Autologous Stem Cell Systemic Sclerosis Immune Suppression Trial

NCT ID: NCT01445821

Last Updated: 2020-07-23

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 44 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-09-15
• Study Completion Date: 2019-10-10

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.

Conditions

Scleroderma, Systemic

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cyclophosphamide rATG/HSCT

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.

Group Type: ACTIVE_COMPARATOR

Peripheral Blood Stem Cells

Intervention Type: BIOLOGICAL

Mobilized leukapheresis product

Cyclophosphamide

Intervention Type: DRUG

An alkylating agent which causes prevention of cell division by forming adducts with DNA

Mesna

Intervention Type: DRUG

Medication used to decrease the risk of hemorrhagic cystitis prophylaxis

rATG

Intervention Type: DRUG

A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells

Methylprednisolone

Intervention Type: DRUG

Steroid

Filgrastim

Intervention Type: DRUG

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

Cyclophosphamide rATG/Fludarabine/HSCT

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.

Group Type: EXPERIMENTAL

Peripheral Blood Stem Cells

Intervention Type: BIOLOGICAL

Mobilized leukapheresis product

Cyclophosphamide

Intervention Type: DRUG

An alkylating agent which causes prevention of cell division by forming adducts with DNA

Mesna

Intervention Type: DRUG

Medication used to decrease the risk of hemorrhagic cystitis prophylaxis

rATG

Intervention Type: DRUG

A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells

Methylprednisolone

Intervention Type: DRUG

Steroid

Filgrastim

Intervention Type: DRUG

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

Fludarabine

Intervention Type: DRUG

Purine analog which inhibits DNA synthesis or repair

Interventions

Peripheral Blood Stem Cells

Mobilized leukapheresis product

Intervention Type: BIOLOGICAL

Cyclophosphamide

An alkylating agent which causes prevention of cell division by forming adducts with DNA

Intervention Type: DRUG

Mesna

Medication used to decrease the risk of hemorrhagic cystitis prophylaxis

Intervention Type: DRUG

rATG

A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells

Intervention Type: DRUG

Methylprednisolone

Steroid

Intervention Type: DRUG

Filgrastim

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

Intervention Type: DRUG

Fludarabine

Purine analog which inhibits DNA synthesis or repair

Intervention Type: DRUG

Other Intervention Names

Cytoxan; Neosar; Endoxan; Mesnex; Thymoglobulin; Solu-Medrol; Neupogen; G-CSF; Granix; Zarxio; Fludara

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

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

• Minimum Eligible Age: 17 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Northwestern University

OTHER

Sponsor Role: lead

Responsible Party

Richard Burt, MD

Chief, Division of Medicine-Immunotherapy and Autoimmune Diseases; Professor in Medicine-Immunotherapy and Autoimmune Diseases

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Richard Burt, MD

Role: PRINCIPAL_INVESTIGATOR

Northwestern University

Locations

Northwestern University

Chicago, Illinois, United States

Countries

United States

Other Identifiers

ASSIST IIb

Identifier Type: -

Identifier Source: org_study_id