Trial of Belimumab in Early Lupus
Primary Purpose
Lupus Erythematosus, Systemic, Lupus Erythematosus
Status
Recruiting
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Belimumab
Belimumab/Placebo
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Lupus Erythematosus, Systemic focused on measuring lupus, early lupus, belimumab, autoreactivity
Eligibility Criteria
Inclusion Criteria:
- Diagnosis of SLE per current ACR classification criteria
- Date of SLE diagnosis within 2 years of screening
- ANA positive (with a titer ≥ 80)
- anti-ds DNA antibody positive
- Mild to moderate disease activity define by a SLEDAI-2K ≥4
- Stable corticosteroid dose in the 4 weeks prior to screening ≤ 30mg/day.
- Concomitant treatment with hydroxychloroquine unless documented inability to tolerate
- Able and willing to give written informed consent and comply with the requirements of the study protocol
- Negative serum pregnancy test (for women of child bearing potential)
- Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for 16 weeks after completion of treatment
Exclusion Criteria:
- Previous exposure to disease modifying drugs such as azathioprine, mycophenolate mofetil, cyclophosphamide, methotrexate, or cyclosporine.
- Previous exposure to biologic therapies including rituximab, belimumab or other agents that have been investigated for SLE.
- Active renal or nervous system disease or disease activity fulfilling BILAG A criteria
- Use of high dose steroids (>0.5 mg/kg/ day) within the 4 weeks prior to screening
- Expectation (by the investigator) that the subject will require treatment with a disease modifying drug within the first 52 weeks of the study
- Hemoglobin: < 8.0 gm/dL
- Platelets: < 50,000/mm
- ANC < 1.0 x 103/mm
- AST or ALT >2.5 x Upper Limit of Normal unless related to primary disease.
- Creatinine clearance ≤ 25ml/min per 1.73 m2
- Positive Hepatitis B or C serology (Hep B Surface antigen, Hep B core Ab or Hepatitis C antibody)
- History of positive HIV (HIV conducted during screening if applicable)
- Treatment with any investigational agent within 4 weeks of screening or 5 half-lives of the investigational drug (whichever is longer)
- Receipt of a live vaccine within 30 days prior to baseline or concurrently with belimumab
- Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies
- Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria)
- Hospitalization for treatment of infection within 60 days of Day 0.
- Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or anti parasitic agents) within 60 days of Day 0
- History of serious recurrent or chronic infection
- Lack of peripheral venous access
- History of drug, alcohol, or chemical abuse within 365 days prior to Day 0
- Pregnancy (a negative serum pregnancy test must be obtained for all women of childbearing potential at screening; a urine pregnancy test must be negative < 7 days prior to first dose and monthly)
- Lactation
- History of psychiatric disorder that would interfere with normal participation in this protocol
- Significant cardiac or pulmonary disease (including obstructive pulmonary disease)
- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
- History of malignant neoplasm within the last 5 years with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
- Evidence of serious suicide risk including any history of suicidal behaviour in the last 6 months and/or any suicidal ideation in the last 2 months or who in the investigator's judgment, pose a significant suicide risk
- History of a primary immunodeficiency
- Have a significant IgG deficiency (IgG level < 400 mg/dL)
- Have an IgA deficiency (IgA level < 10 mg/dL)
- Have any other clinically significant abnormal laboratory value in the opinion of the investigator
- Comorbidities requiring corticosteroid therapy, including those which have required two or more courses of systemic courses of systemic corticosteroids within the previous 12 months
- Inability to comply with study and follow-up procedures
Sites / Locations
- Feinstein InstituteRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Active Comparator
Experimental
Placebo Comparator
Arm Label
Belimumab
Belimumab/Placebo
Placebo
Arm Description
Subjects in this arm will receive 200mg belimumab for self administration subcutaneously weekly for 2 years
Subjects in this arm will receive 200mg belimumab for self administration subcutaneously weekly for 1 year and then placebo injections subcutaneously for 1 year.
Subjects in this arm will receive placebo for self administration subcutaneously weekly for 2 years
Outcomes
Primary Outcome Measures
Frequency of anergic autoreactive naïve B cells
The frequency of autoreactive B cells in the naïve subset will be identified by flow cytometry.
Secondary Outcome Measures
Frequency of anergic autoreactive naïve B cells
The frequency of autoreactive B cells in the naïve subset will be identified by flow cytometry.
Frequency of autoreactivity in transitional B cells
The frequency of autoreactive B cells in the transitional B cell subset will be identified by flow cytometry.
Frequency of autoreactivity in transitional B cells
The frequency of autoreactive B cells in the transitional B cell subset will be identified by flow cytometry.
Time to reconstitution of B cell subsets in subjects in belimumab/placebo arm randomized to receive placebo after 1 year of belimumab therapy
B cell numbers decrease following belimumab; the time for B cell reconstituion will be determined
SRI (SLE Response Index) modified
Systemic lupus response index
SRI modified
Systemic lupus response index
Low lupus disease activity state (LLDAS)
LLDAS as defined by the Asia-Pacific Lupus Association
Low lupus disease activity state
LLDAS as defined by the Asia-Pacific Lupus Association
Remission
Remission defined by DORIS (Definition of Remission in SLE)
Remission
Remission defined by DORIS (Definition of Remission in SLE)
Flare of lupus disease
Lupus flare will be measure using the SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment --Systemic Lupus Erythematosus Disease Activity Index) flare instrument or British Isles Lupus Assessment Group (BILAG) disease activity index
New Classification Criteria for SLE.
Accumulation of new American College of Rheumatology (ACR) Classification criteria or Systemic Lupus International Cooperative Clinics (SLICC) criteria
Serologies
Changes in titers of anti-DNA antibody levels
Complement levels
Changes in measures of C3 and C4 (mg/dL)
Complement levels
Changes in measures of C3, C4 (mg/dL)
Serum immunoglobulin levels
Change from baseline of serum IgG, IgM and IgA (mg/dL)
Damage
Damage accrual assessed using a SLE damage index
Cardiovascular biomarkers
IgM phosphocholine antibody titers and proinflammatory HDL
Safety and tolerability (adverse events)
All adverse events and serious adverse events will be collected
Frequency of autoreactivity in CD27+, IgD+ memory B cells
The frequency of autoreactive B cells in the CD27+, IgD+ B cell subset will be identified by flow cytometry.
Frequency of autoreactivity in CD27+, IgD+ memory B cells
The frequency of autoreactive B cells in the CD27+, IgD+ B cell subset will be identified by flow cytometry.
Frequency of autoreactivity in CD27+, IgD- B cells
The frequency of autoreactive B cells in the CD27+, IgD- B cell subset will be identified by flow cytometry.
Frequency of autoreactivity in CD27+, IgD- B cells
The frequency of autoreactive B cells in the CD27+, IgD- B cell subset will be identified by flow cytometry.
Frequency of autoreactivity in CD27-, IgD- B cells
The frequency of autoreactive B cells in the CD27-, IgD- B cell subset will be identified by flow cytometry.
Frequency of autoreactivity in CD27-, IgD- B cells
The frequency of autoreactive B cells in the CD27-, IgD- B cell subset will be identified by flow cytometry.
The absolute numbers of transitional B cells
The number of transitional B cells will be determined by flow cytometry.
The absolute numbers of transitional B cells
The number of transitional B cells will be determined by flow cytometry.
The absolute numbers of naïve B cells
The number of transitional B cells will be determined by flow cytometry.
The absolute numbers of naïve B cells
The number of naïve B cells will be determined by flow cytometry.
The absolute numbers of memory B cells
The number of memory B cells will be determined by flow cytometry.
The absolute numbers of memory B cells
The number of memory B cells will be determined by flow cytometry.
The absolute number of plasmablasts
The number of plasmablasts will be determined by flow cytometry.
The absolute number of plasmablasts
The number of plasmablasts will be determined by flow cytometry.
The absolute number of plasma cells
The number of plasma cells will be determined by flow cytometry.
The absolute number of plasma cells
The number of plasma cells will be determined by flow cytometry.
Full Information
NCT ID
NCT03543839
First Posted
April 12, 2018
Last Updated
February 7, 2023
Sponsor
Northwell Health
Collaborators
GlaxoSmithKline
1. Study Identification
Unique Protocol Identification Number
NCT03543839
Brief Title
Trial of Belimumab in Early Lupus
Official Title
Pilot Trial of Belimumab in Early Lupus
Study Type
Interventional
2. Study Status
Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 15, 2020 (Actual)
Primary Completion Date
August 2025 (Anticipated)
Study Completion Date
December 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Northwell Health
Collaborators
GlaxoSmithKline
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This two year study will evaluate the effects of giving belimumab (Benlysta) to patients with Early Lupus. Early lupus is a diagnosis of lupus within 2 years. Subjects will be randomized to receive belimumab or placebo during the first year. During the second year, subjects who were randomized to belimumab will be rerandomized to continue to receive belimumab or to receive placebo. The study will look at clinical effects as well as effects on the immune system.
Detailed Description
This protocol proposes that early treatment of Systemic Lupus Erythematous (SLE) may prevent tissue damage and may even lead to long-term remission of disease. This concept is supported by reports of SLE-associated autoimmunity that are detected serologically many years prior to any constitutional symptoms or specific tissue inflammation and immune dysregulation precedes the development of clinically apparent SLE. Belimumab (Benlysta) is an FDA approved medication and is a monoclonal antibody directed against B cell-activating factor (BAFF)/ B Lymphocyte Stimulator (BLyS). B cells maturing in environments with high BAFF levels are more likely to be autoreactive B cells. This is a double-blind placebo controlled trial of belimumab, in patients with early lupus, ie lupus diagnosed within 2 years. Thirty subjects will be randomized (2:1) to receive subcutaneous belimumab weekly or placebo. After a year of treatment, subjects receiving belimumab will be rerandomized (1:1) to receive belimumab or placebo. The primary outcome is B cell autoreactivity. Clinical efficacy including disease activity, flares, attainment of low disease activity or remission as well as surrogate cardiovascular biomarkers will also be assessed.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lupus Erythematosus, Systemic, Lupus Erythematosus
Keywords
lupus, early lupus, belimumab, autoreactivity
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Model Description
This is not a true cross-over study. Subjects are randomized to receive true drug or placebo in the initial phase and then those patients who were randomized to receive belimumab will be rerandomized to receive either study drug or placebo. Subjects randomized at baseline to receive placebo continue to receive placebo through the study.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Study drug or placebo look identical.
Allocation
Randomized
Enrollment
30 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Belimumab
Arm Type
Active Comparator
Arm Description
Subjects in this arm will receive 200mg belimumab for self administration subcutaneously weekly for 2 years
Arm Title
Belimumab/Placebo
Arm Type
Experimental
Arm Description
Subjects in this arm will receive 200mg belimumab for self administration subcutaneously weekly for 1 year and then placebo injections subcutaneously for 1 year.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Subjects in this arm will receive placebo for self administration subcutaneously weekly for 2 years
Intervention Type
Biological
Intervention Name(s)
Belimumab
Intervention Description
Subjects in this arm will receive 200mg belimumab subcutaneously weekly for 2 years
Intervention Type
Biological
Intervention Name(s)
Belimumab/Placebo
Intervention Description
Subjects in this arm will receive weekly subcutaneous injections of 200mg belimumab for 1 year and then placebo subcutaneous injections for 1 year.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Subjects in this arm will receive weekly subcutaneous injections of placebo for 2 years
Primary Outcome Measure Information:
Title
Frequency of anergic autoreactive naïve B cells
Description
The frequency of autoreactive B cells in the naïve subset will be identified by flow cytometry.
Time Frame
Assessment at year 1
Secondary Outcome Measure Information:
Title
Frequency of anergic autoreactive naïve B cells
Description
The frequency of autoreactive B cells in the naïve subset will be identified by flow cytometry.
Time Frame
Assessment at year 2
Title
Frequency of autoreactivity in transitional B cells
Description
The frequency of autoreactive B cells in the transitional B cell subset will be identified by flow cytometry.
Time Frame
Year 1
Title
Frequency of autoreactivity in transitional B cells
Description
The frequency of autoreactive B cells in the transitional B cell subset will be identified by flow cytometry.
Time Frame
Year 2
Title
Time to reconstitution of B cell subsets in subjects in belimumab/placebo arm randomized to receive placebo after 1 year of belimumab therapy
Description
B cell numbers decrease following belimumab; the time for B cell reconstituion will be determined
Time Frame
Year 2
Title
SRI (SLE Response Index) modified
Description
Systemic lupus response index
Time Frame
Year 1
Title
SRI modified
Description
Systemic lupus response index
Time Frame
Year 2
Title
Low lupus disease activity state (LLDAS)
Description
LLDAS as defined by the Asia-Pacific Lupus Association
Time Frame
Year 1
Title
Low lupus disease activity state
Description
LLDAS as defined by the Asia-Pacific Lupus Association
Time Frame
Year 2
Title
Remission
Description
Remission defined by DORIS (Definition of Remission in SLE)
Time Frame
Year 1
Title
Remission
Description
Remission defined by DORIS (Definition of Remission in SLE)
Time Frame
Year 2
Title
Flare of lupus disease
Description
Lupus flare will be measure using the SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment --Systemic Lupus Erythematosus Disease Activity Index) flare instrument or British Isles Lupus Assessment Group (BILAG) disease activity index
Time Frame
Through year 2
Title
New Classification Criteria for SLE.
Description
Accumulation of new American College of Rheumatology (ACR) Classification criteria or Systemic Lupus International Cooperative Clinics (SLICC) criteria
Time Frame
Through year 2
Title
Serologies
Description
Changes in titers of anti-DNA antibody levels
Time Frame
Through year 2
Title
Complement levels
Description
Changes in measures of C3 and C4 (mg/dL)
Time Frame
Through year 2
Title
Complement levels
Description
Changes in measures of C3, C4 (mg/dL)
Time Frame
Through year 2
Title
Serum immunoglobulin levels
Description
Change from baseline of serum IgG, IgM and IgA (mg/dL)
Time Frame
Through year 2
Title
Damage
Description
Damage accrual assessed using a SLE damage index
Time Frame
Through year 2
Title
Cardiovascular biomarkers
Description
IgM phosphocholine antibody titers and proinflammatory HDL
Time Frame
Through year 2
Title
Safety and tolerability (adverse events)
Description
All adverse events and serious adverse events will be collected
Time Frame
Through year 2
Title
Frequency of autoreactivity in CD27+, IgD+ memory B cells
Description
The frequency of autoreactive B cells in the CD27+, IgD+ B cell subset will be identified by flow cytometry.
Time Frame
Year 1
Title
Frequency of autoreactivity in CD27+, IgD+ memory B cells
Description
The frequency of autoreactive B cells in the CD27+, IgD+ B cell subset will be identified by flow cytometry.
Time Frame
Year 2
Title
Frequency of autoreactivity in CD27+, IgD- B cells
Description
The frequency of autoreactive B cells in the CD27+, IgD- B cell subset will be identified by flow cytometry.
Time Frame
Year 1
Title
Frequency of autoreactivity in CD27+, IgD- B cells
Description
The frequency of autoreactive B cells in the CD27+, IgD- B cell subset will be identified by flow cytometry.
Time Frame
Year 2
Title
Frequency of autoreactivity in CD27-, IgD- B cells
Description
The frequency of autoreactive B cells in the CD27-, IgD- B cell subset will be identified by flow cytometry.
Time Frame
Year 1
Title
Frequency of autoreactivity in CD27-, IgD- B cells
Description
The frequency of autoreactive B cells in the CD27-, IgD- B cell subset will be identified by flow cytometry.
Time Frame
Year 2
Title
The absolute numbers of transitional B cells
Description
The number of transitional B cells will be determined by flow cytometry.
Time Frame
Year 1
Title
The absolute numbers of transitional B cells
Description
The number of transitional B cells will be determined by flow cytometry.
Time Frame
Year 2
Title
The absolute numbers of naïve B cells
Description
The number of transitional B cells will be determined by flow cytometry.
Time Frame
Year 1
Title
The absolute numbers of naïve B cells
Description
The number of naïve B cells will be determined by flow cytometry.
Time Frame
Year 2
Title
The absolute numbers of memory B cells
Description
The number of memory B cells will be determined by flow cytometry.
Time Frame
Year 1
Title
The absolute numbers of memory B cells
Description
The number of memory B cells will be determined by flow cytometry.
Time Frame
Year 2
Title
The absolute number of plasmablasts
Description
The number of plasmablasts will be determined by flow cytometry.
Time Frame
Year 1
Title
The absolute number of plasmablasts
Description
The number of plasmablasts will be determined by flow cytometry.
Time Frame
Year 2
Title
The absolute number of plasma cells
Description
The number of plasma cells will be determined by flow cytometry.
Time Frame
Year 1
Title
The absolute number of plasma cells
Description
The number of plasma cells will be determined by flow cytometry.
Time Frame
Year 2
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Diagnosis of SLE per current ACR classification criteria
Date of SLE diagnosis within 2 years of screening
ANA positive (with a titer ≥ 80)
anti-ds DNA antibody positive
Mild to moderate disease activity define by a SLEDAI-2K ≥4
Stable corticosteroid dose in the 4 weeks prior to screening ≤ 30mg/day.
If on methotrexate, dose must be stable for 4 weeks
Concomitant treatment with hydroxychloroquine unless documented inability to tolerate
Able and willing to give written informed consent and comply with the requirements of the study protocol
Negative serum pregnancy test (for women of child bearing potential)
Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for 16 weeks after completion of treatment
Exclusion Criteria:
Previous exposure to disease modifying drugs such as azathioprine, mycophenolate mofetil, cyclophosphamide, or cyclosporine.
Previous exposure to biologic therapies including rituximab, belimumab or other agents that have been investigated for SLE.
Active renal or nervous system disease or disease activity fulfilling BILAG A criteria
Use of high dose steroids (>0.5 mg/kg/ day) within the 4 weeks prior to screening
Expectation (by the investigator) that the subject will require treatment with a disease modifying drug within the first 52 weeks of the study
Hemoglobin: < 8.0 gm/dL
Platelets: < 50,000/mm
ANC < 1.0 x 103/mm
AST or ALT >2.5 x Upper Limit of Normal unless related to primary disease.
Creatinine clearance ≤ 25ml/min per 1.73 m2
Positive Hepatitis B or C serology (Hep B Surface antigen, Hep B core Ab or Hepatitis C antibody)
History of positive HIV (HIV conducted during screening if applicable)
Treatment with any investigational agent within 4 weeks of screening or 5 half-lives of the investigational drug (whichever is longer)
Receipt of a live vaccine within 30 days prior to baseline or concurrently with belimumab
Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies
Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria)
Hospitalization for treatment of infection within 60 days of Day 0.
Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or anti parasitic agents) within 60 days of Day 0
History of serious recurrent or chronic infection
Lack of peripheral venous access
History of drug, alcohol, or chemical abuse within 365 days prior to Day 0
Pregnancy (a negative serum pregnancy test must be obtained for all women of childbearing potential at screening; a urine pregnancy test must be negative < 7 days prior to first dose and monthly)
Lactation
History of psychiatric disorder that would interfere with normal participation in this protocol
Significant cardiac or pulmonary disease (including obstructive pulmonary disease)
Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
History of malignant neoplasm within the last 5 years with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
Evidence of serious suicide risk including any history of suicidal behaviour in the last 6 months and/or any suicidal ideation in the last 2 months or who in the investigator's judgment, pose a significant suicide risk
History of a primary immunodeficiency
Have a significant IgG deficiency (IgG level < 400 mg/dL)
Have an IgA deficiency (IgA level < 10 mg/dL)
Have any other clinically significant abnormal laboratory value in the opinion of the investigator
Comorbidities requiring corticosteroid therapy, including those which have required two or more courses of systemic courses of systemic corticosteroids within the previous 12 months
Inability to comply with study and follow-up procedures
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Sanita Kandasami, BS
Phone
516 562-2401
Email
skandasami@northwell.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Cynthia Aranow, MD
Phone
516 562-3845
Email
caranow@northwell.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Cynthia Aranow, MD
Organizational Affiliation
Feinstein Institute for Medical Research, Northwell Health
Official's Role
Principal Investigator
Facility Information:
Facility Name
Feinstein Institute
City
Manhasset
State/Province
New York
ZIP/Postal Code
11030
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sanita Kandasami
Phone
516-562-2401
Email
skandasami@northwell.edu
First Name & Middle Initial & Last Name & Degree
Cynthia Aranow, M.D.
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Learn more about this trial
Trial of Belimumab in Early Lupus
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