Canakinumab to Treat Neonatal-Onset Multisystem Inflammatory Disease
Condition: NOMID; CINCA Syndrome
MeSH terms: Cryopyrin-Associated Periodic Syndromes; Syndrome
Intervention: Canakinumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 7.0
Sex: All
Minimum age: 2 Years
Maximum age: 25 Years
Healthy volunteers: No
Keywords: NOMID; CINCA Syndrome; Canakinumab

Summary:

      This study will examine whether a medicine called canakinumab is safe and effective for
      treating patients with neonatal-onset multisystem inflammatory disease (NOMID), also known as
      chronic infantile neurologic, cutaneous, articular (CINCA) syndrome. This disease can cause
      rash, joint deformities, brain inflammation, problems with the eyes and learning
      difficulties. Canakinumab is an experimental drug that inhibits the action of a protein
      produced by the body called human IL-1beta, which is responsible for the symptoms in NOMID
      and also contributes to many other kinds of inflammatory diseases.

      Patients 2 years of age and older with NOMID / CINCA may be eligible for this study.
      Participants undergo the following procedures:

      Screening Phase

        -  Medical history and review of medical records

        -  Blood tests

        -  Daily diary of symptoms and medicines take

      Washout/Lead-in Phase

        -  Discontinuation of anakinra or other medications, a 6 to 48-hour run-in period (only for
           patients who discontinued anakinra or other IL-1 blocking therapy).

      Treatment Phase

        -  Injection of canakinumab under the skin every 8 weeks for 6 months

        -  Monitoring and evaluations during treatment, including:

        -  Quality-of-life questionnaires and daily diary

        -  Vital signs measurements (heartbeat, blood pressure, temperature)

        -  Blood tests

        -  Electrocardiogram

        -  Tuberculosis skin test

        -  Neurological, eye and skin examinations at beginning and end of study

        -  Cognitive evaluation at beginning and end of study

        -  Lumbar puncture (spinal tap) at the beginning of the study, 2 weeks after the second
           dosing of canakinumab and at the end of the study

        -  X-rays and bone density scan at beginning and end of study

        -  Magnetic resonance imaging (MRI) of the head at beginning and end of study

      Follow-up Phase

        -  Monthly clinic visits after the last dose of canakinumab for a minimum of 60 days

      End-of-Study Evaluation

        -  Series of tests 8 weeks after last dose of canakinumab to evaluate treatment response
           and side effects
    

Eligibility criteria:

        -INCLUSION CRITERIA:

          1. Male and female patients of greater than or equal to 2 years of age at the time of the
             screening visit.

          2. Patient's informed consent (for greater than or equal to 18 years of age), or in
             pediatric patients, parents' or legal guardian's informed consent and patient's assent
             to the protocol whenever possible.

          3. Females of childbearing potential (young women who have had at least one menstrual
             period regardless of age) and/or aged greater than or equal to 8 years must have a
             negative serum pregnancy test at screening and a negative urine pregnancy test at each
             baseline prior to performance of any radiologic procedure or administration of study
             medication.

          4. Women of childbearing age and men able to father a child, who are sexually active,
             must agree to use a form of effective method of contraception (e.g. birth control
             pills, abstinence, double-barrier contraception, etc.) during the study (from the date
             of screening) and for at least 3 months following the last dose. Periodic abstinence
             (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are
             not acceptable methods of contraception.

          5. Presence, or history (prior to anakinra treatment), of at least 2 of the following
             clinical manifestations:

               -  Typical NOMID urticarial rash.

               -  Central nervous system (CNS) involvement: increased intracranial pressure
                  (greater than 180 mm water), papilledema, cerebral spinal fluid pleocytosis
                  (white cell count greater than 6 cells/mm(3)), stroke, seizures, and/or
                  sensorineural hearing loss.

               -  Typical arthropathic changes on X-rays: epiphysial and/or patellar overgrowth.

          6. Onset of NOMID/CINCA before or at 6 months of age.

          7. Patients requiring oral steroids, NSAIDs and/or disease-modifying antirheumatic drugs
             (DMARDs) can be enrolled if they are on a stable dose (oral steroids: less than 20
             mg/day or less than or equal to 0.4 mg/kg prednisone or prednisone equivalent,
             whichever applies) for at least 4 weeks prior to the screening visit. Steroid therapy
             may be tapered during treatment with canakinumab after the first canakinumab treatment
             period / cycle, at the discretion of the investigator.

          8. Negative tuberculin skin test reaction (PPD 5 tuberculin units or as according to
             local standard practice) (less than 5mm induration) at 48 to 72 hours after
             administration at the screening visit or within 2 months prior to the screening visit,
             according to national guidelines. Patients who have a positive PPD skin test with a
             documentation of BCG vaccination, who are at low environmental risk for tuberculosis
             (TB) infection or reactivation, and have a negative chest X-ray can be included. A
             positive PPD test will be defined using the MMWR 2000 guidance, summarized as criteria
             for tuberculin positivity by risk group.

          9. Able to comply with the requirements of the study.

        EXCLUSION CRITERIA:

        Subjects meeting any of the following criteria will be excluded from entry into or
        continuation in the study unless sponsor approval is obtained:

          1. Pregnant or breastfeeding women.

          2. Participation in any clinical trial investigation within 4 weeks prior to dosing or
             longer if required by local regulation, with the exception of trials with anakinra
             and/or canakinumab.

          3. In case of previous treatment with biologic agents or DMARDs, an appropriate washout
             period (as according to the recognized duration of effect and half lives) will be
             required for such patients to be eligible to participate in the trial, e.g.:

             Previous treatment and required washout period prior to baseline and thereafter:

               -  Rituximab, 26 weeks

               -  Infliximab, 12 weeks

               -  Adalimumab, 8 weeks

               -  Etanercept, 4 weeks

               -  Anakinra, 1 day

               -  Any other investigational biologics, 8 weeks

               -  Leflunomide, 4 weeks

               -  Thalidomide, 4 weeks

               -  Cyclosporine, 4 weeks

               -  i.v. immunoglobulin (i.v. Ig), 8 weeks

               -  Dapsone, mycophenolate mofetil, 3 weeks

               -  Corticosteroids greater than or equal to 20 mg/day or greater than 0.4 mg/kg
                  prednisone or prednisone equivalent, whichever applies, 1 week

          4. Donation or loss of 300 mL or more of blood within 8 weeks prior to dosing.

          5. A past medical history of clinically significant ECG abnormalities or a family history
             of a prolonged QT-interval syndrome.

          6. History of immunocompromise.

          7. Positive test for or prior history of HIV (ELISA and Western blot), Hepatitis B
             (Hepatitis B surface antigen) or Hepatitis C.

          8. Presence of active infections or a history of pulmonary TB infection with or without
             documented adequate therapy. Subjects with current active TB, or recent close exposure
             to an individual with active TB are excluded from the study.

          9. Presence of any additional rheumatic disease or significant systemic disease. For
             example, major chronic infectious/ inflammatory/ immunologic disease (such as
             inflammatory bowel disease, psoriatic arthritis, spondyloarthropathy, systemic lupus
             erythematosus in addition to the autoinflammatory disease).

         10. Treatment with a live virus vaccine during 3 months prior to baseline visit. No live
             vaccines will be allowed throughout the course of this study and up to 3 months
             following the last dose.

         11. History of renal transplant.

         12. History of malignancy. Subjects deemed cured of superficial malignancies such as
             cutaneous basal or squamous cell carcinomas, or in situ cervical cancer may be
             enrolled.

         13. Presence of any of the following laboratory abnormalities: ALT or AST greater than 2
             times the upper limit of normal (ULN), platelet count less than 100x10(9)/L.