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Rituximab and Belimumab for Lupus Nephritis (CALIBRATE)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Immune Tolerance Network (ITN)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT02260934
First received: October 6, 2014
Last updated: June 6, 2017
Last verified: June 2017
  Purpose
In this experimental study, researchers will try to find out if treatment of lupus nephritis with a combination of rituximab and cyclophosphamide (CTX), or a combination of rituximab and CTX followed by treatment with belimumab is safe and if this drug combination can block the immune system attacks.

Condition Intervention Phase
Lupus Nephritis Biological: Rituximab Drug: Cyclophosphamide Drug: Prednisone Drug: Methylprednisolone Drug: Diphenhydramine Drug: Acetaminophen Biological: Belimumab Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis (ITN055AI)

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Proportion of participants who experience at least one Grade 3 or higher infectious adverse event. [ Time Frame: At or prior to week 48 ]

Secondary Outcome Measures:
  • Proportion of participants who experience at least one Grade 3 or higher infectious adverse event. [ Time Frame: At or prior to week 24, and at or prior to week 96 ]
  • Proportion of participants with B cell reconstitution. [ Time Frame: At week 24, 48, and 96 ]
    B cell reconstitution defined as the participant's baseline B cell count, or the lower limit of normal, whichever is lower.

  • Proportion of participants with hypogammaglobulinemia. [ Time Frame: At or before week 24, 48, and 96. ]
    Hypogammaglobulinemia defined as IgG <450 mg/dL on at least two consecutive visits.

  • Proportion of participants with a complete response. [ Time Frame: At week 24 ]

    Complete response is defined as meeting all of the following criteria:

    • Urine protein-to-creatinine ratio (UPCR) < 0.5, based on a 24-hour collection
    • Estimated glomerular filtration rate (eGFR) >=120 ml/min/1.73m^2 calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula [104] or, if <120 ml/min/1.73m^2, then >80% of eGFR at entry.
    • Prednisone dose tapered to 10 mg/day, or as specified in section 5.5.2.
    • Hematuria <=10 Red blood cell per high powered field (RBC/hpf) with no RBC casts, in the absence of menses and infection.

  • Proportion of participants with an overall response (complete or partial response). [ Time Frame: At week 24 ]

    A partial response is defined as meeting all of the following criteria:

    • >= 50% improvement in the UPCR from study entry, based on a 24-hour collection
    • Estimated glomerular filtration rate (eGFR) >=120 ml/min/1.73m2 calculated by the CKD-EPI formula [104] or, if < 120 ml/min/1.73m2, then >80% of eGFR at entry.
    • Prednisone dose tapered to 10 mg/day, or as specified in section 5.5.2.

  • Proportion of participants with complete response. [ Time Frame: At week 48 ]
  • Proportion of participants with an overall response (complete or partial response) [ Time Frame: At week 48 ]
  • Proportion of participants with complete response (cumulative complete response) [ Time Frame: At week 96 ]
  • Proportion of participants with sustained complete response(representing "clinical tolerance"). [ Time Frame: At week 96. ]
    Sustained complete response is defined as a complete response measured at 48 and 96 weeks.

  • The proportion of participants with an overall response (complete or partial response) [ Time Frame: At week 96 ]
  • Proportion of participants with treatment failure. [ Time Frame: At or before week 24, 48, and 96 ]
    Treatment failure as defined by withdrawal from the protocol due to worsening nephritis, infection, or study medication toxicity.

  • Frequency of non-renal flares. [ Time Frame: At or before week 24, 48, and 96 ]
    Frequency of non-renal flares defined by the British Isles Lupus Assessment Group (BILAG) criteria.

  • Anti-dsDNA antibodies and C3, C4 levels. [ Time Frame: At week 24, 48, and 96 ]
  • Frequency of any event leading to death. [ Time Frame: At week 24, 48, and 96 ]
  • Frequency of Grade 2 or greater leukopenia. [ Time Frame: At week 24, 48, and 96 ]
  • Frequency of Grade 2 or greater thrombocytopenia. [ Time Frame: At week 24, 48, and 96 ]
  • Frequency of premature ovarian failure. [ Time Frame: At week 24, 48, and 96 ]
  • Frequency of malignancy. [ Time Frame: At week 24, 48, and 96 ]
  • Frequency of venous thromboembolic event (deep venous thrombosis or pulmonary embolism). [ Time Frame: At week 24, 48, and 96 ]
  • Frequency of disease- or study medication-related event leading to hospitalization. [ Time Frame: At week 24, 48, and 96 ]
  • Frequency of infusion reactions (within 24 hours of infusion) that result in the cessation of further infusions (including cytokine-release allergic reaction). [ Time Frame: At week 24, 48, and 96 ]

Enrollment: 43
Study Start Date: October 2014
Estimated Study Completion Date: June 2019
Estimated Primary Completion Date: June 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Rituximab/Cyclophosphamide (RC)
Prednisone taper to 10 mg/day by week 12 and continue prednisone 10 mg/day to week 96.
Biological: Rituximab
Rituximab 1000mg intravenously (IV) at week 0 and week 2
Other Name: Rituxan
Drug: Cyclophosphamide
Cyclophosphamide (750 mg) intravenously (IV) at week 0 and week 2.
Other Name: Cytoxan
Drug: Prednisone
  • Week 0 and Week 2: Prednisone (40 mg/day; taper to 10 mg/day by week 12)
  • Continue prednisone 10 mg/day to week 96
Other Name: Deltasone
Drug: Methylprednisolone

Week 0 and Week 2:

Solumedrol (100 mg) IV

Other Name: Solu-Medrol
Drug: Diphenhydramine
Diphenhydramine (50 mg, or equivalent dose of similar antihistamine) will be given orally 1 hour (plus or minus 15 minutes) before each infusion of rituximab.
Drug: Acetaminophen
Acetaminophen (650 mg) will be given orally 1 hour (plus or minus 15 minutes) before each infusion of rituximab.
Other Name: Tylenol
Experimental: Rituximab/Cyclophosphamide/Belimumab (RCB)
  1. Belimumab (10 mg/kg IV) at weeks 4, 6, 8, and every 4 weeks to week 48.
  2. Prednisone taper to 10 mg/day by week 12, and continue prednisone 10 mg/day to week 96.
Biological: Rituximab
Rituximab 1000mg intravenously (IV) at week 0 and week 2.
Other Name: Rituxan
Drug: Cyclophosphamide
Cyclophosphamide (750 mg) intravenously (IV) at week 0 and week 2.
Other Name: Cytoxan
Drug: Prednisone
  • Week 0 and Week 2: Prednisone (40 mg/day; taper to 10 mg/day by week 12)
  • Continue prednisone 10 mg/day to week 96
Other Name: Deltasone
Drug: Methylprednisolone
Week 0 and Week 2: Solumedrol (100 mg) IV
Other Name: Solu-Medrol
Drug: Diphenhydramine
Diphenhydramine (50 mg, or equivalent dose of similar antihistamine) will be given orally 1 hour (plus or minus 15 minutes) before each infusion of rituximab.
Drug: Acetaminophen
Acetaminophen (650 mg) will be given orally 1 hour (plus or minus 15 minutes) before each infusion of rituximab.
Other Name: Tylenol
Biological: Belimumab
The RCB Group will receive IV belimumab 10mg/kg at weeks 4, 6, 8, and then every 4 weeks through week 48
Other Name: Benlysta

Detailed Description:

Lupus nephritis is a severe form of systemic lupus erythematosus (SLE) with active disease in the kidneys. SLE is a complex disease in which the body's own immune system attacks some of the body parts: the skin, the joints, the kidneys, the nervous system, the heart, the lungs and the blood. The cause of SLE is not known. Treatment for SLE usually involves drugs that are designed to block the immune system attacks. When SLE affects the kidneys (nephritis), stronger immune suppressing treatment is usually needed.

The drugs used in treatment of lupus nephritis often do not cure the disease and can cause serious side effects, including lowering the immune system too much. When the immune system is too low, a person is at a higher risk of getting infections. Therefore, research into new treatments with fewer serious side effects is needed for lupus nephritis.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Diagnosis of Systemic Lupus Erythematosus (SLE) by American College of Rheumatology (ACR) criteria.
  2. Positive antinuclear antibody (ANA) or positive anti-ds DNA test results at visit -1 or any time within 14 days before visit -1.
  3. Active proliferative lupus nephritis, as defined by either of the following:

    • Kidney biopsy documentation within the last 3 months of International Society of Nephrology/Renal Pathology Society (ISN/RPS) proliferative nephritis: Class III, Class IV, or Class V in combination with Class III or IV.
    • Active urinary sediment and kidney biopsy documentation within the last 12 months of ISN/RPS proliferative nephritis: Class III, Class IV, or Class V in combination with Class III or IV. Active urinary sediment is defined as any one of the following:
    • >5 RBC/hpf in the absence of menses and infection;
    • >5 White blood cell per high powered field (WBC/hpf) in the absence of infection; or
    • Cellular casts limited to RBC or WBC casts.
  4. Urine protein-to-creatinine ratio (UPCR) >1 at study entry based on a 24-hour collection.
  5. Ability to provide informed consent.

Exclusion Criteria:

  1. New onset lupus nephritis, defined as lupus nephritis for which the participant has not yet been treated with either mycophenolate mofetil or cyclophosphamide.
  2. Neutropenia (absolute neutrophil count <1500/mm^3).
  3. Thrombocytopenia (platelets <50,000/mm^3).
  4. Moderately severe anemia (Hgb < mg/dL).
  5. Moderately severe hypogammaglobulinemia (IgG <450 mg/dL) or Immunoglobulin A (IgA) <10mg/dL.
  6. Positive QuantiFERON -Tuberculosis (TB) Gold test results.
  7. Pulmonary fibrotic changes on chest radiograph consistent with prior healed tuberculosis.
  8. Active bacterial, viral, fungal, or opportunistic infections.
  9. Evidence of infection with human immunodeficiency virus (HIV), hepatitis B (as assessed by HBsAg and anti-HBc) or hepatitis C.
  10. Hospitalization for treatment of infections, or parenteral (IV or IM) antibacterials, antivirals, anti-fungals, or anti-parasitic agents within the past 60 days.
  11. Chronic infection that is currently being treated with suppressive antibiotic therapy, including but not limited to tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster, and atypical mycobacteria.
  12. History of significant infection or recurrent infection that, in the investigator's opinion, places the participant at risk by participating in this study.
  13. Receipt of a live-attenuated vaccine within 3 months of study enrollment.
  14. End-stage renal disease (eGFR <20 mL/min/1.73m^2).
  15. Concomitant malignancies or a history of malignancy, with the exception of adequately treated basal and squamous cell carcinoma of the skin, or carcinoma in situ of the cervix.
  16. History of transplantation.
  17. History of primary immunodeficiency.
  18. Pregnancy.
  19. Breastfeeding.
  20. Unwillingness to use an FDA-approved form of birth control (including but not limited to a diaphragm, an intrauterine device, progesterone implants or injections, oral contraceptives, the double-barrier method, or a condom).
  21. Use of cyclophosphamide within the past 6 months.
  22. Use of anti-Tumor Necrosis Factor (TNF) medication, other biologic medications, or experimental non- biologic therapeutic agents within the past 90 days, or 5 half-lives prior to screening, whichever is greater.
  23. Intravenous immunoglobulin (IVIG), plasmapheresis, or leukopheresis within the past 90 days.
  24. Use of investigational biologic agent within the past 12 months.
  25. Prior treatment with rituximab, belimumab, atacicept, or other biologic B cell therapy.
  26. Liver function test [aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase] results that are >=2 times the upper limit of normal.
  27. Severe, progressive, or uncontrolled renal, hepatic, hematological,gastrointestinal, pulmonary, cardiac, or neurological disease, either related or unrelated to SLE, with the exception of active lupus nephritis (or, in the investigator's opinion, any other concomitant medical condition that places the participant at risk by participating in this study).
  28. Comorbidities requiring corticosteroid therapy, including those which have required three or more courses of systemic corticosteroids within the previous 12 months.
  29. Current substance abuse or history of substance abuse within the past year.
  30. History of severe allergic or anaphylactic reactions to chimeric or fully human monoclonal antibodies.
  31. History of anaphylactic reaction to parenteral administration of contrast agents.
  32. Lack of peripheral venous access.
  33. History of severe depression or severe psychiatric condition.
  34. History of suicidal thoughts within the past 2 months or suicidal behavior within the past 6 months, or a significant suicide risk in the investigator's opinion.
  35. Inability to comply with study and follow-up procedures.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02260934

Locations
United States, Alabama
University of Alabama, Birmingham
Birmingham, Alabama, United States, 35294
United States, California
UCLA Medical Center: Division of Rheumatology
Los Angeles, California, United States, 90095
University of California, San Francisco
San Francisco, California, United States, 94143
United States, Colorado
University of Colorado Denver: School of Medicine: Division of Rheumatology
Aurora, Colorado, United States, 80045
Colorado Kidney Care
Denver, Colorado, United States, 80218
United States, Georgia
Emory University School of Medicine
Atlanta, Georgia, United States, 30303
United States, Missouri
Washington University in St. Louis
Saint Louis, Missouri, United States, 36110
United States, New York
Feinstein Institute, North Shore Hospital
Manhasset, New York, United States, 10030
New York University, Langone Medical Center
New York, New York, United States, 10016
Weill Cornell Medical College: Hospital for Special Surgery -
New York, New York, United States, 10021
Columbia University Medical Center
New York, New York, United States, 10032
United States, North Carolina
University of North Carolina School of Medicine:
Chapel Hill, North Carolina, United States, 27599
United States, Ohio
Ohio State University Wexner Medical Center:
Columbus, Ohio, United States, 43213
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
United States, Texas
University of Texas Southwestern
Dallas, Texas, United States, 75390
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Immune Tolerance Network (ITN)
Investigators
Study Chair: Betty Diamond, M.D. Feinstein Institute for Medical Research: Center for Autoimmune and Musculoskeletal Diseases
Study Chair: David Wofsy, M.D. University of California San Francisco School of Medicine: Division of Rheumatology
Study Chair: Maria Dall'Era, M.D. University of California San Francisco School of Medicine: Division of Rheumatology
Study Chair: Cynthia Aranow, M.D. Feinstein Institute for Medical Research: Center for Autoimmune and Musculoskeletal Diseases
  More Information

Additional Information:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT02260934     History of Changes
Other Study ID Numbers: DAIT ITN055AI
CALIBRATE ( Other Identifier: Immune Tolerance Network )
Study First Received: October 6, 2014
Last Updated: June 6, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Participant level data access will be made available to the public at some point in the future via the mechanisms of : 1.) the Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts; and 2.) TrialShare, the Immune Tolerance Network (ITN) Clinical Trials Research Portal.

Additional relevant MeSH terms:
Nephritis
Lupus Nephritis
Kidney Diseases
Urologic Diseases
Glomerulonephritis
Lupus Erythematosus, Systemic
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Cyclophosphamide
Belimumab
Rituximab
Prednisone
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Methylprednisolone acetate
Methylprednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Acetaminophen
Diphenhydramine
Promethazine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 25, 2017