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Autologous Stem Cell Transplantation in Patients With Systemic Sclerosis (SSc)

Primary Purpose

Systemic Sclerosis, Diffuse Sclerosis Systemic, Interstitial Lung Disease

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Cyclophosphamide
Mesna
Rituximab
Alemtuzumab
Thiotepa
GM-CSF
Intravenous immunoglobulin
Total Body Irradiation
Anti Thymocyte Globulin
Sponsored by
Paul Szabolcs
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Systemic Sclerosis focused on measuring Stem Cell Transplantation, Systemic Sclerosis, Scleroderma, Interstitial Lung Disease, ILD (Interstitial Lung Disease), Pulmonary Hypertension, BMT ( bone marrow transplantation), Autologous

Eligibility Criteria

8 Years - 60 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Cohort 1: Children, Adolescents and Young Adults (Cohort 1)

Inclusion:

Individuals must meet all the following criteria to be eligible for this study.

  1. Patient, parent, or legal guardian must have given written informed consent. For patients ≥ 168 years of age who are developmentally able, assent or affirmation will be obtained.
  2. Age 8-24, inclusive, at time of consent.
  3. Diagnosed with Systemic Sclerosis (SSc) at the age of ≤19.
  4. Failure to respond, specifically no improvement or progression of disease, to at least 2 disease-modifying antirheumatic drugs (DMARDS) within 12 months of consent with any of the following conditions:

    1. Progression of skin thickening over the past 6 months or Modified Rodnan skin score (mRSS) ≥ 20
    2. Progression of ILD within 18 months prior to consent. Progression to be determined by either of the following:

      • CT scan showing increased ground glass opacities or reticulations OR
      • Pulmonary function testing (PFTs) showing a decrease in FVC% or DLCO% predicted value of ≥10%.
    3. Myositis - CPK > 2x upper limit of normal or MRI consistent with myositis
    4. Childhood Myositis Assessment Score < 30
    5. Arthritis
    6. Digital tip ulcerations
  5. Cardiology clearance to undergo stem cell transplantation (documented in subject's medical chart)
  6. Negative for human immunodeficiency virus (HIV), hepatitis B virus and hepatitis C virus, all confirmed by PCR testing.
  7. Negative pregnancy test for females. who have reached menarche.

87. All females of childbearing potential and sexually active males must agree to use an FDA approved method of birth control for up to 24 months after BMT or for as long as they are taking any medication that may harm a pregnancy, an unborn child or may cause a birth defect.

Exclusion:

Individuals who meet any of these criteria are not eligible for this study.

  1. FVC <35%, determined by pulmonary function tests for those able to complete spirometry adequately (per investigator's determination)
  2. O2 sat <92% at rest in room air
  3. Estimated CrCl <40 mL/min,using Cockcroft-Gault formula based on actual body weight.
  4. Active, untreated SSc renal crisis at the time of consent.
  5. ALT > 4x upper limit of normal.
  6. Active, uncontrolled infection that would be a contraindication to safe use of high-dose immunosuppressive therapy or cyclophosphamide.
  7. Hematologic abnormalities as defined by any of the following peripheral blood counts:

    1. ANC < 1500 cell/µL.
    2. Platelets < 100,000 cells/ µL.
    3. Hemoglobin < 9.0 g/dL.
  8. Malignancy within 2 years prior to enrollment, excluding adequately treated squamous cell cancer, basal cell carcinoma or carcinoma in situ. Treatment should have been completed with cure/remission status documented for at least 2 years.
  9. Past or current medical problems or findings from medical history, physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.

Cohort 2 for Adults

Inclusion:

Individuals must meet all the following criteria to be eligible for this study.

  1. Patient, parent, or legal guardian must have given written informed consent. For patients ≥ 16 years of age who are developmentally able, assent or affirmation will be obtained.
  2. Age 1618-705560, inclusive, at time of consent. Patients up to age 24, diagnosed with SSc at age ≤ 19, will be included in Cohort 1 and evaluated according to the Pediatric and Young Adult criteria listed in sections 3.1.1 and 3.1.2.
  3. Diagnosed with Systemic Sclerosis (SSc), according to the 2013 ACR/EULAR criteria (van den Hoogen et al., 2013).
  4. All patients must meet either the following skin or ILD criteria. Disease duration is defined as time from first non-Raynaud symptom.

    Skin Criteria: Diffuse SSc, defined by presence of proximal skin thickening and:

    A. If disease duration is of <2 years, patients must have a calculated mortality risk prediction score which places them in the intermediate or high- risk category (Domsic et al., 2016). Refer to Appendix 5 for calculation criteria.

    B. If disease duration is of >2 years, patients must have evidence of active cutaneous disease based upon 1) a worsening Modified Rodnan Skin Score (MRSS) in the preceding three months or 2) the presence of palpable tendon friction rubs.

    ILD Criteria:

    A. The presence of recognized fibrosis on imaging of <2 years AND either > 10% of lung involvement by CT scan or FVC% pred <80% or B. Fibrosis on imaging of any duration with a decline in FVC% pred of ≥10% over the preceding 12-18 months.

  5. Negative for human immunodeficiency virus (HIV), hepatitis B virus and hepatitis C virus, all confirmed by PCR testing.
  6. Negative pregnancy test for females.
  7. All females of childbearing potential and sexually active males must agree to use an FDA approved method of birth control for up to 24 months after BMT or for as long as they are taking any medication that may harm a pregnancy, an unborn child or may cause a birth defect.

Exclusion Criteria Individuals who meet any of these criteria are not eligible for this study.

  1. Moderate to severe cardiac involvement defined by any of the following:

    1. New York Heart Association classification of heart failure ≥3.
    2. Left ventricular ejection fraction (LVEF) <50% as determined by cardiac MRI.
    3. Significant pulmonary hypertension, for subjects ≥ 18 years of age, defined as mean PASP ≥30 mmHg determined by right heart catheterization, or for subjects ≤ 17 years of age, defined as mean PASP >45 mmHg, determined by echocardiogram.
    4. Atrial tachycardia, atrial fibrillation or atrial flutter of ≥1-minute duration, determined by electrocardiogram (EKG) or, cardiac event monitor and/or implanted loop recorder (if applicable), or on anti-arrhythmic therapy for the arrhythmias listed above.
    5. Ventricular tachycardia of ≥6 beats at rate of ≥100 beats per minute, determined by EKG or, cardiac event monitor and/or implanted loop recorder (if applicable), or on an anti-arrhythmic therapy for any ventricular arrhythmia.
    6. Left bundle branch block, bifascicular heart block, Mobitz 2 heart block, complete heart block or infarction pattern as determined by EKG or, cardiac event monitor and/or implanted loop recorder
    7. Presence of pacemaker or implantable cardioverter defibrillator.
  2. Moderate to severe pulmonary involvement defined by any of the following:

    1. Hemoglobin-corrected DLCO <45%, determined by pulmonary function tests.
    2. FVC <45%, determined by pulmonary function tests.
    3. pO2 <70 mmHg, determined by an arterial blood gas (not applicable for subjects ≤17 years of age).
    4. pCO2 ≥45 without supplemental O2 determined by an arterial blood gas (not applicable for subjects ≤17 years of age).
    5. O2 sat <92% at rest without supplemental O2, determined by an arterial blood gas (not applicable for subjects ≤17 years of age).
    6. Six-minute walk (6MW) results <400 feet.
  3. Steroid therapy defined by either of the following:

    1. Subjects who received > 10 mg/day prednisone or equivalent within 30 days prior to start of conditioning regimen on Day -21.
    2. Subjects who have been treated for concurrent illnesses (eg, asthma) with the equivalent of prednisone 1 mg/kg/day or its equivalent for > 5 days on > 2 occasions during the previous 12 months (prior to conditioning) or > 1 occasion in the prior 6 months (prior to conditioning).
  4. Estimated CrCl <40 mL/min,using Cockcroft-Gault formula based on actual body weight.
  5. Serum creatinine >2.0 mg/dL.
  6. Active, untreated SSc renal crisis at the time of consent.
  7. Dependence on nutritional supplementation/hyperalimentation.
  8. Active gastric antral vascular ectasia (GAVE), defined by a decrease in hemoglobin greater than 1 g/dL in the preceding 60 days, attributed to GAVE.
  9. Active hepatitis defined by any of the following:

    1. AST > 2x upper limit of normal.
    2. ALT > 2x upper limit of normal.
    3. Bilirubin >2x upper limit of normal.
  10. Evidence of moderate to severe periportal fibrosis, determined by liver biopsy, if applicable.
  11. Active, uncontrolled infection that would be a contraindication to safe use of high-dose immunosuppressive therapy or cyclophosphamide.
  12. Hematologic abnormalities as defined by any of the following peripheral blood counts:

    1. ANC < 1500 cell/µL.
    2. Platelets < 100,000 cells/ µL.
    3. Hemoglobin < 9.0 g/dL.
  13. Evidence of myelodysplasia (MDS), confirmed by bone marrow aspirate, if applicable.
  14. Malignancy within 2 years prior to enrollment, excluding adequately treated squamous cell cancer, basal cell carcinoma or carcinoma in situ. Treatment should have been completed with cure/remission status documented for at least 2 years, with the exception of hormonal therapy for breast cancer.
  15. Females who are pregnant or who are lactating.
  16. Tobacco use, by subject admission, within previous 4 weeks of time of consent.
  17. History of sensitivity to murine proteins or E. coli proteins.
  18. Known history of substance abuse, determined by medical record or subject admission, within 6 months of time of consent.
  19. Patient with systemic reaction to anti-thymocyte globulin or any other equine gamma globulin preparation
  20. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.

Sites / Locations

  • Children's Hospital of Pittsburgh of UPMCRecruiting
  • University of Pittsburgh Medical CenterRecruiting
  • University of Pittsburgh Medical CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Autologous Stem Cell Transplantation

Arm Description

CD34-selected autologous stem cell being performed on CliniMACS depletion device. Conditioning regimen will not start sooner than 3 weeks, and ideally no more than 90 days, after cyclophosphamide dose in the mobilization regimen.

Outcomes

Primary Outcome Measures

High Dose Immunoablative therapy-Safety
Safety will be determined by monitoring for death of any cause, regimen-related toxicities, and severe or life-threatening infections.
Death
How many, if any, patients die
Respiratory Failure
defined by one of the following 3 criteria without explanation for causation other than disease progression: 1. decline in DLCO of ≥30% or FVC≥20% as measured by actual difference in percent predicted units; 2. Resting arterial p02 < 60 mmHg or pCO2 > 50 mmHg supplemental oxygen;3. Resting pulse oximetry of 88% or lower measured by forehead probe.
Renal Failure
Defined by chronic dialysis for >6 months or renal transplantation
The occurrence of cardiomyopathy
confirmed by clinical congestive heart failure (New York Heart Association) or LVEF (left ventricular ejection fraction) <30% on echocardiogram
Treatment-related mortality (TRM)
defined as death occurring at any time after stem cell mobilization and definitely or probably resulting from treatment given in the study. TRM will be determined yearly with a focus on the first 2 years.
High Dose Immunoablative therapy-Treatment Effect
Treatment effect will be determined by assessing event-free survival in comparison to a SSc observational cohort control group treated with standard of care medication (mycophenolate mofetil) at 12 and 36 months post hematopoietic stem cell transplant (HSCT).

Secondary Outcome Measures

An increase of mRSS (modified Rodnan skin score ) by ≥5 points for skin score
To assess cutaneous response the modified Rodnan skin score (mRSS) will be used.
Increase by ≥25% if the baseline mRSS > 20.
To assess cutaneous response the modified Rodnan skin score (mRSS) will be used.
Worsening of > 10% of FVC (pulmonary function testing)
to evaluate interstitial lung disease an increase of ≥15% in DLCO or ≥10% of FVC (actual change in % predicted units from baseline) sustained for ≥3 months on 2 determinations.
Decrease in DLCO sustained for 3 months or longer on pulmonary function tests (PFT)
to evaluate interstitial lung disease an increase of ≥15% in DLCO or ≥10% of FVC (actual change in % predicted units from baseline) sustained for ≥3 months on 2 determinations.
Worsening of cardiac involvement
With use of Imaging, EKG, Echocardiogram, Cardiac MRI, right heart cauterization, implanted loop recorder and 2 week cardiac event monitor. Defined as new or worsening arrhythmias that require medical treatment of 3 months or longer, or require ablative therapy, pacemaker or defibrillator insertion or defined as a decline in ejection fraction of ≥10 EF units, determined by echocardiogram.
Development of scleroderma renal crisis (hypertensive or non-hypertensive)
Hypertensive renal crisis can be defined as a rise in SBP ≥ 30 points or DBP ≥ 20 points from baseline and one of the following: 1) Increase in baseline serum creatinine of ≥ 50%, 2) thrombocytopenia < 100,000 plts/mm3 or 3. hemolysis by blood smear or increased reticulocyte count.

Full Information

First Posted
August 7, 2018
Last Updated
September 7, 2023
Sponsor
Paul Szabolcs
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1. Study Identification

Unique Protocol Identification Number
NCT03630211
Brief Title
Autologous Stem Cell Transplantation in Patients With Systemic Sclerosis
Acronym
SSc
Official Title
Autologous Stem Cell Transplantation With CD34-Selected Peripheral Blood Stem Cells (PBSC) in Patients With Treatment Resistant Systemic Sclerosis (SSc)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 31, 2018 (Actual)
Primary Completion Date
August 1, 2024 (Anticipated)
Study Completion Date
August 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Paul Szabolcs

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to determine whether a regimen of high-dose immunoablative therapy will demonstrate safety that is consistent or improved with other published regimens in SSc patients, while maintaining a treatment effect.
Detailed Description
This is a single center, phase II trial where after a process of stem cell mobilization and conditioning, subjects receive a CD34-selected autologous peripheral blood stem cell rescue. By virtue of positive selection for the stem/progenitor cell marker of CD34, the graft will be depleted for T, B and NK lymphocytes and other immune cells such as monocytes that may be pathogenic. This is an open label study and there will be no randomization or blinding as a part of this study. The proposed regimen of high-dose immunoablative therapy will demonstrate safety that is consistent or improved with other published regimens in SSc patients, while maintaining a treatment effect. The primary objectives of this study are to determine the safety and treatment effect of high-dose immunoablative therapy followed by transplantation of CD34+ positively selected peripheral blood stem cells (PBSC) for systemic scleroderma (SSc) patients using a regimen designed to maximize patient safety while also aiming to eradicate autoreactive clones responsible for the disease. Safety will be determined by monitoring for death of any cause, and severe or life-threatening infections. Treatment effect will be determined by assessing event-free survival in comparison to a SSc observational cohort control group treated with standard of care medication (mycophenolate mofetil) at 12 and 36 months post hematopoietic stem cell transplant (HSCT). Enrolled subjects will be followed for survival, secondary malignancies, and SSC activity at least yearly up to 36 months post-HSCT. The secondary objectives of this study are to: To assess cutaneous disease response to high dose immunosuppressive therapy (HDIT) by comparing pre- and post-transplant measurements of the modified Rodnan skin score (mRSS). To assess pulmonary disease response by longitudinally tracking FVC (pulmonary function test) and DLCO (diffusing capacity of the lung for carbon monoxide) yearly up to 36 months post-HSCT. To evaluate the treatment effect on disease activity/progression, as indicated by severity measures of cardiac, pulmonary, musculoskeletal, gastrointestinal, vascular and renal organ involvement, and need for concomitant disease-modifying antirheumatic drugs (DMARD) use. To evaluate quality of life by comparing pre- and post-transplant quality of life measurements. These measurements will include the Scleroderma Health Assessment Questionnaire (SHAQ), the Medical Outcomes Study Questionnaire Short Form 36 Health Survey (SF-36) and the Scleroderma Skin Patient Reported Outcome (SSPRO) pre- and post-mobilization.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Systemic Sclerosis, Diffuse Sclerosis Systemic, Interstitial Lung Disease, Pulmonary Hypertension
Keywords
Stem Cell Transplantation, Systemic Sclerosis, Scleroderma, Interstitial Lung Disease, ILD (Interstitial Lung Disease), Pulmonary Hypertension, BMT ( bone marrow transplantation), Autologous

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
8 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Autologous Stem Cell Transplantation
Arm Type
Experimental
Arm Description
CD34-selected autologous stem cell being performed on CliniMACS depletion device. Conditioning regimen will not start sooner than 3 weeks, and ideally no more than 90 days, after cyclophosphamide dose in the mobilization regimen.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
Stem Cell Mobilization
Intervention Type
Drug
Intervention Name(s)
Mesna
Intervention Description
Stem Cell Mobilization
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Rituxan
Intervention Description
Transplantation Conditioning
Intervention Type
Drug
Intervention Name(s)
Alemtuzumab
Other Intervention Name(s)
Campath-1H
Intervention Description
Transplantation Conditioning
Intervention Type
Drug
Intervention Name(s)
Thiotepa
Intervention Description
Transplantation Conditioning
Intervention Type
Drug
Intervention Name(s)
GM-CSF
Other Intervention Name(s)
Neupogen, Filgrastim
Intervention Description
Transplantation Conditioning
Intervention Type
Drug
Intervention Name(s)
Intravenous immunoglobulin
Intervention Description
Transplantation Conditioning
Intervention Type
Radiation
Intervention Name(s)
Total Body Irradiation
Intervention Description
Transplantation Conditioning
Intervention Type
Drug
Intervention Name(s)
Anti Thymocyte Globulin
Other Intervention Name(s)
Thymoglobulin
Intervention Description
Transplantation Conditioning
Primary Outcome Measure Information:
Title
High Dose Immunoablative therapy-Safety
Description
Safety will be determined by monitoring for death of any cause, regimen-related toxicities, and severe or life-threatening infections.
Time Frame
Up to 36 months post HSCT
Title
Death
Description
How many, if any, patients die
Time Frame
Post Transplant through study completion, an average of 36 months
Title
Respiratory Failure
Description
defined by one of the following 3 criteria without explanation for causation other than disease progression: 1. decline in DLCO of ≥30% or FVC≥20% as measured by actual difference in percent predicted units; 2. Resting arterial p02 < 60 mmHg or pCO2 > 50 mmHg supplemental oxygen;3. Resting pulse oximetry of 88% or lower measured by forehead probe.
Time Frame
Post Transplant through study completion, an average of 36 months
Title
Renal Failure
Description
Defined by chronic dialysis for >6 months or renal transplantation
Time Frame
Post Transplant through study completion, an average of 36 months
Title
The occurrence of cardiomyopathy
Description
confirmed by clinical congestive heart failure (New York Heart Association) or LVEF (left ventricular ejection fraction) <30% on echocardiogram
Time Frame
Post Transplant through study completion, an average of 36 months
Title
Treatment-related mortality (TRM)
Description
defined as death occurring at any time after stem cell mobilization and definitely or probably resulting from treatment given in the study. TRM will be determined yearly with a focus on the first 2 years.
Time Frame
Mobilization through study completion, an average of 36 months
Title
High Dose Immunoablative therapy-Treatment Effect
Description
Treatment effect will be determined by assessing event-free survival in comparison to a SSc observational cohort control group treated with standard of care medication (mycophenolate mofetil) at 12 and 36 months post hematopoietic stem cell transplant (HSCT).
Time Frame
up to 36 months post HSCT (hematopoietic stem cell transplantation)
Secondary Outcome Measure Information:
Title
An increase of mRSS (modified Rodnan skin score ) by ≥5 points for skin score
Description
To assess cutaneous response the modified Rodnan skin score (mRSS) will be used.
Time Frame
Disease response will be defined as subject improvement. This will be assessed for both skin and interstitial lung disease at 12 and 24 months post-HSCT.
Title
Increase by ≥25% if the baseline mRSS > 20.
Description
To assess cutaneous response the modified Rodnan skin score (mRSS) will be used.
Time Frame
Disease response will be defined as subject improvement. This will be assessed for both skin and interstitial lung disease at 12 and 24 months post-HSCT.
Title
Worsening of > 10% of FVC (pulmonary function testing)
Description
to evaluate interstitial lung disease an increase of ≥15% in DLCO or ≥10% of FVC (actual change in % predicted units from baseline) sustained for ≥3 months on 2 determinations.
Time Frame
1 year post transplant through study completion, an average of 36 months
Title
Decrease in DLCO sustained for 3 months or longer on pulmonary function tests (PFT)
Description
to evaluate interstitial lung disease an increase of ≥15% in DLCO or ≥10% of FVC (actual change in % predicted units from baseline) sustained for ≥3 months on 2 determinations.
Time Frame
1 year post transplant through study completion, an average of 36 months
Title
Worsening of cardiac involvement
Description
With use of Imaging, EKG, Echocardiogram, Cardiac MRI, right heart cauterization, implanted loop recorder and 2 week cardiac event monitor. Defined as new or worsening arrhythmias that require medical treatment of 3 months or longer, or require ablative therapy, pacemaker or defibrillator insertion or defined as a decline in ejection fraction of ≥10 EF units, determined by echocardiogram.
Time Frame
Post Transplant through study completion, an average of 36 months
Title
Development of scleroderma renal crisis (hypertensive or non-hypertensive)
Description
Hypertensive renal crisis can be defined as a rise in SBP ≥ 30 points or DBP ≥ 20 points from baseline and one of the following: 1) Increase in baseline serum creatinine of ≥ 50%, 2) thrombocytopenia < 100,000 plts/mm3 or 3. hemolysis by blood smear or increased reticulocyte count.
Time Frame
Post Transplant through study completion, an average of 36 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
8 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Cohort 1: Children, Adolescents and Young Adults (Cohort 1) Inclusion: Individuals must meet all the following criteria to be eligible for this study. Patient, parent, or legal guardian must have given written informed consent. For patients ≥ 168 years of age who are developmentally able, assent or affirmation will be obtained. Age 8-24, inclusive, at time of consent. Diagnosed with Systemic Sclerosis (SSc) at the age of ≤19. Failure to respond, specifically no improvement or progression of disease, to at least 2 disease-modifying antirheumatic drugs (DMARDS) within 12 months of consent with any of the following conditions: Progression of skin thickening over the past 6 months or Modified Rodnan skin score (mRSS) ≥ 20 Progression of ILD within 18 months prior to consent. Progression to be determined by either of the following: CT scan showing increased ground glass opacities or reticulations OR Pulmonary function testing (PFTs) showing a decrease in FVC% or DLCO% predicted value of ≥10%. Myositis - CPK > 2x upper limit of normal or MRI consistent with myositis Childhood Myositis Assessment Score < 30 Arthritis Digital tip ulcerations Cardiology clearance to undergo stem cell transplantation (documented in subject's medical chart) Negative for human immunodeficiency virus (HIV), hepatitis B virus and hepatitis C virus, all confirmed by PCR testing. Negative pregnancy test for females. who have reached menarche. 87. All females of childbearing potential and sexually active males must agree to use an FDA approved method of birth control for up to 24 months after BMT or for as long as they are taking any medication that may harm a pregnancy, an unborn child or may cause a birth defect. Exclusion: Individuals who meet any of these criteria are not eligible for this study. FVC <35%, determined by pulmonary function tests for those able to complete spirometry adequately (per investigator's determination) O2 sat <92% at rest in room air Estimated CrCl <40 mL/min,using Cockcroft-Gault formula based on actual body weight. Active, untreated SSc renal crisis at the time of consent. ALT > 4x upper limit of normal. Active, uncontrolled infection that would be a contraindication to safe use of high-dose immunosuppressive therapy or cyclophosphamide. Hematologic abnormalities as defined by any of the following peripheral blood counts: ANC < 1500 cell/µL. Platelets < 100,000 cells/ µL. Hemoglobin < 9.0 g/dL. Malignancy within 2 years prior to enrollment, excluding adequately treated squamous cell cancer, basal cell carcinoma or carcinoma in situ. Treatment should have been completed with cure/remission status documented for at least 2 years. Past or current medical problems or findings from medical history, physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study. Cohort 2 for Adults Inclusion: Individuals must meet all the following criteria to be eligible for this study. Patient, parent, or legal guardian must have given written informed consent. For patients ≥ 16 years of age who are developmentally able, assent or affirmation will be obtained. Age 1618-705560, inclusive, at time of consent. Patients up to age 24, diagnosed with SSc at age ≤ 19, will be included in Cohort 1 and evaluated according to the Pediatric and Young Adult criteria listed in sections 3.1.1 and 3.1.2. Diagnosed with Systemic Sclerosis (SSc), according to the 2013 ACR/EULAR criteria (van den Hoogen et al., 2013). All patients must meet either the following skin or ILD criteria. Disease duration is defined as time from first non-Raynaud symptom. Skin Criteria: Diffuse SSc, defined by presence of proximal skin thickening and: A. If disease duration is of <2 years, patients must have a calculated mortality risk prediction score which places them in the intermediate or high- risk category (Domsic et al., 2016). Refer to Appendix 5 for calculation criteria. B. If disease duration is of >2 years, patients must have evidence of active cutaneous disease based upon 1) a worsening Modified Rodnan Skin Score (MRSS) in the preceding three months or 2) the presence of palpable tendon friction rubs. ILD Criteria: A. The presence of recognized fibrosis on imaging of <2 years AND either > 10% of lung involvement by CT scan or FVC% pred <80% or B. Fibrosis on imaging of any duration with a decline in FVC% pred of ≥10% over the preceding 12-18 months. Negative for human immunodeficiency virus (HIV), hepatitis B virus and hepatitis C virus, all confirmed by PCR testing. Negative pregnancy test for females. All females of childbearing potential and sexually active males must agree to use an FDA approved method of birth control for up to 24 months after BMT or for as long as they are taking any medication that may harm a pregnancy, an unborn child or may cause a birth defect. Exclusion Criteria Individuals who meet any of these criteria are not eligible for this study. Moderate to severe cardiac involvement defined by any of the following: New York Heart Association classification of heart failure ≥3. Left ventricular ejection fraction (LVEF) <50% as determined by cardiac MRI. Significant pulmonary hypertension, for subjects ≥ 18 years of age, defined as mean PASP ≥30 mmHg determined by right heart catheterization, or for subjects ≤ 17 years of age, defined as mean PASP >45 mmHg, determined by echocardiogram. Atrial tachycardia, atrial fibrillation or atrial flutter of ≥1-minute duration, determined by electrocardiogram (EKG) or, cardiac event monitor and/or implanted loop recorder (if applicable), or on anti-arrhythmic therapy for the arrhythmias listed above. Ventricular tachycardia of ≥6 beats at rate of ≥100 beats per minute, determined by EKG or, cardiac event monitor and/or implanted loop recorder (if applicable), or on an anti-arrhythmic therapy for any ventricular arrhythmia. Left bundle branch block, bifascicular heart block, Mobitz 2 heart block, complete heart block or infarction pattern as determined by EKG or, cardiac event monitor and/or implanted loop recorder Presence of pacemaker or implantable cardioverter defibrillator. Moderate to severe pulmonary involvement defined by any of the following: Hemoglobin-corrected DLCO <45%, determined by pulmonary function tests. FVC <45%, determined by pulmonary function tests. pO2 <70 mmHg, determined by an arterial blood gas (not applicable for subjects ≤17 years of age). pCO2 ≥45 without supplemental O2 determined by an arterial blood gas (not applicable for subjects ≤17 years of age). O2 sat <92% at rest without supplemental O2, determined by an arterial blood gas (not applicable for subjects ≤17 years of age). Six-minute walk (6MW) results <400 feet. Steroid therapy defined by either of the following: Subjects who received > 10 mg/day prednisone or equivalent within 30 days prior to start of conditioning regimen on Day -21. Subjects who have been treated for concurrent illnesses (eg, asthma) with the equivalent of prednisone 1 mg/kg/day or its equivalent for > 5 days on > 2 occasions during the previous 12 months (prior to conditioning) or > 1 occasion in the prior 6 months (prior to conditioning). Estimated CrCl <40 mL/min,using Cockcroft-Gault formula based on actual body weight. Serum creatinine >2.0 mg/dL. Active, untreated SSc renal crisis at the time of consent. Dependence on nutritional supplementation/hyperalimentation. Active gastric antral vascular ectasia (GAVE), defined by a decrease in hemoglobin greater than 1 g/dL in the preceding 60 days, attributed to GAVE. Active hepatitis defined by any of the following: AST > 2x upper limit of normal. ALT > 2x upper limit of normal. Bilirubin >2x upper limit of normal. Evidence of moderate to severe periportal fibrosis, determined by liver biopsy, if applicable. Active, uncontrolled infection that would be a contraindication to safe use of high-dose immunosuppressive therapy or cyclophosphamide. Hematologic abnormalities as defined by any of the following peripheral blood counts: ANC < 1500 cell/µL. Platelets < 100,000 cells/ µL. Hemoglobin < 9.0 g/dL. Evidence of myelodysplasia (MDS), confirmed by bone marrow aspirate, if applicable. Malignancy within 2 years prior to enrollment, excluding adequately treated squamous cell cancer, basal cell carcinoma or carcinoma in situ. Treatment should have been completed with cure/remission status documented for at least 2 years, with the exception of hormonal therapy for breast cancer. Females who are pregnant or who are lactating. Tobacco use, by subject admission, within previous 4 weeks of time of consent. History of sensitivity to murine proteins or E. coli proteins. Known history of substance abuse, determined by medical record or subject admission, within 6 months of time of consent. Patient with systemic reaction to anti-thymocyte globulin or any other equine gamma globulin preparation Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Paul Szabolcs, MD
Phone
412-692-6225
Email
paul.szabolcs@chp.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Shawna McIntyre, RN
Phone
412-692-5552
Email
mcintyresm@upmc.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Paul Szabolcs, MD
Organizational Affiliation
University of Pittsburgh
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital of Pittsburgh of UPMC
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Shawna McIntyre, RN
Phone
412-692-5552
Email
mcintyresm@upmc.edu
First Name & Middle Initial & Last Name & Degree
Paul Szabolcs, MD
First Name & Middle Initial & Last Name & Degree
Robyn Domsic, MD, MPH
First Name & Middle Initial & Last Name & Degree
Annie Im, MD
First Name & Middle Initial & Last Name & Degree
Daniel Kass, MD
First Name & Middle Initial & Last Name & Degree
Geoffrey Kurland, MD
First Name & Middle Initial & Last Name & Degree
Robert Lafyatis, MD
First Name & Middle Initial & Last Name & Degree
Adam Olson, MD
First Name & Middle Initial & Last Name & Degree
Kathryn Torok, MD
First Name & Middle Initial & Last Name & Degree
Allison Morris, MD, MS
First Name & Middle Initial & Last Name & Degree
Jessie Barnum, MD
First Name & Middle Initial & Last Name & Degree
Kirsten Rose-Felker, MD
First Name & Middle Initial & Last Name & Degree
Franziska Rosser, MD, MPH
First Name & Middle Initial & Last Name & Degree
Paulina Horvei, MD
First Name & Middle Initial & Last Name & Degree
Joshua Levenson, MD
Facility Name
University of Pittsburgh Medical Center
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15261
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Robyn Domsic, MD, MPH
Phone
412-383-8000
Email
domsicrt@upmc.edu
Facility Name
University of Pittsburgh Medical Center
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15261
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Robert Lafyatis, MD
Phone
412-647-6700
Email
lafyatisra@upmc.edu

12. IPD Sharing Statement

Plan to Share IPD
No

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Autologous Stem Cell Transplantation in Patients With Systemic Sclerosis

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