Scleroderma, Systemic
Conditions
Keywords
Autologous Stem Cell Transplantation
Brief summary
ASSIST I was the first randomized trial in patients with scleroderma to not just slow disease progression but rather actually reverse it. It is the first treatment to have ever demonstrated reversal of lung disease in scleroderma with improvement in FVC, total lung capacity (TLC), high-resolution computed tomography (HRCT), and QOL. We now, therefore, purpose to compare the ASSIST I conditioning regimen of cyclophosphamide and rATG to a less intense regimen of rATG/cyclophosphamide/Fludarabine. In the new regimen the cyclophosphamide dose is decreased to 120mg/kg (60mg/kg/day x 2) compared to 200mg/kg (50mg/kg/day) in the standard regimen. The lower dose of cyclophosphamide will be less cardiotoxic. This study will determine if the less cardiotoxic regimen will be safer than the standard regimen and as effective as the standard regimen.
Detailed description
Mobilization. For patients in both arms undergoing hematopoietic stem cell transplantation (HSCT), peripheral blood stem cells (PBSC) will be mobilized with cyclophosphamide (2 g/m2) followed by 5-10 mcg/kg subcutaneous filgrastrim daily from day 5 until completion of apheresis. Mobilized hematopoietic stem cells (HSC) will be collected by apheresis on day 10 and cryopreserved without selection or manipulation. There will be an interval of at least 17 days between mobilization of PBSC and start of conditioning regimen.
Interventions
BIOLOGICALPeripheral Blood Stem Cells
Mobilized leukapheresis product
DRUGCyclophosphamide
An alkylating agent which causes prevention of cell division by forming adducts with DNA
DRUGMesna
Medication used to decrease the risk of hemorrhagic cystitis prophylaxis
DRUGrATG
A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells
DRUGMethylprednisolone
Steroid
DRUGFilgrastim
Granulocyte-colony stimulating factor (G-CSF); a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream
DRUGFludarabine
Purine analog which inhibits DNA synthesis or repair
Sponsors
Northwestern University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
17 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
1. Age 17- 60 years old at the time of pretransplant evaluation 2. An established diagnosis of scleroderma 3. Diffuse cutaneous scleroderma with involvement proximal to the elbow or knee and a Rodnan score (see Appendix V) of \> 14 AND Scleroderma with 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 (CXR) (ground glass appearance of alveolitis). 3. Abnormal EKG \[non-specific ST-segment and T-wave (ST-T) (pattern in electrocardiogram) wave abnormalities, low QRS (a pattern seen in an electrocardiogram that indicates the pulses in a heart beat and their duration) voltage, or ventricular hypertrophy\], or pericardial effusion or pericardial enhancement 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 due to valvulae packing i.e. dilated and crowded circular folds may be present. GI involvement may also be confirmed by D-xylose malabsorption, patulous esophagus on HRCT, or esophageal manometry. OR 4. As published in New England Journal of Medicine (NEJM), 2006, 345:25 2655-2709. Limited or diffuse Systemic Sclerosis with (SSCL) with lung involvement defined as active alveolitis on Bronchoalveolar Lavage (BAL) or ground-glass opacity on CT, a DLCO \< 80% predicted or decrease in lung function (DLCO/VA, DLCO, FVC) of 10% or more in last 12 months.
Exclusion criteria
1. Significant end organ damage such as: 1. Left Ventricular Function (LVEF) \< 40% on echocardiogram. 2. Untreated life-threatening arrhythmia. 3. Active ischemic heart disease or heart failure. 4. End-stage lung disease characterized by TLC\<45% of predicted value, or DLCO hemoglobin corrected \< 30% predicted . 5. Pulmonary arterial hypertension defined on right heart catheterization as: 1. a resting Mean Pulmonary Artery Pressure (mPAP) \> 25 mmHg; 2. a mPAP \> 30 mmHg following a 500-1000 ml normal saline bolus; 3. pulmonary vascular resistance (PVR) \> 240 dynes\*s/cm5 (\> 3 Wood units) ; or 4. a decrease in cardiac output with fluid challenge (500 - 1000 cc Normal Saline (NS) in 10 minutes) If fluid challenge cannot be done because right atrial (RA) pressure \> 12mm Hg or pulmonary capillary wedge pressure (PCWP) \> 15 m Hg at rest or must be stopped due to safety concerns, patient is excluded as candidate. 6. Serum creatinine \> 1.4 mg/dl. 7. Liver cirrhosis, transaminases \> 3x of normal limits or bilirubin \> 2.0 unless due to Gilbert's disease. 8. Pericardial effusion \> 1 cm on cardiac MRI unless successful pericardiocentesis has been performed 9. Occult or clinical constrictive pericarditis 10. On echocardiogram tricuspid annular peak systolic excursion (TAPSE) ≤ 1.8 cm or, grade II or worse Right Ventricular (RV) or Left Ventricular (LV) diastolic dysfunction 11. On cardiac MRI, a diastolic septal bounce or diastolic septal flattering (D-sign), or diffuse myocardial gadolinium enhancement, or diffuse hypokinesis (patchy late gadolinium myocardial enhancement are not
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Failure | up to and post 12 months of treatment | Treatment failure will not occur until a minimum of 12 months after treatment at which time failure is defined as: 1. Increase of skin score (if \> 14 on enrollment) by \> 25% above enrollment value and must be documented on 2 occasions at least 6 months apart 2. Deterioration in percent predicted FVC by 10% below enrollment level, due to systemic sclerosis, and documented on 2 occasion at least 6 months apart |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Survival of Treatment | up to 12 months post treatment | Survival of Hematopoietic Stem Cell Transplant. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cyclophosphamide rATG/HSCT Conditioning regimen: 200 mg/kg of intravenous cyclophosphamide given in 4 equal fractions on days -5 through -2 with intravenous mesna. Rabbit antithymocyte globulin (rATG) (Thymoglobulin®) will be dosed at 0.5 mg/kg on day-5 and then 1.5 mg/kg from day-4 thru day -1. Methylprednisolone 1000 mg will be used infused intravenously before each dose of rATG. Peripheral blood stem cells (PBSC) will be infused intravenously on day 0. Filgrastim 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment.
Peripheral Blood Stem Cells: Mobilized leukapheresis product
Cyclophosphamide: An alkylating agent
Mesna: Used to decrease the risk of hemorrhagic cystitis
rATG: Immunosuppressive agent which contains antibodies specific to the antigens
Methylprednisolone: Steroid
Filgrastim: Granulocyte-colony stimulating factor (G-CSF); a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells | 22 |
| Cyclophosphamide rATG/Fludarabine/HSCT Conditioning regimen: 120 mg/kg of IV cyclophosphamide given in 2 equal fractions on days -3 and -2 with IV mesna. Rabbit antithymocyte globulin (rATG) (Thymoglobulin®) will be dosed at 0.5 mg/kg on day-5 and then 1.5 mg/kg from day-4 thru day -1. Fludarabine 30 mg/m2 will be given IV on days -5, -4, and -3. Methylprednisolone 1000 mg will be used infused IV before each dose of rATG. PBSC will be infused IV on day 0. Filgrastim 5-10 mcg/kg will be started on day + 5 and cont. until neutrophil engraftment.
Peripheral Blood Stem Cells: Mobilized leukapheresis product
Cyclophosphamide: Alkylating agent
Mesna: Used to decrease the risk of hemorrhagic cystitis
rATG: Immunosuppressive agent which contains antibodies specific to the antigens
Methylprednisolone: Steroid
Filgrastim: Granulocyte-colony stimulating factor (G-CSF);glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells
Fludarabine: Purine analog which inhibits DNA synthesis/repair | 22 |
| Total | 44 |
Baseline characteristics
| Characteristic | Cyclophosphamide rATG/HSCT | Cyclophosphamide rATG/Fludarabine/HSCT | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants | 22 Participants | 44 Participants |
| Age, Continuous | 42.8 years | 45.6 years | 44.2 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 20 Participants | 17 Participants | 37 Participants |
| Region of Enrollment United States | 22 participants | 22 participants | 44 participants |
| Sex: Female, Male Female | 16 Participants | 18 Participants | 34 Participants |
| Sex: Female, Male Male | 6 Participants | 4 Participants | 10 Participants |
| Skin Score Prior to Treatment | 26.1 units on a scale | 22.8 units on a scale | 24.14 units on a scale |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 22 | 3 / 22 |
| other Total, other adverse events | 3 / 22 | 2 / 22 |
| serious Total, serious adverse events | 2 / 22 | 3 / 22 |
Outcome results
Primary
Number of Participants With Treatment Failure
Treatment failure will not occur until a minimum of 12 months after treatment at which time failure is defined as: 1. Increase of skin score (if \> 14 on enrollment) by \> 25% above enrollment value and must be documented on 2 occasions at least 6 months apart 2. Deterioration in percent predicted FVC by 10% below enrollment level, due to systemic sclerosis, and documented on 2 occasion at least 6 months apart
Time frame: up to and post 12 months of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cyclophosphamide rATG/HSCT | Number of Participants With Treatment Failure | 2 Participants |
| Cyclophosphamide rATG/Fludarabine/HSCT | Number of Participants With Treatment Failure | 2 Participants |
Secondary
Survival of Treatment
Survival of Hematopoietic Stem Cell Transplant.
Time frame: up to 12 months post treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cyclophosphamide rATG/HSCT | Survival of Treatment | 22 Participants |
| Cyclophosphamide rATG/Fludarabine/HSCT | Survival of Treatment | 21 Participants |