Autologous Stem Cell Systemic Sclerosis Immune Suppression Trial (DIScl2011)

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by Northwestern University
Sponsor:
Information provided by (Responsible Party):
Richard Burt, MD, Northwestern University
ClinicalTrials.gov Identifier:
NCT01445821
First received: September 29, 2011
Last updated: February 5, 2014
Last verified: February 2014
  Purpose

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, TLC, 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.


Condition Intervention Phase
Scleroderma
Procedure: Cytoxan rATG/Fludarabine/HSCT
Procedure: Cytoxan rATG/HSCT
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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)

Resource links provided by NLM:


Further study details as provided by Northwestern University:

Primary Outcome Measures:
  • 2.1 Time to Treatment Failure [ Time Frame: 12 mo ] [ Designated as safety issue: No ]

    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
    3. Renal failure due to systemic sclerosis and defined as chronic dialysis for more than 12 months
    4. Gastrointestinal failure due to systemic sclerosis and defined as initiation of TPN for more than 12 months


Secondary Outcome Measures:
  • survival [ Time Frame: six moths, then yearly for 5 years ] [ Designated as safety issue: No ]
    survival


Estimated Enrollment: 160
Study Start Date: September 2011
Estimated Study Completion Date: September 2018
Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Cytoxan 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. PBSC will be infused intravenously on day 0. Filgrastrim 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment.
Procedure: Cytoxan 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. PBSC will be infused intravenously on day 0. Filgrastrim 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment.
Other Name: stem cell injection
Experimental: Cytoxan 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 25 g/m2 will be given IV on days -5, -4, -3, -2 and -1. Methylprednisolone 1000 mg will be used infused intravenously before each dose of rATG. PBSC will be infused intravenously on day 0. Filgrastrim 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment.
Procedure: Cytoxan 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 anti-thymocyte 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 25 g/m2 will be given IV on days -5, -4, -3, -2 and -1. Methylprednisolone 62.5mg to 250 mg will be used infused intravenously before each dose of rATG. PBSC will be infused intravenously on day 0. Filgrastrim 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment.
Other Name: stem cell injection

Detailed Description:

Mobilization. For patients in both arms undergoing hematopoietic stem cell transplantation, 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.

Control arm. 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 anti-thymocyte 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. PBSC will be infused intravenously on day 0. Filgrastrim 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment.

Cytoxan rATG/Fludarabine arm

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 anti-thymocyte 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 25 g/m2 will be given IV on days -5, -4, -3, -2 and -1. Methylprednisolone 62.5mg to 250 mg will be used infused intravenously before each dose of rATG. PBSC will be infused intravenously on day 0. Filgrastrim 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age < or = 60 years old at the time of pretransplant evaluation
  2. An established diagnosis of scleroderma (125)
  3. Diffuse cutaneous scleroderma with involvement proximal to the elbow or knee and a Rodnan score (see Appendix V) of > 14 (126)

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 CXR (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 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 +/- diverticulae, or pseudodiverticulae. 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, or esophageal manometry.

OR

4. As published in NEJM, 2006, 345:25 2655-2709. Limited or diffuse SSL with lung involvement defined as active alveolitis on 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. Poor performance status (ECOG >2) at the time of entry.
  2. Significant end organ damage such as:

    1. 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 corrected < 40 .
    5. e) Pulmonary arterial hypertension defined on right heart catheterization as: (1) a resting mPAP > 25 mmHg; (2) a mPAP > 30 mmHg following a 500-1000 ml normal saline bolus; (3) PVR > 240 dynes*s/cm5 (> 3 Wood units) ; or (4) a decrease in cardiac output with fluid challenge (500 - 1000 cc NS in 10 minutes) If fluid challenge cannot be done because RA pressure > 12mm Hg or PCWP > 15 m Hg at rest or must be stopped due to safety concerns, patient is excluded as candidate.
    6. Serum creatinine > 2.0 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 RV or 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
  3. HIV positive.
  4. 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.
  5. Prior history of malignancy
  6. 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.
  7. Psychiatric illness or mental deficiency making compliance with treatment or informed consent impossible.
  8. Inability to give informed consent.
  9. Major hematological abnormalities such as platelet count < 100,000/ul or ANC < 1000/ul.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01445821

Contacts
Contact: Dzemila Spahovic, MD 312-695-4960 d-spahovic@northwestern.edu

Locations
United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Sub-Investigator: Sanjiv Shah, MD         
Sub-Investigator: Eric Ruderman, MD         
Sub-Investigator: James Schroeder, MD         
Principal Investigator: Richard Burt, MD         
Sponsors and Collaborators
Northwestern University
Investigators
Principal Investigator: Richard Burt, MD Northwestern University
  More Information

No publications provided

Responsible Party: Richard Burt, MD, Associate Professor, Chief, Division of Medicine-Immunotherapy for Autoimmune Diseases, Northwestern University
ClinicalTrials.gov Identifier: NCT01445821     History of Changes
Other Study ID Numbers: ASSIST IIb
Study First Received: September 29, 2011
Last Updated: February 5, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Northwestern University:
systemic scleroderma
autologous stem cell transplantation

Additional relevant MeSH terms:
Scleroderma, Systemic
Scleroderma, Diffuse
Connective Tissue Diseases
Skin Diseases
Cyclophosphamide
Fludarabine phosphate
Antilymphocyte Serum
Fludarabine
Methylprednisolone Hemisuccinate
Prednisolone
Methylprednisolone acetate
Prednisolone acetate
Methylprednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Anti-Inflammatory Agents
Antiemetics

ClinicalTrials.gov processed this record on September 22, 2014