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Cyclophosphamide and rATG With Hematopoietic Stem Cell Support in Systemic Scleroderma

Primary Purpose

SYSTEMIC SCLERODERMA

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
standard of care
stem cell transplantation
Sponsored by
Northwestern University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for SYSTEMIC SCLERODERMA

Eligibility Criteria

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

Inclusion Criteria: Age 60 year or < 60 year old at the time of pretransplant evaluation. An established diagnosis of scleroderma. Diffuse cutaneous scleroderma with involvement proximal to the elbow or knee and a Rodnan score of > 14 AND Scleroderma with any one of the following: Diffusing capacity of the lung for carbon monoxide (DLCO) < 80% of predicted or decrease in lung function [DLCO, diffusing capacity divided by the alveolar volume (DLCO/VA) or forced vital capacity (FVC) ] of 10% or more over 12 months. Active alveolitis on bronchoalveolar lavage. Pulmonary fibrosis or alveolitis on computed tomography (CT) scan or chest x-ray (CXR) (ground glass appearance of alveolitis). Renal disease that is not explained by a bacterial infection or other renal disorders. (Subjects must have two or more of the following: proteinuria - greater than trace on dipstick, hematuria - urine blood on dipstick or sediment, hypertension that requires treatment with anti-hypertensive medications or untreated but with a diastolic blood pressure (BP) > 95 mm/hg.) Abnormal electrocardiogram (EKG) (non-specific ST-T wave abnormalities, low QRS voltage, or ventricular hypertrophy), or pericardial effusion or pericardial enhancement on magnetic resonance imaging (MRI) 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. Gastrointestinal (GI) involvement may also be confirmed by D-xylose malabsorption, patulous esophagus, or esophageal manometry. OR As published in NEJM, 2006, 345:25 2655-2709. Limited or diffuse SSL 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: Poor performance status Eastern Cooperative Oncology Group (ECOG 2) at the time of entry. Significant end organ damage such as: Left Ventricular Ejection Fraction (LVEF) < 40% or deterioration of LVEF during exercise test on Multiple Gated Acquisition (MUGA) or echocardiogram. Untreated life-threatening arrhythmia. Active ischemic heart disease or heart failure. End-stage lung disease characterized by total lung capacity (TLC) <45% of predicted value. Pulmonary hypertension (systolic pulmonary arterial pressure > 40 mmHg or mean pulmonary arterial pressure (PAP) > 25 mmHG measurement by pulmonary arterial catheter). Serum creatinine > 2.0 mg/dl. Liver cirrhosis, transaminases > 3x of normal limits or bilirubin > 2.0 unless due to Gilberts disease. Pericardial effusion> 200ml unless successful pericardiocentesis Tricuspid annular peak systolic excursion (TAPSE) ≤ 1.9 cm MRI of heart showing D sign (intraventricular flattering) Human immunodeficiency virus (HIV) positive. 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. Prior history of malignancy except localized basal cell or squamous skin cancer. Other malignancies for which the patient is judged to be cured by local surgical therapy, such as (but not limited to) head and neck cancer, or stage I or II breast cancer will be considered on an individual basis. 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. Psychiatric illness or mental deficiency making compliance with treatment or informed consent impossible. Inability to give informed consent. Major hematological abnormalities such as platelet count < 100,000/ul or absolute neutrophil count (ANC) < 1000/ul. Patients with duration of disease > 5 years. Exclude if > than 6 prior monthly IV cyclophosphamide treatments.

Sites / Locations

  • Northwestern University, Feinberg School of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

stem cell trasplantation

standard of care

Arm Description

intervention as stem cell transplantation after conditioning regimen

medication as standard of care will be given

Outcomes

Primary Outcome Measures

Time to Treatment Failure
-Data are reporting number of participants that were classified as treatment failures Time to Treatment Failure Definition-Treatment failure will not occur until a minimum of 12 months after enrollment at which time failure is defined as: 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 Deterioration in diffusing capacity of the lung for carbon monoxide (DLCO), diffusing capacity divided by the alveolar volume (DLCO/VA) or forced vital capacity (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 due to systemic sclerosis and defined as chronic dialysis for more than 12 months Gastrointestinal failure due to systemic sclerosis and defined as initiation of total parenteral nutrition(TPN) for more than 12 months
Disease Improvement
Data are reporting number of participants that were classified as disease improvement. Definition of disease improvement: Disease improvement defined by at least 25% improvement in skin score (Rodnan), or 10% improvement in pulmonary function tests [diffusing capacity of the lung for carbon monoxide (DLCO), diffusing capacity divided by the alveolar volume (DLCO/VA), or forced vital capacity (FVC)], or in cardiac tests [pulmonary artery (PA) systolic pressure by right heart cath] that persists > 6 months or ability to wean off total parenteral nutrition (TPN)

Secondary Outcome Measures

Full Information

First Posted
January 15, 2006
Last Updated
March 28, 2014
Sponsor
Northwestern University
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1. Study Identification

Unique Protocol Identification Number
NCT00278525
Brief Title
Cyclophosphamide and rATG With Hematopoietic Stem Cell Support in Systemic Scleroderma
Official Title
Trial of High Dose Cyclophosphamide and Rabbit Antithymocyte Globulin (rATG) With Hematopoietic Stem Cell Support in Patients With Systemic Scleroderma: A Randomized Trial
Study Type
Interventional

2. Study Status

Record Verification Date
March 2014
Overall Recruitment Status
Completed
Study Start Date
September 2005 (undefined)
Primary Completion Date
September 2011 (Actual)
Study Completion Date
December 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Northwestern University

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
Scleroderma is a systemic disorder categorized as an immunologically mediated disease that causes collagen deposition of skin and visceral organs. The molecular pathogenesis of scleroderma has been elusive, although vasculopathy and immune mediated mechanisms are thought to be important. Once extensive cutaneous or visceral disease occurs, prognosis is significantly shorter than the general population. Although various treatments have been tried, none of them seems to have changed the natural history of scleroderma. Standard dose immunosuppressive treatment has been disappointing. Recently, cyclophosphamide at 1-2 mg/kg/day orally or 800-1400 mg intravenous (IV) monthly for 6-9 months has proven effective in treatment of scleroderma alveolitis (1). Recent phase I studies of immunoablation with autologous peripheral blood stem cell transplantation (PBSCT) showed some promising data, but the exact efficacy is undetermined (2,3). We now propose, as a phase II randomized study, autologous unmanipulated PBSCT versus pulse cyclophosphamide in patients with systemic scleroderma.
Detailed Description
To evaluate the efficacy of two treatment modalities: pulse cyclophosphamide versus high dose cyclophosphamide and anti-thymocyte globulin (ATG) rescued with autologous peripheral blood stem cell transplantation (PBSCT). The primary endpoints to be considered in this study are: I)Time to Treatment Failure -Treatment failure will not occur until a minimum of 12 months after enrollment at which time failure is defined as: 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 Deterioration in diffusing capacity of the lung for carbon monoxide (DLCO), diffusing capacity divided by the alveolar volume (DLCO/VA) or forced vital capacity (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 due to systemic sclerosis and defined as chronic dialysis for more than 12 months Gastrointestinal failure due to systemic sclerosis and defined as initiation of total parenteral nutrition (TPN) for more than 12 months II) Disease improvement defined by at least 25% improvement in skin score (Rodnan), or 10% improvement in pulmonary function tests (DLCO, DLCO/VA, or FVC), or in cardiac tests [pulmonary artery (PA) systolic pressure by right heart cath) that persists > 6 months or ability to wean off TPN

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
SYSTEMIC SCLERODERMA

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
19 (Actual)

8. Arms, Groups, and Interventions

Arm Title
stem cell trasplantation
Arm Type
Experimental
Arm Description
intervention as stem cell transplantation after conditioning regimen
Arm Title
standard of care
Arm Type
Active Comparator
Arm Description
medication as standard of care will be given
Intervention Type
Drug
Intervention Name(s)
standard of care
Intervention Description
standard of care medication will be given
Intervention Type
Procedure
Intervention Name(s)
stem cell transplantation
Other Intervention Name(s)
stem cell transplant, stem cell injection
Intervention Description
The following is intervention: stem cell transplantation after conditioning regimen
Primary Outcome Measure Information:
Title
Time to Treatment Failure
Description
-Data are reporting number of participants that were classified as treatment failures Time to Treatment Failure Definition-Treatment failure will not occur until a minimum of 12 months after enrollment at which time failure is defined as: 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 Deterioration in diffusing capacity of the lung for carbon monoxide (DLCO), diffusing capacity divided by the alveolar volume (DLCO/VA) or forced vital capacity (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 due to systemic sclerosis and defined as chronic dialysis for more than 12 months Gastrointestinal failure due to systemic sclerosis and defined as initiation of total parenteral nutrition(TPN) for more than 12 months
Time Frame
12 months
Title
Disease Improvement
Description
Data are reporting number of participants that were classified as disease improvement. Definition of disease improvement: Disease improvement defined by at least 25% improvement in skin score (Rodnan), or 10% improvement in pulmonary function tests [diffusing capacity of the lung for carbon monoxide (DLCO), diffusing capacity divided by the alveolar volume (DLCO/VA), or forced vital capacity (FVC)], or in cardiac tests [pulmonary artery (PA) systolic pressure by right heart cath] that persists > 6 months or ability to wean off total parenteral nutrition (TPN)
Time Frame
12 months

10. Eligibility

Sex
All
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age 60 year or < 60 year old at the time of pretransplant evaluation. An established diagnosis of scleroderma. Diffuse cutaneous scleroderma with involvement proximal to the elbow or knee and a Rodnan score of > 14 AND Scleroderma with any one of the following: Diffusing capacity of the lung for carbon monoxide (DLCO) < 80% of predicted or decrease in lung function [DLCO, diffusing capacity divided by the alveolar volume (DLCO/VA) or forced vital capacity (FVC) ] of 10% or more over 12 months. Active alveolitis on bronchoalveolar lavage. Pulmonary fibrosis or alveolitis on computed tomography (CT) scan or chest x-ray (CXR) (ground glass appearance of alveolitis). Renal disease that is not explained by a bacterial infection or other renal disorders. (Subjects must have two or more of the following: proteinuria - greater than trace on dipstick, hematuria - urine blood on dipstick or sediment, hypertension that requires treatment with anti-hypertensive medications or untreated but with a diastolic blood pressure (BP) > 95 mm/hg.) Abnormal electrocardiogram (EKG) (non-specific ST-T wave abnormalities, low QRS voltage, or ventricular hypertrophy), or pericardial effusion or pericardial enhancement on magnetic resonance imaging (MRI) 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. Gastrointestinal (GI) involvement may also be confirmed by D-xylose malabsorption, patulous esophagus, or esophageal manometry. OR As published in NEJM, 2006, 345:25 2655-2709. Limited or diffuse SSL 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: Poor performance status Eastern Cooperative Oncology Group (ECOG 2) at the time of entry. Significant end organ damage such as: Left Ventricular Ejection Fraction (LVEF) < 40% or deterioration of LVEF during exercise test on Multiple Gated Acquisition (MUGA) or echocardiogram. Untreated life-threatening arrhythmia. Active ischemic heart disease or heart failure. End-stage lung disease characterized by total lung capacity (TLC) <45% of predicted value. Pulmonary hypertension (systolic pulmonary arterial pressure > 40 mmHg or mean pulmonary arterial pressure (PAP) > 25 mmHG measurement by pulmonary arterial catheter). Serum creatinine > 2.0 mg/dl. Liver cirrhosis, transaminases > 3x of normal limits or bilirubin > 2.0 unless due to Gilberts disease. Pericardial effusion> 200ml unless successful pericardiocentesis Tricuspid annular peak systolic excursion (TAPSE) ≤ 1.9 cm MRI of heart showing D sign (intraventricular flattering) Human immunodeficiency virus (HIV) positive. 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. Prior history of malignancy except localized basal cell or squamous skin cancer. Other malignancies for which the patient is judged to be cured by local surgical therapy, such as (but not limited to) head and neck cancer, or stage I or II breast cancer will be considered on an individual basis. 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. Psychiatric illness or mental deficiency making compliance with treatment or informed consent impossible. Inability to give informed consent. Major hematological abnormalities such as platelet count < 100,000/ul or absolute neutrophil count (ANC) < 1000/ul. Patients with duration of disease > 5 years. Exclude if > than 6 prior monthly IV cyclophosphamide treatments.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Richard Burt, MD
Organizational Affiliation
Northwestern University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Northwestern University, Feinberg School of Medicine
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
35904231
Citation
Bruera S, Sidanmat H, Molony DA, Mayes MD, Suarez-Almazor ME, Krause K, Lopez-Olivo MA. Stem cell transplantation for systemic sclerosis. Cochrane Database Syst Rev. 2022 Jul 29;7(7):CD011819. doi: 10.1002/14651858.CD011819.pub2.
Results Reference
derived
PubMed Identifier
21777972
Citation
Burt RK, Shah SJ, Dill K, Grant T, Gheorghiade M, Schroeder J, Craig R, Hirano I, Marshall K, Ruderman E, Jovanovic B, Milanetti F, Jain S, Boyce K, Morgan A, Carr J, Barr W. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Lancet. 2011 Aug 6;378(9790):498-506. doi: 10.1016/S0140-6736(11)60982-3. Epub 2011 Jul 21.
Results Reference
derived

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Cyclophosphamide and rATG With Hematopoietic Stem Cell Support in Systemic Scleroderma

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