INFLUENCE OF B CELL DEPLETION BY MONOCLONAL ANTI-CD20 ANTIBODIES IN SYSTEMIC SCLERODERMA - RItuximab In Scleroderma ( RITIS)

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2008-007180-16-NL
• Date of registration: 24/11/2008
• Prospective Registration: Yes
• Primary sponsor: LUMC
• Public title: INFLUENCE OF B CELL DEPLETION BY MONOCLONAL ANTI-CD20 ANTIBODIES IN SYSTEMIC SCLERODERMA - RItuximab In Scleroderma ( RITIS)
• Scientific title: INFLUENCE OF B CELL DEPLETION BY MONOCLONAL ANTI-CD20 ANTIBODIES IN SYSTEMIC SCLERODERMA - RItuximab In Scleroderma ( RITIS)
• Date of first enrolment: 13/05/2009
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2008-007180-16
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Netherlands

Key inclusion & exclusion criteria

Inclusion criteria:
1. Age between 18 and 70 years.
2. Established diagnosis of systemic sclerosis according to ARA-criteria (appendix).
3. Informed consent

Appendix . Definition and classification of systemic sclerosis

Systemic sclerosis can be classified according to criteria set up by the American Rheumatism Association:


ARA scleroderma criteria cooperative study: Preliminary criteria for the classifica¬tion of
syste¬mic sclerosis (scleroderma)
_____________________________________________________________________

1. Major criterion: - Proximal scleroderma
2. Minor criteria : - Sclerodactyly
- Digital pitting scars or loss of substance of the digital finger pad
- Bibasilar pulmonary fibrosis


One major or two or more minor criteria are necessary to establish a diagnosis of SSc. A further subclas¬sification can be made in limited (cuta¬neous) SSc (lSSc) and diffuse (cutaneous) SSc (dSSc).
Limited SSc is characterized by skin involvement limited to hands, feet, face and/or fore¬arms, is associ¬ated with a high incidence of anticentro¬mere autoantibodies (70-80%), the existen¬ce for years of Ray¬naud's phenomenon and a significant late incidence of pulmonary hyper¬tensi¬on. The acronym CREST (Ca¬lcinosis, Raynaud's phenom¬enon, Esophageal dysmo¬tility, Sclero¬dac¬tyly and Telean¬giectasia) fits into this subclassification.
Diffuse SSc is characterized by skin involvement on upperarms and trunk, is as¬sociated with an early incidence of interstitial lung disease, hypertensive crisis and renal failure, diffuse gastrointesti¬nal disease and myocardial involvement.


Reference:

Subcommittee for scleroderma criteria of the American Rheumatism Association diagnostic and therapeutic criteria commit¬tee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980;23:581-590.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
. Pregnancy or unwillingness to use adequate contraception during study
2. Previous treatments with biological agents, cell depleting therapies including investigational
agents.
3. Significant exposure to bleomycin, tainted rapeseed oil, vinyl chloride, trichlorethylene or silica; eosinophilic myalgia syndrome; eosinophilic fasciitis.
5. History of allergic or anaphylactic reaction to a biological agent or known hypersensitivity to any component of anti-CD20 monoclonal antibodies or to murine proteins.
6. History of deep tissue infection (e.g. Fasciitis, abscess, osteomyelitis) within 1 year prior to baseline.
7. History of serious chronic or recurrent infection within 12 weeks prior to baseline, including HIV, HTLV-1,2 positivity.
8. History of cancer, including solid tumors, hematological malignancies and carcinoma in situ (except for basal cell and squamous cell carcinoma of the skin that have been treated and cured).
9. Concurrent liver failure as defined by a sustained 3-fold increase in serum transaminase or bilirubin.
10. Active drug or alcohol abuse or persistent psychiatric disorders that prevent inclusion.
11. Uncontrolled hypertension.
12. Poor compliance of the patient as assessed by the referring physicians.
13. Receipt of any vaccine 28 days prior to baseline.
14. Intolerance or contraindications to IV glucocorticoids.
15. Positive tests for HbsAg, Hepatitis core antibody or hepatitis C serology.
16. Concentrations of serum IgG and /or IgM below 5.0 and 0.40 mg/ mL.
17. Absolute neutrophil count of less than 1.0x 109/L.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

systemic sclerosis
MedDRA version: 9.1 Level: PT Classification code 10039710 Term: Scleroderma

Intervention(s)

Trade Name: Rituximab
Product Name: Mabthera
Pharmaceutical Form: Powder for infusion*
Pharmaceutical form of the placebo: Solution for infusion
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

Main Objective: To evaluate the safety and efficacy of anti-CD20 therapy with respect to:
- Clinical and laboratory adverse events, as measured every three months.
- Survival and prevention of major organ failure (referred to as ‘event-free survival’ which is considered the primary endpoint).
- Impact on skin thickening, visceral involvement, functional status, and quality of life.

Secondary Objective: - To evaluate whether disease activity correlates with immunological parameters, including immunopathology of skin, immune reconstitution, and autoantibodies.
- To search for predictive factors (clinical and immunological) of response.

Primary end point(s): - The major endpoints of the study are treatment related mortality and treatment toxicity, and efficacy of rituximab.
Treatment related mortality is defined as any death during the study period that cannot be attributed to progression of the disease according to the consensus opinion.
Treatment toxicity will be assessed using WHO toxicity parameters (expressed as maximum grade toxicity per organ system) (Appendix) in consecutive 3-month periods following randomization.

Efficacy will be assessed as progression-free survival, defined as the time in days since the day of randomization until any of the following changes from baseline has been documented at two consecutive 3-month evaluations:
- death,
- > 10% drop in (F)VC and/or ? 15% drop in DLCO (of predicted values),
- > 15% drop in LVEF by MUGA,
- > 15% drop in body weight,
- > 30% drop in creatinine clearance,
- > 30% increase in Modified Rodnan skin score,
- > 0.5 increase in SHAQ
Changes during the study period (from baseline until completion of 2 years follow-up) in the following parameters :
- Modified Rodnan Skin score
- (F)VC and DLCO
- LVEF
- Weight (Kg)

Secondary ID(s)

RITIS