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Autologous Stem Cell Systemic Sclerosis Immune Suppression Trial (DIScl2011)

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ClinicalTrials.gov Identifier: NCT01445821
Recruitment Status : Terminated (Developed a better regimen: DIAD. Cast. 2018 NCT03593902)
First Posted : October 4, 2011
Results First Posted : July 23, 2020
Last Update Posted : July 23, 2020
Sponsor:
Information provided by (Responsible Party):
Richard Burt, MD, Northwestern University

Tracking Information
First Submitted Date  ICMJE September 29, 2011
First Posted Date  ICMJE October 4, 2011
Results First Submitted Date  ICMJE June 15, 2020
Results First Posted Date  ICMJE July 23, 2020
Last Update Posted Date July 23, 2020
Actual Study Start Date  ICMJE September 15, 2011
Actual Primary Completion Date January 5, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 7, 2020)
Number of Participants With Treatment Failure [ Time Frame: 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
Original Primary Outcome Measures  ICMJE
 (submitted: September 30, 2011)
  • Change in skin score (Rodnan) from baseline at 6 months [ Time Frame: base line, 6 months ]
    Failure of skin score (if > 14 on enrollment) to improve or increase in skin score by a 25% above lowest post treatment value and must be documented on 2 occasion 6 months apart
  • Change in FVC from baseline at 6 months [ Time Frame: base line, 6 moths ]
    Deterioration in FVC by 10% below enrollment level or 10% below best post treatment value, due to systemic sclerosis, and documented on 2 occasion 6 months apart
  • Renal failure [ Time Frame: 12 months ]
    Renal failure due to systemic sclerosis and defined as chronic dialysis for more than 12 months
  • Gastrointestinal failure [ Time Frame: 12 months ]
    Gastrointestinal failure due to systemic sclerosis and defined as initiation of TPN for more than 12 months
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 7, 2020)
Survival of Treatment [ Time Frame: up to 12 months post treatment ]
Survival of Hematopoietic Stem Cell Transplant.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 30, 2011)
Survival [ Time Frame: six moths, then yearly for 5 years ]
survival
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Autologous Stem Cell Systemic Sclerosis Immune Suppression Trial
Official Title  ICMJE 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)
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Scleroderma, Systemic
Intervention  ICMJE
  • Biological: Peripheral Blood Stem Cells
    Mobilized leukapheresis product
  • Drug: Cyclophosphamide
    An alkylating agent which causes prevention of cell division by forming adducts with DNA
    Other Names:
    • Cytoxan
    • Neosar
    • Endoxan
  • Drug: Mesna
    Medication used to decrease the risk of hemorrhagic cystitis prophylaxis
    Other Name: Mesnex
  • Drug: rATG
    A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells
    Other Name: Thymoglobulin
  • Drug: Methylprednisolone
    Steroid
    Other Name: Solu-Medrol
  • 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
    Other Names:
    • Neupogen
    • G-CSF
    • Granix
    • Zarxio
  • Drug: Fludarabine
    Purine analog which inhibits DNA synthesis or repair
    Other Name: Fludara
Study Arms  ICMJE
  • Active Comparator: 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.
    Interventions:
    • Biological: Peripheral Blood Stem Cells
    • Drug: Cyclophosphamide
    • Drug: Mesna
    • Drug: rATG
    • Drug: Methylprednisolone
    • Drug: Filgrastim
  • Experimental: 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.
    Interventions:
    • Biological: Peripheral Blood Stem Cells
    • Drug: Cyclophosphamide
    • Drug: Mesna
    • Drug: rATG
    • Drug: Methylprednisolone
    • Drug: Filgrastim
    • Drug: Fludarabine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: July 7, 2020)
44
Original Estimated Enrollment  ICMJE
 (submitted: September 30, 2011)
160
Actual Study Completion Date  ICMJE October 10, 2019
Actual Primary Completion Date January 5, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 17 Years to 60 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01445821
Other Study ID Numbers  ICMJE ASSIST IIb
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Richard Burt, MD, Northwestern University
Study Sponsor  ICMJE Northwestern University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Richard Burt, MD Northwestern University
PRS Account Northwestern University
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP