Scleroderma: Cyclophosphamide or Transplantation (SCOT)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00114530
First received: June 15, 2005
Last updated: February 22, 2013
Last verified: February 2013
  Purpose

Severe systemic sclerosis (SSc) is a serious autoimmune disorder in which a person's own immune cells attack organs in the body. SSc affects the skin, joints, lungs, heart, intestinal tract, and kidneys, and half of the patients with the most severe organ involvement die within 5 years. Treatment for SSc usually includes supportive care or immunosuppressive drugs (drugs to suppress the immune system). As the immune cells are believed to be causing the disease, researchers are looking for new therapies that either slow down or stop this process, while not being too toxic.

The main purpose of this study is to determine the safety and effectiveness of high-dose immunosuppressive therapy followed by reinfusion (transplantation) of the participant's own autologous (self) peripheral blood stem cells (PBSCs) compared to treatment with monthly (for 12 months) intravenous doses of cyclophosphamide (Cytoxan) therapy for the treatment of severe systemic sclerosis (SSc). These treatments are being given in order to determine if they will slow down or stop SSc from becoming more severe, and if they can reverse the effects of the disease. The researchers are evaluating the effects of the two treatments on serious organ damage and survival related to SSc, while also looking at the side effects of the two treatments.

This trial also includes three optional mechanistic sub-studies open to a subset of participants enrolled in the SCOT trial:

  1. Pharmokinetics of 4-hydroxycyclophosphamide in Patients Receiving Cyclophosphamide for the SCOT trial (Originally listed separately as DAIT SCSSc-01-01, NCT00848614). The purpose of this study is to determine the plasma concentration and exposure time required for cyclophosphamide to produce optimal immunosuppressive activity with minimal toxicity in participants with severe systemic sclerosis.
  2. Vascular Progenitor Cells and the Pathogenesis of Systemic Sclerosis(Originally listed separately as DAIT SCSSc-01-02, NCT00871221). The purpose of this study is to measure and characterize the circulating endothelial progenitor cells from the blood of 30 participants and also to determine the extent of vascular cell apoptosis and proliferation in cutaneous microvasculature in these participants before and after the receipt of the two SCOT treatment regimens.
  3. Molecular Analysis of T Cell Immune Recovery for the SCOT Trial(Originally listed separately as DAIT SCSSc-01-03, NCT00872508). The purpose of this study is [1] to describe the condition of peripheral T cell reactivity and repertoire diversity in SSc patients and evaluate evidence for potential defects prior to randomization, [2] to gain a better understanding of the impact of cyclophosphamide (Cytoxan) and high-dose immunosuppressive therapy with autologous stem cell transplantation on thymopoiesis, and [3] to describe the kinetics and breadth of T cell immune recovery in SSc patients treated with these interventions.

Condition Intervention Phase
Scleroderma, Systemic
Sclerosis
Autoimmune Disease
Procedure: Autologous stem cell transplantation
Drug: Cyclophosphamide
Drug: Antithymocyte globulin, equine
Drug: Methylprednisolone
Drug: Growth colony stimulating factor (G-CSF)
Radiation: Total body irradiation (TBI)
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized, Open-Label, Phase II Multicenter Study of High-Dose Immunosuppressive Therapy Using Total Body Irradiation, Cyclophosphamide, ATGAM, and Autologous Transplantation With Auto-CD34+HPC Versus Intravenous Pulse Cyclophosphamide for the Treatment of Severe Systemic Sclerosis (SCSSc-01)

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Global rank composite score (GRCS) at 54 months post- randomization. [ Time Frame: At 54 Months Post-Randomization ] [ Designated as safety issue: Yes ]
    The GRCS reflects each participant's "order" relative to every other participant based on the following hierarchy of component outcomes: death, event-free survival (EFS), forced vital capacity (FVC), Modified Scleroderma Health Questionnaire (SHAQ), and modified Rodnan Skin Score (mRSS).The analysis for the global rank composite score is based on an extension of the Wilcoxon signed-rank test.


Secondary Outcome Measures:
  • Treatment-related mortality [ Time Frame: Month 72 ] [ Designated as safety issue: Yes ]
    defined as death occurring at any time after randomization and definitely or probably resulting from treatment given in the study.

  • Mortality due to any cause [ Time Frame: Month 72 ] [ Designated as safety issue: Yes ]
  • Regimen-related toxicities defined as adverse events (AEs) Grade 3 or worse [ Time Frame: Month 72 ] [ Designated as safety issue: Yes ]
  • Infectious complications [ Time Frame: Month 72 ] [ Designated as safety issue: Yes ]
  • Engraftment (for the High-dose immunosuppressive therapy followed by stem cell transplantation arm only) [ Time Frame: Month 72 ] [ Designated as safety issue: Yes ]
  • A decrease of more than in 0.4 on two successive Modified Scleroderma Health Assessment Questionnaires (SHAQ)taken within 3 months of each other [ Time Frame: Month 72 ] [ Designated as safety issue: No ]
  • Quality of life as measured by the Short Form 36 (SF-36) [ Time Frame: Month 72 ] [ Designated as safety issue: No ]
  • Pulmonary function measured by Diffusion in Liters of Carbon Monoxide (DLCO) [ Time Frame: Month 72 ] [ Designated as safety issue: Yes ]
  • Pulmonary function measured by Forced Vital Capacity (FVC) [ Time Frame: Month 72 ] [ Designated as safety issue: Yes ]
  • Skin condition as indicated by Modified Rodnan Skin Score (mRSS) [ Time Frame: Month 72 ] [ Designated as safety issue: No ]
  • New or worsening arrhythmias, congestive heart failure (CHF), or pericardial effusion [ Time Frame: Month 72 ] [ Designated as safety issue: Yes ]
    New or worsening arrhythmias that require medical treatment of 3 months or more or require ablative therapy or pacemaker insertion OR congestive heart failure (CHF) requiring clinical treatment for 3 months or more OR pericardial effusion occurs that requires pericardial window

  • New or worsening pulmonary hypertension [ Time Frame: Month 72 ] [ Designated as safety issue: Yes ]
  • Occurrence of scleroderma renal crisis [ Time Frame: Month 72 ] [ Designated as safety issue: Yes ]
  • Documented myositis, requiring more than 30 mg per day of prednisone for over 1 month [ Time Frame: Month 72 ] [ Designated as safety issue: No ]
  • Increase in Modified Scleroderma Health Assessment Questionnaire (SHAQ) by more than 0.4 from baseline on 2 successive occasions within 3 months [ Time Frame: Month 72 ] [ Designated as safety issue: No ]
  • Decrease in quality of life as measured by the Short Form 36 (SF-36) [ Time Frame: Month 72 ] [ Designated as safety issue: No ]
  • Initiating use of disease-modifying antirheumatic drugs [ Time Frame: Month 72 ] [ Designated as safety issue: No ]
  • Global rank composite score (GRCS) at 48 months post-randomization. [ Time Frame: At 48 Months Post-Randomization ] [ Designated as safety issue: Yes ]
  • Event-free Survival (EFS) at 48 and 54 months after randomization. [ Time Frame: At 48 and 54 Months Post-Randomization ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 114
Study Start Date: June 2005
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: High-dose immunosuppressive therapy followed by HSCT
Participants 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 autologous stem cell transplantation to reintroduce the purified stem cells to re-establish their immune system.
Procedure: Autologous stem cell transplantation
transplantation of blood stem cells from participant's bone marrow or blood
Drug: Cyclophosphamide
Other Name: Cytoxan
Drug: Antithymocyte globulin, equine Drug: Methylprednisolone Drug: Growth colony stimulating factor (G-CSF) Radiation: Total body irradiation (TBI)
used to eradicate the immune system thought to be causing the systemic sclerosis
Experimental: High-dose pulse IV cyclophosphamide (Cytoxan)
Participants will receive high doses of intravenous cyclophosphamide. The dose being used in this study is about 50% higher than that commonly used by most physicians to treat many other autoimmune diseases. 12 monthly pulses of IV CTX (initial dose of 500 mg/m2, followed by 11 doses of 750 mg/m2) are administered.
Drug: Cyclophosphamide
Other Name: Cytoxan

  Eligibility

Ages Eligible for Study:   18 Years to 69 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 certain disease-modifying antirheumatic drugs (DMARDs) for the treatment of SSc
  • Presence of clinically significant rheumatic diseases other than scleroderma requiring significant immunosuppression
  • Any active uncontrolled infection that would interfere with high-dose therapy or pulse cyclophosphamide regimens
  • Hepatitis B virus infected
  • Hepatitis C virus 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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00114530

Locations
United States, California
City of Hope National Medical Center
Duarte, California, United States, 91010-3000
UCLA Medical School
Los Angeles, California, United States, 90095-1670
United States, Kentucky
University of Kentucky
Lexington, Kentucky, United States, 40536-0284
United States, Massachusetts
Boston University School of Medicine
Boston, Massachusetts, United States, 02118
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
United States, Missouri
Washington University School of Medicine
St. Louis, Missouri, United States, 63110
United States, North Carolina
Duke University
Durham, North Carolina, United States, 27709
United States, Ohio
University of Toledo Health Science Campus
Toledo, Ohio, United States, 43606
United States, Pennsylvania
University of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15261
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77230
University of Texas-Houston Medical School
Houston, Texas, United States, 77030
United States, Washington
Fred Hutchinson Cancer Research Center (FHCRC)
Seattle, Washington, United States, 98109
United States, Wisconsin
Medical College of Wisconsin
Milwaukee, Wisconsin, United States, 53226
Canada, Alberta
University of Calgary
Calgary, Alberta, Canada
Canada, Saskatchewan
Dr. Markland Medical Professional Corporation
Saskatoon, Saskatchewan, Canada, S7K OH6
Sponsors and Collaborators
Investigators
Study Chair: Keith Sullivan, MD Division of Cellular Therapy, Duke University
Study Chair: Daniel Furst, MD Rheumatology Division, UCLA Medical School
Study Chair: Peter McSweeney, MD Blood and Marrow Transplant Program, Presbyterian/St. Luke's Medical Center, Rocky Mountain Cancer Center
Principal Investigator: Leslie Crofford, MD University of Kentucky
Principal Investigator: Maureen Mayes, MD, MPH The University of Texas Health Science Center, Houston
Principal Investigator: Richard Nash, MD Fred Hutchinson Cancer Research Center
  More Information

Additional Information:
Publications:
McSweeney, PA, Furst DE, Crofford, L, et al. High-dose immunosuppressive therapy (HDIT) for severe systemic sclerosis (SSc): Long-term survivors show continued improvement of function and skin with stability in the lungs. Blood 2004;104:46a (abstract).

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00114530     History of Changes
Obsolete Identifiers: NCT00472277, NCT00545038, NCT00848614, NCT00871221, NCT00872508
Other Study ID Numbers: DAIT SCSSc-01, SCOT
Study First Received: June 15, 2005
Last Updated: February 22, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
autoimmune disease

Additional relevant MeSH terms:
Autoimmune Diseases
Scleroderma, Systemic
Scleroderma, Diffuse
Sclerosis
Immune System Diseases
Connective Tissue Diseases
Skin Diseases
Pathologic Processes
Antilymphocyte Serum
Cyclophosphamide
Immunosuppressive Agents
Methylprednisolone Hemisuccinate
Prednisolone
Methylprednisolone acetate
Prednisolone acetate
Methylprednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Anti-Inflammatory Agents
Antiemetics

ClinicalTrials.gov processed this record on April 17, 2014