 
for ≥28 days prior to the first dose of TAK-079 or matching placebo.
Antimalarials
Stable dosing maintained for ≥28 days and is likely to maintain the current dose 
throughout the dosing period, as determined by the principal investigator. 
a Dose limitations not applicable to topical agents.
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Criteria for Discontinuation or Withdrawal of a Patient
7.4
Laboratory findings in which TAK-079 dosing should be temporarily held, or permanently 
discontinued, are outlined in Table 6.b. Patients exhibiting these or other clinical findings for 
which the principal investigator considers that continued TAK-079 dosing may place the patient at 
undue risk, should be immediately held from further TAK-079 dosing and continue to be followed 
for safety. In such instances, TAK-079 may be resumed under consultation with the study MM and 
in accordance to protocol-defined dosing criteria.
Treatment with study drug may be discontinued permanently for any of the following reasons: 

AE and/or SAE.

Withdrawal by subject.

Protocol violation.

Study terminated by sponsor.

Lost to follow-up.

Other.
Once study drug has been discontinued, all study procedures outlined for follow up will be 
completed as specified in the schedule of events (SOE) (see Table 3.b). Patients withdrawing from 
study treatment will be asked if they will permit follow-up assessment or not. If the patient 
completely withdraws consent, no further follow-up assessments can be completed. The primary 
reason for study drug discontinuation will be recorded on the eCRF. 
Procedures for Discontinuation or Withdrawal of a Patient
7.5
Patients withdrawing from study dosing should remain on study, completing all assessments and 
procedures associated with the 12-week safety follow-up period. If the principal investigator or 
patient determines it’s in the patient’s best interest to withdraw from the study, procedures and 
assessments associated with a final study visit, as outlined in Table 3.b, should be completed.
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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
Refer to the pharmacy manual for detailed instructions regarding the storage and preparation of 
TAK-079 study supply.
Clinical Study Drug 
8.1
TAK-079 is a recombinant human IgG1 mAb supplied as 100 mg TAK-079 in 1 mL (100 mg/mL) 
solution, to be administered as a single SC injection every 21 days (ie, 3 weeks) over the course of 
12 weeks for 4 total doses as part of each study cohort.
TAK-079 drug product and matching placebo are supplied in aseptically filled, single-use, clear, 
type I, borosilicate glass vials with fluoropolymer-coated butyl rubber stoppers and aluminum 
crimp seals with flip-off caps.
8.1.1
Clinical Study Drug Labeling
Supplies of TAK-079 and matching placebo are labeled according to the current International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
guidelines on Good Clinical Practices (GCP) and Good Manufacturing Practices (GMP) and 
include any locally required statements. 
8.1.2
Clinical Study Drug Inventory, and Storage 
8.1.2.1
Receipt of Study Drug 
The investigator is responsible for ensuring that deliveries of TAK-079 and other study materials 
from the sponsor are correctly received, recorded, and handled, and stored safely and properly in 
accordance with the Code of Federal Regulations (CFR) or national and local regulations, and used 
in accordance with this protocol.
During shipping, vials are to be protected from light and maintained within temperatures provided 
in the Pharmacy Manual. Each TAK-079 shipment includes a packing slip listing the contents of 
the shipment, and any applicable forms. The investigator or designee must confirm that 
appropriate temperature conditions have been maintained for all TAK-079 and matching placebo 
received and that any discrepancies are reported and resolved before use of TAK-079 or matching 
placebo.
Upon receipt of study medication, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, the 
medication is received within the labeled storage conditions, and is in good condition. If quantity 
and conditions are acceptable, investigator or designee should acknowledge the receipt of the 
shipment by signing bottom half of the packing list and faxing per instructions provided on the 
form. If there are any discrepancies between the packing list versus the actual product received, 
Takeda must be contacted to resolve the issue. The packing list should be filed in the investigator’s 
essential document file.
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The sponsor must be notified immediately of any temperature excursions, shipping and handling 
or storage discrepancies.
8.1.2.2
Storage of Study Drug
All clinical trial material must be kept in an appropriate, limited-access, secure location until used 
or returned to the sponsor or designee. 
TAK-079 and matching placebo must be stored according to the manufacturer’s stipulation, as 
specified on the label, and remain in the original container until dispensed. As such, TAK-079 
drug product and matching placebo must be stored under conditions outlined in the pharmacy 
manual. A daily temperature log of the drug storage area must be maintained every day.
8.1.2.3
Study Drug Dispensing and Inventory 
The principal investigator or designee must ensure that the study medication (ie, TAK-079 and 
matching placebo) is used in accordance with the approved protocol and is dispensed only to 
patients enrolled in the study. To document appropriate use of study medication (TAK-079), the 
investigator must maintain records of all study medication (1) delivered to the site, (2) maintained 
in site inventory, (3) dispensed/used by each patient, and (4) returned to the sponsor or designee.
Detailed dosage preparation instructions are provided in the directions for use section of the 
pharmacy manual. Complete receipt, inventory, accountability, reconciliation, and destruction 
records must be maintained for all used and unused study drug vials. Detailed instructions and the 
associated forms for these activities are in the pharmacy manual.
Drug supplies are to be counted and reconciled at the site before being returned to Takeda or 
designee or being destroyed.
The investigator will be notified of any expiry date or retest date extension of clinical study 
material during the study conduct. On expiry date notification from the sponsor or designee, the 
site must complete all instructions outlined in the notification, including segregation of expired 
clinical study material for return to the sponsor or its designee.
Further guidance and information are provided in the pharmacy manual.
8.1.3
Clinical Study Drug Blinding
The assignment of study patients to one of two study arms, within each cohort, is maintained 
through a blinded randomization schedule, available, in instances of medical emergencies, to the 
principal investigator. Otherwise site staff, will remain blinded through the conduct of the study. 
Details on maintaining the study blind, and unblinding procedures are outlined in Section 8.1.5.
8.1.4
Randomization Code Creation and Storage
The randomization and medication schedule will be generated and maintained by an interactive 
voice/web response system (IXRS). All randomization information will be stored in a secured 
area, accessible only by authorized personnel. 
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8.1.5
Clinical Trial Blind Maintenance/Unblinding Procedure
To maintain the integrity of the study, all study personnel, including the investigators, site 
personnel, the contract research organization medical monitor, study clinicians, and the sponsor, 
will be blinded to the treatment assignments during the treatment period. Treatment assignments 
will be obtained through the IXRS according to the procedures outlined in the study manual. 
Information regarding the treatment assignments will be kept securely at Takeda or designee, per 
its standard operating procedures. 

Records of the patient number, the date the study drug was dispensed, and the treatment 
assignment will be maintained by the study site.

Emergency unblinding, if necessary, will be conducted via the IXRS. The following provides 
key factors to be considered regarding breaking the study blind: 
–
If the treatment assignment must be revealed for the safety of the patient, to treat an AE, or 
to inform decisions for subsequent therapy, the investigator will contact the Takeda project 
clinician or designee (in accordance to contact information and procedures outlined in the 
study manual). 
–
A decision to break the blind must be reached by the Takeda project clinician or designee 
and the investigator. The investigator, or designee, may break the blind through the IXRS 
independent of the Takeda project clinician or designee only if the investigator considers 
the situation to be an emergency and requires specific knowledge of the blinded study 
treatment to properly treat the AE/safety issue. 
–
If the treatment of the AE/safety issue is anticipated to be the same regardless of study drug 
assignment, the blind should not be broken. 
–
The event requiring breaking the blind must be documented in the eCRF, including the date 
the blind was broken. 
–
After breaking the blind, the patient will be discontinued from further study drug 
administration in this study. 
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs
The investigator, institution, or head of the medical institution (where applicable) is responsible 
for TAK-079 accountability, reconciliation, and record maintenance (ie, receipt, reconciliation, 
and final disposition records).
The principal investigator must maintain 100% accountability for all study medication (TAK-079 
and matching placebo) received and dispensed during his or her entire participation in the study. 
Proper drug accountability includes, but is not limited to:

Continuously monitoring expiration dates if expiry date/retest date is provided to the 
investigator.

Frequently verifying that actual inventory matches documented inventory.
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
Verifying that the log is completed for the drug lot used to prepare each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
Empty, partially used, and unused TAK-079 are to be disposed of, retained, or returned to the 
sponsor or designee, as detailed in the pharmacy manual. 
The investigator must maintain a current inventory (drug accountability log) of all 
sponsor-supplied study medication delivered to the site, the ongoing inventory at the site, and the 
patients’ usage records. This log must accurately reflect the drug accountability of the study 
medication at all times. The following information, at minimum, will be recorded: protocol 
number and title, name of investigator, site identifier and number, description of sponsor-supplied 
medication, expiry/retest date, and amount dispensed, including the initials of the person 
dispensing and receiving the study medication. The log should include all required information as 
a separate entry for each patient to whom study medication is dispensed.
Further guidance and information are provided in the pharmacy manual.
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9.0
STUDY PROCEDURES
Assessments and procedures should be performed on schedule, within the timeframe and window 
allowance in Table 3.a, Table 3.b, and Table 3.c. Further time allowance for most study procedures 
and assessments, except for PK draw times, are acceptable in extenuating circumstances (ie, 
holidays, vacations, and other administrative reasons) on approval by the MM or delegate; 
however, these time extensions should not deviate more than 7 days from the scheduled 
procedural time.
Administrative Procedures
9.1
9.1.1
Informed Consent Procedure
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care.
9.1.2
Assignment of Randomization Numbers 
At the time of randomization, after completion of all screening assessments and procedures and 
confirmation of eligibility, patients are assigned a 4-digit randomization sequence number. 
Randomization numbers are generated by the sponsor or designee. Randomized schedules are 
available to the unblinded study statistician.
9.1.3
Study Drug Assignment
Patients are randomly assigned in a 3:1 ratio to one of the two study arms as outlined in Figure 2.a
at the completion of study screening and before dosing on study Day 1, in accordance to the 
randomization schedule as generated by the sponsor or designee. Randomization information is 
stored in a secured area, accessible only by authorized personnel, to include the unblinded study 
statistician, and necessary site staff in instances of emergency un-blinding (as outlined in 
Section 8.1.5).
Clinical Procedures and Assessments
9.2
9.2.1
Inclusion and Exclusion
Eligibility criteria and associated screening study assessments must be confirmed during the 
screening period, after a patient has signed the ICF, and before receiving study drug.
Principle investigators must provide the study MM a summary of key eligibility criteria for review 
so eligibility can be verified before enrolling each patient. 
9.2.2
Medical History and Demography
A complete medical history is compiled for each patient during the screening period (ie, ≤28 days 
before study Day 1) and includes assessment and documentation of prior medical history, 
comorbidities and concomitant treatments. This includes assessments of current SLE signs, 
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symptoms, morbidities, as evaluated and scored by disease activity tools and previous and current 
SLE therapies (see Section 9.3.4).
Demographics will include the date of birth, race, ethnicity, and sex of the patient during 
screening. 
9.2.3
Concomitant Medications and Procedures
Concomitant medications, blood products, and procedures will be recorded from the first dose of 
TAK-079 or matching placebo, through the end of the safety follow-up period (ie, end of safety 
follow-up visit in Week 24 or, when applicable, end of long-term safety follow-up visit in 
Week 36). Trade name and international nonproprietary name (if available), indication, and start 
and end dates of the administered medication are to be recorded. 
9.2.3.1
Background SLE Therapy 
Eligible patients will have received SLE background therapy for ≥12 weeks (with stable dosing 
≥8 weeks), before screening. Once enrolled into the study, patients will remain on background 
therapy, as managed by their principal investigator, in accordance with local institutional 
practices, and in alignment with the study protocol, throughout study participation. Background 
SLE therapy ongoing at the time of screening will be recorded in the eCRF, as will any changes to 
this therapy. 
9.2.4
Physical Examination
A symptom-directed physical examination with assessments for SLE signs and symptoms will be 
completed in accordance with standard of care at the times specified in the SOE (see Table 3.a and 
Table 3.b). 
9.2.5
Vital Signs
Vital signs include body temperature, pulse, respiratory rate (RR), and BP. These are to be 
evaluated at visits specified in the SOE Table 3.a and Table 3.b and recorded both on the source 
documentation and in the eCRF. In addition, vital signs should also be assessed at any time it is 
clinically warranted, either in the clinic or home visit setting (ie, patient exhibits signs or 
symptoms of injection reaction, CRS, or hypersensitivity reactions). As indicated in these tables, 
vital signs are to be assessed before each study dose and 4 hours after dosing, as part of postdose 
assessments. 
Pulse and BP should be assessed in similar positions at each study assessment. 
Clinically significant values, as determined by the principal investigator, must be documented as 
an AE and closely monitored for follow-up. 
NOTE: Additional vital signs to include BP measures should be assessed at any time the patient 
reports symptoms consistent with an infusion reaction. If the patient experiences hypotension 
(with or without symptoms), intensive BP monitoring according to local practice should be 
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instituted. The patient should not be released from the study site until BP values have returned to 
Grade 1 or baseline for at least 1 hour.
9.2.6
12-Lead Electrocardiogram
Each ECG recording should be performed according to standard institutional practice.
All study ECGs, to include triplicate ECGs, are interpreted by a qualified person (ie, read locally). 
Further, triplicate 12-lead ECGs are recorded electronically and are to be submitted to a central 
vendor for storage and for future analysis. 
ECGs with clinically significant findings, as judged by the investigator, are to be considered a 
TEAE; (except for ECGs obtained as part of the screening) visit which would be considered part of 
medical history). Clinically significant findings are to be recorded on the source documentation 
and in the eCRF, and undergo continued monitoring as described in Section 10.2.5
A single 12-lead ECG is to be collected at the screening visit (for assessment of eligibility) and at 
the end of safety follow-up visit. 
Triplicate 12-lead ECGs, obtained before each study dose, are to be collected just before PK 
sampling, during timeframes outlined in Table 3.a and Table 3.b. Triplicate ECGs will be stored 
centrally for future analysis. 
When the timing of the triplicate and single (safety) ECGs coincide, the site can use the triplicate 
ECG collection for the safety evaluation. 
9.2.7
AE Monitoring
Monitoring of TEAEs, serious and nonserious, are to be conducted throughout the study as 
specified in the SOE (see Table 3.a and Table 3.b). Refer to Section 10.0 for details regarding 
definitions, documentation, and reporting of TEAEs and SAEs.
Dosing criteria assessment will be completed as per Table 6.b to ensure patients meet parameters 
before study dosing. 
9.2.8
Laboratory Procedures and Assessments
Unless otherwise stated in the protocol, all laboratory samples, with exception to Coombs tests, are 
to be sent to the study central laboratory for analysis, under the conditions for handling and 
shipping as outlined in the study laboratory manual. Coombs test will be done locally. 
9.2.8.1
Clinical Laboratory Tests
Clinical laboratory evaluations are obtained, handled, stored, and shipped to the designated central 
laboratory, in accordance to the laboratory manual. Clinical chemistry and hematologic assays are 
outlined Table 9.a and urinalysis assays are outlined in Table 9.b. Timings of these assessments 
should be in accordance to the study SOE (see Table 3.a and Table 3.b). 
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Table 9.a
Clinical Chemistry and Hematology Assessments
Hematology
Serum Chemistry
ANC
Hematocrit
Hemoglobin
Platelet count 
WBC count 
WBC with differential
Coagulation panel
Coombs test (both direct and 
indirect)
Albumin
ALP
ALT
AST
Bilirubin (total) 
BUN
Calcium
Chloride
CO2 (bicarbonate)
Creatinine 
CRP
Glucose (nonfasting) 
LDH
Potassium
Sodium
Total protein
Urate (uric acid) 
Glomerular filtration rate
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, 
aspartate aminotransferase; BUN, blood urea nitrogen; CRP, C-reactive protein; LDH, lactate dehydrogenase; WBC, 
white blood cell. 
9.2.8.2
Glomerular Filtration Rate
The GFR should be calculated using the MDRD formula, as follows: 
 = 175 × ( ). ×  ().  

For female patients, multiply sum by 0.742.

For African American patients, multiply sum by 1.212.
9.2.8.3
Urinalysis
A full urinalysis 
 will be conducted by the study central 
laboratory, as defined in Table 9.b, and are to be performed as part of the predosing assessment 
1 week before each dosing day, and on each follow-up safety visit (see Table 3.a and Table 3.b) 
Subsequently, on each dosing day, before dosing, and on each safety follow-up visit, urine should 
be assessed for the presence of protein and nitrates as analyzed by the local laboratory (ie, dipstick 
analysis). 
Any abnormal findings from the local laboratory urine 
 assessments 
should be followed by a confirming evaluation by the study central laboratory. The central 
laboratory will perform urine microscopy if the urinalysis is abnormal. Microscopy consists of 
RBC/high-power field, white blood cells (WBC)/high-power field, and casts.
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Table 9.b
Clinical Urinalysis Assessments
Urinalysis 
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite a
Occult blood
pH
Protein
 a
Specific gravity
Turbidity and color
Urobilinogen
a Protein and nitrates are to be assessed as part of the full urinalysis, analyzed by the central laboratory 1 week before 
each dosing day. In addition, before dosing on study dosing days, protein and nitrates should be assessed by local 
laboratory (ie, dipstick). Abnormal findings by local laboratory assessment must be confirmed by full urinalysis by 
central laboratory. Further details on assessment timings are provided in Table 3.a and Table 3.b.
9.2.9
Pregnancy Test
All study pregnancy testing may be conducted at a designated local laboratory as determined and 
confirmed by the sponsor, with appropriate laboratory documentation provided in advance of 
study testing.
9.2.9.1
Definition of Women of Child-bearing Potential
A woman of child-bearing potential is a sexually mature woman who: 

Has not undergone a hysterectomy or bilateral oophorectomy; or, 

Has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule 
out child-bearing potential) for at least 24 consecutive months (ie, has had menses at any time 
in the preceding 24 consecutive months).
9.2.9.2
Timings of Pregnancy Testing 
Women of child-bearing potential must have pregnancy testing completed in accordance to the 
timings outlined as follows: 

Before Initial Study Dosing: 
–
Screening period: a negative serum pregnancy tests (human chorionic gonadotropin [hCG] 
<5 mIU/mL).
–
Baseline: (within 24 hours before the start of study drug) a negative urine pregnancy test 
with a sensitivity of at least 50 mIU/mL. If the urine test is indeterminate, a serum 
pregnancy test is mandatory.

During Study Enrollment:
–
On each dosing day, before dosing; (urine pregnancy test).
–
End of dosing period, as outlined in Table 3.a (serum pregnancy test).
–
During safety follow-up period, as outlined in Table 3.b (serum pregnancy test).
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Table 9.c
End-of-Study Clinical Parameters
Safety Parameter Laboratory 
Investigations
End-of-Study Criteria 
Continuation to Long-Term Follow-up
B cells
≥LLN or study baseline levels
≤LLN or study baseline levels that is directly 
related to dosing of investigational product. 
Neutrophils
Platelets
T cells
Hgb
IgG, IgA, and IgM levels 
Events of clinical interest
TAK-079–related infusion 
reaction (systemic signs and 
symptoms) to include CRS
≤Grade 1 a
≥Grade 2 reaction a
CRS leading to moderate clinical symptoms 
based on a global assessment of symptoms, as 
classified by the CTCAE version 4.03 
(symptoms to include but not be limited to 
headache, fever, chills/rigors, nausea, 
vomiting, diarrhea, arthralgia, myalgia, and 
hypotension)
Systemic infection
≥Grade 2 
Dosing is to be held until the infection is 
resolved 
Abbreviations: CRS, cytokine release syndrome; CTCAE, Common Terminology Criteria for Adverse Events 
(CTCAE); LLN, lower limit of normal. 
a Grading based on Lee, 2014 [17].
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10.0
ADVERSE EVENTS
Pretreatment Events
10.1
A pretreatment event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed ICF form to participate in a study but before administration of 
any study medication; it does not necessarily have to have a causal relationship with study 
participation. 
Definitions and Elements of AEs
10.2
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed ICF to participate in a study; it does not necessarily have to have a causal relationship with 
the treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition (intermittent 
events for pre-existing conditions or underlying disease should not be considered PTEs or 
AEs).

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a PTE(s) or an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
re-test and/or continued monitoring of an abnormal value are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention.
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
If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of ICF) is considered a concurrent 
medical history condition and should NOT be recorded as a PTE or AE. A baseline evaluation 
(eg, laboratory test, ECG, radiograph) should NOT be recorded as a PTE unless related to a 
study procedure. However, if the subject experiences a worsening or complication of such a 
concurrent medical history condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study medication) or 
an AE (worsening or complication occurs after start of study medication). Investigators should 
ensure that the event term recorded captures the change in the condition (eg, “worsening 
of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should only be captured as an PTE/AE if the episodes become more frequent, serious, 
or severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change from baseline in the condition (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, RA), worsening of the 
condition should only be captured as a PTE/AE if occurring to a greater extent than that which 
would be expected. Again, investigators should ensure that the AE term recorded captures the 
change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of a PTE after the first administration of 
study medication, or a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”).
Changes in severity of AEs:

If the subject experiences a change in the severity of an AE that is not associated with a change 
in study medication, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled before signing of ICF are 
not considered AEs. However, if a preplanned procedure is performed early (eg, as an 
emergency) due to a worsening of the pre-existing condition, the worsening of the condition 
should be captured appropriately as an AE. Complications resulting from any planned surgery 
should be reported as AEs.
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Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. 

All cases of overdose (with or without associated AEs) are to be documented on an overdose 
page of the (e)CRF to capture this important safety information consistently in the database. 
AEs associated with an overdose will be documented on AE CRF(s) according to Section 10.0.

SAEs of overdose should be reported according to the procedure outlined in Section 10.2.6.

In the event of drug overdose, the subject should be treated symptomatically.

If an overdose does occur, close monitoring and supportive treatment as medically required are 
recommended.
10.2.1 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent the preceding items 1 through 5.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
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Table 10.a
General List of Takeda Medically Significant AEs
Term
Acute respiratory failure/acute respiratory 
distress syndrome
Hepatic necrosis
Acute liver failure
Torsade de pointes/ventricular fibrillation / 
ventricular tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizures
Pulmonary fibrosis
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Neuroleptic malignant syndrome/malignant hyperthermia
Spontaneous abortion/stillbirth and fetal death
AEs that fulfill 1 or more of the preceding serious criteria are to be considered SAEs and should be 
reported and followed in the same manner (see Section 10.2.1).
10.2.2 AEs of Clinical Interest 
AEs of clinical interest are based on the mechanism of action of TAK-079, reports from other 
biologic agents, the nonclinical data to date, and the limited data from Study TAK-079-101 in 
healthy human subjects. These AEs may include, but are not limited to, the following: ISRs, CRS, 
hypersensitivity reactions, changes in hematologic parameters, and infections. Patients will be 
monitored closely for these AEs in clinical studies with TAK-079. Refer to Section 6.5 for a 
discussion of these events and recommendations on the Management of Events of Clinical 
Interest, and Section 6.2.1 for a description of the required premedications before TAK-079 
dosing. Section 4.4 provides a summary of the overall benefit-risk profile. 
10.2.3 Assigning Severity/Intensity of Adverse Events
The different categories of severity/intensity are:
Table 10.b
AE Definitions for Severity/Intensity by Category
Mild
An AE that is usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily living.
Moderate
An AE that is usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no significant or 
permanent risk of harm to the research participant.
Severe
An AE that interrupts usual activities of daily living, significantly affects clinical status, or may 
require intensive therapeutic intervention.
Abbreviation: AE, adverse event.
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10.2.4 Assigning Causality of Adverse Events
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Table 10.c
AE Definitions for Causality 
Related
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which a causal relationship is at least a reasonable 
possibility (ie, the relationship cannot be ruled out, although factors other than the drug, such as 
underlying diseases, complications, concomitant drugs and concurrent treatments, may also be 
responsible).
Not related
An AE that does not follow a reasonable temporal sequence from administration of a drug 
and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant medications and concurrent treatments.
10.2.5 Collection and Reporting of AEs, SAEs, and AEs of Clinical Interest
10.2.5.1 Collection Period
Collection of AEs (ie, AEs, SAEs, AEs of clinical interest, and abnormal liver function tests) will 
commence at the time the subject signs the ICF. AEs ongoing at EOT should be monitored until 
they are resolved, return to baseline, are clearly determined to be due to a patient’s stable or 
chronic condition or intercurrent illness(es), or 6 months after EOT has occurred, whichever 
comes first. For patients who withdraw before the administration of study medication, AEs will be 
followed until the subject discontinues study participation.
10.2.5.2 Reporting AEs
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Patients experiencing an 
SAE before the first exposure to investigational product must be monitored until the symptoms 
subside and any clinically relevant changes in laboratory values have returned to baseline, or until 
there is a satisfactory explanation for the change. Nonserious AEs that begin before the first 
exposure to investigational product, related or unrelated to the study procedure, need not be 
monitored for the purposes of the protocol.
All patients experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All AEs will be documented in the AE page of the eCRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:

Event term.

Start and end date and time.
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
Pattern of AE (frequency).

Severity/intensity.

Causality (investigator’s opinion of the causal relationship between the event and 
administration of study drug[s]).

Action taken with trial drug.

Outcome of event.

Seriousness.
10.2.5.3 Reporting SAEs
When an SAE occurs through the AE collection period, it should be reported according to the 
following procedure:
A Takeda SAE form must be completed, in English, and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed as 
follows:
SAE Reporting Contact Information
Cognizant
United States and Canada
Toll-free fax #: 1-800-963-6290
E-mail: takedaoncocases@cognizant.com
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of SAEs that begin before first administration of investigational product will follow the 
same procedure for SAEs occurring on treatment.
SAE Follow-up
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
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(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be monitored until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.2.6 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected SAEs and any other 
applicable SAEs to regulatory authorities, investigators and IRBs or independent ethics committee 
(IECs), as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, Serious Unexpected Serious Adverse Reaction (SUSAR) reports will be 
submitted within 7 days for fatal and life-threatening events and within15 days for other serious 
events, unless otherwise required by national regulations. The sponsor will also prepare an 
expedited report for other safety issues where these might materially alter the current benefit-risk 
assessment of an investigational medicinal product or that would be sufficient to consider changes 
in the investigational medicinal products administration or in the overall conduct of the trial. The 
investigational site also will forward a copy of all expedited reports to his or her IRB or IEC in 
accordance with national regulations.
Drug Safety Monitoring Board
10.3
In accordance with Takeda standard procedures, each clinical trial is evaluated to determine if a 
Drug Safety Monitoring Board (DSMB) should be convened. Applicable regulation and guidance 
are used to evaluate each trial in terms of potential confounding factors that complicate evaluation 
of the study safety and/or efficacy data, and potential risks of the study design or treatment to study 
participants [25]. A DSMB is not indicated at this time for this study given that Takeda’s standards 
and processes, which include continuous review and evaluation of safety data reported from all 
participating sites through the conduct of the study, are appropriate for the ongoing monitoring of 
patient safety and data integrity. Additionally, as noted in detail in Section 6.3, Takeda clinicians/ 
designee conduct ongoing safety oversight at the patient and study level as well as review of safety 
of a full cohort in the dose escalation phase. However, taking into consideration the evolving 
benefit-risk profile of TAK-079, the decision to convene a DSMB could be taken at any time 
during the conduct of Study TAK-079-2001.
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related AEs. AEs leading to study drug discontinuation and SAEs will be listed. Data listings will 
be provided for all AEs including PTE, TEAEs, AEs leading to study drug discontinuation, and 
SAEs.
11.1.6.2 Clinical Laboratory Evaluation
Individual results of laboratory tests from hematology, chemistry, and urinalysis that meet 
abnormal criteria to be defined in the SAP will be listed and summarized. Baseline, postdose, and 
change from baseline to postdose laboratory data will be summarized. All clinical laboratory data 
will be listed. Clinical significant laboratory results will be captured as AEs.
11.1.6.3 Vital Signs
Individual results of vital signs that meet abnormal criteria will be defined as an AE as per the 
principal investigator; to be defined in the SAP will be listed and summarized. Baseline, post-dose, 
and change from baseline in vital sign measurements will be summarized. All vital signs data will 
be provided in the data listings.
Interim Analysis and Criteria for Early Termination
11.2
No interim analysis is planned.
Determination of Sample Size
11.3
This study is not statistically powered for any hypothesis testing. The sample size of 6 active and 2 
placebo patients for each of the 45 mg, 90 mg, and 135 mg dose groups (Cohorts A, B, and C, 
respectively) are considered to be sufficient to fulfill the study objectives of the evaluation of 
safety, tolerability, and PK of each cohort.
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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
Study Site Monitoring Visits
12.1
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the sponsor or its 
designee contract research organization and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or the 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
investigator’s binder, trial drug, patient medical records, ICF documentation, and review of eCRFs 
and associated source documents. It is important that the investigator and other study personnel are 
available during the monitoring visits and that sufficient time is devoted to the process.
Protocol Deviations
12.2
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to trial patients. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the patient, or confound interpretation of primary study assessment. 
Quality Assurance Audits and Regulatory Agency Inspections
12.3
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the Food and Drug Administration [FDA], the United Kingdom 
Medicines and Healthcare Products Regulatory Agency, the Pharmaceuticals and Medical Devices 
Agency of Japan). If the study site is contacted for an inspection by a regulatory body, the sponsor 
should be notified immediately. The investigator guarantees access for quality assurance auditors 
to all study documents as described in Section 12.1.
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13.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects, 
patients) according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix D. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for ICF and investigator responsibilities.
IRB and/or IEC Approval
13.1
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those American sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federalwide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the investigator’s brochure, a copy of 
the ICF form, and, if applicable, subject recruitment materials and/or advertisements and other 
documents required by all applicable laws and regulations, must be submitted to a central or local 
IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and subject ICF 
must be obtained and submitted to the sponsor or designee before commencement of the study (ie, 
before shipment of the sponsor-supplied drug or study specific screening activity). The IRB or IEC 
approval must refer to the study by exact protocol title, number, and version date; identify versions 
of other documents (eg, ICF) reviewed; and state the approval date. The sponsor will ship 
drug/notify site once the sponsor has confirmed the adequacy of site regulatory documentation 
and, when applicable, the sponsor has received permission from competent authority to begin the 
trial. Until the site receives drug/notification no protocol activities, including screening, may 
occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by patients, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee.
Subject incentives should not exert undue influence for participation. Payments to patients must be 
approved by the IRB or IEC and sponsor.
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Subject Information, Informed Consent, and Subject Authorization
13.2
Written consent documents will embody the elements of the ICF as described in the Declaration of 
Helsinki and the ICH Guidelines for GCP and will be in accordance with all applicable laws and 
regulations. The ICF, subject authorization form (if applicable), and subject information sheet (if 
applicable) describe the planned and permitted uses, transfers, and disclosures of the subject’s 
personal and personal health information for purposes of conducting the study. The ICF and the 
subject information sheet (if applicable) further explain the nature of the study, its objectives, and 
potential risks and benefits, as well as the date informed consent is given. The ICF will detail the 
requirements of the participant and the fact that he or she is free to withdraw at any time without 
giving a reason and without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and, if applicable, the subject authorization form. The ICF, subject authorization form (if 
applicable), and subject information sheet (if applicable) must be approved by both the IRB or IEC 
and the sponsor before use.
The ICF, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, subject authorization 
form (if applicable), and subject information sheet (if applicable) to the subject. Information 
should be given in both oral and written form whenever possible and in the manner deemed 
appropriate by the IRB or IEC. In the event the subject is not capable of rendering adequate written 
ICF, then the subject’s legally acceptable representative may provide such consent for the subject 
in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study, and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the ICF and subject authorization form (if applicable) must be signed and dated by 
the subject, or the subject’s legally acceptable representative, at the time of consent and before the 
subject enters into the study. The subject or the subject’s legally acceptable representative should 
be instructed to sign using their legal names, not nicknames, using blue or black ballpoint ink. The 
investigator must also sign and date the ICF and subject authorization (if applicable) at the time of 
consent and prior to subject entering into the study; however, the sponsor may allow a designee of 
the investigator to sign to the extent permitted by applicable law.
Once signed, the original ICF, subject authorization form (if applicable), and subject information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the subject signs the ICF in the subject’s medical record. Copies of the signed ICF, the 
signed subject authorization form (if applicable), and subject information sheet (if applicable) 
shall be given to the subject.
All revised ICF must be reviewed and signed by relevant patients or the relevant patient’s legally 
acceptable representative in the same manner as the original informed consent. The date the 
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revised consent was obtained should be recorded in the subject’s medical record, and the subject 
should receive a copy of the revised ICF.
Subject Confidentiality
13.3
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Guidelines for GCP and to verify compliance with this 
protocol, the sponsor requires the investigator to permit its monitor or designee’s monitor, 
representatives from any regulatory authority (eg, FDA, Medicines and Healthcare Products 
Regulatory Agency, Pharmaceuticals and Medical Devices Agency), the sponsor’s designated 
auditors, and the appropriate IRBs and IECs to review the subject’s original medical records 
(source data or documents), including, but not limited to, laboratory test result reports, ECG 
reports, admission and discharge summaries for hospital admissions occurring during a subject’s 
study participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent process (see Section 13.2).
Copies of any subject source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
Publication, Disclosure, and Clinical Trial Registration Policy
13.4
13.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the clinical study site agreement. In the event of any discrepancy between the 
protocol and the clinical study site agreement, the clinical study site agreement will prevail.
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13.4.2 Clinical Trial Registration 
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for American investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once patients receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to the sponsor providing this information to callers must provide the 
sponsor with a written notice requesting that their information not be listed on the registry site.
13.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
Insurance and Compensation for Injury
13.5
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study patients. Refer to 
the study site agreement regarding the sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the sponsor 
or sponsor’s designee.
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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
Administrative Information
14.1
14.1.1 Study Contact Information 
Contact Type / Role
Contact
SAE and pregnancy reporting
Pharmacovigilance
Takeda Development Center Americas, Inc.
Fax: 224-554-1052
Abbreviation: SAE, serious adverse event.
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14.1.2 Investigator Agreement 
I confirm that I have read and that I understand this protocol, the investigator’s brochure, package 
insert, and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study patients in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.2.6 of this protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator Appendix D.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix E of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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14.1.3 Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
study-related responsibilities template. The vendors identified for specific study-related activities 
will perform these activities in full or in partnership with the sponsor.
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15.0
LIST OF ABBREVIATIONS
ADA
antidrug antibody(ies)
AE
adverse events
AUC
area under the concentration-time curve
BP
blood pressure
CFR
Code of Federal Regulations
Cmax
maximum observed concentration 
COPD
chronic obstructive pulmonary disease
CRS
cytokine release syndrome
CTCAE
Common Terminology Criteria for Adverse Events
%CV
percent coefficient of variation
dsDNA
double-stranded DNA
DSMB
drug safety monitoring board
ECG
electrocardiogram
eCRF
electronic case report form (refers to any media used to collect study data 
[ie, paper or electronic])
ENA
extractable nuclear antigens
FDA
Food and Drug Administration
FEV1
forced expiratory volume in 1 second
FIH
first in human
FSH
follicle-stimulating hormone
GCP
Good Clinical Practices
GFR
glomerular filtration rate
GLP
Good Laboratory Practice 
GMP
Good Manufacturing Practices
hCG
human chorionic gonadotropin
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
independent ethics committee
IRB
institutional review board
IRR
infusion-related reaction
ISR
injection site reaction
IV
intravenous
IXRS
interactive voice/web response system
LLN
lower limit of normal
mAb
monoclonal antibody 
MESF
quantified in molecules of equivalent soluble fluorochrome
MDRD
Modification of Diet in Renal Disease 
MedDRA
Medical Dictionary for Regulatory Activities
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MM
medical monitor
NK
natural killer 
NOAEL
no observed adverse effect level
PB
plasmablast
PD
pharmacodynamic
PK
pharmacokinetics 
PPD
purified protein derivative
PT
preferred term
PTE
pretreatment events
RA
rheumatoid arthritis 
RBC
red blood cell
RR
respiratory rate
RRMM
relapsed/refractory multiple myeloma
SAE
serious adverse event
SAP
statistical analysis plan 
SC
subcutaneous 
SD
standard deviation
SLE
systemic lupus erythematosus
SLEDAI-2K
systemic Lupus Erythematosus Disease Activity Index 2000
SOE
schedule of events
TB
tuberculosis
TEAE
treatment-emergent adverse event
TIGRA
T-cell interferon-γ release assay
TNF-α
tumor necrosis factor-alpha
ULN
upper limit of normal
WBC
white blood cell
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16.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the data management plan. 
AEs, medical history, and concurrent conditions will be coded using MedDRA. Drugs will be 
coded using the World Health Organization Drug Dictionary.
CRFs (Electronic and Paper)
16.1
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should additionally be included. 
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the eCRFs should be made by the investigator with use of change and modification records of 
the eCRFs. The principal investigator must review the data change for completeness and accuracy, 
and must sign and date. 
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
Record Retention
16.2
The investigator agrees to keep the records stipulated in Section 16.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating patients, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
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documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, ICH 
E6 requires the investigator to retain essential documents specified in ICH E6 until at least 2 years 
after the last approval of a marketing application for a specified drug indication being investigated 
or, if an application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 states that the study records should be 
retained until an amount of time specified by applicable regulatory requirements or for a time 
specified in the clinical study site agreement between the investigator and sponsor.
Refer to the clinical study site agreement for the sponsor’s requirements on record retention. The 
investigator and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents.
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REFERENCES
1. Merrill JT, Manzi S, Aranow C, Askenase A, Bruce I, Chakravarty E, et al. Lupus community 
panel proposals for optimising clinical trials: 2018. Lupus Sci Med 2018;5(1):e000258.
2. Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med 2008;358(9):929-39.
3. D'Cruz DP. Systemic lupus erythematosus. BMJ 2006;332(7546):890-4.
4. Lateef A, Petri M. Unmet medical needs in systemic lupus erythematosus. Arthritis Res Ther 
2012;14 Suppl 4:S4.
5. Hoyer BF, Manz RA, Radbruch A, Hiepe F. Long-lived plasma cells and their contribution to 
autoimmunity. Ann N Y Acad Sci 2005;1050:124-33.
6. Jacobi AM, Mei H, Hoyer BF, Mumtaz IM, Thiele K, Radbruch A, et al. 
HLA-DRhigh/CD27high plasmablasts indicate active disease in patients with systemic lupus 
erythematosus. Ann Rheum Dis 2010;69(1):305-8.
7. Liu Z, Zou Y, Davidson A. Plasma cells in systemic lupus erythematosus: the long and short of 
it all. Eur J Immunol 2011;41(3):588-91.
8. Sullivan HC, Gerner-Smidt C, Nooka AK, Arthur CM, Thompson L, Mener A, et al. 
Daratumumab (anti-CD38) induces loss of CD38 on red blood cells. Blood 
2017;129(22):3033-7.
9. Ramaschi G, Torti M, Festetics ET, Sinigaglia F, Malavasi F, Balduini C. Expression of cyclic 
ADP-ribose-synthetizing CD38 molecule on human platelet membrane. Blood 
1996;87(6):2308-13.
10. Sanada C, Xavier-Ferrucio J, Lu YC, Min E, Zhang PX, Zou S, et al. Adult human 
megakaryocyte-erythroid progenitors are in the CD34+CD38mid fraction. Blood 
2016;128(7):923-33.
11. Clemens PL, Yan X, Lokhorst HM, Lonial S, Losic N, Khan I, et al. Pharmacokinetics of 
Daratumumab Following Intravenous Infusion in Relapsed or Refractory Multiple Myeloma 
After Prior Proteasome Inhibitor and Immunomodulatory Drug Treatment. Clin 
Pharmacokinet 2017;56(8):915-24.
12. Wang X, Dahl M, Nguyen D, Jenks S, Cashman K, Lee FEH, et al. The Anti-CD38 
Monoclonal Antibody TAK-079 Depletes Antibody Secreting Cells from Normal and SLE 
Patients [abstract]. Arthritis Rheumatol 2016;68(suppl 10). 2016 ACR/ARHP Annual 
Meeting, 1085.
13. Guidance for industry: S6 addendum to preclinical safety evaluation of biotechnology-derived 
pharmaceuticals. US Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER).
14. Regan DM, Markowitz MA. Mitigating the Anti-CD38 Interference with Serology Testing. 
Advancing Transfusion and Cellular Therapies World wide Association Bulletin #16-02 
2016:1-4.
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15. Darzalex (daratumumab) [package insert]. Horsham, PA: Janssen Biotech, Inc.
16. Rituxan (rituximab) [package insert]. South San Francisco, CA: Genentech, Inc., 2013.
17. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the 
diagnosis and management of cytokine release syndrome. Blood 2014;124(2):188-95.
18. Darzalex (daratumumab) [prescribing information]. Horsham, Pennsylvania: Janssen Biotech, 
Inc., 2017.
19. Chari A, Nahi H, Mateos M, Lokhorst H, Kaufman J, Moreau P, et al. Subcutaneous Delivery 
of Daratumumab in Patients (pts) with Relapsed or Refractory Multiple Myeloma (RRMM): 
Pavo, an Open-Label, Multicenter, Dose Escalation Phase 1b Study. Blood (ASH Annual 
Meeting Abstracts) 2017;130(838).
20. Ellis AK, Day JH. Diagnosis and management of anaphylaxis. CMAJ 2003;169(4):307-11.
21. Delforge M, Ludwig H. How I manage the toxicities in myeloma drugs. Blood (ASH Annual 
Meeting Abstracts) 2017;129:2359-67.
22. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary 
report--Second National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network symposium. J Allergy Clin Immunol 2006;117(2):391-7.
23. Lieberman P, Kemp SF, Oppenheimer J, Lang DM, Bernstein L, Nicklas RA, et al. The 
diagnosis and management of anaphylaxis: an updated practice parameter. J Allergy Clin 
Immunol 2005;115(3 Suppl 2):S483-523.
24. Richter RJ, Martin TG, Vij R, Cole C, Atanackovic D, Zonder JA, et al. Updated data from a 
phase II dose finding trial of single agent isatuximab (SAR650984, anti-CD38+ mAB) in 
relapsed/refractory multiple myeloma (RRMM). J Clin Oncol 2016;34(15). 8005.
25. Guidance for Clinical Trial Sponsors. Establishment and Operation of Clinical Trial Data 
Monitoring Committees. U.S. Department of Health and Human Services Food and Drug 
Administration March 2006. Publication No. OMB Control No. 0910-0581.
26. Mankarious S, Lee M, Fischer S, Pyun KH, Ochs HD, Oxelius VA, et al. The half-lives of IgG 
subclasses and specific antibodies in patients with primary immunodeficiency who are 
receiving intravenously administered immunoglobulin. J Lab Clin Med 1988;112(5):634-40.
27. Suzuki T, Ishii-Watabe A, Tada M, Kobayashi T, Kanayasu-Toyoda T, Kawanishi T, et al. 
Importance of neonatal FcR in regulating the serum half-life of therapeutic proteins containing 
the Fc domain of human IgG1: a comparative study of the affinity of monoclonal antibodies 
and Fc-fusion proteins to human neonatal FcR. J Immunol 2010;184(4):1968-76.
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APPENDICES
Appendix A
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the study, and for 90 days or 5 
half-lives after last dose of study drug, all male subjects who are sexually active with a female 
partner of child-bearing potential* must use barrier contraception (eg, condom with spermicidal 
cream or jelly). In addition, they must be advised not to donate sperm during this period. Women 
of child-bearing potential who are partners of male subjects are also advised to use additional 
contraception as shown in the list containing highly effective/effective contraception found at the 
end of this Appendix. Note the half-life of TAK-079 has not yet been determined. Based on 
conservative information in the literature regarding the half-life of IgG1 immunoglobulins as well 
as other IgG1 human monoclonal antibodies [26,27] a conservative timeframe to continue 
contraception would be 150 days. 
Female Subjects and Their Male Partners
From signing of informed consent, throughout the duration of the study, and for 90 days or 5 
half-lives after last dose of study drug, female subjects of child-bearing potential* who are 
sexually active with a nonsterilized male partner** must use a highly effective/effective method of 
contraception (from the list that follows). As the half-life of TAK-079 has not yet been determined, 
based on conservative information in the literature regarding the half-life of IgG1 
immunoglobulins as well as other IgG1 human monoclonal antibodies [Mankarious et al 1088; 
Suzuki et al 2019], a conservative timeframe to continue contraception would be 150 days.
In addition, they must be advised not to donate ova during this period.
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* A woman is considered to be of child-bearing potential (ie, fertile) following menarche and until 
becoming postmenopausal unless permanently sterile. Permanent sterilization methods include 
hysterectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 
months without an alternative medical cause and a high FSH concentration (>40 IU/L) before any 
study medication is administered. However, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient.
** Sterilized males should have undergone bilateral vasectomy at least 1 year before entering the 
study and able to provide documentation of the absence of sperm in the ejaculate or bilateral 
orchiectomy.
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The following procedures apply for contraception and pregnancy avoidance.
Highly effective methods of contraception are defined as “those, alone or in combination, that 
1.
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). In this study, the only acceptable methods of contraception are: 

Nonhormonal methods: 
–
Intrauterine device (IUD).
–
Bilateral tubal occlusion.
–
Vasectomized partner (provided that partner is the sole sexual partner of the trial 
participant and that the vasectomized partner has received medical assessment of the 
surgical success).
–
True sexual abstinence, only if this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, and 
postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception.

Hormonal methods: Hormonal contraception may be susceptible to interaction with the 
investigative compound, comparator, or concomitant medications, which may reduce the 
efficacy of the contraception method.
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months prior to the first dose of study drug 
OR combined with a barrier method (male condom, female condom, or diaphragm) if 
for shorter duration until she has been on a contraceptive for 3 months;

Oral †.

Intravaginal † (eg, ring).

Transdermal †.
–
Progestogen-only hormonal contraception associated with inhibition of ovulation 
initiated at least 3 months before the first dose of study drug OR combined with a 
barrier method (male condom, female condom, or diaphragm) until she has been on a 
contraceptive for 3 months;

Oral †.

Injectable.

Implantable.
Other effective methods of contraception (there may be a higher than 1% failure rate) are: 
2.

Double-barrier method (contraceptive sponge, diaphragm or cervical cap with spermicidal 
jellies or creams PLUS male condom).
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
Progestogen only hormonal contraception, where inhibition of ovulation is not the primary 
mode of action PLUS condom with or without spermicide.
Unacceptable methods of contraception are:
3.

Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.

Sexual abstinence is NOT an acceptable method of contraception.
Subjects will be provided with information on highly effective/effective methods of 
4.
contraception as part of the subject informed consent process and will be asked to sign a 
consent form stating that they understand the requirements for avoidance of pregnancy, 
donation of ova, (and sperm donation) during the course of the study.
During the study, regular serum/or urine hCG pregnancy tests will be performed only for 
5.
women of child-bearing potential, and all subjects (male and female) will receive continued 
guidance with respect to the avoidance of pregnancy and sperm donation as part of the study 
procedures. Such guidance should include a reminder of the following:
a) Contraceptive requirements of the study
b) Reasons for use of barrier methods (ie, condom) in males with pregnant partners
c) Assessment of subject compliance through such questions as:
i. Have you used the contraception consistently and correctly since the last visit?
ii. Have you forgotten to use contraception since the last visit?
iii. Are your menses late (even in women with irregular or infrequent menstrual cycles, a 
pregnancy test must be performed if the answer is “yes”)
iv. Is there a chance you could be pregnant?
In addition, negative pregnancy results must be confirmed in female subjects of child-bearing 
6.
potential, during the following timeframes: 
a) Screening and baseline: 
i. During screening; a negative serum pregnancy test (hCG < 5 mIU/mL).
ii. Before first dose of investigational drug (within 24 hours); a negative urine pregnancy 
test (with sensitivity < 50 mIU/mL). 
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Note: Before administration of the first dose of investigational drug, the subject must 
confirm menses within the past month before dosing (ie, no delayed menses).
b) Study dosing period: urine screening
i. Prior to each study dosing day.
c) At any time point during study enrollment: serum screening
i. If a menstrual period is delayed. 
ii. On request by an IRB or if required by local regulations.
If any subject is found to be pregnant during the study, she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued. In addition, any pregnancies in the 
partner of a male subject during the study or for 90 days after the last dose should also be recorded 
following authorization from the subject’s partner. 
If the female subject agrees to the primary care physician being informed, the investigator should 
notify the primary care physician that the subject was participating in a clinical study at the time 
she became pregnant and provide details of the study drug the subject received (blinded or 
unblinded, as applicable).
All pregnancies, including female partners of male subjects, in subjects on active study drug will 
be followed up to final outcome, using the pregnancy form. The outcome, including any premature 
termination, must be reported to the sponsor. An evaluation after the birth of the child will also be 
conducted.
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Appendix B
Clinical Signs and Symptoms of Cytokine Release Syndrome
Organ System
Symptoms
Constitutional
Fever with or without rigors, malaise, fatigue, anorexia, myalgias, arthalgias, nausea, 
vomiting, headache
Skin
Rash
Gastrointestinal
Nausea, vomiting, diarrhea
Respiratory
Tachypnea, hypoxemia
Cardiovascular
Tachycardia, widened pulse pressure, hypotension, increased cardiac output (early), 
potentially diminished cardiac output (late)
Coagulation
Elevated D-dimer, hypofibrinogenemia with or without bleeding
Renal
Azotemia
Hepatic
Transaminitis, hyperbilirubinemia
Neurologic
Headache, mental status changes, confusion, delirium, word-finding difficulty or frank 
aphasia, hallucinations, tremor, dysmetria, altered gait, seizures 
Source: Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and 
management of cytokine release syndrome. Blood 2014;124(2):188-95.
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Appendix C
Grading System for Cytokine Release Syndrome
Grade
Toxicity
Grade 1
Symptoms are not life threatening and require symptomatic treatment only (eg, fever,
nausea, fatigue, headache, myalgias, malaise)
Grade 2
Symptoms require and respond to moderate intervention
Oxygen requirement <40% or
Hypotension responsive to fluids or low dose of one vasopressor or 
Grade 2 organ toxicity
Grade 3
Symptoms require and respond to aggressive intervention
Oxygen requirement ≥40% or
Hypotension requiring high dose or multiple vasopressors or
Grade 3 organ toxicity or 
Grade 4 transaminitis
Grade 4
Life-threatening symptoms
Requirements for ventilator support or
Grade 4 organ toxicity (excluding transaminitis)
Grade 5
Death
Source: Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and 
management of cytokine release syndrome. Blood 2014;124(2):188-95.
Grades 2 to 4 refer to the CTCAE v4.03 grading.
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Appendix D
Responsibilities of the Investigator
Clinical research studies sponsored by the Sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. Ensure that study-related procedures, including study-specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects before the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to patients. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a subject authorization section that 
describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not include 
such a subject authorization, then the investigator must obtain a separate subject authorization 
form from each subject or the subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, and laboratory results, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
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contact and receive written approval from the sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the Sponsor. 
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix E
Investigator Consent to the Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix F
Elements of the Subject’s Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of patients involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written ICF, the subject or the subject’s 
legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 
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legally acceptable representative may discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
23. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
That personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
It is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
patients the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
That personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
That patients agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
That the subject’s identity will remain confidential in the event that study results are 
published.
24. Female patients of child-bearing potential (eg, nonsterilized, premenopausal female patients) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from signing the informed consent through 90 days or 5 half-lives of study drug, 
whichever is longer, after the last dose of study drug. Regular pregnancy tests will be 
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performed throughout the study for all female patients of child-bearing potential. If a subject is 
found to be pregnant during study, study drug will be discontinued and the investigator will 
offer the subject the choice to receive unblinded treatment information. 
25. Male patients must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study and for 90 days after 
the last dose of study drug. If the partner or wife of the subject is found to be pregnant during 
the study, the investigator will offer the subject the choice to receive unblinded treatment 
information. 
26. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.
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Appendix G
Dose Modeling of TAK-079
The selection of doses and the frequency of administration of TAK-079 for the TAK-079-2001 
study are based on the following: (1) a comprehensive review and analysis of data derived from the 
dosing of healthy subjects with TAK-079 (TAK-079-101); (2) repeat dosing of monkeys with 
TAK-079 (TAK-079-10015, TAK-079-1018, and TAK-079-10019); and, (3) data derived from 
repeat dosing of patients with multiple myeloma with daratumumab (Darzalex), a related 
anti-CD38 cytolytic antibody [11].
A semimechanistic population PK/PD model for TAK-079 with target-mediated drug disposition, 
incorporated the existing knowledge mentioned above. The model was subsequently used to 
conduct simulations of different doses to project human PK and estimate changes in PB, NK cells, 
B cells, and T cells (as outlined in Figure 1).
The 45 mg dose for the initial dosing cohort (ie, Cohort A) is selected based on the favorable safety 
profile and therapeutic target effect (ie, a sustained reduction of PBs) observed after a 0.6 mg/kg 
dose was administered to healthy subjects (Study TAK-079-101). A single SC dose of 0.6 mg/kg 
TAK-079 reduced the level of PBs in peripheral blood >90% and NK cells >80% without 
comparable reductions in monocytes and B and T cells. Levels of PBs and NK cells recovered to 
50% of baseline levels 21 days after administration, on average (Figure 2). Two subsequent dosing 
cohorts are planned at doses of 90 mg (2-fold increase from the first dose cohort) and 135 mg (a 
50% increase from the previous cohort), keeping in mind a balance of benefit-risk.
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Figure 1
Levels of Plasmablasts, Monocytes, and B, T, and NK Cells in Peripheral 
Blood of Healthy Subjects After a Single Administration of Placebo or 
0.6 mg/kg TAK-079 on Day 0
Source: TAK-079-101 Report
Abbreviation: NK, natural killer; SC, subcutaneous.
Graph indicates change of immuno-inflammatory cells following a single SC dose of 0.1 mg/kg, 0.3 mg/kg, or 
0.6 mg/kg of TAK-079 or matching placebo; medians indicated by solid lines; 95% CI indicated by associated 
shading.
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Figure 2
Summary of Dose Modeling Overview by Dose
Predicted plasmablast % change from baseline 
following a single TAK-079 SC dose of 45 mg, 90 mg, 
and 135 mg
Predicted T-cell levels change from baseline following 
a single TAK-079 SC dose of 45 mg, 90 mg, and 135 mg
A. Plasmablasts following 45 mg SC Dose a
D. T cell levels following 45 mg SC dose a
B. Plasmablasts following 90 mg SC dose a
E. T cell levels following 90 mg SC dose a
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Appendix H
Detailed Description of Amendment to Text 
The primary sections of the protocol affected by the changes in Amendment 01 are indicated. The 
corresponding text has been revised throughout the protocol. 
Change 1: Clarification that the assessment of systemic lupus erythematosus antibodies (Ab) is 
expected at baseline.
The primary change occurs in Table 3.a Schedule of Events
Description of 
change: 
In the row SLE Ab, in the cell spanning Screening column, X was added.
Rationale for Change: Table 3a in original protocol did not align with SLE Ab timings in original 
protocol.
Change 2: Clarification that no dosing criteria assessments are to be conducted as part of 
screening.
The primary change occurs in Table 3.a Schedule of Events
Description of 
Change: 
In the row Dosing criteria assessment, in the cell spanning Screening column, 
X was removed, with footnote o.
Rationale for Change: Table 3.a in original protocol did not align with dosing criteria assessment
timings in original protocol.
Change 3: Removal of redundant RNA sampling schedule in Table 3.a.
The primary change occurs in Table 3.a Schedule of Events
Description of 
Change: 
The row RNA, was removed.
Rationale for Change: RNA assessment timings are adequately covered in other areas of the 
protocol, removal reduced redundancy, and improving protocol clarity.
Change 4: Addition of a one-day window (+/- 1 day) for visits: HV7, HV8 and HV9, has been 
added for consistency with other visits.
The primary change occurs in Table 3.a Schedule of Events
Description 
of Change: 
In the header cells for columns rows HV7, HV8 and HV9, (+/- 1 day) has been added to 
each header cell.
Rationale for Change: All HV visits have a visit window allowance of +/- 1 day. Adding the +/-
1 day allowance for HV7, HV8, and HV9 in Table 3.a, provides the necessary consistency.
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Change 5: Removal of details for urine sample collection.
The primary change occurs in Table 3.a Schedule of Events footnote k
Initial 
wording:
k Urinalysis, including 
 and nitrates, will be performed by 
central laboratory 1 week before dosing; additional protein and nitrate assessments are 
to be performed by local laboratory (ie, dipstick) on study dosing days, before dosing; 
abnormal findings by local laboratory assessment must be confirmed by central 
laboratory evaluation. Samples must be first morning urine collected by patients in 
specimen containers provided by the study site. Further detail is provided in 
Section 9.2.8.3. 
Amended 
or new 
wording:
k Urinalysis, including 
 and nitrates, will be performed by 
central laboratory 1 week before dosing; additional protein and nitrate assessments are 
to be performed by local laboratory (ie, dipstick) on study dosing days, before dosing; 
abnormal findings by local laboratory assessment must be confirmed by central 
laboratory evaluation. Samples must be first morning urine collected by patients in 
specimen containers provided by the study site. Further detail is provided in 
Section 9.2.8.3. 
Rationale for Change: Instructions within protocol are unnecessary as such details will be 
provided in site trainings and associated study documents for the site staff 
Change 6: Clarification of T-cell safety parameters as they pertain to dosing criteria. This 
clarification takes into consideration the natural history of SLE on background therapy, the 
patient’s T-cell baseline values, as well as changes from baseline that would warrant the 
continuation or holding of a dose of TAK-079.
The primary change occurs in Table 6.b Summary of Dosing Criteria
Initial 
wording:

In the row T-cells, in the cell spanning Continuing Dosing column, original 
text read, “T cells ≥500 cells/uL”

In the row T-cells, in the cell spanning Dosing Hold column, original text read, 
“T cells <500 cells/uL”
Amended 
or new 
wording:

In the row T-cells, in the cell spanning Continuing Dosing column, new text 
was added to existing text: “NOTE: Dosing may continue in instances of 
T cells <500 cells/uL if CD3 + cell count is ≥70% of the baseline level”.

In the row T-cells, in the cell spanning Dosing Hold column, text was 
amended: “CD3+ cells count <500 cells/uL and is < 70% of baseline CD3+ 
cell count level.”
The following sections also contain this change: No other areas of the protocol are impacted by 
this change.
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Rationale for Change: This clarification incorporates consideration of the natural history of SLE 
on background therapy, the patient’s T-cell baseline values, as well as changes from baseline that 
would warrant the continuation or holding of a dose of TAK-079. This clarification now
incorporates all available T-cell count information into the dosing decisions.
Change 7: Changes to dosing criteria in the event of infusion related reaction, to better align 
actions with the appropriate grading criteria. Grade 2 or higher reactions still require dose 
discontinuation.
The primary change occurs in Table 6.b Summary of Dosing Criteria
Initial 
wording:
In the row TAK-079-related infusion reaction, in the cell spanning Continuing Dosing 
column, original text read, “Grade 1”.
Amended 
or new 
wording:
In the row TAK-079-related infusion reaction, in the cell spanning Continuing Dosing 
column, new text was added to existing text: “≥ Grade 1 with symptomatic treatment 
allowed in accordance with Appendix C. NOTE: Dosing may resume after symptoms 
have resolved f “
The following sections also contain this change: No other areas of the protocol are impacted by 
this change.
Rationale for Change: Added statement allows for alignment with referenced grading criteria.
Change 8: Clarification of dosing criteria in the event of hypersensitivity-related events, to better 
align with the CTCAE criteria for allergic reactions, as originally intended. Any symptom of an 
anaphylactic reaction continues to require TAK-079 discontinuation.
The primary change occurs in Table 6.b Summary of Dosing Criteria
Initial 
wording:
1. Under the column, Laboratory Investigations, original text in cell 
“Hypersensitivity”,
Amended or 
new wording:
1. Under the column, Laboratory Investigations, new text added to cell 
“Hypersensitivity”, is as follows “(allergic reaction or anaphylaxis)”.
2. In the row Hypersensitivity”, in the cell spanning Continuing Dosing 
column, new text was added “≤Grade 2 In accordance with NCI CTCAE, 
version 4.03 grading for allergic reactions which respond promptly to 
symptomatic measures”.
3. In the row Hypersensitivity”, in the cell spanning Dose Hold column, the 
following text was deleted, “Grade 1 as per NCI CTCAE grading for 
allergic reactions. Hold and reassess as per protocol timings for next dose”
4. In the row Hypersensitivity”, in the cell spanning Dose Discontinuation 
column, the text was amended as follows, “ ≥Grade 3 c2 In accordance 
with NCI CTCAE (version 4.03) grading for allergic reaction
or any signs or symptoms of an anaphylactic reaction.”
5. In the row Hypersensitivity”, in the cell spanning Dose Discontinuation 
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column, a citation to the following reference was added: 
Regan DM, Markowitz MA. Mitigating the Anti-CD38 Interference 
with Serology Testing. Advancing Transfusion and Cellular 
Therapies World wide Association Bulletin #16-02 2016:1-4.
6. Footnote c, text was amended as follows: “Laboratory grading, allergic 
reactions, and infection grading is based on NCI CTCAE v3.0.4.03.”
The following sections also contain this change: No other areas of the protocol are impacted by 
this change.
Rationale for Change: Changes were made to better align with the CTCAE criteria for allergic 
reactions as originally intended. No changes were made to anaphylactic reactions.
Change 9: Clarification that Common Terminology Criteria for Adverse Events version 4.03 must 
be used in the study.
The primary change occurs in Table 6.b Summary of Dosing Criteria.
Added text:
NCI CTCAE, version 4.03
Rationale for Change: To ensure consistent use of NCI CTCAE version as intended.
Change 10: Clarification of excluded and dose limited concomitant medications
The primary change occurs in Section 7.3 in Table 7.a and Table 7.b.
Initial 
wording:

Table 7.a Under the column, Exclusion Criteria, in cell spanning 
Immunosuppressant regimen original text was “To include 
calcineurin-inhibitors (eg, systemic cyclosporine and tacrolimus), 
leflunomide, to be excluded throughout study participation”

Table 7.b Under the column Dosing Criteria, in the cell spanning 
Immunosuppressants, original text was “Regimens consisting of ≥ 2 agents 
while on study (not applicable to topical agents; see dose restrictions outlined 
in Table 7.a”

Table 7.b Under the column Dosing Criteria, in the cell spanning 
Corticosteriods, original text was “Stable dosing equivalent to ≤20 mg/day of 
oral predisolone maintained for ≥28 days prior to the first dose of TAK-079 or 
matching placebo.”
Amended 
or new 
wording:

Table 7.a Under the column, Exclusion Criteria, in cell spanning 
Immunosuppressant regimen new text added to original text, “To include 
calcineurin-inhibitors (eg, systemic cyclosporine and tacrolimus), 
leflunomide, to be excluded throughout study participation. Must be 
discontinued at least 3 months before screening visit.”

Table 7.b Under the column Dosing Criteria, in the cell spanning 
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Immunosuppressants, amended text is “Regimens consisting of <2 agents
while on study (not applicable to topical agents; see dose restrictions outlined 
in Table 7.a”

Table 7.b Under the column Dosing Criteria, in the cell spanning 
Corticosteriods, amended text is “Stable dosing equivalent to ≤20 mg/day of 
oral prednisone predisolone maintained for ≥28 days prior to the first dose of 
TAK-079 or matching placebo.”
The following sections also contain this change: No other areas of the protocol are impacted by 
this change.
Rationale for Change: Statement regarding timeframe for discontinuation of 
immunosuppressants was added for consistency. Other changes were corrections of typographical 
errors in the original protocol.
Change 11: The addition of a protocol subsection to provide clarification regarding potential 
interference with serological testing.
The primary change occurs in Section 6.4
Added text:6.4.3 Interference with Serological Testing
Anti-CD38 monoclonal antibodies have been reported to bind to CD38 on red 
blood cells (RBCs) and results in a positive indirect coombs test, which may 
persist for up to 6 months. The determination of a patient’s ABO and Rh blood 
type are not impacted, but the RBC binding may mask detection of antibodies to 
minor antigens in the patient’s serum [14,15]. It is possible TAK-079 may affect 
the results of these blood tests, this is being evaluated. Until those tests are 
known, it is recommended that baseline type and serological screening be 
established before starting TAK-079. Patients should keep these results in case 
future transfusions are needed. Blood transfusion centers should also be 
informed of this interference with serological testing as necessary. 
Rationale for Change: The impact that TAK-079 may have on minor antibodies is still to be 
determined through ongoing analysis. The newly added section provides clarity on this potential 
impact, and the importance of establishing baseline blood and serology levels at screening, as a 
precautionary safety measure should future transfusions be required while the patient is on study.
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Change 12: Clarifications made regarding the management of hypersensitivity reactions to better 
align with the CTCAE criteria for allergic reactions, as originally intended.
The primary change occurs in Section 6.5.1.1
Initial 
wording:
Grade 1:
Study Management: Hold further TAK-079 dosing until symptoms resolve. Resume 
dose of TAK-079 at same dose level at the time of symptom resolution with 
appropriate prophylactic medical care.
Patient Support: Provide symptomatic treatment, to include epinephrine as needed.
Grade 2:
Study Management: Discontinue study dosing and advance to the safety follow-up 
period of the study.
Patient Support: For anaphylaxis, provide symptomatic treatment, to include 
epinephrine. 
Grade 3 or Greater: (symptomatic bronchospasm with or without urticaria, 
angioedema, hypotension). 
Study Management: Patients are to discontinue study dosing and advance to the safety 
follow-up period of the study.
Patient Support: Provide symptomatic treatment, including epinephrine, until 
symptoms resolve. 
Local injection site abnormalities have not been observed in monkey and rat 
nonclinical studies after SC and/or IV administration of TAK-079. In the clinical 
study of healthy subjects (TAK-079-101), mild injection site AEs were reported; most
were Grade 1 and included primarily erythema or tenderness. All injection reactions 
resolved within a few days.
Grade 3 or Greater: (symptomatic bronchospasm with or without urticaria, 
angioedema, hypotension). 
Study Management: Patients are to discontinue study dosing and advance to the safety 
follow-up period of the study.
Patient Support: Provide symptomatic treatment, including epinephrine, until 
symptoms resolve. 
Amended 
or new 
wording:
Grade 1 
a) Study Management: 
Hold further TAK-079 dosing until symptoms resolve. Resume dose of 
TAK 079 at same dose level at the time of symptom resolution with 
appropriate prophylactic medical care. If the full dose of TAK-079 has not 
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yet been administered, hold dosing until symptoms resolve, at which time 
the remainder of TAK-079 dose may be administered.
b) Patient Support
Provide symptomatic treatment, to include epinephrine as needed. Monitor 
closely until resolution of symptoms. 
Grade 2 
c) Study Management: 
Discontinue study dosing and advance to the safety follow up period of the 
study. If the full dose of TAK-079 has not yet been administered, hold 
dosing until symptoms resolve, at which time the remainder of TAK-079 
dose may be administered. 
d) Patient Support
For anaphylaxis, provide symptomatic treatment, to include epinephrine.

Administer appropriate symptomatic and prophylactic 
medical care; consider post-injection medications as 
outlined in Section 6.2.2.

For allergic reaction, provide symptomatic treatment (e.g. 
antihistimines, nonsteroidal anti-inflammatory drugs, 
narcotics, epinephrine) as medically appropriate and 
consider post-infection medications (as per Section 6.2.2).
Grade 3 or Greater: (symptomatic bronchospasm with or without urticaria, 
angioedema, hypotension). 
a) Study Management: 

Patients are to discontinue study dosing and advance to the 
safety follow-up period of the study.
b) Patient Support:

Provide symptomatic treatment, including epinephrine, until 
symptoms resolve. 

Consider hospitalization as appropriate.
The following sections also contain this change: No other areas of the protocol are impacted by 
this change.
Rationale for Change: Revised text provides clarification for appropriate symptom management
to better align with appropriate toxicity grading criteria guidance, while providing patients the 
opportunity to continue study dosing if and when symptoms should resolve.
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Change 13: Removal of any reference to an unblinded pharmacist.
The primary change occurs in Section 8.1.3
Initial 
wording:
The assignment of study patients to one of two study arms, within each cohort, is 
maintained through a blinded randomization schedule, available to the study site 
pharmacist, and in instances of medical emergencies, to the principal investigator. 
Details on maintaining the study blind, and unblinding procedures are outlined in 
Section 8.1.5.
Amended 
or new 
wording:
The assignment of study patients to one of two study arms, within each cohort, is 
maintained through a blinded randomization schedule, available, to the study site 
pharmacist, and in instances of medical emergencies, to the principal investigator. 
Otherwise site staff, will remain blinded through the conduct of the study. Details 
on maintaining the study blind, and unblinding procedures are outlined in 
Section 8.1.5.
The following sections also contain this change: Section 8.1.5, Section 9.1.2, and Section 9.1.3
Rationale for Change: Pharmacist is not unblinded in this study
Change 14: Clarification that ECGs are to be read locally, to include readings of triplicate 
electrocardiograms for safety assessments. Otherwise, triplicate ECGs will be submitted for 
subsequent central reading at a future time.
The primary change occurs in Section 9.2.6
Initial 
wording:
A single 12-lead ECG is to be collected at the screening visit (for assessment of 
eligibility) and at the end of safety follow-up visit, and will be read locally. 
Triplicate 12-lead ECGs, obtained before each study dose, are to be collected just 
before PK sampling, during timeframes outlined in Table 3.a and Table 3.b. Triplicate 
ECGs will be read centrally. 
When the timing of the triplicate and single (safety) ECGs coincide, the site can use 
the triplicate ECG collection for the safety evaluation. 
Each ECG recording should be performed according to standard institutional practice. 
It is recommended that patients refrain from eating or limit themselves to bland food 
for 1 hour before dosing and for 1 hour before each scheduled triplicate ECG 
measurement. Each ECG is recorded electronically, interpreted by a qualified person,
and transmitted to a central vendor for storage.
NOTE: Any ECG finding that is judged by the investigator as clinically significant 
(except at the screening visit) is considered a TEAE; as such clinically significant 
findings are to be recorded on the source documentation and in the eCRF, and undergo 
continued monitoring as described in Section 10.2.5.
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Amended 
or new 
wording:
Each ECG recording should be performed according to standard institutional practice.
All study ECGs, to include triplicate ECGs, are interpreted by a qualified person (ie, 
read locally). Further, triplicate 12-lead ECGs are recorded electronically and are to be 
submitted to a central vendor for storage and for future analysis. 
ECGs with clinically significant findings, as judged by the investigator, are to be 
considered a TEAE; (except for ECGs obtained as part of the screening) visit which 
would be considered part of medical history). Clinically significant findings are to be 
recorded on the source documentation and in the eCRF, and undergo continued 
monitoring as described in Section 10.2.5
A single 12-lead ECG is to be collected at the screening visit (for assessment of 
eligibility) and at the end of safety follow-up visit, and will be read locally. 
Triplicate 12-lead ECGs, obtained before each study dose, are to be collected just 
before PK sampling, during timeframes outlined in Table 3.a and Table 3.b. Triplicate 
ECGs will be read stored centrally for future analysis. 
When the timing of the triplicate and single (safety) ECGs coincide, the site can use 
the triplicate ECG collection for the safety evaluation.
Each ECG recording should be performed according to standard institutional practice. 
It is recommended that patients refrain from eating or limit themselves to bland food 
for 1 hour before dosing and for 1 hour before each scheduled triplicate ECG 
measurement. Each ECG is recorded electronically, interpreted by a qualified person,
and transmitted to a central vendor for storage.
NOTE: Any ECG finding that is judged by the investigator as clinically significant 
(except at the screening visit) is considered a TEAE; as such clinically significant 
findings are to be recorded on the source documentation and in the eCRF, and undergo 
continued monitoring as described in Section 10.2.5.
Rationale for Change: Additional text has been added to alleviate and avoid confusion regarding 
central reads, which will be conducted later in the study; and, to clarify that all ECG (both those 
obtain in single and triplicate) must be read locally.
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Change 15: Clarification of Coombs testing to be analyzed by local labs; with further clarification 
that all other laboratory tests, unless otherwise noted, should be submitted for central analysis.
The primary change occurs in Section 9.2.8.
Initial 
wording:
Unless otherwise stated in the protocol, all laboratory samples are to be sent to the 
study central laboratory for analysis, under the conditions for handling and shipping as 
outlined in the study laboratory manual.
Amended 
or new 
wording:
Unless otherwise stated in the protocol, all laboratory samples, with exception to 
Coombs tests, are to be sent to the study central laboratory for analysis, under the 
conditions for handling and shipping as outlined in the study laboratory manual. 
Coombs test will be done locally.
The following sections also contain this change: No other areas of the protocol are impacted by 
this change.
Rationale for Change: Central lab vendor does not perform Coombs testing, so test needs to be 
completed by local lab.
Change 16: Adjustments to pregnancy test methodology during screening and just prior to the 
first dose of TAK-079, though 2 negative pregnancy tests are still needed prior to dosing. Details 
about the duration of continued contraception after the last dose of study medication have been 
added.
The primary change occurs in Section 9.2.9.2
Initial 
wording:
Women of child-bearing potential must have pregnancy testing completed in 
accordance to the timings outlined as follows: 

Before Initial Study Dosing: Two negative serum pregnancy tests (human 
chorionic gonadotropin [hCG] <5 mIU/mL) to include: 
–
Screening period (within 10 to 14 days before the start of study drug).
–
Baseline (within 24 hours before the start of study drug).
Amended 
or new 
wording:
Women of child-bearing potential must have pregnancy testing completed in 
accordance to the timings outlined as follows: 

Before Initial Study Dosing: Two
–
Screening period: a negative serum pregnancy tests (human chorionic 
gonadotropin [hCG] <5 mIU/mL) to include: 
1.
Screening period (within 10 to 14 days before the start of study drug).
–
Baseline (within 24 hours before the start of study drug) a negative urine 
pregnancy test with a sensitivity of at least 50 mIU/mL. If the urine test is 
indeterminate, a serum pregnancy test is mandatory.
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The following sections also contain this change: Table 3.a, footnote j and Appendix A
Rationale for Change: 
Changes to Pregnancy Testing Criteria: To reduce the need for blood draws within study, while 
maintaining appropriate measures for pregnancy assessments.
Changes to Barrier Contraception After Last Dose On-Study: Change made to provide 
specific detail about suggested duration of contraception after last dose on study drug and rationale 
for the duration recommended.
Change 17: Removal of British Isles Lupus Assessment Group assessments and all associated 
trainings and site/study activities.
The primary change occurs in Section 9.3.4
Deleted 
Text 
9.3.4.2BILAG 2004 Index
All investigative site personnel performing BILAG 2004 Index evaluations must be 
trained and certified before conducting study assessments. 
The BILAG 2004 Index is a clinical measure of lupus disease activity reported in 9 
body systems. The BILAG score is based on clinical presentations of present, new, 
worse, the same, or improving, in comparison to the previous assessment. General 
BILAG categories are as follows: 

BILAG A: The presence of one or more serious features of lupus. 

BILAG B: Moderate features of the disease. 

BILAG C: Mild symptomatic features. 

BILAG D: Prior activity with no current symptoms due to active lupus. 

BILAG E: An organ that has never been involved.
The following sections also contain this change Footnotes to Table 3.a, Table 3.b, Section 4.3.4.3, 
Section 5.2.3.
Rationale for Change: Considering the primary objective of the study is safety and tolerability 
and not efficacy, and given the number of SLE assessment tools currently incorporated into the 
protocol, the BILAG assessment was determined to not be necessary and was removed.
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Change 18: Clarification that the statistical analysis plan will be prepared before database lock.
The primary change occurs in Section 11.1
Deleted 
Text 
A statistical analysis plan (SAP) will be prepared and finalized before unblinding of 
patients’ treatment and before database lock. This document will provide further 
details regarding the definition of analysis variables and analysis methodology to 
address all study objectives.
Rationale for Change: To provide clarification that the statistical analysis plan will be prepared 
before database lock. 
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SAP_001.pdf: 


STATISTICAL ANALYSIS PLAN 
Study Number: TAK-079-2001 
Study Title: A Phase 1b Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics 
of TAK-079 in Combination With Standard Background Therapy in Patients With Moderate to 
Severe Systemic Lupus Erythematosus 
Phase: 1b 
Version: Final, v2.0 
Date: 19-NOV-2021 
Prepared by: 
 
Based on: 
Protocol Version: Amendment 01 
Protocol Date: 19 February 2019 
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TAK-079-2001 
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Statistical Analysis Plan Final v2.0 
19-NOV-2021
 
 
REVISION HISTORY 
Version  
Approval Date 
Primary Rationale for Revision 
Original version 
21-DEC-2020 
Not applicable 
2.0 
19-NOV-2021 
To make SAP consistent with Amendment 01 of the protocol and 
to clarify statistical analysis methods, as outlined in Section 9.1.  
 
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Statistical Analysis Plan Final v2.0 
19-NOV-2021
 
 
TABLE OF CONTENTS 
1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS ............................................................7 
1.1 
Objectives ......................................................................................................................7 
1.1.1 
Primary Objective ..................................................................................................7 
1.1.2 
Secondary Objective(s) .........................................................................................7 
1.1.3 
Exploratory Objective(s) .......................................................................................7 
1.2 
Endpoints .......................................................................................................................7 
1.2.1 
Primary Endpoint(s) ..............................................................................................7 
1.2.2 
Secondary Endpoint(s) ..........................................................................................7 
1.2.3 
Exploratory Endpoint(s) ........................................................................................7 
2.0 
STUDY DESIGN.................................................................................................................8 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES ...............................................9 
3.1 
Statistical Hypotheses ....................................................................................................9 
3.2 
Multiplicity Adjustment .................................................................................................9 
4.0 
SAMPLE-SIZE DETERMINATION ..................................................................................9 
5.0 
ANALYSIS SETS .............................................................................................................10 
5.1 
Safety Analysis Set ......................................................................................................10 
5.2 
PK Analysis Set ...........................................................................................................10 
5.3 
PD Analysis Set ...........................................................................................................10 
5.4 
Immunogenicity Analysis Set ......................................................................................10 
6.0 
STATISTICAL ANALYSIS .............................................................................................10 
6.1 
General Considerations ................................................................................................10 
6.1.1 
Handling of Treatment Misallocations ................................................................11 
6.2 
Disposition of Subjects ................................................................................................11 
6.3 
Demographic and Other Baseline Characteristics .......................................................11 
6.3.1 
Demographics ......................................................................................................11 
6.3.2 
Medical History ...................................................................................................12 
6.4 
Prior and Concomitant Medications ............................................................................12 
6.5 
Efficacy Analysis .........................................................................................................12 
6.5.1 
Primary Endpoints Analysis ................................................................................12 
6.5.2 
Secondary Endpoints Analysis ............................................................................12 
6.5.3 
Exploratory Endpoints Analysis ..........................................................................12 
6.6 
Safety Analysis ............................................................................................................14 
6.6.1 
Adverse Events ....................................................................................................14 
6.6.2 
Clinical Laboratory Evaluations ..........................................................................15 
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6.6.3 
Vital Signs ...........................................................................................................16 
6.6.4 
12-Lead ECGs .....................................................................................................16 
6.6.5 
Extent of Exposure and Compliance ...................................................................17 
6.7 
Pharmacokinetic, Pharmacodynamic, 
 Analyses .................................17 
6.7.1 
Pharmacokinetic Analysis ...................................................................................17 
6.7.2 
Pharmacodynamic 
 Analysis .......................................................17 
6.8 
Immunogenicity Analysis ............................................................................................18 
6.9 
Interim Analyses ..........................................................................................................18 
7.0 
REFERENCES ..................................................................................................................18 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES ...................................................18 
9.0 
APPENDIX ........................................................................................................................19 
9.1 
Changes From the Previous Version of the SAP .........................................................19 
9.2 
Analysis Software ........................................................................................................19 
9.3 
Pharmacodynamic Parameters .....................................................................................19 
 
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ABBREVIATIONS 
Abbreviation 
Term 
ADA 
antidrug antibody(ies) 
AE 
adverse event 
AUC 
area under the concentration-time curve 
CI 
confidence interval 
 
 
Cmax 
maximum observed concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
trough concentration 
%CV 
percent coefficient of variation 
 
 
ECG 
electrocardiogram 
eCRF 
electronic case report form (refers to any media used to collect study data [ie, paper or 
electronic]) 
 
 
ICF 
informed consent form 
Ig 
Immunoglobulin 
IgA 
Immunoglobulin A 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
MedDRA 
Medical Dictionary for Regulatory Activities 
NK 
natural killer 
PB 
plasmablast 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PT 
preferred term 
PTE 
pretreatment event 
QTc 
corrected QT interval 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
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Abbreviation 
Term 
SLE 
systemic lupus erythematosus 
 
 
SOC 
system organ class 
SOE 
schedule of events 
TEAE 
treatment-emergent adverse event 
 
 
WHO 
World Health Organization 
 
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Protocol Figure 2.a TAK-079-2001 Study Cohort Reviews 
 
 
 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES  
3.1 
Statistical Hypotheses 
No formal tests of statistical hypotheses are planned. 
3.2 
Multiplicity Adjustment 
No multiplicity adjustments are planned. 
4.0 
SAMPLE-SIZE DETERMINATION 
This study is not statistically powered for any hypothesis testing. The sample size of 6 active and 
2 placebo patients for each of the 45 mg, 90 mg, and 135 mg dose groups (Cohorts A, B, and C, 
respectively) are considered to be sufficient to fulfill the study objectives of the evaluation of 
safety, tolerability, and PK of each cohort. 
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5.0 
ANALYSIS SETS 
5.1 
Safety Analysis Set 
The safety analysis set will consist of all patients who are enrolled and received at least 1 dose of 
study drug. Patients in this analysis set will be used for demographic, baseline characteristics 
and safety summaries. 
5.2 
PK Analysis Set 
The PK analysis set will consist of all patients who receive study drug and have at least 1 
measurable serum concentration. 
5.3 
PD Analysis Set 
The PD analysis set will consist of all patients who receive study drug and have at least 1 
postdose PD measurement. 
5.4 
Immunogenicity Analysis Set 
The immunogenicity analysis set will consist of all subjects from the safety population who have 
the baseline immunogenicity sample and at least 1 postdose immunogenicity sample assessment. 
6.0 
STATISTICAL ANALYSIS  
6.1 
General Considerations 
Continuous data will be summarized using the following descriptive statistics: number of 
subjects (N), mean, standard deviation (SD), median, minimum, and maximum, where 
appropriate. Where indicated, the coefficient of variation (%CV) and geometric mean may also 
be included in the summary of continuous data. Arithmetic means, geometric means, and 
medians will be presented to 1 more decimal place than the recorded data, and SDs will be 
presented to 2 more decimal places than the recorded data, where appropriate. 
For PK related tables, mean, SD, median, minimum, and maximum will be rounded to 3 
significant digits and CV% will presented to 1 decimal place. 
Categorical data will be summarized using the number and percent of subjects for each category, 
where appropriate. Percentages will be reported to 1 decimal place. 
Unless otherwise stated, baseline value is defined as the last observed value before the first dose 
of study medication. 
There will be no visit windows. 
For values with several non-missing measurements, for example triplicate ECGs, the average of 
triplicate assessments will be used. 
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Subjects who receive placebo in each cohort will be pooled across the cohorts. All summaries 
will be presented by the pooled placebo group, TAK-079 doses, TAK-079 overall subjects in the 
study separately. 
6.1.1 
Handling of Treatment Misallocations 
For analyses based on the safety, PK, PD, or immunogenicity analysis sets, subjects will be 
analyzed as treated, i.e., actual treatment. For analyses based on all randomized subjects, subjects 
will be analyzed as randomized, i.e., planned treatment. 
6.2 
Disposition of Subjects 
The summary and listing of disposition of subjects will be based on all randomized subjects. The 
number of subjects in the safety set will be presented. Disposition will be tabulated in terms of 
subjects who prematurely discontinued from study treatment, subjects who completed study 
treatment, subjects who prematurely discontinued from the study, and subjects who completed 
the study. Primary reasons for premature discontinuation from study or study treatment, as 
entered on the electronic case report form (eCRF), will also be tabulated. Percentages will be 
based on the number of subjects in the safety set. 
In addition, the number of subjects randomized will be summarized for each country and site. 
Major protocol deviations will be summarized and listed based on all randomized subjects. 
Protocol deviations related to COVID-19 will be summarized and listed.  
The date of first dose, date of last dose, duration of treatment and the reason for premature 
discontinuation of study drug/study visit will be presented for each subject in listings. 
 
6.3 
Demographic and Other Baseline Characteristics 
6.3.1 
Demographics 
Summary statistics will be presented for continuous variables (for example, age and weight). The 
number and percentage subjects within each category will be presented for categorical variables 
(for example, race and sex). Individual subject demographic and baseline characteristic data will 
be listed. Placebo data will be pooled across the cohorts. 
Demographic variables of screen failure subjects and reasons for screen failures will be 
summarized for subjects who are screened, but not enrolled in the study.  
Individual demographic characteristics, date of informed consent form (ICF), and reason for 
screen failure will be listed. 
The analysis and listing of demographics and baseline characteristics will be based on the safety 
analysis set. 
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6.6 
Safety Analysis 
Safety measures include AEs, clinical laboratory parameters, vital sign parameters, 12-lead ECG 
results, and other safety parameters. The safety analysis set will be used for all summaries of 
safety parameters.  
For all safety summary tables stated under this section, the tables will be summarized by 
placebo, each TAK-079 dose level, and TAK-079 overall. Placebo data will be pooled across the 
dose levels. 
6.6.1 
Adverse Events 
A Pre-Treatment Event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed informed consent to participate in a study, but prior to 
administration of any study medication; it does not necessarily have to have a causal relationship 
with study participation. 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment. PTE and AE verbatim terms will be coded by SOC and PT using MedDRA (version 
23.1 or higher). 
Treatment-Emergent Adverse Events (TEAE)s will be defined as AEs that occur after the first 
dose of study drug received in the treatment period and until the end of safety follow up. 
TEAEs will be presented by intensity. Serious TEAEs, TEAEs leading to study drug 
discontinuation, TEAEs leading to dose modification (e.g. described as dose delay, dose skipped) 
and TEAEs leading to death will also be summarized using SOC and PT. 
When calculating the frequency and percentage of subjects who reported TEAEs, a subject will 
be counted only once for each SOC or PT when multiple TEAEs are coded to the same SOC or 
PT. For the intensity or relatedness summaries, if a patient reports multiple TEAEs coded to the 
same SOC or PT, the TEAE with maximum intensity or strongest relationship will be included in 
the summary. 
AEs with missing intensity will be listed as such in the AE listings, but will be summarized as 
severe in summary tables. Similarly, if the relationship of an event is missing, the event will be 
considered as related but in listings it will be presented as missing. 
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In general, AEs will be tabulated at the following levels: overall summary (subjects with at least 
1 AE in any dose or treatment), the MedDRA SOC, and the MedDRA PT. The tables will 
include the number and percentage (N [%]) of subjects. The following summary tables will be 
generated for all cohorts: 
• Overview of Treatment-Emergent Adverse Events. 
• Treatment-Emergent Adverse Events by System Organ Class and Preferred Term. 
• Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term. 
• Most Frequent (N>2) Non-Serious Adverse Events by Preferred Term. AE events of 
TAK-079 overall will be used to decide whether the event of AEs >2.  
• Most Frequent (N>2) Non-Serious Adverse Events by System Organ Class and Preferred 
Term. AE events of TAK-079 overall will be used to decide whether the event of AEs >2. 
• Drug-Related Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term. 
• Intensity of Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term. 
• TEAE Overall, by Toxicity, Seriousness, Relatedness, and Discontinuation by SOC, HLT 
and PT. 
Data listings will be provided for PTEs, TEAEs, TEAEs leading to study drug discontinuation, 
TEAEs leading to dose modification of study drug with modification including dose delay and 
dose skipped, SAEs and AEs that resulted in death. 
There will be no imputation for missing adverse events dates. 
6.6.2 
Clinical Laboratory Evaluations 
Unless otherwise stated in the protocol, all laboratory samples are to be sent to the study central 
laboratory for analysis, under the conditions for handling and shipping as outlined in the study 
laboratory manual. If a patient has repeated laboratory values for a given time point, the value 
from the last evaluation will be used. 
Clinical laboratory evaluations are obtained, handled, stored, and shipped to the designated 
central laboratory, in accordance to the laboratory manual. Clinical chemistry and hematologic 
assays are outlined Protocol Table 9.a and urinalysis assays are outlined in Protocol Table 9.b. 
Timings of these assessments should be in accordance to the study SOE (see Protocol Table 3.a 
and Protocol Table 3.b). 
All laboratory test parameters will be displayed in individual subject data listings in both SI units 
and conventional (CV) units. For test results not in SI units, the conversion to SI units will be 
done using the known conversion factors. If necessary, SI units from the central laboratory may 
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be converted to Takeda’s preferred SI units. All summaries and analyses will be based on the 
values using these preferred SI units. 
Study baseline will be used for change from baseline. 
The actual values, change from baseline, and percent change from baseline in clinical laboratory 
parameters will be summarized. Figures of mean actual values and changes from baseline by 
visit will also be generated. Individual subject profiles over time for selected parameters may be 
plotted as needed. 
CTCAE grading (version 4.03) for lab values are summarized by creating a shift table for the 
toxicity grades for baseline to worst toxicity grade post-baseline.  All clinical laboratory data will 
be presented in both SI and conventional units in data listings. 
6.6.3 
Vital Signs 
Individual results of vital signs that meet abnormal criteria and are clinically significant per the 
PI will be captured as an AE by the investigator.  
A summary table of vital sign parameters by visit will be generated. All vital signs will be listed 
in a data listing. 
6.6.4 
12-Lead ECGs 
A single 12-lead ECG is to be collected at the screening visit (for assessment of eligibility) and 
at the end of safety follow-up visit, and will be read locally. 
Pre-dose triplicate 12-lead ECGs, obtained before each study dose, are to be collected just before 
PK sampling, during timeframes outlined in Protocol Table 3.a and Table 3.b.  
Overall ECG interpretation category (normal, abnormal not clinically significant, abnormal 
clinically significant, not evaluable) is collected by eCRF at baseline and at each scheduled 
postbaseline visit. Shifts in ECG interpretation will be presented as cross-tabulations (baseline 
versus each post-baseline visit) of numbers of subjects with normal, abnormal not clinically 
significant, and abnormal clinically significant interpretations, not evaluable, with missing, if 
applicable, and total categories overall.  
Rate-corrected QT interval (millisec) of electrocardiograph (QTc) will be calculated using 
Bazett’s correction and Fridericia’s correction, if necessary. The formulas are: 
QTc (Bazett) = QT / (RR^0.5) 
QTc (Fridericia) = QT / (RR^0.33) 
where RR = 60 / heart rate (bpm) 
All ECG parameters will be listed in a data listing. 
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6.6.5 
Extent of Exposure and Compliance 
The total number of doses taken and the total amount of dose taken will be summarized 
descriptively in the pooled placebo group and TAK-079 arms. 
Treatment compliance will be summarized in terms of the percent of scheduled doses received in 
the pooled placebo group and TAK-079 arms.  The percent of scheduled doses received for each 
subject is defined as: [(Actual total number of doses taken) ÷ (Planed number of doses)] *100. 
The date and time of each dose for each subject will be reported in a data listing. 
6.7 
Pharmacokinetic, Pharmacodynamic, 
 Analyses 
6.7.1 
Pharmacokinetic Analysis 
Due to sparse PK sampling, no noncompartmental analysis will be conducted. TAK-079 
concentration-time profile will be summarized using descriptive statistics. Individual TAK-079 
concentration-time data, individual Ctrough parameter (the last concentration reached before the 
next dose administration) and individual Cmax parameter (the maximum observed concentration) 
will be presented in listings and tabulated using summary statistics by treatment group. 
Individual and mean concentration-time profiles will be plotted by treatment group. The PK 
analysis set will be used for summaries and analyses of PK parameters. 
A population PK model may be developed. If developed, the population PK model may be 
reported separately. The analysis plan for the population PK analysis may be separately defined, 
and the results of these analyses may be reported separately. 
6.7.2 
Pharmacodynamic 
 Analysis 
Individual values, change from baseline, and mean change from baseline and/or percent change 
from baseline at different timepoints for placebo and each TAK-079 dose level will be calculated 
for the pharmacodynamic measures listed in Appendix 9.3 
 listed below. 
• Serum immunoglobulin levels. 
 
 
• Autoantibodies. Only subjects who are positive for a specific SLE antibody at baseline 
will be summarized for that autoantibody.  
 
 
Descriptive summaries may include geometric mean and CV% where needed. 
For PD
parameters, figures of mean values and mean percent change from baseline 
will be generated. Mean percent change from baseline will not be plotted for measures related to 
receptor occupancy, instead mean change from baseline will be generated. Individual subject 
profiles over time for selected parameters may be plotted as needed. 
The PD analysis set will be used for summaries, listings and analyses of PD
 
parameters. 
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