Clinical trial NCT01276522: Efficacy and Safety of Canakinumab in Schnitzler Syndrome
Official title: Efficacy and Safety of Canakinumab in Schnitzler Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Schnitzler Syndrome
Keywords: Schnitzler syndrome
IL-1 beta
Canakinumab
Ilaris
Treatment
Efficacy
Safety
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Novartis
First posted: 2011-01-13
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Schnitzler syndrome is a disabling inflammatory disease, characterized by chronic urticaria, fever, arthralgia, bone pain and gammopathy, which can so far only be effectively treated with anakinra, an interleukin-1 receptor antagonist. However, this drug is not registered for use in Schnitzler syndrome, and it needs to be injected daily, which is uncomfortable and unpractical. Therefore other treatments targeting IL-1 are needed. Canakinumab is a long-acting monoclonal antibody against IL-1β that has been registered for bimonthly use in the rare autoinflammatory disease Cryopyrin-associated periodic syndrome (CAPS). We hypothesize that it will be effective in Schnitzler syndrome too in view of clinical similarities to CAPS and the targeting of IL-1B, which is also blocked by anakinra (which blocks both IL-1B and IL-1A).

This is a 6-month open-label, single treatment arm study of canakinumab 150 or 300 mg (in case of insufficient response to 150 mg) subcutaneous injection once per month in patients with active Schnitzler syndrome, in which efficacy and safety will be assessed.

Detailed description: More on Canakinumab:

Canakinumab is a high-affinity human monoclonal anti-human interleukin-1β (IL-1β)antibody of the IgG1/k isotype), developed for the treatment of IL-1β driven inflammatory diseases. Canakinumab binds human IL-1β and functionally neutralizes the bioactivity of this pro-inflammatory cytokine. IL-1β is produced mainly by mononuclear phagocytes in response to injury and infection and plays a dominant role in the pathobiology of autoinflammatory syndromes (e.g. Cryopyrin associated periodic syndrome, CAPS), systemic Juvenile Idiopathic Arthritis and gout. Canakinumab is expected to treat the signs and symptoms of inflammation and the underlying structural damage of disease. Canakinumab has been administered in clinical trials as an intravenous (i.v.) infusion or as a subcutaneous (sc) injection and has been approved under the trade name ILARIS® in the US for patients ≥ 4 years of age with CAPS and in the European Union and Switzerland for CAPS patients ≥ 4 years of age.

Eligibility criteria: Inclusion Criteria:

* Patients with a diagnosis of Schnitzler syndrome as per criteria (ref 1).
* Patients that have been / are treated with Anakinra must have demonstrated a partial or complete clinical response with an associated normalization of their biomarkers of inflammation (CRP).
* Male and female patients at least 18 years of age at the time of the screening visit.
* Patient's informed consent.
* Negative QuantiFERON test or negative Purified Protein Derivative (PPD) test (\< 5 mm induration) at screening or within 1 month prior to the screening visit, according to the national guidelines. Patients with a positive PPD test (≥ 5 mm induration) at screening may be enrolled only if they have either a negative chest x-ray or a negative QuantiFERON test (QFT-TB G In-Tube).
* Adequate contraception in premenopausal females

Exclusion Criteria:

* Pregnant or nursing (lactating) women
* History of being immunocompromised, including a positive HIV at screening (ELISA and Western blot).
* Serologic evidence of hepatitis B or C infection
* Live vaccinations within 3 months prior to the start of the trial, during the trial, and up to 3 months following the last dose
* History of significant medical conditions, which in the Investigator's opinion would exclude the patient from participating in this trial
* History of recurrent and/or evidence of active bacterial, fungal, or viral infection(s)
* Use of the following therapies:

  * Anakinra within 24 hours prior to Baseline visit XML File Identifier : tl8ybe8lI1o6DeawQocCBa8TF/w=
  * Corticosteroids (oral prednisone (or equivalent)) \> 1.0 mg/kg/day (or greater than the maximum of 60 mg/day for children over 60 kg) within 3 days prior to the Baseline visit
  * Intra-articular, peri-articular or intramuscular corticosteroid injections within 4 weeks prior to the Baseline visit
  * Any other investigational biologics within 8 weeks prior to the Baseline visit
  * Any other investigational drugs, other than investigational biologic treatment, within 30 days (or 3 months for investigational monoclonal antibodies) or 5 half-lives prior to the Baseline visit, whichever is longer
* History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes

Primary outcomes:
measure: Complete or clinical remission at Day 14.
timeFrame: Day 14
Secondary outcomes:
measure: Complete or clinical remission at Day 3 and Day 7
timeFrame: Day 3 and day 7
measure: The prevention of disease relapse in patients who demonstrated complete remission at Day 14
timeFrame: Day 15 until end
measure: The change in biomarkers (CRP and SAA) and clinical parameters (physician and patient global assessment of disease activity) during the treatment and follow-up periods
timeFrame: Whole study
measure: Time to relapse after the last canakinumab dose
timeFrame: Month 6 - 9
measure: Safety and tolerability as well as PK/PD/IG properties of canakinumab in the treatment of patients with Schnitzler syndrome.
timeFrame: Whole study
measure: Changes in patient quality of life by using: Medical Outcome Short Form (36) Health Survey (SF-36®).
timeFrame: Whole study
measure: Optimal canakinumab dose and frequency in patients with Schnitzler syndrome
timeFrame: Whole study
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen Medical Centre
Study officials:
affiliation: Radboud University Medical Center
name: Anna Simon, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: de Koning HD, Bodar EJ, van der Meer JW, Simon A; Schnitzler Syndrome Study Group. Schnitzler syndrome: beyond the case reports: review and follow-up of 94 patients with an emphasis on prognosis and treatment. Semin Arthritis Rheum. 2007 Dec;37(3):137-48. doi: 10.1016/j.semarthrit.2007.04.001. Epub 2007 Jun 21.
citation: de Koning HD, Bodar EJ, Simon A, van der Hilst JC, Netea MG, van der Meer JW. Beneficial response to anakinra and thalidomide in Schnitzler's syndrome. Ann Rheum Dis. 2006 Apr;65(4):542-4. doi: 10.1136/ard.2005.045245. Epub 2005 Aug 11.
citation: Ryan JG, de Koning HD, Beck LA, Booty MG, Kastner DL, Simon A. IL-1 blockade in Schnitzler syndrome: ex vivo findings correlate with clinical remission. J Allergy Clin Immunol. 2008 Jan;121(1):260-2. doi: 10.1016/j.jaci.2007.09.021. Epub 2007 Oct 22. No abstract available.
citation: Schuster C, Kranke B, Aberer E, Arbab E, Sturm G, Aberer W. Schnitzler syndrome: response to anakinra in two cases and a review of the literature. Int J Dermatol. 2009 Nov;48(11):1190-4. doi: 10.1111/j.1365-4632.2009.04151.x.
citation: Martinez-Taboada VM, Fontalba A, Blanco R, Fernandez-Luna JL. Successful treatment of refractory Schnitzler syndrome with anakinra: comment on the article by Hawkins et al. Arthritis Rheum. 2005 Jul;52(7):2226-7. doi: 10.1002/art.21101. No abstract available.
citation: Lipsker D, Veran Y, Grunenberger F, Cribier B, Heid E, Grosshans E. The Schnitzler syndrome. Four new cases and review of the literature. Medicine (Baltimore). 2001 Jan;80(1):37-44. doi: 10.1097/00005792-200101000-00004.
citation: Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, Leslie KS, Hachulla E, Quartier P, Gitton X, Widmer A, Patel N, Hawkins PN; Canakinumab in CAPS Study Group. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med. 2009 Jun 4;360(23):2416-25. doi: 10.1056/NEJMoa0810787.
citation: Lachmann HJ, Lowe P, Felix SD, Rordorf C, Leslie K, Madhoo S, Wittkowski H, Bek S, Hartmann N, Bosset S, Hawkins PN, Jung T. In vivo regulation of interleukin 1beta in patients with cryopyrin-associated periodic syndromes. J Exp Med. 2009 May 11;206(5):1029-36. doi: 10.1084/jem.20082481. Epub 2009 Apr 13.
citation: de Koning HD, Schalkwijk J, van der Ven-Jongekrijg J, Stoffels M, van der Meer JW, Simon A. Sustained efficacy of the monoclonal anti-interleukin-1 beta antibody canakinumab in a 9-month trial in Schnitzler's syndrome. Ann Rheum Dis. 2013 Oct;72(10):1634-8. doi: 10.1136/annrheumdis-2012-202192. Epub 2012 Oct 19.