Ilaris (Canakinumab) in the Schnitzler Syndrome
Condition: Schnitzler Syndrome
MeSH terms: Schnitzler Syndrome; Syndrome
Study type: Interventional
Phase: Phase 2

Summary: 
      Schnitzler syndrome:

      Schnitzler syndrome is a rare disabling autoinflammatory syndrome characterized by a chronic
      urticarial rash and monoclonal gammopathy, accompanied by intermittent fever, arthralgia or
      arthritis or bone pain. Diagnostic criteria have been established. The disease never remits
      spontaneously. Although there is no standard of care, there have been promising developments
      in therapeutic options, especially anti-interleukin-1 therapy. Anakinra, a synthetic analogue
      of the endogenous interleukin-1 receptor antagonist, has caused rapid clinical remission in
      24 patients with Schnitzler syndrome. However, to sustain remission, continuous daily
      administration (100 mg sc) is required. The level of monoclonal protein does not decrease.
      Side effects of anakinra include painful injection site reactions and neutropenia.

      Interleukin-1 and the autoinflammatory diseases:

      As a key proinflammatory cytokine mediating local and systemic responses to infection and
      tissue injury, interleukin-1 can induce a range of responses, including fever, pain
      sensitization, bone and cartilage destruction, and the acute-phase inflammatory response. The
      so-called autoinflammatory diseases are mediated entirely by interleukin-1; reducing
      interleukin-1 activity brings about a rapid and sustained remission. Autoinflammatory
      diseases include relatively uncommon disorders such as familial Mediterranean fever, adult
      and juvenile Still's disease, the hyper-IG D syndrome, Behçet's syndrome, the
      cryoporin-associated periodic syndrome (CAPS), deficiency of the interleukin-1 receptor
      antagonist (DIRA) and Schnitzler's syndrome. Some common conditions such as gout and type 2
      diabetes, are also likely to be autoinflammatory diseases.

      Canakinumab:

      Canakinumab (Ilaris, Novartis Pharma) is a fully human anti-interleukin-1-bèta monoclonal
      antibody. Treatment with subcutaneous canakinumab (150 mg) once every 8 weeks was associated
      with a rapid remission of symptoms in the great majority of children and adults with CAPS.
      Serum inflammatory markers quickly returned to normal. In general, the side effects seen in
      this small study (35 patients) were not serious, though suspected infections ware
      significantly more prevalent in patients receiving canakinumab than in those receiving
      placebo. The prolonged duration of action of canakinumab and low incidence of injection-site
      reactions may confer certain advantages over other interleukin-1 inhibitors (anakinra and
      rilonacept), since both are frequently associated with injection-site reactions, and both
      require more frequent administration (daily for anakinra and weekly for rilonacept).

      Canakinumab was approved for the treatment of CAPS by the US Food and Drug Administration in
      June 2009 and by the European Medicines Agency in October 2009.

      Canakinumab is currently being evaluated for its potential in the treatment of systemic-onset
      juvenile idiopathic arthritis, diabetes mellitus, and difficult-to-treat gouty arthritis.
    

Detailed description: 
      Description of the study:

      Objectives:

        -  Primary objective: To evaluate if canakinumab 150mg every 8 weeks can induce and
           maintain clinical remission in patients with the Schnitzler syndrome.

        -  Secondary objectives:

             -  To test if canakinumab 150mg can induce a complete clinical response at Day 7.

             -  To assess if addition canakinumab 150mg given at Day 7 for patients demonstrating
                only a partial response can induce a complete clinical response at Day 14.

             -  To evaluate if canakinumab 300mg every 8 weeks can maintain clinical remission in
                those patients who required canakinumab 150 mg additional dose on Day 7 and
                achieved clinical remission at Day 14.

             -  To evaluate the safety of canakinumab treatment in patients with the Schnitzler
                syndrome.

             -  To assess the changes in C-reactive protein (CRP) levels during the treatment
                period.

      Study rationale:

      Although no standard therapy has been established for the Schnitzler syndrome, given the
      rarity of this auto-inflammatory syndrome, reports on the use of Anakinra, a synthetic analog
      of the endogenous interleukin-1 receptor antagonist, have been encouraging. However, side
      effects (including local infusion site reactions and neutropenia) and the need for daily sc
      administration have hampered its use. The anti-interleukin-1-inhibitor canakinumab may
      constitute an effective and more convenient alternative.
    

Intervention name(s): Ilaris
Intervention type(s): Drug
Intervention description(s): Canakinumab 150 mg (or 2 mg/kg for patients weighing <40kg) every 8 weeks over a 6 months treatment period (i.e., weeks 0, 8, 16 and 24).
At Day 7, patients who show an improvement, but not a clinical remission, will be given another 150 mg (or 2 mg/kg for patients weighing <40 kg) injection and continue at 300 mg (or 4 mg/kg for patients weighing <40 kg) every 8 weeks beginning at Week 8.
Patients who show no improvement of symptoms and signs of Schnitzler's syndrome will not receive any additional canakinumab dose and will be offered corticosteroid therapy. These patients will return for a follow-up visit 2 weeks later (Day 21) for safety reasons and will be discontinued from the trial.
If a patient flares twice during the study, physician may optionally change the dosing frequency to every 4 weeks.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Schnitzler syndrome