Scleroderma: Cyclophosphamide or Transplantation (SCOT)

National Institute of Allergy and Infectious Diseases (NIAID)

Status and phase: Completed; Phase 3; Phase 2

Conditions: Sclerosis; Scleroderma, Systemic; Autoimmune Disease

Treatments: Biological: mHSCT; Drug: cyclophosphamide

Study type: Interventional

Funder types: Industry; NIH

Identifiers

NCT00114530

DAIT SCSSc-01

NIAID CRMS ID#: 20133 (Other Identifier)

Details and patient eligibility

About

SCOT is a clinical research study designed for people with severe forms of scleroderma. SCOT stands for Scleroderma: Cyclophosphamide Or Transplantation. The SCOT study will compare the potential benefits of stem cell transplant and high-dose monthly cyclophosphamide (Cytoxan) in the treatment of scleroderma.

Full description

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. Pharmacokinetics 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.

Enrollment: 75 patients

Sex: All

Ages: 18 to 69 years old

Volunteers: No Healthy Volunteers

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; and
• 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/m^2; 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 or
  • 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 Escherichia coli (e.g., E. coli) proteins; History of noncompliance with prior medical care;

• History of substance abuse within 5 years prior to study entry; or

• Pregnancy.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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75 participants in 2 patient groups

mHSCT

Experimental group

Description:

Myeloablative Hematopoietic Stem Cell Transplant (mHSCT) 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.

Treatment:

Biological: mHSCT

cyclophosphamide

Experimental group

Description:

Cyclophosphamide (CY) 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. Administration of 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m\^2, followed by 11 doses of 750 mg/m\^2).

Treatment:

Drug: cyclophosphamide