A Randomized, Open-Label Phase II/III Multicenter Study of High Dose Immunosuppr

The primary objective is to evaluate the potential benefit of high-dose immunosuppressive therapy as treatment for severe SSc by comparing event-free survival (EFS) after HDIT followed by stem cell transplantation with high-dose pulse cyclophosphamide therapy. Event-free survival will be defined as survival without death or significant organ damage. An event based on organ dysfunction must be documented on at least 2 occasions „d 3 months apart, or sustained for a 3-month period. The secondary objectives for this study are: 1. To evaluate and compare safety of HDIT transplantation and pulse cyclophosphamide, as evidenced by regimen-related toxicities, infectious complications, treatment-related mortality, overall total mortality, and time to engraftment. 2.To evaluate and compare disease responses after HDIT transplantation and pulse cyclophosphamide, assessing skin disease by modified Rodnan Skin Score (mRSS), pulmonary function as measured by DLCO and FVC, Modified Scleroderma Health Assessment Questionnaire (SHAQ), and Quality of Life using Short Form 36 (SF-36). 3. To evaluate treatment effect on disease activation/progression, as indicated by measures of cardiac, pulmonary, and renal status, as well as skin integrity, gastrointestinal disease, health assessment (SHAQ), use of concomitant DMARDs, and occurrence of myositis. 3.To evaluate mechanistic measures of immune recovery and reconstitution with clinical correlative studies. Subject Selection: Subjects with poor prognosis diffuse cutaneous systemic sclerosis (dcSSc), with an extensive skin involvement and early internal organ involvement, will be recruited to participate in this study. The study population will include subjects with an anticipated 50% 5-year mortality, as shown by a diffuse disease skin score of „d 16. Subjects of all genders, races, and ethnicities between the ages of 18 and 65, inclusive, who meet eligibility criteria and provide consent will participate in this study. The majority of subjects will be recruited in outpatient clinics, although some subjects may be recruited from inpatient hospital settings. The primary endpoint for this study is EFS at 44 months after subject randomization. An event based on organ dysfunction must be documented on at least 2 occasions „d 3 months apart, or sustained for a 3-month period (documented from the first occurrence). The exception is the renal failure endpoint, for which duration of dialysis less than 6 months for treatment of SSc-related renal crisis would not be considered a primary endpoint. The events will be defined as any one of the following: Secondary endpoints identified by examining physicians that are subject to clinical interpretation will be submitted to a masked independent review committee at the end of the study for validation of the endpoint assessment. Endpoints that will be reviewed include, but are not limited to, mortality causation, assessment of scleroderma renal crisis, and determination of whether a therapy is a DMARD.