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Cardiac Safe Transplants for Systemic Sclerosis (CAST)

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ClinicalTrials.gov Identifier: NCT03593902
Recruitment Status : Recruiting
First Posted : July 20, 2018
Last Update Posted : April 8, 2019
Sponsor:
Information provided by (Responsible Party):
Richard Burt, MD, Northwestern University

Brief Summary:
This study is designed to treat systemic sclerosis (scleroderma) patients with an autologous stem cell transplant using a regimen of immune suppressant drugs and chemotherapy that is less toxic to your heart.

Condition or disease Intervention/treatment Phase
Systemic Sclerosis Scleroderma Drug: Rituximab Drug: Fludarabine Drug: Cyclophosphamide Drug: Mesna Drug: rATG Drug: Methylprednisolone Drug: G-CSF Biological: IVIg Biological: Autologous Stem Cells Phase 2 Phase 3

Detailed Description:
The autologous hematopoietic stem cell transplant used in this research study is an investigational procedure that uses cyclophosphamide and fludarabine (chemotherapy), rabbit anti-thymocyte globulin (rATG) (a protein that kills the immune cells that are thought to be causing your disease), and rituximab (a biologic drug that targets B cells of your immune system). After use of these treatments, the patient will receive their own previously collected blood stem cells (autologous stem cell transplant). The ability of these experimental treatments to stop relapses and progression (worsening) of your systemic sclerosis will be assessed.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Autologous Hematopoietic Stem Cell Transplant for Patients With Systemic Sclerosis and Cardiac Dysfunction
Actual Study Start Date : September 7, 2018
Estimated Primary Completion Date : January 2025
Estimated Study Completion Date : January 2026

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Scleroderma

Arm Intervention/treatment
Experimental: Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cell Therapy will be performed as follows: Autologous stem cells will be infused after conditioning with rituximab, fludarabine, cyclophosphamide, Mesna, rATG (rabbit), and methylprednisolone. Granulocyte-colony stimulating factor (G-CSF) and intravenous immunoglobulin (IVIg) will be administered post-transplant.
Drug: Rituximab
Monoclonal antibody therapy used to treat certain autoimmune diseases and types of cancer
Other Name: Rituxan

Drug: Fludarabine
A chemotherapy medication commonly used in the treatment of leukemia and lymphoma
Other Name: Fludara

Drug: Cyclophosphamide
A medication used as chemotherapy and to suppress the immune system
Other Name: Cytoxan

Drug: Mesna
A medication used in those taking cyclophosphamide or ifosfamide to decrease the risk of bleeding from the bladder
Other Name: Mesnex

Drug: rATG
A rabbit polyclonal antibody to lymphocytes
Other Names:
  • Thymoglobulin
  • Anti-Thymocyte Globulin (Rabbit)

Drug: Methylprednisolone
A corticosteroid medication used to suppress the immune system and decrease inflammation
Other Names:
  • Solu-Medrol
  • Depo-Medrol

Drug: G-CSF
A glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream
Other Names:
  • Neupogen
  • Filgrastim
  • Granix
  • Zarxio

Biological: IVIg
Pooled immunoglobulin (IgG) from thousands of plasma donors that has immunomodulatory and anti-inflammatory effects
Other Names:
  • Bivagam
  • Carimune NF
  • Gammagard
  • Privigen
  • Octagam

Biological: Autologous Stem Cells
Infusion of patient's own stem cells




Primary Outcome Measures :
  1. Change in skin score by mRSS [ Time Frame: 6 months, 1 year, 2 years, 3 years, 4 years, 5 years ]
    Defined by at least a 25% improvement (decline) in skin score by modified Rodnan skin score (mRSS) if skin score is greater than 14 on enrollment. If skin score is less than 14 on enrollment, improvement is defined by at least a 5% improvement on mRSS.

  2. Change in FVC on pulmonary function test [ Time Frame: 6 months, 1 year, 2 years, 3 years, 4 years, 5 years ]
    Defined as at least a 10% improvement (increase) in percent predicted forced vital capacity (FVC)


Secondary Outcome Measures :
  1. Treatment related mortality [ Time Frame: 5 years ]
    Treatment related mortality

  2. Survival [ Time Frame: 5 years ]
    Survival of participants

  3. Cardiac function, LVEF [ Time Frame: 6 months, 1 year, 2 years, 3 years, 4 years, 5 years ]
    Improvement in left ventricular ejection fraction (LVEF).)

  4. Cardiac function, RVEF [ Time Frame: 6 months, 1 year, 2 years, 3 years, 4 years, 5 years ]
    Improvement in right ventricular ejection fraction (RVEF).

  5. Cardiac function, PASP [ Time Frame: 6 months, 1 year, 2 years, 3 years, 4 years, 5 years ]
    Improvement in pulmonary artery systolic pressure (PASP).

  6. Cardiac function, mPAP [ Time Frame: 6 months, 1 year, 2 years, 3 years, 4 years, 5 years ]
    Improvement in mean pulmonary artery pressure (mPAP).

  7. Cardiac function, ECV [ Time Frame: 6 months, 1 year, 2 years, 3 years, 4 years, 5 years ]
    Improvement in extracellular volume (ECV).

  8. Renal outcome, creatinine clearance [ Time Frame: 6 months, 1 year, 2 years, 3 years, 4 years, 5 years ]
    Evaluation of changes in creatinine clearance.

  9. Renal outcome, episodes of renal crisis [ Time Frame: 6 months, 1 year, 2 years, 3 years, 4 years, 5 years ]
    Evaluation of changes in episodes of renal crisis.

  10. Renal outcome, dialysis [ Time Frame: 6 months, 1 year, 2 years, 3 years, 4 years, 5 years ]
    Evaluation of changes in need/duration of dialysis.

  11. Pulmonary function tests, TLC [ Time Frame: 6 months, 1 year, 2 years, 3 years, 4 years, 5 years ]
    Improvement in total lung capacity (TLC).

  12. Pulmonary function tests, DLCO [ Time Frame: 6 months, 1 year, 2 years, 3 years, 4 years, 5 years ]
    Improvement in diffusing capacity of the lung for carbon monoxide (DLCO).



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age 18 - 65 years old at the time of pre-transplant evaluation
  2. An established diagnosis of systemic sclerosis
  3. Diffuse cutaneous systemic sclerosis with involvement proximal to the elbow or knee and a modified Rodnan Skin Score of ≥ 14 (see Appendix A)

AND

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 (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 without constriction 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 may be present (e.g. dilated and crowded circular folds). GI involvement may also be confirmed by D-xylose malabsorption, patulous esophagus on high-resolution computed tomography (HRCT), or esophageal manometry.

OR

Limited cutaneous systemic sclerosis (SSc) (modified Rodnan Skin Score <14) with lung involvement defined as active alveolitis on bronchoalveolar lavage (BAL), ground-glass opacity on CT scan, a DLCO < 80% predicted, or decrease in lung function (DLCO/VA, DLCO, FVC) of 10% or more in last 12 months.

Other Inclusion Criteria for "CAST" Conditioning Regimen (presence of any of the following):

  1. Septal flattening or D-sign on MRI (without deep breathing)
  2. PASP >40 mm Hg or >45 mm Hg with fluid challenge*
  3. mPAP >25 mm Hg or >30 mm Hg with fluid challenge*
  4. Non-ischemia diffuse ventricular hypokinesis or non-ischemia wall hypokinesis

    • Fluid challenge is 1000 ml normal saline over 10 minutes. Fluid challenge will not be done if right atrial pressure is >13 mm Hg at rest or pulmonary capillary wedge pressure is >20 mm Hg at rest.

Exclusion Criteria:

  1. Active ischemic heart disease or untreated coronary artery disease
  2. Untreated life-threatening cardiac arrhythmia on EKG or 24-hour holter
  3. Pericardial effusion > 1 cm on cardiac MRI unless successful pericardiocentesis has been performed
  4. LVEF <35%
  5. End-stage lung disease characterized by TLC<45% of predicted value, or DLCO hemoglobin corrected < 30 % predicted.
  6. Creatinine clearance <40 by 24-hour urine
  7. History of breast implants that have not been removed (unless they cannot be surgically removed due to risks of surgery)
  8. Liver cirrhosis, transaminases >2x of normal limits, or bilirubin > 2.0 unless due to Gilbert's disease
  9. 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
  10. Prior history of malignancy
  11. Positive pregnancy test, inability or unable to pursue effective means of birth control, or failure to willingly accept or comprehend irreversible sterility as a side effect of therapy
  12. Psychiatric illness or mental deficiency making compliance with treatment or informed consent impossible
  13. Major hematological abnormalities such as platelet count < 100,000/ul or absolute neutrophil count (ANC) < 1000/ul
  14. HIV positive
  15. Hepatitis B or C positive
  16. PASP >50 mmHg without fluid challenge
  17. mPAP >34 mmHg without fluid challenge
  18. Coronary artery disease not reversed by cardiology and interventional radiology

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03593902


Contacts
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Contact: Kathleen Quigley, RN 312-695-8192 kathleen.quigley@nm.org

Locations
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United States, Illinois
Northwestern University, Feinberg School of Medicine Recruiting
Chicago, Illinois, United States, 60611
Contact: Kathleen Quigley    312-695-4960    k-quigley@northwestern.edu   
Principal Investigator: Richard Burt, MD         
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Kathleen Quigley, RN    312-695-8192    kathleen.quigley@nm.org   
Principal Investigator: Richard Burt, MD         
Sponsors and Collaborators
Northwestern University
Investigators
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Principal Investigator: Richard Burt, MD Northwestern University

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Responsible Party: Richard Burt, MD, Professor, Northwestern University
ClinicalTrials.gov Identifier: NCT03593902     History of Changes
Other Study ID Numbers: DIAD.CAST.2018
First Posted: July 20, 2018    Key Record Dates
Last Update Posted: April 8, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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

Keywords provided by Richard Burt, MD, Northwestern University:
Autologous Stem Cell Transplantation
Hematopoietic Stem Cell Transplant

Additional relevant MeSH terms:
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Scleroderma, Systemic
Scleroderma, Diffuse
Sclerosis
Pathologic Processes
Connective Tissue Diseases
Skin Diseases
Cyclophosphamide
Fludarabine phosphate
Thymoglobulin
Antilymphocyte Serum
Rituximab
Fludarabine
Methylprednisolone Hemisuccinate
Prednisolone
Methylprednisolone
Methylprednisolone Acetate
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Mesna
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological