Abatacept and Cyclophosphamide Combination Therapy for Lupus Nephritis

Study Overview
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Brief Summary
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This study is for individuals with lupus who have developed complications in their kidneys, or lupus nephritis. The study will determine whether adding the experimental medication abatacept to standard cyclophosphamide therapy is more effective in improving lupus nephritis than standard cyclophosphamide therapy by itself.

Detailed Description
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Lupus nephritis is an inflammation of the kidney that occurs in patients with systemic lupus erythematosus (SLE). It is caused by the immune system attacking the kidney and is among the most serious complications of SLE: left untreated it can cause long term damage to the kidneys or, in some cases, result in kidney failure. One of the more common treatments for lupus nephritis is the Euro-lupus therapy. In this therapy, patients receive three different drugs - cyclophosphamide, azathioprine and prednisone - over the course of several months. However, some patients do not respond to this therapy and many only show some improvement. In this ACCESS trial for lupus nephritis, an experimental medication known as abatacept will be added to the Euro-lupus therapy to assess if it works better than Euro-lupus therapy alone. Abatacept is a man-made protein that suppresses parts of the immune system that can cause autoimmune disease. While abatacept is experimental for lupus, it has been approved by the FDA to treat rheumatoid arthritis. Abatacept is also being studied for use in other autoimmune diseases, like multiple sclerosis and type 1 diabetes. Participants in the ACCESS trial for lupus nephritis will receive bi-weekly intravenous infusions of cyclophosphamide for 3 months, then will take azathioprine tablets daily for at least 3 months more. Abatacept or a placebo will be administered every 2 weeks initially, then every 4 weeks for at least the first 6 months. Treatment of abatacept or placebo and azathioprine may continue for the remainder of the year. All participants will take prednisone tablets daily during the entire study. Because the ACCESS trial is a randomized, controlled study, each participant has a 50-50 chance (like flipping a coin) of receiving abatacept. Others will receive an inactive, placebo form of the drug. Note however, that all participants will receive the Euro-lupus therapy. As a blinded (masked) study, neither participants nor study physicians will know to which group a person has been assigned. All participants will undergo regular physical examinations, medical history and various blood and urine tests. Many of these tests will be repeated throughout the study. Participants will be asked to attend 18 study visits in the first year, and one study visit at the end of the second year. The study will reimburse participants for certain expenses incurred as part of the study.

Official Title
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A Randomized, Double-Blind, Controlled, Phase II Multicenter Trial of CTLA4Ig (Abatacept) Plus Cyclophosphamide vs Cyclophosphamide Alone in the Treatment of Lupus Nephritis

Conditions
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Lupus Nephritis, Lupus Erythematosus, Systemic

Intervention / Treatment
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* Drug: abatacept
* Drug: cyclophosphamide
* Drug: azathioprine
* Drug: prednisone
* Drug: abatacept placebo
* Drug: azathioprine placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of systemic lupus erythematosus (SLE) by American College of Rheumatology (ACR) criteria Active lupus nephritis (defined by: kidney biopsy documentation within the last 12 months using International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification- proliferative nephritis, active urinary sediment, urine protein-to-creatinine ratio > 1, low complement C3) Positive antinuclear antibody (ANA) test result at time of study entry Exclusion Criteria: End stage renal disease Use of cyclophosphamide in the past year Neutropenia, thrombocytopenia, moderately severe anemia Active infection, including HIV, hepatitis B or C History of cancer, except carcinoma in situ and treated basal and squamous cell carcinomas Pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Abatacept plus Euro-lupus regimen | Drug: abatacept<br>* Intravenous infusion (500-1000 mg, dep on weight) at weeks 0, 2, and 4, then every 4 weeks until week 24; continue to week 48 only if partial response at 24 weeks<br>* Other names: Orencia;Drug: cyclophosphamide<br>* 500 mg intravenous infusion every 2 weeks for 12 weeks<br>* Other names: Neosar;Drug: azathioprine<br>* 2 mg/kg/day orally from weeks 12-28; continue until week 52 if only partial response observed at week 24<br>* Other names: Azasan;Drug: prednisone<br>* 60 mg/day for 2 weeks, then taper to 10 mg/day by 12 weeks, then continue on stable dose<br>* Other names: Sterapred;Drug: azathioprine placebo<br>* Oral capsule, daily from weeks 28 to 52, only if complete response observed at week 24<br>|
| Placebo Comparator: Control<br>Abatacept placebo plus Euro-lupus regimen | Drug: cyclophosphamide<br>* 500 mg intravenous infusion every 2 weeks for 12 weeks<br>* Other names: Neosar;Drug: azathioprine<br>* 2 mg/kg/day orally from weeks 12-28; continue until week 52 if only partial response observed at week 24<br>* Other names: Azasan;Drug: prednisone<br>* 60 mg/day for 2 weeks, then taper to 10 mg/day by 12 weeks, then continue on stable dose<br>* Other names: Sterapred;Drug: abatacept placebo<br>* Intravenous infusion at weeks 0, 2, and 4, then every 4 weeks until week 24; continue to week 48 only if partial response at 24 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Complete Response | Complete response definition: a serum creatinine <= 1.2 mg/dL or <=125% of the higher value at either screening or baseline visit, protein-to-creatinine ratio <0.5, and prednisone dose tapered to <=10 mg/day or prednisone dosing allowances in protocol. Participants had to meet all of the referenced criteria to be considered a complete responder (CR). Participants who discontinued treatment and/or terminated from the study in the first 24 weeks were defined as CR failures for all subsequent visits. CRs are those who successfully responded to treatment and have minimal activity of their lupus nephritis. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Partial Response | Outcome measure description: Partial response definition: a serum creatinine <= 1.2 mg/dL or <= to 125% of the higher value at either screening or baseline visit, and improvement (reduction) >= to 50% in the urine protein to creatinine ratio at either screening or baseline visit, and prednisone dose has been tapered to 10 mg/day or according to protocol dosing allowances in protocol. Participants who discontinued treatment and/or terminated from the study in the first 24 weeks were defined as complete response failures for all subsequent visits. Partial responders are those who showed some response to treatment and low activity of their lupus nephritis. | Week 24 | 
| Number of Participants With a Complete or Partial Response | Complete response: a serum creatinine <= 1.2 mg/dL or <=125% of the higher value at either screening or baseline visit, protein-to-creatinine ratio <0.5, and prednisone dose tapered to <=10 mg/day or prednisone dosing allowances in protocol. Participants had to meet all of the referenced criteria to be considered a complete responder. Partial response: a serum creatinine <= 1.2 mg/dL or <= to 125% of the higher value at either screening or baseline visit, and improvement >= to 50% in the urine protein to creatinine ratio at either screening or baseline visit, and prednisone dose has been tapered to 10 mg/day or according to protocol dosing allowances in protocol. Participants who discontinued treatment and/or terminated from the study were defined as response failures for all subsequent visits. CRs successfully responded to treatment and have minimal activity of their lupus nephritis. Partial responders showed some response to treatment and low activity of their lupus nephritis. | Week 52 | 
| Number of Participants Who Achieved a Complete Response by Week 24 and Maintained the Complete Response Through Week 52 | Complete response definition: a serum creatinine <= 1.2 mg/dL or <=125% of the higher value at either screening or baseline visit, protein-to-creatinine ratio <0.5, and prednisone dose tapered to <=10 mg/day or prednisone dosing allowances in protocol. Participants had to meet all of the referenced criteria to be considered a complete responder (CR). Participants who discontinued treatment and/or terminated from the study were defined as response failures for all subsequent visits. CRs are those who successfully responded to treatment and had minimal activity of their lupus nephritis. | Week 52 | 
| Number of Participants Fulfilling the Proteinuria and Prednisone Criteria of a Complete Response | A complete proteinuria and prednisone response is defined as urine protein-to-creatinine ratio <0.5 and prednisone dose tapered to <= 10mg/day. Subjects who discontinued treatment or terminated from the study in the first 24 weeks are defined as response failures for all subsequent visits. Complete responders are those who successfully responded to treatment and have minimal activity of their lupus nephritis. | Week 24 | 
| Number of Participants Fulfilling the Proteinuria and Prednisone Criteria of a Partial Response | A partial proteinuria and prednisone response is defined as an improvement (reduction) of >=50% in the urine protein-to-creatinine ratio at either visit -1 or 0, and prednisone dose has been tapered to 10 mg/day. Subjects who discontinued treatment or terminated from the study in the first 24 weeks are defined as response failures for all subsequent visits. Partial responders are those who showed some response to treatment and low activity of their lupus nephritis. | Week 24 | 
| Number of Participants Who Achieved No Response at 24 Weeks and Continued in the Study | A participant who did not meet the criteria for either a complete response or a partial response at Week 24 was considered a non-responder. After Week 24, non-responders were terminated from the study and treated according to best clinical judgment unless the site investigator judged that the participant could benefit from continued participation. Non responders did not respond to treatment and lupus activity is moderate to severe. | Week 104 | 
| Number of Participants Who Achieved No Response at 24 Weeks and Continued in the Study , Achieving a Complete or Partial Response | A participant who did not meet the criteria for either a complete response (CR) or a partial response (PR) at Week 24 was considered a non-responder. After Week 24, non-responders were terminated from the study and treated according to best clinical judgment unless the investigator judged that the participant may benefit from continued participation. CR definition: a serum creatinine <= 1.2 mg/dL or <=125% of the higher value at either screening or baseline visit, protein-to-creatinine ratio <0.5, and prednisone dose tapered to <=10 mg/day or prednisone dosing allowances in protocol. Participants had to meet all of the referenced criteria to be considered a CR. PR definition: a serum creatinine <= 1.2 mg/dL or <= to 125% of the higher value at either screening or baseline, and improvement (reduction) >= to 50% in the urine protein to creatinine ratio at either screening or baseline, and prednisone dose has been tapered to 10 mg/day. | Week 52 | 
| Lupus Disease Activity - Participants Who Were Anti-dsDNA Positive at Baseline and Negative at Week 104 | Lupus disease activity was assessed by 7 different measures: reduction in anti-dsDNA, negative anti-dsDNA, resolution of hypocomplementemia (C3, C4), frequency of flares, patient global assessment, SF36 total scores, and BILAG-2004 scores. Participants with systemic lupus erythematosus (SLE) may have autoantibodies (e.g., self against self) to double-stranded DNA. Double-stranded DNA is one of multiple diagnostic tests for SLE and levels may be associated with disease activity. One measure used to assess disease activity is the number of participants who were anti-dsDNA positive at baseline but negative at Week 104. Going from positive to negative is indicative of lowered lupus activity. | Week 104 | 
| Lupus Disease Activity - Negative Anti-dsDNA | Lupus disease activity was assessed by 7 different measures: reduction in anti-dsDNA, negative anti-dsDNA, resolution of hypocomplementemia (C3, C4), frequency of flares, patient global assessment, SF36 total scores, and BILAG-2004 scores. Participants with systemic lupus erythematosus (SLE) may have autoantibodies (e.g., self against self) to double-stranded DNA. Double-stranded DNA is one of multiple diagnostic tests for SLE and levels may be associated with disease activity. This measure was the number of participants who had negative anti-dsDNA at Week 104. Having a negative score is indicative of low lupus disease activity. | Week 104 | 
| Lupus Disease Activity - Presence of Hypocomplementemia | Lupus disease activity was assessed by 7 different measures: anti-dsDNA, negative anti-dsDNA, resolution of hypocomplementemia (C3, C4), frequency of flares, patient global assessment, SF36 total scores, and BILAG-2004 scores. Participants were categorized as having hypocomplementemia if their serum complement test results (C3, and C4) were below the normal range at the site. Below normal complement test results are indicative of active lupus erythematosus. | Week 104 | 
| Lupus Disease Activity - Frequency of Flares | Lupus disease activity was assessed by 7 different measures: anti-dsDNA, negative anti-dsDNA, resolution of hypocomplementemia (C3, C4), frequency of flares, patient global assessment, SF36 total scores, and BILAG-2004 scores. Flares can be renal or non-renal. A renal flare is defined as two successive evaluations at least 1 week apart as proteinuria >1 gm/24h for participants who attain a complete response at Week 12 and for all other participants either 1) Increasing serum creatinine and persistent proteinuria, or 2) Worsening proteinuria. A non-renal flare is defined as any new post-baseline BILAG A in a non-renal organ system using BILAG-2004. This outcome measures the number of participants with the presence of renal and non-renal flares from Week 24 through Week 52 by response status. Having flares is indicative of more lupus disease activity. | Week 52 | 
| Lupus Disease Activity - Patient Global Assessment | Lupus disease activity was assessed by 7 different measures: anti-dsDNA, negative anti-dsDNA, resolution of hypocomplementemia (C3, C4), frequency of flares, patient global assessment (PGA), SF36 total scores, and BILAG-2004 scores. PGA is measured on a 100mm scale and assessed at Weeks 0, 12, 24, 52, and 104. Higher values indicate greater burden of disease. | Week 104 | 
| Lupus Disease Activity - Patient Global Assessment Percent Change From Baseline | Lupus disease activity was assessed by 7 different measures: anti-dsDNA, negative anti-dsDNA, resolution of hypocomplementemia (C3, C4), frequency of flares, patient global assessment (PGA), SF36 total scores, and BILAG-2004 scores. PGA is measured on a 100mm scale and assessed at Weeks 0, 12, 24, 52, and 104. Higher values indicate greater burden of disease. | Week 104 | 
| Lupus Disease Activity - SF-36 Scores | Lupus disease activity was assessed by 7 different measures: anti-dsDNA, negative anti-dsDNA, resolution of hypocomplementemia (C3, C4), frequency of flares, patient global assessment, SF36 total scores, and BILAG-2004 scores. The SF-36 is a quality of life assessment that was performed at Weeks 9, 24, 36, 52, and 104. Eight scale scores are derived from responses to the 36 items of the SF-36 questionnaire which were combined to produce the Physical Component Score and the Mental Component Score. The Physical Component Score is based on the Physical Functioning Scale (10 items), the Role-Physical Scale (4 items), the Bodily Pain Scale (2 items), and the General Health Scale (5 items). The Mental Component Score is based upon the Vitality Scale (4 items), the Social Functioning Scale (2 items), the Role-Emotional Scale (3 items) and the Mental Health Scale (5 items). Each component score is transformed into a 0-100 scale, with higher numbers indicating greater quality of life. | Week 104 | 
| Lupus Disease Activity - SF-36 Scores Percent Change From Baseline | Lupus disease activity was assessed by 7 different measures: anti-dsDNA, negative anti-dsDNA, resolution of hypocomplementemia (C3, C4), frequency of flares, patient global assessment, SF36 total scores, and BILAG-2004 scores. The SF-36 is a quality of life assessment that was performed at Weeks 9, 24, 36, 52, and 104. Eight scale scores are derived from responses to the 36 items of the SF-36 questionnaire which were combined to produce the Physical Component Score and the Mental Component Score. The Physical Component Score is based on the Physical Functioning Scale (10 items), the Role-Physical Scale (4 items), the Bodily Pain Scale (2 items), and the General Health Scale (5 items). The Mental Component Score is based upon the Vitality Scale (4 items), the Social Functioning Scale (2 items), the Role-Emotional Scale (3 items) and the Mental Health Scale (5 items). Each component score is transformed into a 0-100 scale, with higher numbers indicating greater quality of life. | Week 104 | 
| Lupus Disease Activity - Total BILAG-2004 | BILAG-2004 has 5 categories of scoring.Category A:defined by severe disease activity requiring any of the following treatments: 1) systemic high dose oral glucocorticoids, 2) IV pulse glucocorticoids, 3) systemic immunomodulators, or 4)therapeutic high dose anticoagulation in the presence of high dose steroids or immunomodulators. Category B:defined by moderate disease activity requiring any of the following treatments:1) systemic low dose oral glucocorticoids, 2) intramuscular or intra-articular or soft tissue glucocorticoids injection,3) topical glucocorticoids, 4) topical immunomodulators,5) antimalarials or thalidomide or prasterone or acitretin, or 6) symptomatic therapy.Category C:defined by mild disease.Category D is defined by inactive disease, previously affected.Category E is defined as the system never being involved.The categories are converted to a numeric score (A=9, B=3, C=1, D=0, E=0) and treated as a continuous variable. Higher score= more severe disease activity. | Week 52 | 
| Proportion of Vaccinated Participants With a Competent Immune Response | Among participants who are vaccinated, the number of who have a competent immune response at Week 52 as defined as having met both of the following criteria: Pneumococcal vaccination response - absolute value >= 0.35 ug/mL and, when measured 4-6 weeks after vaccination, a >=2-fold increase from baseline in serotype-specific antibody titer for at least 50% of the serotypes tested. Tetanus toxoid vaccination response - absolute value >=0.015 IU/mL and, when measured 4-6 weeks after vaccination, a 2-fold increase from baseline in antigen-specific antibody titer Competent immune response is indicative of low disease activity. | Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lupus, systemic lupus erythematosus, lupus nephritis, SLE, abatacept, CTLA4, CTLA4Ig, glomerulonephritis