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Lupus NephritisPhase 1NCT02176486

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

A Phase 1 study testing Ixazomib in people with Lupus Nephritis, run by Takeda at 35 sites in 7 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 75 years
Conditions the study is for
Lupus Nephritis
What is being tested?
Ixazomib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
12 participants
Where
35 sitesin 7 countries
Study dates
9 Jun 2014to 19 Jan 2018
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • In the opinion of the investigator, is capable of understanding and complying with protocol requirements.
  • 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.
  • Is female or male and aged 18 to 75 years, inclusive.
  • 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.
  • 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).
  • If no biopsy was done within 2 year of Screening Visit, biopsy can be done during the screening period as a study procedure.
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  • Co-existence of classes is permitted.
  • 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:
  • 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.
  • Low complement (either C3 or C4) at Screening (>= 25 percent [%] lower than lower limit of normal [LLN]).
  • 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.
  • 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).
  • 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.
  • Male participants who are sexually active with women of child bearing potential (WOCBP), even if surgically sterilized (that is, status post-vasectomy), must:
  • Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug.
  • Female participants who are of child bearing potential must:
  • 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.
  • 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.
  • Must be receiving Standard of Care (SOC) treatment with an immunosuppressant drug for the treatment of LN (example, MMF, MA or AZA).

Who cannot join

  • 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.
  • Has received ixazomib, bortezomib, or another proteasome inhibitor in a previous clinical study or as a therapeutic agent.
  • 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.
  • Has an autoimmune disease other than SLE as their main diagnosis.
  • Has drug-induced SLE.
  • Has severe, active central nervous system (CNS) lupus (British Isles Lupus Assessment Group [BILAG] A or B).
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  • 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.
  • 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.
  • 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.
  • Has one of the following laboratory test values:
  • IgG<75% of LLN
  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the central laboratory's ULN
  • 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).
  • Platelets <75,000 per cubic millimeter (/mm^3)
  • Neutrophils <1500/ mm^3 or > 11,000/ mm^3
  • Hemoglobin <8 grams per deciliter (g/dL)
  • Positive for Hepatitis B Surface Antigen.
  • Positive for Hepatitis C antibody.
  • 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.
  • 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.
  • 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.
  • 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.
  • Is taking excluded medications.
  • 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.
  • Has been treated with CYC within 4 weeks of the Screening Visit.
  • Has been treated with > 3 g/day of MMF within 4 weeks of the Screening Visit.
  • Has been treated with belimumab, abatacept or tocilizumab within 3 months of the Screening Visit.
  • Has been treated with eprazutumab, alemtuzumab, rituximab or other cell depleting biological agents within 6 months of the Screening Visit.
  • 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.

Trial locations and contacts

35 sites in 7 countries.

35 sites in 7 countries

United States12 sites

  • Study site

    Brooklyn, New York

  • Study site

    Charleston, South Carolina

  • Study site

    Evergreen Park, Illinois

  • Study site

    Great Neck, New York

  • Study site

    Jackson, Tennessee

  • Study site

    La Jolla, California

  • Study site

    Lancaster, Pennsylvania

  • Study site

    Manhasset, New York

  • Study site

    Middleburg Heights, Ohio

  • Study site

    New York, New York

  • Study site

    Port Charlotte, Florida

  • Study site

    Upland, California

Other trials in United States

Germany7 sites

  • Study site

    Aachen, North Rhine-Westphalia

  • Study site

    Berlin

  • Study site

    Düsseldorf, North Rhine-Westphalia

  • Study site

    Essen

  • Study site

    Frankfurt am Main, Hesse

  • Study site

    Freiburg im Breisgau

  • Study site

    Mainz, Rhineland-Palatinate

Other trials in Germany

France4 sites

  • Study site

    Amiens, Somme

  • Study site

    Lille, Nord

  • Study site

    Paris

  • Study site

    Strasbourg

Other trials in France

Italy4 sites

  • Study site

    Padova, Veneto

  • Study site

    Pisa, Tuscany

  • Study site

    Rome, Lazio

  • Study site

    Turin, Piedmont

Other trials in Italy

Russia3 sites

  • Study site

    Kazan'

  • Study site

    Kemerovo

  • Study site

    Saint Petersburg

Other trials in Russia

Spain3 sites

  • Study site

    Bilbao, Vizcaya

  • Study site

    Madrid, Madrid, Communidad Delaware

  • Study site

    Madrid

Other trials in Spain

United Kingdom2 sites

  • Study site

    London, London, City of

  • Study site

    London

Other trials in United Kingdom

About this study

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

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.

Read the 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.

Conditions
Lupus Nephritis
Being tested
Ixazomib, Placebo
Keywords
Drug Therapy
Medical subject headings
Lupus Nephritis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • IxazomibDrug

    Also called MLN9708

    Ixazomib capsules.

  • PlaceboDrug

    Ixazomib placebo-matching capsules.

Study groups in NCT02176486
Study groupRoleWhat they receive
Cohort A: Ixazomib 0.5 milligram (mg)ExperimentalIxazomib 0.5 mg, capsules, orally, once, on Day 1, 8 and 15 in 28-day cycles, Cycles 1 through 3.
Receives: Drug: Ixazomib
Cohort B: Ixazomib 2 mgExperimentalIxazomib 2 mg, capsules, orally, once, on Day 1, 8 and 15 in 28-day cycles, Cycles 1 through 3.
Receives: Drug: Ixazomib
Cohort C: Ixazomib 3 mgExperimentalIxazomib 3 mg, capsules, orally, once, on Day 1, 8 and 15 in 28-day cycles, Cycles 1 through 3.
Receives: Drug: Ixazomib
Cohort D: Ixazomib 4 mgExperimentalIxazomib 4 mg, capsules, orally, once, on Day 1, 8 and 15 in 28-day cycles, Cycles 1 through 3.
Receives: Drug: Ixazomib
Cohorts A through D: PlaceboPlacebo comparatorIxazomib placebo-matching capsules, orally, once on Days 1, 8 and 15 in 28-day cycle, Cycles 1 through 3.
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Percentage of Participants Who Experienced at Least One Grade Greater Than or Equal to (>=) 2 Treatment Emergent Adverse Event (TEAE)

    Measured: 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)

    Measured: 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

    Measured: Baseline up to Day 168

  4. Percentage of Participants With at Least One Markedly Abnormal Value (MAV) for Hematologic Parameters

    Measured: Baseline up to Day 168

Secondary outcomes (6)

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

    Measured: Baseline and Day 84

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

    Measured: Baseline and Day 84

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

    Measured: Baseline and Day 84

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

    Measured: Baseline and Day 84

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

    Measured: Baseline and Day 84

  6. Plasma Concentrations of Ixazomib at Each Scheduled Collection Time

    Measured: Cycle 1 Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length is equal to [=] 28 days)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Jun 2014 (estimated)
  2. Study start9 Jun 2014
  3. Primary completion30 Mar 2017
  4. Study completion19 Jan 2018

Why it stopped: Insufficient enrollment, no safety or efficacy concerns

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
12 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02176486
Sponsor's protocol ID
MLN9708_101
Other IDs
U1111-1152-6999, 2014-000125-21, 14/LO/1087, 2014
Status last verified
Jan 2019
First submitted
25 Jun 2014
Last updated
8 Apr 2019
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: Takeda makes patient-level, de-identified data sets and associated documents available after applicable marketing approvals and commercial availability have been received, an opportunity for the primary publication of the research has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com/Approach for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Ixazomib in people with Lupus Nephritis, run by Takeda at 35 sites in 7 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 25 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 8 Apr 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 35 sites in United States, Germany, France, Italy, Russia and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 8 Apr 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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)). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02176486.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Apr 2019.

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