Clinical trial NCT02260934: Rituximab and Belimumab for Lupus Nephritis
Official title: Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis (ITN055AI)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Lupus Nephritis
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Immune Tolerance Network (ITN)
First posted: 2014-10-09
Enrollment: 43
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 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.

Primary outcomes:
measure: Percentage of Participants With At Least One Grade 3 or Higher Infectious Adverse Event By Week 24, Week 48 and Week 96
timeFrame: Week 0 to Week 96
Secondary outcomes:
measure: Percentage of Participants With B Cell Reconstitution at Week 24, Week 48 and Week 96
timeFrame: Week 24, Week 48 and Week 96
measure: Percentage of Participants With Grade 4 Hypogammaglobulinemia by Week 24, Week 48, and Week 96
timeFrame: Week 24, Week 48 and Week 96
measure: Percentage of Participants With a Complete Response at Week 24, Week 48, and Week 96
timeFrame: Week 24, Week 48 and Week 96
measure: Percentage of Participants With an Overall Response at Week 24, Week 48, and Week 96
timeFrame: Week 24, Week 48 and Week 96
measure: Percentage of Participants With a Sustained Complete Response
timeFrame: Week 48, Week 96
measure: Percentage of Participants With Treatment Failure by Week 24, Week 48, and Week 96
timeFrame: Week 24, Week 48 and Week 96
measure: Count of Participants: Frequency of Non-renal Flares by Week 24
timeFrame: Week 24
measure: Count of Participants: Frequency of Non-renal Flares by Week 48
timeFrame: Week 48
measure: Count of Participants: Frequency of Non-renal Flares by Week 96
timeFrame: Week 96
measure: Percentage of Participants With an Negative Anti-dsDNA Result at Week 24, Week 48, and Week 96
timeFrame: Week 24, Week 48 and Week 96
measure: Percentage of Participants Hypocomplementemic for Complement Component C3 at Week 24, Week 48, and Week 96
timeFrame: Week 24, Week 48 and Week 96
measure: Percentage of Participants Hypocomplementemic for Complement Component C4 at Week 24, Week 48, and Week 96
timeFrame: Week 24, Week 48 and Week 96
measure: Frequency of Specific Adverse Events of Interest By Event by Week 96
timeFrame: Week 96
measure: Frequency of Specific Adverse Events of Interest By Participant, By Week 96
timeFrame: Week 96
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama, Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: UCLA Medical Center: Division of Rheumatology
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Aurora
country: United States
facility: University of Colorado Denver: School of Medicine: Division of Rheumatology
state: Colorado
city: Denver
country: United States
facility: Colorado Kidney Care
state: Colorado
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Saint Louis
country: United States
facility: Washington University in St. Louis
state: Missouri
city: Manhasset
country: United States
facility: Feinstein Institute, North Shore Hospital
state: New York
city: New York
country: United States
facility: New York University, Langone Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College: Hospital for Special Surgery -
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina School of Medicine:
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University Wexner Medical Center:
state: Ohio
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: University of Texas Southwestern
state: Texas
Study officials:
affiliation: Feinstein Institute for Medical Research
name: Betty Diamond, M.D.
role: STUDY_CHAIR
affiliation: University of California San Francisco, Department of Medicine
name: David Wofsy, M.D.
role: STUDY_CHAIR
affiliation: University of California San Francisco, Department of Medicine
name: Maria Dall'Era, M.D.
role: STUDY_CHAIR
affiliation: Feinstein Institute for Medical Research
name: Cynthia Aranow, M.D.
role: STUDY_CHAIR
References:
citation: 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.