Scleroderma, also known as systemic sclerosis (SSc), is a disabling disease. The body attacks its own tissues, causing an overproduction of collagen. Collagen is a fiber-like protein which holds all of the structures in the body together. Patients often suffer fatigue, joint swelling and/or pain, and a loss of appetite and weight. Scleroderma can be difficult to diagnose because it overlaps with or resembles other conditions. Severe forms of the disease typically cause significant thickening and stiffening of the skin. Internal organs are affected, resulting in damage to the heart, lungs, kidneys, and gastrointestinal tract.

Severe forms of the disease, particularly rapidly progressive diffuse SSc with involvement of internal organs, are associated with a high death rate. Studies have shown poor prognosis of patients with internal organ involvement and suggest that clinicians can identify a subpopulation of SSc subjects of high risk for death who may benefit from a more aggressive therapeutic approach. The progression of SSc and the development of new organ disease despite conventional treatment is another signal for clinicians to be more aggressive in therapy.

Many treatments have been tried for severe SSc, but none has been proven effective in preventing disease progression or reversing fibrosis in randomized, controlled trials. Although the exact cause of scleroderma is unknown, the immune system is thought to play a major role in the development of the disease, and there is some evidence to suggest that immune-based therapies are beneficial. There is anecdotal evidence that high-dose cyclophosphamide is effective in slowing down SSc-induced lung disease. Cyclophosphamide may improve the skin disease as well. This therapy has not been evaluated in a formal controlled clinical trial and is one of the treatments evaluated in this study.

In response to the absence of an effective treatment for SSc, autologous hematopoietic stem cell transplantation (HSCT) has been proposed as a potential therapy. Hematopoietic stem cells are immature blood cells that can develop into all of the different blood and immune cells your body uses. Researchers believe that resetting the immune system may stop the progression of the disease. The main purpose of this study is to compare the two ways of treating SSc: 1) high-dose immunosuppressive therapy (HDIT) followed by HSCT and 2) high-dose pulse IV cyclophosphamide (CTX).

Condition	Intervention	Phase
Scleroderma, Systemic Sclerosis	Procedure: Self blood cell transplantation (HSCT)  Drug: High-dose immunosuppressive therapy (HDIT)  Drug: Cyclosphosphamide  Drug: Equine antithymocyte globulin  Drug: Methylprednisolone  Drug: Growth colony stimulating factor (G-CSF)	Phase II Phase III

Further Study Details: 

Primary Outcomes: Survival without significant organ damage
Expected Total Enrollment:  226

SSc is a disabling autoimmune disease that is characterized by both diffuse inflammation and subsequent fibrosis of skin and internal organs. Severe forms of the disease are associated with high death rates. Studies have demonstrated the benefits of immune-based therapies; however, no single treatment has been effective in preventing disease progression or reversing fibrosis associated with SSc. The main purpose of this study is to compare the two ways of treating SSc: 1) high-dose immunosuppressive therapy (HDIT) followed by HSCT and 2) high-dose pulse IV cyclophosphamide (CTX).

1) One group of study participants will have hematopoietic stem cell transplantation. With this treatment, they will first have hematopoietic stem cells removed from their blood. They then will receive high doses of chemotherapy and radiation to eliminate their developed and presumably abnormal immune system, followed by the reintroduction of the purified stem cells to re-establish their immune system.

Medications are used to mobilize (i.e., encourage) blood cell precursors to multiply and move from the bone marrow to the bloodstream. These precursors (or autologous stem cells) can be harvested from the bloodstream during a process called apheresis and then be transplanted back into the patient''''s body after radiation and chemotherapy. Autologous stem cells are preferred over donor bone marrow because there is no risk of rejection. HDIT can maximally suppress the immune system, reducing the effectiveness or perhaps eliminating most of the immune cells that cause the progression of SSc. When autologous hematopoietic stem cell transplantation (HSCT) follows HDIT, the body''''s ability to produce blood cells is restored. HDIT with HSCT has been identified as a potential treatment alternative to standard chemotherapy treatments.

Participants assigned to the first treatment will have a central venous line (plastic tube) inserted into the neck or chest vein. This tube will be used for drawing blood and to administer stem cells and medications. G-CSF will be injected under the skin for several days to boost the body’s production of blood precursor cells. These precursor cells will be collected through the central venous line in a process called apheresis. In this process, whole blood is collected through a needle in an arm vein and directed to a cell-separating machine where the white cells are collected and the rest of the blood is returned to the patient through the same needle. Several apheresis procedures will be required to collect enough cells.

After the precursor cells have been collected, the participants will be admitted to the hospital and will undergo a five-day conditioning regimen including whole body irradiation and the medications CTX and equine thymocyte globulin (ATGAM). This regimen will kill or eradicate the SSc patient’s malfunctioning immune system and will prepare the patient’s body to receive back the precursor cells collected during apheresis. The return of those precursor cells is called autologous stem cell transplantation. Patients will be hospitalized and monitored by a team of physicians and nurses until their bone marrow has recovered and they are well enough to be discharged. Most participants in this part of the study will spend approximately 21 days in the hospital after their autologous stem cell transplants, followed by a period of close monitoring in the vicinity of the transplant center, until they are stable enough to return home.

2) The other group of study participants will receive high doses of intravenous cyclophosphamide, a chemotherapy drug used for the treatment of rheumatic diseases and cancer. Cyclophosphamide is often used to treat autoimmune diseases such as scleroderma and lupus. However, the dose used in the SCOT study is higher than what doctors typically prescribe, and the length of treatment is longer. In the high-dose pulse CTX arm, 12 monthly pulses of IV CTX (initial dose of 500 mg/m2, followed by 11 doses of 750 mg/m2) are administered. This treatment has not been directly compared in a research study to other therapies or to no therapy in SSc, but has been used by physicians to treat autoimmune diseases including SSc. CTX has emerged as the current standard of care in the rheumatology community. The dose being used in this study is about 50% higher than that commonly used by most physicians to treat many other autoimmune diseases. It has been reported that this treatment has resulted in stabilization and/or improvement in the disease, particularly at the higher dose being used in this study. It has also been reported to be effective in slowing down damage in the lungs caused by SSc and may have improved the skin, and is therefore being evaluated in this clinical trial.

All participants will be followed for a minimum of 44 months after study entry. After 44 months, researchers will evaluate the occurrence of new significant organ damage and death. Participants will be randomly assigned to one of two arms after eligibility is confirmed. Arm 1 participants will first take growth colony stimulating factor (G-CSF) for cell mobilization, which will be followed by apheresis. Participants will then undergo a five-day conditioning regimen of total body irradiation, CTX, and equine thymocyte globulin. The conditioning regimen will be followed by autologous stem cell transplantation. Participants will be hospitalized for an average of 21 days. Arm 2 patients will receive 12 IV pulses of CTX, with pulses administered approximately 28 to 32 days apart. Doses of CTX will be determined by body weight.

All study participants will need to come in for follow-up visits every 4 weeks (or more often if needed) for the first 46 weeks, then at selected months until the end of the study. Visits may include physical exams, echocardiograms, electrocardiograms (ECGs, or heart tests), pulmonary tests, chest x-rays and chest CT, blood and urine tests, quality of life assessments, and other tests as needed to monitor health status. Participants will be contacted by phone approximately 1 month after each scheduled visit for additional follow-up and as a reminder for future visits. There is travel involved in the study because of the expertise needed at different times during the study. Currently, seven transplant centers and 19 rheumatology centers across the U.S., all leaders in the fields of either transplantation or rheumatology, are participating in this research.

Ages Eligible for Study:  18 Years   -   65 Years,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

• Severe systemic sclerosis (SSc) as defined by the American College of Rheumatology (ACR)
• SSc, including extensive skin and internal organ involvement involving either the lungs or the kidneys, that threatens participant''''s life
• Willingness to use accepted methods of contraception for at least 15 months after starting study treatment

Exclusion Criteria:

• Lung, heart, liver, or kidney impairment that would interfere with the study or compromise participant''''s survival
• Active blood vessel dilation in the stomach (Active Gastric Antral Vascular Ectasia/GAVE, also known as "watermelon stomach). Patients found to have this disorder at study screening can receive treatment outside the study and then be re-screened. For more information about this study criterion, refer to the study protocol.
• Previous treatment with cyclophosphamide, as defined by: a) prior IV cyclophosphamide administration for more than 6 months OR a total cumulative IV dose greater than 3 g/m2; b) prior oral cyclophosphamide administration for more than 4 months, regardless of dose; or c) combination of prior oral and IV cyclophosphamide administration for more than 6 months, independent of dose.
• Steroid therapy at doses of greater than 10 mg/day, or more than 2 pulses for concurrent illnesses within prior 12 months
• Unwillingness or inability to discontinue disease-modifying antirheumatic drugs (DMARDs) for the treatment of SSc
• Presence of anti-dsDNA or other laboratory values characteristic of other autoimmune diseases (overlap syndrome)
• Any active uncontrolled infection that would interfere with high-dose therapy or pulse cyclophosphamide regimens
• Hepatitis B infected
• HIV infected
• Blood abnormalities
• Diagnosis of cancer within 2 years prior to study entry. Participants with adequately treated squamous cell skin cancer, basal cell carcinoma, and carcinoma in situ are not excluded.
• Other comorbid illnesses with an estimated life expectancy of less than 5 years
• Defective formation of bone marrow cells (myelodysplasia)
• Uncontrolled hypertension
• History of hypersensitivity to murine or E. coli proteins
• History of noncompliance with prior medical care
• History of substance abuse within 5 years prior to study entry
• Pregnancy

Please refer to this study by ClinicalTrials.gov identifier  NCT00114530

Keith Sullivan, MD      919-668-1011    sulli025@mc.duke.edu

Alabama
      The University of Alabama at Birmingham, Birmingham,  Alabama,  35249,  United States; Not yet recruiting
Arizona
      Mayo Clinic Scottsdale, Scottsdale,  Arizona,  85259,  United States; Not yet recruiting
California
      California Pacific Medical Center, San Francisco,  California,  94115,  United States; Not yet recruiting
      UCLA Medical School, Los Angeles,  California,  90095-1670,  United States; Not yet recruiting
      City of Hope National Medical Center, Duarte,  California,  91010-3000,  United States; Not yet recruiting
Colorado
      Rocky Mountain Cancer Center, Denver,  Colorado,  80218,  United States; Not yet recruiting
      University of Colorado Health Sciences Center, Denver,  Colorado,  80262,  United States; Not yet recruiting
District of Columbia
      Georgetown University, Washington,  District of Columbia,  20007,  United States; Not yet recruiting
Florida
      University of Florida at Gainesville, Gainesville,  Florida,  32610,  United States; Not yet recruiting
Illinois
      The University of Chicago, Chicago,  Illinois,  60637,  United States; Not yet recruiting
Iowa
      Mercy Arthritis Center, Des Moines,  Iowa,  50322,  United States; Not yet recruiting
Kentucky
      University of Kentucky, Lexington,  Kentucky,  40536-0284,  United States; Not yet recruiting
Massachusetts
      Boston University School of Medicine, Boston,  Massachusetts,  02118,  United States; Not yet recruiting
      Harvard Partners: Massachusetts General Hospital, Boston,  Massachusetts,  02114,  United States; Not yet recruiting
Michigan
      University of Michigan, Ann Arbor,  Michigan,  48109,  United States; Not yet recruiting
Missouri
      Washington University School of Medicine, St. Louis,  Missouri,  63110,  United States; Not yet recruiting
New Jersey
      UMDNJ-Scleroderma Program, New Brunswick,  New Jersey,  08903,  United States; Not yet recruiting
New York
      North Shore University Hospital, Manhasset,  New York,  11030,  United States; Not yet recruiting
      St. Peters Hospital – Albany Medical College, Albany,  New York,  12206,  United States; Not yet recruiting
      Beth Israel Medical Center, New York,  New York,  10128,  United States; Not yet recruiting
North Carolina
      Duke University, Durham,  North Carolina,  27709,  United States; Recruiting
Ohio
      Medical College of Ohio, Toledo,  Ohio,  43699,  United States; Not yet recruiting
      Christ Hopital/University of Cincinnati, Cincinnati,  Ohio,  45267,  United States; Not yet recruiting
South Carolina
      Medical University of South Carolina, Charleston,  South Carolina,  29425,  United States; Not yet recruiting
Tennessee
      University of Tennessee, Memphis, Memphis,  Tennessee,  38163,  United States; Not yet recruiting
Texas
      UT Southwestern Med Center, Dallas,  Texas,  75390-8884,  United States; Not yet recruiting
      MD Anderson Cancer Center, Houston,  Texas,  77230,  United States; Not yet recruiting
      University of Texas-Houston Medical School, Houston,  Texas,  77030,  United States; Not yet recruiting
Washington
      Virginia Mason Research Center and the University of Washington, Seattle,  Washington,  98101,  United States; Not yet recruiting
      Fred Hutchinson Cancer Research Center, Seattle,  Washington,  98109,  United States; Not yet recruiting
Wisconsin
      University of Wisconsin, Madison,  Wisconsin,  53792-2454,  United States; Not yet recruiting
      Medical College of Wisconsin, Milwaukee,  Wisconsin,  53226,  United States; Not yet recruiting
      Medical College of Wisconsin, Milwaukee,  Wisconsin,  53226,  United States; Not yet recruiting

Study chairs or principal investigators

Keith Sullivan, MD,  Study Chair,  Duke University   
Daniel Furst, MD,  Study Chair,  Rheumatology Division, UCLA Medical School   
Peter McSweeny, MD,  Study Chair,  Blood and Marrow Transplant Program, Presbyterian/St. Luke''''s Medical Center, Rocky Mountain Cancer Center   

Study ID Numbers:  DAIT SCSSc-01; SCOT
Record last reviewed:  June 2005
Last Updated:  June 30, 2005
Record first received:  June 15, 2005
ClinicalTrials.gov Identifier:  NCT00114530
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2005-07-05