Human Anti-Tac (Daclizumab) to Treat Juvenile Idiopathic Arthritis (JIA)-Associated Uveitis
Condition: Anterior Uveitis; Arthritis, Juvenile Idiopathic; Iritis; Immunosuppression
MeSH terms: Arthritis; Arthritis, Juvenile; Uveitis; Uveitis, Anterior; Iridocyclitis; Iritis
Study type: Interventional
Phase: Phase 2

Summary: 
      This study will examine the safety and effectiveness of a monoclonal antibody called
      humanized anti-Tac (HAT, also called daclizumab) to treat children and adolescents with
      uveitis (chronic inflammatory eye disease) associated with juvenile idiopathic arthritis
      (JIA). Monoclonal antibodies are genetically engineered proteins made in large quantities and
      directed against a specific target in the body. The HAT antibody is designed to prevent a
      specific chemical interaction needed for immune cells to produce inflammation. Current
      treatments for uveitis include steroids and immune-suppressing drugs. These treatments do not
      always work or they may cause significant side effects. This study will determine whether
      daclizumab can improve uveitis in children and reduce the need for other medicines.

      Patients between 6 and 18 years of age with active non-infectious JIA-associated uveitis
      requiring treatment with anti-inflammatory medications as often as three times a day or more
      may be eligible for this study.

      Each candidate is screened with a medical history, physical examination, blood tests, eye
      examination, and the following specialized tests:

        -  Fluorescein angiography to evaluate the eye's blood vessels. A yellow dye is injected
           into an arm vein and travels to the blood vessels in the eyes. Pictures of the retina
           are taken using a camera that flashes a blue light into the eye. The pictures show if
           any dye has leaked from the vessels into the retina, indicating the presence of
           inflammation.

        -  Optical coherence tomography to measure retinal thickness. The eyes are examined through
           a machine that produces cross-sectional pictures of the retina. These measures are
           repeated during the study to determine changes, if any, in retinal thickening.

        -  Stereoscopic color fundus photography to examine the back of the eye. The pupils are
           dilated with eye drops to examine and photograph the back of the eye.

      Upon entering the study, participants receive a 90-minute infusion of daclizumab through a
      catheter (plastic tube) placed in an arm vein. They return to the clinic after 14 days and
      again after 28 days for repeat eye examinations, blood tests, and daclizumab infusions. Four
      weeks after the third infusion, patients are examined for response to treatment. Those who
      have benefited from daclizumab may continue receiving monthly infusions of the drug for up to
      one year. A blood test and eye examination are done at the time of each infusion. Patients
      whose disease has remained active 12 weeks after the first infusion are taken off the study
      and treated with other medications.
    

Detailed description: 
      Pediatric uveitis represents 5-10 % of all patients with uveitis. Uveitis refers to
      intraocular inflammatory diseases. The most common type of non-infectious pediatric uveitis,
      associated with a systemic disease, is JIA-associated chronic, anterior uveitis. Therapeutic
      considerations for pediatric uveitis are often very challenging. Current therapeutic
      modalities include corticosteroids and other immunosuppressive agents. These modalities are
      not always effective at controlling the disease. In addition they can also be associated with
      a higher rate of ocular side effects. To further add to this challenge, pediatric uveitis has
      a higher rate of ocular complications, even with the current therapies. Consequently, an
      effective treatment with a safer side effect profile is highly desirable. Daclizumab is a
      humanized monoclonal antibody directed against the high affinity interleukin-2 (IL-2)
      receptor CD25 or Tac subunit. The IL-2 receptor system plays a central role in mediating
      immune responses. Blocking this system impedes immune responses and can inhibit local
      inflammatory responses, including uveitis. Pilot studies using intravenous or subcutaneous
      daclizumab treatments suggest that daclizumab treatments at 2 mg/kg every 2-4 weeks for
      quiescent uveitis may effectively replace the other immunosuppressive medications in a
      majority of cases.

      Because we have little experience using daclizumab for active uveitis in a pediatric
      population, this feasibility study will enroll seven study participants that would normally
      be treated with systemic, high-dose corticosteroids or other cytotoxic, systemic
      immunosuppressive medications. Since daclizumab for other indications can be tolerated with
      repeated dosing at 8-10 mg/kg, we will administer daclizumab to reach high serum levels with
      a pair of doses at 8 mg/kg and 4 mg/kg two weeks apart. The primary objective of this study
      is to collect preliminary information on the utility of acute daclizumab therapy on active
      ocular inflammation in a pediatric population. The primary outcome is resolution of active
      disease defined as a two step reduction in the anterior chamber cell scale from baseline.
      Safety assessment will be made at 28 days and efficacy assessment at 8 weeks after the
      initial daclizumab injection. Secondary outcomes will include fluorescein retinal vascular
      leakage, cystoid macular edema, vitreous haze and visual acuity. In addition all adverse
      events will be collected regardless of possible relation to daclizumab. Participants who do
      not meet the safety end point at day 28 will be permitted to continue IV daclizumab
      maintenance treatments beginning at Day 28 with 2 mg/kg every 4 weeks. An efficacy assessment
      will be made at 8 weeks, and patients who show a 2 step reduction in their intraocular
      inflammation, and has not met the safety end point, will continue daclizumab treatment with
      2mg/kg every 4 weeks for a total of 52 weeks in the study. At any time during the follow-up
      period, if a participant loses greater than 3 lines of visual acuity from baseline study, or
      meet the safety end point, treatments will be discontinued.

      The primary objective of this feasibility study is to gain preliminary information regarding
      the safety and possible efficacy of daclizumab to treat active uveitis, associated with JIA.

      The primary focus of this feasibility study is a short or acute response trial to relatively
      high-dose daclizumab infusions to observe if the anterior cell and flare associate with
      active JIA-associated uveitis can be promptly reduced. In order to qualify for enrollment,
      each participant must meet all of the inclusion criteria and not meet any of the exclusion
      criteria. This study will enroll seven participants at the National Eye Institute (NEI) who
      currently have active JIA-associated active uveitis. Enrollment is expected to take
      approximately three months. The two induction treatments will be completed within 14 days,
      with the primary safety evaluation at Day 14 and Day 28 and primary efficacy assessment at 12
      weeks. An induction regimen of intravenous (IV) daclizumab at 8 mg/kg is given on Day 0
      followed by another IV dose of 4 mg/kg at Day 14, provided the safety endpoint has not been
      met.

      An efficacy assessment will be made at 12 weeks, and patients who show a 2-step reduction in
      their intraocular inflammation, and has not met the safety endpoint, will continue with
      daclizumab therapy. Meeting the safety failure criterion or having a serious adverse affect
      attributable to the daclizumab therapy will be cause for termination from further daclizumab
      study treatments. Continuing follow-up and standard-of-care alternative treatments with a
      potentially reduced visit schedule will be provided through the duration of the trial if
      daclizumab treatments are suspended. After the trial, participants may seek other
      standard-of-care treatments from their own physician or ophthalmologist or they may be
      eligible to enroll in other research trials if these are available.

      Participants who show a 2-step reduction in their ocular inflammation or a decrease to
      inactivity, without serious adverse events, will have the option to receive extended
      treatments of 2 mg/kg IV daclizumab treatments at 4-week intervals, beginning day 28, for up
      to a total of 52 weeks in the study.
    

Intervention name(s): Daclizumab
Intervention type(s): Drug
Other intervention name(s): Human Anti-Tac
Intervention MeSH terms: Daclizumab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Anterior Uveitis; Arthritis, Juvenile Idiopathic; Daclizumab; Iritis; Immunosuppression; Chronic Inflammatory Eye-Disease; Juvenile Idiopathic Arthritis