Primary: To determine whether IL-1 inhibition by Canakinumab is efficacious in treatment of Schnitzler syndrome.Secondary:1. To assess the effect of canakinumab on Schnitzler syndrome (clinical signs/symptoms and inflammatory biomarkers C-reactive…
ID
Source
Brief title
Condition
- Haematological disorders NEC
- Immune disorders NEC
- Angioedema and urticaria
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Complete or clinical remission at Day 14.
Secondary outcome
1. Complete or clinical remission at Day 3 and Day 7
2. The prevention of disease relapse in patients who demonstrated complete
remission at Day 14
3. 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
4. Time to relapse after the last canakinumab dose
5. Safety and tolerability as well as PK/PD properties of canakinumab in the
treatment of patients with Schnitzler syndrome.
Exploratory:
1. Changes in patient quality of life by using: Medical Outcome Short Form (36)
Health Survey (SF-36®).
2. Optimal canakinumab dose and frequency in patients with Schnitzler syndrome
Background 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. We hypothesize that it will be effective in Schnitzler
syndrome.
Study objective
Primary: To determine whether IL-1 inhibition by Canakinumab is efficacious in
treatment of Schnitzler syndrome.
Secondary:
1. To assess the effect of canakinumab on Schnitzler syndrome (clinical
signs/symptoms and inflammatory biomarkers C-reactive protein and serum amyloid
A).
2. To evaluate the safety and tolerability of canakinumab in the treatment of
patients with Schnitzler syndrome.
3. To assess PK/PD properties of canakinumab by measuring canakinumab and
IL-1beta levels
Exploratory:
1. To explore the changes in patient quality of life during canakinumab
treatment in patients with Schnitzler syndrome by using: Medical Outcome Short
Form (36) Health Survey (SF-36®).
2. To explore potential biomarkers and pharmacogenomic characterization of
these patients at baseline as predictors of total clinical response with
canakinumab treatment
3. To explore an optimal canakinumab dose frequency in patients with Schnitzler
syndrome.
Study design
Study design: This is a 6-month open-label, single treatment arm, safety and
efficacy study of canakinumab subcutaneous injection in patients with active
Schnitzler syndrome, with a maximum 6 month run-out observation period after
cessation of treatment.
Study dose: Canakinumab 150mg/month or 2mg/kg/month for patients <40kg.
Intervention
Monthly subcutaneaous administration of Canakinumab 150mg.
Study burden and risks
In view of specific analogies of CAPS and Schnitzler syndrome, e.g. chronic
urticaria and systemic inflammation and complete remission of symptoms upon
anakinra treatment, we expect canakinumab to be highly effective in Schnitzler
syndrome as well. This would eliminate the burden of daily injections, which
are required in anakinra treatment, and offer more insight in which cytokines -
IL-1α and/or IL-1β - are critically involved in the pathophysiology of
Schnitzler syndrome. Namely, a major difference between anakinra an canakinumab
is that the former blocks the effects of both IL-1α and IL-1β, whereas the
latter specifically inhibits IL-1β. Theoretically, it could have less side
effects by being more specific. As yet, it is unclear if in Schnitzler
syndrome, blocking solely IL-1β is as effective as blocking both IL-1α and
IL-1β. It is therefore important to find this out.
Interleukin -1 blockade may interfere with the immune response to infections.
Clinical data with anakinra and rilanocept have demonstrated a slight increase
in the overall risk for serious infections, the majority of which are upper
respiratory tract infections. Other reported side effects were gastrointestinal
symptoms, such as abdominal pain, and vertigo. No deaths were attributed to
canakinumab use. One could question the use of an anti-inflammatory agent in a
disease in which in 12% of patients a lymphoproliferative disorder ensues after
10 years of symptomatic disease (de Koning et al., 2007). However, we rather
expect a protecting effect of anti-IL-1 therapy, if any, since a recent study
showed that in patients with smoldering or indolent multiple myeloma who were
at risk of progression to active myeloma, treatment with IL-1 inhibitors
decreased the myeloma proliferative rate and CRP levels in those who responded
(Lust et al., 2009a).
For further information we refer to the Canakinumab Investigator*s Brochure Ed
7.
Patients will be requested to visit our clinic 12-15 times, and to complete a
diary of symptoms and potential adverse effects. 12-15 blood samples will be
taken of 20-60 ml each. In order to start this study, treatment with the IL-1
receptor antagonist anakinra will have to be withdrawn; we expect patients to
experience symptoms within 72 hours of this withdrawal. As soon as they are
symptomatic, patients will start on canakinumab treatment. Rescue treatment has
been stipulated in the event that canakinumab is not as efficacious as
anakinra; if treatment fails, patients are returned to anakinra treatment. The
benefit of this study: if canakinumab is as effective as anakinra, it will mean
one subcutaneous injection a month instead of a painful injection once a day.
If this study shows good results, steps will be taken towards registration of
canakinumab for use in Schnitzler syndrome.
Postbus 9101
6500 HB Nijmegen
NL
Postbus 9101
6500 HB Nijmegen
NL
Listed location countries
Age
Inclusion criteria
1. Patients with a diagnosis of Schnitzler syndrome as fulfilling the criteria (see table 1).
2. Patients with Schnitzler syndrome who have been treated with the biological agent Anakinra must have demonstrated a partial or complete clinical response with an associated decrease in their biomarkers of inflammation (CRP and SAA) below 10mg/L.
3. Active Schnitzler syndrome (if applicable after stop of current treatment) at time of start of study treatment.
4. Male and female patients at least 18 years of age at the time of the screening visit.
5. Patient*s informed consent prior to the study
6. 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.
7. Adequate contraception in premenopausal women
Exclusion criteria
1. Pregnant or nursing (lactating) women
2. History of being immunocompromised, including a positive HIV at screening (ELISA and Western blot).
3. Live vaccinations within 3 months prior to the start of the trial, during the trial, and up to 3 months following the last dose
4. History of significant medical conditions, which in the Investigator*s opinion would exclude the patient from participating in this trial
5. History of recurrent and/or evidence of active bacterial, fungal, or viral infection(s)
6. Use of any other medication to control the symptoms of active Schnitzler syndrome.
7. Corticosteroids > 0.1 mg/kg/day in the 1 week prior to the baseline visit
8. Use of the following therapies:
• Anakinra within 24 hours prior to Baseline visit
• Rilonacept within 1 week prior to Baseline visit
• Toclizumab within 3 weeks prior to Baseline visit
• Etanercept within 4 weeks prior to Baseline visit
• Adalimumab within 8 weeks prior to the Baseline visit
• Infliximab within 12 weeks prior to the Baseline visit
• Rituximab within 26 weeks prior to the Baseline visit
• Leflunomide within 4 weeks prior to the Baseline visit. Documentation of a completion of a full cholestyramine elimination treatment after most recent leflunomide use will be required.
• Thalidomide within 4 weeks prior to the Baseline visit
• Cyclosporine within 4 weeks prior to the Baseline visit
• Intravenous immunoglobulin (i.v. Ig) within 8 weeks prior to the Baseline visit
• 6-Merceptopurine, azathioprine, cyclophosphamide, or chlorambucil within 12 weeks prior to the Baseline visit
• Dapsone, mycophenolate mofetil within 3 weeks prior to the Baseline visit
• Growth hormone within 4 weeks prior to the Baseline visit
• 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
9. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes
10. Severe co-morbidity (as judged by investigator).
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-021166-30-NL |
| CCMO | NL32191.091.10 |