Autologous Stem Cell Systemic Sclerosis Immune Suppression Trial
Condition: Scleroderma, Systemic
MeSH terms: Scleroderma, Systemic; Scleroderma, Diffuse
Intervention: Peripheral Blood Stem Cells; Cyclophosphamide; Mesna; rATG; Methylprednisolone; Filgrastim; Fludarabine
Intervention description: Mobilized leukapheresis product; An alkylating agent which causes prevention of cell division by forming adducts with DNA; Medication used to decrease the risk of hemorrhagic cystitis prophylaxis; A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells; Steroid; 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; Purine analog which inhibits DNA synthesis or repair
Intervention MeSH terms: Methylprednisolone; Methylprednisolone Hemisuccinate; Cyclophosphamide; Fludarabine; Thymoglobulin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 44.0
Sex: All
Minimum age: 17 Years
Maximum age: 60 Years
Healthy volunteers: No
Keywords: Autologous Stem Cell Transplantation

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.
    

Eligibility criteria:

        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 exclusion criteria)

              12. Ventricular tachycardia (sustained or non-sustained, multifocal or unifocal) on
                  EKG or 24 hour Holter

          2. HIV positive.

          3. 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.

          4. Prior history of malignancy

          5. Positive pregnancy test, inability or unable to pursue effective means of birth
             control, failure to willingly accept or comprehend irreversible sterility as a side
             effect of therapy.

          6. Psychiatric illness or mental deficiency making compliance with treatment or informed
             consent impossible.

          7. Inability to give informed consent.

          8. Major hematological abnormalities such as platelet count < 100,000/ul or absolute
             neutrophil count (ANC) < 1000/ul.

          9. Hepatitis B or C positive