Systemic Sclerosis, Scleroderma
Conditions
Keywords
Autologous Stem Cell Transplantation, Hematopoietic Stem Cell Transplant
Brief summary
This study is designed to treat systemic sclerosis (scleroderma) patients with an autologous stem cell transplant using a regimen of immune suppressant drugs and chemotherapy that is less toxic to your heart.
Detailed description
The autologous hematopoietic stem cell transplant used in this research study is an investigational procedure that uses cyclophosphamide and fludarabine (chemotherapy), rabbit anti-thymocyte globulin (rATG) (a protein that kills the immune cells that are thought to be causing your disease), and rituximab (a biologic drug that targets B cells of your immune system). After use of these treatments, the patient will receive their own previously collected blood stem cells (autologous stem cell transplant). The ability of these experimental treatments to stop relapses and progression (worsening) of your systemic sclerosis will be assessed.
Interventions
DRUGRituximab
Monoclonal antibody therapy used to treat certain autoimmune diseases and types of cancer
DRUGFludarabine
A chemotherapy medication commonly used in the treatment of leukemia and lymphoma
DRUGCyclophosphamide
A medication used as chemotherapy and to suppress the immune system
DRUGMesna
A medication used in those taking cyclophosphamide or ifosfamide to decrease the risk of bleeding from the bladder
DRUGrATG
A rabbit polyclonal antibody to lymphocytes
DRUGMethylprednisolone
A corticosteroid medication used to suppress the immune system and decrease inflammation
DRUGG-CSF
A glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream
BIOLOGICALIVIg
Pooled immunoglobulin (IgG) from thousands of plasma donors that has immunomodulatory and anti-inflammatory effects
BIOLOGICALAutologous Stem Cells
Infusion of patient's own stem cells
Sponsors
Northwestern University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Age 18 - 65 years old at the time of pre-transplant evaluation 2. An established diagnosis of systemic sclerosis 3. Diffuse cutaneous systemic sclerosis with involvement proximal to the elbow or knee and a modified Rodnan Skin Score of ≥ 14 (see Appendix A) AND Any one of the following: 1. DLCO \< 80% of predicted or decrease in lung function (DLCO, DLCO/VA or FVC) of 10% or more over 12 months. 2. Pulmonary fibrosis or alveolitis on CT scan or chest x-ray (ground glass appearance of alveolitis). 3. Abnormal EKG (non-specific ST-T wave abnormalities, low QRS voltage, or ventricular hypertrophy), or pericardial effusion or pericardial enhancement without constriction on MRI 4. Gastrointestinal tract involvement confirmed on radiological study. Radiologic findings of scleroderma are small bowel radiographs showing thickened folds with dilated loops, segmentation, and flocculation +/- diverticula, or pseudodiverticula. A hide-bound appearance may be present (e.g. dilated and crowded circular folds). GI involvement may also be confirmed by D-xylose malabsorption, patulous esophagus on high-resolution computed tomography (HRCT), or esophageal manometry. OR Limited cutaneous systemic sclerosis (SSc) (modified Rodnan Skin Score \<14) with lung involvement defined as active alveolitis on bronchoalveolar lavage (BAL), ground-glass opacity on CT scan, a DLCO \< 80% predicted, or decrease in lung function (DLCO/VA, DLCO, FVC) of 10% or more in last 12 months. Other Inclusion Criteria for CAST Conditioning Regimen (presence of any of the following): 1. Septal flattening or D-sign on MRI (without deep breathing) 2. PASP \>40 mm Hg or \>45 mm Hg with fluid challenge\* 3. mPAP \>25 mm Hg or \>30 mm Hg with fluid challenge\* 4. Non-ischemia diffuse ventricular hypokinesis or non-ischemia wall hypokinesis * Fluid challenge is 1000 ml normal saline over 10 minutes. Fluid challenge will not be done if right atrial pressure is \>13 mm Hg at rest or pulmonary capillary wedge pressure is \>20 mm Hg at rest.
Exclusion criteria
1. Active ischemic heart disease or untreated coronary artery disease 2. Untreated life-threatening cardiac arrhythmia on EKG or 24-hour holter 3. Pericardial effusion \> 1 cm on cardiac MRI unless successful pericardiocentesis has been performed 4. LVEF \<35% 5. End-stage lung disease characterized by TLC\<45% of predicted value, or DLCO hemoglobin corrected \< 30 % predicted. 6. Creatinine clearance \<40 by 24-hour urine 7. History of breast implants that have not been removed (unless they cannot be surgically removed due to risks of surgery) 8. Liver cirrhosis, transaminases \>2x of normal limits, or bilirubin \> 2.0 unless due to Gilbert's disease 9. Uncontrolled diabetes mellitus or any other illness that in the opinion of the investigators would jeopardize the ability of the patient to tolerate aggressive treatment 10. Prior history of malignancy 11. Positive pregnancy test, inability or unable to pursue effective means of birth control, or failure to willingly accept or comprehend irreversible sterility as a side effect of therapy 12. Psychiatric illness or mental deficiency making compliance with treatment or informed consent impossible 13. Major hematological abnormalities such as platelet count \< 100,000/ul or absolute neutrophil count (ANC) \< 1000/ul 14. HIV positive 15. Hepatitis B or C positive 16. PASP \>50 mmHg without fluid challenge 17. mPAP \>34 mmHg without fluid challenge 18. Coronary artery disease not reversed by cardiology and interventional radiology
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Skin Score by mRSS | Pre Treatment and Post Treatment | Defined by at least a 25% improvement (decline) in skin score by modified Rodnan skin score (mRSS) if skin score is greater than 14 on enrollment. If skin score is less than 14 on enrollment, improvement is defined by at least a 5% improvement on mRSS. The modified Rodnan skin score (MRSS) is a measure for skin disease in scleroderma and is calculated by summation of skin thickness in 17 different body sites. The scale ranges from at total score of normal skin thickness (0) to severe thickness (51). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Survival of Treatment | During Treatment and Post Treatment up to 1 year | Survival of Hematopoietic Stem Cell Transplant during treatment and post treatment up to 1 year. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Hematopoietic Stem Cell Transplantation Hematopoietic Stem Cell Therapy will be performed: Autologous stem cells will be infused after conditioning with rituximab, fludarabine, cyclophosphamide, Mesna, rATG (rabbit), and methylprednisolone. Granulocyte-colony stimulating factor (G-CSF) and intravenous immunoglobulin (IVIg) will be administered post-transplant.
Rituximab: Monoclonal antibody therapy used to treat certain autoimmune diseases and types of cancer
Fludarabine: A chemotherapy medication commonly used in the treatment of leukemia and lymphoma
Cyclophosphamide: A medication used as chemotherapy and to suppress the immune system
Mesna: A medication used in those taking cyclophosphamide or ifosfamide to decrease the risk of bleeding from the bladder
rATG: A rabbit polyclonal antibody to lymphocytes
Methylprednisolone: A corticosteroid medication used to suppress the immune system and decrease inflammation
G-CSF: A glycoprotein that stimulates the bone marrow to produce granulocytes and | 9 |
| Total | 9 |
Baseline characteristics
| Characteristic | Hematopoietic Stem Cell Transplantation |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Modified Rodnan skin score | 25 units on a scale |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 9 |
| other Total, other adverse events | 0 / 9 |
| serious Total, serious adverse events | 0 / 9 |
Outcome results
Primary
Change in Skin Score by mRSS
Defined by at least a 25% improvement (decline) in skin score by modified Rodnan skin score (mRSS) if skin score is greater than 14 on enrollment. If skin score is less than 14 on enrollment, improvement is defined by at least a 5% improvement on mRSS. The modified Rodnan skin score (MRSS) is a measure for skin disease in scleroderma and is calculated by summation of skin thickness in 17 different body sites. The scale ranges from at total score of normal skin thickness (0) to severe thickness (51).
Time frame: Pre Treatment and Post Treatment
Population: The number analyzed in one or more rows differs from the overall number analyzed because some patients did not follow up after the treatment.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Hematopoietic Stem Cell Transplantation | Change in Skin Score by mRSS | Pre Treatment | 25 units on a scale |
| Hematopoietic Stem Cell Transplantation | Change in Skin Score by mRSS | Post Treatment | 16 units on a scale |
Secondary
Survival of Treatment
Survival of Hematopoietic Stem Cell Transplant during treatment and post treatment up to 1 year.
Time frame: During Treatment and Post Treatment up to 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hematopoietic Stem Cell Transplantation | Survival of Treatment | 9 Participants |