Abatacept and Cyclophosphamide Combination Therapy for Lupus Nephritis

Lupus Nephritis Clinical Trial

— ACCESS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00774852
• Other study ID #: DAIT ITN034AI
• Status: Completed
• Phase: Phase 2
• First received: October 16, 2008
• Last updated: January 15, 2016
• Start date: November 2008
• Est. completion date: June 2014

Study information

• Verified date: January 2016
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationMexico: Federal Commission for Sanitary Risks Protection
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 137
• Est. completion date: June 2014
• Est. primary completion date: December 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 16 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Lupus Erythematosus, Systemic
• Lupus Nephritis
• Nephritis

Intervention

Drug:
• abatacept
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
• cyclophosphamide
500 mg intravenous infusion every 2 weeks for 12 weeks
• azathioprine
2 mg/kg/day orally from weeks 12-28; continue until week 52 if only partial response observed at week 24
• prednisone
60 mg/day for 2 weeks, then taper to 10 mg/day by 12 weeks, then continue on stable dose
• abatacept placebo
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
• azathioprine placebo
Oral capsule, daily from weeks 28 to 52, only if complete response observed at week 24

Locations

Country	Name	City	State
Mexico	Unidad de investigación en enfermedades crónico - degenerativas SC	Guadalajara	Jalisco
Mexico	El Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INNSZ)	Mexico City
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	University of Alabama, Birmingham	Birmingham	Alabama
United States	UNC Chapel Hill	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Chicago	Chicago	Illinois
United States	Ohio State University Medical Center	Columbus	Ohio
United States	UT Southwestern	Dallas	Texas
United States	Wayne State University	Detroit	Michigan
United States	University of California San Diego	La Jolla	California
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Feinstein Institute	Manhasset	New York
United States	University of Miami	Miami	Florida
United States	Columbia University	New York	New York
United States	Seligman Center for Advanced Therapeutics (NYU)	NY	New York
United States	Oklahoma Medical Research Foundation	Oklahoma City	Oklahoma
United States	Temple University	Philadelphia	Pennsylvania
United States	University of Pittsburgh Lupus Center of Excellence	Pittsburgh	Pennsylvania
United States	University of Rochester	Rochester	New York
United States	University of California San Francisco	San Francisco	California

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Immune Tolerance Network (ITN)

Countries where clinical trial is conducted

United States,  Mexico, 

References & Publications (2)

ACCESS Trial Group. Treatment of lupus nephritis with abatacept: the Abatacept and Cyclophosphamide Combination Efficacy and Safety Study. Arthritis Rheumatol. 2014 Nov;66(11):3096-104. doi: 10.1002/art.38790. Erratum in: Arthritis Rheumatol. 2015 Feb;67( — View Citation

Wofsy D, Diamond B, Houssiau FA. Crossing the Atlantic: the Euro-Lupus Nephritis regimen in North America. Arthritis Rheumatol. 2015 May;67(5):1144-6. doi: 10.1002/art.39067. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No

External Links

•   Immune Tolerance Network website
•   Lupus Nephritis Trials Network Research
•   National Institute of Allergy and Infectious Diseases (NIAID)