Autologous Stem Cell Systemic Sclerosis Immune Suppression Trial

Study Overview
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Brief Summary
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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
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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.

Official Title
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Randomized Study of Different Non-myeloablative Conditioning Regimens With Hematopoietic Stem Cell Support in Patients With Scleroderma (Autologous Systemic Sclerosis Immune Suppression Trial - II ASSIST-IIb)

Conditions
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Scleroderma, Systemic

Intervention / Treatment
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* Biological: Peripheral Blood Stem Cells
* Drug: Cyclophosphamide
* Drug: Mesna
* Drug: rATG
* Drug: Methylprednisolone
* Drug: Filgrastim
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 17- 60 years old at the time of pretransplant evaluation An established diagnosis of scleroderma 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: DLCO < 80% of predicted or decrease in lung function (DLCO, DLCO/VA or FVC) of 10% or more over 12 months. Pulmonary fibrosis or alveolitis on CT scan or chest X-ray (CXR) (ground glass appearance of alveolitis). 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 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 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: Significant end organ damage such as: Left Ventricular Function (LVEF) < 40% on echocardiogram. Untreated life-threatening arrhythmia. Active ischemic heart disease or heart failure. End-stage lung disease characterized by TLC<45% of predicted value, or DLCO hemoglobin corrected < 30% predicted . Pulmonary arterial hypertension defined on right heart catheterization as: a resting Mean Pulmonary Artery Pressure (mPAP) > 25 mmHg; a mPAP > 30 mmHg following a 500-1000 ml normal saline bolus; pulmonary vascular resistance (PVR) > 240 dynes*s/cm5 (> 3 Wood units) ; or 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. Serum creatinine > 1.4 mg/dl. Liver cirrhosis, transaminases > 3x of normal limits or bilirubin > 2.0 unless due to Gilbert's disease. Pericardial effusion > 1 cm on cardiac MRI unless successful pericardiocentesis has been performed Occult or clinical constrictive pericarditis 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 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) Ventricular tachycardia (sustained or non-sustained, multifocal or unifocal) on EKG or 24 hour Holter HIV positive. 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. Prior history of malignancy 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. Psychiatric illness or mental deficiency making compliance with treatment or informed consent impossible. Inability to give informed consent. Major hematological abnormalities such as platelet count < 100,000/ul or absolute neutrophil count (ANC) < 1000/ul. Hepatitis B or C positive

Ages Eligible for Study
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Minimum Age: 17 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cyclophosphamide rATG/HSCT<br>The control arm will have the same conditioning regimen used in ASSIST study. The conditioning regimen will be 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. | Biological: Peripheral Blood Stem Cells<br>* Mobilized leukapheresis product<br>Drug: Cyclophosphamide<br>* An alkylating agent which causes prevention of cell division by forming adducts with DNA<br>* Other names: Endoxan;Drug: Mesna<br>* Medication used to decrease the risk of hemorrhagic cystitis prophylaxis<br>* Other names: Mesnex;Drug: rATG<br>* A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells<br>* Other names: Thymoglobulin;Drug: Methylprednisolone<br>* Steroid<br>* Other names: Solu-Medrol;Drug: Filgrastim<br>* 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<br>* Other names: Zarxio;|
| Experimental: Cyclophosphamide rATG/Fludarabine/HSCT<br>The conditioning regimen will be 120 mg/kg of intravenous cyclophosphamide given in 2 equal fractions on days -3 and -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. Fludarabine 30 mg/m2 will be given IV on days -5, -4, and -3. Methylprednisolone 1000 mg will be used infused intravenously before each dose of rATG. PBSC will be infused intravenously on day 0. Filgrastim 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment. | Biological: Peripheral Blood Stem Cells<br>* Mobilized leukapheresis product<br>Drug: Cyclophosphamide<br>* An alkylating agent which causes prevention of cell division by forming adducts with DNA<br>* Other names: Endoxan;Drug: Mesna<br>* Medication used to decrease the risk of hemorrhagic cystitis prophylaxis<br>* Other names: Mesnex;Drug: rATG<br>* A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells<br>* Other names: Thymoglobulin;Drug: Methylprednisolone<br>* Steroid<br>* Other names: Solu-Medrol;Drug: Filgrastim<br>* 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<br>* Other names: Zarxio;Drug: Fludarabine<br>* Purine analog which inhibits DNA synthesis or repair<br>* Other names: Fludara;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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: 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 Deterioration in percent predicted FVC by 10% below enrollment level, due to systemic sclerosis, and documented on 2 occasion at least 6 months apart | up to and post 12 months of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival of Treatment | Survival of Hematopoietic Stem Cell Transplant. | up to 12 months post treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autologous Stem Cell Transplantation