Tocilizumab in Patients With Schnitzler's Syndrome (TOCISCH)
Primary Purpose
Schnitzler's Syndrome
Status
Completed
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
Tocilizumab
Sponsored by
About this trial
This is an interventional treatment trial for Schnitzler's Syndrome
Eligibility Criteria
Inclusion Criteria:
- Adults (18 years or older)
- SchS diagnosis based on Strasbourg clinical criteria
- Active SchS, refractory to treatment with antihistamines, NSAIDS or colchicine, hydroxychloroquine or dapsone
- Patients who have a symptom score (PGA) of at least 8 (0-20) at baseline
- If necessary, concurrent/ongoing treatment with a stable dose of systemic corticosteroids not greater than 10mg/d for 14 days prior to screening
- If necessary, concurrent/ongoing treatment with a stable dose of antihistamines and NSAIDs for 7 days prior to screening
- Able to read, understand and willing to sign the informed consent form and abide with study procedures
- Willing, committed and able to return for all clinic visits and complete all study-related procedures, including willingness to have SC injections administered by a qualified person
- In females of childbearing potential: Negative pregnancy test within 28 days of randomization; males and females willing to use highly effective contraception (Pearl-Index < 1) during study treatment and for a minimum of 3 months after last dose of TCZ. Pregnancies occurring up to 90 days after the completion of the study medication must be reported to the investigator. A woman will be considered not of childbearing potential if she is post-menopausal for greater than two years or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy)
- Subjects are considered eligible, if they meet the following tuberculosis (TB) screening criteria: no history of latent or active TB prior to screening, no signs or symptoms suggestive of active TB, no recent close contacts with a person with active TB, and negative QuantiFERON-TB test at screening (if QuantiFERON-TB test is positive, the patient can only be included if active TB is ruled out with appropriate measurements according to standard of care, e.g. the patient is pre-treated with isoniazide for 4 weeks).
- No participation in other clinical trials 4 weeks before and after participation in this study
Exclusion criteria:
- Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization.
Concurrent/ongoing treatment with biologics or recent treatment (less than 5 half lives)
- With Anakinra within 7 days prior to screening, with canakinumab within 100 days prior to screening
- with oral/parental corticosteriods greater than 10 mg/d within 2 weeks prior to screening
- with Cyclosporin A Methotrexate, Dapsone, Chloroquine, Hydroxychloroquine, Azathioprine, Cyclophosphamide within 4 weeks prior to screening
- other immunosuppressives within 4 weeks or 5 half lives prior to screening, whichever is longer
- Previous treatment within six months of randomization with any cell-depleting therapies, including investigational agents or approved therapies, some examples include: CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19 and anti-CD20.
- Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of baseline.
- Treatment with a live (attenuated) virus vaccine within 4 weeks prior to Baseline visit
- Significant medical condition rendering the patient immunocompromised or not suitable for a clinical trial
- Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation.
- History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies.
- An abnormal chest radiograph consistent with clinical signs of prior or present tuberculosis infection whether or not previously treated with anti-tuberculosis agents
- Significant concomitant illness such as, but not limited to, cardiac, renal, neurological, endocrinological, metabolic, or lymphatic disease that would adversely affect the subject's participation or evaluation in this study
- Evidence of current HIV, Hepatitis B, or Hepatitis C infection by clinical or serological history
- Presence of any of the following laboratory abnormalities at enrollment visit: serum creatinine > 1.6 mg/dL (141 µmol/L) in female patients and > 1.9 mg/dL (168 µmol/L) in male patients, WBC <3,000/µl; platelet count <100000/µl ; ALT or AST >2 x ULN or total bilirubin >ULN, Hemoglobin <8.0 g/dL, neutrophil count <2,000 cells/µl or lymphocyte count <500/ µl
- Evidence of active, recurrent or latent systemic infection
- Active systemic inflammatory condition other than SchS including, but not limited to, rheumatoid arthritis
- History of malignancies within five years prior to screening other than a successfully treated non-metastatic cutaneous, basal, or squamous cell carcinoma and/or in situ cervical cancer
- Lactating females or pregnant females
- Enrollment in another investigational treatment or device study or use of an investigational agent, or less than 4 weeks or 5 half-lives, whichever is longer, since end of another investigational device or drug trial
- Subjects for whom there is concern about compliance with the protocol procedures
- Any medical condition which, in the opinion of the Investigator, would interfere with participation in the study or place the subject at risk
- History of substance abuse (drug or alcohol) or any other factor (e.g., serious psychiatric condition) that could limit the subject's ability to comply with study procedures.
- Patients with known hypersensitivity to tocilizumab
Sites / Locations
- Charité - Universitätsmedizin Berlin, Dpt. of Dermatology and Allergy
Arms of the Study
Arm 1
Arm Type
Other
Arm Label
Tocilizumab
Arm Description
Tocilizumab 162mg 1x weekly as subcutaneous syringe
Outcomes
Primary Outcome Measures
Physician global assessment
Change in the investigator's assessment of total disease activity (physician global assessment [PGA]) between baseline and TCZ Treatment
Secondary Outcome Measures
Complete responders
Proportion of patients with complete response (based on PGA with no or minimal overall autoinflammatory disease activity and CRP </= 10 mg/l)
Schnitzler Activity Score
Change in the patient based Schnitzler Activity Score (SchAS) during the treatment period (The SchAS combines the key symptoms of SchS).
Inflammation marker CRP
Change in CRP levels during the treatment period
Inflammation marker SAA
Change in SAA levels during the treatment period
Inflammation marker S100 A8/9
Change in S100 A8/9 levels during the treatment period
Overall quality of life
Change in the patient's quality of life (assessed by the SF-36)
Dermatology-specific quality of life
Change in the patient's quality of life (assessed by the Dermatology Life Quality Index)
Safety and tolerability assessed by adverse event reporting over the whole study period
Adverse event reporting over the whole study period
Full Information
NCT ID
NCT03046381
First Posted
January 5, 2017
Last Updated
February 13, 2020
Sponsor
Karoline Krause
Collaborators
Roche Pharma AG
1. Study Identification
Unique Protocol Identification Number
NCT03046381
Brief Title
Tocilizumab in Patients With Schnitzler's Syndrome
Acronym
TOCISCH
Official Title
A Pilot Open-label Study to Assess the Efficacy and Safety of Tocilizumab in Patients With Active Schnitzler's Syndrome
Study Type
Interventional
2. Study Status
Record Verification Date
February 2020
Overall Recruitment Status
Completed
Study Start Date
July 19, 2017 (Actual)
Primary Completion Date
March 11, 2019 (Actual)
Study Completion Date
April 10, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Karoline Krause
Collaborators
Roche Pharma AG
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Schnitzler's Syndrome (SchS) is a late-onset multifactorial autoinflammatory disease characterized by chronic urticarial skin lesions and a monoclonal gammopathy usually belonging to the immunoglobulin M (IgM) or IgG class. Symptoms associated with SchS are recurrent fever attacks, bone and muscle pain, arthralgia or arthritis, fatigue and lymphadenopathy. SchS is a rare disease with approximately 300 cases reported in the literature. The nature of SchS is chronic without known reports about spontaneous remissions. Disease onset occurs around the age of 50. About 15% of patients eventually develop a lymphoproliferative disorder, most often Waldenström's macroglobulinemia. The pathogenesis of SchS is still not well defined. Functional ex vivo studies showed excessive cytokine production (IL-1ß, IL-6 and IL-18) of peripheral blood monocytes (PBMCs) in SchS as compared to healthy controls. In addition to excessive IL-6 secretion from PBMCs IL-6 has repeatedly been reported to be elevated in the serum of SchS patients too. As IL-6 plays a major role in the development of multiple myeloma, IL-6 may also be associated with the formation of lymphoproliferative disorders in SchS.
Until now, there is no approved standard therapy available for the treatment of SchS. Non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and other immunosuppressive agents have been reported to provide variable relief from symptoms of bone pain and arthralgia. Case reports and small studies about successful treatment of SchS with anti-IL-1 blockers (anakinra, rilonacept and canakinumab) accumulate. However, there have been complete and partial treatment failures to anti-IL-1 blockade in SchS. In these patients, anti-IL-6 treatment (tocilizumab [TCZ]) demonstrated to be very effective in reducing the clinical symptoms and inflammation markers in SchS. TCZ treatment has proved to be very effective, well-tolerated and safe in other acquired autoinflammatory disorders, systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease that share many clinical features (rash, fever, joint involvement, lymphadenopathy, fatigue) and excessive cytokine production with SchS. The study consists of a run-in baseline period of 1-4 weeks followed by an open-label 20-week TCZ treatment phase with weekly s.c. injections (TCZ 162mg), followed by an optional study extension up to a total of 1 year with ongoing once weekly TCZ 162mg injections and a 4 week period of follow-up.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Schnitzler's Syndrome
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
8 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Tocilizumab
Arm Type
Other
Arm Description
Tocilizumab 162mg 1x weekly as subcutaneous syringe
Intervention Type
Drug
Intervention Name(s)
Tocilizumab
Other Intervention Name(s)
RoActemra®
Intervention Description
Tocilizumab 162mg 1x weekly s.c.
Primary Outcome Measure Information:
Title
Physician global assessment
Description
Change in the investigator's assessment of total disease activity (physician global assessment [PGA]) between baseline and TCZ Treatment
Time Frame
Baseline vs. week 20
Secondary Outcome Measure Information:
Title
Complete responders
Description
Proportion of patients with complete response (based on PGA with no or minimal overall autoinflammatory disease activity and CRP </= 10 mg/l)
Time Frame
Week 20
Title
Schnitzler Activity Score
Description
Change in the patient based Schnitzler Activity Score (SchAS) during the treatment period (The SchAS combines the key symptoms of SchS).
Time Frame
60 weeks
Title
Inflammation marker CRP
Description
Change in CRP levels during the treatment period
Time Frame
60 weeks
Title
Inflammation marker SAA
Description
Change in SAA levels during the treatment period
Time Frame
60 weeks
Title
Inflammation marker S100 A8/9
Description
Change in S100 A8/9 levels during the treatment period
Time Frame
60 weeks
Title
Overall quality of life
Description
Change in the patient's quality of life (assessed by the SF-36)
Time Frame
60 weeks
Title
Dermatology-specific quality of life
Description
Change in the patient's quality of life (assessed by the Dermatology Life Quality Index)
Time Frame
60 weeks
Title
Safety and tolerability assessed by adverse event reporting over the whole study period
Description
Adverse event reporting over the whole study period
Time Frame
60 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Adults (18 years or older)
SchS diagnosis based on Strasbourg clinical criteria
Active SchS, refractory to treatment with antihistamines, NSAIDS or colchicine, hydroxychloroquine or dapsone
Patients who have a symptom score (PGA) of at least 8 (0-20) at baseline
If necessary, concurrent/ongoing treatment with a stable dose of systemic corticosteroids not greater than 10mg/d for 14 days prior to screening
If necessary, concurrent/ongoing treatment with a stable dose of antihistamines and NSAIDs for 7 days prior to screening
Able to read, understand and willing to sign the informed consent form and abide with study procedures
Willing, committed and able to return for all clinic visits and complete all study-related procedures, including willingness to have SC injections administered by a qualified person
In females of childbearing potential: Negative pregnancy test within 28 days of randomization; males and females willing to use highly effective contraception (Pearl-Index < 1) during study treatment and for a minimum of 3 months after last dose of TCZ. Pregnancies occurring up to 90 days after the completion of the study medication must be reported to the investigator. A woman will be considered not of childbearing potential if she is post-menopausal for greater than two years or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy)
Subjects are considered eligible, if they meet the following tuberculosis (TB) screening criteria: no history of latent or active TB prior to screening, no signs or symptoms suggestive of active TB, no recent close contacts with a person with active TB, and negative QuantiFERON-TB test at screening (if QuantiFERON-TB test is positive, the patient can only be included if active TB is ruled out with appropriate measurements according to standard of care, e.g. the patient is pre-treated with isoniazide for 4 weeks).
No participation in other clinical trials 4 weeks before and after participation in this study
Exclusion criteria:
Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization.
Concurrent/ongoing treatment with biologics or recent treatment (less than 5 half lives)
With Anakinra within 7 days prior to screening, with canakinumab within 100 days prior to screening
with oral/parental corticosteriods greater than 10 mg/d within 2 weeks prior to screening
with Cyclosporin A Methotrexate, Dapsone, Chloroquine, Hydroxychloroquine, Azathioprine, Cyclophosphamide within 4 weeks prior to screening
other immunosuppressives within 4 weeks or 5 half lives prior to screening, whichever is longer
Previous treatment within six months of randomization with any cell-depleting therapies, including investigational agents or approved therapies, some examples include: CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19 and anti-CD20.
Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of baseline.
Treatment with a live (attenuated) virus vaccine within 4 weeks prior to Baseline visit
Significant medical condition rendering the patient immunocompromised or not suitable for a clinical trial
Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation.
History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies.
An abnormal chest radiograph consistent with clinical signs of prior or present tuberculosis infection whether or not previously treated with anti-tuberculosis agents
Significant concomitant illness such as, but not limited to, cardiac, renal, neurological, endocrinological, metabolic, or lymphatic disease that would adversely affect the subject's participation or evaluation in this study
Evidence of current HIV, Hepatitis B, or Hepatitis C infection by clinical or serological history
Presence of any of the following laboratory abnormalities at enrollment visit: serum creatinine > 1.6 mg/dL (141 µmol/L) in female patients and > 1.9 mg/dL (168 µmol/L) in male patients, WBC <3,000/µl; platelet count <100000/µl ; ALT or AST >2 x ULN or total bilirubin >ULN, Hemoglobin <8.0 g/dL, neutrophil count <2,000 cells/µl or lymphocyte count <500/ µl
Evidence of active, recurrent or latent systemic infection
Active systemic inflammatory condition other than SchS including, but not limited to, rheumatoid arthritis
History of malignancies within five years prior to screening other than a successfully treated non-metastatic cutaneous, basal, or squamous cell carcinoma and/or in situ cervical cancer
Lactating females or pregnant females
Enrollment in another investigational treatment or device study or use of an investigational agent, or less than 4 weeks or 5 half-lives, whichever is longer, since end of another investigational device or drug trial
Subjects for whom there is concern about compliance with the protocol procedures
Any medical condition which, in the opinion of the Investigator, would interfere with participation in the study or place the subject at risk
History of substance abuse (drug or alcohol) or any other factor (e.g., serious psychiatric condition) that could limit the subject's ability to comply with study procedures.
Patients with known hypersensitivity to tocilizumab
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Karoline Krause, MD
Organizational Affiliation
Charite University, Berlin, Germany
Official's Role
Principal Investigator
Facility Information:
Facility Name
Charité - Universitätsmedizin Berlin, Dpt. of Dermatology and Allergy
City
Berlin
State/Province
Germay
ZIP/Postal Code
10117
Country
Germany
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Citations:
PubMed Identifier
33545397
Citation
Bonnekoh H, Frischbutter S, Roll S, Maurer M, Krause K. Tocilizumab treatment in patients with Schnitzler syndrome: An open-label study. J Allergy Clin Immunol Pract. 2021 Jun;9(6):2486-2489.e4. doi: 10.1016/j.jaip.2021.01.024. Epub 2021 Feb 2. No abstract available.
Results Reference
derived
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Tocilizumab in Patients With Schnitzler's Syndrome
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