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Trial record 1 of 56 for:    Systemic Lupus Erythematosus with Nephritis 2
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A Study of KZR-616 in Patients With Systemic Lupus Erythematosus With and Without Nephritis

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ClinicalTrials.gov Identifier: NCT03393013
Recruitment Status : Recruiting
First Posted : January 8, 2018
Last Update Posted : May 20, 2019
Sponsor:
Information provided by (Responsible Party):
Kezar Life Sciences, Inc.

Brief Summary:

This is a Phase 1b/2, multi-center study in which patients will receive KZR-616, administered as a subcutaneous (SC) injection weekly for 13 weeks.

The study consists of 2 parts. Part 1, the Phase 1b, is an open-label multiple dose escalation study to evaluate the safety and tolerability of KZR-616 in patients with systemic lupus erythematosus (SLE) with and without nephritis. Part 2, the Phase 2, is a randomized, placebo-controlled, double-blind study to evaluate the safety and efficacy of KZR-616 in patients with active proliferative lupus nephritis (LN).


Condition or disease Intervention/treatment Phase
Systemic Lupus Erythematosus Lupus Nephritis Drug: KZR-616 Drug: Placebo Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 1b/2 Study of KZR-616 in Patients With Systemic Lupus Erythematosus With and Without Nephritis
Actual Study Start Date : March 7, 2018
Estimated Primary Completion Date : February 2020
Estimated Study Completion Date : May 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lupus

Arm Intervention/treatment
Experimental: KZR-616 Dose Level 1 + standard therapy
1 of 2 dose levels of KZR-616 selected based on data from the Phase 1 dose escalation and administered in combination with Mycophenolate Mofetil (MMF) and prednisone
Drug: KZR-616
Subcutaneous Injection of KZR-616

Experimental: KZR-616 Dose Level 2 + standard therapy
1 of 2 dose levels of KZR-616 selected based on data from the Phase 1 dose escalation and administered in combination with MMF and prednisone
Drug: KZR-616
Subcutaneous Injection of KZR-616

Placebo Comparator: Placebo + standard therapy
Placebo administered with MMF and prednisone
Drug: Placebo
Subcutaneous injection of matching placebo




Primary Outcome Measures :
  1. Phase 1 and Phase 2: Safety and Tolerability assessed by monitoring incidence and severity of adverse events (AEs) [ Time Frame: Baseline through 25 weeks ]

Secondary Outcome Measures :
  1. Phase 1: Identify Recommended Phase 2 dose levels (RP2Ds) of KZR-616 [ Time Frame: 4 weeks ]
    Determined through assessment of all AEs and any dose limiting toxicities (DLTs)

  2. Phase 1: Peak plasma concentration (Cmax) following injection with KZR-616 [ Time Frame: Day 1 ]
  3. Phase 1: Peak plasma concentration (Cmax) following injection with KZR-616 [ Time Frame: Day 29 ]
  4. Phase 1: Time to peak plasma concentration (Tmax) of KZR-616 [ Time Frame: Day 1 ]
  5. Phase 1: Time to peak plasma concentration (Tmax) of KZR-616 [ Time Frame: Day 29 ]
  6. Phase 1: Area under the plasma concentration versus time curve (AUC) of KZR-616 [ Time Frame: Day 1 ]
  7. Phase 1: Area under the plasma concentration versus time curve (AUC) of KZR-616 [ Time Frame: Day 29 ]
  8. Phase 1: Half-life of KZR-616 (T1/2) [ Time Frame: Day 1 ]
  9. Phase 1: Half-life of KZR-616 (T1/2) [ Time Frame: Day 29 ]
  10. Phase 2: The number of patients with a 50% reduction in urine protein to creatinine ratio (UPCR) [ Time Frame: Baseline and every 4 weeks through 25 weeks ]
  11. Phase 2: The number of patients with a complete renal response [ Time Frame: Every 4 weeks through 25 weeks ]
    UPCR of ≤ 0.5; estimated Glomerular Filtration Rate (eGFR) of ≥ 60 mL/min or no worsening of eGFR from baseline of > 20%; No discontinuation of investigational product or use of restricted medication beyond the protocol-allowed thresholds from Days 1 to 85

  12. Phase 2: Change from baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) [ Time Frame: Baseline and every 4 weeks through 25 weeks ]
  13. Phase 2: Change from baseline in British Isles Lupus Assessment Group (BILAG) score [ Time Frame: Baseline and every 4 weeks through 25 weeks ]
  14. Phase 2: Change from baseline in Levels of Autoantibodies (ANA and anti-dsDNA) and Complement (C3 and C4) [ Time Frame: Baseline and every 4 weeks through 25 weeks ]
  15. Phase 2: Change from baseline in UPCR [ Time Frame: Baseline and every 4 weeks through 25 weeks ]
  16. Phase 2: Change from baseline in eGFR [ Time Frame: Baseline and every 4 weeks through 25 weeks ]
  17. Phase 2: Change from baseline in daily glucocorticoid use [ Time Frame: Baseline and every 4 weeks through 25 weeks ]

Other Outcome Measures:
  1. Phase 1 and 2: Inhibition of chymotrypsin-like (CT-L) activity in whole blood and peripheral blood mononuclear cells (PBMCs); [ Time Frame: Day 1 ]
  2. Phase 1 and 2: Inhibition of chymotrypsin-like (CT-L) activity in whole blood and peripheral blood mononuclear cells (PBMCs); [ Time Frame: Day 29 ]
  3. Phase 1 and 2: Assessment of proteasome sub-unit occupancy in whole blood and PBMCs [ Time Frame: Day 1 ]
  4. Phase 1 and 2: Assessment of proteasome sub-unit occupancy in whole blood and PBMCs [ Time Frame: Day 29 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

PHASE 1b:

  1. Male or female patients aged 18 to 75 (inclusive)
  2. Body Mass Index (BMI) of 18-40 kg/m2
  3. Fulfills the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE
  4. Have at least one of the following at screening per central lab:

    1. Positive antinuclear antibody (ANA) test (1:80 or higher); or
    2. Anti-double stranded deoxyribonucleic acid (dsDNA) antibodies elevated to above normal (i.e. positive results); or
    3. Anti-Smith antibody elevated to above normal (i.e., positive results)
  5. Active SLE as indicated by a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) total score ≥ 4 at screening
  6. Must have received 1 or more therapies for SLE
  7. Acceptable screening laboratory values of concern, including:

    1. Adequate hematologic criteria:
    2. Adequate hepatic function:
    3. Pancreatic enzymes
    4. eGFR ≥ 40 mL/min/1.73 m2 (estimated based on Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula)
    5. IgG ≥ 500 mg/dL
  8. If taking the following SLE therapies:

    1. Oral glucocorticoids (up to 20 mg/day prednisone or equivalent): must be on a stable dosage regimen of oral corticosteroid at least 4 weeks prior to screening and maintain stable dose until randomization
    2. Hydroxychloroquine (≤ 400 mg/day) or chloroquine (≤ 500 mg/day) orally or other anti-malarials: must be started or stopped at least 12 weeks prior to screening, with stable dosage regimen for at least 4 weeks prior to screening
    3. Immunosuppressive agents: must be started or stopped at least 12 weeks prior to screening, with stable dosage regimen, including route of administration, for at least 4 weeks prior to screening:

      • Mycophenolate mofetil (≤ 3 g/day) or mycophenolic acid (≤ 2.16 g/day) orally
      • Azathioprine (≤ 200 mg/day) orally
      • Methotrexate (≤ 25 mg/week) orally, SC, or intramuscularly (patients must be on concomitant folic or folinic acid supplementation if using methotrexate)
      • Leflunomide (≤ 20 mg/day) orally
  9. Women of childbearing potential must have a negative serum beta-human chorionic gonadotropin (hCG) pregnancy test at screening and a negative urine pregnancy test prior to the first dose and must agree to use a highly effective method of birth control from signing the informed consent form (ICF) until their completion of the study (or 30 days following the last dose of study drug in case of early withdrawal). Hormonal contraception may not be effective in women on concomitant MMF/MPA; women on MMF/MPA using hormonal contraception must agree to use a highly effective non-hormonal method of contraception. Abstinence is not an acceptable method of birth control for this study. Women of nonchildbearing potential must be postmenopausal (no menses for at least 2 years before the screening visit), permanently sterilized (e.g., bilateral tubal occlusion, hysterectomy, bilateral salpingectomy), or congenitally sterile
  10. Male patients must use an effective contraception method (e.g., condom with spermicide) from signing the ICF until their completion of the study (or 12 weeks following the last dose of study drug in case of withdrawal) or be congenitally or surgically sterile (e.g., vasectomy with documented confirmation of post-surgical aspermia)
  11. Willing and able to provide written informed consent prior to any study-related procedures and to comply with all study requirements

PHASE 2:

  1. Male or female patients aged 18 to 75 years (inclusive)
  2. BMI of 18-40 kg/m2
  3. Fulfills the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE.
  4. Undergoing an ACR-recommended MMF- or MPA-based induction therapy regimen for lupus nephritis for 4 to 12 weeks, and willing to continue at least the MMF/MPA portion of the regimen unaltered throughout the duration of the study. Must be receiving a stable regimen of oral corticosteroids for at least 2 weeks prior to screening
  5. The patient has at least one of the following at screening per central lab:

    1. Positive ANA test (1:80 or higher) or
    2. Anti-dsDNA antibodies elevated to above normal (i.e., positive results); or
    3. Anti-Smith antibody at screening elevated to above normal (i.e., positive results)
  6. Kidney biopsy within 26 weeks prior to randomization with a histologic diagnosis of LN (International Society of Nephrology/Renal Pathology Society 2003 classification of lupus nephritis [ISN/RPS]) Classes III, IV-S or IV-G, (A) or (A/C); Patients with Class III or IV and concomitant Class V will be permitted (NOTE: Patients meeting all inclusion criteria with a kidney biopsy of greater than 26 weeks will be allowed following a repeat biopsy which shows the necessary histologic diagnosis prior to study entry)
  7. UPCR of ≥ 1.0 in 24-hour urine collection
  8. Acceptable screening laboratory values of concern, including:

    1. Adequate hematologic criteria:
    2. Adequate hepatic function:
    3. Pancreatic enzymes
    4. eGFR ≥ 40 mL/min/1.73 m2 estimated based on CKD-EPI formula
    5. IgG ≥ 500 mg/dL
  9. Women of childbearing potential must have a negative serum beta-hCG pregnancy test at screening and negative urine pregnancy test prior to the first dose and must agree to use a highly effective method of birth control from signing the ICF until their completion of the study (or 30 days following the last dose of study drug in case of early withdrawal). Hormonal contraception may not be effective in women on concomitant MMF/MPA; women on MMF or MPA using hormonal contraception must agree to use a highly effective non-hormonal method of contraception. Abstinence is not an acceptable method of birth control for this study. Women of nonchildbearing potential must be postmenopausal (no menses for at least 2 years before the screening visit), permanently sterilized (e.g., bilateral tubal occlusion, hysterectomy, bilateral salpingectomy), or congenitally sterile
  10. Male patients must use an effective contraception method (e.g., condom with spermicide) from signing the ICF until completion of the study (or 12 weeks following the last dose of study drug in case of early withdrawal) or be congenitally or surgically sterile (e.g., vasectomy with documented confirmation of post-surgical aspermia)
  11. Willing and able to provide written informed consent prior to any study-related procedures and to comply with all study requirements

Exclusion Criteria:

PHASE 1b:

  1. Active central nervous system involvement by autoimmune disease requiring specific therapeutic intervention within 60 days prior to first day of study treatment. Headache treated only with acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), or approved doses of triptans is permitted with medical monitor approval.
  2. Presence of another rheumatic (overlap) disease that may confound clinical assessments in the study. Secondary sicca or Sjogren's syndrome, antiphospholipid antibody syndrome, and overlap with rheumatoid arthritis without erosive joint disease ("rhupus") are allowed
  3. History of severe antiphospholipid syndrome within 12 months of screening or not on an adequate anticoagulation regimen. However, presence of antiphospholipid antibodies alone (without a history of thromboembolic event) is not exclusionary.
  4. Receipt of any of the following treatments within the following timeframes before screening

    1. Systemic corticosteroids ≥ 100 mg prednisone or equivalent: 4 weeks
    2. Intra-articular therapies, such as corticosteroids or hyaluronic acid preparations: 4 weeks
    3. Intravenous Immunoglobulin (IVIg): 4 weeks
    4. Other non-biologic immunosuppressive agents, such as cyclosporine, tacrolimus: 4 weeks
    5. Cyclophosphamide: 12 weeks
    6. Cytokine antagonists: 12 weeks
    7. B-cell-depleting therapies (e.g., rituximab): 24 weeks
    8. Belimumab, abatacept, or atacicept: 12 weeks
    9. Other biologics or investigational drugs: 8 weeks or 5 half-lives, whichever is longer
    10. Transfusion with blood, packed red blood cells, platelets or treatment with plasmapheresis or plasma exchange: 6 weeks
  5. Patient has had recent serious or ongoing infection, or risk for serious infection
  6. History of any concurrent illness that has required treatment with oral or parenteral corticosteroids for more than a total of 2 weeks within the last 24 weeks prior to signing the ICF
  7. Clinical evidence of significant unstable or uncontrolled acute or chronic diseases that, in the opinion of the investigator or sponsor, could confound the results of the study, put the patient at undue risk, or interfere with protocol adherence
  8. History of cancer, except for in situ cancer that has been completely excised or has been curatively treated cancer with no sign of disease for > 5 years
  9. Major surgery within 4 weeks before signing the ICF or major surgery planned during the study period

PHASE 2:

  1. Active central nervous system involvement by autoimmune disease requiring specific therapeutic intervention within 60 days prior to first day of study treatment. Headache treated only with acetaminophen, NSAIDs, or approved doses of triptans is permitted with medical monitor approval.
  2. Isolated Class V membranous LN on a renal biopsy obtained within 26 weeks prior to signing ICF or during the screening period
  3. Known intolerance to MMF or MPA
  4. History of dialysis within 12 months prior to signing the ICF or expected need for renal replacement therapy (dialysis or renal transplant) within a 6-month period after enrollment
  5. History of Rapidly Progressive Glomerulonephritis (RPGN) and/or other renal disease
  6. History of chronic kidney disease not directly due to LN
  7. Uncontrolled blood pressure (systolic blood pressure ≥160 mmHg and diastolic blood pressure ≥100 mmHg at rest)

    o If currently on RAS blockade (ACE-I, ARB, direct renin inhibitors), dose must be stable for at least 4 weeks prior to screening

  8. Receipt of any of the following treatments within the following timeframes before first day of study treatment:

    1. IVIg: 4 weeks
    2. Corticosteroids ≥ 1 g/day prednisone or equivalent: 4 weeks
    3. Intra-articular therapies, such as corticosteroids or hyaluronic acid preparations: 4 weeks
    4. Conventional disease-modifying antirheumatic drugs, including methotrexate, leflunomide, sulfasalazine, cyclosporine, tacrolimus: 12 weeks
    5. MMF of ≥ 3 g (or 2.16 g of MPA) for ≥ 4 weeks, cyclophosphamide: 24 weeks
    6. Cytokine antagonists: 12 weeks
    7. B-cell-depleting therapies (e.g., rituximab): 24 weeks
    8. Other biologics or investigational drugs: 8 weeks or 5 half-lives, whichever is longer
    9. Hydroxychloroquine (>400 mg/day) or chloroquine (>500 mg/day) or other antimalarials above the recommended dose. Antimalarials, if used, must have been started or stopped at least 12 weeks prior to first dose, with stable dosage regimen for at least 4 weeks prior to first dose of study treatment
    10. Abatacept: 12 weeks
  9. Major surgery within 4 weeks before signing the ICF or major surgery planned during the study period
  10. History of any other concurrent illness, including drug induced SLE, that has required treatment with oral or parenteral corticosteroids for more than a total of 2 weeks within the last 24 weeks prior to signing the ICF
  11. Patient has had recent serious or ongoing infection, or risk for serious infection
  12. Clinical evidence of significant unstable or uncontrolled acute or chronic diseases in the opinion of the investigator
  13. History of cancer, except for in situ cancer that has been completely excised or has been curatively treated with no sign of disease for > 5 years
  14. Presence of another rheumatic (overlap) disease that nay confound clinical assessment in the study.
  15. History of antiphospholipid syndrome with history of thromboembolic event within 12 months of screening or not an adequate anticoagulation regimen. However history of antiphospholipid antibodies alone (without history of thromboembolic event) is not exclusionary.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03393013


Contacts
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Contact: Clinical Operations 650 822-5600 clinicaltrials@kezarbio.com

Locations
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United States, California
KZR Research Site Recruiting
Upland, California, United States, 91786
United States, Florida
KZR Research Site Recruiting
Coral Gables, Florida, United States, 33134
KZR Research Site Recruiting
Miami, Florida, United States, 33136
KZR Research Site Recruiting
Miami, Florida, United States, 33165
KZR Research Site Recruiting
Orlando, Florida, United States, 32810
KZR Research Site Recruiting
Palm Harbor, Florida, United States, 34684
KZR Research Site Recruiting
Tampa, Florida, United States, 33613
United States, New York
KZR Research Site Recruiting
Great Neck, New York, United States, 11021
KZR Research Site Recruiting
Manhasset, New York, United States, 11030
KZR Research Site Recruiting
Rochester, New York, United States, 14642
United States, Ohio
KZR Research Site Recruiting
Columbus, Ohio, United States, 43210
United States, Tennessee
KZR Research Site Recruiting
Memphis, Tennessee, United States, 38119
United States, Texas
KZR Research Site Recruiting
Houston, Texas, United States, 77034
KZR Research Site Recruiting
Houston, Texas, United States, 77084
Australia, Victoria
KZR Research Site Recruiting
Parkville, Victoria, Australia, 3052
Colombia
KZR Research Site Not yet recruiting
Barranquilla, Atlantico, Colombia
KZR Research Site Not yet recruiting
Bucaramanga, Santander, Colombia
KZR Research Site Not yet recruiting
Cali, Valle Del Cauca, Colombia
Mexico
KZR Research Site Recruiting
Guadalajara, Jalisco, Mexico
KZR Research Site Recruiting
Monterrey, Nuevo Leon, Mexico
KZR Research Site Recruiting
Mexico City, Mexico
Sponsors and Collaborators
Kezar Life Sciences, Inc.
Investigators
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Study Director: Kezar Kezar

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Responsible Party: Kezar Life Sciences, Inc.
ClinicalTrials.gov Identifier: NCT03393013     History of Changes
Other Study ID Numbers: KZR-616-002
First Posted: January 8, 2018    Key Record Dates
Last Update Posted: May 20, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Kezar Life Sciences, Inc.:
immunoproteasome inhibition
selective proteasome inhibition
proteasome

Additional relevant MeSH terms:
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Lupus Erythematosus, Systemic
Nephritis
Lupus Nephritis
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Kidney Diseases
Urologic Diseases
Glomerulonephritis