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Understanding Systemic Sclerosis (SSc) and SCOT

Introduction to SCOT and the Investigational Approaches

The SCOT study is a pivotal, prospective, randomized, clinical research study for individuals with diffuse systemic sclerosis (SSc). Subjects between the ages of 18 and 69 years (inclusive) will be enrolled across North America and randomly assigned in a 1:1 ratio to one of two groups:

High-dose immunosuppressive therapy (HDIT) with autologous stem cell transplantation

The active procedure period will be approximately 3 months. All subjects will be followed up to 54 months after randomization.

Rationale for Autologous Transplantation

  • Systemic sclerosis is an autoimmune disease, and disease effectors include mature lymphocytes
  • High-dose therapy may eliminate or substantially reduce effector population
  • Re-establish hematopoiesis and immunity from progenitors
  • Data from pilot study support potential efficacy of HDIT

Monthly pulse IV cyclophosphamide (Cytoxan)

The active procedure period will be approximately 12 months. All subjects will be followed up to 54 months after randomization.

Rationale for High-Dose Cyclophosphamide

  • Cyclophosphamide is widely used by clinicians in the treatment of SSc, although at lower doses. Standard doses of cyclophosphamide are 0.5-1.0 g/m2. The initial dose to be used in SCOT is 500 mg/m2 and 750 mg/m2 for all subsequent doses. A total of 12 monthly doses will be administered.
  • Data from non-randomized studies support the potential efficacy of high-dose cyclophosphamide in SSc
  • Current data suggest high-dose cyclophosphamide has an acceptable safety profile
  • Cyclophosphamide schedule in SCOT is similar to the schedule in the ongoing, European ASTIS trial, which will allow eventual comparison of the 2 studies

Study Endpoints

The primary study endpoint for the SCOT study is "event-free" survival at 54 months after randomization. Events are defined as:

  • Death
  • Respiratory failure
  • Chronic renal dialysis
  • Cardiomyopathy (NYHA heart failure class III or IV) or LVEF < 30% by echocardiogram sustained for 3 months

Risks and Potential Side Effects

Serious side effects, including death, have been associated with these study procedures. Past experience has shown that approximately 510% of the individuals who receive autologous (self) stem cell transplant die from transplant complications.

Other potential side effects associated with these study procedures include nausea, vomiting, stomatitis, diarrhea, alopecia, decreased appetite, fatigue, leukopenia, thrombocytopenia, increased risk for carcinogenesis, increased risk for major organ damage, and sterility.

Mechanistic Studies

The SCOT study will serve as the framework to research the mechanisms of disease in SSc and its response to the two different regimens being studied. Investigators will profile immune function before and serially after intervention and correlate findings with outcome. In addition, basic investigations will detail:

  • Molecular mechanisms of fibrosis
  • Vascular progenitor cells and endothelial activation
  • Autoantibody microarray profiles
  • Cyclophosphamide pharmacokinetics
  • Immunology of SSc lung disease
  • CMV and TOPO-1 specific tetramers
  • Microchimerism in autoimmune disease

In future investigations, PBMC, RNA, and DNA samples will be stored in a repository.

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