Rituximab and Belimumab for Lupus Nephritis

NCT02260934 | Completed Phase 2 Results DMC

• 2 other identifiers: DAIT ITN055AICALIBRATE
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 15

Brief Summary

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.

Conditions

Lupus Nephritis

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With At Least One Grade 3 or Higher Infectious Adverse Event By Week 24, Week 48 and Week 96

  The percentage of participants who experienced at least one Grade 3 or higher treatment-emergent infectious adverse event. The severity of adverse events (AEs) was classified into grades using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, v4.03:June 14, 2010). Treatment-emergent AEs are those: * with an onset date on or after the first dose of study medication, * with onset before first dose but that worsened in severity after first dose, and * for which the start of the AE in relation to the start of study medication could not be established. AEs were classified by system organ class and preferred term according to the Medical Dictionary for Regulatory Activities (MedDRA) version 17.0. Grade 3 or higher AEs were classified infectious based on the study team's review of the MedDRA body systems and preferred terms of the AEs.

  Week 0 to Week 96

Secondary Outcomes (14)

• Percentage of Participants With B Cell Reconstitution at Week 24, Week 48 and Week 96

  Week 24, Week 48 and Week 96

• Percentage of Participants With Grade 4 Hypogammaglobulinemia by Week 24, Week 48, and Week 96

  Week 24, Week 48 and Week 96

• Percentage of Participants With a Complete Response at Week 24, Week 48, and Week 96

  Week 24, Week 48 and Week 96

• Percentage of Participants With an Overall Response at Week 24, Week 48, and Week 96

  Week 24, Week 48 and Week 96

• Percentage of Participants With a Sustained Complete Response

  Week 48, Week 96

Study Arms (2)

Rituximab/Cyclophosphamide (RC)

ACTIVE COMPARATOR

Prednisone taper to 10 mg/day by week 12 and continue prednisone 10 mg/day to week 96.

Biological: Rituximab; Drug: Cyclophosphamide; Drug: Prednisone; Drug: Methylprednisolone; Drug: Diphenhydramine; Drug: Acetaminophen

Rituximab/Cyclophosphamide/Belimumab (RCB)

EXPERIMENTAL

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; Drug: Cyclophosphamide; Drug: Prednisone; Drug: Methylprednisolone; Drug: Diphenhydramine; Drug: Acetaminophen; Biological: Belimumab

Interventions

Rituximab BIOLOGICAL

Rituximab 1000mg intravenously (IV) at week 0 and week 2

Also known as: Rituxan

Rituximab/Cyclophosphamide (RC)

Cyclophosphamide DRUG

Cyclophosphamide (750 mg) intravenously (IV) at week 0 and week 2.

Also known as: Cytoxan

Rituximab/Cyclophosphamide (RC)

Prednisone DRUG

* 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

Also known as: Deltasone

Rituximab/Cyclophosphamide (RC)

Methylprednisolone DRUG

Week 0 and Week 2: Solumedrol (100 mg) IV

Also known as: Solu-Medrol

Rituximab/Cyclophosphamide (RC)

Diphenhydramine DRUG

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.

Rituximab/Cyclophosphamide (RC)

Acetaminophen DRUG

Acetaminophen (650 mg) will be given orally 1 hour (plus or minus 15 minutes) before each infusion of rituximab.

Also known as: Tylenol

Rituximab/Cyclophosphamide (RC)

Belimumab BIOLOGICAL

The RCB Group will receive IV belimumab 10mg/kg at weeks 4, 6, 8, and then every 4 weeks through week 48

Also known as: Benlysta

Rituximab/Cyclophosphamide/Belimumab (RCB)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of Systemic Lupus Erythematosus (SLE) by American College of Rheumatology (ACR) criteria.
• Positive antinuclear antibody (ANA) or positive anti-ds DNA test results at visit -1 or any time within 14 days before visit -1.
• 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.
• Urine protein-to-creatinine ratio (UPCR) \>1 at study entry based on a 24-hour collection.
• Ability to provide informed consent.

You may not qualify if:

• New onset lupus nephritis, defined as lupus nephritis for which the participant has not yet been treated with either mycophenolate mofetil or cyclophosphamide.
• Neutropenia (absolute neutrophil count \<1500/mm\^3).
• Thrombocytopenia (platelets \<50,000/mm\^3).
• Moderately severe anemia (Hgb \< mg/dL).
• Moderately severe hypogammaglobulinemia (IgG \<450 mg/dL) or Immunoglobulin A (IgA) \<10mg/dL.
• Positive QuantiFERON -Tuberculosis (TB) Gold test results.
• Pulmonary fibrotic changes on chest radiograph consistent with prior healed tuberculosis.
• Active bacterial, viral, fungal, or opportunistic infections.
• Evidence of infection with human immunodeficiency virus (HIV), hepatitis B (as assessed by HBsAg and anti-HBc) or hepatitis C.
• Hospitalization for treatment of infections, or parenteral (IV or IM) antibacterials, antivirals, anti-fungals, or anti-parasitic agents within the past 60 days.
• 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.
• History of significant infection or recurrent infection that, in the investigator's opinion, places the participant at risk by participating in this study.
• Receipt of a live-attenuated vaccine within 3 months of study enrollment.
• End-stage renal disease (eGFR \<20 mL/min/1.73m\^2).
• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Immune Tolerance Network (ITN): collaborator

Study Sites (15)

University of Alabama, Birmingham

Birmingham, Alabama, 35294, United States

Location

UCLA Medical Center: Division of Rheumatology

Los Angeles, California, 90095, United States

Location

University of California, San Francisco

San Francisco, California, 94143, United States

Location

University of Colorado Denver: School of Medicine: Division of Rheumatology

Aurora, Colorado, 80045, United States

Location

Colorado Kidney Care

Denver, Colorado, 80218, United States

Location

Emory University School of Medicine

Atlanta, Georgia, 30303, United States

Location

Washington University in St. Louis

St Louis, Missouri, 36110, United States

Location

Feinstein Institute, North Shore Hospital

Manhasset, New York, 10030, United States

Location

New York University, Langone Medical Center

New York, New York, 10016, United States

Location

Weill Cornell Medical College: Hospital for Special Surgery -

New York, New York, 10021, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

University of North Carolina School of Medicine:

Chapel Hill, North Carolina, 27599, United States

Location

Ohio State University Wexner Medical Center:

Columbus, Ohio, 43213, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

University of Texas Southwestern

Dallas, Texas, 75390, United States

Location

Related Publications (1)

• Atisha-Fregoso Y, Malkiel S, Harris KM, Byron M, Ding L, Kanaparthi S, Barry WT, Gao W, Ryker K, Tosta P, Askanase AD, Boackle SA, Chatham WW, Kamen DL, Karp DR, Kirou KA, Sam Lim S, Marder B, McMahon M, Parikh SV, Pendergraft WF 3rd, Podoll AS, Saxena A, Wofsy D, Diamond B, Smilek DE, Aranow C, Dall'Era M. Phase II Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis. Arthritis Rheumatol. 2021 Jan;73(1):121-131. doi: 10.1002/art.41466. Epub 2020 Dec 1.

  PMID: 32755035 RESULT

Related Links

• National Institute of Allergy and Infectious Diseases website
• Division of Allergy, Immunology, and Transplantation (DAIT)
• Immune Tolerance Network (ITN) website
• ITN CALIBRATE study website

MeSH Terms

Conditions

Lupus Nephritis

Interventions

Rituximab; Cyclophosphamide; Prednisone; Methylprednisolone; Methylprednisolone Hemisuccinate; Diphenhydramine; Acetaminophen; belimumab

Condition Hierarchy (Ancestors)

Glomerulonephritis; Nephritis; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Lupus Erythematosus, Systemic; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Prednisolone; Pregnadienetriols; Ethylamines; Amines; Benzhydryl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Acetanilides; Anilides; Amides; Aniline Compounds

Results Point of Contact

• Title: Director, Clinical Research Operations Program
• Organization: DAIT/NIAID

DAITClinicalTrialsGov@niaid.nih.gov

301-594-7669

Study Officials

• Betty Diamond, M.D.

  Feinstein Institute for Medical Research

  STUDY CHAIR

• David Wofsy, M.D.

  University of California San Francisco, Department of Medicine

  STUDY CHAIR

• Maria Dall'Era, M.D.

  University of California San Francisco, Department of Medicine

  STUDY CHAIR

• Cynthia Aranow, M.D.

  Feinstein Institute for Medical Research

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 6, 2014
• First Posted: October 9, 2014
• Study Start: July 9, 2015
• Primary Completion: March 12, 2018
• Study Completion: February 8, 2019
• Last Updated: December 1, 2020
• Results First Posted: April 8, 2019

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will share
• Time Frame: The aim is to share IPD within 24 months upon study completion.
• Access Criteria: ImmPort public data access.

Locations

US (15)