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)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 75
- 试验地点
- 17
- 主要终点
- Global Rank Composite Score (GRCS) (Month 54, ITT)
研究概览
简要总结
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.
详细描述
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:
- 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.
- 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.
- 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 69 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
mHSCT
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.
干预措施: mHSCT (Biological)
cyclophosphamide
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).
干预措施: cyclophosphamide (Drug)
结局指标
主要结局
Global Rank Composite Score (GRCS) (Month 54, ITT)
时间窗: 54 Months Post-Randomization
The GRCS is an analytic tool that accounts for multiple disease manifestations simultaneously. It does not measure clinical disease activity or severity but reflects how participants compared to one another based on a hierarchy of ordered outcomes: death, event-free survival (EFS), forced vital capacity (FVC), Health Assessment Questionnaire - Disability Index (HAQ-DI), and Modified Rodnan Skin Score (mRSS). Participants alive ranked higher than those who died; those who survived event-free ranked higher than EFS failures. EFS failure included death, respiratory failure (decrease from baseline of \>30% in DLCO % predicted or \>20% in FVC % predicted ), renal failure (chronic dialysis \> 6 month or renal transplant), or cardiac failure (clinical congestive heart failure or left ventricular ejection fraction \<30%). The lowest 3 GRCS components are ordinal; improvement, stability, or worsening from baseline (±10% change in FVC % predicted, ±0.4 change in HAQ-DI, ±25% change in mRSS).
次要结局
- Global Rank Composite Score (GRCS) (Month 54, PP)(54 Months Post-Randomization)
- Global Rank Composite Score (GRCS) (Month 48, PP)(48 Months Post-Randomization)
- Treatment-Related Mortality (Month 54, ITT)(54 Months Post-Randomization)
- Event-Free Survival (EFS) (Month 54, ITT)(54 Months Post-Randomization)
- Event-Free Survival (EFS) (Month 54, PP)(54 Months Post-Randomization)
- All-Cause Mortality (Month 54, ITT)(54 Months Post-Randomization)
- All-Cause Mortality (Month 48, ITT)(48 Months Post-Randomization)
- Global Rank Composite Score (GRCS) (Month 48, ITT)(48 Months Post-Randomization)
- Event-Free Survival (EFS) (Month 48, ITT)(48 Months Post-Randomization)
- Event-Free Survival (EFS) (Month 48, PP)(48 Months Post-Randomization)
- Treatment-Related Mortality (Month 54, PP)(54 Months Post-Randomization)
- Treatment-Related Mortality (Month 48, PP)(48 Months Post-Randomization)
- Treatment-Related Mortality (Month 48, ITT)(48 Months Post-Randomization)
- All-Cause Mortality (Month 54, PP)(54 Months Post-Randomization)
- Change From Baseline to Month 54 in Short Form 36 Health Survey (SF-36) (ITT)(54 Months Post-Randomization)
- All-Cause Mortality (Month 48, PP)(48 Months Post-Randomization)
- Change From Baseline to Month 54 in Health Assessment Questionnaire - Disability Index (HAQ-DI) (ITT)(54 Months Post-Randomization)
- Change From Baseline to Month 54 in Health Assessment Questionnaire - Disability Index (HAQ-DI) (PP)(54 Months Post-Randomization)
- New or Worsening Arrhythmias, Congestive Heart Failure, or Pericardial Effusion (PP)(54 Months Post-Randomization)
- Occurrence of Scleroderma Renal Crisis (ITT)(54 Months Post-Randomization)
- New or Worsening Arrhythmias, Congestive Heart Failure, or Pericardial Effusion (ITT)(54 Months Post-Randomization)
- Occurrence of Scleroderma Renal Crisis (PP)(54 Months Post-Randomization)
- Documented Myositis (PP)(54 Months Post-Randomization)
- Regimen-Related Toxicities(Randomization through end of study follow-up (up to Month 72 post-randomization))
- Infectious Complications(Randomization through end of study follow-up (up to Month 72 post-randomization).)
- Change From Baseline to Month 54 in Short Form 36 Health Survey (SF-36) (PP)(54 Months Post-Randomization)
- Change From Baseline to Month 54 in Diffusion in Liters of Carbon Monoxide (DLCO) (ITT)(54 Months Post-Randomization)
- Change From Baseline to Month 54 in Forced Vital Capacity (FVC) (PP)(54 Months Post-Randomization)
- Documented Myositis (ITT)(54 Months Post-Randomization)
- Change From Baseline to Month 54 in Diffusion in Liters of Carbon Monoxide (DLCO) (PP)(54 Months Post-Randomization)
- Change From Baseline to Month 54 in Forced Vital Capacity (FVC) (ITT)(54 Months Post-Randomization)
- Change From Baseline to Month 54 in Modified Rodnan Skin Score (mRSS) (ITT)(54 Months Post-Randomization)
- Change From Baseline to Month 54 in Modified Rodnan Skin Score (mRSS) (PP)(54 Months Post-Randomization)
- New or Worsening Pulmonary Hypertension (ITT)(54 Months Post-Randomization)
- New or Worsening Pulmonary Hypertension (PP)(54 Months Post-Randomization)
- Initiating Use of Disease-Modifying Antirheumatic Drugs (DMARDs) by Month 54 (ITT)(54 Months Post-Randomization)
- Time to Absolute Neutrophil Count Engraftment(28 days post-transplant)
- Initiating Use of Disease-Modifying Antirheumatic Drugs by Month 54 (DMARDs) (PP)(54 Months Post-Randomization)
- Number of Subjects With Infectious Complications(Randomization through end of study follow-up (up to Month 72 post-randomization).)
- Number of Subjects With Regimen-Related Toxicities(Randomization through end of study follow-up (up to Month 72 post-randomization).)