Diffuse cutaneous systemic sclerosis according to the ACR/EULAR criteria
Conditions
Interventions
Pharmaceutical Form: Powder for solution for injection
Trade Name: Mycophenolate mofetil
Pharmaceutical Form: Capsule, hard
Sponsors
UMC Utrecht
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age between 18 and 65 years. 2. Fulfilling the 2013 ACR-EULAR classification criteria 3. Disease duration = 2 years (from onset of first non-Raynaud’s symptoms) and - progressive skin involvement with a mRSS = 15 (diffuse skin pattern) and/or - major organ involvement as defined by either: a) clinically significant respiratory involvement b) clinically significant renal involvement c) clinically significant cardiac involvement 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 120 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: A potential subject who meets any of the following criteria will be excluded from participation in this study: 1. Pregnancy or unwillingness to use adequate contraception during study 2. Concomitant severe disease (respiratory, renal, cardiac, liver failure, psychiatric disorders including active drug or alcohol abuse, concurrent neoplasms or myelodysplasis, bone marrow insufficiency, uncontrolled hypertension, uncontrolled acute or chronic infection, including HIV, HTLV-1,2 positivity, ZUBROD-ECOG-WHO Performance Status Scale > 2, known hypersensitivity to any of the study drug constituents) 3. Previous treatments with immunosuppressants > 6 months including mycophenolate mofetil, methotrexate, azathioprine, rituximab, tocilizumab, glucocorticosteroids. 4. Previous treatments with TLI, TBI or alkylating agents including cyclophosphamide. 5. Significant exposure to bleomycin, tainted rapeseed oil, vinyl chloride, trichlorethylene or silica; 6. eosinophilic myalgia syndrome; eosinophilic fasciitis. 7. Poor compliance of the patient as assessed by the referring physicians.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine the optimal treatment strategy in early dcSSc: the effect of HSCT as upfront therapy compared with that of immunosuppressive medication in early dcSSc, with respect to survival and prevention of major organ failure (referred to as ‘event-free survival’ which is considered as primary endpoint), safety and the impact on skin thickening, visceral involvement, functional status, and quality of life.;Secondary Objective: To evaluate (in both treatment arms) whether disease activity correlates with immunological parameters, including immunopathology of skin, immune reconstitution, and autoantibodies. We will also determine the cost-effectiveness of HSCT as first line treatment versus usual care and try to identify factors associated with response to treatment;Primary end point(s): The primary endpoint is event-free survival. Event-free survival is defined as the time in days from the day of randomisation until the occurrence of death due to any cause or the development of persistent major organ failure (heart, lung, kidney) defined as follows: • Heart: left ventricular ejection fraction 6.7 kPa (> 50 mmHg) without oxygen supply • Kidney: need for renal replacement therapy Note 1. When major organ failure has occurred, its persistence is to be confirmed by repeated evaluation after 3 months. Note 2. Cardiac MR is considered the gold standard for assessment of LVEF. LVEF measurements by cardiac echo (instead of cardiac MR) will be accepted when baseline and follow-up evaluations have been performed by the same experienced echocardiologist. ;Timepoint(s) of evaluation of this end point: 3, 6, 9, 12, 15, 18, 21, 24 months after treatment | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Progression-free survival, defined as the time in days since the day of randomisation until any of the following relative changes from baseline has been documented: • death, • = 10% drop in (F)VC predicted and/or = 15% drop in DLCO predicted, • = 15% drop in LVEF by echo or cardiac MR, • = 15% drop in body weight, • = 30% drop in creatinine clearance, • = 30% increase in skin score, • = 0.5 increase in SHAQ. - Treatment related mortality is defined as any death during the study period following randomisation that cannot be attributed to progression of the disease according to the consensus opinion of the DSMB. - Treatment toxicity will be assessed using WHO toxicity parameters (adverse events =/> grade 3) in consecutive 3-month periods following randomisation until two years follow-up. - The area under the curve (AUC) of the CRISS over time, measuring the ‘predicted probability of being im-proved’ over 2 years.(22) This AUC is calculated based on 4 repeated measures (6, 12, 18 and 24 months) with back translation to the original scale between 0 and 1. - Change over years follow-up of the following parameters: • modified Rodnan skin score by independent assessor (appendix G) • Pulmonary involvement = diffusion capacity for carbon monoxide (DLCO and DLCO/VA), (forced)vital capacity ((F)VC), total lung capacity (TLC), residual volume (RV), mean pulmonary artery pressure by cardiac echo (or right heart catheterization), lung density measurement by thoracic CT • Renal involvement = urine portion: creatinin/ protein ratio Myocardial involvement= left ventricular function as measured by cardiac MR (at baseline and 12 months), ECG and cardiac echo (annually) and semiquantitative measurement of cardiac involvement with the cardiac score (based on the presence or absence of left axis deviation on ECG and moderate or large pericardial effusion on echo).(23) Quality-of-life (EuroQol (EQ-5D-5L)) (appendix H) Customized version (focussing on the impor | — |
Countries
Italy, Netherlands
Contacts
Public Contactprincipal investigator
UMC Utrecht
Outcome results
None listed