Human Anti-Tac (Daclizumab) to Treat Juvenile Idiopathic Arthritis (JIA)-Associated Uveitis
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.
|Anterior Uveitis Arthritis, Juvenile Idiopathic Iritis Immunosuppression||Drug: Daclizumab||Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||Treatment of Active Anterior Uveitis Associated With JIA, Using Humanized Anti-Tac (HAT, Daclizumab)|
- Number of Participants With a Two-step Reduction in Inflammation [ Time Frame: 12 weeks ]Number of participants with a two-step reduction (or down to 0 out of a scale of 0 to 4+) of anterior chamber (AC) inflammation according to Standardization of Uveitis Nomenclature (SUN) criteria, while on a topical corticosteroid schedule of less than 3 times a day. Grade 0 is the best score on this scale with <1 cell in the field and 4+ is the worst score on this scale with >50 cells in the field.
- Number of Participants Reporting a Serious Adverse Event (SAE) [ Time Frame: 52 weeks ]Safety of acute daclizumab use in JIA-associated uveitis was assessed through serious adverse events (SAE).
|Study Start Date:||August 2005|
|Study Completion Date:||May 2008|
|Primary Completion Date:||May 2008 (Final data collection date for primary outcome measure)|
Other Name: Human Anti-Tac
Hide 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00130637
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00130637
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|