Clarification of Abatacept Effects in SLE With Integrated Biologic and Clinical Approaches
Condition: Systemic Lupus Erythematosus
MeSH terms: Lupus Erythematosus, Systemic
Study type: Interventional
Phase: Phase 2

Summary: 
      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      suppressants withdrawn at entry.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
    

Detailed description: 
      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 Background Immune Suppressants will be withdrawn at any time between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.
    

Intervention name(s): Abatacept; Placebo
Intervention type(s): Biological; Other
Other intervention name(s): Orencia
Intervention MeSH terms: Abatacept
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment