Clinical trial NCT02176486
Conditions: Lupus Nephritis
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2014-06-09; Completion date: 2018-01-19
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to characterize the safety and tolerability of ixazomib when administered as multiple oral doses at escalating dose levels in participants with lupus nephritis.

Detailed description:
The drug being tested in this study is called ixazomib. Ixazomib is being tested to find a safe and well tolerated dose in participants with lupus nephritis. This study will look at side effects and lab results in participants who take ixazomib, along with the characterization of its pharmacokinetics (PK). This study is designed as a randomized, sequential-panel, multiple rising dose study.

The study will enroll approximately 40 participants. The study population will consist of 4 Cohorts. At least 5 participants (4:1 active:placebo) will be recruited into the 0.5 mg dose group (Cohort A), at least 5 participants (4:1 active:placebo) in the 2.0 mg dose group (Cohort B), 8 participants (6:2 active:placebo) in the 3.0 mg dose group (Cohort C), and 8 participants (6:2 active:placebo) in the 4.0 mg dose group (Cohort D). Participants in each Cohort will be asked to take one capsule on Days 1, 8 and 15 in 28-day cycle, for 3 cycles. PK samples will be collected to measure concentrations of ixazomib. The starting dose in Cohort A will be 0.5 mg followed by administrations of 2, 3 and 4 mg in subsequent cohorts.

This multi-center trial will be conducted in the United States and Europe. The overall time to participate in this study is up to 196 days. Participants will make 19 visits to the clinic during the treatment period and will make follow-up visits monthly for 3 months for follow-up assessments.

Arms: arm 1: Ixazomib 0.5 mg, capsules, orally, once, on Day 1, 8 and 15 in 28-day cycles, Cycles 1 through 3. arm 2: Ixazomib 2 mg, capsules, orally, once, on Day 1, 8 and 15 in 28-day cycles, Cycles 1 through 3. arm 3: Ixazomib 3 mg, capsules, orally, once, on Day 1, 8 and 15 in 28-day cycles, Cycles 1 through 3. arm 4: Ixazomib 4 mg, capsules, orally, once, on Day 1, 8 and 15 in 28-day cycles, Cycles 1 through 3. arm 5: Ixazomib placebo-matching capsules, orally, once on Days 1, 8 and 15 in 28-day cycle, Cycles 1 through 3.
Interventions: intervention 1: Ixazomib intervention 2: Placebo
Intervention descriptions: intervention 1: Ixazomib capsules. intervention 2: Ixazomib placebo-matching capsules.

Protocol documents:
Prot_001.pdf: 
This may include, but is not limited to, redaction of the following: 


•
Title: A Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Safety, Tolerability and
Pharmacokinetic Study of Multiple Rising Doses of MLN9708 for the Treatment of Subjects
With ISN/RPS Class III or IV Lupus Nephritis
NCT Number: NCT02176486
Protocol Approve Date: 30 November 2017
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information. 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.


1.0 TITLE PAGE
PHASE 1 PROTOCOL AMENDMENT
A Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Safety, Tolerability and 
Pharmacokinetic Study of Multiple Rising Doses of MLN9708 for the Treatment of Subjects 
With ISN/RPS Class III or IV Lupus Nephritis
MLN9708_101 MRD Study in Lupus Nephritis
Sponsor:
Takeda Development Center Americas, Inc. 
One Takeda Parkway
Deerfield, IL 60015
Takeda Development Centre Europe Ltd. 
61 Aldwych
London WC2B 4AE, UK
Study Number:
MLN9708_101
IND Number:
119,025
EudraCT Number:
2014-000125-21
Compound:
Ixazomib (MLN9708)
Date:
30 November 2017
Amendment Number: 
11
Date
Amendment Number
Amendment Type
Region
18 December 2013
Initial Protocol
Not applicable
Global
28 April 2014
1
Substantial
Global
26 August 2014
2
Substantial
United Kingdom
06 February 2015
3
Substantial
Global
16 March 2015
04
Substantial
United Kingdom
08 June 2015
05
Substantial
Global
01 July 2015
06
Substantial
United Kingdom
07 August 2015
07
Substantial
Global
08 August 2015
08
Substantial
United Kingdom
24 May 2016
09
Substantial
Global
23 June 2016
10
Substantial
United Kingdom
30 November 2017
11
Substantial
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her 
staff, and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided.
Issue
US Contact
Europe Contact
Serious adverse event and pregnancy 
reporting
Medical Monitor (medical advice on 
protocol, compound, and medical 
management of subjects)
Responsible Medical Officer (carries 
overall responsibility for the conduct 
of the study)
Personal Protected Data


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1.2
Approval
REPRESENTATIVES OF TAKEDA
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also 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, clinical 
trial disclosure laws, and regulations.
SIGNATURES
Electronic Signatures may be found on the last page of this document.
Personal Protected Data


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1.3
Protocol Amendment 11 Summary of Changes
This document describes the changes in reference to the protocol incorporating Amendment 
No. 11. Through feedback from investigators, the Sponsor has determined the need to refine the 
study's eligibility criteria to be more reflective of the current clinical practice without affecting 
the objective integrity of the study. In addition, this amendment adds an Open-Label Treatment 
Extension Period to allow subjects to receive up to 3 additional cycles of open-label ixazomib 
treatment at the discretion of the investigator.
Minor grammatical, editorial, and formatting changes are included for clarification purposes 
only.
Full details on changes of text are given in Appendix K.
Changes in Amendment 11
1. Updated the drug metabolism and concomitant medication information to reflect recent 
population pharmacokinetic (PK) analyses and drug-drug interaction study results from an 
ixazomib study (Study C16009) demonstrating that cytochrome P-450 inhibitors do not 
affect ixazomib PK and clarified details about PK assessments.
2. Added optional Open-Label Treatment Extension Period to the Study Design to allow 
treatment with up to 3 additional cycles of ixazomib at the discretion of the investigator.
3. Updated the safety summary conclusion with latest safety data from the Investigator's 
Brochure.
4. Revised Inclusion Criterion 5 to allow subjects who have proteinuria ≥1 g/day due to a recent 
lupus nephritis (LN) flare, and who are refractory to current standard of care for those 
subjects who do not have a kidney biopsy within 2 years of the Screening.
5. Revised Inclusion Criterion 6 to allow subjects with Class V or Class V with Class II 
nephritis and urine protein creatinine ratio levels of ≥1 into the study rather than current 
criteria of >3.
6. Revised Inclusion Criterion 11 to allow subjects who received ≤2.0 mg ixazomib in earlier 
cohorts, rather than <2 mg ixazomib, to be re-enrolled into Cohorts B and C (2.0 mg and 
3.0 mg).
7. Revised Exclusion Criterion 10 to add a stipulation to IgG <75% of lower limit of normal to 
allow subjects with IgG >4.2 g/dL into the study if the cause of low IgG is due to LN 
proteinuria and all other causes of hypo-gammaglobulinemia have been ruled out.


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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 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 protect the rights, safety, privacy, and 
well-being of study subjects 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 serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix B – Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State)
Location of Facility (Country)


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 11 Summary of Changes ..........................................................4
2.0
STUDY SUMMARY ....................................................................................................12
3.0
STUDY REFERENCE INFORMATION ......................................................................20
3.1
Study-Related Responsibilities.................................................................................20
3.2
Principal Investigator...............................................................................................20
3.3
List of Abbreviations ...............................................................................................21
3.4
Corporate Identification...........................................................................................23
4.0
INTRODUCTION.........................................................................................................24
4.1
Background .............................................................................................................24
4.1.1
Systemic Lupus Erythematosus..........................................................................24
4.1.2
Lupus Nephritis .................................................................................................24
4.1.3
Proteasome Inhibition in SLE and LN................................................................25
4.1.4
Proteasome Inhibitor Ixazomib...........................................................................26
4.1.4.1 Nonclinical Toxicology................................................................................26
4.1.4.2 Drug Metabolism and PK.............................................................................28
4.1.4.3 Clinical Experience ......................................................................................29
4.2
Rationale for the Proposed Study.............................................................................34
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................35
5.1
Objectives................................................................................................................35
5.1.1
Primary Objective(s)..........................................................................................35
5.1.2
Secondary Objectives.........................................................................................35
5.2
Endpoints.................................................................................................................35
5.2.1
Primary Endpoints .............................................................................................35
5.2.2
Secondary Endpoints..........................................................................................35
5.2.3
Exploratory Endpoints .......................................................................................36
5.2.4
Additional Safety Endpoints...............................................................................37
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................38
6.1
Study Design ...........................................................................................................38
6.2
Justification for Study Design, Dose and Endpoints .................................................43
6.3
Premature Termination or Suspension of Study or Investigational Site.....................46
6.3.1
Criteria for Premature Termination or Suspension of the Study..........................46


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6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites .........46
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)................................................................46
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............47
7.1
Inclusion Criteria .....................................................................................................47
7.2
Exclusion Criteria ....................................................................................................49
7.3
Excluded and Restricted Medications, Procedures and Dietary Products..................51
7.4
Diet, Fluid, and Activity Control..............................................................................52
7.4.1
Criteria for Discontinuation or Withdrawal of a Subject .....................................53
7.4.2
Dose Escalation Criteria.....................................................................................54
7.4.3
DLTs, Dose Modifications, and Stopping Rules.................................................55
7.5
Procedures for Discontinuation or Withdrawal of a Subject......................................59
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................60
8.1
Study Medication and Materials...............................................................................60
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................60
8.1.1.1 Investigational Drug.....................................................................................60
8.1.1.2 Concomitant Medications for Treatment of SLE While on Study 
Medication...................................................................................................61
8.1.1.3 Corticosteroids Taper and Rescue Therapy...................................................62
8.1.2
Storage...............................................................................................................63
8.1.3
Dose and Regimen .............................................................................................63
8.1.4
Overdose............................................................................................................64
8.2
Study Medication Assignment and Dispensing Procedures.......................................65
8.3
Randomization Code Creation and Storage..............................................................65
8.4
Investigational Drug Blind Maintenance ..................................................................65
8.5
Unblinding Procedure..............................................................................................65
8.6
Accountability and Destruction of All Study Medication .........................................66
9.0
STUDY PLAN ..............................................................................................................68
9.1
Study Procedures.....................................................................................................68
9.1.1
Informed Consent Procedure..............................................................................68
9.1.2
Pharmacogenomic Informed Consent Procedure ................................................68
9.1.3
Demographics, Medical History, and Medication History Procedure..................68
9.1.4
Safety Assessments............................................................................................68
9.1.4.1 Tuberculosis Screening ................................................................................68
9.1.5
Physical Examination Procedure ........................................................................69
9.1.6
Weight, Height, and Body Mass Index...............................................................69


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9.1.7
Vital Sign Procedure..........................................................................................70
9.1.8
Documentation of Concomitant Medications......................................................70
9.1.9
Documentation of Concurrent Medical Conditions.............................................70
9.1.10 Procedures for Clinical Laboratory Samples.......................................................70
9.1.11 Contraception and Pregnancy Avoidance Procedure...........................................73
9.1.12 Pregnancy ..........................................................................................................74
9.1.13 ECG Procedure..................................................................................................74
9.1.14 Additional Assessments .....................................................................................75
9.1.14.1
Urinalysis...............................................................................................75
9.1.14.2
eGFR......................................................................................................75
9.1.14.3
Definition of Complete and Partial Renal Responses ..............................75
9.1.14.4
........................................................................76
9.1.14.5
FACT/GOG-NTX ..................................................................................77
9.1.15 Pharmacodynamic Sample Collection ................................................................77
9.1.16 Pharmacogenomic and Other Sample Collection................................................77
9.1.17 PK Sample Collection........................................................................................78
9.1.17.1
Collection of plasma and 
for PK Sampling for Ixazomib ....78
9.1.17.2
Bioanalytical Methods............................................................................79
9.1.18 PK Parameters ...................................................................................................79
9.1.19 Preparation, Reconstitution, and Dispensation....................................................79
9.1.20 Documentation of Screen Failure .......................................................................80
9.1.21 Documentation of Randomization......................................................................80
9.2
Monitoring Subject Treatment Compliance..............................................................80
9.3
Schedule of Observations and Procedures................................................................80
9.3.1
Screening...........................................................................................................80
9.3.1.1 Screening Visit.............................................................................................81
9.3.2
Randomization...................................................................................................82
9.3.2.1 Day 1 (Cycle 1, 2 and 3)...............................................................................82
9.3.2.2 Day 2 (Cycle 1)............................................................................................84
9.3.2.3 Day 8 (Cycle 1, 2 and 3)...............................................................................84
9.3.2.4 Day 15 (Cycle 1, 2 and 3).............................................................................84
9.3.2.5 Day 16 (Cycle 3 only) ..................................................................................85
9.3.2.6 Day 22 (Cycle 1, 2 and 3).............................................................................85
9.3.3
End of Treatment Visit/Early Termination/Final Visit ........................................85
9.3.3.1 Day 28 (Cycle 3)/Final Visit/ET/EOT ..........................................................86
Confidential Company 
Information
Confidential
Company
Information


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9.3.4
Open-Label Treatment Extension.......................................................................87
9.3.5
Follow-up Visit..................................................................................................88
9.4
Blood Volume .........................................................................................................89
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................91
10.1
Definitions...............................................................................................................91
10.1.1 Pretreatment Events ...........................................................................................91
10.1.2 AEs....................................................................................................................91
10.1.3 Additional Points to Consider for PTEs and AEs................................................91
10.1.4 SAEs..................................................................................................................93
10.1.5 Management of Clinical AEs of Interest.............................................................94
10.1.5.1
Diarrhea .................................................................................................94
10.1.5.2
Nausea and/or Vomiting .........................................................................94
10.1.5.3
Volume Depletion ..................................................................................94
10.1.5.4
Renal AEs ..............................................................................................94
10.1.5.5
Erythematous Rash With or Without Pruritus .........................................95
10.1.5.6
Thrombocytopenia..................................................................................95
10.1.5.7
Prophylaxis Against Risk of Infection.....................................................95
10.1.5.8
Peripheral Neuropathy............................................................................96
10.1.5.9
Hypoglobulinemia..................................................................................96
10.1.6 Severity of PTEs and AEs..................................................................................96
10.1.7 Causality of AEs ................................................................................................96
10.1.8 Relationship to Study Procedures.......................................................................96
10.2
Procedures...............................................................................................................97
10.2.1 Collection and Reporting of AEs........................................................................97
10.2.1.1
PTE and AE Collection Period ...............................................................97
10.2.1.2
PTE and AE Reporting ...........................................................................97
10.2.2 Collection and Reporting of SAEs......................................................................98
10.2.3 Reporting of Abnormal Liver Function Tests .....................................................98
10.3
Follow-up of SAEs ..................................................................................................98
11.0
STUDY-SPECIFIC COMMITTEES ...........................................................................100
12.0
DATA HANDLING AND RECORDKEEPING..........................................................101
12.1
Electronic CRFs.....................................................................................................101
12.2
Record Retention ...................................................................................................101
13.0
STATISTICAL METHODS........................................................................................103
13.1
Statistical and Analytical Plans ..............................................................................103


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13.1.1 Analysis Sets....................................................................................................103
13.1.2 Analysis of Demographics and Other Baseline Characteristics .........................103
13.1.3 Medical History and Concurrent Medical Conditions .......................................103
13.1.4 Medication History and Concomitant Medication.............................................104
13.1.5 PK Analysis .....................................................................................................104
13.1.6 Pharmacodynamic and Exploratory Analysis....................................................104
13.1.7 Safety Analysis ................................................................................................104
13.1.7.1
AEs ......................................................................................................104
13.1.7.2
Kidney function Evaluation ..................................................................105
13.1.7.3
Clinical Laboratory Evaluation.............................................................105
13.1.7.4
Vital Signs............................................................................................105
13.1.7.5
Electrocardiograms...............................................................................105
13.2
Interim Analysis and Criteria for Early Termination ..............................................105
13.3
Determination of Sample Size................................................................................105
14.0
QUALITY CONTROL AND QUALITY ASSURANCE.............................................106
14.1
Study-Site Monitoring Visits .................................................................................106
14.2
Protocol Deviations................................................................................................106
14.3
Quality Assurance Audits and Regulatory Agency Inspections ..............................107
15.0
ETHICAL ASPECTS OF THE STUDY......................................................................108
15.1
IRB and/or IEC Approval ......................................................................................108
15.2
Subject Information, Informed Consent, and Subject Authorization .......................109
15.3
Subject Confidentiality ..........................................................................................110
15.4
Publication, Disclosure, and Clinical Trial Registration Policy...............................110
15.4.1 Publication and Disclosure...............................................................................110
15.4.2 Clinical Trial Registration................................................................................111
15.4.3 Clinical Trial Results Disclosure ......................................................................111
15.5
Insurance and Compensation for Injury..................................................................111
16.0
REFERENCES............................................................................................................112
LIST OF IN-TEXT TABLES
Table 4.a
Study C16004 Most Common (>30% of Subjects in MTD Cohort) AEs 
Regardless of Causality by Dose Cohort.............................................................31
Table 4.b 
Summary of MLN9708 (ixazomib) Clinical Oncology Studies With Once 
Weekly Oral Dosing...........................................................................................32


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Table 6.a
Summary of the Simulated Human Exposures Margins Relative to Nonclinical 
Toxicity Studies and Clinical MTD....................................................................45
Table 7.a
Prohibited Medications ......................................................................................52
Table 7.b
Dose Increase Factors ........................................................................................54
Table 7.c
Monitoring of Hematologic Toxicities and Dose Modification/Drug Stopping 
Rules..................................................................................................................57
Table 7.d
Monitoring of Non-Hematologic Toxicities and Dose Modification/Drug 
Stopping Rules...................................................................................................58
Table 8.a
Treatment Groups ..............................................................................................64
Table 9.a
Clinical Laboratory Tests...................................................................................71
Table 9.b
Collection of Blood Samples for PK Analysis during the Double-Blind 
Treatment Period................................................................................................78
Table 9.c
Approximate Blood Volume ..............................................................................89
Table 10.a
Takeda Medically Significant AE List................................................................94
Table 14.a
Windows for PK Sample Collection (Cycle 1 and Cycle 3) ..............................106
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................41
Figure 6.b
Overall Design of the Double-Blind Treatment Period, With Proposed Dose 
Escalation ..........................................................................................................43
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures: Double-Blind Treatment Period .......................114
Appendix B
Responsibilities of the Investigator...................................................................122
Appendix C
Elements of the Subject Informed Consent.......................................................124
Appendix D
Investigator Consent to Use of Personal Information........................................127
Appendix E
Collection, Storage, and Shipment of Bioanalytical Samples............................128
Appendix F
Total Blood Volume of Blood Withdrawal.......................................................132
Appendix G
Instructions for Processing and Shipping of Plasma Samples for 
Pharmacogenomics ..........................................................................................134
Appendix H
Criteria for Classification of Systemic Lupus Erythematosus ...........................136
Appendix I
Pathology Classification of LN ........................................................................141
Appendix J
Diagnostic Criteria for Psychoactive Substance Dependence............................143
Appendix K
Detailed Description of Amendments to Text...................................................145


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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc., Takeda 
Development Centre Europe Ltd.
Compound:
ixazomib (MLN9708)
Title of Protocol: A Phase 1b, Randomized, Double-
Blind, Placebo-Controlled, Safety, Tolerability and 
Pharmacokinetic Study of Multiple Rising Doses of 
MLN9708 for the Treatment of Subjects With ISN/RPS 
Class III or IV Lupus Nephritis 
IND No.: 119,025
EudraCT No.: 2014-
000125-21
Study Number: MLN9708_101
Phase: 1b
Study Design:
This study is a phase 1b, randomized, double-blind, placebo-controlled, safety, tolerability, and pharmacokinetic 
(PK) study of multiple-rising doses (MRD) of ixazomib for the treatment of subjects with International Society of 
Nephrology (ISN)/Renal Pathology Society (RPS) Class III, IV or V changes [excluding Class III (C), IV-S (C), and 
IV-G (C)] or WHO 1982 classification of Class III, IV, or V (excluding Class IIIc and IVd) lupus nephritis (LN). It 
is anticipated that 4 ixazomib dose levels will be examined. At least 5 subjects (4:1) will be recruited into the 0.5 mg 
dose group (Cohort A), at least 5 subjects (4:1) in the 2.0 mg dose group (Cohort B), 8 subjects (6:2) in the 3.0 mg 
dose group (Cohort C), and 8 subjects (6:2) in the 4.0 mg dose group (Cohort D). Subjects will be considered 
eligible on the basis of study inclusion and exclusion criteria, verified by an adjudication committee, and 
randomized. Following each of the 0.5, 2.0, and 3.0 mg dose cohorts, available PK and safety data will be evaluated 
before escalation. For each dose level cohort, the Safety Review Committee (SRC) will carefully review the 
available safety, tolerability, and PK data to determine if dosing should be escalated in the next cohort, lowered, or 
expanded within the same dose cohort to obtain additional information before a dose-escalation decision, or stopped. 
After 5 subjects are recruited in the 4.0 mg dose group (Cohort D) and complete at least 1 cycle of ixazomib or 
placebo, an analysis may be conducted on available PK data and blinded safety data from all cohorts. Subject 
numbers may be increased as appropriate per cohort to a total number not to exceed 40 subjects in all cohorts 
combined. Two subjects with Class V or Class V with Class II nephritis are permitted per cohort. Subjects will be 
treated with three 28-day cycles of ixazomib or placebo. Subjects who successfully completed 12 weeks of double-
blind treatment without any AE resulting in dose modification or discontinuation of the study drug (defined in 
Section 7.4.3) will be eligible to receive up to 3 additional cycles of open-label ixazomib at the discretion of the 
investigator and confirmed by the Takeda medical monitor/designee following the end of the Double-Blind 
Treatment Period. The subjects need to begin the Open-Label Treatment Extension Period within 4 weeks of 
completing Cycle 3 of double-blind treatment.
Each 28-day cycle will consist of 3 once-weekly oral doses of 0.5, 2.0, 3.0, or 4.0 mg of ixazomib (dosage strength 
is stated as the active boronic acid ixazomib) or placebo, depending on the cohort. Subjects who received a dose 
≤2.0 mg and completed all cycles including the Follow-up Period, will be permitted to re-enroll into the 2.0 and 
3.0 mg dose groups, provided they have no drug-related adverse events (AEs) >Grade 1 that required study drug 
dose modification, no AEs >Grade 2, continue to meet all inclusion and exclusion criteria, and the SRC (consisting 
of sponsor personnel and the coordinating investigator) have reviewed and approved re-enrollment. Subjects must be 
receiving standard of care treatment for LN and remain on their current stable and allowed therapies during the 
Screening Period and throughout the duration of the study (Section 8.1.1.2).
The study consists of the following Periods: a Screening Period (up to 35 days), a Double-Blind Treatment Period 
(Day 1 to Day 84) and either a Follow-up Period or an Open-Label Treatment Extension Period (Day 85 to Day 
168). For those subjects who enter the Open-Label Treatment Extension Period, the last study visit will be 30 days 
after the last open-label treatment cycle or Day 168, whichever is longer. Subjects can be randomized 24 (+11) days 
after Screening (between Days -24 and -35) and once safety laboratory tests and inclusion/exclusion criteria have 
been reviewed and confirmed by the investigator. Diagnostic criteria, disease activity measures, and treatment 
history will be documented, and required laboratory investigations initiated. Subject eligibility will be reviewed by 
an adjudication committee. The responsibilities and criteria of this committee will be defined in an adjudication 


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charter. 
Following verification of eligibility, subjects will return to the clinic on Day 1, undergo baseline assessments, 
laboratory testing, and will be randomized to either ixazomib or placebo within each cohort/dose level. The Double-
Blind Treatment Period will consist of three 28-day treatment cycles (Cycles 1, 2, and 3) without intra-subject dose 
escalation. Subjects will receive ixazomib treatment on Days 1, 8, and 15 of each 28-day cycle. The second and third 
cycles will commence on the first day following Day 28 of the preceding cycle (ie, with a period of 13 days between 
the third drug administration of a cycle and the first drug administration of the following cycle). The Double-Blind 
Treatment Period will be limited to 3 complete cycles with ixazomib or placebo, over an expected duration of 
12 weeks. However, the total treatment period may be longer than the standard 12 weeks if delays between cycles 
are necessary due to AEs. After completion of Cycle 3 of the Double-Blind Treatment Period, the subject will either 
enter the Follow-up Period or enter an optional Open-Label Treatment Extension Period at the investigator’s 
discretion and confirmed by the Takeda physician/designee. The Follow-up Period or the Open-Label Treatment 
Extension Period consisting of follow-up visits every 4 weeks will start after the end of the Double-Blind Treatment 
Period (Day 84). The Open-Label Treatment Extension Period will be limited to up to 3 cycles of treatment with 
ixazomib on the same dose and schedule that subjects were receiving in the double blind period over an expected 
duration of 12 weeks.
Subjects will receive ixazomib cycles consisting of doses of 0.5 mg (Cohort A), 2 mg (Cohort B), 3 mg (Cohort C), 
or 4 mg (Cohort D), or placebo. The ascending dose cohorts will be enrolled sequentially. Dosing of subsequent 
cohorts will not commence until at least 5 subjects in Cohorts A and B and 8 subjects in Cohort C have received at 
least 1 dose of investigational drug and have reached Day 28 of Cycle 1 or have completed their last evaluation 
within Cycle 1 with a satisfactory review of all available safety and tolerability data. Subjects discontinued or 
withdrawn after randomization for nonsafety reasons will only be replaced if the number of subjects per cohort 
evaluable for safety on Day 28 of Cycle 1 is reduced below 6 subjects for Cohorts C and D, below 5 subjects for 
lower than 3.0 mg dose cohorts, or the SRC recommends expanding with the same dose to obtain additional 
information before a dose-escalation decision. Down-titration of ixazomib is permitted for individual subjects for 
safety and tolerability reasons at any time during the Treatment Period, except for subjects receiving 0.5 mg in 
Cohort A. If necessary for safety or tolerability reasons or in the judgment of the investigator, ixazomib treatment 
should be stopped altogether an End of Study Visit should be completed. The subject should then complete the 
remainder of the study period as the Follow-up Period. Dose modification and dose deferral should be discussed 
with the Sponsor’s Medical Monitor; guidelines for the modification or deferral of doses will be provided.
During the Double-Blind Treatment Period, ixazomib will always be dosed at the study site and subjects will return 
to the clinic for each administration of ixazomib. During the Open-Label Treatment Extension Period, subjects will 
receive the first dose of each cycle at the clinic and the other 2 weekly doses can be given to the subjects to take at 
home. All subjects will return to the clinic every 4 weeks to receive the first dose of each cycle. For scheduling 
flexibility, study visits can take place ± 2 days from each scheduled day during the Treatment Period and ±1 week 
during the Follow-up Period. A minimum of 120 hours should occur between ixazomib doses. Any variance in the 
dosing schedule should not alter the schedule of subsequent dosing. 
Subjects will undergo safety laboratory assessments, total immunoglobulin G, M, and A (IgG/IgM/IgA), LN 
assessments including but not limited to urine protein to creatinine ratio (UPCR), estimated glomerular filtration rate 
(eGFR), anti-double-stranded deoxyribonucleic acid (dsDNA) antibodies, and complement C3 and C4 levels via a 
central laboratory according to the schedule in Appendix A. Pharmacogenomic (PGx) and exploratory biomarker 
samples will also be sent to a central laboratory for analysis. 
Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor with an estimated terminal elimination 
half-life (t1/2) of ~ 4 to 9 days in plasma. For Cohorts A to D, plasma concentrations of ixazomib over time will be 
evaluated following the first dose of Cycle 1 and following the last dose of Cycle 3 of the Double-Blind Treatment 
Period. Predose samples will be collected before each dose in Cycles 1, 2, and 3 of the Double-Blind Treatment 
Period. Available PK data will be reviewed as part of the overall safety and tolerability evaluation of ixazomib in 
LN and for the dose escalation decision.
Recent evidence suggests that genetic variation accounts for differing responses to bortezomib therapy. A single 
nucleotide polymorphism (SNP) at position 11 in the PSMB1 gene (in the region encoding the leader sequence for 


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the beta subunit of the 20S proteasome) has been associated with reduced proteasome activity and is associated with 
enhanced bortezomib activity in multiple myeloma and relapsed follicular lymphoma. 
 
 
 
 
 
In addition, hematology and chemistry safety laboratory assessments will be collected before each dose of ixazomib 
during the Double-Blind Treatment Period and before each cycle of open-label treatment; the results of all available 
laboratory tests will be reviewed by the investigator before administration of the scheduled dose of ixazomib. If the 
central laboratory results are not available for the Open-Label Treatment Extension Period an additional safety 
laboratory assessment can be conducted at the local laboratory before dosing and they will be recorded in the 
electronic case report forms (eCRFs). A negative urine pregnancy test result is required before each administration 
of investigational drug at the visits specified in the schedule of events table.
In common with other immunosuppressant agents, ixazomib may have additional effects on host defense. The 
subject’s immunization status should be reviewed at the Screening Visit, and all appropriate vaccinations should be 
completed at least 1 month before treatment. These may include but are not limited to pneumococcal and inactivated 
influenza vaccines.
If lymphopenia is noted, subjects may be at an increased risk of infection. In particular, lymphopenia can be 
associated with reactivation of herpes zoster and herpes simplex viruses, and cytomegalovirus. Antiviral therapy 
such as acyclovir or valacyclovir may be initiated at the onset of infection after administration of ixazomib. Other 
antivirals are also acceptable. Provision of medication will be arranged by the investigator from local suppliers and 
will be reimbursed by the Sponsor. 
Each investigator will review any safety findings and laboratory results to determine if a subject should receive the 
next dose within each cycle. For the Double-Blind Treatment Period, the investigator will evaluate safety and 
tolerability for each subject on Day -1 and before each dose during every cycle. On Day 22 of each cycle, the 
investigator-led team will evaluate all available safety information for the subject to determine eligibility to initiate 
the subsequent cycle. For the Open-Label Treatment Extension Period the investigator will evaluate safety and 
tolerability for each subject before each cycle as specified in the Table of Events. A schematic of the study design is 
presented below:
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Schematic of Study Design:
Double-Blind Treatment Period
Placebo (Once a week for the first 3 weeks of Cycle [N˃6]) 
Ixazomib (Once a week for the first 3 weeks of Cycle [N≥20]) 
Double-Blind Treatment Period (84 days)
Visits at Days 1, 2, 
8, 15 & 22
Visits at Days 1, 
8, 15 & 22
Visits at Days 1, 8, 
15, 16, 22 & 28
Visits at Months 4, 5 
& 6
Cycle 1
Cycle 2
Cycle 3
3-Month Follow-up 
Day -24(-
11) 
to -1
    
             
   
Screening 
Visit
(a) Day 1 
/ 
Randomization
Day 84
Day 168
(a) At randomization, subjects will be assigned 0.5, 2.0, 3.0, or 4.0 mg of ixazomib or placebo, each 4-week cycle 
will consist of 3 once-a-week oral doses. In case abnormal, clinically significant findings are observed upon 
discharge, subjects may be brought back to the clinic for re-evaluation per investigator’s discretion.
Open Label Treatment Period
Ixazomib (Once a week for the first 3 weeks of Cycle) 
Open Label Treatment Period (84 days)
Visits at Days 1
Visits at Days 1
Visits at Days 1 & 
28
30 days after last 
cycle
Cycle 1
Cycle 2 (a)
Cycle 3 (a)
Follow-up (a)
    
             
   
(a) Day 85
Day 168
Day 198 
(a) All subjects who enter the Open-Label Treatment Extension Period will have monthly visit up to at least 
Day 168. If open-label treatment is terminated before the completion of all 3 cycles, an end of treatment visit will be 
performed (Day 28 of current cycle) and the subsequent cycle Day 1 visits will be replaced with a follow-up visit.
Dose escalation will be sequential, with escalation only considered after all the following conditions have been met; 
1.
All subjects in the preceding cohort have been randomized;
2.
All subjects of the preceding cohorts have received at least 1 dose of investigational drug and have reached 
Day 28 of Cycle 1 or have completed their last evaluation within Cycle 1.
3.
Before any dose escalation, the SRC will review all the available safety, tolerability and PK data of the entire 
dose-level cohort to decide if dose escalation is appropriate.


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Overall Design of Double-Blind Treatment Period, With Proposed Dose Escalation
Primary Objective:
To characterize the safety and tolerability of ixazomib when administered as multiple oral doses at escalating dose 
levels in subjects with LN. 
Secondary Objectives:
1.
To assess changes from Baseline in UPCR in LN subjects following multiple administrations of ixazomib. 
2.
To evaluate the effect of ixazomib on kidney function, as assessed by changes from Baseline in serum 
creatinine and eGFR.
3.
To evaluate the effect of ixazomib on antibody to double-stranded DNA (anti-dsDNA) antibodies titer and 
complement C3/C4 levels.
4.
To characterize the PK of ixazomib in LN subjects when ixazomib is administered over 3 cycles consisting of 
3 doses per cycle.
Subject Population: Male or female subjects aged 18 to 75 years inclusive, with ISN/RPS class III, IV or V LN, 
who have had inadequate response to at least 3 months of treatment with an immunosuppressive regimen including 
single or sequential use of either cyclophosphamide (CYC), mycophenolate mofetil (MMF), mycophenolic acid 
(MA) or azathioprine (AZA).
Number of Subjects:
Estimated total: ≤40 subjects
Number of Sites: 
Approximately 21 sites in the US and Europe (such as 
UK, Germany, Spain, Russia and Ukraine)


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Dose Level(s):
active compound 0.5 mg or matching placebo 
active compound 2 mg or matching placebo
active compound 3 mg or matching placebo
active compound 4 mg or matching placebo
Each capsule contains ixazomib equivalent to the stated 
dose in mg of the active boronic acid ixazomib. 
Route of Administration:
Oral
Duration of Treatment:
Double-Blind Treatment Period:
Total of 3 cycles over approximately 84 days of duration. 
Each 28-day cycle consists of once weekly dosing for 3 
weeks followed by 13 days without ixazomib or placebo
Open-Label Treatment Extension Period:
Up to a total of 3 cycles over approximately 84 days of 
duration. Each 28-day cycle consists of once weekly 
dosing for 3 weeks followed by 13 days without ixazomib
Period of Evaluation:
~210 days including Screening period
Main Criteria for Inclusion:
Male or female subjects with ISN/RPS class III, IV, V or WHO classification of class III, IV, or V LN with 
coexisting classes permitted who have inadequate response to at least 3 months of treatment with an 
immunosuppressive regimen including single or sequential use of either CYC, MMF, MA or AZA; and non-
pregnant, non-lactating female subjects who are 18 to 75 years of age inclusive, at the time of signing consent; 
capable of understanding and complying with protocol requirements; must be able to understand and sign a written 
informed consent. Subjects with a confirmed diagnosis of LN who have not had a renal biopsy within 2 years of 
screening and who cannot have a renal biopsy during the Screening Period may be eligible for the study if they have 
proteinuria of ≥1 g/24 hours due to a LN renal flare occurring within 1 year of the screening. A LN renal flare is 
defined as at least a doubling of proteinuria with no other explanation such as a secondary pathology (eg, diabetic 
nephropathy) or change in medication (eg, reduction of angiotensin-converting enzyme/angiotensin II receptor 
blocker).
Main Criteria for Exclusion:
Subjects having severe, active central nervous system lupus; (British Isles Lupus Assessment Group [BILAG] A or 
B); or an autoimmune disease other than SLE as their main diagnosis; or have drug-induced SLE.
Use of any excluded or prohibited medications or supplements outlined in the protocol.
Main Criteria for Evaluation and Analyses:
Safety: 
Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and TEAEs leading to withdrawal.
Changes in clinical laboratory values including chemistry, hematology. Changes in vital signs including body 
temperature, respiration, sitting and standing blood pressure, or heart rate.
Electrocardiogram (ECG) findings. 
Subject-reported peripheral neuropathy (functional assessment of cancer therapy [FACT]/GOG-NTX version 4).
PK: 
During the Double-Blind Treatment Period, blood samples (3 mL) will be collected for the determination of plasma 
concentrations of ixazomib 
 
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Sample 
Type
Time Postdose
Plasma
Cycle 1
Predose (within 0.5 hour before dosing) on Days 1, 8, and 15. On Day 1 of Cycle 1, 
samples will be collected at 0.25, 0.5, 1, 1.5, 2, 4, 8, 24, and 168 hours (predose Day 8) 
following the first dose. 
Cycle 2
Predose (within 0.5 hour before dosing) on Days 1, 8, and 15. Sample will be collected on 
Day 22 (168 hours postdose on Day 15) in Cycle 2.
Cycle 3
Predose (within 0.5 hour before dosing) on Days 1, 8, and 15. On Day 15 of Cycle 3 
following the third dose, samples will be collected at 0.25, 0.5, 1, 1.5, 2, 4, 8, 24, 168 and 
312 hours postdose in Cycle 3.
PK parameters of ixazomib will be derived using non-compartmental analysis methods. The PK parameters of 
ixazomib will be determined from the plasma concentration-time data from all evaluable subjects. Actual sampling 
times, rather than scheduled sampling times, will be used in all computations involving sampling times. The 
following PK parameters may be determined, as permitted by the data, from concentrations of ixazomib in plasma: 
maximum observed plasma concentration (Cmax), time of first occurrence of Cmax (tmax), area under the plasma 
concentration-time curve from time 0 to time of last quantifiable concentration (AUClast), area under the plasma 
concentration-time curve from time 0 to 24 hours (AUC24) and area under the plasma concentration-time curve from 
time 0 to 168 hours (AUC168).
 
.
Pharmacodynamics: 
Changes in the levels of anti-dsDNA antibodies, complement C3/C4 levels, and UPCR.
Exploratory Assessments: 
Laboratory tests: 
Clinical laboratory tests including hematology, urinalysis, and blood chemistry will be performed at Screening and 
during the 3-month Double-Blind Treatment Period, and the Open-Label Treatment Extension Period and follow-up 
periods. 
Estimated total volume of blood drawn:
453.5 mL (during the Double-Blind Treatment Period and Follow-up)
493.5 mL (during the Double-Blind Treatment Period, Open-Label Treatment Extension Period, and Follow-up)
Statistical Considerations:
Safety:
Safety summaries will be performed for each dose cohort.
All AEs will be presented in listings. Treatment-emergent AEs will be summarized for each ixazomib dose level and 
placebo. 
Baseline, postdose and change from Baseline to postdose laboratory data will be summarized for each ixazomib 
dose level and placebo. Individual results of laboratory tests from hematology, chemistry and urinalysis that meet 
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Takeda Development Center Americas, Inc. (TDC) markedly abnormal criteria to be defined in the statistical 
analysis plan (SAP) will be listed and summarized for each ixazomib dose level and placebo. 
Individual results of vital signs will be listed and observed values and changes from Baseline in vital signs will be 
summarized for each ixazomib dose level and placebo. Individual results of vital signs that meet TDC’s markedly 
abnormal criteria to be defined in the SAP will be listed and summarized by ixazomib dose level and placebo.
Individual results of quantitative ECG parameters from the 12-lead safety ECGs will be listed and observed values 
and changes from Baseline in quantitative ECG parameters will be summarized for each ixazomib dose level and 
placebo. Individual results of ECG parameters that meet TDC’s markedly abnormal criteria to be defined in the SAP 
will be listed and summarized by ixazomib dose level and placebo. Individual results of safety ECG parameters will 
be listed.
The placebo group mentioned in the safety summaries will be the pooled placebo subjects from all cohorts.
Physical examination findings will be presented in data listings.
PK Measures:
Concentrations of ixazomib in plasma will be summarized by ixazomib dose level at each scheduled sampling time 
using descriptive statistics. Individual plasma concentration data versus time will be presented in a data listing. PK 
parameters of ixazomib will be summarized by ixazomib dose level and subject using descriptive statistics. Dose 
proportionality will be assessed graphically and using the power model. 
 
Pharmacodynamics and Exploratory Endpoints:
Pharmacodynamic and exploratory measurements will be listed and summarized as appropriate by time points for 
each ixazomib dose level and placebo. Additional statistical analyses will be conducted if applicable.
Sample Size Justification: 
This study is not statistically powered for any hypothesis testing. The sample size of 4 active and 1 placebo in 
Cohorts A and B, 6 active and 2 placebo in Cohorts C and D is considered to be sufficient to fulfill the study 
objectives of the evaluation of safety, tolerability, and PK of each cohort.
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator
TDC will select a Signatory Principal Investigator from the investigators who participate in the 
study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required 
to review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.


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3.3
List of Abbreviations
z
terminal elimination rate constant
AE
adverse event
ACR
American College of Rheumatology
ALT
alanine aminotransferase
ANA
antinuclear antibodies 
anti-dsDNA
antibody to double-stranded DNA
AST
aspartate aminotransferase
AUC24
area under the plasma concentration-time from 0 to 24 hours
AUC168
area under the plasma concentration-time curve from 0 to 168 hours
AZA
azathioprine
BILAG
British Isles Lupus Assessment Group
BMI
body mass index
BSA
body surface area
CI
confidence interval
Cmax
maximum observed plasma concentration
CrCl
creatinine clearance
CS
clinically significant
CTCAE
Common Terminology Criteria for Adverse Events
CYC
cyclophosphamide
CYP
cytochrome P-450
DDI
drug-drug interaction
DLT
dose-limiting toxicity
dsDNA
double-stranded deoxyribonucleic acid
eCRF
electronic case report form 
eGFR
estimated glomerular filtration rate
ECG
electrocardiogram
ESRD
end-stage renal disease
EOT
End of Treatment
ET
Early Termination
FACT
functional assessment of cancer therapy
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GI
gastrointestinal
GN
Glomerulonephritis
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus


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IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
independent ethics committee
Ig
Immunoglobulin
IgA
Immunoglobulin A
IgG
immunoglobulin G
IgM
immunoglobulin M
IRB
institutional review board
ISN
International Society of Nephrology 
ISV
insufficient sample volume
IVRS/IWRS 
interactive voice response system/interactive web response system
K2EDTA
dipotassium ethylenediamine-tetraacetic acid
LLN
lower limit of normal
LN
lupus nephritis
MedDRA
Medical Dictionary for Regulatory Activities
MMF
mycophenolate mofetil
MRD
multiple-rising dose
MTD
maximum tolerated dose
NCS
not clinically significant
NOAEL
no-observed-adverse-effect level
NSAID
nonsteroidal anti-inflammatory drug
PGx
pharmacogenomics
PK
pharmacokinetic(s)
PO
orally
PT
preferred term
PTE
pretreatment event
QTcF
QT interval with Fridericia correction method
RBC
red blood cell
RNA
ribonucleic acid 
RPS
Renal Pathology Society
RRAL
relapsed or refractory AL amyloidosis
RRMM
relapsed and refractory multiple myeloma
SAE
serious adverse event
SAP
statistical analysis plan
SCr
serum creatinine
SLE
systemic lupus erythematosus
SNP
single nucleotide polymorphism
SOC
system organ class
SRC
Safety Review Committee
t1/2
terminal elimination half-life
TB
tuberculosis


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TEAE
treatment-emergent adverse event
tmax
time of first occurrence of Cmax
ULN
upper limit of normal
UPCR
urine protein to creatinine ratio 
WBC
white blood cell
WHO
World Health Organization
3.4
Corporate Identification
TDC Asia
Takeda Development Center Asia, Pte. Ltd.
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Asia, TDC Europe and/or TDC Americas, as applicable
TPC
Takeda Pharmaceutical Company Limited
Takeda
TDC Asia, TDC Americas, TDC Europe, and/or TPC, as applicable


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4.0
INTRODUCTION
4.1
Background
4.1.1
Systemic Lupus Erythematosus
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 
and production of autoantibodies. A hallmark of the disease is the production of pathogenic 
autoantibodies to double-stranded deoxyribonucleic acid (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 [1]. Virtually any organ or system in the body can 
be affected by SLE [2,3]. The estimated prevalence of SLE ranges from 40 cases per 
100,000 among Northern Europeans to 200 cases per 100,000 among blacks [1]. SLE affects 
approximately 280,000 adults in the United States, with an estimated prevalence rate of 129 per 
100,000 in adults aged 18 years and over [4]. The incidence rates of SLE range from 
approximately 1 to 10 per 100,000 person-years around the world [5]. Disease onset is more 
common between the third and fourth decade of life and 90% of patients with SLE are females.
4.1.2
Lupus Nephritis
Lupus nephritis (LN), an inflammatory autoimmune disease of the kidney caused by SLE, is the 
most common life-threatening manifestation of systemic lupus. Approximately 60% of the SLE 
patients will develop renal involvement during the course of disease, with substantial morbidity 
or mortality either secondary to kidney disease or toxicities related to intensive 
immunosuppressive drug regimens [6,7]. The prevalence of LN is significantly higher in African 
Americans and Hispanics than in whites, and is higher in women than in men [8].
A diagnosis of LN can be made in subjects with SLE if clinical and laboratory manifestations 
meet any of the American College of Rheumatology (ACR) criteria. LN can be divided in 
6 classes and several subclasses (Appendix I), according to the World Health Organization 
(WHO) and the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 
classifications [6]. Glomerulonephritis (GN) is the most common form of renal disease in SLE, 
but is frequently accompanied by tubulointerstitial and vascular lesions. Proliferative GN classes 
III and IV are the most severe manifestations of renal pathology and the ones requiring 
aggressive immunosuppressive treatment to prevent progression to end-stage renal disease 
(ESRD) and minimize associated morbidity and mortality. LN Class III by glomerular pathology 
is defined as focal LN involving less than 50% of all glomeruli and Class IV is defined as diffuse 
LN involving 50% or more of glomeruli in the biopsy [6,7]. Standard of care in subjects with 
ISN/RPS class III/IV LN is not universal, but generally consists of an induction period of more 
intensive therapy to achieve meaningful and sustained responses, followed by a less intensive 
maintenance therapy in responders. The ACR Task Force Panel recommend mycophenolate 
mofetil ([MMF], 2 to 3 g total daily orally) or intravenous cyclophosphamide (CYC) along with 
glucocorticoids for induction therapy for a period of 6 months. Subjects who achieve partial or 


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complete response to induction therapy are then placed on maintenance regimens with either 
azathioprine or MMF. In subjects who fail to respond after 6 months to treatment with 
glucocorticoids plus CYC or MMF, the Task Force Panel recommends a switch to an alternative 
immunosuppressive agent, with these changes accompanied by intravenous pulses of 
glucocorticoids for 3 days [8]. Alternative agents include rituximab, a chimeric monoclonal 
antibody against the protein monoclonal antibody CD20, calcineurin inhibitors, cyclosporine, 
and recently tacrolimus [8].
In addition, a recent study retrospectively analyzing a trial showed that after 8 weeks of 
induction treatment with either CYC or MMF, subjects with LN who showed a 25% reduction in 
proteinuria and/or normalization of C3 and/or C4 were likely to show good clinical renal 
response [9]. Similarly, after 6 months of treatment, a decrease in serum creatinine and in 
proteinuria to 1 gram/24 hours predicts good long-term outcomes. Therefore, if a patient is not 
meeting these targets at 3 or 6 months it may be appropriate to modify treatment [10]. 
Despite improvements in standard of care therapy only 25% to 50% of patients achieve full 
remission by 2 years and the majority experiences a relapse within 5 years, with 10% to 20% 
progressing to end-stage renal disease requiring dialysis and / or kidney transplantation [11]. 
Moreover, existing therapies cause significant drug-related morbidity and use of glucocorticoids 
is one of the major causes of organ damage in patients with SLE [12].
Class V GN is also associated with chronic kidney disease and ESRD. Decreased glomerular 
filtration rate (GFR) occurs in about 20% of cases and ESRD in about 8-12% after 7-12 years. In 
one small RCT trial examining the treatment of class V LN patients responded to 
immunosuppression but failure to achieve sustained remission was a risk factor for decline in 
renal function. The Kidney Disease Improving Global Outcomes recommends that patients with 
class V and persistent nephrotic proteinuria be treated with corticosteroids plus an additional 
immunosuppressive agent CYC, CNI, MMF or azathioprine [13].
Pathogenic autoantibodies produced by B cells, plasmablasts and plasma cells are critically 
involved in SLE pathogenesis, particularly LN, where renal deposition of immune complexes is 
a hallmark of the disease. Current available treatments can at different levels target B cells, 
plasmablasts and short-lived plasma cells, although long-lived plasma cells remain resistant to 
these treatments, and even to autologous and allogeneic stem cell transplantations [14,15].
4.1.3
Proteasome Inhibition in SLE and LN
Proteasomes are intracellular enzyme complexes which play a key role in degradation of a 
variety of proteins, including many that regulate cell cycle, adhesion, angiogenesis, cytokine 
production, and apoptosis. Proteasome inhibitors have antiproliferative effects on activated 
immune cells by inhibiting the proteasomal degradation of numerous regulatory ubiquitinated 
proteins. Proteasome inhibition also results in the accumulation of poly-ubiquitinated substrates 
within the cell leading to cell cycle disruption, with concomitant activation of apoptotic 
pathways, cell death, and the UPR [16]. Cells with high protein synthesis such as plasmablasts 
and plasma cells are particularly sensitive to proteasome inhibition [17]. Additionally, 
proteasome inhibitors also suppress survival and immunostimulatory functions of human 


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plasmacytoid dendritic cells, which play a central role in SLE, by producing high levels of 
IFN-α, interfering with Toll-like receptor intracellular trafficking and endoplasmic reticulum 
homeostasis [18].
Nonmalignant plasma cells, which are key contributors to autoantibody production, are known to 
be depleted by bortezomib (VELCADE), a 20S proteasome inhibitor currently approved for the 
treatment of multiple myeloma and which is administered intravenously or subcutaneously. 
Nonclinical evidence of efficacy of proteasome inhibition in SLE and LN was demonstrated in 
the NZB/W F1 and MRL/lpr mouse models of SLE. Treatment with bortezomib reduced 
antibody to double-stranded DNA (anti-dsDNA) antibodies, reduced proteinuria and kidney 
damage, and prolonged survival [19,20].
 
 
 
 Importantly, reduction or even normalization of proteinuria was observed in 
the subjects with LN. Proteasome inhibition may therefore be a useful approach to removing the 
plasma cells that produce pathogenic autoantibodies involved in LN. 
4.1.4
Proteasome Inhibitor Ixazomib 
Ixazomib citrate is an orally active, small molecule proteasome inhibitor. Ixazomib citrate refers 
to the citrate ester of ixazomib. In water or aqueous systems, the equilibrium shifts from 
ixazomib citrate to the biologically active boronic acid form, ixazomib. Ixazomib is a potent 
reversible inhibitor of the 20S proteasome in mammalian cells, inhibiting β5 site 20S proteasome 
activity in vitro with a 50% inhibitory concentration of 3.4 nM (1.2 ng/mL). In both animals and 
in humans, extensive red blood cell (RBC) partitioning was noted. In Study C16007, plasma and 
whole blood pharmacokinetic (PK) profiles of ixazomib were compared and concentrations were 
higher in blood than plasma throughout the dosing interval.
Ixazomib demonstrates strong antitumor activity in xenograft models derived from human cancer 
cell lines or primary human tumors. It also reduces anti-keyhole limpet hemocyanin and anti-
dsDNA antibodies, plasma cell, and plasmacytoid dendritic cell populations in animal models 
comparable to that for bortezomib, supporting efficacy in LN.
Ixazomib has potential advantages over bortezomib, including oral administration, dosing 
independent of body size, and, as observed in the current oncology program, a reduced 
propensity for the neuropathy. Ixazomib is currently under investigation in 3 phase 3 registration 
studies including relapsed and refractory multiple myeloma (RRMM), newly diagnosed multiple 
myeloma, and relapsed amyloid light-chain (AL) amyloidosis.
4.1.4.1
Nonclinical Toxicology
A total of 10 repeat-dose toxicity studies have been completed with ixazomib with intravenous 
(IV) or oral (PO) administration to Sprague-Dawley rats and beagle dogs. For the repeat-dose 
toxicity studies of up to 10 cycles of twice a week dosing (20 doses over 95 days), one 21-day 
cycle consisted of twice a week dosing for 2 weeks; multiple cycles were separated by a 10-day 
Company Confidential Information


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nondosing period. The doses used in the rat studies were 0.2, 0.4, and 0.8 mg/kg (reduced to 
0.6 mg/kg after the first 2 cycles). In the dog studies, doses were 0.05, 0.10, and 0.20 mg/kg.
The toxicity of ixazomib was evaluated in Sprague-Dawley rats administered ixazomib via PO 
gavage (0, 0.2, 0.4, 0.8/0.6 mg/kg/dose) for 6 months (7 dosing cycles, with each 28-day cycle 
consisting of once weekly doses for 3 consecutive weeks separated by a 13 day non-dosing 
period). Cycle 7 was followed by a 2-week recovery period (WIL-416165). The target organs 
identified were the gastrointestinal (GI) tract and lymphoid organs, with findings either fully or 
nearly reversible. 
Five females in the 0.8/0.6 mg/kg/dose group died between Days 9 to 170 and the cause of death 
was determined to be likely due to the young age of the animals (7 weeks of age), higher 
exposures compared to male rats, and test article-related findings in the intestine, liver, and 
lymphoid organs. At all doses, there were minimal-to-moderate, dose-dependent effects in the GI 
tract, which included epithelial hyperplasia, neutrophilic infiltrates, and single cell necrosis in the 
lamina propria in the small and large intestines. The changes observed at 0.2 mg/kg/dose were 
minimal and fully reversible. At ≥0.4 mg/kg/dose, minimal-to-moderate changes included 
increases in mandibular salivary gland mucin and inflammation of the glandular/nonglandular 
stomach and, at the highest dose, erosion and ulceration of the glandular and nonglandular 
stomach, respectively. At ≥0.4 mg/kg/dose, hematological changes (increased white blood cells, 
neutrophils, lymphocytes, monocytes, and basophils), reduced body weight gains, and clinical 
signs (diarrhea, small/soft/decreased feces, hypoactivity, thin appearance, and yellow material 
around the urogenital/anogenital areas and forelimbs) correlated with GI changes. 
Dose-dependent, minimal-to-mild changes in lymphoid organs were reported at ≥0.2 mg/kg/dose 
and included mesenteric lymphoid necrosis, neutrophilic infiltrates in the spleen (red pulp), and 
bone marrow hypocellularity. Minimal-to-mild microscopic effects were reported in the 
endocrine system (decreased vacuolation of the zona fasciculata of the adrenal cortex), 
reproductive tissues (increased lobulo-alveolar hyperplasia and increased secretion of the 
mammary gland, spermatid retention in the testes), and blood vessels (mononuclear 
perivasculitis of the meninges of the brain and spinal cord and the submucosa of the intestine). 
Although it is uncertain if these microscopic findings were treatment-related, they were fully 
reversible after the 2-week recovery period. Based on the results of this study, the no-observed-
adverse-effect-level (NOAEL) was determined to be 0.2 mg/kg/dose in males and females. At 
this dose, the mean maximum observed plasma concentration (Cmax) and area under the plasma 
concentration-time curve from time 0 to 168 hours (AUC168) values (Day 168) for males:females 
(M:F) were 5.42:6.55 ng/mL and 489:476 ng·hr/mL, respectively.
The toxicity profile of ixazomib was evaluated in beagle dogs via PO gavage (0, 0.05, 0.10, and 
0.20 mg/kg/dose) for 9 months (10 dosing cycles, with each 28-day cycle consisting of 3 once 
weekly doses separated by a 13 day nondosing period). Cycle 10 was followed by a 2-week 
recovery period (WIL-416164). Test article-related organ toxicity was reported in the GI tract, 
lymphoid tissues, and peripheral nervous system (PNS). 
There were no deaths in this study. At ≥0.10 mg/kg/dose, minimal test article-related effects 
were reported in the GI tract and lymphoid tissue and included neutrophilic infiltration in the 


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stomach, intestines, mesenteric lymph node and/or Peyer’s patches, and stomach erosions. The 
neutrophilic infiltrates correlated with increased white blood cells, neutrophils, and monocytes. 
The erosion in the stomach and the neutrophilic infiltration were fully or nearly reversible at the 
end of the 2-week recovery period. In the PNS at 0.20 mg/kg/dose, test article-related findings 
included neuronal degeneration of the sympathetic, dorsal root, and end organ ganglia, secondary 
axonal/nerve fiber degeneration of the peripheral nerves (vagus and sciatic nerves, dorsal roots 
and mixed spinal nerves), ascending tracts in the dorsal column of the spinal cord and white 
matter tracts in the medulla oblongata, gliosis of the dorsal column of the spinal cord and white 
matter tracts in the brain, with the latter two secondary to axonal degeneration of the ascending 
tracts. At the end of the 2-week recovery period, the only neuronal findings were nerve fiber 
degeneration of the dorsal root ganglion and an increase in axonal degeneration in the dorsal 
columns of the spinal cord. The lack of ongoing neuronal degeneration and no changes in the 
functional observational battery are indicative of no persistent neuronal toxicity and no 
functional impact on the nervous system. In addition to these findings, decreased lymphocyte 
counts, increased aspartate aminotransferase, and decreased serum phosphorus were reported at 
0.20 mg/kg/dose. Based on these findings, the NOAEL was determined to be 0.10 mg/kg/dose in 
males and females. At this dose, the mean Cmax and AUC168 values (Day 252) were 136 ng/mL 
and 1940 ng·hr/mL, respectively.
In summary, the target tissues for rats and dogs were similar and consisted of the bone marrow, 
peripheral ganglia, GI tract, and lymphoid tissues. In the longer cycle, repeat-dose toxicity 
studies, the kidney, adrenal, lacrimal, and perianal glands were identified as target organs in 
either the rat or dog. The most sensitive hematology indicator of a test article-related effect in 
rats was thrombocytopenia and, in dogs, decreased reticulocyte counts. Peripheral ganglia 
effects, although qualitatively similar in rats, were more severe in dogs. All of the effects seen in 
both rats and dogs were fully or nearly reversible.
4.1.4.2
Drug Metabolism and PK
Ixazomib citrate is hydrolyzed to the boronic acid form ixazomib which is mainly cleared via 
metabolism; clinical PK data indicate that renal clearance contributes little to the total 
elimination of ixazomib (≤10% is renally cleared following intravenous administration). 
Consistently, no relationship between creatinine clearance (CrCl) and systemic clearance has 
been observed in the preliminary population PK analysis (N=137) over a wide range of renal 
function categories (CrCl range: 22-236 mL/min). Therefore, it is expected that there will be no 
increases in ixazomib exposures when administered to subjects with mild to moderate renal 
impairment [21,22].
In vitro studies indicate that ixazomib is metabolized by multiple cytochrome P-450 (CYPs) and 
non-CYP enzymes/proteins. At clinically relevant concentrations of ixazomib, in vitro studies 
using human complementary DNA-expressed CYP isozymes showed that no specific CYP 
isozyme predominantly contributes to ixazomib clearance. At concentrations exceeding those 
observed clinically (10 μM), ixazomib was metabolized by multiple CYP isoforms with 
estimated relative contributions of 3A4 (42.3%), 1A2 (26.1%), 2B6 (16.0%), 2C8 (6.0%), 2D6 
(4.8%), 2C19 (4.8%) and 2C9 (<1%). In contrast, at 0.1 μM and 0.5 μM substrate concentrations, 


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which are closer to clinical concentrations of ixazomib, non-CYP-mediated clearance was 
observed and seemed to play a major role in ixazomib clearance in vitro. These data indicate that 
at clinically relevant concentrations of ixazomib, minimal CYP-mediated drug-drug interactions
(DDIs) with a selective CYP inhibitor would be expected. In addition, ixazomib is neither a 
reversible nor a time-dependent inhibitor of CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. 
Prednisone and MMF treatment is allowed in this study. Prednisone is metabolized via CYP3A4 
and is a known inducer of CYP2C19, MMFs major metabolic pathway is mediated via 
glucuronosyltransferases; therefore, the likelihood of a drug interaction with ixazomib in both 
cases is considered to be low. Overall, the potential for ixazomib treatment to produce DDIs via 
CYP inhibition is inferred to be low.
In a phase 1 DDI study, the PK of ixazomib was similar with and without co-administration of 
clarithromycin, a strong CYP3A inhibitor (Study C16009, Arm 5); hence, no dose adjustment is 
necessary when ixazomib is administered with strong CYP3A inhibitors [21]. These findings are 
explained by the in vitro metabolism data indicating the lack of a discernible contribution of 
CYP-mediated metabolism at clinically relevant ixazomib concentrations. As discussed earlier, 
no CYP isoforms have been identified to contribute meaningfully to ixazomib metabolism at 
clinically relevant concentrations and CYP3A contribution to total metabolism was highest 
across all CYP isoforms when characterized at a supratherapeutic concentration of 10 μM. 
Therefore, based on the totality of information from the clinical clarithromycin DDI study and 
the in vitro CYP phenotyping data, it can be concluded that ixazomib PK is not likely to be 
altered upon co-administration with any CYP isoform-selective inhibitor, including strong 
CYP1A2 inhibitors. Consistently in the population PK analysis, co-administration of strong 
CYP1A2 inhibitors did not affect ixazomib clearance [22]. Therefore, no dose adjustment is 
required for patients receiving strong inhibitors of CYP1A2.
In a phase 1 DDI study, coadministration of ixazomib with rifampin decreased ixazomib Cmax by 
54% and area under the plasma concentration-time curve by 74% (Study C16009, Arm 4) [21]. 
Accordingly, concomitant administration of ixazomib with strong CYP3A inducers should be 
avoided (see Section 7.3). Please refer to the prescribing information for ixazomib for further 
details [23].
4.1.4.3
Clinical Experience
Ixazomib is currently in phase 3 development for oncology indications. As of the 27 March 2013 
data cut, 637 oncology subjects have received at least 1 dose of ixazomib either as a single agent 
or in combination with regimens commonly used in clinical practice for the particular 
malignancy (safety population). A total of 146 subjects were enrolled in IV studies and 491 in 
uncontrolled studies with oral ixazomib. Additionally, 817 subjects have been treated with oral 
ixazomib or placebo in blinded phase 3 trials. For initial studies with ixazomib the IV doses 
ranged from 0.125 to 3.11 mg/m2 and PO doses ranged from 0.24 to 3.95 mg/m2 with once or 
twice weekly dose schedules. For the ongoing and planned studies, a weekly administration 
schedule is used that consists of dosing on Days 1, 8, and 15 followed by a 13-day drug holiday, 
which allows for adverse event (AE) recovery before starting the next planned cycle.


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Ixazomib has been evaluated as a single agent in phase 1 studies that have included subjects with 
advanced solid tumors (C16001, IV, and C16009, PO), lymphoma (C16002, IV), RRMM 
(C16003 and C16004, PO) and relapsed or refractory AL amyloidosis (RRAL) (C16007, PO). 
The actual initial doses of oral ixazomib used in the oncology program ranged from 0.2 to 
10.6 mg (as a single-agent from 0.2 to 8.9 mg; in combination studies from 2.9 to 10.6 mg) and 
fixed doses of 3.0 to 5.5 mg. The initial doses of IV ixazomib used in the single-agent oncology 
studies (both twice weekly and weekly) ranged from 0.2 to 6.8 mg (weekly only from 0.23 to 
6.8 mg). Maximum tolerated doses (MTDs) determined in the oncology studies ranged between 
4.0 and 5.5 mg. Pooled mean (SD) number of cycles in 9 PO and 2 IV dosing studies combined 
for oncology is 5.4 (5.85) cycles, [median 3.0, range 1-46]. In the 9 PO studies, the mean (SD) 
number of cycles is 6.4 (6.16) [range 1-46] and in the 2 completed IV studies the mean (SD) was 
3.0 (4.05) [range 1-34] treatment cycles.
The emerging safety profile indicates that ixazomib is generally well tolerated with manageable 
and reversible AEs with both the IV and PO formulations. The types of AEs reported are similar 
for the 2 formulations, yet the frequency and severity differ. Refer to the ixazomib Investigator’s 
Brochure (IB) for details on ixazomib safety experience and doses ranges used. The adverse drug 
reactions that occurred at ≥10% in the single-agent oral administration studies include 
thrombocytopenia, diarrhea, nausea, vomiting, fatigue, pyrexia, and skin rash. Additional 
adverse drug reactions that occurred at ≥10% in the oral combination therapy studies include 
anemia, neutropenia, constipation, dysgeusia, neuropathy peripheral, and insomnia. Adverse 
effects reported in the clinical studies with ixazomib to date may have been due to the subject’s 
underlying disease, treatment with ixazomib, other medications, or some combination of these. 
The observed AEs are generally consistent with the class-based effects of proteasome inhibition 
and are similar to what has been previously reported with bortezomib. While some of these 
potential toxicities may be severe, they can be managed by clinical monitoring and standard 
medical intervention.
Table 4.a outlines the most common AEs regardless of grade or causality reported across dose 
levels which are approximately equivalent to those proposed for this study. Fatigue, 
thrombocytopenia, diarrhea, nausea, and vomiting were reported. At doses higher than proposed 
in this study all of these common AEs were reported in at least 45% of the subjects. Looking at 
pooled data across the lower doses, only fatigue, which may have been due to either disease, 
study drug, or both, was reported at this rate. Additionally, no subject treated at the lower doses 
experienced an AE which required a dose reduction; whereas 45% of those treated at the MTD 
(2.97 mg/m2 [~ equivalent to 5.5 mg fixed]) did experience an AE requiring a dose reduction.


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Table 4.a
Study C16004 Most Common (>30% of Subjects in MTD Cohort) AEs 
Regardless of Causality by Dose Cohort
Number of Subjects/AE
Number of Subjects/CTCAE Grade
Ixazomib Dose
MedDRA Preferred 
Term
0.48 mg/m2
(~ equivalent to 1 
mg fixed)
N=3
1.2 mg/m2
(~ equivalent to 2 
mg fixed)
N=3
1.68 mg/m2
(~ equivalent to 3 
mg fixed)
N=4
2.23 mg/m2
(~ equivalent to 
4 mg fixed)
N=3
2.97 mg/m2
(~ equivalent to 
5.5 mg fixed)
N=31
Fatigue
2
2/Grade 2
2
1/Grade 1
1/Grade 2
2
2/Grade 1
0
17
2/Grade 1
10/Grade 2
5/Grade 3
Thrombocytopenia
1
1/Grade 2
2
1/Grade 1
1/Grade 3
1
1/Grade 3
1
1/Grade 3
17
1/Grade 1
1/Grade 2
5/Grade 3
10/Grade 4
Diarrhea
0
0
0
2
2/Grade 1
17
4/Grade 1
6/Grade 2
7/Grade 3
Nausea
1
1/Grade 1
1
1/Grade 1
1
1/Grade 2
1
1/Grade 1
15
9/Grade 1
5/Grade 2
1/Grade 3
Vomiting
1
1/Grade 1
0
0
2
2/Grade 1
14
10/Grade 1
3/Grade 2
1/Grade 3
Decreased appetite
0
0
0
0
14
6/Grade 1
4/Grade 2
4/Grade 3
Neutropenia
0
0
0
0
11
3/Grade 2
8/Grade 3
Source: Ixazomib IB version 8; C16004 CSR Table 14.4.1.4.
CTCAE=Common Terminology Criteria for Adverse Events v. 4.0, MedDRA=Medical Dictionary for Regulatory 
Activities.
In study 16005, where weekly ixazomib was given in combination with a standard dose of 
lenalidomide and dexamethasone in a 28-day cycle, the MTD was defined as 2.97 mg/m2. The 
dose-limiting toxicities (DLTs) at the dose level above MTD (3.95 mg/m2) were dizziness, 
orthostatic hypotension, nausea, vomiting, syncope in 3/3 subjects and Grade 2 peripheral 
neuropathy in 1 subject. At this dose, the actual initial doses of ixazomib administered were 
8.2 to 10.6 mg. The DLT at the 2.97 mg/m2 dose level was rash in 1/6 subjects, where the initial 


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doses of ixazomib administered were 4.6 to 6.2 mg. The recommended phase 2 dose estimation 
was established following evaluation of the available data from the phase 1 portion of this study, 
which included, but was not limited to, analyses of efficacy results and safety (Grade 3/4 AEs, 
serious adverse events [SAEs], all grades of peripheral neuropathy, and treatment 
discontinuation). Given that the dose of 2.97 mg/m2 ixazomib compromised the maximal dosing 
of lenalidomide and that the dose of 2.23 mg/m2 (approximately equivalent to a 4 mg fixed dose) 
was well tolerated and clinically active, the 2.23 mg/m2 dose was designated as the 
recommended phase 2 and 3 dose. The actual initial doses of ixazomib administered to the 
subjects in the 2.23 mg/m2 Cohort were 3.4 to 4 mg.
As can be noted in Table 4.b, in most of the phase 1 PO studies, this dose was determined as the 
MTD for ixazomib, either as a single agent or in combination with standard oncology treatments, 
when given once weekly 3 out of 4 weeks in a 28-day cycle. DLTs across these studies were also 
similar and primarily included thrombocytopenia and GI symptoms (nausea, vomiting, and 
diarrhea).
The relevant clinical studies following oral weekly administration of ixazomib citrate are
illustrated in Table 4.b.
Table 4.b
Summary of MLN9708 (ixazomib) Clinical Oncology Studies With Once 
Weekly Oral Dosing
Trial/
Population
Description
Doses Investigated
C16004
Phase 1
RRMM
N = 60
PO, W, single agent
0.24-3.95 mg/m2
MTD: 2.97 mg/m2 (4.4 to 7.2 mg)
DLT: rash, nausea, vomiting, diarrhea
Closed to enrollment
Median # cycles: 2.0 (range 1,12)
C16005
Phase 1/2
NDMM
N = 65
PO, W, combination with LenDex 
28-day cycle
1.68-3.95 mg/m2
MTD: 2.97 mg/m2 (4.6 – 6.2 mg)
DLT: nausea, vomiting, diarrhea, syncope, rash, 
dizziness, orthostatic hypotension, and 1 patient with 
Grade 2 peripheral neuropathy
RP2D (a): 4.0 mg fixed (switched to fixed dosing in 
phase 2, equivalent to 2.23 mg/m2)
Closed to enrollment
Median # cycles: 7.0 (range 1,27)
C16006
Phase 1/2
NDMM
N = 25
PO, TW, Arm A-42-day cycle and 
W, Arm B- 28-day cycle
combination with melphalan and 
prednisone 28-day cycle
Arm A: 3.0-3.7 mg fixed dose TW
DLT: rash, thrombocytopenia, subileus
MTD: 3.0 mg
Arm B: 3-5.5 mg fixed dose W 
DLT: Esophageal ulcer nausea, vomiting, hematemesis, 
thrombocytopenia, ileus, neurogenic bladder
MTD = 4.0 mg
Median # cycles: 7.5 (range 1,19)
Footnotes are on last table page.


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Table 4.b 
Summary of MLN9708 (ixazomib) Clinical Oncology Studies With Once 
Weekly Oral Dosing (continued)
Trial/
Population
Description
Doses Investigated
C16007
Phase 1
RRAL
N = 27
PO, W, single agent
4-5.5 mg fixed dose (a) 
DLT: thrombocytopenia, diarrhea, dyspnea, acute rise in 
creatinine, non-fatal cardiac arrest 
Closed to enrollment
MTD: 4.0 mg 
Median # cycles: 4.0 (range 1,12) 
C16009
Phase 1
Solid tumors, 
Lymphomas
N = 54
PO, W, single agent
5.5 mg fixed dose (a) 
Study amended to a 4.0 mg fixed dose (a) with 
allowance for increase to 5.5-mg if tolerated after 
Cycle 4
Median # cycles: 2.0 (range 1,9)
C16010
Phase 3
RRMM
N=54
PO, W, with LenDex versus placebo + 
LenDex
4.0 mg fixed dose
Dex 40 mg PO days 1, 8, 15, and 22
Len 25 mg days 1-21 of a 28-day cycle
Ongoing
C16011
Phase 3
RRAL
N=4
PO, W, with Dex versus physician’s 
choice of a Dex-based regimen
4.0 mg fixed dose
C16013
Phase 1
RRMM
N=10
PO, W, combination with LenDex 28-
day cycle.
4.0 mg, 5.5 mg fixed doses (a) 
DLT: diarrhea, hypertension, hypokalemia, 
hyponatremia, nausea, thrombocytopenia
Single agent MTD 4.0 mg
MTD in combination with LenDex 28-day cycle-TBD
Median # cycles: 2.0 (range 1,3)
Source: Ixazomib IB version 8. 
Dex=dexamethasone, LenDex = lenalidomide plus dexamethasone, NDMM = newly diagnosed multiple myeloma, 
TBD=to be determine, TW= twice weekly, W=weekly.
(a) Approximate body surface area (BSA) and fixed dosing equivalence: 3 mg~ equivalent to 1.68 mg/m2 BSA 
dosing; 4.0 mg ~ equivalent to 2.23 mg/m2 BSA dosing; and 5.5 mg~ equivalent to 2.97 mg/m2 BSA dosing.
As of 27 March 2014, out of the safety population in studies with oral ixazomib, 50 patients 
reported 68 AEs at least possibly related to study treatment that resulted in study drug 
discontinuation. The most common of these events were rash (7 patients), peripheral neuropathy 
or peripheral sensory neuropathy (6 patients), renal impairment/failure (6 patients), 
fatigue/asthenia (6 patients), and thrombocytopenia (5 patients). Furthermore, at least 1 SAE has 
been reported for 474 subjects (36%) across all Takeda-sponsored clinical studies in oncology 
(including ongoing Phase 3 trials) using oral or placebo/control in combination with standard 
therapies. The reported SAEs include effects attributable to disease progression and those related 
to study treatment. Regardless of causality, the most common SAEs included pneumonia 
(62 subjects) and pyrexia (30 subjects). As of 27 March 2014, a total of 42 patients died on study 
(ie, within 30 days after last dose) across all clinical studies in oncology with the oral 
formulation of ixazomib. The most common cause of death in the studies was disease 


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progression. Six deaths were considered at least possibly related to study treatment: 2 occurred in 
open label trials (1 each respiratory syncytial viral pneumonia and cardiopulmonary arrest, both 
of which occurred in clinical trials combining oral ixazomib plus LenDex), and 4 occurred in 
ongoing blinded trials of oral ixazomib or placebo plus LenDex. 
4.2
Rationale for the Proposed Study 
Proteasome inhibition using ixazomib is a novel mechanism of action for the treatment of LN as 
compared to the drugs currently used [24]. Proteasome inhibitors have been approved for use in 
plasma cell malignancies such as multiple myeloma. Non-malignant plasma cells are also 
sensitive to proteasome inhibition, and these cells play a key role in several autoimmune 
diseases, including SLE and LN. Both nonclinical and clinical data support further investigation 
of proteasome inhibitors such as ixazomib in LN.
This study is a phase 1b, randomized, double-blind, placebo-controlled, safety, tolerability, and 
PK study of multiple-rising doses (MRD) of ixazomib for the treatment of subjects with 
ISN/RPS Class III, IV or V changes [excluding Class III (C), IV-S (C) and IV-G (C)] or WHO 
1982 classification of Class III, IV or V (excluding Class IIIc and IVd). It is anticipated that 
4 ixazomib dose levels will be examined. At least 5 subjects (4:1) will be recruited into the 0.5 
mg dose group (Cohort A), at least 5 subjects (4:1) in the 2.0 mg dose group (Cohort B), 8 
subjects (6:2) in the 3.0 mg dose group (Cohort C), and 8 subjects (6:2) in the 4.0 mg dose group 
(Cohort D). Subjects will be considered eligible on the basis of study inclusion and exclusion 
criteria, verified by an independent adjudication committee, and randomized. Following each of 
the 0.5, 2.0, and 3.0 mg dose cohorts, available PK and safety data will be evaluated before
escalation. For each dose level cohort, the Safety Review Committee (SRC) will carefully review 
the available safety, tolerability, and PK data to determine if dosing should be escalated in the 
next cohort, lowered or expanded within the same dose cohort to obtain additional information 
before a dose-escalation decision, or stopped. After 5 subjects are recruited in the 4.0 mg dose 
group (Cohort D) and complete at least 1 cycle of ixazomib or placebo, an analysis may be 
conducted on available PK data and blinded safety data from all cohorts. Subject numbers may 
be increased as appropriate per cohort for a total number not exceeding 40 subjects in all cohorts 
combined. Two subjects with Class V or Class V with Class II nephritis are permitted per cohort. 
Subjects will be treated with three 28-day cycles of ixazomib or placebo during the Double-
Blinded Treatment Period.
This study will provide initial information on the safety and tolerability of ixazomib over 3 
double-blind dosing cycles in subjects who have inadequately responded to at least 3 months of 
an immunosuppressive regimen including single or sequential use of CYC, MMF, mycophenolic 
acid (MA) or azathioprine (AZA). In addition, this phase 1b study will provide data to guide 
dose-range selection for further studies, along with exploratory biomarker and pharmacogenomic 
analyses which may aid subject stratification for future studies.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective(s) 
To characterize the safety and tolerability of ixazomib when administered as multiple oral doses 
at escalating dose levels in subjects with LN. 
5.1.2
Secondary Objectives 

To assess changes from Baseline in urine protein to creatinine ratio (UPCR) in LN subjects 
following multiple administrations of ixazomib. 

To evaluate the effect of ixazomib on kidney function, as assessed by changes from Baseline 
in serum creatinine (SCr) and estimated glomerular filtration rate (eGFR).

To evaluate the effect of ixazomib on anti-dsDNA antibody titers and complement C3/C4 
levels.

To characterize the plasma PK of ixazomib in LN subjects when ixazomib is administered 
over 3 cycles consisting of 3 doses per cycle.
5.2
Endpoints
5.2.1
Primary Endpoints

Percentage of study subjects with at least 1 Grade ≥2 treatment emergent adverse event 
(TEAE) according to CTCAE.

Percentage of study subjects with at least 1 SAE.

Percentage of study subjects with at least 1 AE leading to discontinuation of investigational 
study medication.

Percentage of subjects with at least 1 markedly abnormal laboratory criteria for hematologic 
parameters.
5.2.2
Secondary Endpoints

Change from Baseline to Final Visit of Double-Blind Treatment Period in UPCR.

Change from Baseline to Final Visit of Double-Blind Treatment Period in SCr level.

Change from Baseline to Final Visit of Double-Blind Treatment Period in eGFR 
measurement.

Change from Baseline to Final Visit of Double-Blind Treatment Period in levels of 
autoantibodies (anti-dsDNA) and complement (C3 and C4).


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!
Plasma PK of ixazomib in subjects with LN following administration of ixazomib in the 
Double-Blind Treatment Period.
–
Plasma PK endpoints will be the following PK parameters of ixazomib in all cohorts:
!
Maximum plasma concentration (Cmax).
!
time of first occurrence of Cmax (tmax).
!
Area under the plasma concentration-time curve from time 0 to the last quantifiable 
concentration (AUC(0-tlqc)); or AUC168, if measurable. 
5.2.3
Exploratory Endpoints
!
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5.2.4
Additional Safety Endpoints
Safety assessments will be based on AE reports and the results of vital sign measurements, 
electrocardiograms (ECGs), physical examinations, and clinical laboratory tests.
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This study is a phase 1b, randomized, double-blind, placebo-controlled, safety, tolerability, and 
PK MRD of ixazomib for the treatment of subjects with ISN/RPS Class III, IV or V changes 
[excluding Class III (C), IV-S (C), and IV-G (C)] or WHO 1982 classification of Class III, IV, or 
V (excluding Class IIIc and IVd) LN. It is anticipated that 4 ixazomib dose levels will be 
examined. At least 5 subjects (4:1) will be recruited into the 0.5 mg dose group (Cohort A), at 
least 5 subjects (4:1) in the 2.0 mg dose group (Cohort B), 8 subjects (6:2) in the 3.0 mg dose 
group (Cohort C), and 8 subjects (6:2) in the 4.0 mg dose group (Cohort D). Subjects will be 
considered eligible on the basis of study inclusion and exclusion criteria, verified by an 
adjudication committee, and randomized. Following each of the 0.5, 2.0, and 3.0 mg dose 
cohorts, available PK and safety data will be evaluated before escalation. For each dose level 
cohort, the SRC will carefully review the available safety, tolerability, and PK data to determine 
if dosing should be escalated in the next cohort, lowered, or expanded within the same dose 
cohort to obtain additional information before a dose-escalation decision, or stopped. After 5 
subjects are recruited in the 4.0 mg dose group (Cohort D) and complete at least 1 cycle of 
ixazomib or placebo, an analysis may be conducted on available PK data and safety/tolerability 
data from all cohorts. Subject numbers may be increased as appropriate per cohort to a total 
number not to exceed 40 subjects in all cohorts combined. Two subjects with Class V or Class V 
with Class II nephritis are permitted per cohort. Subjects will be treated with three 28-day cycles 
of ixazomib or placebo. Subjects who successfully completed 12 weeks of double-blind 
treatment without any AE resulting in dose modification or discontinuation of the study drug 
(defined in Section 7.4.3) will be eligible to receive up to 3 additional cycles of open-label 
ixazomib at the discretion of the investigator and confirmed by the sponsor/designee following 
the end of the Double-Blind Treatment Period. The subjects need to begin the Open-Label 
Treatment Extension Period within 4 weeks of completing Cycle 3 of double-blind treatment.
Each 28-day cycle will consist of 3 once-weekly oral doses of 0.5, 2.0, 3.0, or 4.0 mg of 
ixazomib (dosage strength is stated as the active boronic acid ixazomib) or placebo, depending 
on the cohort. Subjects who received a dose ≤2.0 mg and completed all cycles including the 
Follow-up Period, will be permitted to re-enroll into the 2.0 and 3.0 mg dose groups, provided 
they have no drug-related AEs >Grade 1 that required the study drug dose modification, no AEs 
>Grade 2, continue to meet all inclusion and exclusion criteria, and the SRC (consisting of 
sponsor personnel and the coordinating investigator) have reviewed and approved enrollment. 
Subjects must be receiving standard of care treatment for LN and remain on their current stable 
and allowed therapies during the Screening Period and throughout the duration of the study 
(Section 8.1.1.2).
The study consists of the following Periods: a Screening Period (up to 35 days), a Double-Blind 
Treatment Period (Day 1 to Day 84) and either a Follow-up Period or an Open-Label Treatment 
Extension Period (Day 85 to Day 168). For those subjects who enter the Open-Label Treatment 
Extension Period, visits will be monthly (either for dosing or follow-up) until Day 168, with the 
last study visit being 30 days after the last open-label dosing or Day 168 whichever is longer.


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Subjects can be randomized 24 (+11) days after Screening (between Days -24 and -35) and once 
safety laboratory tests and inclusion/exclusion criteria have been reviewed and confirmed by the 
investigator. Diagnostic criteria, disease activity measures, and treatment history will be 
documented, and required laboratory investigations initiated. Subject eligibility will be reviewed 
by an adjudication committee. The responsibilities and criteria of this committee will be defined 
in an adjudication charter. 
Following verification of eligibility, subjects will return to the clinic on Day 1, undergo baseline 
assessments, laboratory testing, and will be randomized to either ixazomib or placebo within 
each cohort/dose level. The Double-Blind Treatment Period will consist of three 28-day 
treatment cycles (Cycles 1, 2, and 3) without intra-subject dose escalation. Subjects will receive 
ixazomib treatment on Days 1, 8, and 15 of each 28-day cycle. The second and third cycles will 
commence on the first day following Day 28 of the preceding cycle (ie, with a period of 13 days 
between the third drug administration of a cycle and the first drug administration of the 
following cycle). The Double-Blind Treatment Period will be limited to 3 complete cycles with 
ixazomib or placebo, over an expected duration of 12 weeks. However, the total treatment period 
may be longer than the standard 12 weeks if delays between cycles are necessary due to AEs. 
After completion of Cycle 3 of the Double-Blind Treatment Period, the subject will either enter 
the Follow-up Period or enter an optional Open-Label Treatment Extension Period at the 
investigator’s discretion and confirmed by the Takeda physician/designee. The Follow-up Period 
or the Open-Label Treatment Extension Period consisting of follow-up visits every 4 weeks will 
start after the end of the Double-Blind Treatment Period (Day 84). The Open-Label Treatment 
Extension Period will be limited to up to 3 cycles of treatment with ixazomib on the same dose 
and schedule that they were receiving in the double blind period over an expected duration of 12 
weeks.
Subjects will receive ixazomib cycles consisting of doses of 0.5 mg (Cohort A), 2 mg (Cohort 
B), 3 mg (Cohort C), or 4 mg (Cohort D), or placebo. The ascending dose cohorts will be 
enrolled sequentially. Dosing of subsequent cohorts will not commence until at least 5 subjects 
in Cohorts A and B and 8 subjects in Cohort C have received at least 1 dose of investigational 
drug and have reached Day 28 of Cycle 1 or have completed their last evaluation within Cycle 1 
with a satisfactory review of all available safety and tolerability data. Subjects discontinued or 
withdrawn after randomization for nonsafety reasons will only be replaced if the number of 
subjects per cohort evaluable for safety on Day 28 of Cycle 1 is reduced below 6 subjects for 
Cohorts C and D, below 5 subjects for lower than 3.0 mg dose cohorts, or the SRC recommends 
expanding with the same dose to obtain additional information before a dose-escalation decision. 
Down-titration of ixazomib is permitted for individual subjects for safety and tolerability reasons 
at any time during the Treatment Period, except for subjects receiving 0.5 mg in Cohort A. If 
necessary for safety or tolerability reasons or in the judgment of the investigator, ixazomib 
treatment should be stopped altogether an End of Study Visit should be completed. The subject 
should then complete the remainder of the study period as the Follow-up Period. Dose 
modification and dose deferral should be discussed with the Sponsor’s Medical Monitor; 
guidelines for the modification or deferral of doses will be provided.
During the Double-Blind Treatment Period, ixazomib will always be dosed at the study site and 


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subjects will return to the clinic for each administration of ixazomib. During the Open-Label 
Treatment Extension Period, subjects will receive the first dose of each cycle at the clinic and the 
other 2 weekly doses can be given to the subjects to take at home. All subjects will return to the 
clinic every 4 weeks to receive the first dose of each cycle. For scheduling flexibility, study visits 
can take place ± 2 days from each scheduled day during the Treatment Period and ±1 week 
during the Follow-up Period. A minimum of 120 hours should occur between ixazomib doses. 
Any variance in the dosing schedule should not alter the schedule of subsequent dosing. 
Subjects will undergo safety laboratory assessments, total immunoglobulin G, M, and A 
(IgG/IgM/IgA), LN assessments including but not limited to UPCR, eGFR, anti-dsDNA 
antibodies, and complement C3 and C4 levels via a central laboratory according to the schedule 
in Appendix A. Pharmacogenomic (PGx) and exploratory biomarker samples will also be sent to a 
central laboratory for analysis. 
Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor with an estimated 
t1/2 of ~ 4 to 9 days in plasma. For Cohorts A to D, plasma concentrations of ixazomib over time 
will be evaluated following the first dose of Cycle 1 and following the last dose of Cycle 3 of the 
Double-Blind Treatment Period. Predose samples will be collected before each dose in Cycles 1, 
2, and 3 of the Double-Blind Treatment Period. Available PK data will be reviewed as part of the 
overall safety and tolerability evaluation of ixazomib in LN and for the dose escalation decision.
Recent evidence suggests that genetic variation accounts for differing responses to bortezomib 
therapy. A single nucleotide polymorphism (SNP) at position 11 in the PSMB1 gene (in the 
region encoding the leader sequence for the beta subunit of the 20S proteasome) has been 
associated with reduced proteasome activity and is associated with enhanced bortezomib activity 
in multiple myeloma and relapsed follicular lymphoma. 
 
 
 
 
 
 
In addition, hematology and chemistry safety laboratory assessments will be collected before 
each dose of ixazomib during the Double-Blind Treatment Period and before each cycle of open-
label treatment; the results of all available laboratory tests will be reviewed by the investigator 
before administration of the scheduled dose of ixazomib. If the central laboratory results are not 
available for the Open-Label Treatment Extension Period an additional safety laboratory
assessment can be conducted at the local laboratory before dosing and they will be recorded in 
the electronic case report forms (eCRFs). A negative urine pregnancy test result is required 
before each administration of investigational drug at the visits specified in the schedule of events 
table.
In common with other immunosuppressant agents, ixazomib may have additional effects on host 
defense. The subject’s immunization status should be reviewed at the Screening Visit, and all 
appropriate vaccinations should be completed at least 1 month before treatment. These may 
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include but are not limited to pneumococcal and inactivated influenza vaccines.
If lymphopenia is noted, subjects may be at an increased risk of infection. In particular, 
lymphopenia can be associated with reactivation of herpes zoster and herpes simplex viruses, and 
cytomegalovirus. Antiviral therapy such as acyclovir or valacyclovir may be initiated at the onset 
of infection after administration of ixazomib. Other antivirals are also acceptable. Provision of 
medication will be arranged by the investigator from local suppliers and will be reimbursed by 
the Sponsor. 
Each investigator will review any safety findings and laboratory results to determine if a subject 
should receive the next dose within each cycle. The investigator will evaluate safety and 
tolerability for each subject on Day -1 and before each dose during every cycle. On Day 22 of 
each cycle during the Double-Blind Treatment Period, the investigator-led team will evaluate all 
available safety information for the subject to determine eligibility to initiate the subsequent 
cycle.
A schematic of the study design is presented below:
Figure 6.a
Schematic of Study Design
Double-Blind Treatment Period
Placebo (Once a week for the first 3 weeks of Cycle [N˃6]) 
Ixazomib (Once a week for the first 3 weeks of Cycle [N≥20]) 
Double-Blind Treatment Period (84 days)
Visits at Days 1, 2, 8, 
15 & 22
Visits at Days 1, 8, 
15 & 22
Visits at Days 1, 8, 15, 
16, 22 & 28
Visits at Months 4, 5 & 
6
Cycle 1
Cycle 2
Cycle 3
3-Month Follow-up 
Day -24(-11) 
to -1
    
             
   
Screening 
Visit
(a) Day 1 
/ Randomization
Day 84
Day 168
(a) At randomization, subjects will be assigned 0.5, 2.0, 3.0, or 4.0 mg of ixazomib or placebo, each 4-week cycle will consist of 
3 once-a-week oral doses. In case abnormal, clinically significant findings are observed upon discharge, subjects may be brought 
back to the clinic for re-evaluation per investigator’s discretion.


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Open Label Treatment Period
Ixazomib (Once a week for the first 3 weeks of Cycle) 
Open Label Treatment Period (84 days)
Visits at Days 1
Visits at Days 1
Visits at Days 1 & 28
30 days after last cycle
Cycle 1
Cycle 2 (a)
Cycle 3 (a)
Follow-up (a)
    
             
   
(a) Day 85
Day 168
Day 198 
(a) all subjects who enter the open label treatment period will have monthly visit up to at least Day 168. If open-label treatment is 
terminated before the completion of all 3 cycles, an end of treatment visit will be performed (Day 28 of current cycle) and the 
subsequent cycle Day 1 visits will be replaced with a follow-up visit. 
Dose escalation will be sequential with escalation only considered after all the following 
conditions have been met (see Section 7.4.2 for dose escalation criteria):
1. All subjects in the preceding cohort have been randomized;
2. All subjects have received at least 1 dose of investigational drug and have reached Day 28 of 
Cycle 1 or have completed their last evaluation within cycle 1.
3. Before any dose escalation, the SRC (at the minimum consisting of sponsor personnel and 
principal investigator), will review all the available safety, tolerability and PK data of the 
entire dose-level cohort to decide if dose escalation is deemed safe.


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Figure 6.b
Overall Design of the Double-Blind Treatment Period, With Proposed Dose 
Escalation
6.2
Justification for Study Design, Dose and Endpoints
The primary objective of the study is to characterize the safety and tolerability of ixazomib 
following multiple oral dose administration in subjects with LN. The study is therefore designed 
as a double-blind, placebo-controlled study in order to avoid subjective bias in the assessment of 
the safety and tolerability of ixazomib in this population. The ixazomib doses are 0.5 to 4 mg, 
dosed orally in three 4-week cycles, each cycle consisting of once-a-week doses given for 
3 weeks followed by a 13-day break from the last dose. Subjects who received a dose ≤2.0 mg 
and completed all cycles including the Follow-up Period, will be permitted to re-enroll into the 
2.0 and 3.0 mg dose groups, as appropriate. The dosing schedule is based on the oncology dosing 
schedule which is currently employed in phase 3 oncology studies.
The justification for the dose range in the proposed study is primarily based on data from the
oncology program. The doses of oral ixazomib used in the oncology program range from 0.24 to 
3.95 mg/m2 and fixed doses of 3 to 5.5 mg, as a single agent or in combination with lenalidomide 
and/or dexamethasone. The starting dose of 0.5 mg is lower than that used in oncology subjects, 
with only 3 subjects in the oncology program have received an estimated fixed dose of ~1.0 mg.
The top dose in this MRD study in LN of 4 mg is lower than the single-agent MTD of 
2.97 mg/m2 (approximately equivalent to 5.5 mg fixed dose) administered once weekly in 
subjects with RRMM (study C16004). The dose levels in study C16004 ranged from 0.24 mg/m 2
(~ 0.44 mg) to 3.95 mg/m2 (~7 mg). The starting dose was 0.24 mg/m2, and the escalation 


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proceeded with doses of 2.0-, 1.67-, 1.50-, 1.40-, and 1.33-fold over the previous dose level 
thereafter. Three to 6 subjects were evaluated at each dose level during Cycle 1 for predefined 
DLTs. The actual initial doses administered across these 8 dose levels ranged from 0.2 to 8.9 mg. 
Three subjects had DLTs; 2 of 4 subjects at 3.95 mg/m2 CTCAE Grade 3 nausea, vomiting, and 
diarrhea and Grade 3 erythema multiforme. The actual initial doses of ixazomib administered to 
the subjects in the 3.95 mg/m2 Cohort were 6.5 to 8.9 mg. At the 2.97 mg/m2 dose level, 1 of 
6 subjects had DLTs of Grade 3 nausea, vomiting, and diarrhea. All DLTs were reversible and 
the subjects continued the study at the next lower dose. The actual initial doses of ixazomib 
administered to the subjects in the 2.97 mg/m2 Cohort were 4.4 to 7.2 mg. Overall, the maximum 
tolerated doses (MTD) determined in the oncology studies ranged between 4 (in combination) 
and 5.5 mg (as single agent) (Section 4.1.4).
A population pharmacokinetic model was constructed based on the PK data of 4 clinical phase 1 
trial in oncology patients (C16001, C16002, C16003, C16004). Using this model it was 
investigated whether body size covariates (weight or body surface area [BSA]) significantly 
affect the clearance of ixazomib. Based on this analysis, neither weight nor BSA were 
significant, therefore the clinical development of ixazomib transitioned from BSA-based dosing 
to fixed dosing (see the ixazomib IB for further details). The recommended phase 2 and 3 dose of 
2.23 mg/m2 translated into a fixed dose of 4 mg based on the results from this population PK 
analysis; thus, all subjects in the phase 2 portion of the C16005 study received a fixed dose of 
4 mg weekly. The MTDs of both ixazomib as a single-agent and when combined with 
lenalidomide and dexamethasone were the same, 2.97 mg/m2 (5.5 mg). The current dose of 4 mg 
(fixed) used for the phase 3 combination studies in oncology for the once weekly schedule is 1 
dose level lower than the MTD. 
Anticipated human exposures in terms of median AUC168 at the planned clinical doses up to 4 
mg are lower than the exposures in the dog toxicology study at the NOAEL dose and higher than 
that observed at the NOAEL dose in the rat toxicology study (Table 6.a). However, although the 
margins are <1 for the 4 mg dose for both Cmax and AUC168 in rat, the exposures reached at the 
top dose proposed within this study of 4 mg are still lower than those observed in the dog studies 
at the NOAEL dose and in the current clinical MTD of 2.97 mg/m2 (~5.5 mg). In terms of 
median AUC168 values the predicted exposure at the MTD is 1.87 µghr/mL and the value at the 
4 mg dose is 1.35 µghr/mL, therefore, ~1.4-fold lower than the exposure at the MTD (see Table 
6.a). The low incidence and mainly mild to moderate severity of AEs that occurred in study 
C16004 at doses up to ~4 mg (lower than the MTD) suggest that the risk of treatment-related 
SAEs in the planned MRD over the proposed dose range is likely to be manageable. 
For subjects who are re-enrolled in the 2.0 or 3.0 mg dose groups, accumulation of ixazomib in 
plasma is not expected or will be minimal, as the apparent terminal half-life of ixazomib is 
approximately 4 to 9 days, the Follow-Up Period following the end of treatment (Day 84) is 3 
months (Day 168), which provides a total washout of ixazomib approximately 9 times longer 
than the upper terminal half-life estimate of 9 days. Before re-enrollment, subjects will be 
required to undergo screening and to meet the inclusion criteria; therefore, re-enrollment is not 
expected to be an additional risk to eligible subjects.


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Table 6.a
Summary of the Simulated Human Exposures Margins Relative to 
Nonclinical Toxicity Studies and Clinical MTD
MLN9708 
Dose
(mg)
Predicted Human Exposure 
Parameters (a)
(95% Prediction Interval)
Estimated Human Exposure Margins (fold)
Rat (b)
Dog (c)
MTD (d)
Cmax
ng/mL
AUC168
µg·hr/mL
Cmax
AUC168
Cmax
AUC168
Cmax
AUC168
0.5
10.02 
(2.90, 35.98)
0.168 
(0.058, 0.478)
0.60
2.87
13.6
11.5
11.06
11.10
2
38.67
(12.28, 160.56)
0.644
(0.215, 1.998)
0.15
0.75
3.52
3.01
2.87
2.90
3
56.34
(18.61, 214.25)
0.986
(0.344, 2.872)
0.11
0.49
2.41
1.97
1.97
1.89
4
80.20
(23.12, 288.59)
1.350
(0.425, 4.248)
0.07
0.36
1.70
1.44
1.38
1.38
(a) A population PK model for ixazomib in plasma was developed earlier based on the available PK data of clinical trials in the 
oncology program [Ixazomib IB version 8, Section 5.4]. Using that model PK parameters were estimated based on data from the 
oncology trials C16003 and C16004, which resemble most closely the planned MRD trial with respect to the dosing schedule. 
The model was then used for the simulation of 1000 PK profiles for each dose group of the planned trial in LN. For these profiles 
individual Cmax and AUC168 values representing the exposure following the final dose in Cycle 3 (Day 15 of Cycle 3) were 
calculated and their distributions summarized as median and 95% prediction interval. 
(b) Rat exposures (Cmax and AUC168) at the NOAEL (0.2 mg/kg/dose) are from study WIL-416165. The mean (Day 168) Cmax 
and AUC168 values are 5.99 ng/mL and 482 ng·hr/mL, respectively (mean of both sexes).
(c) Dog exposures (Cmax and AUC[0-168]) at the NOAEL (0.10 mg/kg/dose) from study WIL-416164. The mean (Day 252) 
Cmax and AUC168 values are 136 ng/mL and 1940 ng·hr/mL, respectively, (mean of both sexes).
(d) Estimates were based on population-based clinical exposure at the MTD (5.5 mg) in Study C16004. The derived Cmax and 
AUC168 are 110.83 ng/mL and 1.87 µg∙hr/mL, respectively, (Day 15 Cycle 3).
In conclusion, the safety of ixazomib is supported by clinical experience gained from the 
ongoing oncology program. As of 27 March 2017, data are available from 941 patients known to 
have received at least 1 dose of either the IV or oral ixazomib formulations across the oncology 
clinical development program; in addition, 2682 patients have been enrolled in phase 3 clinical 
studies in RRMM, newly diagnosed MM and RRAL. The emerging safety profile indicates that 
ixazomib administration can lead to AEs that are generally manageable and reversible with dose 
reduction and supportive care. Additionally, the AEs in the combination studies are consistent 
with the safety profile of the individual agents in the combination regimen (eg, myelosuppression 
is common in regimens containing melphalan, and rash is common in regimens containing 
lenalidomide). While some of these potential toxicities may be severe, they can be managed by 
clinical monitoring and standard medical intervention.
Differences in the PK of ixazomib between oncology and LN subjects are expected to be 
minimal. In terms of demographic parameters the main differences between the 2 populations are 
age and renal function, which are anticipated to have only a minimal impact on systemic 
exposure. Participants in this study will be closely monitored, with once-a-week clinic visits 
during the Double-Blind Treatment Period, at least monthly visits at the Open-Label Treatment 
Extension Period and additional clinical assessment/interventions as needed. Overall the risk to 
LN subjects is expected to be minimal.


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6.3
Premature Termination or Suspension of Study or Investigational Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the compound, such that the 
risk/benefit is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)
In the event that the sponsor, an institutional review board (IRB)/ independent ethics committee 
(IEC), or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites 
during the course of termination or study suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed before first dose of study drug on 
Day 1.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria:
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject or, when applicable, the subject’s legally acceptable representative signs and 
dates a written informed consent form and any required privacy authorization before the 
initiation of any study procedures. 
3. The subject is female or male and aged 18 to 75 years, inclusive.
4. Subject has a diagnosis of SLE defined by meeting either the 2012 Systemic Lupus 
International Collaborating Clinics (SLICC) criteria or the ACR criteria for the classification 
of SLE. The 4 criteria required by ACR classification are not required to be present at 
Screening for eligibility (see Appendix H).
5. The subject has a definite diagnosis of LN based on a kidney biopsy done within 2 years of 
the Screening Visit which demonstrated ISN/RPS Class III, IV or V changes [excluding 
Class III (C), IV-S (C) and IV-G (C)] or WHO 1982 classification Class III, IV or V 
(excluding Class IIIc and IVd)(see Appendix I).
a) If no biopsy was done within 2 years of Screening Visit, biopsy can be done 
during the screening period as a study procedure.
b) Co-existence of classes is permitted.
c) Subjects with a confirmed diagnosis of LN who have not had a renal biopsy 
within 2 years of screening and cannot have a renal biopsy during the screening, 
may be eligible for the study if they have proteinuria of ≥1 g/24 hours due to a LN 
renal flare occurring within 1 year of the screening. A LN renal flare is defined as 
at least a doubling of proteinuria with no other explanation such as a secondary 
pathology (eg, diabetic nephropathy) or change in medication (eg, reduction of 
angiotensin-converting enzyme /angiotensin II receptor blocker).
6. The subject has a renal biopsy demonstrating either ISN/RPS or WHO Class V or Class V 
with Class 2 nephritis with a UPCR of ≥1 or the subject has a renal biopsy demonstrating 
either active ISN/RPS or WHO Class III or IV nephritis, defined by either one of the 
following criteria:
a) A UPCR* of ≥1.0 at Screening
OR


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b) A UPCR* >0.5 at Screening and at least one of the following:
i.
Active urine sediment in the absence of infection or other cause within 3 months of 
screening, defined as at least one of the following:

≥5 red blood cells (RBC) per high power field, not due to causes other than LN.

≥5 white blood cells (WBC) per high power field in the absence of infection.

Presence of cellular casts. 
ii.
The subject has increased levels (above upper limit of normal [ULN] serum dsDNA 
autoantibodies at screening. 
iii.
Low complement (either C3 or C4) at Screening (≥25% lower than the lower limit 
of normal [LLN]).
iv.
Biopsy within 3 months before screening visit indicating active proliferative lupus 
glomerulonephritis ISN/RPS class III or IV changes [excluding Class III (C), IV-S 
(C) and IV-G (C)] or WHO 1982 classification Class III or IV (excluding Class IIIc 
and IVd), with co-existing Class V permitted.
*Subjects may be re-screened once for urinary sediment, proteinuria or complement 
levels within 2 weeks of the original screening visit.
* UPCR value for eligibility will be based on the average UPCR obtained from the 
3 specimens collected during screening.
7. The subject has had an inadequate response, in the judgment of the investigator, to at least 
3 months of an immunosuppressive regimen including single or sequential use of at least one 
of the following: CYC, mycophenolate mofetil (MMF), mycophenolic acid (MA) or AZA.
8. If the subject is on glucocorticosteroids, must be on stable dose equivalent to 20 mg/day or 
less of prednisone for at least 2 weeks before the first dose of study medication. Subjects who 
are on a stable dose equivalent to >20 mg/day and ≤30 mg/day of prednisone may be allowed 
to the study reviewed by the adjudication committee and approved by the medical monitor; 
however, the steroid dose should be tapered as specified in Section 8.1.1.3.
9. Male subjects who are sexually active with women of child bearing potential, even if 
surgically sterilized (ie, status post-vasectomy), must:
a) Agree to practice effective barrier contraception during the entire study treatment period 
and through 90 days after the last dose of study drug.
10. Female subjects who are of child bearing potential must: 
a) Agree to practice 2 effective methods of contraception, at the same time, from the time of 
signing the informed consent through 90 days after the last dose of study.
11. This study permits the re-enrollment of a subject that has discontinued the study as a 
pre-treatment failure (ie, subject has not been randomized) and subjects who received a dose 


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≤2.0 mg and have completed all cycles including the Follow-up Period. If re-enrolled, the 
subject must be re-consented. 
* The re-enrollment of all subjects who received a dose ≤2.0 mg and completed all cycles 
including the Follow-up Period is permitted to Cohort B and C (2.0 mg and 3.0 mg dose 
cohorts) after completion of all cycles including the follow-up period if they had no drug-
related AEs greater than Grade 1 which required study drug dose modification, no AEs 
greater than Grade 2, continue to meet all inclusion and exclusion criteria, and the SRC has 
reviewed and approved enrollment of the subject into a higher dose cohort.
12. Subjects must be receiving Standard of Care treatment with an immunosuppressant drug for 
the treatment of LN (eg, mycophenolate mofetil, mycophenolic acid or azathioprine, see 
Section 8.1.1.2).
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
1. The subject has received any investigational compound within 30 days or 5 half-lives, 
whichever is the longer, before Screening or is currently participating in another 
interventional clinical study. 
2. The subject has received ixazomib, bortezomib, or another proteasome inhibitor in a previous 
clinical study or as a therapeutic agent.
3. The subject is a sponsor employee, an immediate family member, study site employee, or is 
in a dependent relationship with a study site employee who is involved in conduct of this 
study (eg, spouse, parent, child, sibling), or may consent under duress.
4. The subject has an autoimmune disease other than SLE as their main diagnosis.
5. The subject has drug-induced SLE.
6. The subject has severe, active central nervous system lupus (BILAG A or B).
7. The subject has an eGFR of <30 mL/min/1.73m2, or is on dialysis, or is expected to have a 
renal transplant within 1 year of randomization, or has had a renal transplant. 
8. The subject has a severe acute infectious disease (eg, untreated active tuberculosis (TB),
acute viral hepatitis, human immunodeficiency virus), untreated latent tuberculosis (TB), or 
infections requiring IV anti-microbial treatment within 2 months preceding the Screening 
Visit.
9. The subject has a history of a malignant disease (except successfully treated basal cell 
carcinoma, squamous cell carcinoma, or cervical carcinoma in situ) within 5 years before
Screening.
10. The subject has one of the following laboratory test values:


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a) IgG <75% of LLN. If low IgG is due to significant proteinuria due to LN activity, 
subjects with IgG >4.2 g/dL can be included. The cause of low IgG must be due to LN 
proteinuria and all other causes of hypo-gammaglobulinemia must be ruled out.
b) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the 
central laboratory’s ULN.
c) Bilirubin >1.5 x ULN (Note: subjects with Gilbert Syndrome with a confirmed diagnosis 
and documented in the subject’s medical record will not be excluded based on this 
criterion).
d) Platelets <75,000/mm3.
e) Neutrophils <1500/ mm3.
f)
Hemoglobin <8 g/dL.
g) Positive for Hepatitis B Surface Antigen.
h) Positive for Hepatitis C antibody.
11. The subject has a history of drug or alcohol abuse or dependence (as defined by Diagnostic 
and Statistical Manual of Mental Disorders, fourth Edition [DSM-IV]) within 1 year before
screening visit (see Appendix J).
12. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 3 months after participating in this study; or intending to donate ova during such 
time period.
13. If male, the subject intends to donate sperm during the course of this study or for 90 days 
after the last dose. Male subjects planning to father during clinical trial conduct or within 
90 days after the last planned dose of trial treatment.
14. The subject has moderate or severe liver disease (Child-Pugh B or C), and/or positive 
serological tests for hepatitis B (other than due to prior immunization) or hepatitis C.
15. The subject is taking excluded medications (Section 7.3).
16. The subject has a history of clinically significant neuropathies of National Cancer Institute 
CTCAE v 4.03 Grade 2 or higher.
17. The subject has been treated with cyclophosphamide within 4 weeks of the Screening Visit.
18. The subject has been treated with >3 g/day of mycophenolate mofetil within 4 weeks of the 
Screening Visit.
19. The subject has been treated with belimumab, abatacept, or tocilizumab within 3 months of 
the Screening Visit.
20. The subject has been treated with epratuzumab, alemtuzumab, rituximab or other cell 
depleting biological agents within 6 months of the Screening Visit.


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21. Current symptoms of severe, progressive, or uncontrolled non-SLE related renal, hepatic, 
hematological, gastrointestinal (including hypomotility and ulcerative/inflammatory 
conditions), pulmonary, cardiac, neurological, or cerebral disease, or other concomitant 
medical conditions that, in the opinion of the investigator, might place the subject at 
unacceptable risk for participation in this study.
7.3
Excluded and Restricted Medications, Procedures and Dietary Products
Subjects should remain on their current stable and allowed therapies during the screening period 
and throughout the duration of the study. Initiation of therapy with any of the following 
medications or treatments after randomization (Study Day 1) is not allowed (see Table 7.a):
Angiotensin converting enzyme inhibitors, angiotensin II receptor blocking agents
Methotrexate, Leflunomide
Azathioprine
Calcineurin inhibitors (cyclosporine, tacrolimus, etc)
Cyclophosphamide
mTOR inhibitors (sirolimus or everolimus)
Belimumab, Rituximab or any other biologic agents for the treatment of lupus
Thalidomide
Gold compounds
Experimental therapies for the treatment of SLE
Intravenous immunoglobulin
Plasmapheresis, Lymphopheresis, Prosorba column
Dialysis
The prescribing label of all concomitant medications used as concomitant therapy should be 
evaluated by the investigator for continued administration during the study for known toxicities, 
DDIs, or any anticipated risks associated with co-administration with the investigational drug 
ixazomib.
Restrictions on use or starting of certain medications during the duration of the study are 
specified in Table 7.a (prescription or nonprescription). 


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Table 7.a
Prohibited Medications
28 days before Day 1 and 
during the study
14 days before Day 1
Starting Treatment after Day 1 and during the 
study
Cyclophosphamide
Nutraceuticals (eg, St. John’s wort)
Angiotensin converting enzyme inhibitors, 
angiotensin II receptor blocking agents
Methotrexate, Leflunomide
Azathioprine
Calcineurin inhibitors (cyclosporine, tacrolimus, 
etc)
mTOR inhibitors (sirolimus or everolimus)
Belimumab, Rituximab or any other biologic 
agents for the treatment of lupus
Thalidomide, Gold compounds
Experimental therapies for the treatment of SLE
Intravenous immunoglobulin
Plasmapheresis, Lymphapheresis, Prosorba 
column
Dialysis
Influenza vaccines or 
immunization with a live 
vaccine
Clinically significant CYP3A 
inducers: rifampin, rifapentine, 
rifabutin, carbamazepine, phenytoin, 
and phenobarbital
Clinically significant CYP3A inducers: rifampin, 
rifapentine, rifabutin, carbamazepine, phenytoin, 
and phenobarbital
Systemic treatment with any of the metabolizing enzyme inducers listed in Table 7.a is not 
permitted in this study given the risk of DDI with an inducer and the potential decrease in 
ixazomib exposure.
All necessary supportive care consistent with optimal patient care shall be available to subjects 
as necessary.
The prescribing label of all concomitant medications used as concomitant therapy should be 
evaluated by the investigator for continued administration during the study for known toxicities, 
DDIs, or any anticipated risks associated with coadministration with the investigational drug 
ixazomib. During participation in the study, subjects must be instructed not to take any 
medications, including over-the-counter medications, without first consulting the investigator.
7.4
Diet, Fluid, and Activity Control
Subjects should be encouraged to drink at least 1.5 liter of fluids a day, especially on days 
requiring fasting (for characterization of glucose responses, as per protocol). Particular attention 
should be given to adequate fluid intake in case of gastrointestinal toxicities (eg, vomiting, 
diarrhea, loss of appetite) to avoid dehydration.


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7.4.1
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study should be 
recorded in the eCRF using the following categories. For screen failure subjects, refer to 
Section 9.1.19.
1. Pretreatment event or AE. The subject has experienced a pretreatment event or AE that 
requires early termination because continued participation imposes an unacceptable risk to 
the subject’s health or the subject is unwilling to continue because of the pretreatment event 
or AE.

Liver Function Test Abnormalities
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.10), if the following circumstances occur at any 
time during study medication treatment:
–
ALT or AST >8 × ULN, or
–
ALT or AST >5 × ULN and persists for more than 2 weeks, or
–
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio >1.5, or ALT or AST >3 × ULN with appearance of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or 
eosinophilia (>5%).
–
If ALT or AST >3 ×ULN, but <5XULN, laboratory tests should be repeated until 
recovery of observed (see Table 7.d) and ixazomib withheld. Upon recovery, 
ixazomib may be resumed at lower dose. If the ALT or AST remains elevated >3 
×ULN on these 2 consecutive occasions, and this observation cannot be explained by 
concomitant disease or another alternative etiology, the investigator should contact 
the Medical Monitor for considerate on permanent discontinuation of study 
medication, discussion of the relevant subject details and possible alternative 
etiologies.
2. Major protocol deviation. The discovery after administration of the first dose of study drug 
that the subject failed to meet protocol entry criteria or did not adhere to protocol 
requirements, and continued participation poses an unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented.
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (ie, withdrawal due to 
an AE should not be recorded in the “voluntary withdrawal” category).


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5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
6. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.12. 
7. Initiation of therapy with a recombinant granulocyte colony stimulating factor (G-CSF), 
including filgrastim or lenograstim, or intravenous immunoglobulin (IVIG).
8. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.4.2
Dose Escalation Criteria
All decisions concerning dose escalation will be made by Takeda (at a minimum, the clinical 
science representative(s) and pharmacovigilance physician) and the principal investigator. The 
following dose escalation is planned outlined in Table 7.b.
Table 7.b
Dose Increase Factors
Dose (mg)
Dose Increase Factor
0.5
(starting)
2.0
4.00
3.0
1.5
4.0
1.33
During the Double-Blind Treatment Period, safety labs will be performed at each dosing day, as 
well as Day 22 of each cycle. The PK will be assessed following the first dose of Cycle 1 and the 
last dose of Cycle 3. 
For each dose level Cohort, the SRC will carefully review the available safety, tolerability, and 
PK data and determine whether dosing should be escalated in the next Cohort, or lowered or 
expanded with same dose to obtain additional information before dose-escalation decision or 
stopped. Additionally, based upon review of available data, unblinding may be considered if 
deemed critical by the sponsor and investigator(s) to make a decision regarding the conduct of 
the study or for subject safety. Safety review will include all available AEs, vital signs, ECGs, 
and laboratory parameters, as well as available PK data.
Dose escalation will depend upon the safety clinical profile of the doses up to and including the 
preceding dose group and it will not occur until the following conditions are met:
1. All subjects randomized in the preceding dose Cohort, have received at least one dose of 
study medication (except in case of pre-treatment dropouts) and have reached Day 28 of 
Cycle 1 or have completed their last evaluation within Cycle 1;


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2. Safety (including report of TEAEs, clinical laboratory results and vital signs) and tolerability 
data of all subjects of the preceding Cohort are reviewed by a SRC and deemed safe to 
proceed with dose escalation.
Subjects discontinued or withdrawn after randomization for non-safety reasons will only be 
replaced if the number of subjects per Cohort evaluable for safety on Day 28 of Cycle 1 is 
reduced below 6 subjects.
All TEAEs reported during the Treatment Period, both within and across cohorts, up to the time 
of discharge, will be evaluated to assess the need for subject and/or study termination in 
accordance with the pre-specified criteria for discontinuation/termination. 
Following assessment of the TEAE data and predefined criteria for study termination, dose 
escalation may be interrupted/stopped and the blind broken for further analysis. Based on review 
of unblinded data, Takeda in consultation with the principal investigator(s) will decide whether 
and how it is appropriate for the study to proceed.
Within each dose level, if at least 2 subjects develop a DLT, the subjects will be unblinded for 
any dose-escalation joint safety review meeting. If both subjects are on ixazomib, no further dose 
escalation beyond that dose will be allowed. If at least 2 subjects develop a DLT leading to 
discontinuation of ixazomib, then the subjects will be immediately unblinded and if both subjects 
are on ixazomib, no further dosing will occur in that dose Cohort.
Although DLTs may occur at any point during treatment, primarily the DLTs occurring during 
Cycle 1 of treatment will be used to make a decision regarding dose escalation, expansion of a 
dose level, or evaluation of intermediate dose levels.
7.4.3
DLTs, Dose Modifications, and Stopping Rules
DLT is defined as any of the following TEAEs that occur after a subject has received blinded 
study medication and that do not have a clear alternate causality (Grades are CTCAE v 4.03):
1. Grade 3 or greater neutropenia (absolute neutrophil count [ANC] <1000/mm3), confirmed by 
repeat test.
2. Grade 3 or greater thrombocytopenia (platelets <50,000/mm3), confirmed by repeat test.
3. Grade 2 peripheral neuropathy with pain or Grade 3 or greater peripheral neuropathy.
4. Grade 3 or greater nausea, emesis, or diarrhea.
5. Serious infections defined as infections requiring hospitalization or IV antibiotics (more than 
1 dose), systemic antifungal or antiviral intervention.
6. ECG with QT interval with Fridericia correction method (QTcF) >500 msec confirmed by 
repeat ECG.
7. Any other Grade 3 or greater nonhematologic toxicity with the following exceptions:
Grade 3 arthralgia/myalgia.
Brief (<1 week) Grade 3 fatigue.


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8. A delay of more than 2 weeks in the initiation of Cycles 2 or 3 of treatment because of a lack 
of adequate recovery of hematological or nonhematologic toxicities.
9. A Grade 2 or greater toxicity that requires discontinuation of therapy with ixazomib.
If an individual subject meets the DLT criteria, then specific rules outlined on Table 7.c and 
Table 7.d will be applied depending on the toxicity.


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Table 7.c
Monitoring of Hematologic Toxicities and Dose Modification/Drug Stopping 
Rules
Toxicity
Repeat Laboratory Test
Ixazomib 
Neutropenia
<1,500/mm3 (1.5 x 
109/L)
Repeat test as appropriate based on
investigator’s clinical judgment
No change
<1000/mm3 (1.0 x 
109/L)
Repeat test within 72 hours and then repeat test at 
least 2× a week until neutrophil counts are 
≥1,000/mm3. Then, repeat test as appropriate 
based on investigator’s clinical judgment.
Withhold ixazomib until neutrophil 
counts are >1,500/mm3.
Upon recovery, ixazomib may be 
resumed at lower dose.
If neutropenia is accompanied by fever 
≥38.5°C or infection, then discontinue 
ixazomib.
<500/mm3 (0.5 x 109/L) Repeat test within 72 hours and then repeat test at 
least 3× a week until neutrophil counts are 
≥1,000/mm3. Then, repeat test as appropriate 
based on investigator’s clinical judgment.
Discontinue ixazomib permanently. 
Subjects who require treatment with 
Filgrastim G-CSF (filgrastim, 
lenograstim or similar) should be 
discontinued from the study.
Thrombocytopenia
<75,000/mm3 (75 x 
109/L)
Repeat test as appropriate based on
investigator’s clinical judgment
No change
<50,000/mm3 (50 x 
109/L)
Repeat test within 72 hours and then repeat test at 
least 2× a week until platelet counts are 
≥50,000/mm3. Then, repeat test as appropriate 
based on investigator’s clinical judgment.
Withhold ixazomib until platelet counts 
are >75,000/mm3.
Upon recovery, ixazomib may be 
resumed at lower dose.
If thrombocytopenia recurs or is 
accompanied by clinically significant 
bleeding, then discontinue ixazomib.
<25,000/mm3 (25 x 
109/L)
Repeat test within 72 hours and then repeat test at 
least 3× a week until platelet counts are 
≥50,000/mm3. Then, repeat test as appropriate 
based on investigator’s clinical judgment.
Discontinue ixazomib permanently.
Other Hematologic Toxicities
Grade 3 (severe) 
hematologic toxicities
Repeat test within 72 hours and then repeat test at 
least 2× a week until recovery to Grade 2 is
observed. Then, repeat test as appropriate based on 
investigator’s clinical judgment.
Withhold ixazomib until toxicity is 
≤Grade 1.
Grade 4 (very severe) 
hematologic toxicities
Repeat test within 72 hours and then repeat test at 
least 3× a week until recovery to Grade 2 is 
observed. Then, repeat test as appropriate based on 
investigator’s clinical judgment.
Discontinue ixazomib permanently.


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Table 7.d
Monitoring of Non-Hematologic Toxicities and Dose Modification/Drug 
Stopping Rules
Toxicity
Repeat Laboratory Test
Ixazomib 
Severe Cutaneous Skin 
Reactions
Stevens-Johnson Syndrome, 
Toxic Epidermal Necrolysis, 
drug reaction with eosinophilia 
and systemic symptoms (DRESS 
syndrome) or pemphigus 
vulgaris
Discontinue ixazomib permanently.
Infections
Serious infection requiring 
hospitalization, IV antibiotics 
(more than 1 dose), systemic 
antifungal or antiviral 
intervention
Discontinue ixazomib permanently.
Peripheral Neuropathy
Newly developed Grade 1 
peripheral neuropathy with pain 
or Grade 2 peripheral neuropathy
Reduce dose of ixazomib to the 
previous dose level, except for the 0.5 
mg cohort.
Grade 2 peripheral neuropathy 
with pain or Grade 3 peripheral 
neuropathy
Withhold ixazomib until toxicity is 
≤Grade 1
Upon recovery, ixazomib may be 
resumed at lower dose except for the 0.5 
mg cohort.
Grade 4 peripheral neuropathy
Discontinue ixazomib permanently.
Other AEs considered related to ixazomib 
ECG with QTcF >500 msec 
confirmed by repeat ECG
Repeat ECG within the same day of 
initial finding.
Discontinue ixazomib immediately.
Decrease in eGFR >25% from 
Baseline or doubling of serum 
creatinine from Baseline
Repeat test within 72 hours from initial 
finding.
Discontinue ixazomib immediately.
IgG <50% of LLN
Repeat test within 72 hours from initial 
finding.
Discontinue ixazomib immediately. 
Subjects who require treatment with 
IVIg should be discontinued from the 
study.
Grade 3 toxicities
If applicable, repeat test within 72 hours 
and then repeat test 2× a week until 
recovery to Grade 2 is observed. 
Thereafter, repeat test as appropriate 
based on investigator’s clinical judgment.
Withhold ixazomib until toxicity is 
≤Grade 1 or returned to the subject’s 
baseline condition.
Upon recovery, ixazomib may be 
resumed at lower dose except for the 0.5 
mg cohort.
Grade 4 toxicities
If applicable, repeat test within 72 hours 
and then repeat test 3× a week until 
recovery to Grade 2 is observed. 
Thereafter, repeat test as appropriate 
based on investigator’s clinical judgment.
Discontinue ixazomib permanently.


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The blinded treatment cycles with ixazomib will be repeated every 28 days for a total of 3 cycles.
Subjects can also receive up to 3 additional cycles of open label treatment with ixazomib at the 
discretion of investigator. For a new cycle of treatment to begin, the subject’s absolute neutrophil 
count must be ≥1,500 mm3 and the platelet count must be ≥75,000 mm3. In addition, all other 
toxicities considered to be related to treatment with ixazomib must have resolved to ≤Grade 1 or 
to the subject’s baseline values before a new cycle of treatment may begin. 
If the subject fails to meet the above-cited criteria for retreatment, initiation of the next cycle of 
treatment should be delayed for 1 week. At the end of that time, the subject should be re-
evaluated to determine whether the criteria for retreatment have been met. If a delay in the 
initiation of the next cycle of more than 2 weeks is required because of incomplete recovery from 
treatment-related toxicity, then this event will be considered a DLT. If toxicity does not resolve 
by 2 weeks, then the subject should be considered for removal from the study. This decision will 
be made in the context of emerging clinical data about our understanding of ixazomib in subjects 
with LN and in consultation with the investigators and Takeda medical monitor and 
pharmacovigilance physician. If, in the opinion of the investigator and the Takeda physicians, it 
is in the subject’s best interest to continue treatment with ixazomib, then ixazomib will only be 
resumed after recovery from the toxicity or toxicities in question to ≤Grade 1 or to baseline 
values and the dose of ixazomib should be reduced by at least 1 dose level.
Similarly, if dosing with ixazomib needs to be withheld within a given cycle because of toxicity, 
then ixazomib will only be resumed after recovery of the toxicity or toxicities in question to 
≤Grade 1 (if a laboratory parameter, recovery should be confirmed by repeat test) and the dose of 
ixazomib should be reduced by at least 1 dose level. When a dose reduction of ixazomib is 
required, no re-escalation of dose will be permitted for that subject. For the first Cohort (0.5 mg 
dose), no reduction will be made. If the DLT recurs upon resuming ixazomib at a lower dose, 
then ixazomib should be immediately discontinued.
7.5
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may terminate a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.4.1. In addition, a subject 
may discontinue his or her participation without giving a reason at any time during the study. 
Should a subject’s participation be discontinued, the primary criterion for termination must be 
recorded. In addition, efforts should be made to perform all procedures scheduled for the Final 
Visit/Early Termination (ET).
Subjects discontinued or withdrawn after randomization for nonsafety reasons will only be 
replaced if the number of subjects per cohort evaluable for safety on Day 28 of Cycle 1 is 
reduced below 6 subjects for Cohorts C and D, below 5 subjects for lower than 3.0 mg dose 
cohorts, or the SRC recommends expanding with the same dose to obtain additional information 
before a dose-escalation decision.


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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material.
8.1
Study Medication and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
8.1.1.1
Investigational Drug
Double-Blind Treatment Period
In the Double-Blind Treatment Period of protocol, the term study medication refers to all or any 
of the drugs defined below:

MLN9708 (ixazomib) capsules 0.5 mg (as boronic acid) and matching placebo in dark green 
size 3 capsules.

MLN9708 (ixazomib) capsules 2 mg (as boronic acid) and matching placebo in Swedish 
orange size 2 capsules.
The active capsule strengths contain both drug substance and inactive ingredients. The 
corresponding placebo capsules contain all of the same components of active MLN9708 
(ixazomib) with the exception of the active ingredient, which is substituted with an equivalent 
amount of Mannitol. The manufacturer of MLN9708 (ixazomib) is Haupt Pharma Amareg 
GmbH Germany. The investigational drug will be packaged in foil/foil blistered child resistant 
wallets as weekly doses administered on Days 1, 8 and 15 of each cycle. Each wallet of 
MLN9708 (ixazomib) active or placebo will bear a single-panel label or booklet that includes 
pertinent study information, medication ID numbers for interactive voice response 
system/interactive web response system (IVRS/IWRS) dispensing purposes and local regulatory 
requirements. Wallets will contain either 1, 2, or 3 capsules based on dose required. See Table 
8.a.
Open-Label Treatment Extension
In the Open-Label Treatment Extension of this protocol, the term study medication refers to all 
or any of the drugs defined below:

MLN9708 (ixazomib) capsules 2 mg (as boronic acid) in Swedish orange size 2 capsules.

MLN9708 (ixazomib) capsules 3 mg (as boronic acid) in light grey size 4 capsules.

MLN9708 (ixazomib) capsules 4 mg (as boronic acid) in ivory size 3 capsules.
The manufacturer of MLN9708 (ixazomib) is Haupt Pharma Amareg GmbH Germany. The 
investigational drug will be packaged in foil/foil blistered child resistant wallets as monthly 
doses administered on Days 1, 8, and 15 of each cycle. Each wallet of MLN9708 (ixazomib) will 
bear a single-panel label or booklet that includes pertinent study information, medication ID 


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numbers for IVRS/IWRS dispensing purposes and local regulatory requirements. Wallets will 
contain 3 capsules (see Table 8.a).
8.1.1.2
Concomitant Medications for Treatment of SLE While on Study Medication
Corticosteroids
If receiving corticosteroids, subjects should remain on their stable screening dose at least until 
completion of dosing with investigational drug in the first cycle on Day 15, when tapering the 
dose of corticosteroid, can start as specified in Section 8.1.1.3. Temporary increases in the dose 
of corticosteroids are allowed as a rescue therapy (see Section 8.1.1.3).
Immunosuppressants
Subjects should remain on their stable dose of immunosuppressive therapies throughout the 
study and consistent with labeling recommendations. On the days of dosing with ixazomib, 
subjects should skip their immunosuppressant medication. On the next day, regular dosing with 
the immunosuppressant agent should be resumed.
Decreases in the dose of immunosuppressants are allowed at the discretion of the investigator 
due to toxicity. Increase in the dose of immunosuppressants is allowed after completion of the 
last cycle with ixazomib (or 2 weeks after last dose). The concomitant use of cyclophosphamide 
is not allowed during the study.
Anti-proteinuric agents
Subjects with active LN and significant proteinuria should receive anti-proteinuric agents, such 
as angiotensin II receptor blockers, angiotensin-convertase enzyme inhibitors or any combination 
of these drugs, unless contraindicated, not tolerated, previously demonstrated to be not effective, 
or not consistent with local standard of care.
Subjects should have started treatment with anti-proteinuric agents before randomization and the 
dose should remain stable throughout the treatment period of the study and doses should not be 
increased. Reduction in the dose of anti-proteinuric agents is allowed for tolerability or toxicity 
reasons.
Use of other antihypertensives medications (eg, calcium channel blocking agents) is permitted 
for blood pressure control as needed.
Anti-malarials and topical therapies
Chloroquine, hydroxychloroquine, quinacrine should be continued at stable doses and their 
safety monitored using standard and accepted monitoring regimens. Topical therapies (including 
eye, ear, nose treatments) may be continued and their use modified as indicated.
Nonsteroidal Anti-inflammatory Drug
Nonsteroidal anti-inflammatory drugs (NSAIDs) (including aspirin/acetylsalicylic acid) use is 
not prohibited, although their use is generally discouraged in the setting of active renal disease.


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Other medications
Use of concomitant medications used by the subject for treatment of diseases or symptoms not 
related to SLE is permitted during the study, unless the medication is prohibited. Use of vitamins 
is permitted throughout the study. For a list of restricted or prohibited medications, see 
Section 7.3.
8.1.1.3
Corticosteroids Taper and Rescue Therapy
Corticosteroids (Prednisone or Prednisone Equivalent) Taper After Randomization
Subjects Taking Glucocorticosteroids Equivalent to ≤20 mg of Prednisone at Baseline:
After completion of dosing in the first cycle, a decision on tapering the corticosteroid dose can 
be made at the discretion of the investigator. To start tapering the corticosteroid, a subject must 
meet all of the following criteria:
1. UPCR: no more than 25% above the greater of the values at the Screening or Randomization 
(Study Day 1) visit.
2. eGFR: no more than 15% worse than the lesser of the values at Screening or Day 1 Visit.
3. No clinically significant increase activity of the urine sediment, as determined by the 
investigator.
4. No clinically significant progressive active extra-renal lupus as determined by the 
investigator.
Tapering the corticosteroid should be initiated in the next visit and the proposed goal is to 
achieve ≥50% reduction in the dose of corticosteroid by the end of the next cycle with ixazomib 
(around week 8 in the study). Further tapering can continue during the last cycle with ixazomib 
at the discretion of the investigator.
If a subject is unable to initiate taper of corticosteroids during the study AND the investigator
determines that a medication not allowed in the protocol is needed to treat the renal or non-renal 
manifestations of SLE, the subject must be discontinued from treatment with study drug.
Subjects Taking Glucocorticosteroids Equivalent to ˃20 mg to ≤30 mg of Prednisone at 
Baseline:
The investigator should attempt to taper subjects’ steroid dose to ≤25 mg/day prednisone after 
Day 15 of Cycle 1 (Week 4) and to ≤20 mg after Day 15 of Cycle 2 (Week 8) of treatment 
considering the aforementioned criteria. 
Rescue Therapy With Corticosteroids
If, in the judgment of the investigator, there is need for increase in corticosteroid dosage during 
the first or second cycles, the dosage may be increased to a dose that is less than or equal to 
0.5 mg/kg/day or 40 mg/day, whichever is lower. However, dose should be tapered to the pre-
flare level or 10 mg/day, whichever is greater, within 4 weeks or less. If tapering is not possible 


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AND the investigator determines that a medication not allowed in the protocol is needed to treat 
the renal or non-renal manifestations of SLE, the subject must be discontinued from treatment 
with study drug.
Subjects who require increase in corticosteroid dose above 0.5 mg/kg/day or 40 mg/day of 
prednisone or equivalent for control of LN activity or control a flare of non-renal lupus activity 
during the study will be discontinued from study drug.
8.1.2
Storage
All clinical trial material must be kept in an appropriate, limited-access, secure location until it is 
used or returned to the sponsor or designee for destruction. All study medication must be stored 
under the conditions specified on the label, and remain in the original container until dispensed. 
A daily temperature log of the drug storage area must be maintained every working day. See 
pharmacy manual for specific receipt instructions, temperature excursion notification process, 
and capsule handling instructions. 
Recent stability testing has expanded the permitted ixazomib/placebo temperature range. All new 
ixazomib/placebo capsules batches will be labeled with the expanded range: Do not store above 
25°C/Do not freeze or Do not store above 30°C/Do not freeze. Earlier batches of 
ixazomib/placebo capsules (labeled with the initial storage range: Store at 2°C to 8°C/36°F to 
46°F) remain acceptable for use until expired. Sites may receive ixazomib/placebo capsules with 
new or initial labeling as supplies are transitioned. In either case, sites must store 
ixazomib/placebo as directed on the label. The investigator should ensure that study medication 
is used only in accordance with the approved protocol. Study medication will be dispensed only 
for subjects enrolled in the study.
8.1.3
Dose and Regimen
The investigator or investigator’s designee will instruct each subject to swallow 
ixazomib/placebo capsules whole with water and not to break, chew or open the capsules. Study 
drug should be taken on an empty stomach, at least one hour before or no sooner than two hours 
after a meal. Each capsule should be swallowed with a sip of water. A total of approximately 
240 mL of water should be taken with the capsules.
During the Double-Blind Treatment period, all dosing will occur while subjects are in the clinic 
under the supervision of the principal investigator or designee as indicated in Table 8.a. During 
the Open-Label Treatment Extension, the first dose of each cycle will occur while subjects are in 
the clinic, and the remaining doses will be self-administered at home.


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Table 8.a
Treatment Groups
Cohort
Treatment Group
Active Dose (N=6)
Placebo Dose (N=2)
A
MLN9708 (ixazomib) 0.5 
mg (as boronic acid) or 
matching placebo 
One MLN9708 (ixazomib) 0.5 mg 
(as boronic acid) dark green size 3 
capsule 
One Placebo for MLN9708 (ixazomib) 
0.5 mg (as boronic acid) dark green size 3 
capsules
B
MLN9708 (ixazomib) 2 mg 
(as boronic acid) or 
matching placebo
One MLN9708 (ixazomib) 2 mg 
(as boronic acid) Swedish orange 
size 2 capsule
One Placebo for MLN9708 (ixazomib) 2 
mg (as boronic acid) Swedish orange size 
2 capsule
C
MLN9708 (ixazomib) 3 mg 
(as boronic acid) or 
matching placebo
One MLN9708 (ixazomib) 2 mg 
(as boronic acid) Swedish orange 
size 2 capsule
and
Two MLN9708 (ixazomib) 0.5 
mg (as boronic acid) dark green 
size 3 capsules
One Placebo for MLN9708 (ixazomib) 2 
mg Swedish orange size 2 capsule
and
Two Placebo for MLN9708 (ixazomib) 
0.5 mg (as boronic acid) dark green size 3 
capsules
D
MLN9708 (ixazomib) 4 mg 
(as boronic acid) or 
matching placebo
Two MLN9708 (ixazomib) 2 mg 
(as boronic acid) Swedish orange 
size 2 capsules
Two Placebo for MLN9708 (ixazomib) 2. 
mg (as boronic acid) Swedish orange size 
2 capsules
OLE
MLN9708 (ixazomib) 2 mg (as 
boronic acid) capsules in Swedish 
orange size 2 capsules
MLN9708 (ixazomib) 3 mg (as 
boronic acid) capsules in light 
grey size 4 capsules
MLN9708 (ixazomib) 4 mg (as 
boronic acid) capsules in ivory 
size 3 capsules
OLE=Open-Label Treatment Extension Period
8.1.4
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. If overdose occurs, consider close observation including 
hospitalization for hemodynamic support. Gastric lavage may be considered if instituted within 1 
hour of ingestion of ixazomib overdose.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order 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, 
Pretreatment Events and Adverse Events.
SAEs of overdose should be reported according to the procedure outlined in Section 10.2.2, 
Collection and Reporting of SAEs.
In the event of drug overdose, consider close observation including hospitalization for 
hemodynamic support (see Section 10.1.5).


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8.2
Study Medication Assignment and Dispensing Procedures
The investigator or the investigator’s designee will use the IVRS/IWRS to randomize the subject 
into the study. During this contact, the investigator or designee will provide the necessary 
subject-identifying information, including the subject number. The medication identification 
(MED ID) number of the investigational drug to be dispensed will then be provided by the 
IVRS/IWRS. If the sponsor supplied drug for Cohorts A to D is lost or damaged, the site can 
request a replacement from the IVRS/IWRS. The randomization sequence number will be 
entered onto the eCRF. At subsequent drug dispensation visits, the investigator or designee will 
again contact the IVRS/IWRS to request additional investigational drug for a subject. 
For each Dosing Cohort, randomized subjects will be assigned a 4-digit randomization sequence 
number in the order which they are enrolled. Randomization sequence numbers will start from 
X001 based on cohort assignment. For example, the randomization sequence numbers will start 
from 1001 for Cohort A and 2001 for Cohort B, etc. Additional randomization numbers will be 
generated to accommodate the replaced subjects. The replacement subject will receive the same 
treatment as the subject being replaced.
This randomization sequence number will be used by the clinical site to facilitate the pre labeling 
of PK samples, and will be the only subject identifier used on all sample collections. It should 
also be contained on the PK transport vials shipped to the bioanalytical laboratory, and will be 
used by the laboratory to report the subject data results. This 4-digit number should only be used 
for the purposes described in this section. It does not replace the 3-digit subject number which is 
assigned at the time the informed consent is obtained and which is used for all other procedures 
to identify the subjects throughout the study.
8.3
Randomization Code Creation and Storage
IVRS/IWRS will generate and maintain the randomization and medication schedules. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel.
8.4
Investigational Drug Blind Maintenance
The investigational drug blind is maintained through IVRS/IWRS.
8.5
Unblinding Procedure
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational blind is necessary for the medical treatment of the subject. In the 
event of a medical emergency, if possible, the sponsor’s medical monitor or designee should be 
contacted before the investigational drug blind is broken to discuss the need for unblinding.
The sponsor must be notified as soon as possible if the investigational drug blind is broken. The 
date, time, and reason the blind is broken must be recorded in the source documents.
For unblinding a subject, the investigational drug blind can be obtained by accessing the 
IVRS/IWRS. 


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8.6
Accountability and Destruction of All Study Medication
Drug supplies will be counted and reconciled at the site before being returned to Takeda or 
designee or being destroyed by the site.
The investigator or designee must ensure that the study medication is used in accordance with 
the approved protocol and is dispensed only to subjects enrolled in the study. To document 
appropriate use of study drug, the investigator must maintain records of all study medication 
delivery to the site, site inventory, use by each subject, and return to the sponsor or designee.
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. See 
pharmacy manual for receipt of shipments. 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 notifying Takeda 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.
The investigator must maintain 100% accountability for all study medication 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 is provided to the investigator.

Frequently verifying that actual inventory matches documented inventory.

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.
The investigator must record the current inventory of all study medication on a sponsor-approved 
drug accountability log. The following information will be recorded at a minimum: protocol 
number and title, name of investigator, site identifier and number, description of study 
medication, expiry and/or retest date, 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 subject to who study medication is dispensed.
Before site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform clinical study material accountability and reconciliation before clinical study 
materials are returned to the sponsor or its designee for destruction or destroyed at the site, as 
applicable. The investigator will retain the original documentation regarding clinical study 


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material accountability, return, and/or destruction, and copies will be sent to the sponsor or 
designee.
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 for destruction.


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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each 
procedure, subjects are to be assessed by the same investigator or site personnel whenever 
possible. The Schedule of Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained before the subject enters into the study, and before any 
protocol-directed procedures are performed.
A unique subject identification number (7 digit subject ID) will be assigned to each subject at the 
time that informed consent is obtained; this subject number will be used throughout the study.
9.1.2
Pharmacogenomic Informed Consent Procedure 
Pharmacogenomics informed consent is a component of the overall study informed consent. The 
requirements are described in Section 15.2.
9.1.3
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth, sex, Hispanic ethnicity, race 
as described by the subject, alcohol and smoking status of the subject at Screening. 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the condition/disease under study that stopped at or before 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.9).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 1 year before signing of informed consent.
9.1.4
Safety Assessments
On Day 1, all the assessments must be reviewed by the investigator before randomization to 
assure eligibility requirements have been met. During the study, all assessments should be done 
before administration of study drug unless otherwise indicated.
9.1.4.1
Tuberculosis Screening 
All subjects must have a screening test for tuberculosis. Either a tuberculin skin test or 
QuantiFERON® is acceptable. If a tuberculin skin test is done, it should be interpreted according 
to the applicable local Health Authority or Medical Society guidelines providing 
recommendations for interpretation of tuberculin skin testing in subjects who are 
immunosuppressed or have a prior history of BCG vaccination or have a prior positive test.


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Subjects with a positive screening test for tuberculosis will not be eligible for the study unless 
active tuberculosis infection is ruled out and treatment for latent tuberculosis has been completed 
at least 4 weeks before randomization.
9.1.5
Physical Examination Procedure
A baseline physical examination (defined as the pretreatment assessment immediately before the 
start of investigational drug) will consist of the following body systems: (1) eyes; (2) ears, nose, 
throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; 
(6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; 
(10) lymph nodes; and (11) other. 
The physical examination should be done at Screening Visit, Baseline (defined as the 
pretreatment assessment immediately before the start of investigational drug), at the beginning of 
each cycle and, at the End of Treatment Period. Additional physical examinations can be done at 
any visit if necessary based on investigator’s clinical judgment.
In particular the investigator should be alert for symptoms and signs of fluid disturbance from 
Gastro-Intestinal events, skin rashes and peripheral neuropathy. Ixazomib therapy may need to 
be interrupted, down titrated or stopped if these events occur (see Section 7.4.2)
Any abnormal change from the baseline physical examination (Day -1) must be assessed as not 
clinically significant (NCS) or clinically significant (CS) by the investigator and recorded in the 
source document and eCRF.
Any clinically significant change, as determined by the investigator, from the baseline physical 
examination will be recorded as an AE or pretreatment event in source documentation and on the 
Pretreatment Event/AE eCRF.
On subsequent examinations, any abnormal change from the pretreatment physical examination 
assessment must be assessed as NCS or CS by the investigator and recorded in the source 
document and eCRF. Any CS change, as determined by the investigator, will be recorded as an 
AE in source documentation and on the pretreatment event/AE eCRF described in Section 10.0.
9.1.6
Weight, Height, and Body Mass Index 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The body mass index (BMI) is calculated using metric units with the formula provided 
below:
Metric:
BMI = weight (kg)/[height (m)]2
Height will be collected in centimeters without decimal places and weight will be collected in 
kilograms to 1 decimal place. Results for BMI will be expressed with 1 decimal place.
Example:
-Height=176 cm (or 1.76 m), weight=79.2 kg; BMI=79.2/1.762=25.6 kg/m2.


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9.1.7
Vital Sign Procedure
During the Double-Blind Treatment Period, vital signs will be collected at Screening (Day -35 to 
-1) and on Cycle 1 and Cycle 2 at Days 1, 8, 15, and 22. In Cycle 3 vital signs will be collected 
on day 1, day 8, day 15, day 22 and Day 28 (Final Visit/End of Treatment (EOT)/ET) and at 
every follow-up visit. During the Open-Label Treatment Extension Period, vital signs will be 
collected before the first dose of each treatment cycle. Vital signs will include body temperature, 
sitting blood pressure (after 5 minutes resting), respiration rate, and pulse (beats per minute).
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within approximately 0.5 hour before or after the scheduled 
blood draw.
9.1.8
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by Takeda. At each study visit, subjects will be asked whether they have taken any 
medication other than the study medication (used from signing of informed consent through the 
end of the study), and all medication, including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the eCRF. Documentation will 
include generic medication name, dose, unit, frequency, route of administration, start and end 
dates, and reason for use. 
9.1.9
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. This includes clinically significant laboratory, ECG, or 
physical examination abnormalities noted at the Screening examination. The condition 
(ie, diagnosis) should be described.
9.1.10 Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. The 
approximate total volume of blood for the study is 453.5 mL if the subject does not participate in 
the Open-Label Treatment Extension Period or 493.5 mL if the subject does participate in the 
Open-Label Treatment Extension Period. Laboratory samples on Day 1 of each Cycle will be 
collected following a minimum 10-hour overnight fast on the days stipulated in the Schedule of 
Study Procedures (Appendix A).
Table 9.a lists the tests that will be obtained for each laboratory specimen.


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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry 
Urinalysis
Special 
Red blood cells
Reticulocytes
White blood cells 
with differential
Hemoglobin
Hematocrit
Platelets
Alanine aminotransferase
Alkaline phosphatase
Aspartate aminotransferase
-Glutamyl transferase
Total bilirubin
Direct bilirubin
Albumin
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
Potassium
Sodium
Glucose
Chloride
Phosphorus
Calcium
To be done at local 
laboratory
pH
Specific gravity
Protein
Glucose
Blood 
Nitrite
Microscopic Analysis:
RBC/high power field
WBC/high power field
Epithelial cells, casts, etc
To be done at central
laboratory
Urine protein and creatinine 
for UPCR
Urine Biomarkers
To be done at the site
Standard urinalysis using 
dipstick (protein only)
To be done at local 
laboratory
Coomb’s test
Platelets, red blood cells, 
white blood cells with 
differential
To be done at central 
laboratory
Lipid panel (fasted):
Total cholesterol
LDL-cholesterol
HDL-cholesterol
Triglycerides
Serum complement
C3 and C4
Total IgM, IgG and IgA
Autoantibodies:
Anti-double-stranded DNA
Anti-nuclear antibody
Anti-Ro (SS-A)
Anti-La (SS-B)
Anti-RNP
Anti-Sm
Anti-phospholipids
Serum biomarkers
Tetanus antibody titers
HBsAb titers
Serum
Serum hCG (a)
At Screening Only:
Hepatitis panel, including HBsAg, and anti-HCV
FSH (b)
DNA=deoxyribonucleic acid, FSH=follicle-stimulating hormone, HBsAb=hepatitis B surface antibody, 
hCG=human chorionic gonadotropin, HDL=high-density lipoprotein, LDL=low-density lipoprotein.
(a) Serum hCG pregnancy test will be done on all female subjects of childbearing potential at Screening.
(b) The FSH level will be obtained for female subjects at Screening if they are postmenopausal by history (ie, last 
regular menstrual cycle >2 years) and not surgically sterile. The FSH result must be >40 IU/L for the subject to be 
permitted not to use adequate contraception.
All Samples will be processed at the central laboratory with the exception of, urine microscopic 
analysis (RBC/high power field, WBC/high power field, epithelial cells, casts, etc) and Coomb’s 
test, which should be processed at a local laboratory. Standard urinalysis (dipstick) should be 
done at study site. An additional sample for blood cell counting should be collected within 


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48 hours before each dosing and processed locally. Results from the blood cell counting done 
locally should be available before each dosing during the Double-Blind Treatment Period and 
before each cycle of the Open-Label Treatment Extension Period as specified in the Schedule of 
Events (Appendix A).
Urine samples for determination of UPCR should be processed by the central laboratory. Urine 
samples for UPCR analysis should be collected by the subject at home from the first void urine 
of the day on the 2 days before the visit and on the day of visit, totaling 3 samples as specified in 
Appendix A.
The central laboratory will also perform hematology and serum chemistry tests. The results of 
laboratory tests will be sent to the investigator, who is responsible for reviewing and filing these 
results. All laboratory safety data will be transferred electronically to Takeda or designee in the 
format requested by Takeda. If the laboratory is unable to electronically transfer data, the study 
site coordinator or designee is responsible for transcribing laboratory results to the eCRF. The 
investigator will maintain a copy of the laboratory accreditation and the reference ranges for the 
laboratory used.
Detailed instructions for the handling and shipping of samples are provided in the laboratory 
manual.
Laboratory reports must be signed and dated by the principal investigator or sub investigator 
indicating that the report has been reviewed and any abnormalities have been assessed for 
clinical significance.
All clinically significant laboratory abnormalities must be recorded as a pretreatment (PTE)/AE 
in the subject’s source documents and on the appropriate eCRF. A clinically significant 
laboratory abnormality that has been verified by retesting will be followed until the abnormality 
returns to an acceptable level or a satisfactory explanation has been obtained.
Please refer to Section 7.4.1 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests. Follow-up laboratory tests for 
abnormal liver function test should include at a minimum, serum alkaline phosphatase, ALT, 
AST, total bilirubin, -glutamyl transferase, and international normalized ratio.
Markedly Abnormal Laboratory Criteria for Hematology
The following markedly abnormal values will be used for hematology tests as part of the safety 
assessments defined in the primary endpoint of this study:
Parameter
Markedly Abnormal Value
Red blood cells
Hemoglobin

<0.8× LLN if Baseline is ≥LLN, OR

<0.8× pre-treatment value if Baseline is <LLN
Neutrophils
Lymphocytes
Platelets

<0.65× LLN if Baseline is ≥LLN, OR

<0.65× pre-treatment value if Baseline is <LLN


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9.1.11 Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, and for 90 days after last 
dose of study medication, female subjects of childbearing potential must use 2 forms of adequate 
contraception. In addition they must be advised not to donate ova during this period.
Abstinence is not an acceptable method of contraception.
From signing of informed consent, throughout the duration of the study, and for 90 days after last 
dose of study medication, all male subjects who are sexually active with a female partner of 
childbearing 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.
*Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal (defined as 
continuous amenorrhea of at least 2 years and FSH>40 IU/L confirmed before any study 
medication is administered).
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate.
An acceptable method of contraception is defined as one that has no higher than a 1% failure 
rate. Female subjects must use 2 effective methods of contraception, at the same time. In this 
study, the only acceptable methods of contraception are: 
Barrier methods (each time the 
subject has intercourse):
Intrauterine devices:
Hormonal contraceptives:

Cap (plus spermicidal cream or 
jelly) PLUS male condom and 
spermicide.

Diaphragm (plus spermicidal 
cream or jelly) PLUS male 
condom and spermicide.

Copper T PLUS condom 
and spermicide.

Progesterone T PLUS 
condom and spermicide.

Implants PLUS male 
condom and spermicide.

Hormone shot/injection 
PLUS male condom and 
spermicide.

Combined pill PLUS male 
condom and spermicide.

Minipill PLUS male 
condom and spermicide.

Patch PLUS male condom 
and spermicide.

Vaginal ring PLUS male 
condom and spermicide.
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 


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understand the requirements for avoidance of pregnancy, donation of ova during the course of 
the study.
During the course of the study, regular serum or urine hCG pregnancy tests will be performed 
only for women of childbearing potential and subjects will receive continued guidance with 
respect to the avoidance of pregnancy as part of the Schedule of Study Procedures (Appendix A). 
In addition to a negative serum hCG pregnancy test at Screening, subjects also must have a 
negative urine pregnancy test on Day 1 and throughout the study. 
9.1.12 Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any sponsor-
supplied drug should be immediately discontinued. If the pregnancy occurs during administration 
of active study medication, eg, after Day 1 of Cycle 1 or within 90 days of the last dose of active 
study medication, the pregnancy should be reported immediately, using a pregnancy notification 
form, to the contact listed in Section 1.0.
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 treatment the subject received (blinded or unblinded, 
as applicable).
All reported pregnancies in a subject receiving active study medication 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.
9.1.13 ECG Procedure 
A standard 12-lead ECG will be recorded at Screening, on Day 1 of each cycle and ET/EOT. 
Additional unscheduled ECGs may be recorded where clinically necessary for subject safety. 
When an ECG is scheduled at the same time as blood draws or vital signs then the blood draws 
and vital signs will take priority and the ECG will be obtained within 1.5 hours before or after 
the scheduled blood draw/vital sign assessment.
Twelve-lead ECGs will be recorded using an ECG machine that automatically calculates the 
heart rate and measures PR interval, RR interval, QRS interval, QT interval, and QTcF and 
QTcB (Fredericia’s and Bazett’s correction) intervals.
One copy of the 12-lead ECG with the physician’s signature and date of assessment will be filed 
with the source documents and captured in the appropriate eCRF. If the original ECG is printed 
on thermal paper, the ECG report must be photocopied and certified. The photocopy will be filed 
with the original ECG in the source.
All ECGs will be recorded at the time points detailed in the Schedule of Study Procedures 
(Appendix A). 


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9.1.14 Additional Assessments
9.1.14.1 Urinalysis
The urine sediment should be assessed at a local laboratory in a timely manner by an analyst 
trained in the assessment of cellular casts. Attention should be given to assure that hematuria or 
pyuria are clearly due to SLE and not due to menses, infection or contamination of the urine 
specimen. Investigators should make every effort to prevent urine sample contamination is 
avoided and exclude possible urinary tract infections. If abnormal white blood cell counts are 
observed in the urine specimen, the site should obtain additional urine samples for repeat 
analysis and urine culture to be done at the local laboratory.
For UPCR determination, urine samples will be collected at home and brought to the site by the 
subjects. The samples should be collected from the first void urine of the day on the 2 days 
before the visit and on the day of visit, totaling 3 samples and kept under refrigeration during 
storage. These urine samples will be sent to a central laboratory for analysis of protein and 
creatinine levels. All subjects enrolled in the study must be trained by a qualified member of the 
investigational site personnel to collect the urine sample in “clean catch” technique. UPCR will 
be calculated as mg/mg ratio.
9.1.14.2 eGFR
Renal function will be assessed through eGFR using the CKD-EPI formula below and expressed 
as mL/min/1.73 m2:
eGFR = 141 x min(SCr/k, 1)α x max(SCr /k, 1)-1.209 x 0.993Age x (1.018 [if female]) x (1.159 [if 
black])
Where SCr is serum creatinine in mg/dL, k is 0.7 for females and 0.9 for males, α is -0.329 for 
females and -0.411 for males, min indicates the minimum of SCr/k or 1 and max indicates the 
maximum of SCr/k or 1, and age in years.
9.1.14.3 Definition of Complete and Partial Renal Responses
For complete renal response, all of the following criteria must be met:
Renal Function
eGFR is normal OR no less than 85% of the lesser of the values at 
screening or randomization (Day 1)
Proteinuria (UPCR)
UPCR <0.5
Urine sediment
No cellular casts, based on assessment performed at local laboratory


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For partial renal response, all of the following criteria must be met:
Complete response
Subject does not meet criteria for complete response
Renal Function
eGFR is no less than 85% of the lesser of the values at screening or 
randomization (Day 1)
Proteinuria (UPCR) !
≥50% reduction in UPCR from Baseline and one of the following:
a) UPCR <1 if baseline value was ≤3, OR
b) UPCR <3 if baseline value was >3.
Baseline is defined as the greater of the values at Screening or 
Randomization (Study Day 1)
Urine sediment
No cellular casts, based on assessment performed at local laboratory
No renal response is defined when subjects did not meet the criteria for either Complete Renal 
Response or Partial Renal Response.
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9.1.14.5
 
9.1.15 Pharmacodynamic Sample Collection
Pharmacodynamic measures will include hematologic measures of serum anti dsDNA antibody, 
other autoantibodies and complement C3/C4 levels. Samples will be collected as noted in 
Appendix A. These assays are routinely performed in the central laboratory.
9.1.16 Pharmacogenomic and Other Sample Collection
 
Also because PGx is an evolving science, many genes and their functions are not yet fully 
understood. Future data may suggest a role of these genes in drug response, which may lead to 
additional hypothesis-generating exploratory research and diagnostic development on stored 
DNA and RNA samples.
The PGx samples will be stored for no longer than 15 years after completion of the ixazomib 
study and/or until the drug development of ixazomib is no longer actively pursued by Takeda or 
its collaborators. No samples will be stored for longer than permitted by the applicable law and 
samples will be destroyed upon notification from Takeda. Each pharmacogenomic sample for a 
study subject should be identifiable on the requisition form with a 7 digit subject ID (with 4 digit 
the site + 3 digit subject number) issued by TDC. The dataset with masked identity are intended 
for the association analysis of ixazomib.
Protein and other biomarker profiling, serum and urine (10 mL samples) will be collected at 
multiple endpoints as indicated in Appendix A. Samples will be stored at -20°C until shipped. 
Frozen samples will be shipped on dry ice to laboratories with appropriate expertise in analysis 
of these markers. Both the urine and serum will be analyzed for markers relevant to 
inflammation. 
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Detailed instructions for the handling and shipping of samples are provided in the laboratory 
manual.
9.1.17 PK Sample Collection
9.1.17.1 Collection of plasma 
for PK Sampling for Ixazomib 
Serial blood samples for determination of ixazomib concentrations will be collected according to 
Table 9.b for the Double-Blind Treatment Period. Detailed instructions for the handling and 
shipping of samples are provided in the laboratory manual.
Table 9.b
Collection of Blood Samples for PK Analysis during the Double-Blind 
Treatment Period
Sample 
Type
Time Postdose 
Plasma
Cycle 1
Predose (within 0.5 hour before dosing) on Days 1, 8, and 15. On Day 1 of Cycle 1, 
sample will be collected at 0.25, 0.5, 1, 1.5, 2, 4, 8, 24, and 168 (predose Day 8) hours 
following the first dose. 
Cycle 2
Predose (within 0.5 hour before dosing) on Days 1, 8, and 15. Samples will be collected 
on Day 22 (168 hours postdose on Day 15) in Cycle 2.
Cycle 3
Predose (within 0.5 hour before dosing) on Days 1, 8, and 15. On Day 15 following the 
third dose, samples will be collected at 0.25, 0.5, 1, 1.5, 2, 4, 8, 24, 168, and 312 hours 
postdose in Cycle 3.
The actual time of sample collection will be recorded on the source document and eCRF.
There will be no PK sampling during the Open-Label Treatment Extension Period.
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9.1.17.2 Bioanalytical Methods
Plasma concentrations of ixazomib will be measured by high-performance liquid 
chromatography with tandem mass spectrometry within a validated range of 0.500 to 500 ng/mL.
 
9.1.18 PK Parameters 
The PK parameters of ixazomib will be determined from the concentration-time profiles for all 
evaluable subjects using non-compartmental analysis methods. Actual sampling times, rather 
than scheduled sampling times, will be used in all PK computations involving sampling times. 
The following PK parameters may be calculated, as permitted by the data, from plasma 
concentrations of ixazomib:
Symbol/Term
Definition
AUC∞
Area under the plasma concentration-time curve from time 0 to infinity.
AUClast
Area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration.
AUCt
Area under the plasma concentration-time curve from the time 0 to time t.
AUC168
Area under the plasma concentration-time curve from 0 to 168 hours
CL/F
Apparent clearance after oral administration, calculated as CL/F=Dose/AUC∞
Cmax
Maximum observed plasma concentration.
tmax
time of first occurrence of Cmax 
Additional PK parameters may be calculated as appropriate.
A population PK model-based analysis may be performed in addition to the noncompartmental 
analysis to describe the PK of ixazomib in LN patients. If performed, the details of the analysis 
will be provided in a separate analysis plan and report.
9.1.19 Preparation, Reconstitution, and Dispensation
The investigational pharmacist or designee will prepare the study treatment under standard 
aseptic conditions. More details on the preparation of study treatment are provided in the 
Pharmacy Manual.
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9.1.20 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent. If the subject is found to 
be not eligible at this visit, the investigator should complete the eCRF.
The primary reason for screen failure is recorded in the eCRF using the following categories:

Pretreatment event/AE.

Did not meet inclusion criteria or did meet exclusion criteria.

Major protocol deviation.

Lost to follow-up.

Voluntary withdrawal, specify reason.

Study termination.

Other, specify reason.
Subject numbers assigned to subjects who fail screening should not be reused.
9.1.21 Documentation of Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment phase.
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF.
9.2
Monitoring Subject Treatment Compliance
Study medication will be administered on Days 1, 8, and 15 of each cycle while subjects are 
under observation in the clinical research site. The date and time of each dose will be recorded in 
the source documents and on the eCRFs. An inventory of the study medication supplies 
dispensed will be performed by the site pharmacist or authorized study designee and recorded 
onto the Drug Accountability Log in the subject’s source document records or equivalent. The 
exact dose time of consecutive subjects may be staggered to facilitate logistics at the site.
During the Open-Label Treatment Extension, the first dose of each cycle will occur while 
subjects are in the clinic, and the remaining doses will be self-administered at home.
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s).
9.3.1
Screening 
Subjects will be screened for the study within 24 (+11) days before the first dose of study 
medication. Subjects will be screened in accordance with predefined inclusion and exclusion 


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criteria as described in Section 7.0. See Section 9.1.19 for procedures for documenting screening 
failures. If the elapsed time between Screening Visit and Randomization (Day 1) is greater than 
allowed screening period, then the eligibility criteria must be re-confirmed in a second screening 
visit before randomization.
9.3.1.1
Screening Visit 
Procedures to be completed at Screening Visit include:

Informed consent.

Inclusion/exclusion criteria review.

Demographics, medical history, and medication history.

Physical examination.

Renal biopsy history.

Stabilize concomitant medications (if needed).

Vital signs.

Weight, height, and BMI.

Concomitant medications.

Concurrent medical conditions.

ECG procedure.

Pregnancy test [Serum hCG test (females of childbearing potential only)].

Pretreatment event assessment.

TB screening.

FSH (only postmenopausal women by history and not surgically sterile). 

HBsAg and Anti-HCV.

Hematology panel.

Chemistry panel.

Urinalysis (including microscopic analysis). 

Urine sample for protein/creatinine ratio. 

Urine dipstick protein.

Serum complement (C3, C4). 

Anti-dsDNA.

Coomb’s test direct.


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!
Quantitative IgG.
!
.
!
Pregnancy avoidance counseling.
!
Access IVRS/IWRS to obtain subject number. 
!
Dispense urine cups for UPCR collection before Day 1 Visit (on Day -2, Day-1 and Day 1).
Procedures to be completed at the second Screening Visit include (if visit is needed):
!
Hematology panel.
!
Chemistry panel.
!
Urinalysis (including microscopic analysis). 
!
Urine sample for protein/creatinine ratio. 
!
Urine dipstick protein.
!
Serum complement (C3, C4). 
!
Coomb’s test direct.
!
Anti-dsDNA.
!
Urine pregnancy test.
!
.
9.3.2
Randomization 
If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized as described in Section 8.2. Subjects will be 
administered the first dose of study medication in the unit under the supervision of the 
investigator or designee, as described in Section 8.2. The procedure for documenting Screening 
failures is provided in Section 9.1.19.
9.3.2.1
Day 1 (Cycle 1, 2 and 3)
!
Inclusion/exclusion criteria review [Day 1 of Cycle 1]. 
!
Physical examination.
!
Neuropathy assessment (functional assessment of cancer therapy [FACT]/GOG-NTX).
!
Vital signs assessment.
!
Weight. 
!
Medical history [Day 1 of Cycle 1 only].
!
Review of concomitant medications.
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!
Concurrent medical conditions [Day 1 of Cycle 1 only].
!
Hematology panel.
!
Chemistry panel.
!
Lipid panel.
!
Urinalysis (including microscopic analysis).
!
Urine sample for protein/creatinine ratio.
!
Serum complement (C3, C4).
!
Anti-dsDNA.
!
Coomb’s test direct.
!
Quantitative IgG, IgM, and IgA [Day 1 of Cycle 1 only].
!
Serum collection for biomarkers [Day 1 of Cycle 1only].
!
Urine collection for biomarkers [Day 1 of Cycle 1only].
!
RNA collection [Day 1 of Cycle 1 only].
!
DNA collection [Day 1 of Cycle 1 only].
!
PK blood collection.
!
ECG.
!
.
!
!
Urine dipstick protein.
!
Urine pregnancy test.
!
Tetanus antibody titers.
!
Hepatitis B surface antibody titer.
!
Platelets, red blood cells, white blood cells with differential (within 48 hours before dosing).
!
Access IVRS/IWRS.
!
Pregnancy avoidance counseling.
!
Study medication dosing in the clinic.
!
Overnight fast.
!
AE assessment.
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9.3.2.2
Day 2 (Cycle 1)

PK blood collection.

RNA collection.

AE assessment. 

Serum collection for biomarkers.

Urine collection for biomarkers.
9.3.2.3
Day 8 (Cycle 1, 2 and 3) 

Vital signs assessment.

Review of concomitant medications.

Hematology panel.

Chemistry panel.

PK blood collection.

Urine pregnancy test.

Access IVRS/IWRS.

Pregnancy avoidance counseling.

Study medication dosing in the clinic.

AE assessment.

Serum collection for biomarkers [Day 8 of Cycle 1 only]. 

Urine collection for biomarkers [Day 8 of Cycle 1 only]. 

Platelets, red blood cells, white blood cells with differential (within 48 hours before dosing).

Dispense urine cups for UPCR collection before Day 15 Visit.
9.3.2.4
Day 15 (Cycle 1, 2 and 3)

Vital signs assessment.

Review of concomitant medications.

Hematology panel.

Chemistry panel.

Urine sample for protein/creatinine ratio.

Serum complement (C3, C4).


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
Anti-dsDNA.

PK blood collection.

Urinalysis (including microscopic analysis).

Urine pregnancy test.

Platelets, red blood cells, white blood cells with differential (within 48 hours before dosing).

Access IVRS/IWRS.

Pregnancy avoidance counseling.

Study medication dosing in the clinic. 

AE assessment.
9.3.2.5
Day 16 (Cycle 3 only)

PK blood collection.

AE assessment.
9.3.2.6
Day 22 (Cycle 1, 2 and 3)

Vital signs assessment.

Review of concomitant medications.

Hematology panel.

Chemistry panel.

Quantitative IgG, IgM, and IgA [Day 22 of Cycle 1 and 2].

PK blood collection [Day 22 of Cycle 2 and Cycle 3]. 

Pregnancy avoidance counseling.

AE event assessment. 

Dispense urine cups for UPCR collection before Day 1 [Day 1 of Cycle 2 and Cycle 3] and 
before Day 28 of Cycle 3.
9.3.3
End of Treatment Visit/Early Termination/Final Visit
End of Treatment / Final Visit will be scheduled on Day 84 (±2 days) of the Double-Blind 
Treatment Period and Day 168 (±2 days) of the Open Label Treatment Extension Period. For an 
Early Termination Visit the reason for an early discontinuation must be documented in the 
source document and eCRF.


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9.3.3.1
Day 28 (Cycle 3)/Final Visit/ET/EOT 
!
Physical examination.
!
Neuropathy assessment (FACT/GOG/NTX).
!
Weight.
!
Vital signs assessment.
!
Review of concomitant medications.
!
Hematology panel.
!
Chemistry panel.
!
Lipid panel.
!
Serum complement (C3, C4).
!
Anti-dsDNA.
!
!
Coomb’s test-direct.
!
Quantitative IgG, IgM, and IgA.
!
PK blood collection (not applicable in the Open Label-Treatment Extension Period).
!
Urinalysis (including microscopic analysis).
!
Urine sample for protein/creatinine ratio.
!
Urine dipstick protein.
!
RNA collection (not applicable in the Open Label-Treatment Extension Period). 
!
ECG.
!
!
!
Urine pregnancy test. 
!
Tetanus antibody titers.
!
Hepatitis B surface antigen antibody titer.
!
Access IVRS/IWRS.
!
Pregnancy avoidance counseling.
!
AE assessment. 
!
Overnight fasting. 
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9.3.4
Open-Label Treatment Extension
!
Physical examination (Day 1 of each Cycle).
!
Concurrent medical conditions [Day 1 of Cycle 1 only].
!
Weight (Day 1 of each Cycle).
!
Vital signs assessment (Day 1 of each Cycle).
!
AE assessment. 
!
Review of concomitant medications (Day 1 of each Cycle).
!
Pregnancy avoidance counseling (Day 1 of each Cycle).
!
Urine pregnancy test.
!
Study drug dosing (Days 1, 8, 15 of each Cycle).
!
ECG (day 1 of each Cycle).
!
Hepatitis B surface antibody titer (Day 1 of Cycles 1 and 3).
!
Tetanus antibody titers (Day 1 of Cycles 1 and 3).
!
Hematology panel (Day 1 of each Cycle).
!
Platelets, red blood cells, white blood cells with differential (within 48 hours before dosing as 
specified in Appendix A.
!
Chemistry panel (Day 1 of each Cycle).
!
Urinalysis (including microscopic analysis) (Day 1 of each Cycle).
!
Urine sample for protein/creatinine ratio (Day 1 of each Cycle).
!
Serum complement (C3, C4) (Day 1 of each Cycle).
!
Anti-dsDNA (Day 1 of Cycle 1 only).
!
!
Coomb’s test direct (Day 1 of each Cycle).
!
Quantitative IgG, IgM, and IgA (Day 1 of each Cycle).
!
Neuropathy assessment (FACT/GOG/NTX).
!
!
!
Access IVRS/IWRS (Day 1 of each Cycle).
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9.3.5
Follow-up Visit
The Follow-up Visit for the Double-Blind Treatment Period will occur monthly from Days 85 to 
168 (±7 days). The Follow-up Visit for the Open Label Treatment Extension Period will occur 
30 days after the last open label treatment cycle (Cycle 3 Day 28; ±7 days). All subjects who 
enter the open label treatment period will have monthly visits up to at least Day 168. If open 
label treatment is terminated before the completion of all 3 cycles, an end of treatment visit will 
be performed (Day 28 of current cycle) and the subsequent cycle day 1 visits will be replaced 
with a follow-up visit. Follow procedures listed in Appendix A.
!
Physical examination [last follow-up only]. 
!
Weight [last follow-up only].
!
Vital signs assessment.
!
Chemistry panel.
!
Hematology panel.
!
Lipid panel [last follow-up only].
!
Serum complement (C3, C4).
!
Anti-dsDNA. 
!
!
Coomb’s test-direct.
!
Quantitative IgG, IgM, and IgA [last follow-up only].
!
.
!
!
Urinalysis (including microscopic analysis).
!
Urine sample for protein/creatinine ratio
!
Urine dipstick protein.
!
Urine pregnancy test.
!
Tetanus antibody titers [last follow-up only].
!
Hepatitis B surface antigen antibody titer [last follow-up only].
!
AE assessment. 
!
Dispense urine cups for UPCR collection. 
!
Pregnancy avoidance counseling.
!
Overnight fasting [last follow-up only].
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!
Neuropathy assessment (FACT/GOG/NTX) (last follow-up of Open Label Treatment 
Extension Period only).
9.4
Blood Volume
Total blood sampling volume for an individual subject is shown in Table 9.c.
Table 9.c
Approximate Blood Volume
Blood Volume Collected (mL)
Cycle 1 (Double-Blind Treatment)
Day
-24(-11) to -1
1
2
8
15
22
Total (mL)
Sample Type
Safety laboratory 
samples
22
23 (b) (f)
13(b) (f)
23 (b) (f)
10
91
Plasma PK samples 
24 (a)
3
3 (a,b)
3 (b)
33
Serum biomarkers
3 (b)
3
3
9
DNA sample
10
10
RNA samples 
12.5
2.5
15
Total Blood Volume for Screening and in Cycle 1
170
Cycle 2 (Double-Blind Treatment)
Day
1
8
15
22
Total (mL)
Sample Type
Safety laboratory samples (b)
20
13 (f)
23 (f)
10
66
Plasma PK samples
3 (b)
3 (b)
3 (b)
3
12
Total Blood Volume in Cycle 2
80
Cycle 3 (Double-Blind Treatment)
Day
1
8
15
16
22
28
Total (mL)
Sample Type
Safety laboratory samples (b)
24
13 (f)
23 (f)
10
20
90
Plasma PK samples
3 (b)
3 (b)
24 (c)
3
3
3
39
RNA samples
2.5
2.5
Total Blood Volume in Cycle 3
143.5
Footnotes are on last table page.
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Table 9.c
Approximate Blood Volume (continued)
Follow-up Period (d) (No Open Label Treatment)
Total (mL)
Month
Month 4
Month 5
Month 6
Sample Type
Safety laboratory samples 
20
20
20
60
Total Blood Volume in the Follow-up Period
60
Open Label Treatment Period and Follow-up (g)
Total (mL)
Cycle 1
Cycle 2
Cycle 3
ET/EOT/Fin
al Visit
Follow-up 
visit
Safety laboratory samples
20 (b) (f)
20(b) (f)
20 (b) (f)
20 
20
100
Total Blood Volume in the Follow-up Period
100
Total Approximate Blood Volume (mL) to be over the study duration collected per Subject (no 
open label treatment)
453.5
OR
Total Approximate Blood Volume (mL) to be over the study duration collected per Subject (with 
open label treatment)
493.5
Direct venipuncture is the only acceptable method of blood collection.
(a) Plasma PK samples collected in Cycle 1 on Day 1: Predose (within 0.5 hour before dosing) on Days 1, 8, and 15. On Day 1 of 
Cycle 1, following the first dose, sample will be collected at 0.25, 0.5, 1, 1.5, 2, 4, 8, 24, and 168 (predose Day 8) hours postdose.
(b) Predose. 
(c) Plasma PK samples collected in Cycle 3 Predose (within 0.5 hour before dosing) on study Days 1, 8, and 15. On Day 15 of 
Cycle 3 following the third dose, samples will be collected at 0.25, 0.5, 1, 1.5, 2, 4, 8, 24, 168 and 312 hours postdose in Cycle 3.
(d) Follow-up visits on Days 112, 140, and 168. 
(e) 
(f) Collection should occur within 48 hours before visits on the day of dosing of each cycle with results required back to the site 
before dosing.
(g) Open Label Treatment Period and Follow-up consists of up to 3 additional cycles of treatment (Day 85 to 168) with a Follow-
up visit 30 days after the last dosing.
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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1 Pretreatment Events
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent 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.
10.1.2 AEs
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.
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.
10.1.3 Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions 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 vs 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 as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters are only considered to be PTEs or 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 retest and/or continued monitoring of an abnormal value are not considered an 


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intervention. In addition, repeated or additional noninvasive testing for verification, 
evaluation or monitoring of an abnormality is not considered an intervention.

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 a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent 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 a 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 in the condition from Baseline (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to 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 PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after starting administration 
of the study medication, the worsening or complication should be recorded appropriately as 
an AE. Investigators should ensure that the AE term recorded captures the change in the 
condition (eg, “worsening of…”).

If the subject experiences 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 /Serious PTEs:

If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded.


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Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled before signing of 
informed consent are not considered PTEs or 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 a PTE or an AE. 
Complications resulting from any planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page 
of the eCRF.
10.1.4 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. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

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
Takeda Medically Significant AE List
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
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and 
should be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5 Management of Clinical AEs of Interest
10.1.5.1 Diarrhea
Prophylactic antidiarrheals will not be used in this protocol. However, the administration of 
antidiarrheals once infectious causes are excluded may be considered. Fluid intake should be 
strictly maintained to avoid dehydration.
10.1.5.2 Nausea and/or Vomiting
Although this study will not initially employ prophylactic anti-emetics, there is no prohibition 
against their use in the management of a patient who develops nausea and/or vomiting after 
receiving ixazomib. The use of anti-emetics such as serotonin receptor antagonists may be 
considered if clinically required.
10.1.5.3 Volume Depletion
Dehydration should be avoided. Two cases of acute renal failure have been reported in patients 
treated at or above the MTD for IV ixazomib. NSAIDs should be avoided with impaired renal 
function given reported NSAID-induced renal failure in patients with decreased renal function. 
Additionally, volume depletion should be corrected before initiation of study drug.
10.1.5.4 Renal AEs
Urinary excretion of the parent compound is negligible, but modest transient increase in 
creatinine and infrequent (<10%) cases of reversible renal failure have been reported in oncology 
subjects receiving ixazomib, albeit with confounding factors such as GI fluid loss or high does 


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NSAIDs, factors which are addressed above. Subjects in this study will have weekly monitoring 
of laboratory parameters including creatinine and ixazomib will be discontinued if a >25% 
decrease in eGFR or a doubling in serum creatinine are observed. 
10.1.5.5 Erythematous Rash With or Without Pruritus
Rash with or without pruritus has been reported with ixazomib, primarily at the higher doses 
tested. The rash has been transient and has resolved either spontaneously or with standard 
symptomatic measures such as oral or topical antihistamines. The rash may range from some 
erythematous areas, macular and/or small papular bumps that may or may not be pruritic over a 
few areas of the body, to a more generalized eruption that is predominately on the trunk or 
extremities. Rash has been most commonly characterized as maculopapular or macular. 
Prophylactic measures should also be considered if a patient develops a rash (eg, using a thick, 
alcohol-free emollient cream on dry areas of the body). In the case of rash, the use of a topical or 
oral steroid (eg, prednisone <10 mg per day or equivalent is permitted. 
Severe, life-threatening or fatal conditions that may involve rash, blistering, skin peeling and 
mouth sores including Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, drug reaction 
with eosinophilia and systemic symptoms (DRESS syndrome) and pemphigus vulgaris are a rare 
risk which have been reported in ixazomib oncology studies when given in combination with 
other drugs. Due to limited experience and because these conditions occurred while patients were 
receiving other drugs as well, it is not known whether they were caused by ixazomib. The subject 
should be discontinued from study drug if they are diagnosed with any of these conditions and 
should be managed symptomatically according to standard medical practice. In addition, all 
subjects with rash grade 3 or greater must have punch biopsies and dermatology consult. It is 
recommended taking pictures of the rash.
10.1.5.6 Thrombocytopenia
Thrombocytopenia has been reported to date primarily at the higher doses tested. Blood counts 
should be monitored regularly as outlined in Section 7.4.3 with additional testing obtained 
according to standard clinical practice. Thrombocytopenia may be severe but has been 
manageable with platelet transfusions according to standard clinical practice. Administration of 
ixazomib should be modified as noted as per dose modification recommendations as described in 
Section 7.4.3 when thrombocytopenia occurs. Therapy with ixazomib can be reinitiated at a 
reduced level upon recovery of platelet counts.
10.1.5.7 Prophylaxis Against Risk of Infection
If lymphopenia is noted, patients may be at an increased risk of infection. In particular, 
lymphopenia can be associated with reactivation of herpes zoster and herpes simplex viruses. 
Antiviral therapy such as acyclovir or valacyclovir may be initiated at the onset of administration 
of ixazomib. Other antivirals are also acceptable.


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10.1.5.8 Peripheral Neuropathy
With preliminary clinical data collected thus far, mild and reversible peripheral neuropathy has 
been reported. Therefore, patients on ixazomib should be monitored for symptoms of 
neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, 
neuropathic pain, or weakness. In cases of new or worsening sensory peripheral neuropathy, with 
or without pain, dose adjustment or stopping of ixazomib may be required.
10.1.5.9 Hypoglobulinemia
In case that total immunoglobulin levels drops to less than 50% of the lower limits of normal, 
ixazomib should be discontinued and IV Immunoglobulins (IVIg) therapy is recommended to 
increase total immunoglobulin levels.
10.1.6 Severity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.7 Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Yes:
An AE that follows a reasonable temporal sequence from administration of a drug (including 
the course after withdrawal of the drug), or for which possible involvement of the drug can be 
argued, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible.
No:
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 drugs and concurrent treatments.
10.1.8 Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and AEs.
The relationship should be assessed as Yes if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be 
assessed as No.


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10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1 PTE and AE Collection Period
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication 
(Day 1) or until screen failure. For subjects who discontinue before study medication 
administration, PTEs are collected until the subject discontinues study participation.
Collection of AEs will commence from the time that the subject is first administered study 
medication (Day 1). Routine collection of AEs will continue until the Final Visit (168 ±7 days) 
after the first dose of study drug).
10.2.1.2 PTE and AE Reporting
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. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes 
in laboratory values have returned to Baseline or there is a satisfactory explanation for the 
change. Non-serious PTEs, related or unrelated to the study procedure, need not to be followed-
up for the purposes of the protocol.
All subjects 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 PTEs and AEs will be documented in the PTE/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 stop date and time.

Severity.

Investigator’s opinion of the causal relationship between the event and administration of 
study medication(s) (yes or no) (not completed for PTEs).

Investigator’s opinion of the causal relationship to study procedure(s), including the details 
of the suspected procedure.

Action concerning study medication (not applicable for PTEs).

Outcome of event.

Seriousness.


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10.2.2 Collection and Reporting of 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 the eCRF, 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 completed in the eCRF within 24 hours of first onset or notification of 
the event. In the event that the EDC system is unavailable for SAE reporting, the back-up SAE 
paper form should be completed and transmitted to Takeda Pharmacovigilance or designee 
within 24 hours of first onset or notification of the event to the attention of the contact listed in 
Section 1.0.
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 Serious PTEs will follow the procedure described for SAEs.
10.2.3 Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, a liver function test increases eCRF must 
be completed providing additional information on relevant recent history, risk factors, clinical 
signs and symptoms and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease. Follow-up laboratory tests as described in Section 9.1.10 must also be 
performed. In addition, a liver function test increases eCRF must be completed and transmitted 
with the Takeda SAE form (as per Section 10.2.2).
10.3
Follow-up of SAEs
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 followed up 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.
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
and any other applicable SAEs to regulatory authorities, investigators and IRBs or 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, suspected unexpected serious adverse reactions will be submitted within 7 days for 
fatal and life-threatening events and 15 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.


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11.0
STUDY-SPECIFIC COMMITTEES
Eligibility for the study is intended to be confirmed by an adjudication committee consisting of 
Takeda and external experts not directly involved in the study.


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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization (WHO) Drug Dictionary.
12.1
Electronic CRFs 
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 entered 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 to eCRFs 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 database lock of 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 eCRFs (Data Clarification Form) provided by the sponsor. The principal investigator 
must review the Data Clarification Form for completeness and accuracy, and must sign, and date 
the form.
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.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper should 
be copied and certified, source worksheets, all original signed and dated informed consent forms, 


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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. Furthermore, International Conference on Harmonisation (ICH) E6 Section 4.9.5 
requires the investigator to retain essential documents specified in ICH E6 (Section 8) 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 
Section 4.9.5 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 Phase 1 Site Specifications document for the sponsor’s requirements on record 
retention. The investigator should contact and receive written approval from the sponsor before 
disposing of any such documents.


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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized before unblinding of subject’s 
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.
A targeted data review will be conducted before database lock. This review will assess the 
accuracy and completeness of the study database, subject evaluability, and appropriateness of the 
planned statistical methods.
13.1.1 Analysis Sets
Safety Set:
The Safety Analysis Set will consist of all subjects who are enrolled and received at least 1 dose 
of study drug. Subjects in this analysis set will be used for demographic, baseline characteristics 
and safety summaries.
PK Set:
The PK set will consist of all subjects who receive study drug and have at least 1 measurable 
plasma concentration.
Pharmacodynamic Set:
The PD set will consist of all subjects who receive study drug and have at least 1 postdose PD 
measurement.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be generated for 
continuous demographic variables and baseline characteristics variables (age, height, weight, and 
BMI) for pooled placebo, each ixazomib dose level, and ixazomib overall. The number and 
percentage of subjects in each class of the categorical demographic variables and baseline 
characteristics variables (gender, ethnicity, and race) will be tabulated for pooled placebo group, 
each ixazomib dose level, and ixazomib overall. Individual subject demographic and baseline 
characteristics 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 overall for subjects who are screened, but not enrolled in the study. Individual 
demographic characteristics, date of informed consent, and reason for screen failure will be 
listed.
13.1.3 Medical History and Concurrent Medical Conditions
Medical history and concurrent medical condition verbatim reported terms will be coded to the 
closest matching lower level term and then to the first listed preferred term (PT) and system 


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organ class (SOC) using MedDRA. All medical history and concurrent medical conditions will 
be listed.
13.1.4 Medication History and Concomitant Medication
Medications taken within 28 days before the Screening Visit and stopped before the Screening 
Visit will be recorded in the medication history eCRF. Medications taken during or after the 
Screening Visit will be considered as concomitant medications. Medications started before the 
Screening Visit and continued will also be considered as concomitant medications. Medication 
history and concomitant medications will be coded using WHO Drug. All medication history and 
concomitant medications data will be listed.
13.1.5 PK Analysis 
Concentrations of ixazomib in plasma and 
will be summarized by ixazomib dose 
level at each scheduled sampling time using descriptive statistics (N, arithmetic mean, SD, 
median minimum, maximum and percent coefficient of variation (%CV)). Individual plasma 
concentration data versus time will be presented in a data listing.
PK parameters of ixazomib will be summarized for each dose level using descriptive statistics. In 
addition, geometric mean will be computed for Cmax and AUCs. Dose proportionality will be 
assessed graphically and using the power model.
Plots of Cmax and AUCs, as well as dose-normalized Cmax and AUCs, versus doses will be 
generated. 
Other analyses or methods may be used, if appropriate. 
13.1.6 Pharmacodynamic and Exploratory Analysis
Individual values and changes in the levels of anti-dsDNA antibodies, complement C3/C4 levels, 
and UPCR will be summarized. 
Individual changes from baseline in serum and urine biomarkers will be summarized.
13.1.7 Safety Analysis
For all safety summary tables stated under this section, the tables will be summarized by 
placebo, each ixazomib dose level and ixazomib overall. Placebo data will be pooled across the 
dose levels.
13.1.7.1 AEs
All PTEs and TEAEs will be coded by SOC and PT using MedDRA. TEAEs with onset 
occurring within 30 days (onset date – last date of dose +1≤30) after the last study drug 
administration will be listed, and included in the summary tables.
The TEAEs will be summarized by SOC and PT. The following summary tables will be included 
in the report: summary of TEAEs and drug-related AEs, relationship of AEs to study drug 
Company
Confidential
Information


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(related vs. not-related), severity of AEs and 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.
13.1.7.2 Kidney function Evaluation
Baseline, postdose, and change from Baseline to postdose data will be summarized. All SCr and 
eGFR data will be listed.
13.1.7.3 Clinical Laboratory Evaluation
Individual results of laboratory tests from hematology, chemistry, and urinalysis that meet 
TDC’s markedly abnormal criteria to be defined in the SAP will be listed and summarized in 
groups. Baseline, postdose, and change from Baseline to postdose laboratory data will be 
summarized. All clinical laboratory data will be listed.
13.1.7.4 Vital Signs
Individual results of vital signs that meet TDC’s markedly abnormal criteria to be defined in the 
SAP will be listed and summarized. Baseline, postdose, and change from Baseline in vital sign 
measurements will be summarized. All vital signs data will be provided in the data listings.
13.1.7.5 Electrocardiograms
Individual results of quantitative ECG parameters from the 12-lead safety ECGs that meet 
TDC’s markedly abnormal criteria to be defined in the SAP will be listed and summarized. 
Baseline, postdose, and change from Baseline in quantitative ECG parameters will be 
summarized. Shift tables will be generated for the investigator’s ECG interpretations. All ECG 
data will be provided in the data listings.
13.2
Interim Analysis and Criteria for Early Termination
There will be no unblinded interim analysis. A blinded safety analysis may be conducted after 
5 subjects are enrolled in the 4 mg cohort. An independent physician/designee will periodically 
monitor the overall conduct of the study to safeguard the interests of study participants including 
to make recommendations relating to the eligibility of subjects entering the Open-Label 
Treatment Extension Period, as well as monitoring their progress while receiving extended 
treatment.
13.3
Determination of Sample Size
This study is not statistically powered for any hypothesis testing. The sample size of at least 
4 active and 1 placebo subjects for each of the 0.5 mg and 2.0 mg dose groups (Cohorts A and B, 
respectively), 6 active and 2 placebo subjects for each of the 3.0 and 4.0 mg dose groups 
(Cohorts C and D, respectively) is considered to be sufficient to fulfill the study objectives of the 
evaluation of safety, tolerability, and PK of each cohort.


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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
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 institution 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 
designee (as long as blinding is not jeopardized), including but not limited to the Investigator’s 
Binder, study medication, subject medical records, informed consent documentation, 
documentation of subject authorization to use personal health information (if separate from the 
informed consent forms), 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.
14.2
Protocol Deviations
There will be no exemptions (a prospective approved deviation) from the inclusion or exclusion 
criteria 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
medical monitor (and IRB or IEC, as required) to determine the appropriate course of action.
Every attempt will be made to collect each PK blood sample at the designated time point, and the 
actual time of each blood sample will be recorded on the source document and eCRF. However, 
blood samples not collected within the interval specified for the scheduled sample time should be 
reported to Takeda and recorded in the source documents.
The Significant Protocol Deviation eCRF is to be completed for deviations that are identified by 
the sponsor before study start.
Table 14.a
Windows for PK Sample Collection (Cycle 1 and Cycle 3)
Time Window
Nominal Sampling Time
no more than 0.5 h predose
0 hour
±0.5 min
15 and 30 min
±0.25 h
1 h, 1.5 h, 2
± 0.75 h
4 h
± 1.0 h
8 h 
± 2.0 h
24 h
± 8 h
>72 h to 316 h


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14.3
Quality Assurance Audits and Regulatory Agency Inspections
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 and institution 
guarantee access for quality assurance auditors to all study documents as described in 
Section 14.1.


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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
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 B. The principles of Helsinki are addressed through the protocol and through 
appendices containing requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
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 US sites unwilling to provide names and
titles of all members due to privacy and conflict of interest concerns should instead provide a 
Federal Wide 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 informed consent 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 informed consent 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, informed 
consent form) 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 written 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 informed consent 
form, recruitment materials intended for viewing by subjects, 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 subjects must 
be approved by the IRB or IEC and sponsor.


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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent 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 informed consent form, 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 informed consent form 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 informed consent form 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 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, 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 informed consent form, 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 informed 
consent form, 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 informed consent, 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 informed consent form 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 entering 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 informed consent form and subject authorization (if applicable) at the time of consent and 
before 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 informed consent form, 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 informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization 
form (if applicable), and subject information sheet (if applicable) shall be given to the subject.


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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
Subjects who consented and provided a pharmacogenomic sample for DNA analysis can 
withdraw their consent and request disposal of a stored sample at any time. Notify sponsor of 
consent withdrawal.
15.3
Subject Confidentiality
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 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 15.2).
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).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 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 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 


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accordance with this section and the Master Services Agreement or equivalent agreement. In the 
event of any discrepancy between the protocol and the Master Services Agreement or equivalent 
agreement the Master Services Agreement or equivalent agreement will prevail.
15.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable law, regulation and guidance, Takeda will, at a minimum, register all 
clinical trials conducted in patients that it sponsors anywhere in the world on ClinicalTrials.gov 
or other publicly accessible websites before trial initiation. 
15.4.3 Clinical Trial Results Disclosure
Takeda will minimally post the results of clinical trials conducted in patients, regardless of 
outcome, on ClinicalTrials.gov or other publicly accessible websites, as required by applicable 
laws and/or regulations.
15.5
Insurance and Compensation for Injury
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 clinical study 
subjects. Refer to the Master Services Agreement or equivalent 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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16.0
REFERENCES
1. Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med 2008;358(9):929-39.
2. Lateef A, Petri M. Unmet medical needs in systemic lupus erythematosus. Arthritis Res Ther 
2012;14 Suppl 4:S4.
3. Grossman JM. Lupus arthritis. Best Pract Res Clin Rheumatol 2009;23(4):495-506.
4. Sacks JJ, Luo Y-H, Helmick CG. Prevalence of specific types of arthritis and other rheumatic 
conditions in the ambulatory health care system in the United States, 2001-2005. Arthritis 
care & research 2010;62(4):460-4.
5. Pons-Estel GJ, Alarcon GS, Scofield L, Reinlib L, Cooper GS. Understanding the 
epidemiology and progression of systemic lupus erythematosus. Semin Arthritis Rheum 
2010;39(4):257-68.
6. Weening JJ, D'Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The 
classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc 
Nephrol 2004;15(2):241-50.
7. Borchers AT, Leibushor N, Naguwa SM, Cheema GS, Shoenfeld Y, Gershwin ME. Lupus 
nephritis: a critical review. Autoimmun Rev 2012;12(2):174-94.
8. Hahn BH, McMahon MA, Wilkinson A, Wallace WD, Daikh DI, Fitzgerald JD, et al. 
American College of Rheumatology guidelines for screening, treatment, and management of 
lupus nephritis. Arthritis Care Res (Hoboken) 2012;64(6):797-808.
9. Dall'Era M, Stone D, Levesque V, Cisternas M, Wofsy D. Identification of biomarkers that 
predict response to treatment of lupus nephritis with mycophenolate mofetil or pulse 
cyclophosphamide. Arthritis Care Res (Hoboken) 2011;63(3):351-7.
10. Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, de Ramon Garrido E, Danieli MG, 
et al. Early response to immunosuppressive therapy predicts good renal outcome in lupus 
nephritis: lessons from long-term followup of patients in the Euro-Lupus Nephritis Trial. 
Arthritis Rheum 2004;50(12):3934-40.
11. Smith RM, Clatworthy MR, Jayne DR. Biological therapy for lupus nephritis-tribulations and 
trials. Nat Rev Rheumatol 2010;6(9):547-52.
12. Houssiau FA, Isenberg D. Towards treating lupus nephritis without oral steroids: a dream-
come-true? Ann Rheum Dis 2013;72(8):1271-2.
13. Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical 
Practice Guideline for Glomerulonephritis. Kidney inter, Supple 2012;2:139-274.
14. Manz RA, Radbruch A. Plasma cells for a lifetime? Eur J Immunol 2002;32(4):923-7.
15. van Tol MJ, Gerritsen EJ, de Lange GG, van Leeuwen AM, Jol-van der Zijde CM, 
Oudeman-Gruber NJ, et al. The origin of IgG production and homogeneous IgG components 
after allogeneic bone marrow transplantation. Blood 1996;87(2):818-26.


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16. Mohty M, Brissot E, Savani BN, Gaugler B. Effects of bortezomib on the immune system: a 
focus on immune regulation. Biol Blood Marrow Transplant 2013;19(10):1416-20.
17. Perry DK, Burns JM, Pollinger HS, Amiot BP, Gloor JM, Gores GJ, et al. Proteasome 
inhibition causes apoptosis of normal human plasma cells preventing alloantibody 
production. Am J Transplant 2009;9(1):201-9.
18. Hirai M, Kadowaki N, Kitawaki T, Fujita H, Takaori-Kondo A, Fukui R, et al. Bortezomib 
suppresses function and survival of plasmacytoid dendritic cells by targeting intracellular 
trafficking of Toll-like receptors and endoplasmic reticulum homeostasis. Blood 
2011;117(2):500-9.
19. Neubert K, Meister S, Moser K, Weisel F, Maseda D, Amann K, et al. The proteasome 
inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from 
nephritis. Nat Med 2008;14(7):748-55.
20. Hainz N, Thomas S, Neubert K, Meister S, Benz K, Rauh M, et al. The proteasome inhibitor 
bortezomib prevents lupus nephritis in the NZB/W F1 mouse model by preservation of 
glomerular and tubulointerstitial architecture. Nephron Exp Nephrol 2012;120(2):e47-58.
21. Gupta N, Diderichsen PM, Hanley MJ, Berg D, van de Velde H, Harvey RD, et al. 
Population Pharmacokinetic Analysis of Ixazomib, an Oral Proteasome Inhibitor, Including 
Data from the Phase III TOURMALINE-MM1 Study to Inform Labelling. Clinical 
Pharmacokinetics 2017:1-14.
22. Gupta N, Zhao Y, Hui AM, Esseltine DL, Venkatakrishnan K. Switching from body surface 
area-based to fixed dosing for the investigational proteasome inhibitor ixazomib: a 
population pharmacokinetic analysis. Br J Clin Pharmacol 2015;79(5):789-800.
23. NINLARO® (Ixazomib) [Package Insert]. 25 Efal St., Petach Tikva 4951125: Takeda Israel 
Ltd., August, 2016.
24. van der Vlag J, Berden JH. Proteasome inhibition: a new therapeutic option in lupus 
nephritis? Nephrol Dial Transplant 2008;23(12):3771-2.


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Appendix A
Schedule of Study Procedures: Double-Blind Treatment Period
Screening 
(a)
Cycles 1 (28-Day Cycle) 
Visit Window ±2 days
Cycles 2 (28-Day Cycle) 
Visit Window ±2 days
Cycles 3 (28-Day Cycle) 
Visit Window ±2 days
Follow Up Visits 
every 4 weeks 
from Day 85 to 
Study 
completion Day 
168 (±7 days)
ET /EOT/ 
Final Visit
Days
-24 (-11) to 
-1
1
2
8
15
22
1
8
15
22
1
8
15
16
22
28
Study Procedure
Informed consent (b)
X
Inclusion/ exclusion 
criteria
X
X
Demographics
X
Medical history
X
X (c)
Medication history
X
Renal biopsy history
X
Physical examination 
(c)
X
X (c)
X
X
X
X(m)
Concurrent medical 
conditions
X
X
Stabilize concomitant 
medications (if needed)
X
Weight 
X
X
X
X
X
X(m)
BMI
X
Height
X
Vital signs (d)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Footnotes are on last table page.


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Appendix A
Schedule of Study Procedures: Double-Blind Treatment Period (continued)
Screening 
(a)
Cycles 1 (28-Day Cycle) 
Visit Window ±2 days
Cycles 2 (28-Day Cycle) 
Visit Window ±2 days
Cycles 3 (28-Day Cycle) 
Visit Window ±2 days
Follow Up Visits 
every 4 weeks 
from Day 85 to 
Study 
completion Day 
168 (±7 days)
ET /EOT/ 
Final Visit
Days
-24 (-11) to 
-1
1
2
8
15
22
1
8
15
22
1
8
15
16
22
28
Study Procedure
PTE assessment
X
AE Assessments
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Monitoring of 
concomitant 
medications 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy avoidance 
counseling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Overnight fast
X
X
X
X
X(m)
Study drug dosing
X
X
X
X
X
X
X
X
X
12-lead ECG (e)
X
X
X
X
X
TB screening
X
HBsAb and TT 
antibody titers 
X
X
X
X(m)
FSH (l)
X
HBsAg and Anti-HCV
X
Hematology (f)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry panel (f)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Footnotes are on last table page.


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Appendix A
Schedule of Study Procedures: Double-Blind Treatment Period (continued)
Screening 
(a)
Cycles 1 (28-Day Cycle) 
Visit Window ±2 days
Cycles 2 (28-Day Cycle) 
Visit Window ±2 days
Cycles 3 (28-Day Cycle) 
Visit Window ±2 days
Follow Up Visits 
every 4 weeks 
from Day 85 to 
Study 
completion Day 
168 (±7 days)
ET /EOT/ 
Final Visit
Days
-24 (-11) to 
-1
1
2
8
15
22
1
8
15
22
1
8
15
16
22
28
Study Procedure
Lipid panel (fasted):
X
X
X
X
X(m)
Platelets counts white 
blood cells with 
differentiation and red 
blood cells (p)
X
X
X
X
X
X
X
X
X
Pregnancy test (g)
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis (including 
microscopic analysis) 
X
X
X
X
X
X
X
X
X
Urine sample for 
protein/creatinine ratio
X(o)
X(o)
X(o)
X(o)
X(o)
X(o)
X(o)
X
X(o)
Serum complement 
(C3, C4)
X
X
X
X
X
X
X
X
X
Anti-dsDNA
X
X
X
X
X
X
X
X
X
Coomb’s test-direct
X
X
X
X
X
X
Quantitative IgM and 
IgA
X
X
X
X
X(m)
Footnotes are on last table page.
Company Confidential Information


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Appendix A
Schedule of Study Procedures: Double-Blind Treatment Period (continued)
Screening 
(a)
Cycles 1 (28-Day Cycle) 
Visit Window ±2 days
Cycles 2 (28-Day Cycle) 
Visit Window ±2 days
Cycles 3 (28-Day Cycle) 
Visit Window ±2 days
Follow Up Visits 
every 4 weeks 
from Day 85 to 
Study 
completion Day 
168 (±7 days) (q)
ET /EOT/ 
Final Visit
Days
-24 (-11) to 
-1
1
2
8
15
22
1
8
15
22
1
8
15
16
22
28
Study Procedure
Quantitative IgG
X
X
X
X
X
X(m)
DNA collection (h)
X
RNA collection(i)
X
X
X
Urine dipstick protein
X
X
X
X
X
X
Urine collection for 
biomarker 
X
X
X
Serum collection for 
biomarker
X
X
X
PK Blood Collection
plasma (j)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Neuropathy assessment 
(FACT/GOG-NTX) (k)
X
X
X
X
IVRS/IWRS
X
X
X
X
X
X
X
X
X
X
X
ET/EOT=early termination/end of treatment.
(a) Subjects can be randomized 24 (+11) days after Screening (between Days -24 and -35). If the elapsed time between the Screening Visit and randomization (Day 1) is greater 
than allowed, then the eligibility criteria must be reconfirmed before randomization. If the subject fulfils eligibility criteria at randomization, but the visit is postponed because of 
reasons other than eligibility criteria logistical matters, the subject can be randomized within 7 days after approval of the medical monitor; however, safety laboratory tests must be 
repeated and the investigator must reconfirm eligibility criteria. If rescreening occurs within one month of the original screening period, then only the following procedures are 
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required, disease activity parameters (UPCR, anti-dsDNA, urine sediment and complement levels) and safety laboratory tests must be repeated to re-confirm eligibility. Subjects 
will be randomized once safety laboratory tests and inclusion/exclusion criteria have been reviewed and confirmed by the investigator. Subjects may be rescreened once for urinary 
sediment, proteinuria or complement levels within 2 weeks of the original Screening Visit.
CBC with platelet count, chemistries, including liver function tests and urinalysis may be repeated one time to determine eligibility with approval from the medical monitor.
(b) Informed consent must be signed before any study-specific procedures are performed.
(c) The Cycle 1, Day 1 physical examination and medical history are not required if the screening physical examination was conducted and medical history obtained within 4 days 
before administration of the first dose of study drug (Cycle 1, Day 1). The physical examination must be conducted within 3 days before dosing on Day 1 of each subsequent 
treatment cycle visit. 
(d) Vital sign measurements are to be made before dosing, when applicable. The blood pressure measurement should be made with the subject in a seated position, after the subject 
has been sitting quietly for 5 minutes.
(e) A single 12-lead ECG will be collected at screening to assess eligibility, on Day 1 of each cycle, and at the Final Visit/ET/EOT visit. The ECG may be repeated as clinically 
indicated during the study at the discretion of the investigator. ECG assessments are to be performed with the subject supine and rested for 5 minutes. When an ECG is scheduled 
at the same time as blood draws or vital signs then the blood draws and vital signs will take priority and the ECG will be obtained within 1.5 hours before or after the scheduled 
blood draw/vital sign assessment.
(f) A blood sample for hematology will be obtained at Screening, Days 1, 8, 15 and 22 of Cycle 1, Days 1, 8, 15, and 22 of Cycle 2 and Cycle 3 before dosing and Day 28/Final 
Visit of Cycle 3 or ET/EOT visit, and at each Follow Up Visit up to Month 6 from the first dose. Serum chemistry will be obtained at Screening, Days 1, 8, 15 and 22 of each cycle 
before dosing and Day 28/Final Visit of Cycle 3 or ET/EOT visit, and at each follow up visit up to Month 6 from the first dose. The hematology and chemistry blood samples for 
Cycle 1, Day 1 may be collected within 4 days before dosing to ensure subject eligibility on study Day 1. If the clinical laboratory testing was performed for screening within 4 
days before the Cycle 1, Day 1 dose, it need not be repeated on Cycle 1, Day 1.
(g) Serum pregnancy test will be performed at Screening. A urine pregnancy test will be performed only for subjects of childbearing potential before each dosing occasion in each 
cycle, at Final Visit/ET/EOT visits and at each Follow up Visit. The results must be negative within 4 days before the first dose of ixazomib is administered (ie, within the 4 days 
before Cycle 1, Day 1), or as otherwise required by local regulations. Additional pregnancy testing may be performed during the study at the discretion of the investigator, at the 
request of an independent ethics committee/institutional review board, or if required by local regulations.
(h) One blood sample (10.0 mL) will be collected for pharmacogenomic analysis before dosing on study Day 1.
(i) Blood samples will be collected for RNA analysis during Cycle 1 and Cycle 3.
(j) Blood samples for ixazomib analysis will be collected on Study Day 1 Cycle 1 predose (within 0.5 hour before dosing) on days 1, 8 and 15. On Day 1 of Cycle 1, sample will be 
collected at 0.25, 0.5, 1, 1.5, 2, 4, 8, 24, and 168 (predose Day 8) hours following the first dose. In Cycle 2, samples will be collected predose on Days 1, 8, and 15. Samples will 
also be collected on Day 22 following first dose in Cycle 2. In Cycle 3 samples will be collected predose on Days 1, 8, and 15. On Day 15 of Cycle 3 following the third dose, 
samples will be collected at 0.25, 0.5, 1, 1.5, 2, 4, 8, 24, 168 and 312 hours postdose. 
(k) Neuropathy assessment must be performed and evaluated before administration Ixazomib if a dose is scheduled for that visit
(l) Postmenopausal women by history (ie, last regular menstrual cycle >2 years) and not surgically sterile. The FSH result must be >40 IU/L for the subject to be permitted not to 
use adequate contraception.
(m) Samples/procedures will be collected only at the last Follow-up Visit (Month 6). A Follow-up Period of up to 3 months consisting of monthly follow-up visits will start after 
Cycle 3 to assess any safety issues.
(n)
 
(o) Dispense cups for collection of UPCR (three collections to be done prior the visit).
(p) Collection should occur within 48 hours before visits on the day of dosing of each cycle with results required back to the site before dosing.
(q) For subjects not moving on to the optional Open-Label Treatment Extension Period.
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Appendix A
Schedule of Study Procedures: Optional Open-Label Treatment Extension Period
Open-Label Treatment Extension Period
Follow Up Visit 
30 Days after 
last OL 
Treatment 
Cycle
Cycles 1 (28-Day Cycle) 
Visit Window ±2 days
Cycles 2 (28-Day Cycle) 
Visit Window ±2 days
Cycles 3 (28-Day Cycle) 
Visit Window ±2 days
ET /EOT/ 
Final Visit
Days
1
8
15
22
1
8
15
22
1
8
15
22
28
Physical examination (c)
X (c)
X
X
X
X(m)
Concurrent medical conditions
X
Weight 
X
X
X
X
X(m)
Vital signs (d)
X
X
X
X
X
PTE assessment
AE Assessments
X
X(b)
X(b)
X
X(b)
X(b)
X
X(b)
X(b)
X
X
Monitoring of concomitant 
medications 
X
X
X
X
Pregnancy avoidance counseling
X
X(b)
X(b)
X
X(b)
X(b)
X
X(b)
X(b)
X
X
Overnight fast
X
X(m)
Study drug dosing
X(a)
X(b)
X(b)
X(a)
X(b)
X(b)
X(a)
X(b)
X(b)
12-lead ECG (e)
X
X
X
X
HBsAb and TT antibody titers 
X
X
X
X(m)
Hematology (f)
X
X
X
X
X
Chemistry panel (f)
X
X
X
X
X
Lipid panel (fasted):
X
X(m)
Platelets counts white blood cells 
with differentiation and red blood 
cells (p)
X
X
X
Pregnancy test (g)
X
X
X
X
X
Urinalysis (including microscopic 
analysis) 
X
X
X
X
X
Footnotes are on last table page.


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Appendix A
Schedule of Study Procedures: Optional Open-Label Treatment Extension Period (continued)
Open-Label Treatment Extension Period
Follow Up Visit 
30 Days after 
last OL 
Treatment 
Cycle
Cycles 1 (28-Day Cycle) 
Visit Window ±2 days
Cycles 2 (28-Day Cycle) 
Visit Window ±2 days
Cycles 3 (28-Day Cycle) 
Visit Window ±2 days
ET /EOT/ 
Final Visit
Days
1
8
15
22
1
8
15
22
1
8
15
22
28
Serum complement (C3, C4)
X
X
X
X
X
Anti-dsDNA
X
X
X
X
X
Coomb’s test-direct
X
X
X
X
X
Quantitative IgM and IgA
X
X
X
X
X(m)
Quantitative IgG
X
X
X
X
X(m)
Urine dipstick protein
X
X
Neuropathy assessment 
(FACT/GOG-NTX) (k)
X
X
X
X
X
IVRS/IWRS
X
X
X
X
ET/EOT=early termination/end of treatment.
(a) First dose of Open-Label treatment cycle administered.
(b) Call subjects at home to remind about dosing, pregnancy avoidance, and ask about any AEs including symptoms of peripheral neuropathy.
(c) The physical examination must be conducted within 3 days before dosing on Day 1 of each treatment cycle visit. 
(d) Vital sign measurements are to be made before dosing in each cycle and when applicable. The blood pressure measurement should be made with the subject in a seated 
position, after the subject has been sitting quietly for 5 minutes.
(e) The ECG may be repeated as clinically indicated during the study at the discretion of the investigator. ECG assessments are to be performed with the subject supine and rested 
for 5 minutes. When an ECG is scheduled at the same time as blood draws or vital signs then the blood draws and vital signs will take priority and the ECG will be obtained within 
1.5 hours before or after the scheduled blood draw/vital sign assessment.
(f) If the central laboratory blood test is not available before the first dose of each cycle, a blood sample for hematology will be obtained at the local laboratory and results 
reviewed before first dose of each cycle, or before each dose if there is a safety concern. Serum chemistry will be obtained Day 1 of each cycle before dosing and Day 28/Final 
Visit of Cycle 3 or ET/EOT visit, and at the follow up visit. The hematology and chemistry blood samples for Cycle 1, Day 1 may be collected within 7 days before dosing to 
ensure subject eligibility for open label dosing. If the clinical laboratory testing was performed within 7 days before Cycle 1, Day 1 dose, it need not be repeated.
(g) A urine pregnancy test will be performed only for subjects of childbearing potential before each dosing occasion in each cycle, at Final Visit/ET/EOT visits and at each Follow 
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up Visit. The results must be negative within 4 days before the first dose of ixazomib is administered (ie, within the 4 days before Cycle 1, Day 1), or as otherwise required by 
local regulations. Additional pregnancy testing may be performed during the study at the discretion of the investigator, at the request of an independent ethics 
committee/institutional review board, or if required by local regulations.
(k) Neuropathy assessment must be performed and evaluated before administration of ixazomib.
(m) Samples/procedures will be collected only at the last Follow-up Visit. 
(o) Dispense cups for collection of UPCR (3 collections to be done prior the visit).
(p) Collection should occur within 48 hours before visits on the day of dosing of each cycle with results required back to the site before dosing.


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Appendix B
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 who will assist in the protocol.
3. Ensure that study related procedures; including study specific (non-routine/non-standard 
panel) screening assessments are NOT performed on potential subjects, before the receipt of 
written approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform 
to 21 Code of Federal Regulations Part 56, ICH, and local regulatory requirements.
6. 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 subjects. 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.
7. Ensure that requirements for informed consent, as outlined in 21 Code of Federal Regulations 
Part 50, ICH and local regulations, are met.
8. 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 informed consent form 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 informed consent form 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.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
(e)CRFs, hospital records, laboratory results, etc, 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 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.


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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.


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Appendix C
Elements of the Subject 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 subjects 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 informed consent 
form, 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 may 


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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. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. 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:
a) 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;
b) 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 
subjects 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;
c) 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;
d) that subjects 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
e) that the subject’s identity will remain confidential in the event that study results are 
published.


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25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use adequate contraception (as defined in the informed consent) 
from Screening through 90 days after the last dose of trial treatment. Regular pregnancy tests 
will be performed throughout the study for all female subjects of childbearing potential. If a 
subject is found to be pregnant during study, study medication will be discontinued. 
26. Male subjects must use adequate contraception (as defined in the informed consent) from 
Screening through 90 days after the last dose of trial treatment.


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Appendix D
Investigator Consent to 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 E
Collection, Storage, and Shipment of Bioanalytical Samples 
Cycle 1
Day 1
Day 2
Day 8
Day 15
Time point 
(window)
Pre-
dose
15 min 
(∋5
min)
30 min 
(∋5 
min)
1 hr 
(∋15
min)
1.5 hr 
(∋15 
min)
2 hr 
(∋15
min)
4 hr 
(∋45 
min)
8 hr
(∋1 hr)
24 hr 
(∋1 hr)
168 hr 
(∋8 hr)
Pre-
dose
Plasma PK 
blood draw
X (a)
X
X
X
X
X
X
X
X
X (a)
X (a)
RNA
X (a)
X
X
X
X
X
Serum 
biomarkers
X (a)
X
X
Urine 
Biomarkers
X (a)
X
X
Cycle 2
Time point 
(window)
Day 1
Day 8
Day 15
Day 22
Plasma PK 
blood draw
X (a)
X (a)
X (a)
X
Cycle 3
Predose
Day 15 (b)
Day 16
Day 22
Day 28
Day 1
Day 
8
Day 
15
15 min 
(∋5 
min)
30 min 
(∋5 
min)
1 hr 
(∋15 
min)
1.5 hr 
(∋15 
min)
2 hr 
(∋15 
min)
4 hr 
(∋45 
min)
8 hr 
(∋1
hr)
24 hr 
(∋2
hr)
168 hr 
(∋8 hr) 
312 hr 
(∋8 hr)
Plasma 
PK 
blood 
draw
X (a)
X 
(a)
X (a)
X
X
X
X
X
X
X
X
X
X
RNA
X
Follow-up Period
Month 4
Month 5
Month 6 (∋7 days)
EOC = end of cycle. 
(a) Predose within 0.5 hour before dosing.
(b) Sampling times referenced as time post third dose of Cycle 3.
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Collection, Storage, and Shipment of Bioanalytical Samples PK Ixazomib Analysis
Instructions for Processing of Plasma Samples for Bioanalytical Analysis of ixazomib 
1. Collect 3 mL of venous blood into a chilled Becton-Dickinson Vacutainer. All ixazomib 
blood samples should be collected into lavender topped vacutainers containing K2EDTA.
2. Gently invert the vacutainer 8 to 10 times to mix the additive with the collected blood before
centrifugation and place immediately on ice.
3. Within 15 minutes place vacutainers into centrifuge for 10 minutes at approximately 1000 to 
1300 relative centrifugal force (RCF). Note: if using a collection device other than Becton-
Dickinson, refer to manufacturer’s instruction for proper centrifugation force and time.
4. Immediately following centrifugation, gently remove plasma from the packed cells. To 
ensure a more homogeneous sample, all plasma should first be transferred into 1 aliquot. 
From there, add exactly 0.5000 mL of plasma to 2 vials containing a designated amount of 
lyophilized critic acid (250 mg). Vortex the vials after capping. Discard the remaining 
plasma following appropriate biohazard procedures. Labeling may include protocol number 
(MLN9708-101), sample matrix (ie, plasma), analyte (ixazomib), randomization sequence 
number, cycle, profile day (ie, Profile Day 1) and scheduled time points, and either “SET 1” 
(for original sample) or “SET 2” (for duplicate sample).
NOTE: If <0.5 mL plasma is obtained post centrifugation, do not process or store split1 or 
split2, record split1: ISV (insufficient sample volume), split2:ISV. If <1.0 mL plasma is 
obtained post centrifugation, process and store split1 according to procedure; do not process 
or store split2, record split 2:ISV. Discard remaining plasma using appropriate biohazard 
waste disposal procedures. Replace cap on tube and freeze the samples immediately at -20oC 
or -70°C. 
5. Cap the labeled storage tubes and freeze the plasma samples immediately at 
approximately -20oC (for no longer than 25 days) or -70°C until shipment to PPD Global 
Central Lab per the instructions in their laboratory manual. PPD Labs will further ship 
samples to Tandem, New Jersey for analysis. No more than 60 minutes will elapse between 
blood collection and freezing the plasma sample.
 
1.
2.
3.
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4.
Shipping of Plasma Samples for Bioanalytical Analysis of Ixazomib 
1. Biological samples (ie, plasma) should be shipped on dry ice to prevent thawing during 
transit. Samples should be shipped only on Monday, Tuesday, or Wednesday, and at least 2 
days before a national holiday, in order to minimize the possibility of samples in transit over 
a weekend or holiday. If duplicate samples are to be shipped, send SET 1 samples and await 
confirmation of arrival before shipping the duplicate SET 2 samples.
2. Before shipping, make sure the sample tubes are tightly sealed. Separate each subject’s 
samples as follows:
3. Separate the duplicate SET 2 samples from the SET 1 samples.
4. Place SET 1 samples for each subject into self-sealing bag (eg, Ziploc®) containing 
additional absorbent material.
5. Using a permanent marker, write the 4-digit randomization sequence number, sample matrix 
(ie, plasma), analyte (ixazomib), number of samples, and “SET 1” on each self-sealing bag.
6. Place the bags of individual subject’s samples into a larger plastic bag so that samples are 
double bagged. Duplicate SET 2 samples should be returned to the freezer for storage. 
Repeat steps 3 through 6 above when preparing duplicate samples for shipment, except self-
sealing bags should be marked “SET 2.”
7. An inventory of individual samples should accompany each shipment and should include the 
Sponsor’s name (Takeda), study drug (ixazomib), protocol number (MLN9708-101), 
investigator’s name, sample type (ie, plasma), randomization sequence number, cycle, profile 
day and scheduled time point, and intended sample storage conditions. When duplicate SET 
2 samples are being shipped, make a copy of the original SET 1 sample inventory and mark 
as “SET 2.” Place the inventory paperwork into a large self-sealing bag. SET 1 samples will 
be shipped first on dry ice, followed by shipment of duplicate SET 2 samples after SET 1 
samples have been received by the analytical laboratory.
8. For sample packing, use dry ice generously (eg, 20 25 pounds per day of transit) to safeguard 
against longer than expected shipping times and delays. Use newspaper or other material to 
insulate the double-bagged samples from direct contact with the dry ice. Place the sample 
bundles into a styrofoam container (or other suitable container) and fill the excess space with 
dry ice slabs or ice pellets (preferably the latter). Make a note of the estimated weight of the 
dry ice used per shipping container.
9. Place the inventory paperwork (in a large self-sealing bag) on top of the dry ice in the 
styrofoam container. Place the lid on the styrofoam container and seal completely with 
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strapping tape. Place the styrofoam container in a cardboard shipping carton and seal 
securely with strapping tape.
10. Mark the outside of shipping carton(s) with a tally number (eg, 1 of 5, 2 of 5).
11. Affix the appropriate address label to each shipping carton and ship to Global Central Lab 
per the instructions in their laboratory manual. 


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Appendix F
Total Blood Volume of Blood Withdrawal
Blood Volume Collected (mL)
Cycle 1 (Double-Blind Treatment)
Day
-24(-11) to -1
1
2
8
15
22
Total (mL)
Sample Type
Safety laboratory samples
22
23 (b) (f)
13(b) (f)
23 (b) (f)
10
91
Plasma PK samples 
24 (a)
3
3 (a,b)
3 (b)
33
Serum biomarkers
3 (b)
3
3
9
DNA sample
10
10
RNA samples 
12.5
2.5
15
Total Blood Volume for Screening and in Cycle 1
170
Cycle 2 (Double-Blind Treatment)
Day
1
8
15
22
Total (mL)
Sample Type
Safety laboratory samples (b)
20
13 (f)
23 (f)
10
66
Plasma PK samples
3 (b)
3 (b)
3 (b)
3
12
Total Blood Volume in Cycle 2
80
Cycle 3 (Double-Blind Treatment)
Day
1
8
15
16
22
28
Total (mL)
Sample Type
Safety laboratory samples (b)
24
13 (f)
23 (f)
10
20
90
Plasma PK samples
3 (b)
3 (b)
24 (c)
3
3
3
39
RNA samples
2.5
2.5
Total Blood Volume in Cycle 3
143.5
Follow-up Period (d) (No Open Label Treatment)
Total (mL)
Month
Month 4
Month 5
Month 6
Sample Type
Safety laboratory samples 
20
20
20
60
Total Blood Volume in the Follow-up Period
60
Open Label Treatment Period and Follow-up (g)
Total (mL)
Cycle 1
Cycle 2
Cycle 3
ET/EOT/Final 
Visit
Follow-up 
visit
Safety laboratory samples
20 (b) (f)
20(b) (f)
20 (b) (f)
20 
20
100
Total Blood Volume in the Follow-up Period
100
Total Approximate Blood Volume (mL) to be over the study duration collected per Subject (no open label 
treatment)
453.5
OR
Total Approximate Blood Volume (mL) to be over the study duration collected per Subject (with open label 
treatment)
493.5
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Direct venipuncture is the only acceptable method of blood collection.
(a) Plasma PK samples collected in Cycle 1 on Day 1: Predose (within 0.5 hour before dosing) on Days 1, 8 and 15. On Day 1 of 
Cycle 1, following the first dose, sample will be collected at 0.25, 0.5, 1, 1.5, 2, 4, 8, 24, and 168 (predose Day 8) hours postdose.
(b) Predose. 
(c) Plasma PK samples collected in Cycle 3 Predose (within 0.5 hour before dosing) on study Days 1, 8, and 15. On Day 15 of 
Cycle 3 following the third dose, samples will be collected at 0.25, 0.5, 1, 1.5, 2, 4, 8, 24, 168 and 312 hours postdose in Cycle 3.
(d) Follow-up visits on Days 112, 140, and 168.
(e) 
(f) Collection should occur within 48 hours before visits on the day of dosing of each cycle with results required back to the site 
before dosing.
(g) Open Label Treatment Period and Follow-up consists of up to 3 additional cycles of treatment (Day 85 to 168) with a Follow-
up visit 30 days after the last dosing.
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Appendix G
Instructions for Processing and Shipping of Plasma Samples for 
Pharmacogenomics
DNA Sample Collection
!
 
 
RNA Sample Collection
!
!
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Sample Shipment
!
Ship samples only on Monday, Tuesday, or Wednesday, and at least 2 days before a national 
holiday, to minimize the possibility of samples in transit over a weekend or holiday. The 
laboratory must confirm arrival of the shipped samples.
!
!
For shipment and /or storage longer than 5 calendar days, samples should be frozen at -20°C 
until shipment. Samples must be shipped frozen on dry ice to the central laboratory for 
processing.
!
Before shipping, ensure the sample tubes are tightly sealed.
RNA samples may be shipped to additional testing facility for transcriptional analysis.
Sample Storage
The sponsor designated long term storage provider will store the PGx samples in a secure storage 
space with adequate measures to protect confidentiality. The sponsor designated long term 
storage provider has validated procedures in place for transport, delivery, retention, retrieval, and 
destruction of the specimens. The samples will be retained while research on study drug/ disease 
state continues for up to but no longer than 15 years or as required by applicable law.
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Appendix H
Criteria for Classification of Systemic Lupus Erythematosus
The 1982 Revised American College of Rheumatology (ACR) Criteria for Classification of 
Systemic Lupus Erythematosus.
1. Malar Rash 
Fixed erythema, flat or raised, over the malar eminences, tending to 
spare the nasolabial folds 
2. Discoid rash 
Erythematous raised patches with adherent keratotic scaling and 
follicular plugging; atrophic scarring may occur in older lesions 
3. Photosensitivity 
Skin rash as a result of unusual reaction to sunlight, by patient 
history or physician observation 
4. Oral ulcers 
Oral or nasopharyngeal ulceration, usually painless, observed by 
physician 
5. Nonerosive Arthritis 
Involving 2 or more peripheral joints, characterized by tenderness, 
swelling, or effusion 
6. Pleuritis or Pericarditis 
1. Pleuritis--convincing history of pleuritic pain or rubbing heard by 
a physician or evidence of pleural effusion 
OR
2. Pericarditis--documented by electrocardiogram or rub or 
evidence of pericardial effusion
7. Renal Disorder 
1. Persistent proteinuria >0.5 grams per day or >than 3+ if 
quantitation not performed 
OR 
2. Cellular casts--may be red cell, hemoglobin, granular, tubular, or 
mixed
8. Neurologic Disorder 
1. Seizures--in the absence of offending drugs or known metabolic 
derangements; eg, uremia, ketoacidosis, or electrolyte imbalance 
OR
2. Psychosis--in the absence of offending drugs or known metabolic 
derangements, eg, uremia, ketoacidosis, or electrolyte imbalance


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9. Hematologic Disorder 
1. Hemolytic anemia--with reticulocytosis 
OR
2.Leukopenia--<4,000/mm3 on ≥2 occasions 
OR
3. Lymphopenia--<1,500/ mm3 on ≥2 occasions 
OR
4. Thrombocytopenia--<100,000/ mm3 in the absence of offending 
drugs
10. Immunologic Disorder 1. Anti-DNA: antibody to native DNA in abnormal titer 
OR
2. Anti-Sm: presence of antibody to Sm nuclear antigen 
OR
3. Positive finding of antiphospholipid antibodies on: 
a) an abnormal serum level of IgG or IgM anticardiolipin 
antibodies, 
b) a positive test result for lupus anticoagulant using a standard 
method, or 
c) a false-positive test result for at least 6 months confirmed by 
Treponema pallidum immobilization or fluorescent treponemal 
antibody absorption test
11.
 
The proposed classification is based on 11 criteria. For the purpose of identifying patients in 
clinical studies, a person shall be said to have systemic lupus erythematosus if any 4 or more of 
the 11 criteria are present, serially or simultaneously, during any interval of observation.
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The 2012 Systemic Lupus International Collaborating Clinics (SLICC) Criteria for Classification 
of Systemic Lupus Erythematosus
Clinical criteria
1. Acute cutaneous lupus, including:

Lupus malar rash (do not count if malar discoid).

Bullous lupus.

Toxic epidermal necrolysis variant of SLE.

Maculopapular lupus rash.

Photosensitive lupus rash.
in the absence of dermatomyositis

OR subacute cutaneous lupus (nonindurated psoriaform and/or annular polycyclic lesions 
that resolve without scarring, although occasionally with postinflammatory 
dyspigmentation or telangiectasias).
2. Chronic cutaneous lupus, including:

Classic discoid rash.

Localized (above the neck).

Generalized (above and below the neck).

Hypertrophic (verrucous) lupus.

Lupus panniculitis (profundus).

Mucosal lupus.

Lupus erythematosus tumidus.

Chillblains lupus.

Discoid lupus/lichen planus overlap.
3. Oral ulcers

Palate.
–
Buccal.
–
Tongue.

OR nasal ulcers.
in the absence of other causes, such as vasculitis, Behçet’s disease, infection (herpesvirus), 
inflammatory bowel disease, reactive arthritis, and acidic foods


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4. Nonscarring alopecia (diffuse thinning or hair fragility with visible broken hairs).
in the absence of other causes such as alopecia areata, drugs, iron deficiency, and 
androgenic alopecia
5. Synovitis involving 2 or more joints, characterized by swelling or effusion 
OR tenderness in 2 or more joints and at least 30 minutes of morning stiffness.
6. Serositis.

Typical pleurisy for more than 1 day.
–
OR pleural effusions.
–
OR pleural rub.

Typical pericardial pain (pain with recumbency improved by sitting forward) for more 
than 1 day.
–
OR pericardial effusion.
–
OR pericardial rub.
–
OR pericarditis by electrocardiography.
in the absence of other causes, such as infection, uremia, and Dressler’s pericarditis
7. Renal.

Urine protein–to-creatinine ratio (or 24-hour urine protein) representing 500 mg 
protein/24 hours.

OR red blood cell casts.
8. Neurologic.

Seizures.

Psychosis.

Mononeuritis multiplex.
in the absence of other known causes such as primary vasculitis

Myelitis.

Peripheral or cranial neuropathy.
in the absence of other known causes such as primary vasculitis, infection, and diabetes 
mellitus

Acute confusional state.
in the absence of other causes, including toxic/metabolic, uremia, drugs
9. Hemolytic anemia.


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10. Leukopenia (<4,000/mm3 at least once).
in the absence of other known causes such as Felty’s syndrome, drugs, and portal 
hypertension
OR
Lymphopenia (<1,000/mm3 at least once)
in the absence of other known causes such as corticosteroids, drugs, and infection
11. Thrombocytopenia (<100,000/mm3) at least once.
in the absence of other known causes such as drugs, portal hypertension, and thrombotic 
thrombocytopenic purpura
Immunologic criteria
1.
2. Anti-dsDNA antibody level above laboratory reference range (or >2-fold the reference range 
if tested by ELISA).
3. Anti-Sm: presence of antibody to Sm nuclear antigen.
4. Antiphospholipid antibody positivity as determined by any of the following:
!
Positive test result for lupus anticoagulant.
!
False-positive test result for rapid plasma reagin.
!
Medium- or high-titer anticardiolipin antibody level (IgA, IgG, or IgM).
!
Positive test result for anti–β2-glycoprotein I (IgA, IgG, or IgM).
5. Low complement.
!
Low C3.
!
Low C4.
!
Low CH50.
6. Direct Coombs’ test in the absence of hemolytic anemia.
Criteria are cumulative and need not to be present concurrently
Requirements to classify a patient as having SLE: ≥ 4 criteria (at least 1 clinical criterion and 1 
laboratory criterion) OR biopsy-proven nephritis compatible with SLE in the presence of ANA 
or anti- dsDNA antibodies.
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Appendix I
Pathology Classification of LN
International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 Classification 
of Lupus Nephritis:
Class I - Minimal mesangial lupus nephritis
Normal glomeruli by light microscopy, but mesangial immune deposits by immunofluorescence
Class II - Mesangial proliferative lupus nephritis
Purely mesangial hypercellularity of any degree or mesangial matrix expansion by light 
microscopy, with mesangial immune deposits
May be a few isolated subepithelial or subendothelial deposits visible by immunofluorescence or 
electron microscopy, but not by light microscopy
Class III - Focal lupus nephritis
Active or inactive focal, segmental or global endo- or extracapillary glomerulonephritis 
involving <50% of all glomeruli, typically with focal subendothelial immune deposits, with or 
without mesangial alterations
Class IV - Diffuse lupus nephritis
Active or inactive diffuse, segmental or global endo- or extracapillary glomerulonephritis 
involving ≥ 50% of all glomeruli, typically with diffuse subendothelial immune deposits, with or 
without mesangial alterations. This class is divided into diffuse segmental (IV-S) lupus nephritis 
when ≥50% of the involved glomeruli have segmental lesions, and diffuse global (IV-G) lupus 
nephritis when ≥ 50% of the involved glomeruli have global lesions. Segmental is defined as a 
glomerular lesion that involves less than half of the glomerular tuft. This class includes cases 
with diffuse wire loop deposits but with little or no glomerular proliferation

Class IV-S (A): Active lesions: diffuse segmental proliferative lupus nephritis.

Class IV-G (A): Active lesions: diffuse global proliferative lupus nephritis.

Class IV-S (A/C): Active and chronic lesions: diffuse segmental proliferative and sclerosing 
lupus nephritis.

Class IV-G (A/C): Active and chronic lesions: diffuse global proliferative and sclerosing 
lupus nephritis.

Class IV-S (C): Chronic inactive lesions with scars: diffuse segmental sclerosing lupus 
nephritis.

Class IV-G (C) Chronic inactive lesions with scars: diffuse global sclerosing lupus nephritis.
Class V: Membranous lupus nephritis 

Pure membranous glomerulonephritis.

Associated with lesions of class II.


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
Associated with lesions of class III.

Associated with lesions of class IV.
Class VI Advanced sclerosing glomerulonephritis
WORLD HEALTH ORGANIZATION (WHO) CLASSIFICATION OF LUPUS
NEPHRITIS (modified in 1982)
Class I Normal glomeruli
a. Nil (by all techniques)
b. Normal by light microscopy, but deposits by 
electron or immunofluorescence microscopy
Class II Pure mesangial alterations 
(mesangiopathy)
a. Mesangial widening and/or mild 
hypercellularity (+)
b. Moderate hypercellularity (++)
Class III Focal Segmental glomerulonephritis 
(associated with mild or moderate mesangial 
alterations)
a. With “active” necrotizing lesions
b. With “active” and sclerosing lesions
c. With sclerosing lesions
Class IV Diffuse glomerulonephritis (severe 
mesangial, endocapillary or mesangio-capillary 
proliferation and/or extensive subendothelial 
deposits
a. Without segmental lesions
b. With “active” necrotizing lesions
c. With “active” and sclerosing lesions
d. With sclerosing lesions
Class V Diffuse membranous 
glomerulonephritis
a. Pure membranous glomerulonephritis
b. Associated with lesions of class II
c. Associated with lesions of class III
d. Associated with lesions of class IV
Class VI
Advanced sclerosing glomerulonephritis


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Appendix J
Diagnostic Criteria for Psychoactive Substance Dependence
The following is taken from DSM-IV:
A maladaptive pattern of substance use, leading to clinically significant impairment or distress as 
manifested by 3 (or more) of the following, occurring at any time in the same 12-month period:
1. Tolerance, as defined by either of the following:

A need for markedly increased amounts of the substance to achieve intoxication or 
desired effect,

Markedly diminished effect with continued use of the same amount of the substance.
2. Withdrawal, as manifested by either of the following:

The characteristic withdrawal syndrome for the substance,

The same (or closely related) substance is taken to relieve or avoid withdrawal 
symptoms.
3. The substance is often taken in larger amounts or over a longer period than was intended.
4. There is a persistent desire or unsuccessful efforts to cut down or control substance use.
5. A great deal of time is spent in activities necessary to obtain the substance (eg, visiting 
multiple doctors or driving long distances), use the substance (eg, chainsmoking) or recover 
from its effects.
6. Important social, occupational or recreational activities are given up or reduced because of 
substance use.
7. The substance use is continued despite knowledge of having a persistent or recurring 
physical or psychological problem that is likely to have been caused or exacerbated by the 
substance (eg, current cocaine use despite recognition of cocaine-induce depression, or 
continued drinking despite recognition that an ulcer was made worse by alcohol 
consumption.

Criteria for Severity of Psychoactive Substance Dependence.

Mild: Few, if any, symptoms in excess of those required to make the diagnosis, and the 
symptoms result in no more than mild impairment in occupational functioning or in usual 
social activities or relationships with others.

Moderate: Symptoms or functional impairment between “mild” and “severe”.

Severe: Many symptoms in excess of those required to make the diagnosis, and the 
symptoms markedly interfere with occupational functioning or with usual social activities 
or relationships with others.

In Partial Remission: During the past six months, some use of the substance and some 
symptoms of dependence.


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
In Full Remission: During the past six months, either no use of the substance, or use of 
the substance and no symptoms of dependence.
Diagnostic Criteria for Psychoactive Substance Abuse
1. A maladaptive pattern of psychoactive substance use, leading to clinically significant 
impairment or distress as manifested by one (or more) of the following, occurring at any time 
in the same 12-month period:
a) Recurrent substance use resulting in a failure to fulfill major role obligations at work, 
school, or home (eg, repeated absences or poor work performance related to substance 
use; substance-related absences, suspensions, or expulsions from school, neglect of 
children or household).
b) Recurrent substance use in situations in which it is physically hazardous (eg, driving an 
automobile or operating a machine when impaired by substance use).
c) Recurrent substance-related legal problems (eg, arrests for substance-related disorderly 
conduct).
d) Continued substance use despite having persistent or recurrent social or interpersonal 
problems caused or exacerbated by the effects of the substance (eg, arguments with 
spouse about consequences of intoxication, physical fights).
2. The symptoms have never met the criteria for substance dependence for this class of 
substance.


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Appendix K
Detailed Description of Amendments to Text
This document describes changes in reference to Protocol Incorporating Amendment No. 11.
Change 1: Updated the drug metabolism and concomitant medication information to reflect 
recent population pharmacokinetic (PK) analyses and drug-drug interaction study results from an 
ixazomib study (Study C16009) demonstrating that cytochrome P-450 inhibitors do not affect 
ixazomib PK and clarified details about PK assessments.
The primary change occurs in Section 4.1.4.2 Drug Metabolism and PK
Initial 
wording:
Ixazomib citrate is hydrolyzed to the boronic acid form ixazomib which is mainly 
cleared via metabolism; clinical PK data indicate that renal clearance contributes 
little to the total elimination of ixazomib (≤10% is renally cleared following 
intravenous administration). Consistently, no relationship between creatinine 
clearance (CrCl) and renal clearance has been observed in the preliminary population 
PK analysis (N=137) over a wide range of renal function categories (CrCl range: 22-
236 mL/min). Therefore, it is expected that there will be no increases in ixazomib 
exposures when administered to subjects with mild to moderate renal impairment. In 
vitro studies show that ixazomib is metabolized by multiple cytochrome P450 (CYP) 
enzymes and non-CYP enzymes/proteins. Ixazomib is not an inhibitor of CYP1A2, 
2C9, 2C19, 2D6, or 3A4, nor is it a time-dependent inhibitor of CYP3A4/5. 
Prednisone and MMF treatment is allowed in this study. Prednisone is metabolized 
via CYP3A4 and is a known inducer of CYP 2C19, MMFs major metabolic pathway 
is mediated via glucuronosyltransferases therefore the likelihood of a drug 
interaction with ixazomib in both cases is considered to be low. Overall, the potential 
for ixazomib treatment to produce drug-drug interactions (DDIs) via CYP inhibition 
is inferred to be low. In study C16009 coadministration of ixazomib with 
ketoconazole caused an increase of ~ 2-fold in area under the plasma concentration-
time curve from 0 to 264 hours (range 1.9-2.3). In contrast, Cmax values were similar 
with and without ketoconazole, the mechanism of the interaction appears to be a 
decrease in the systemic clearance of ixazomib as opposed to an increase in oral 
bioavailability, therefore strong 3A4 inhibitors are excluded co-medications in this 
study (see Section 7.3).
Amended 
or new 
wording:
Ixazomib citrate is hydrolyzed to the boronic acid form ixazomib which is mainly 
cleared via metabolism; clinical PK data indicate that renal clearance contributes 
little to the total elimination of ixazomib (≤10% is renally cleared following 
intravenous administration). Consistently, no relationship between creatinine 
clearance (CrCl) and renalsystemic clearance has been observed in the preliminary 
population PK analysis (N=137) over a wide range of renal function categories (CrCl 
range: 22-236 mL/min). Therefore, it is expected that there will be no increases in 
ixazomib exposures when administered to subjects with mild to moderate renal 
impairment [21, 22].


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In vitro studies showindicate that ixazomib is metabolized by multiple cytochrome 
P450 (CYP) enzymesCYPs and non-CYP enzymes/proteins. Ixazomib is not an 
inhibitor of CYP1A2, 2C9, 2C19, 2D6, or 3A4, nor is itAt clinically relevant 
concentrations of ixazomib, in vitro studies using human complementary DNA-
expressed CYP isozymes showed that no specific CYP isozyme predominantly 
contributes to ixazomib clearance. At concentrations exceeding those observed 
clinically (10 μM), ixazomib was metabolized by multiple CYP isoforms with 
estimated relative contributions of 3A4 (42.3%), 1A2 (26.1%), 2B6 (16.0%), 
2C8 (6.0%), 2D6 (4.8%), 2C19 (4.8%) and 2C9 (<1%). In contrast, at 0.1 μM 
and 0.5 μM substrate concentrations, which are closer to clinical concentrations 
of ixazomib, non-CYP-mediated clearance was observed and seemed to play a 
major role in ixazomib clearance in vitro. These data indicate that at clinically 
relevant concentrations of ixazomib, minimal CYP-mediated drug-drug 
interactions (DDIs) with a selective CYP inhibitor would be expected. In 
addition, ixazomib is neither a reversible nor a time-dependent inhibitor of 
CYPCYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Prednisone and MMF 
treatment is allowed in this study. Prednisone is metabolized via CYP3A4 and is a 
known inducer of CYP 2C19, MMFs major metabolic pathway is mediated via 
glucuronosyltransferases; therefore, the likelihood of a drug interaction with 
ixazomib in both cases is considered to be low. Overall, the potential for ixazomib 
treatment to produce DDIs via CYP inhibition is inferred to be low. 
In study C16009 coadministration of ixazomib with ketoconazole caused an increase 
of ~ 2-fold in AUC(0-264) (range 1.9-2.3). In contrast, Cmax values were similar 
with and without ketoconazole, the mechanism of the interaction appears to be a 
decrease in the systemic clearance of ixazomib as opposed to an increase in oral 
bioavailability, therefore strong 3A4 inhibitors are excluded co-medications in this 
study (see Section 7.3).a phase 1 DDI study, the PK of ixazomib was similar with 
and without co-administration of clarithromycin, a strong CYP3A inhibitor 
(Study C16009, Arm 5); hence, no dose adjustment is necessary when ixazomib 
is administered with strong CYP3A inhibitors [21]. These findings are 
explained by the in vitro metabolism data indicating the lack of a discernible 
contribution of CYP-mediated metabolism at clinically relevant ixazomib 
concentrations. As discussed earlier, no CYP isoforms have been identified to 
contribute meaningfully to ixazomib metabolism at clinically relevant 
concentrations and CYP3A contribution to total metabolism was highest across 
all CYP isoforms when characterized at a supratherapeutic concentration of 
10 μM. Therefore, based on the totality of information from the clinical 
clarithromycin DDI study and the in vitro CYP phenotyping data, it can be 
concluded that ixazomib PK is not likely to be altered upon co-administration 
with any CYP isoform-selective inhibitor, including strong CYP1A2 inhibitors. 
Consistently in the population PK analysis, co-administration of strong 
CYP1A2 inhibitors did not affect ixazomib clearance [22]. Therefore, no dose 


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adjustment is required for patients receiving strong inhibitors of CYP1A2.
In a phase 1 DDI study, coadministration of ixazomib with rifampin decreased 
ixazomib Cmax by 54% and area under the plasma concentration-time curve by 
74% (Study C16009, Arm 4) [21]. Accordingly, concomitant administration of 
ixazomib with strong CYP3A inducers should be avoided (see Section 7.3). 
Please refer to the prescribing information for ixazomib for further details [23].
Rationale for Change:
To reflect updated information regarding drug metabolism and DDIs for ixazomib as per the 
United States Prescribing Information and EU SmPC.
The following sections also contain this change:
7.3 Excluded and Restricted Medications, Procedures and Dietary Products
16.0 REFERENCES
Change 2: Added optional Open-Label Treatment Extension Period to the Study Design to 
allow treatment with up to 3 additional cycles of ixazomib at the discretion of the investigator.
The primary change occurs in Section 6.1 Study Design
Initial 
wording:
This study is a phase 1b, randomized, double-blind, placebo-controlled, safety, 
tolerability, and PK study of MRD of ixazomib for the treatment of subjects with 
ISN / RPS Class III, IV, V or V changes [excluding Class III (C), IV-S (C) and IV-G 
(C)] or WHO 1982 classification of Class III, IV or V (excluding Class IIIc and 
IVd). It is anticipated that 4 ixazomib dose levels will be examined. 
At least 5 subjects (4:1) will be recruited into the 0.5 mg dose group (Cohort A), at 
least 5 subjects (4:1) in the 2.0 mg dose group (Cohort B), 8 subjects (6:2) in the 3.0 
mg dose group (Cohort C), and 8 subjects (6:2) in the 4.0 mg dose group (Cohort D). 
Subjects will be considered eligible on the basis of study inclusion and exclusion 
criteria, verified by an independent adjudication committee, and randomized. 
Following each of the 0.5, 2.0, and 3.0 mg dose cohorts, available PK and safety data 
will be evaluated prior to escalation. For each dose level cohort, the SRC will 
carefully review the available blinded safety, tolerability, and PK data to determine if 
dosing should be escalated in the next cohort, lowered or expanded within the same 
dose cohort to obtain additional information prior to a dose-escalation decision, or 
stopped. After 5 subjects are recruited in the 4.0 mg dose group (Cohort D) and 
complete at least 1 cycle of ixazomib or placebo, an analysis will be conducted on 
available PK data and blinded safety data from all cohorts. Subject numbers may be 
increased as appropriate per cohort for a total number not exceeding 40 subjects in 
all cohorts combined. Two subjects with Class V or Class II with Class V lupus 
nephritis are permitted per cohort. Subjects will be treated with three 28-day cycles 
of ixazomib or placebo.


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Each 28 day cycle will consist of 3 once-weekly oral doses of 0.5, 2.0, 3.0, or 4.0 mg 
of ixazomib (dosage strength is stated as the active boronic acid ixazomib) or 
placebo, depending on the cohort. Subjects who received a dose <2.0 mg and 
completed all cycles including the Follow-up Period, will be permitted to re-enroll 
into the 2.0 and 3.0 mg dose groups, provided they have no drug-related adverse 
events >Grade 1, no adverse events >Grade 2, continue to meet all inclusion and 
exclusion criteria, and the SRC (consisting of sponsor personnel and the 
coordinating investigator) have reviewed and approved enrollment. Subjects must be 
receiving standard of care treatment for LN and remain on their current stable and 
allowed therapies during the screening period and throughout the duration of the
study (Section 8.1.1.2).
Subjects can be randomized on Day 1, 24 days after first screening visit (between 
day -24 and -35) and once safety laboratory tests and inclusion/exclusion criteria 
have been reviewed and confirmed by the investigator. If the elapsed time between 
the Screening Visit and Randomization (Day 1) is greater than the allowed screening 
period, then the eligibility criteria must be re-confirmed in a second screening visit 
prior to randomization. Disease activity parameters (eg, UPCR, anti-dsDNA, urine 
sediment and/or complement levels) and safety laboratory tests (hematology and 
chemistry panel) must be repeated to re-confirm eligibility.
The study consists of the following Periods: a Screening Period (up to 35 days), a 
Treatment Period (Day 1 to Day 84) and a Follow-up Period (Day 85 to Day 168). 
Subjects can be randomized 24 (+11) days after Screening (between Days -24 and -
35) and once safety laboratory tests and inclusion/exclusion criteria have been 
reviewed and confirmed by the investigator. Diagnostic criteria, disease activity 
measures, and treatment history will be documented, and required laboratory 
investigations initiated. Subject eligibility will be reviewed by an adjudication 
committee. The responsibilities and criteria of this committee will be defined in an 
adjudication charter.
Following verification of eligibility, subjects will return to the clinic on Day 1, 
undergo baseline assessments, laboratory testing, and will be randomized to either 
ixazomib or placebo within each cohort/dose level. The Treatment Period consists of 
three 28-day treatment cycles (Cycles 1, 2, and 3) without intra-subject dose 
escalation. Subjects will receive ixazomib consisting of drug administration on Days 
1, 8, and 15 of each 28-day cycle. The second and third cycle will commence on the 
first day following Day 28 of the preceding cycle (ie, with a period of 13 days 
between the third drug administration of a cycle and the first drug administration of 
the following cycle). The treatment period will be limited to 3 complete cycles with 
ixazomib, with an expected duration of 12 weeks. However, the total treatment 
period may be longer than the standard 12 weeks if delays between cycles are 
necessary due to adverse events. After completion of Cycle 3, the subject will enter 
the Follow-up Period. A Follow-up Period of up to 3 months, consisting of monthly 
follow-up visits, will start after the end of the Treatment Period (Day 84) to assess 


Ixazomib 
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any safety issues.
Subjects will receive ixazomib cycles consisting of doses of 0.5 mg (Cohort A), 2 
mg (Cohort B), 3 mg (Cohort C), and 4 mg (Cohort D) or placebo. The ascending 
dose cohorts will be enrolled sequentially. Dosing of subsequent cohorts will not 
commence until at least 5 subjects in Cohorts A and B and 8 subjects in Cohort C 
have received at least 1 dose of investigational drug and have reached Day 28 of 
Cycle 1 or have completed their last evaluation within Cycle 1 with a satisfactory 
review of all available safety and tolerability data. Subjects discontinued or 
withdrawn after randomization for nonsafety reasons will only be replaced if the 
number of subjects per cohort evaluable for safety on Day 28 of Cycle 1 is reduced 
below 6 subjects for Cohorts C and D, below 5 subjects for lower than 3.0 mg dose 
cohorts, or the SRC recommends expanding with the same dose to obtain additional 
information prior to a dose-escalation decision. Down-titration of ixazomib is 
permitted for individual subjects for safety and tolerability reasons at any time 
during the Treatment Period, except for subjects receiving 0.5 mg in Cohort A. If 
necessary for safety or tolerability reasons or in the judgment of the investigator, 
ixazomib treatment should be stopped altogether, and an End of Study Visit should 
be completed. The subject should then complete the remainder of the study period as 
the Follow-up Period. Dose modification and dose deferral should be discussed with 
the Sponsor’s Medical Monitor; guidelines for the modification or deferral of doses 
will be provided.
During the Double-Blind Treatment Period ixazomib will always be dosed at the 
study site and subjects will return to the clinic for each administration of ixazomib. 
For scheduling flexibility, study visits can occur ± 2 days from each scheduled day 
during the Treatment Period and ±1 week during the Follow-Up Period. A minimum 
of 120 hours should occur between ixazomib doses. Any variances in the dosing 
schedule should not alter the schedule of subsequent dosing.
Subjects will undergo safety laboratory assessments, total IgG/IgM/IgA, LN 
assessments including but not limited to UPCR, eGFR anti-dsDNA antibodies, and 
complement C3 and C4 levels via a central laboratory according to the Schedule in 
Appendix A. Pharmacogenomic (PGx) and exploratory biomarker samples will also 
be sent to a central lab for analysis. 
Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor with an 
estimated terminal elimination half-life of ~ 4 to 9 days in plasma. For Cohorts A to 
D, plasma concentrations of ixazomib over time will be evaluated following the first 
dose of Cycle 1 and the last dose of Cycle 3. Predose samples will be collected 
before each dose in Cycles 1, 2, and 3. Available PK data will be reviewed as part of 
the overall safety and tolerability evaluation of ixazomib in LN and for the dose 
escalation decision. 
Recent evidence suggests that genetic variation accounts for differing responses to 
bortezomib therapy. A single nucleotide polymorphism (SNP) at position 11 in the 


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PSMB1 gene (in the region encoding the leader sequence for the beta subunit of the 
20S proteasome) has been associated with reduced proteasome activity and is 
associated with enhanced bortezomib activity in multiple myeloma and relapsed 
follicular lymphoma. 
 
 
 
 
 
In addition, hematology and chemistry safety lab assessments will be collected prior 
to each dose of ixazomib; the results of all available laboratory tests will be reviewed 
by the Investigator prior to administration of the scheduled dose of ixazomib. A 
negative urine pregnancy testing is required prior to administration of investigational 
drug.
In common with other immunosuppressant and cytotoxic agents, ixazomib may have 
additional effects on host defense. The subject’s immunization status should be 
reviewed at the Screening Visit, and all appropriate vaccinations should be 
completed at least 1 month prior to Treatment. These may include but are not limited 
to pneumococcal and inactivated influenza vaccines. 
If lymphopenia is noted after treatment with ixazomib, subjects may be at an 
increased risk of infection. In particular, lymphopenia can be associated with 
reactivation of herpes zoster, herpes simplex viruses and cytomegalovirus. Antiviral 
therapy such as acyclovir or valacyclovir may be initiated at the onset of infection. 
Other antivirals are also acceptable. Provision of medication will be arranged by the 
Investigator from local suppliers and will be reimbursed by the Sponsor. 
In oncology studies with ixazomib GI issues, rash and peripheral neuropathy 
occurred in some subjects. GI effects included diarrhea, nausea and vomiting and to 
minimize the risk of GI toxicities, subjects with LN should skip dosing with their 
immunosuppressant drug (eg, MMF) on days of dosing with ixazomib. Peripheral 
neuropathy will be monitored using the FACT/GOG-NTX neuropathy assessment 
before the start of each cycle. See Section 10.1.5 for management of AEs of special 
interest.
Although renal adverse events have been rare in studies with oncology subjects, 
dehydration due to GI toxicity, concomitant medications and disease progression 
could contribute to renal dysfunction. Chemistry laboratory parameters including 
serum creatinine (sCr) will be monitored weekly and treatment discontinued if a 
decrease >25% in estimated glomerular filtration rate (eGFR) or doubling in sCr 
from baseline is observed (see Section 7.4.3).
Each Investigator will review any safety findings and laboratory results to determine 
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if a subject should receive the next dose within each cycle. The investigator will 
evaluate safety and tolerability for each subject on Day -1 and prior to each dose 
during every cycle, as shown in study schematic (Figure 6.a) below. On Day 22 of 
each cycle, the investigator-led team will evaluate all available safety information for 
the subject.
Amended 
or new 
wording:
This study is a phase 1b, randomized, double-blind, placebo-controlled, safety, 
tolerability, and PK study of MRD of ixazomib for the treatment of subjects with 
ISN/RPS Class III, IV, V or V changes [excluding Class III (C), IV-S (C), and IV-G 
(C)] or WHO 1982 classification of Class III, IV, or V (excluding Class IIIc and 
IVd) LN. It is anticipated that 4 ixazomib dose levels will be examined. At least 5 
subjects (4:1) will be recruited into the 0.5 mg dose group (Cohort A), at least 5 
subjects (4:1) in the 2.0 mg dose group (Cohort B), 8 subjects (6:2) in the 3.0 mg 
dose group (Cohort C), and 8 subjects (6:2) in the 4.0 mg dose group (Cohort D). 
Subjects will be considered eligible on the basis of study inclusion and exclusion 
criteria, verified by an independent adjudication committee, and randomized. 
Following each of the 0.5, 2.0, and 3.0 mg dose cohorts, available PK and safety data 
will be evaluated before escalation. For each dose level cohort, the SRC will 
carefully review the available blinded safety, tolerability, and PK data to determine if 
dosing should be escalated in the next cohort, lowered, or expanded within the same 
dose cohort to obtain additional information before a dose-escalation decision, or 
stopped. After 5 subjects are recruited in the 4.0 mg dose group (Cohort D) and 
complete at least 1 cycle of ixazomib or placebo, an analysis willmay be conducted 
on available PK data and blinded safety/tolerability data from all cohorts. Subject 
numbers may be increased as appropriate per cohort forto a total number not 
exceedingto exceed 40 subjects in all cohorts combined. Two subjects with Class V 
or Class IIV with Class V lupusII nephritis are permitted per cohort. Subjects will be 
treated with three 28-day cycles of ixazomib or placebo. Subjects who successfully 
completed 12 weeks of double-blind treatment without any AE resulting in dose 
modification or discontinuation of the study drug (defined in Section 7.4.3) will 
be eligible to receive up to 3 additional cycles of open-label ixazomib at the 
discretion of the investigator and confirmed by the sponsor clinician/designee 
following the end of the Double-Blind Treatment Period. The subjects need to 
begin the Open-Label Treatment Extension Period within 4 weeks of 
completing Cycle 3 of double-blind treatment.
Each 28-day cycle will consist of 3 once-weekly oral doses of 0.5, 2.0, 3.0, or 4.0 mg 
of ixazomib (dosage strength is stated as the active boronic acid ixazomib) or 
placebo, depending on the cohort. Subjects who received a dose <≤2.0 mg and 
completed all cycles including the Follow-up Period, will be permitted to re-enroll 
into the 2.0 and 3.0 mg dose groups, provided they have no drug-related AEs >Grade 
1, that required the study drug dose modification, no AEs >Grade 2, continue to 
meet all inclusion and exclusion criteria, and the SRC (consisting of sponsor 
personnel and the coordinating investigator) have reviewed and approved 


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enrollment. Subjects must be receiving standard of care treatment for LN and remain 
on their current stable and allowed therapies during the screening periodScreening 
Period and throughout the duration of the study (Section 8.1.1.2).
Subjects can be randomized on Day 1, 24 days after first screening visit (between 
day -24 and -35) and once safety laboratory tests and inclusion/exclusion criteria 
have been reviewed and confirmed by the investigator. If the elapsed time between 
the Screening Visit and Randomization (Day 1) is greater than the allowed screening 
period, then the eligibility criteria must be re-confirmed in a second screening visit 
prior to randomization. Disease activity parameters (eg, UPCR, anti-dsDNA, urine 
sediment and/or complement levels) and safety laboratory tests (hematology and 
chemistry panel) must be repeated to re-confirm eligibility.
The study consists of the following Periods: a Screening Period (up to 35 days), a 
Double-Blind Treatment Period (Day 1 to Day 84) and either a Follow-up Period 
(Day 85 to Day 168)or an Open-Label Treatment Extension Period (Day 85 to 
Day 168). For those subjects who enter the Open-Label Treatment Extension 
Period, visits will be monthly (either for dosing or follow-up) until Day 168, 
with the last study visit being 30 days after the last open-label dosing or Day 168 
whichever is longer. Subjects can be randomized 24 (+11) days after Screening 
(between Days -24 and -35) and once safety laboratory tests and inclusion/exclusion 
criteria have been reviewed and confirmed by the investigator. Diagnostic criteria, 
disease activity measures, and treatment history will be documented, and required 
laboratory investigations initiated. Subject eligibility will be reviewed by an 
adjudication committee. The responsibilities and criteria of this committee will be 
defined in an adjudication charter. 
Following verification of eligibility, subjects will return to the clinic on Day 1, 
undergo baseline assessments, laboratory testing, and will be randomized to either 
ixazomib or placebo within each cohort/dose level. The Double-Blind Treatment 
Period consistswill consist of three 28-day treatment cycles (Cycles 1, 2, and 3) 
without intra-subject dose escalation. Subjects will receive ixazomib consisting of 
drug administrationtreatment on Days 1, 8, and 15 of each 28-day cycle. The 
second and third cyclecycles will commence on the first day following Day 28 of the 
preceding cycle (ie, with a period of 13 days between the third drug administration 
of a cycle and the first drug administration of the following cycle). The treatment 
period will be limited to 3 complete cycles with ixazomib, with an expected duration 
of 12 weeks.Double-Blind Treatment Period will be limited to 3 complete cycles 
with ixazomib or placebo, over an expected duration of 12 weeks. However, the 
total treatment period may be longer than the standard 12 weeks if delays between 
cycles are necessary due to AEs. After completion of Cycle 3, the subject will enter 
the Follow-up Period. A Follow-up Period of up to 3 months, consisting of monthly 
follow-up visits,3 of the Double-Blind Treatment Period, the subject will either 
enter the Follow-up Period or enter an optional Open-Label Treatment 
Extension Period at the investigator’s discretion and confirmed by the Takeda 


Ixazomib 
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physician/designee. The Follow-up Period or the Open-Label Treatment 
Extension Period consisting of follow-up visits every 4 weeks will start after the 
end of the Double-Blind Treatment Period (Day 84) to assess any safety issues.. The 
Open-Label Treatment Extension Period will be limited to up to 3 cycles of 
treatment with ixazomib on the same dose and schedule that they were 
receiving in the double blind period over an expected duration of 12 weeks.
Subjects will receive ixazomib cycles consisting of doses of 0.5 mg (Cohort A), 2 
mg (Cohort B), 3 mg (Cohort C), andor 4 mg (Cohort D), or placebo. The ascending 
dose cohorts will be enrolled sequentially. Dosing of subsequent cohorts will not 
commence until at least 5 subjects in Cohorts A and B and 8 subjects in Cohort C 
have received at least 1 dose of investigational drug and have reached Day 28 of 
Cycle 1 or have completed their last evaluation within Cycle 1 with a satisfactory 
review of all available safety and tolerability data. Subjects discontinued or 
withdrawn after randomization for nonsafety reasons will only be replaced if the 
number of subjects per cohort evaluable for safety on Day 28 of Cycle 1 is reduced 
below 6 subjects for Cohorts C and D, below 5 subjects for lower than 3.0 mg dose 
cohorts, or the SRC recommends expanding with the same dose to obtain additional 
information before a dose-escalation decision. Down-titration of ixazomib is 
permitted for individual subjects for safety and tolerability reasons at any time 
during the Treatment Period, except for subjects receiving 0.5 mg in Cohort A. If 
necessary for safety or tolerability reasons or in the judgment of the investigator, 
ixazomib treatment should be stopped altogether, and an End of Study Visit should 
be completed. The subject should then complete the remainder of the study period as 
the Follow-up Period. Dose modification and dose deferral should be discussed with 
the Sponsor’s Medical Monitor; guidelines for the modification or deferral of doses 
will be provided.
IxazomibDuring the Double-Blind Treatment Period, ixazomib will always be 
dosed at the study site and subjects will return to the clinic for each administration of 
ixazomib. During the Open-Label Treatment Extension Period, subjects will 
receive the first dose of each cycle at the clinic and the other 2 weekly doses can 
be given to the subjects to take at home. All subjects will return to the clinic 
every 4 weeks to receive the first dose of each cycle. For scheduling flexibility, 
study visits can occurtake place ± 2 days from each scheduled day during the 
Treatment Period and ±1 week during the Follow-Upup Period. A minimum of 120 
hours should occur between ixazomib doses. Any variancesvariance in the dosing 
schedule should not alter the schedule of subsequent dosing. 
Subjects will undergo safety laboratory assessments, total immunoglobulin G, M, 
and A (IgG/IgM/IgA), LN assessments including but not limited to UPCR, eGFR 
anti-dsDNA antibodies, and complement C3 and C4 levels via a central laboratory 
according to the Scheduleschedule in Appendix A. Pharmacogenomic (PGx) and 
exploratory biomarker samples will also be sent to a central laboratory for analysis. 


Ixazomib 
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Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor with an 
estimated t1/2 of ~ 4 to 9 days in plasma. For Cohorts A to D, plasma concentrations 
of ixazomib over time will be evaluated following the first dose of Cycle 1 and 
following the last dose of Cycle 3.3 of the Double-Blind Treatment Period.
Predose samples will be collected before each dose in Cycles 1, 2, and 3.3 of the 
Double-Blind Treatment Period. Available PK data will be reviewed as part of the 
overall safety and tolerability evaluation of ixazomib in LN and for the dose 
escalation decision. 
Recent evidence suggests that genetic variation accounts for differing responses to 
bortezomib therapy. A single nucleotide polymorphism (SNP) at position 11 in the 
PSMB1 gene (in the region encoding the leader sequence for the beta subunit of the 
20S proteasome) has been associated with reduced proteasome activity and is 
associated with enhanced bortezomib activity in multiple myeloma and relapsed 
follicular lymphoma. 
 
 
 
 
 
In addition, hematology and chemistry safety laboratory assessments will be 
collected before each dose of ixazomib during the Double-Blind Treatment 
Period and before each cycle of open-label treatment; the results of all available 
laboratory tests will be reviewed by the Investigatorinvestigator before the
administration of the scheduled dose of ixazomib. If the central laboratory results 
are not available for the Open-Label Treatment Extension Period an additional 
safety laboratory assessment can be conducted at the local laboratory before
dosing and they will be recorded in the electronic case report forms (eCRFs). A 
negative urine pregnancy testingtest result is required before each administration of 
investigational drug at the visits specified in the schedule of events table.
In common with other immunosuppressant and cytotoxic agents, ixazomib may have 
additional effects on host defense. The subject’s immunization status should be 
reviewed at the Screening Visit, and all appropriate vaccinations should be 
completed at least 1 month before Treatmenttreatment. These may include but are 
not limited to pneumococcal and inactivated influenza vaccines. 
If lymphopenia is noted after treatment with ixazomib, subjects may be at an 
increased risk of infection. In particular, lymphopenia can be associated with 
reactivation of herpes zoster, and herpes simplex viruses, and cytomegalovirus. 
Antiviral therapy such as acyclovir or valacyclovir may be initiated at the onset of 
infection after administration of ixazomib. Other antivirals are also acceptable. 
Provision of medication will be arranged by the Investigatorinvestigator from local 
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suppliers and will be reimbursed by the Sponsor. 
In oncology studies with ixazomib GI issues, rash and peripheral neuropathy 
occurred in some subjects. GI effects included diarrhea, nausea and vomiting and to 
minimize the risk of GI toxicities, subjects with LN should skip dosing with their 
immunosuppressant drug (eg, MMF) on days of dosing with ixazomib. Peripheral 
neuropathy will be monitored using the FACT/GOG-NTX neuropathy assessment 
before the start of each cycle. See Section 10.1.5 for management of AEs of special 
interest.
Although renal adverse events have been rare in studies with oncology subjects, 
dehydration due to GI toxicity, concomitant medications and disease progression 
could contribute to renal dysfunction. Chemistry laboratory parameters including 
serum creatinine (sCr) will be monitored weekly and treatment discontinued if a 
decrease >25% in estimated glomerular filtration rate () or doubling in sCr from 
baseline is observed (see Section 7.4.3).
Each Investigatorinvestigator will review any safety findings and laboratory results 
to determine if a subject should receive the next dose within each cycle. The 
investigator will evaluate safety and tolerability for each subject on Day -1 and 
before each dose during every cycle, as shown in study schematic (Figure 6.a) 
below. On Day 22 of each cycle during the Double-Blind Treatment Period, the 
investigator-led team will evaluate all available safety information for the subject to 
determine eligibility to initiate the subsequent cycle.
Rationale for Change:
At the time of IND submission of this trial the duration of treatment was limited to 3 months by 
the limited safety data from clinical trial studies (ixazomib was not approved for multiple 
myeloma) and by the lack of nonclinical toxicology studies. Currently ixazomib, under the trade 
name Ninlaro, has been approved in more than 40 countries including the EU and US. Over 3000 
patients have been exposed to at least 1 dose of either the IV or oral ixazomib formulations 
across the clinical development program. Some of these patients have received ixazomib for 
3 years or more. The emerging safety profile indicates that ixazomib administration can lead to 
AEs that are generally manageable and reversible with dose reduction and supportive care. In 
addition the final report for the 6 month (rat) and 9 month (dog) toxicity study reports were 
submitted to IND 104,482 (SN 0770) on April 1, 2015. In addition the current data from 
ixazomib cohort 0.5 mg and 2 mg LN dose cohorts demonstrating tolerability of ixazomib in 
combination with background immunosuppressive, and a PK profile that is similar to what has 
been observed in oncology patients. Therefore, there are sufficient data to allow an optional open 
label period with up to 3 cycles of ixazomib at the same dose cohort. The investigator will decide 
whether their patients may benefit from additional cycles of ixazomib and the sponsor physician 
must confirm eligibility for each patient to enter open label treatment after reviewing safety data 
for that patient. The study principal investigators have requested that additional cycles of 
ixazomib be available as open label treatment for their patients who may benefit as 3 cycles of 


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ixazomib treatment may not be sufficient for an optimal effect in patients with active LN. The 
ACR and European guideline also recommend induction therapy for at least 6 months before 
assessing response and switching treatment. The study is designed to recruit LN patients who 
have significantly active nephritis and have had inadequate response to current standard of care 
therapy. The sponsor believes up to 3 cycles open label therapy allows up to 6 months treatment 
for patients who have been on active drug in the double blind period to assess safety and efficacy 
of ixazomib for LN induction therapy and will also give an opportunity to patients receiving 
placebo to have access to active drug treatment. In addition, a physician who is independent 
from the LN study team will periodically review unblinded clinical data to further safeguard the 
study participants including those patients who enter to the Open-Label Extension Period.
The following sections also contain this change:
Sections 2.0 STUDY SUMMARY. 
7.4.3 DLTs, Dose Modifications, and Stopping Rules
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling. 
8.1.2 Storage. 
8.1.3 Dose and Regimen. 
9.3.4 Open-Label Treatment Extension
13.2 Interim Analysis and Criteria for Early Termination
Appendix A
Schedule of Study Procedures: Double-Blind Treatment Period
Change 3: Updated the safety summary conclusion with latest safety data from the Investigator's 
Brochure.
The primary change occurs in 6.2 Justification for Study Design, Dose and Endpoints
Initial 
wording:
In conclusion, the safety of ixazomib is supported by clinical experience gained from 
the ongoing oncology program. As of 27 March 2015, 901 oncology subjects have 
been treated in unblinded clinical studies with ixazomib as a single agent or in 
combination with lenalidomide, dexamethasone, melphalan, and/or prednisone, with 
a median exposure of 4 cycles (range 0 to 76) in patients receiving oral treatment. 
Additionally, approximately 13% of patients have received more than 12 cycles of 
oral dosing. Currently, the results from completed, repeat-dose, toxicity studies in 
rats and dogs of up to seven or ten 28-day cycles with once-weekly dosing support 
clinical dosing for a total of 10 months in non-oncology indications.
e) Differences in the PK of ixazomib between oncology and LN subjects are 
expected to be minimal. In terms of demographic parameters the main 
differences between the 2 populations are age and renal function, which are 
anticipated to have only a minimal impact on systemic exposure. Participants in 
this study will be closely monitored, with once-a-week clinic visits during the 


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Treatment Period and additional clinical assessment / interventions as needed. 
Overall the risk to LN subjects is expected to be minimal.
Amended 
or new 
wording:
In conclusion, the safety of ixazomib is supported by clinical experience gained from 
the ongoing oncology program. As of 27 March 2015, 901 oncology subjects have 
been treated in unblinded clinical studies with ixazomib as a single agent or in 
combination with lenalidomide, dexamethasone, melphalan, and/or prednisone, with 
a median exposure of 4 cycles (range 0 to 76) in patients receiving oral treatment. 
Additionally, approximately 13% of patients have received more than 12 cycles of 
oral dosing. Currently, the results from completed, repeat-dose, toxicity studies in 
rats and dogs of up to seven or ten 28-day cycles with once-weekly dosing support 
clinical dosing for a total of 10 months in non-oncology indications2017, data are 
available from 941 patients known to have received at least 1 dose of either the 
IV or oral ixazomib formulations across the oncology clinical development 
program; in addition, 2682 patients have been enrolled in phase 3 clinical 
studies in RRMM, newly diagnosed MM and RRAL. The emerging safety 
profile indicates that ixazomib administration can lead to AEs that are 
generally manageable and reversible with dose reduction and supportive care. 
Additionally, the AEs in the combination studies are consistent with the safety 
profile of the individual agents in the combination regimen (eg, 
myelosuppression is common in regimens containing melphalan, and rash is 
common in regimens containing lenalidomide). While some of these potential 
toxicities may be severe, they can be managed by clinical monitoring and 
standard medical intervention.
f)
Differences in the PK of ixazomib between oncology and LN subjects are 
expected to be minimal. In terms of demographic parameters the main 
differences between the 2 populations are age and renal function, which are 
anticipated to have only a minimal impact on systemic exposure. Participants in 
this study will be closely monitored, with once-a-week clinic visits during the 
Double-Blind Treatment Period, at least monthly visits at the Open-Label 
Treatment Extension Period and additional clinical assessment / interventions 
as needed. Overall the risk to LN subjects is expected to be minimal.
Rationale for Change:
To update safety data from the latest IB.


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Change 4: Revised Inclusion Criterion 5 to allow subjects who have proteinuria ≥1 g/day due to 
a recent lupus nephritis (LN) flare, and who are refractory to current standard of care 
for those subjects who do not have a kidney biopsy within 2 years of the Screening.
The primary change occurs in 7.1 Inclusion Criteria
Initial 
wording:
5) The subject has a definite diagnosis of LN based on a kidney biopsy done within 
2 years of the Screening Visit which demonstrated ISN/RPS class III, IV or V 
changes [excluding Class III (C), IV-S (C) and IV-G (C)] or WHO 1982 
classification Class III, IV or V (excluding Class IIIc and IVd) (see Appendix I).
a) If no biopsy was done within 2 years of Screening Visit, biopsy can be done 
during the screening period as a study procedure.
b) Co-existence of classes is permitted.
Amended 
or new 
wording:
5. The subject has a definite diagnosis of LN based on a kidney biopsy done within 
2 years of the Screening Visit which demonstrated ISN/RPS classClass III, IV or 
V changes [excluding Class III (C), IV-S (C) and IV-G (C)] or WHO 1982 
classification Class III, IV or V (excluding Class IIIc and IVd)(see Appendix I).
a) If no biopsy was done within 2 years of Screening Visit, biopsy can be done 
during the screening period as a study procedure.
b) Co-existence of classes is permitted.
c) Subjects with a confirmed diagnosis of LN who have not had a renal 
biopsy within 2 years of screening and cannot have a renal biopsy during 
the screening, may be eligible for the study if they have proteinuria of 
≥1 g/24 hours due to a LN renal flare occurring within 1 year of the 
screening. A LN renal flare is defined as at least a doubling of 
proteinuria with no other explanation such as a secondary pathology (eg, 
diabetic nephropathy) or change in medication (eg, reduction of 
angiotensin-converting enzyme/angiotensin II receptor blocker).
Rationale for Change:
In current clinical practice a significant number of LN patients are treated with standard of care 
therapy (high dose corticosteroids and immunosuppressives) without performing a renal biopsy. 
The ACR or the European League Against Rheumatism guidelines provide recommendations to 
change in immunosuppressive therapy if a patient does not adequately respond to 6 months of 
induction therapy [1]. However the guidelines do not provide recommendations when to repeat 
or perform an initial biopsy or change therapy based on failure of current treatment. Recruiting 
patients who have a significant proteinuria (≥1 g/24 hour) due to LN flare within 1 year of study 
entry and refractory to the current standard of care, will not change the primary objectives of this 
study, which are safety, tolerability, PK characterization, and evaluation of a signal of efficacy 
by assessing a change in proteinuria (UPCR) and SLE autoantibody (eg, anti-dsDNA and serum 
complements). The exclusion of patients with an eGFR of <30 mL/min/1.73 m2 will decrease the 


Ixazomib 
Study No. MLN9708_101
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30 November 2017
CONFIDENTIAL
likelihood that the proteinuria is primarily due to chronic GN. In addition, it is unlikely that Class 
I or II patients will qualify based on this criterion as the patients in this trial are required to be 
receiving maintenance therapy with either mycophenolate or azathioprine, which are effective 
treatments for these classes of LN. Therefore, LN patients who had a recent renal flare and are 
refractory to the current SOC can be recruited without requiring a renal biopsy within 2 years of 
the screening, which will not affect the objectives of the study and may allow a larger proportion 
of patients with GN to potentially benefit from ixazomib.
Change 5: Revised Inclusion Criterion 6 to allow subjects with Class V or Class V with Class II 
nephritis and urine protein creatinine ratio levels of ≥1 into the study rather than current criteria 
of >3.
The primary change occurs in 7.1 Inclusion Criteria
Initial 
wording:
6. The subject has a renal biopsy demonstrating either ISN/RPS or WHO class V or 
class V with class 2 nephritis with a UPCR of >3 or the subject has a renal 
biopsy demonstrating either active ISN/RPS or WHO class III or IV nephritis, 
defined by either one of the following criteria:
a) A UPCR* of ≥1.0 at Screening
OR
i.
A UPCR* >0.5 at Screening and at least one of the following:
i.
Active urine sediment in the absence of infection or other cause within 3 
months of screening, defined as at least one of the following:

≥5 red blood cells (RBC) per high power field, not due to causes 
other than lupus nephritis.

≥5 white blood cells (WBC) per high power field in the absence of 
infection.

Presence of cellular casts. 
ii.
The subject has increased levels (above upper limit of normal [ULN] serum 
dsDNA autoantibodies at screening. 
iii.
Low complement (either C3 or C4) at Screening (≥ 25% lower than LLN).
iv.
Biopsy within 3 months prior to screening visit indicating active proliferative 
lupus glomerulonephritis ISN/RPS class III or IV changes [excluding Class 
III (C), IV-S (C) and IV-G (C)] or WHO 1982 classification Class III or IV 
(excluding Class IIIc and IVd), with co-existing Class V permitted.
*Subjects may be re-screened once for urinary sediment, proteinuria or 
complement levels within 2 weeks of the original screening visit.
* UPCR value for eligibility will be based on the average UPCR obtained 


Ixazomib 
Study No. MLN9708_101
Page 160 of 163
Protocol Incorporating Amendment No. 11
30 November 2017
CONFIDENTIAL
from the 3 specimens collected during screening.
Amended 
or new 
wording:
The subject has a renal biopsy demonstrating either ISN/RPS or WHO classClass V 
or classClass V with classClass 2 nephritis with a UPCR of >3≥1 or the subject has 
a renal biopsy demonstrating either active ISN/RPS or WHO classClass III or IV 
nephritis, defined by either one of the following criteria:
a) A UPCR* of ≥1.0 at Screening
OR
b) A UPCR* >0.5 at Screening and at least one of the following:
i.
Active urine sediment in the absence of infection or other cause within 
3 months of screening, defined as at least one of the following:

≥5 red blood cells (RBC) per high power field, not due to causes 
other than LN.

≥5 white blood cells (WBC) per high power field in the absence of 
infection.

Presence of cellular casts. 
ii.
The subject has increased levels (above upper limit of normal [ULN] 
serum dsDNA autoantibodies at screening. 
iii.
Low complement (either C3 or C4) at Screening (≥25% lower than the 
lower limit of normal [LLN]).
iv.
Biopsy within 3 months before screening visit indicating active 
proliferative lupus glomerulonephritis ISN/RPS class III or IV changes 
[excluding Class III (C), IV-S (C) and IV-G (C)] or WHO 1982 
classification Class III or IV (excluding Class IIIc and IVd), with co-
existing Class V permitted.
*Subjects may be re-screened once for urinary sediment, proteinuria or 
complement levels within 2 weeks of the original screening visit.
g) * UPCR value for eligibility will be based on the average UPCR 
obtained from the 3 specimens collected during screening.
Rationale for Change:
In this amendment, the sponsor has modified the inclusion criteria to allow inclusion of LN 
subjects with class V LN if they have UPCR ≥1. The primary objective of this trial is to 
characterize the safety and tolerability of ixazomib in the LN population and to evaluate if there 
is an efficacy signal. Proteinuria of 1 g/24 hr or greater is considered as indicative of clinically 
active disease and suitable for enrolment into a 12 week study as this group of patients has been 
refractory to standard of care therapy with immunosuppressive drugs and/or corticosteroids. 
Reducing proteinuria to less than 500 mg/day in patients with proteinuria of one or greater, may 


Ixazomib 
Study No. MLN9708_101
Page 161 of 163
Protocol Incorporating Amendment No. 11
30 November 2017
CONFIDENTIAL
have a long term beneficial effect on the disease prognosis. The sponsor proposes that reducing 
threshold of proteinuria in Class V LN from UPCR >3 to UPCR of ≥1 will not affect 
significantly the study primary objectives, which are safety, tolerability, PK characterization, and 
evaluation of a signal of efficacy and may allow a larger proportion of patients with LN who 
may benefit from ixazomib to enter into the trial.
Change 6: Revised Inclusion Criterion 11 to allow subjects who received ≤2.0 mg ixazomib in 
earlier cohorts, rather than <2 mg ixazomib, to be re-enrolled into Cohorts B and C (2.0 mg and 
3.0 mg).
The primary change occurs in 7.1 Inclusion Criteria
Initial 
wording:
11. This study permits the re-enrollment of a subject that has discontinued the study 
as a pre-treatment failure (ie, subject has not been randomized) and subjects who 
received a dose <2.0 mg and have completed all cycles including the Follow-up 
Period. If re-enrolled, the subject must be re-consented. 
* The re-enrollment of all subjects who received a dose <2.0 mg and completed 
all cycles including the Follow-up Period is permitted to Cohort B or C (2.0 mg 
and 3.0 mg dose cohorts) after completion of all cycles including the follow-up 
period if they had no drug-related AEs greater than Grade 1, no AEs greater than 
Grade 2, continue to meet all inclusion and exclusion criteria, and the SRC has 
reviewed and approved enrollment of the subject into a higher dose cohort.
Amended 
or new 
wording:
11. This study permits the re-enrollment of a subject that has discontinued the study 
as a pre-treatment failure (ie, subject has not been randomized) and subjects who 
received a dose <≤2.0 mg and have completed all cycles including the Follow-up 
Period. If re-enrolled, the subject must be re-consented. 
* The re-enrollment of all subjects who received a dose <≤2.0 mg and completed 
all cycles including the Follow-up Period is permitted to Cohort B orand C (2.0 
mg and 3.0 mg dose cohorts) after completion of all cycles including the follow-
up period if they had no drug-related AEs greater than Grade 1 which required 
study drug dose modification, no AEs greater than Grade 2, continue to meet 
all inclusion and exclusion criteria, and the SRC has reviewed and approved 
enrollment of the subject into a higher dose cohort.
Rationale for Change:
In the amendment, it is proposed that subjects in the 2 low dose cohorts (0.5 mg and 2.0 mg dose 
cohorts) are allowed to enrol in the 2.0 mg and 3.0 mg cohorts if they meet the inclusion criteria 
of the protocol and: 1) they have completed the 6-month study period at the 0.5 mg or 2.0 mg 
dose, 2) they continue to meet inclusion and exclusion criteria, 3) they have not had drug-related 
AEs >Grade 1, 4) they have not had any AE >Grade 2, and 5) they are approved to re-enrol by 
the study safety reveiw committee. Due to the proposed study design, there is expected to be no 
additional risk for subjects to re-enroll into a higher dose cohort. As subjects entering the trial 


Ixazomib 
Study No. MLN9708_101
Page 162 of 163
Protocol Incorporating Amendment No. 11
30 November 2017
CONFIDENTIAL
have evidence of active renal disease, the sponsor believes they should be allowed to be 
randomized into the higher dose cohort to increase their chance of receiving benefit from study 
at dose levels closer to those shown to be effective in oncology patients. As a result, following 
investigators' request, this amendment addresses investigators’ concerns by allowing patients 
with active LN refractory to the current standard of care to re-enroll to the 3 mg dose cohort from 
the lower dose cohorts for potential improved efficacy.
Based on the plasma half-life of ixazomib (approximately 9 days), accumulation of ixazomib in 
plasma is anticipated to be minimal following completion of study treatment in the 0.5 mg and 
2.0 mg dose cohorts and the associated 3 month follow up period. The follow-up within this 
study following the end of treatment (Day 84) is 3 months (Day 168), total washout of ixazomib 
of approximately 9 times longer than the terminal half-life. Overall no additional risk is expected 
to be for subjects to re-enroll into a higher dose cohort. 
The following sections also contain this change:
2.0 STUDY SUMMARY
6.1 Study Design
6.2 Justification for Study Design, Dose and Endpoints
Change 7: Revised Exclusion Criterion 10 to add a stipulation to IgG <75% of lower limit of 
normal to allow subjects with IgG >4.2 g/dL into the study if the cause of low IgG is due to LN 
proteinuria and all other causes of hypo-gammaglobulinemia have been ruled out
The primary change occurs in 7.2 Exclusion Criteria
Initial 
wording:
10. The subject has one of the following laboratory test values:
a) IgG <75% of LLN.
Amended 
or new 
wording:
10. The subject has one of the following laboratory test values:
a) IgG <75% of LLN. If low IgG is due to significant proteinuria due to LN 
activity, subjects with IgG >4.2 g/dL can be included. The cause of low 
IgG must be due to LN proteinuria and all other causes of hypo-
gammaglobulinemia must be ruled out.
Rationale for Change:
At the time of IND submission of this trial, ixazomib was not approved for multiple myeloma 
and there were limited safety data available. As a result the current protocol excluded subjects 
with IgG <75% of the normal limit which exclude a significant number of LN patients with 
severe proteinuria because they will also lose immunoglobulin through proteinuria. 
Hypogammaglobulinemia will be improved in these patients only if the disease activity is 
treated. Hypogammaglobulinemia has not been a common side effect in oncology patients 
including those who have received ixazomib for a few years. Therefore, the inclusion criterion 
has been modified to decrease the threshold of IgG at screening to >4.2 g/dl, if due to LN 


Ixazomib 
Study No. MLN9708_101
Page 163 of 163
Protocol Incorporating Amendment No. 11
30 November 2017
CONFIDENTIAL
proteinuria and other causes of low IgG and immunodeficiency have been ruled out. 
Additionally, the patient must not have had a moderate/severe infection in the last 6 months 
before screening. In addition, the current protocol stopping criteria are maintained; if the IgG 
level declines to less than 50% of the LLN, dosing of ixazomib must stop. This modification will 
allow more patients with more severe proteinuria due to LN and who are refractory to current 
SOC to potentially benefit from ixazomib treatment.


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Personal Protected Data

SAP_000.pdf: 
This may include, but is not limited to, redaction of the following: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Safety, Tolerability and
Pharmacokinetic Study of Multiple Rising Doses of MLN9708 for the Treatment of 
Subjects With ISN/RPS Class III or IV Lupus Nephritis
NCT Number: NCT02176486
SAP Approve Date: 6 March 2018
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content 
is masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information or company confidential information. 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
ITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: MLN9708_101
A Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Safety, Tolerability and
Pharmacokinetic Study of Multiple Rising Doses of MLN9708 for the Treatment of Subjects
With ISN/RPS Class III or IV Lupus Nephritis
MRD Study in Lupus Nephritis
PHASE 1b
Version: Final
Date: 6 March 2018
Prepared by:
Based on:
Protocol Version: Amendment 9
Protocol Date: 24 May 2016
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda.
Personal Protected Data


MLN9708_101
Page 2 of 25
Statistical Analysis Plan, Final 
6 March 2018
CONFIDENTIAL
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
Study Title:
A Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Safety, 
Tolerability and Pharmacokinetic Study of Multiple Rising Doses of 
MLN9708 for the Treatment of Subjects With ISN/RPS Class III or IV 
Lupus Nephritis
Approvals:
Date
Date
Date
Date
Date
Personal Protected Data
Personal Protected Data
Personal Protected Data
Personal Protected Data
Personal Protected Data


MLN9708_101
Page 3 of 25
Statistical Analysis Plan, Final 
6 March 2018
CONFIDENTIAL
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE...................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
List of In-Text Tables............................................................................................................4
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................8
4.1
Primary Objective......................................................................................................8
4.2
Secondary Objective..................................................................................................8
4.3
Additional Objectives ................................................................................................8
4.4
Study Design .............................................................................................................8
5.0
ANALYSIS ENDPOINTS...............................................................................................9
5.1.1
Primary Endpoint.................................................................................................9
5.1.2
Secondary Endpoints............................................................................................9
5.1.3
Exploratory Endpoints .........................................................................................9
5.1.4
Additional Safety Endpoints...............................................................................10
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................11
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................12
7.1
General Principles....................................................................................................12
7.1.1
Study Definitions ...............................................................................................12
7.1.2
Definitions of Study Days ..................................................................................12
7.1.3
Definition of Study Visit Windows ....................................................................12
7.1.4
Conventions for Missing Adverse Event Dates...................................................12
7.1.5
Conventions for Missing Concomitant Medication Dates...................................12
7.1.6
Conventions for Missing Data............................................................................12
7.2
Analysis Sets ...........................................................................................................13
7.3
Disposition of Subjects ............................................................................................13
7.4
Demographic and Other Baseline Characteristics.....................................................13
7.5
Medical History and Concurrent Medical Conditions...............................................14
7.6
Medication History and Concomitant Medications...................................................14
7.7
Study Drug Exposure and Compliance.....................................................................14
7.8
Efficacy Analysis.....................................................................................................14
7.8.1
Primary Efficacy Endpoint(s).............................................................................14
7.8.2
Secondary Efficacy Endpoint(s).........................................................................14
7.9
Pharmacokinetic and Pharmacodynamic Analysis....................................................15


MLN9708_101
Page 4 of 25
Statistical Analysis Plan, Final 
6 March 2018
CONFIDENTIAL
7.9.1
Pharmacokinetic Analysis ..................................................................................15
7.9.2
Pharmacodynamic Analysis ...............................................................................15
7.10
Other Outcomes (Secondary Endpoints and Exploratory Endpoints)........................15
7.11
Safety Analysis........................................................................................................16
7.11.1 Adverse Events ..................................................................................................16
7.11.2 Clinical Laboratory Evaluations .........................................................................17
7.11.3 Vital Signs .........................................................................................................20
7.11.4 12-Lead ECGs ...................................................................................................20
7.12
Interim Analysis ......................................................................................................20
7.13
Changes in the Statistical Analysis Plan...................................................................20
8.0
REFERENCES..............................................................................................................21
LIST OF IN-TEXT TABLES
Table 7.a
Clinical Laboratory Tests...................................................................................18
LIST OF APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values .................22
Appendix B
Criteria for Markedly Abnormal Vital Signs.......................................................24
Appendix C
Criteria for Markedly Abnormal 12-Lead ECG Parameters ................................25


MLN9708_101
Page 5 of 25
Statistical Analysis Plan, Final 
6 March 2018
CONFIDENTIAL
3.0
LIST OF ABBREVIATIONS
AE
adverse event
ACR
American College of Rheumatology
ALT
alanine aminotransferase
anti-dsDNA
antibody to double-stranded DNA
AST
aspartate aminotransferase
AUC(0-168)
area under the plasma concentration-time curve from time 0 to 168 hours postdose
AUC(0-t)
area under the plasma/blood/serum concentration-time curve from time 0 to time t 
AUC(0-tlqc)
area under the plasma concentration-time curve from time 0 to time of last quantifiable 
concentration (tlqc)
AZA
azathioprine
BMI
body mass index
BSA
body surface area
CI
confidence interval
Cmax
maximum observed plasma concentration
CrCl
creatinine clearance
CS
clinically significant
CTCAE
Common Terminology Criteria for Adverse Events
CYC
cyclophosphamide
CYP
cytochrome P-450
DDI
drug-drug interaction
DLT
dose-limiting toxicity
dsDNA
double-stranded deoxyribonucleic acid
eCRF
electronic case report form 
eGFR
estimated glomerular filtration rate
ECG
electrocardiogram
ESRD
end-stage renal disease
EOT
End of Treatment
ET
Early Termination
FACT
functional assessment of cancer therapy
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GI
gastrointestinal
GN
Glomerulonephritis
HBsAg
hepatitis B surface antigen
Company
Confidential
Information
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Compan
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Confide
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Informat
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MLN9708_101
Page 6 of 25
Statistical Analysis Plan, Final 
6 March 2018
CONFIDENTIAL
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
independent ethics committee
Ig
Immunoglobulin
IgA
Immunoglobulin A
IgG
immunoglobulin G
IgM
immunoglobulin M
IRB
institutional review board
ISN
International Society of Nephrology 
ISV
insufficient sample volume
IVRS/IWRS 
interactive voice response system/interactive web response system
K2EDTA
dipotassium ethylenediamine-tetraacetic acid
LLN
lower limit of normal
LN
lupus nephritis
MedDRA
Medical Dictionary for Regulatory Activities
MMF
mycophenolate mofetil
MRD
multiple-rising dose
MTD
maximum tolerated dose
NCS
not clinically significant
NOAEL
no-observed-adverse-effect level
NSAID
nonsteroidal anti-inflammatory drug
PGx
pharmacogenomics
PK
pharmacokinetic(s)
PO
Orally
PT
preferred term
PTE
pretreatment event
QTcF
QT interval with Fridericia’s correction method
RBC
red blood cell
RPS
Renal Pathology Society
RRMM
relapsed refractory multiple myeloma
SAE
serious adverse event
SAP
statistical analysis plan
sCR
serum creatinine
SLE
systemic lupus erythematosus
SNP
single nucleotide polymorphism
SOC
system organ class
SRC
Safety Review Committee
Company
Confidential
Information
Com
pany
Confi
denti
al
Infor
matio
n


MLN9708_101
Page 7 of 25
Statistical Analysis Plan, Final 
6 March 2018
CONFIDENTIAL
TB
tuberculosis
TEAE
treatment-emergent adverse event
Tmax
time to reach Cmax
ULN
upper limit of normal
UPCR
urine protein to creatinine ratio 
WBC
white blood cell
WHO
World Health Organization
Com
pany
Confi
denti
al
Infor
mati
on


MLN9708_101
Page 8 of 25
Statistical Analysis Plan, Final 
6 March 2018
CONFIDENTIAL
4.0
OBJECTIVES
4.1
Primary Objective
To characterize the safety and tolerability of ixazomib when administered as multiple oral doses 
at escalating dose levels in subjects with lupus nephritis (LN).
4.2
Secondary Objective

To assess changes from Baseline in urine protein to creatinine ratio (UPCR) in LN subjects 
following multiple administrations of ixazomib. 

To evaluate the effect of ixazomib on kidney function, as assessed by changes from Baseline 
in serum creatinine (sCR), and estimated glomerular filtration rate (eGFR).

To evaluate the effect of ixazomib on anti-dsDNA antibody titers and complement C3/C4 
levels.

To characterize the plasma PK of ixazomib in LN subjects when ixazomib is administered 
over 3 cycles consisting of 3 doses per cycle.
4.3
Additional Objectives
Not applicable.
4.4
Study Design
See Protocol Section 6.


MLN9708_101
Page 9 of 25
Statistical Analysis Plan, Final 
6 March 2018
CONFIDENTIAL
5.0
ANALYSIS ENDPOINTS
5.1.1
Primary Endpoint
∀
Percentage of study subjects with at least 1 Grade ≥2 treatment emergent adverse event 
(TEAE) according to CTCAE.
∀
Percentage of study subjects with at least 1 serious adverse event (SAE).
∀
Percentage of study subjects with at least 1 adverse event leading to discontinuation of 
investigational study medication.
∀
Percentage of subjects with at least 1 markedly abnormal laboratory criteria for hematologic 
parameters.
5.1.2
Secondary Endpoints
∀
Change from Baseline to Final Visit of treatment period in UPCR.
∀
Change from Baseline to Final Visit of treatment period in sCR level.
∀
Change from Baseline to Final Visit of treatment period in eGFR measurement.
∀
Change from Baseline to Final Visit of treatment period in levels of autoantibodies (anti-
dsDNA) and complement (C3 and C4).
∀
Plasma PK of ixazomib in subjects with LN following administration of ixazomib.
–
Plasma PK endpoints will be the following PK parameters of ixazomib in all cohorts: 
∀
Maximum plasma concentration (Cmax).
∀
Time to reach Cmax (Tmax).
∀
Area under the plasma concentration-time curve from time 0 to the last quantifiable 
concentration (AUC(0-tlqc)); or AUC(0-168), if measurable. 
5.1.3
Exploratory Endpoints
∀
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5.1.4
Additional Safety Endpoints
Other safety assessments include vital sign measurements, ECGs, physical examinations and 
clinical laboratory tests.
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6.0
DETERMINATION OF SAMPLE SIZE
This study is not statistically powered for any hypothesis testing. The sample size of at least 4 
active and 1 placebo subjects for each of the 0.5 mg and 2.0 mg dose groups (Cohorts A and B, 
respectively), 6 active and 2 placebo subjects for each of the 3.0 and 4.0 mg dose groups 
(Cohorts C and D, respectively) is considered to be sufficient to fulfill the study objectives of the 
evaluation of safety, tolerability, and pharmacokinetics of each cohort.


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
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 will also 
be included in the summary of continuous data. Categorical data will be summarized using the 
number and percent of subjects for each category, where appropriate.
Unless otherwise stated, baseline value is defined as the last observed value before the first dose 
of study medication.
Subjects who receive placebo in each cohort will be pooled across the cohorts. All study-related 
raw data for randomized subjects will be presented in listings. All summaries will be presented 
by the pooled placebo group, ixazomib doses, ixazomib overall, and overall subjects in the study 
separately. All data analyses and figures will be generated using SAS System® Version 9.2 or 
higher.
7.1.1
Study Definitions 
There are no study-specific definitions.
7.1.2
Definitions of Study Days
Study day will be calculated relative to the date of the first dose of the study drug. Study days 
prior to the first dose of study drug will be calculated as: {date of assessment/event – date of first 
dose of study drug of the subject}. Study days on or after the first dose of study drug will be 
calculated as: {date of assessment/event – date of first dose of study drug of the subject + 1}.
7.1.3
Definition of Study Visit Windows
There will be no visit windows.
7.1.4
Conventions for Missing Adverse Event Dates
There will be no imputation of incomplete, or missing adverse event dates.
7.1.5
Conventions for Missing Concomitant Medication Dates
There will be no imputation of incomplete, or missing concomitant medication dates.
7.1.6
Conventions for Missing Data
There will be no imputation of incomplete or missing data. 


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7.2
Analysis Sets
Safety Set:
The Safety Analysis Set will consist of all subjects who are enrolled and received at least 1 dose 
of study drug. Subjects in this analysis set will be used for demographic, baseline characteristics 
and safety summaries.
Pharmacokinetic Set:
The PK set will consist of all subjects who receive study drug and have at least 1 measurable 
plasma concentration.
Pharmacodynamic Set:
The PD set will consist of all subjects who receive study drug and have at least 1 postdose PD 
measurement.
7.3
Disposition of Subjects
Disposition of all screened subjects (denominator) will be tabulated (count and percent); there 
will be no inferential analysis of subject disposition data.
Summaries will be presented by the pooled placebo group, ixazomib doses, ixazomib overall, 
and overall subjects in the study.
Disposition of all randomized subjects will be tabulated for each part of the study: 

All subjects received at least one dose of study drug (denominator).

Subjects who completed the study drug.

Subjects who prematurely discontinued study drug.

Subjects who completed all study visits.

Subjects who prematurely discontinued study visits.
Primary reasons for discontinuation of study drug/visits, as entered on the electronic case report 
form (eCRF), will be tabulated. 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. 
Primary reasons for failure will be summarized and will be presented in a data listing.
7.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized using the safety set by pooled 
placebo group, ixazomib doses, ixazomib overall, and overall subjects in the study. 
Summary statistics will be presented for continuous variables (age, height, weight, and body 
mass index [BMI]). The number and percentage subjects within each category will be presented 


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for categorical variables (for example, gender, race, etc.). Individual subject demographic and 
baseline characteristic data will be listed.
Demographic variables of screen failure subjects and reasons for screen failures will be 
summarized overall for subjects who are screened but not enrolled in the study.
7.5
Medical History and Concurrent Medical Conditions
Medical history refers to the significant conditions or diseases relevant to the disease under study 
that resolved at or prior to signing of informed consent. Concurrent medical conditions are those 
significant ongoing conditions or diseases present at signing of informed consent.
Medical history and concurrent medical conditions will be coded using the latest version of 
Medical Dictionary for Regulatory Activities (MedDRA, version 20.0) will be presented in 
listings based on safety analysis set.
7.6
Medication History and Concomitant Medications
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and the efficacy or safety evaluations stopped at or within 28 days before signing of 
informed consent. Medications used from signing of informed consent through the end of each 
study part will be considered as concomitant medications for each study part, respectively.
Concomitant medication is defined as the medication that the patient started taking before first 
dose and ongoing in the study. Missing, partial, incomplete date/time for concomitant mediations 
won’t be imputed; these will be listed as such. 
All medication history and concomitant medications data will be presented in listing. This listing 
will be based on safety set.
7.7
Study Drug Exposure and Compliance
The date and time of each dose for each subject will be reported in a data listing. 
Summaries of ixazomib PK concentration data will be provided (See Section 7.9.1). No other 
summary statistics for the extent of exposure to study drug or compliance calculations will be 
performed.
7.8
Efficacy Analysis
Not applicable.
7.8.1
Primary Efficacy Endpoint(s)
Not applicable.
7.8.2
Secondary Efficacy Endpoint(s)
Not applicable.


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7.9
Pharmacokinetic and Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
7.9.1.1
Pharmacokinetic Concentrations
Individual subject plasma and 
 concentration data for ixazomib will be listed for all 
subjects in the safety set. Both scheduled and actual PK sample collection times will be 
presented in listings.
For the pharmacokinetic set, plasma and 
 ixazomib concentration data will be 
summarized by time point for each ixazomib dosing cohort using descriptive statistics (N, mean, 
SD, %CV, median, maximum, and minimum). Summary statistics will be calculated by 
assigning a value of 0 to all values below the limit of quantification (BLQ).
7.9.1.2
Pharmacokinetic Parameters
No PK parameters will be derived due to early termination of the study. 
7.9.2
Pharmacodynamic Analysis
All PD summaries will be based on the PD set.
7.9.2.1
Pharmacodynamic Concentrations
Pharmacodynamic measures will include hematologic measures of serum anti dsDNA antibody, 
other autoantibodies and complement C3/C4 levels. Samples will be collected as noted in 
Appendix A in the Protocol. These assays are routinely performed in the central laboratory.
Baseline value, final visit value, and change from baseline to final visit of the levels of 
autoantibodies (anti-dsDNA) and complement (C3 and C4) will be summarized by pooled 
placebo, ixazomib dose and ixazomib overall (N, mean, SD, median, minimum, and maximum). 
Individual data for each subject will be provided in the listing.
 
For serum and urine cytokine samples, the values at each time point, change from baseline to 
each visit of the levels of each analyte, except analyates in which all values are below LLOQ,
will be summarized by pooled placebo, ixazomib dose and ixazomib overall (N, mean, SD, 
median, minimum, and maximum). Individual data for each subject will be provided in the 
listing.
7.10
Other Outcomes (Secondary Endpoints and Exploratory Endpoints)
Other secondary endpoints include change from baseline to final visit of treatment period in
Urine Protein to Creatinine Ratio (UPCR), serum creatinine (SCr) level and estimated 
glomerular filtration rate (eGFR) measurement.
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Statistical Analysis Plan, Final 
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CONFIDENTIAL
Observed values of UPCR, SCr and eGFR will be listed for each subject by visit. Baseline, final 
visit values and change from baseline at final visit will be summarized by pooled placebo, 
ixazomib dose and ixazomib overall (N, mean, SD, median, minimum and maximum) using the 
safety set.
Due to the fact that the study was terminated before the finalization of this statistical analysis 
plan, no summaries nor analysis will be performed for the exploratory endpoints. Data collected 
on eCRF or from study procedures that are related to the exploratory endpoints will be listed if 
appropriate.
7.11
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. 
7.11.1 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 
20.0 or later).
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 up to 30 days (onset date – last date of 
dose + 1 ≤ 30) after the last dose of study drug or early termination. 
TEAEs will be presented by severity (mild, moderate, and severe). Serious TEAEs, TEAEs 
leading to study drug discontinuation, 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 subject 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 severity will be listed as such in the AE listings, however, 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.
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 


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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 (>5% or N>2) Non-Serious Adverse Events by Preferred Term.

Most Frequent (>5% or N>2) Non-Serious Adverse Events by System Organ Class and 
Preferred Term.

Relationship of Treatment-Emergent Adverse Events to Study Drug by System Organ Class 
and Preferred Term.

Drug-Related Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term. 

Severity of Treatment-Emergent Adverse Events by System Organ Class and Preferred Term. 
In addition, the following summary tables, number and percentage of subjects, will be generated 
for the following primary endpoints in all cohorts:

At least 1 Grade ≥2 treatment emergent adverse event (TEAE) according to CTCAE.
Subject mappings for the TEAEs by SOC and PT will be generated.
Data listings will be provided for PTEs, TEAEs, TEAEs leading to study drug discontinuation 
AEs leading to discontinuation of investigational study medication, SAEs and AEs that resulted 
in death.
7.11.2 Clinical Laboratory Evaluations
Clinical laboratory tests will be assessed using the safety analysis set and will be evaluated and 
presented using International System of Units (SI) unless otherwise stated. Table 7.a shows a list 
of all clinical laboratory tests. 


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Table 7.a
Clinical Laboratory Tests
Hematology
Serum Chemistry 
Urinalysis
Special 
Red blood cells
Reticulocytes
White blood cells 
with differential
Hemoglobin
Hematocrit
Platelets
Alanine aminotransferase
Alkaline phosphatase
Aspartate aminotransferase
-Glutamyl transferase
Total bilirubin
Direct bilirubin
Albumin
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
Potassium
Sodium
Glucose
Chloride
Phosphorus
Calcium
To be done at local 
laboratory
pH
Specific gravity
Protein
Glucose
Blood 
Nitrite
Microscopic Analysis:
RBC/high power field
WBC/high power field
Epithelial cells, casts, etc
To be done at central 
laboratory
Urine protein and creatinine 
for UPCR
Urine Biomarkers
To be done at the site
Standard urinalysis using 
dipstick (protein only)
To be done at local 
laboratory
Coomb’s test
Platelets, red blood cells, 
white blood cells with 
differential
To be done at central 
laboratory
Lipid panel (fasted):
Total cholesterol
LDL-cholesterol
HDL-cholesterol
Triglycerides
Serum complement
C3 and C4
Total IgM, IgG and IgA
Autoantibodies:
Anti-double-stranded DNA
Anti-nuclear antibody
Anti-Ro (SS-A)
Anti-La (SS-B)
Anti-RNP
Anti-Sm
Anti-phospholipids
Serum biomarkers
Tetanus antibody titers
HBsAb titers
Serum
Serum hCG (a)
At Screening Only:
Hepatitis panel, including HBsAg, anti-HCV and 
HIV
FSH (b)
DNA=deoxyribonucleic acid, FSH=follicle-stimulating hormone, HBsAb=hepatitis B surface antibody, 
hCG=human chorionic gonadotropin, HDL=high-density lipoprotein, HIV=human immunodeficiency virus, 
LDL=low-density lipoprotein.
(a) Serum hCG pregnancy test will be done on all female subjects of childbearing potential at Screening.
(b) The FSH level will be obtained for female subjects at Screening if they are postmenopausal by history (ie, last 
regular menstrual cycle >2 years) and not surgically sterile. The FSH result must be >40 IU/L for the subject to be 
permitted not to use adequate contraception.


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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 in derived analysis data sets using the known conversion factors. If necessary, SI units from 
the central laboratory may be converted to Takeda’s preferred SI units in the derived dataset. All 
summaries and analyses will be based on the values using these preferred SI units.
Descriptive statistics (N, mean, SD, median, minimum, and maximum) for the observed baseline, 
post-baseline and change from baseline values will be presented by pooled placebo group, 
ixazomib doses, and ixazomib overall for the following laboratory tests:

Red blood cells.

White blood cells with differential.

Platelets.

Alanine aminotransferase.

Alkaline phosphatase.

Aspartate aminotransferase.

-Glutamyl transferase.

Total bilirubin.

Creatinine.

Blood urine nitrogen.

Urine protein and creatinine for UPCR.

C3 and C4.

Total IgM, IgG and IgA.

Anti-double-stranded DNA.

Tetanus antibody titers.

HBsAb titers.
Study baseline will be used for change from baseline. 
Laboratory Markedly Abnormal Values (MAVs), identified by the criteria defined in Appendix 
A, will be tabulated. If a subject has a MAV for a particular laboratory test, all visits for that 
subject for that parameter will be listed. The number and percentage of subjects with at least 1 
post-dose markedly abnormal laboratory test result will be summarized. The mapping of the 
subjects who meet the MAV criteria will be listed as a table. All observations, including ones at 
unscheduled visits, will be included in the MAV evaluation and summaries if MAV criteria are 
satisfied.
All clinical laboratory data will be presented in both SI and conventional units in data listings.


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7.11.3 Vital Signs
Vital sign MAVs, identified by the criteria defined in Appendix B, will be tabulated. If a subject 
has a MAV for a particular vital signs parameter, all visits for that subject for that parameter will 
be listed. The number and percentage of subjects with at least 1 post-dose markedly abnormal 
vital signs measurement will be summarized. The mapping of the subjects who meet the MAV 
criteria will be listed as a table. All observations, including ones at unscheduled visits, will be 
included in the MAV evaluation and summaries if MAV criteria are satisfied.
All vital signs will be listed in a data listing.
7.11.4 12-Lead ECGs
ECG MAVs, identified by the criteria defined in Appendix C, will be tabulated. If a subject has a 
MAV for a particular 12-lead ECG parameter, all visits for that subject for that parameter will be 
listed. The number and percentage of subjects with at least 1 post-dose markedly abnormal 
12-lead ECG measurement will be summarized. The mapping of the subjects who meet the 
MAV criteria will be listed as a table. All observations, including ones at unscheduled visits, will 
be included in the MAV evaluation and summaries.
Overall ECG interpretation category (normal, abnormal not clinically significant, abnormal 
clinically significant, not evaluable) is collected by eCRF at baseline and at each scheduled post-
baseline 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.
All ECG parameters will be listed in a data listing.
7.12
Interim Analysis 
There is no interim analysis.
7.13
Changes in the Statistical Analysis Plan 
Only analysis on Cohort A and B, and Double-Blind treatment period of the study will be 
presented because study has been terminated early. 
Due to the fact that the study was terminated before the finalization of this statistical analysis 
plan, no summaries nor analysis will be performed for the exploratory endpoints. Data collected 
on eCRF or from study procedures that are related to the exploratory endpoints will be listed if 
appropriate. Additionally, no PK parameters will be derived due to early termination of the 
study.


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CONFIDENTIAL
8.0
REFERENCES
1. A Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Safety, Tolerability and 
Pharmacokinetic Study of Multiple Rising Doses of MLN9708 for the Treatment of Subjects 
With ISN/RPS Class III or IV Lupus Nephritis, Takeda, Protocol Amendment No.9 for 
MLN9708_101, dated 24 May 2016.


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CONFIDENTIAL
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values
Hematology – Criteria for Markedly Abnormal Values (SI units)
Parameter
Unit
Low Abnormal
High Abnormal
Hemoglobin
Both 
< 0.8 × LLN
> 1.2 × ULN
Hematocrit
Both
< 0.8 × LLN
> 1.2 × ULN
RBC count 
Both
< 0.8 × LLN 
> 1.2 × ULN
WBC count 
Both 
<0.5 × LLN
>1.5 × ULN
Platelet count
Conventional
<75 × 103/L
>600 × 103/L
SI
<75 × 109/L
>600 × 109/L
Reticulocytes
Conventional
--
>3 % of erythrocytes
SI
--
>0.030 Fraction of 1
LLN=lower limit of normal, RBC=red blood cell, ULN=upper limit of normal, WBC=white blood cell. 


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Serum Chemistry – Criteria for Markedly Abnormal Values (SI units)
Parameter
Unit 
Low Abnormal
High Abnormal
ALT
Both
--
>3 × ULN
AST
Both
--
>3 × ULN
GGT
Both
--
>3 × ULN
Alkaline phosphatase
Both
--
>3 × ULN
Calcium
Conventional
<7.0 mg/dL
>11.5 mg/dL
SI
<1.75 mmol/L
>2.88 mmol/L
Chloride
Conventional
<75 mEq/L
>126 mEq/L
SI
<75 mmol/L
>126 mmol/L
Total bilirubin
Conventional
--
>2.0 mg/dL
SI
--
>34.2 mol/L
Albumin
Conventional 
<2.5 g/dL
--
SI 
<25 g/L
--
Total protein
Both
<0.8 × LLN
>1.2 × ULN
Creatinine
Conventional 
--
>2.0 mg/dL
SI
--
>177 mol/L
Blood urea nitrogen
Conventional 
--
>30 mg/dL
SI
--
>10.7 mmol/L
Sodium
Conventional
<130 mEq/L
>150 mEq/L
SI
<130 mmol/L
>150 mmol/L
Potassium
Conventional
<3.0 mEq/L
>6.0 mEq/L
SI
<3.0 mmol/L
>6.0 mmol/L
Glucose
Conventional
< 50 mg/dL
>350 mg/dL
SI
< 2.8 mmol/L
>19.4 mmol/L
Bicarbonate
Conventional
<8.0 mEq/L
--
SI
<8.0 mmol/L
--
Creatine kinase
Conventional
--
>5 × ULN
SI
--
>5 × ULN
Total Cholesterol
Conventional
--
>300 mg/dL
SI
--
>7.72 mmol/L
Triglycerides
Both
--
>2.5 × ULN
LDL Cholesterol
Conventional
< 50 mg/dL
>160 mg/dL
SI
<1.30 mmol/L
>4.14 mmol/L
HDL Cholesterol
Conventional
<40 mg/DL
>60mg/DL
SI
<1.04 mmol/L
>1.55 mmol/L
Direct Bilirubin
Conventional
--
>2 x ULN
Phosphorus
Conventional
<1.6mg/dL
>6.2 mg/dL
SI
<0.52 mmol/L
>2mmol/L
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=-glutamyl transferase, LLN=lower limit of 
normal, ULN=upper limit of normal.


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CONFIDENTIAL
Appendix B
Criteria for Markedly Abnormal Vital Signs
Parameter
Unit
Lower Criteria 
Upper Criteria
Pulse
bpm
<50 
>120
Systolic blood pressure
mm Hg
<85 
>180 
Diastolic blood pressure
mm Hg
<50 
>110
Body temperature
oC
< 35.6
>37.7


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CONFIDENTIAL
Appendix C
Criteria for Markedly Abnormal 12-Lead ECG Parameters
Parameter
Unit
Lower Criteria 
Upper Criteria
Heart Rate
bpm
< 50
> 120
PR 
msec
≤ 80
≥ 200
RR 
msec
≤ 600
≥ 1440
QRS 
msec
≤ 80
≥ 180
QT Interval
msec
≤ 50
≥ 460
QTcB Interval
msec
≤ 50
≥ 500 
OR 
≥ 30 change from baseline and ≥ 450
QTcF Interval
msec
≤ 50
≥ 500 
OR 
≥ 30 change from baseline and ≥ 450


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