Safety, Tolerability and Pharmacokinetics of Multiple Rising Doses of Ixazomib in Lupus Nephritis (LN)

• Sponsor: Takeda (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02176486
• Collaborator: (none)
• Enrollment: 12
• Locations: 35
• Arms: 5
• Actual Duration (Months): 43.4
• Patients Per Site: 0.3
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Lupus Nephritis	Drug: Ixazomib; Drug: Placebo	Phase 1

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official 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
• Actual Study Start Date: Jun 9, 2014
• Actual Primary Completion Date: Mar 30, 2017
• Actual Study Completion Date: Jan 19, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A: Ixazomib 0.5 milligram (mg) Ixazomib 0.5 mg, capsules, orally, once, on Day 1, 8 and 15 in 28-day cycles, Cycles 1 through 3.	Drug: Ixazomib; Ixazomib capsules.; Other Names: MLN9708
Experimental: Cohort B: Ixazomib 2 mg Ixazomib 2 mg, capsules, orally, once, on Day 1, 8 and 15 in 28-day cycles, Cycles 1 through 3.	Drug: Ixazomib; Ixazomib capsules.; Other Names: MLN9708
Experimental: Cohort C: Ixazomib 3 mg Ixazomib 3 mg, capsules, orally, once, on Day 1, 8 and 15 in 28-day cycles, Cycles 1 through 3.	Drug: Ixazomib; Ixazomib capsules.; Other Names: MLN9708
Experimental: Cohort D: Ixazomib 4 mg Ixazomib 4 mg, capsules, orally, once, on Day 1, 8 and 15 in 28-day cycles, Cycles 1 through 3.	Drug: Ixazomib; Ixazomib capsules.; Other Names: MLN9708
Placebo Comparator: Cohorts A through D: Placebo Ixazomib placebo-matching capsules, orally, once on Days 1, 8 and 15 in 28-day cycle, Cycles 1 through 3.	Drug: Placebo; Ixazomib placebo-matching capsules.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Who Experienced at Least One Grade Greater Than or Equal to (>=) 2 Treatment Emergent Adverse Event (TEAE) [Baseline up to Day 101 (30 days after last dose of study drug)]

2. Percentage of Participants Who Experienced at Least One Treatment Emergent Serious Adverse Event (SAE) [Baseline up to Day 101 (30 days after last dose of study drug)]

3. Percentage of Participants Who Experienced at Least One AE Leading to Study Drug Discontinuation [Baseline up to Day 168]

4. Percentage of Participants With at Least One Markedly Abnormal Value (MAV) for Hematologic Parameters [Baseline up to Day 168]

Secondary Outcome Measures

1. Change From Baseline in Urine Protein to Creatinine Ratio (UPCR) at Day 84 [Baseline and Day 84]

2. Change From Baseline in Serum Creatinine (sCR) Level at Day 84 [Baseline and Day 84]

3. Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Day 84 [Baseline and Day 84]

4. Change From Baseline in Levels of Autoantibodies (Anti-double-stranded Deoxyribonucleic Acid [dsDNA]) at Day 84 [Baseline and Day 84]

5. Change From Baseline in Complement Protein C3 and C4 at Day 84 [Baseline and Day 84]

6. Plasma Concentrations of Ixazomib at Each Scheduled Collection Time [Cycle 1 Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length is equal to [=] 28 days)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. In the opinion of the investigator, is capable of understanding and complying with protocol requirements.

2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written informed consent form and any required privacy authorization prior to the initiation of any study procedures.

3. Is female or male and aged 18 to 75 years, inclusive.

4. Has a diagnosis of systemic lupus erythematosus (SLE) defined by meeting either the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria or the American College of Rheumatology (ACR) criteria for the classification of SLE. The 4 criteria required by ACR classification are not required to be present at Screening for eligibility.

5. Has a definite diagnosis of LN based on a kidney biopsy done within 2 year of the Screening Visit which demonstrated International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III, IV or V changes [excluding Class III (C), IV-S (C) and IV-G (C)] or World Health Organization (WHO) 1982 classification Class III,IV or V(excluding Class IIIc and IVd).

6. If no biopsy was done within 2 year of Screening Visit, biopsy can be done during the screening period as a study procedure.

7. Co-existence of classes is permitted.

8. Has a renal biopsy demonstrating either ISN/RPS or WHO class V or class V with class 2 nephritis with a UPCR of greater than (>) 3 or the participant has a renal biopsy demonstrating either active ISN/RPS or WHO class III or IV nephritis, defined by either one of the following criteria:

1. 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 lupus nephritis.

• =5 white blood cells (WBC) per high power field in the absence of infection.

• Presence of cellular casts. ii. The participant has increased levels (above upper limit of normal [ULN]) serum dsDNA autoantibodies at screening.

1. Low complement (either C3 or C4) at Screening (>= 25 percent [%] lower than lower limit of normal [LLN]).

2. 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.

• Participants 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.

1. Has had an inadequate response, in the judgment of the Investigator, to at least 6 months of an immunosuppressive regimen including single or sequential use of at least one of the following: cyclophosphamide (CYC), mycophenolate mofetil (MMF), mycophenolic acid (MA), or azathioprine (AZA).

2. If the participant is on glucocorticosteroids, must be on stable dose equivalent to 20 mg/day or less of prednisone for at least 2 weeks prior to first dose of study medication. Participant who are on a stable dose equivalent to >20 mg/day and <=30 milligram per day (mg/day) of prednisone may be allowed to the study if reviewed by the adjudication committee and approved by the medical monitor; however, the steroid dose should be tapered.

3. Male participants who are sexually active with women of child bearing potential (WOCBP), even if surgically sterilized (that is, status post-vasectomy), must:

1. Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug.

1. Female participants who are of child bearing potential must:

1. 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 drug.

1. This study permits the re-enrollment of a participant that has discontinued the study as a pre- treatment failure (ie, participant has not been randomized). If re-enrolled, the participant must be re-consented.

• The re-enrollment of all participants who completed Cohort A and B is permitted to subsequent cohorts (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 adverse events greater than Grade 1, no adverse events greater than Grade 2, continue to meet all inclusion and exclusion criteria, and the Safety Review Committee has reviewed and approved enrollment of the subject into a higher dose cohort.

1. Must be receiving Standard of Care (SOC) treatment with an immunosuppressant drug for the treatment of LN (example, MMF, MA or AZA).

Exclusion Criteria:

1. Has received any investigational compound within 30 days or 5 half-lives, whichever is the longer, prior to Screening or is currently participating in another interventional clinical study.

2. Has received ixazomib, bortezomib, or another proteasome inhibitor in a previous clinical study or as a therapeutic agent.

3. 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 (example, spouse, parent, child, sibling), or may consent under duress.

4. Has an autoimmune disease other than SLE as their main diagnosis.

5. Has drug-induced SLE.

6. Has severe, active central nervous system (CNS) lupus (British Isles Lupus Assessment Group [BILAG] A or B).

7. Has an estimated eGFR of <30 milliliter per minute per 1.73 m^{2 (mL/min/1.73m}2), or is on dialysis, or is expected to have a renal transplant within 1 year of randomization, or has had a renal transplant.

8. Has a severe acute infectious disease (example, untreated active tuberculosis (TB), acute viral hepatitis, human immunodeficiency virus (HIV), untreated latent TB, or infections requiring IV anti-microbial treatment within 2 months preceding the Screening Visit.

9. Has a history of a malignant disease (except successfully treated basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma in situ) within 5 years prior to Screening.

10. Has one of the following laboratory test values:

11. IgG<75% of LLN

12. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the central laboratory's ULN

13. Bilirubin >1.5 x ULN (participants with Gilbert Syndrome with a confirmed diagnosis and documented in the subject's medical record will not be excluded based on this criterion).

14. Platelets <75,000 per cubic millimeter (/mm^3)

15. Neutrophils <1500/ mm^{3 or > 11,000/ mm}3

16. Hemoglobin <8 grams per deciliter (g/dL)

17. Positive for Hepatitis B Surface Antigen.

18. Positive for Hepatitis C antibody.

19. 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 prior to the screening visit.

20. If female, the participant 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.

21. If male, the participant intends to donate sperm during the course of this study or for 90 days after the last dose. Male participants planning to father during clinical trial conduct or within 90 days after the last planned dose of trial treatment.

22. 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.

23. Is taking excluded medications.

24. Has a history of clinically significant neuropathies of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 Grade 2 or higher.

25. Has been treated with CYC within 4 weeks of the Screening Visit.

26. Has been treated with > 3 g/day of MMF within 4 weeks of the Screening Visit.

27. Has been treated with belimumab, abatacept or tocilizumab within 3 months of the Screening Visit.

28. Has been treated with eprazutumab, alemtuzumab, rituximab or other cell depleting biological agents within 6 months of the Screening Visit.

29. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		La Jolla	California	United States
2		Upland	California	United States
3		Port Charlotte	Florida	United States
4		Evergreen Park	Illinois	United States
5		Brooklyn	New York	United States
6		Great Neck	New York	United States
7		Manhasset	New York	United States
8		New York	New York	United States
9		Middleburg Heights	Ohio	United States
10		Lancaster	Pennsylvania	United States
11		Charleston	South Carolina	United States
12		Jackson	Tennessee	United States
13		Lille	Nord	France
14		Amiens	Somme	France
15		Paris		France
16		Strasbourg		France
17		Frankfurt am Main	Hessen	Germany
18		Aachen	Nordrhein-Westfalen	Germany
19		Düsseldorf	Nordrhein-Westfalen	Germany
20		Mainz	Rheinland-Pfalz	Germany
21		Berlin		Germany
22		Essen		Germany
23		Freiburg		Germany
24		Roma	Lazio	Italy
25		Torino	Piemonte	Italy
26		Pisa	Toscana	Italy
27		Padova	Veneto	Italy
28		Kazan		Russian Federation
29		Kemerovo		Russian Federation
30		St Petersburg		Russian Federation
31		Madrid	Madrid, Communidad Delaware	Spain
32		Bilbao	Vizcaya	Spain
33		Madrid		Spain
34		London	London, City Of	United Kingdom
35		London		United Kingdom

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director Clinical Science, Takeda

Study Documents (Full-Text)

• Statistical Analysis Plan - Mar 6, 2018
• Study Protocol - Nov 30, 2017

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02176486
• Other Study ID Numbers: MLN9708_101; U1111-1152-6999; 2014-000125-21; 14/LO/1087
• First Posted: Jun 27, 2014
• Last Update Posted: Apr 8, 2019
• Last Verified: Jan 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Takeda: Drug Therapy
• Additional relevant MeSH terms: Nephritis; Lupus Nephritis; Ixazomib

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 8 investigative sites in the United States, Spain and Russia from 09 June 2014 to 19 January 2018.
Pre-assignment Detail	Participants with a historical diagnosis of lupus nephritis (LN) were enrolled to receive ixazomib as multiple rising doses (MRD) of 0.5 milligram (mg) in Cohort A and 2.0 mg in Cohort B. This study was terminated early after the completion of Cohorts A and B due to lack of sufficient enrollment to complete the study.

Arm/Group Title	Pooled Placebo	Cohort A: Ixazomib 0.5 mg	Cohort B: Ixazomib 2 mg
Arm/Group Description	Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 0.5 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 2 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.
Period Title: Overall Study
STARTED	3	5	4
COMPLETED	3	5	4
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Pooled Placebo	Cohort A: Ixazomib 0.5 mg	Cohort B: Ixazomib 2 mg	Total
Arm/Group Description	Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 0.5 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 2 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Total of all reporting groups
Overall Participants	3	5	4	12
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	3 100%	5 100%	4 100%	12 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	1 33.3%	5 100%	2 50%	8 66.7%
Male	2 66.7%	0 0%	2 50%	4 33.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	1 25%	1 8.3%
Not Hispanic or Latino	3 100%	4 80%	2 50%	9 75%
Unknown or Not Reported	0 0%	1 20%	1 25%	2 16.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	2 66.7%	1 20%	0 0%	3 25%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	1 33.3%	3 60%	2 50%	6 50%
White	0 0%	1 20%	2 50%	3 25%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	3 100%	4 80%	3 75%	10 83.3%
Spain	0 0%	1 20%	0 0%	1 8.3%
Russia	0 0%	0 0%	1 25%	1 8.3%
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	169.3 (0.58)	167.0 (3.39)	171.5 (6.56)	169.1 (4.48)
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	88.67 (4.216)	87.56 (16.891)	92.43 (7.192)	89.46 (11.229)
Body Mass Index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	30.92 (1.441)	31.40 (5.971)	31.64 (4.660)	31.36 (4.399)
Smoking Classification (Count of Participants)
Never smoked	2 66.7%	5 100%	2 50%	9 75%
Current smoker	0 0%	0 0%	1 25%	1 8.3%
Ex-smoker	1 33.3%	0 0%	1 25%	2 16.7%
Alcohol Classification (Count of Participants)
Never drank	1 33.3%	4 80%	2 50%	7 58.3%
Current drinker	2 66.7%	1 20%	2 50%	5 41.7%
Consumption of Alcohol (Count of Participants)
Drank less than or equal to (<=) 4 drinks per day	2 66.7%	1 20%	2 50%	5 41.7%
Not reported	1 33.3%	4 80%	2 50%	7 58.3%
Female Reproductive Status (Count of Participants)
Surgically sterile	0 0%	2 40%	1 25%	3 25%
Female of childbearing potential	1 33.3%	3 60%	1 25%	5 41.7%
Not applicable (participant were male)	2 66.7%	0 0%	2 50%	4 33.3%
Pharmacogenomics (PGx) Consent Obtained (Count of Participants)
PGx was obtained	3 100%	5 100%	3 75%	11 91.7%
PGx was not obtained	0 0%	0 0%	1 25%	1 8.3%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Who Experienced at Least One Grade Greater Than or Equal to (>=) 2 Treatment Emergent Adverse Event (TEAE)
Time Frame	Baseline up to Day 101 (30 days after last dose of study drug)

Outcome Measure Data

Analysis Population Description

The safety analysis set consisted of all participants who were enrolled and received at least 1 dose of study drug.

Arm/Group Title	Pooled Placebo	Cohort A: Ixazomib 0.5 mg	Cohort B: Ixazomib 2 mg
Arm/Group Description	Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 0.5 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 2 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.
Measure Participants	3	5	4
Number [percentage of participants]	33.3 1110%	20.0 400%	25.0 625%

2. Primary Outcome

Title	Percentage of Participants Who Experienced at Least One Treatment Emergent Serious Adverse Event (SAE)
Time Frame	Baseline up to Day 101 (30 days after last dose of study drug)

Outcome Measure Data

Analysis Population Description

The safety analysis set consisted of all participants who were enrolled and received at least 1 dose of study drug.

Arm/Group Title	Pooled Placebo	Cohort A: Ixazomib 0.5 mg	Cohort B: Ixazomib 2 mg
Arm/Group Description	Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 0.5 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 2 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.
Measure Participants	3	5	4
Number [percentage of participants]	0 0%	0 0%	0 0%

3. Primary Outcome

Title	Percentage of Participants Who Experienced at Least One AE Leading to Study Drug Discontinuation
Time Frame	Baseline up to Day 168

Outcome Measure Data

Analysis Population Description

The safety analysis set consisted of all participants who were enrolled and received at least 1 dose of study drug.

Arm/Group Title	Pooled Placebo	Cohort A: Ixazomib 0.5 mg	Cohort B: Ixazomib 2 mg
Arm/Group Description	Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 0.5 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 2 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.
Measure Participants	3	5	4
Number [percentage of participants]	0 0%	0 0%	0 0%

4. Primary Outcome

Title	Percentage of Participants With at Least One Markedly Abnormal Value (MAV) for Hematologic Parameters
Time Frame	Baseline up to Day 168

Outcome Measure Data

Analysis Population Description

The safety analysis set consisted of all participants who were enrolled and received at least 1 dose of study drug.

Arm/Group Title	Pooled Placebo	Cohort A: Ixazomib 0.5 mg	Cohort B: Ixazomib 2 mg
Arm/Group Description	Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 0.5 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 2 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.
Measure Participants	3	5	4
Number [percentage of participants]	0 0%	0 0%	50.0 1250%

5. Secondary Outcome

Title	Change From Baseline in Urine Protein to Creatinine Ratio (UPCR) at Day 84
Time Frame	Baseline and Day 84

Outcome Measure Data

Analysis Population Description

The safety analysis set consisted of all participants who were enrolled and received at least 1 dose of study drug.

Arm/Group Title	Pooled Placebo	Cohort A: Ixazomib 0.5 mg	Cohort B: Ixazomib 2 mg
Arm/Group Description	Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 0.5 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 2 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.
Measure Participants	3	5	4
Baseline	1.7567 (1.66796)	2.6134 (2.11100)	0.7535 (0.40827)
Change at Day 84	-0.1680 (1.03388)	-0.4740 (0.96565)	0.9943 (0.73183)

6. Secondary Outcome

Title	Change From Baseline in Serum Creatinine (sCR) Level at Day 84
Time Frame	Baseline and Day 84

Outcome Measure Data

Analysis Population Description

The safety analysis set consisted of all participants who were enrolled and received at least 1 dose of study drug.

Arm/Group Title	Pooled Placebo	Cohort A: Ixazomib 0.5 mg	Cohort B: Ixazomib 2 mg
Arm/Group Description	Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 0.5 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 2 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.
Measure Participants	3	5	4
Baseline	91.347 (18.4019)	72.488 (54.2779)	81.770 (31.7708)
Change at Day 84	-2.947 (22.2468)	1.768 (7.3961)	13.260 (39.2029)

7. Secondary Outcome

Title	Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Day 84
Time Frame	Baseline and Day 84

Outcome Measure Data

Analysis Population Description

The safety analysis set consisted of all participants who were enrolled and received at least 1 dose of study drug.

Arm/Group Title	Pooled Placebo	Cohort A: Ixazomib 0.5 mg	Cohort B: Ixazomib 2 mg
Arm/Group Description	Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 0.5 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 2 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.
Measure Participants	3	5	4
Baseline	88.7 (28.11)	130.0 (62.02)	103.5 (38.77)
Change at Day 84	6.3 (22.19)	2.6 (29.26)	-0.5 (19.60)

8. Secondary Outcome

Title	Change From Baseline in Levels of Autoantibodies (Anti-double-stranded Deoxyribonucleic Acid [dsDNA]) at Day 84
Time Frame	Baseline and Day 84

Outcome Measure Data

Analysis Population Description

The pharmacodynamics (PD) set consisted of all participants who received study drug and had at least 1 post dose PD measurement. Participants who were evaluable for this measure at given time period for the arm were included in the category.

Arm/Group Title	Pooled Placebo	Cohort A: Ixazomib 0.5 mg	Cohort B: Ixazomib 2 mg
Arm/Group Description	Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 0.5 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 2 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.
Measure Participants	3	5	4
Baseline	18.7 (12.70)	34.3 (32.57)	129.3 (140.66)
Change at Day 84	-4.3 (6.03)	7.5 (9.40)	9.5 (75.76)

9. Secondary Outcome

Title	Change From Baseline in Complement Protein C3 and C4 at Day 84
Time Frame	Baseline and Day 84

Outcome Measure Data

Analysis Population Description

The PD set consisted of all participants who received study drug and had at least 1 post dose PD measurement. Participants who were evaluable for this measure at given time period for the arm were included in the category.

Arm/Group Title	Pooled Placebo	Cohort A: Ixazomib 0.5 mg	Cohort B: Ixazomib 2 mg
Arm/Group Description	Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 0.5 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 2 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.
Measure Participants	3	5	4
Complement Protein C3: Baseline	122.3 (59.47)	82.2 (23.67)	110.3 (40.24)
Complement Protein C3: Change at Day 84	-20.3 (26.76)	-7.4 (10.50)	-19.5 (13.18)
Complement Protein C4: Baseline	29.0 (13.08)	12.4 (8.26)	20.0 (9.56)
Complement Protein C4: Change at Day 84	-4.7 (4.73)	-0.8 (1.92)	-6.0 (1.41)

10. Secondary Outcome

Title	Plasma Concentrations of Ixazomib at Each Scheduled Collection Time
Time Frame	Cycle 1 Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length is equal to [=] 28 days)

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) set consisted of all participants who received one dose of ixazomib and had at least 1 measurable plasma concentration.

Arm/Group Title	Cohort A: Ixazomib 0.5 mg	Cohort B: Ixazomib 2 mg
Arm/Group Description	Ixazomib 0.5 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.	Ixazomib 2 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.
Measure Participants	5	3
Pre-dose	0.0000 (0.00000)	0.0000 (0.00000)
0.25 hour	0.0000 (0.00000)	0.0000 (0.00000)
0.5 hour	0.4244 (0.69887)	2.5033 (4.33590)
1 hour	0.6776 (0.68219)	2.2000 (2.35841)
1.5 hours	0.5056 (0.72535)	2.3400 (2.38627)
2 hours	0.5134 (0.52152)	2.2767 (2.07447)
4 hours	0.1082 (0.24194)	1.1700 (1.01602)
8 hours	0.0000 (0.00000)	0.9967 (0.86327)
24 hours	0.0000 (0.00000)	0.5493 (0.48634)
168 hours	0.0000 (0.00000)	0.0000 (0.00000)

Adverse Events

Time Frame	All AEs that started after the first dose of study drug up to Day 168 (study completion)
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Pooled Placebo		Cohort A: Ixazomib 0.5 mg		Cohort B: Ixazomib 2 mg
Arm/Group Description	Ixazomib placebo-matching capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.		Ixazomib 0.5 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.		Ixazomib 2 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle from Cycle 1 to Cycle 3.
All Cause Mortality
	Pooled Placebo		Cohort A: Ixazomib 0.5 mg		Cohort B: Ixazomib 2 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/5 (0%)		0/4 (0%)
Serious Adverse Events
	Pooled Placebo		Cohort A: Ixazomib 0.5 mg		Cohort B: Ixazomib 2 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/5 (0%)		1/4 (25%)
Vascular disorders
Deep vein thrombosis	0/3 (0%)	0	0/5 (0%)	0	1/4 (25%)	1
Other (Not Including Serious) Adverse Events
	Pooled Placebo		Cohort A: Ixazomib 0.5 mg		Cohort B: Ixazomib 2 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		5/5 (100%)		3/4 (75%)
Blood and lymphatic system disorders
Iron deficiency anaemia	0/3 (0%)	0	0/5 (0%)	0	1/4 (25%)	1
Eye disorders
Eye inflammation	0/3 (0%)	0	0/5 (0%)	0	1/4 (25%)	1
Gastrointestinal disorders
Vomiting	0/3 (0%)	0	1/5 (20%)	1	1/4 (25%)	1
Nausea	0/3 (0%)	0	1/5 (20%)	1	0/4 (0%)	0
General disorders
Influenza like illness	0/3 (0%)	0	1/5 (20%)	1	0/4 (0%)	0
Infections and infestations
Acute sinusitis	0/3 (0%)	0	1/5 (20%)	1	0/4 (0%)	0
Gastroenteritis	0/3 (0%)	0	1/5 (20%)	1	0/4 (0%)	0
Influenza	0/3 (0%)	0	0/5 (0%)	0	1/4 (25%)	1
Oral herpes	0/3 (0%)	0	1/5 (20%)	1	0/4 (0%)	0
Pyuria	0/3 (0%)	0	1/5 (20%)	1	0/4 (0%)	0
Upper respiratory tract infection	0/3 (0%)	0	0/5 (0%)	0	1/4 (25%)	1
Injury, poisoning and procedural complications
Limb injury	1/3 (33.3%)	1	0/5 (0%)	0	0/4 (0%)	0
Muscle strain	1/3 (33.3%)	1	0/5 (0%)	0	0/4 (0%)	0
Metabolism and nutrition disorders
Hypokalaemia	1/3 (33.3%)	1	1/5 (20%)	1	0/4 (0%)	0
Nervous system disorders
Headache	0/3 (0%)	0	2/5 (40%)	2	1/4 (25%)	1
Tremor	0/3 (0%)	0	1/5 (20%)	1	0/4 (0%)	0
Renal and urinary disorders
Proteinuria	0/3 (0%)	0	0/5 (0%)	0	1/4 (25%)	1
Respiratory, thoracic and mediastinal disorders
Laryngeal inflammation	0/3 (0%)	0	1/5 (20%)	1	0/4 (0%)	0
Rhinitis allergic	0/3 (0%)	0	0/5 (0%)	0	1/4 (25%)	1
Skin and subcutaneous tissue disorders
Systemic lupus erythematosus rash	1/3 (33.3%)	1	0/5 (0%)	0	0/4 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Research Organization shall not publish any articles or papers nor make any presentations, nor assist any other person in publishing any articles or papers or in making any presentations relating or referring to the Study or any results, data or insights from or any data, information or materials obtained or generated in the performance of its obligations without the prior written consent of Takeda, which consent may be granted or withheld in Takeda's sole discretion.