Clarification of Abatacept Effects in SLE With Integrated Biologic and Clinical Approaches

This is a randomized, double blind, placebo controlled trial of abatacept for the treatment of lupus arthritis and other manifestations of lupus. Patients with lupus and at least 3 tender and 3 swollen joints and \</= 20 mg prednisone have other background immune suppressants withdrawn at entry. They can elect to receive up to a total of 320 mg depomedrol (in two or more injections) between the screening visit and the visit 2 months after dosing begins. Abatacept (125 mg) or placebo is administered in weekly subcutaneous doses. After 3 months of treatment patients who are not responding may elect to receive open label abatacept with or without additional standard of care therapies. Such patients are considered non responders. The primary endpoint is the British Isles Lupus Assessment Group Index (BILAG)-linked Combined Lupus Assessment (BICLA) which will require a clinically significant improvement in arthritis and other active features of lupus

Research Hypothesis: Abatacept is effective in lupus arthritis and this will be discernible in a small trial with robust endpoints which incorporates withdrawal of background immune suppressants

Study Schematic: Abatacept 125 mg or placebo will be given in a 1:1 randomization subcutaneously each week for six months. All patients may elect to continue six more months on open label Abatacept. Background Immune Suppressants will be withdrawn at any time between screening and the first dosing visit. At or after screening, patients may elect 40-160 mg depomedrol shots prn not to exceed 320 mg total up to and including the Month 2 Visit (two months after the first dosing visit) After that, additional steroids or immune suppressants, if necessary, will be allowed but the patient will be considered a non-responder in the primary endpoint at six months on that basis. At of after the 3 month visit patients with significant clinical flare may also elect to receive open label Abatacept but will be considered non-responders in the primary endpoint at six months.

Primary Objective: To compare response rates between Abatacept-Treated and Placebo-Treated Patients with active lupus arthritis in a trial designed with background immune suppressant withdrawal, limited steroid rescue, and a robust, discriminatory endpoint. The trial design and primary endpoint of response by BICLA (defined below) have been pre-tested by us for safety and ability to ensure placebo group non-response, underscoring our powering of the study. This will support a rational decision about further development of abatacept for SLE at minimal cost.

Secondary clinical outcome measures used as endpoints will include: SRI 4/5, changes in joint counts, SLEDAI, BILAG, CLASI, PGA, and LFA REAL measures.

The definitions of the clinical outcome measures are as follows: BICLA: BILAG-based Combined Lupus Assessment, This is defined as British Isles Lupus Assessment Group (BILAG) index scores that were severe at entry (BILAG A scores) improving to a moderate (BILAG B) level (or better) and all features that were moderate at entry improving to a mild level (BILAG C scores) or resolved (BILAG D scores) without increase in any other BILAG feature or SLEDAI scoring (see SLEDAI definition below), as well as no more than 10% worsening in a Physician's Global Assessment or any additional treatments after the protocolized baseline rescue (e.g. no new SLE treatments after the two month visit). SLEDAI stands for the Systemic Lupus Erythematosis Disease Activity Index. SRI 4/5 is defined as SLEDAI improvement by at least 4 points (or 5 points respectively), no increase in BILAG-measured disease activity and no more than 10% worsening in a Physician's Global Assessment (PGA). CLASI stands for the Cutaneous Lupus Erythematosus Disease Area and Severity Index. PGA stands for Physician's Global Assessment. LFA REAL stands for the Lupus Foundation of America Rapid Evaluation of the Activity of Lupus. This instrument is in a pilot phase but will be tested in the ABC study.

PK and immunogenicity studies will also be performed to help in interpretation of outcomes. Novel biologic discovery will be integrated into the clinical trial to support both pre-specified and exploratory biomarker discovery. Data will be generated that might be used to help select more appropriate patient subsets for future trials and, along with PK data, help to guide optimal dosing strategies. Optimizing patient selection and dosing are important goals for further increasing demonstrable effect size in trials by increasing the response rates in the treatment group.

This study will be performed as a double blind, randomized, placebo-controlled clinical trial with 1:1 randomization of patients to abatacept 125 mg weekly subcutaneous dose or placebo, with the withdrawal of background immune suppressants. Limited steroid rescue is allowed between the screening visit and the Month 2 visit per protocol. Additional standard of care rescue medications may be used after that as needed but will define non-response at the primary endpoint date of six months. Flaring patients may elect to receive open label abatacept at Month 3 but will also be defined as non-responders in the primary endpoint. All patients may elect to receive open label abatacept for an additional six months after the primary endpoint date, with two follow up visits (2 and 4 months post medication withdrawal) to assess withdrawal effects and to complete the safety assessments.

Accrual Goal: This study will continue to recruit until we achieve the goal of 60 patients who complete study visits through the 6 month endpoint.

Correlative Studies: Extensive exploratory protocol-specific and ancillary immune pharmacodynamic studies, focusing first on changes in IFN alpha, BLyS and other B Cell pathways. A major focus will also be on T Cell pathways with a focus on T suppressor/TH17 dichotomy after treatment with abatacept. A responder analysis will be performed in order to generate hypotheses useful for selecting appropriate patients for this treatment and optimizing dosing strategies.

Adverse Events, Serious Adverse Events and Adverse Events of special interest (infusion reactions and infections) will be collected and described. Stopping Rules: Patients may be withdrawn by the investigator for non-compliance or safety. All patients terminating before six months will be considered non responders in the primary analysis. Use of off protocol immune suppressants will not necessarily dictate withdrawal but will determine non-responder status. A DSMB board of at least two physicians (four are currently participating) will review data and may stop the study if needed.

Eligibility Criteria:
Inclusion Criteria:

1. Signed Written Informed Consent
2. Four 1997 revised ACR Classification Criteria for SLE
3. Active polyarticular arthritis meeting at minimum BILAG 2004 B definition with a minimum of 3 tender and 3 swollen joints observed at the screening visit
4. Men and women 18 to 70 years of age.
5. Women of childbearing potential and men with partners of childbearing potential must use an acceptable method of birth control throughout the study
6. Women of childbearing potential must have a negative urine pregnancy test at screening and Study Day 1 (baseline visit) and may not be breast feeding

Exclusion Criteria:

1. Current severe, organ-threatening disease (e.g. acute nephritis appropriate for induction therapy, CNS lupus (excepting chorea, cranial neuropathy, and resolving optic neuritis) or any lupus condition requiring cyclophosphamide, biologic therapy, or IV bolus steroids of \>/= 500 mg.
2. Subjects who are incapable of understanding or completing study-related assessments.
3. Subjects with any condition, whether or not related to SLE, which, in the opinion of the investigator, might place a subject at unacceptable risk for participation in the study.
4. Subjects with a history of cancer in the last 5 years, other than non-melanoma skin cell cancers cured by local resection or carcinoma in situ.
5. Subjects who currently abuse drugs or alcohol.
6. Subjects with acute herpes zoster or cytomegalovirus (CMV) within 2 months of screening.
7. Subjects who have received any live vaccines within 3 months of first dose.
8. Subjects with any serious bacterial infection within the last 3 months, unless treated and resolved with antibiotics, or any chronic bacterial infection (eg, chronic pyelonephritis, osteomyelitis, or bronchiectasis).
9. Subjects at risk for tuberculosis (TB).
10. Subjects known to be positive for hepatitis B surface antigen or hepatitis C unless negative by PCR or RIBA
11. Acute hemolytic anemia with hemoglobin \< 7.0 g/dL or known change in Hg by 2.0 g/dL within four months
12. WBC \< 2500/mm3 (\< 3 x 109/L) unless due to chronic stable lupus activity
13. Platelets \< 40,000/mm3 (\< 3 x 109/L) (If less than 100,000 must have been stable (within a range of 10,000/mm3 ) within two months of screening or in two tests during the screening period.
14. Serum creatinine \> 2 times the ULN
15. Serum ALT or AST \> 2.5 times the ULN
16. Any other laboratory test results that, in the opinion of the investigator, might place a subject at unacceptable risk for participation in the study.
17. Known allergy/sensitivity to the study agent or carrier.
18. Treatment with investigational drug within 28 days (or 5 terminal half-lives) of the Day 1 dose.
19. Cyclophosphamide within 3 months of Day 1 or bolus IV steroids \>/=500 mg within 1 month
20. Prednisone \> 20 mg qd after the screening visit

    -