E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10039710 |
E.1.2 | Term | Scleroderma |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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.
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E.2.2 | Secondary objectives of the trial |
- 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.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.
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E.4 | Principal 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.
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E.5 End points |
E.5.1 | 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)
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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after the last visit at t= 24months of the last subject in the trial |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |