Scleroderma: Cyclophosphamide or Transplantation

NCT ID: NCT00114530

Last Updated: 2023-04-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 75 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-06-30
• Study Completion Date: 2016-04-30

Brief Summary

SCOT is a clinical research study designed for people with severe forms of scleroderma. SCOT stands for Scleroderma: Cyclophosphamide Or Transplantation. The SCOT study will compare the potential benefits of stem cell transplant and high-dose monthly cyclophosphamide (Cytoxan) in the treatment of scleroderma.

Detailed Description

Severe systemic sclerosis (SSc) is a serious autoimmune disorder in which a person's own immune cells attack organs in the body. SSc affects the skin, joints, lungs, heart, intestinal tract, and kidneys, and half of the patients with the most severe organ involvement die within 5 years. Treatment for SSc usually includes supportive care or immunosuppressive drugs (drugs to suppress the immune system). As the immune cells are believed to be causing the disease, researchers are looking for new therapies that either slow down or stop this process, while not being too toxic.

The main purpose of this study is to determine the safety and effectiveness of high-dose immunosuppressive therapy followed by reinfusion (transplantation) of the participant's own autologous (self) peripheral blood stem cells (PBSCs) compared to treatment with monthly (for 12 months) intravenous doses of cyclophosphamide (Cytoxan) therapy for the treatment of severe systemic sclerosis (SSc). These treatments are being given in order to determine if they will slow down or stop SSc from becoming more severe, and if they can reverse the effects of the disease. The researchers are evaluating the effects of the two treatments on serious organ damage and survival related to SSc, while also looking at the side effects of the two treatments.

This trial also includes three optional mechanistic sub-studies open to a subset of participants enrolled in the SCOT trial:

1. Pharmacokinetics of 4-hydroxycyclophosphamide in Patients Receiving Cyclophosphamide for the SCOT trial (Originally listed separately as DAIT SCSSc-01-01, NCT00848614). The purpose of this study is to determine the plasma concentration and exposure time required for cyclophosphamide to produce optimal immunosuppressive activity with minimal toxicity in participants with severe systemic sclerosis.

2. Vascular Progenitor Cells and the Pathogenesis of Systemic Sclerosis(Originally listed separately as DAIT SCSSc-01-02, NCT00871221). The purpose of this study is to measure and characterize the circulating endothelial progenitor cells from the blood of 30 participants and also to determine the extent of vascular cell apoptosis and proliferation in cutaneous microvasculature in these participants before and after the receipt of the two SCOT treatment regimens.

3. Molecular Analysis of T Cell Immune Recovery for the SCOT Trial(Originally listed separately as DAIT SCSSc-01-03, NCT00872508). The purpose of this study is [1] to describe the condition of peripheral T cell reactivity and repertoire diversity in SSc patients and evaluate evidence for potential defects prior to randomization, [2] to gain a better understanding of the impact of cyclophosphamide (Cytoxan) and high-dose immunosuppressive therapy with autologous stem cell transplantation on thymopoiesis, and [3] to describe the kinetics and breadth of T cell immune recovery in SSc patients treated with these interventions.

Conditions

Scleroderma, Systemic; Sclerosis; Autoimmune Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

mHSCT

Myeloablative Hematopoietic Stem Cell Transplant (mHSCT) Participants will first have hematopoietic stem cells removed from their blood. They then will receive high doses of chemotherapy and radiation to eliminate their developed and presumably abnormal immune system, followed by autologous stem cell transplantation to reintroduce the purified stem cells to re-establish their immune system.

Group Type: EXPERIMENTAL

mHSCT

Intervention Type: BIOLOGICAL

Hematopoietic progenitors were mobilized with G-CSF. After leukapheresis and CD34+ cell enrichment, the autologous product was cryopreserved. Fractionated TBI (800 cGy), CY (120 mg/kg) and equine antithymocyte globulin (90 mg/kg) were administered as previously reported (References provided in citation section of this ClinicalTrials.gov record: PubMed ID: 17452515 citation and 2.) PubMed ID: 12176878 citation).

cyclophosphamide

Cyclophosphamide (CY) Participants will receive high doses of intravenous cyclophosphamide. The dose being used in this study is about 50% higher than that commonly used by most physicians to treat many other autoimmune diseases.

Administration of 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).

Group Type: EXPERIMENTAL

cyclophosphamide

Intervention Type: DRUG

An initial intravenous dose of 500 mg/m\^2 was followed by 11 infusions of 750 mg/m\^2 with mesna given for bladder protection.

Interventions

mHSCT

Hematopoietic progenitors were mobilized with G-CSF. After leukapheresis and CD34+ cell enrichment, the autologous product was cryopreserved. Fractionated TBI (800 cGy), CY (120 mg/kg) and equine antithymocyte globulin (90 mg/kg) were administered as previously reported (References provided in citation section of this ClinicalTrials.gov record: PubMed ID: 17452515 citation and 2.) PubMed ID: 12176878 citation).

Intervention Type: BIOLOGICAL

cyclophosphamide

An initial intravenous dose of 500 mg/m\^2 was followed by 11 infusions of 750 mg/m\^2 with mesna given for bladder protection.

Intervention Type: DRUG

Other Intervention Names

Myeloablative Hematopoietic Stem Cell Transplant; cytoxan; CY

Eligibility Criteria

Inclusion Criteria

• Severe systemic sclerosis (SSc) as defined by the American College of Rheumatology (ACR);
• SSc, including extensive skin and internal organ involvement involving either the lungs or the kidneys, that threatens participant's life; and
• Willingness to use accepted methods of contraception for at least 15 months after starting study treatment.

Exclusion Criteria

• Lung, heart, liver, or kidney impairment that would interfere with the study or compromise participant's survival;
• Active blood vessel dilation in the stomach (Active Gastric Antral Vascular Ectasia/GAVE, also known as "watermelon stomach"). Patients found to have this disorder at study screening can receive treatment outside the study and then be re-screened. For more information about this study criterion, refer to the study protocol.
• Previous treatment with cyclophosphamide, as defined by: a) prior IV cyclophosphamide administration for more than 6 months OR a total cumulative IV dose greater than 3 g/m^2; b) prior oral cyclophosphamide administration for more than 4 months, regardless of dose; or c) combination of prior oral and IV cyclophosphamide administration for more than 6 months, independent of dose.
• Steroid therapy at doses of greater than 10 mg/day, or more than 2 pulses for concurrent illnesses within prior 12 months;
• Unwillingness or inability to discontinue certain disease-modifying antirheumatic drugs (DMARDs) for the treatment of SSc;
• Presence of clinically significant rheumatic diseases other than scleroderma requiring significant immunosuppression;
• Any active uncontrolled infection that would interfere with high-dose therapy or pulse cyclophosphamide regimens:

• Hepatitis B virus infected
• Hepatitis C virus infected or
• HIV infected.
• Blood abnormalities;
• Diagnosis of cancer within 2 years prior to study entry. Participants with adequately treated squamous cell skin cancer, basal cell carcinoma, and carcinoma in situ are not excluded.
• Other comorbid illnesses with an estimated life expectancy of less than 5 years;
• Defective formation of bone marrow cells (myelodysplasia);
• Uncontrolled hypertension;
• History of hypersensitivity to murine or Escherichia coli (e.g., E. coli) proteins; History of noncompliance with prior medical care;
• History of substance abuse within 5 years prior to study entry; or
• Pregnancy.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 69 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Rho Federal Systems Division, Inc.

INDUSTRY

Sponsor Role: collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Keith M. Sullivan, MD

Role: STUDY_CHAIR

Duke University

Daniel E. Furst, MD

Role: STUDY_CHAIR

University of California, Los Angeles Rheumatology

Peter A. McSweeney, MD

Role: STUDY_CHAIR

Presbyterian/St. Luke's Medical Center:Rocky Mountain Cancer Center

Leslie J. Crofford, MD

Role: PRINCIPAL_INVESTIGATOR

University of Kentucky, Women's Health Program: Rheumatology

Maureen D. Mayes, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

University of Texas - Houston Health Science Center

Richard A. Nash, MD

Role: PRINCIPAL_INVESTIGATOR

Fred Hutchinson Cancer Research

Locations

City of Hope National Medical Center

Duarte, California, United States

UCLA Medical School

Los Angeles, California, United States

University of Kentucky

Lexington, Kentucky, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Boston University School of Medicine

Boston, Massachusetts, United States

University of Michigan

Ann Arbor, Michigan, United States

Washington University School of Medicine

St Louis, Missouri, United States

Duke University Medical Center

Durham, North Carolina, United States

University of Toledo Health Science Campus

Toledo, Ohio, United States

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

Medical University of South Carolina

Charleston, South Carolina, United States

University of Texas-Houston Medical School

Houston, Texas, United States

MD Anderson Cancer Center

Houston, Texas, United States

Fred Hutchinson Cancer Research Center (FHCRC)

Seattle, Washington, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

University of Calgary

Calgary, Alberta, Canada

Dr. Markland Medical Professional Corporation

Saskatoon, Saskatchewan, Canada

Countries

United States; Canada

References

Nash RA, McSweeney PA, Crofford LJ, Abidi M, Chen CS, Godwin JD, Gooley TA, Holmberg L, Henstorf G, LeMaistre CF, Mayes MD, McDonagh KT, McLaughlin B, Molitor JA, Nelson JL, Shulman H, Storb R, Viganego F, Wener MH, Seibold JR, Sullivan KM, Furst DE. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study. Blood. 2007 Aug 15;110(4):1388-96. doi: 10.1182/blood-2007-02-072389. Epub 2007 Apr 23.

Reference Type: BACKGROUND

PMID: 17452515 (View on PubMed)

Sullivan KM, Shah A, Sarantopoulos S, Furst DE. Review: Hematopoietic Stem Cell Transplantation for Scleroderma: Effective Immunomodulatory Therapy for Patients With Pulmonary Involvement. Arthritis Rheumatol. 2016 Oct;68(10):2361-71. doi: 10.1002/art.39748. No abstract available.

Reference Type: BACKGROUND

PMID: 27213276 (View on PubMed)

Craciunescu OI, Steffey BA, Kelsey CR, Larrier NA, Paarz-Largay CJ, Prosnitz RG, Chao N, Chute J, Gasparetto C, Horwitz M, Long G, Rizzieri D, Sullivan KM. Renal shielding and dosimetry for patients with severe systemic sclerosis receiving immunoablation with total body irradiation in the scleroderma: cyclophosphamide or transplantation trial. Int J Radiat Oncol Biol Phys. 2011 Mar 15;79(4):1248-55. doi: 10.1016/j.ijrobp.2010.05.036. Epub 2010 Aug 26.

Reference Type: RESULT

PMID: 20800376 (View on PubMed)

Hosing C, Nash R, McSweeney P, Mineishi S, Seibold J, Griffith LM, Shulman H, Goldmuntz E, Mayes M, Parikh CR, Crofford L, Keyes-Elstein L, Furst D, Steen V, Sullivan KM. Acute kidney injury in patients with systemic sclerosis participating in hematopoietic cell transplantation trials in the United States. Biol Blood Marrow Transplant. 2011 May;17(5):674-81. doi: 10.1016/j.bbmt.2010.08.003. Epub 2010 Aug 11.

Reference Type: RESULT

PMID: 20708086 (View on PubMed)

Hung EW, Mayes MD, Sharif R, Assassi S, Machicao VI, Hosing C, St Clair EW, Furst DE, Khanna D, Forman S, Mineishi S, Phillips K, Seibold JR, Bredeson C, Csuka ME, Nash RA, Wener MH, Simms R, Ballen K, Leclercq S, Storek J, Goldmuntz E, Welch B, Keyes-Elstein L, Castina S, Crofford LJ, Mcsweeney P, Sullivan KM. Gastric antral vascular ectasia and its clinical correlates in patients with early diffuse systemic sclerosis in the SCOT trial. J Rheumatol. 2013 Apr;40(4):455-60. doi: 10.3899/jrheum.121087. Epub 2013 Feb 15.

Reference Type: RESULT

PMID: 23418384 (View on PubMed)

Keever-Taylor CA, Heimfeld S, Steinmiller KC, Nash RA, Sullivan KM, Czarniecki CW, Granderson TC, Goldstein JS, Griffith LM. Manufacture of Autologous CD34+ Selected Grafts in the NIAID-Sponsored HALT-MS and SCOT Multicenter Clinical Trials for Autoimmune Diseases. Biol Blood Marrow Transplant. 2017 Sep;23(9):1463-1472. doi: 10.1016/j.bbmt.2017.05.018. Epub 2017 Jun 30.

Reference Type: RESULT

PMID: 28602891 (View on PubMed)

Sullivan KM, Goldmuntz EA, Keyes-Elstein L, McSweeney PA, Pinckney A, Welch B, Mayes MD, Nash RA, Crofford LJ, Eggleston B, Castina S, Griffith LM, Goldstein JS, Wallace D, Craciunescu O, Khanna D, Folz RJ, Goldin J, St Clair EW, Seibold JR, Phillips K, Mineishi S, Simms RW, Ballen K, Wener MH, Georges GE, Heimfeld S, Hosing C, Forman S, Kafaja S, Silver RM, Griffing L, Storek J, LeClercq S, Brasington R, Csuka ME, Bredeson C, Keever-Taylor C, Domsic RT, Kahaleh MB, Medsger T, Furst DE; SCOT Study Investigators. Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma. N Engl J Med. 2018 Jan 4;378(1):35-47. doi: 10.1056/nejmoa1703327.

Reference Type: RESULT

PMID: 29298160 (View on PubMed)

Bellocchi C, Ying J, Goldmuntz EA, Keyes-Elstein L, Varga J, Hinchcliff ME, Lyons MA, McSweeney P, Furst DE, Nash R, Crofford LJ, Welch B, Goldin JG, Pinckney A, Mayes MD, Sullivan KM, Assassi S. Large-Scale Characterization of Systemic Sclerosis Serum Protein Profile: Comparison to Peripheral Blood Cell Transcriptome and Correlations With Skin/Lung Fibrosis. Arthritis Rheumatol. 2021 Apr;73(4):660-670. doi: 10.1002/art.41570. Epub 2021 Feb 28.

Reference Type: RESULT

PMID: 33131208 (View on PubMed)

Keyes-Elstein L, Pinckney A, Goldmuntz E, Welch B, Franks JM, Martyanov V, Wood TA, Crofford L, Mayes M, McSweeney P, Nash R, Georges G, Csuka ME, Simms R, Furst D, Khanna D, Clair EWS, Whitfield ML, Sullivan KM. Clinical and Molecular Findings After Autologous Stem Cell Transplantation or Cyclophosphamide for Scleroderma: Handling Missing Longitudinal Data. Arthritis Care Res (Hoboken). 2023 Feb;75(2):307-316. doi: 10.1002/acr.24785. Epub 2022 Nov 16.

Reference Type: RESULT

PMID: 34533286 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35904231 (View on PubMed)

Shah A, Storek J, Woolson R, Pinckney A, Keyes-Elstein L, Wallace PK, Sempowski GD, McSweeney P, Mayes MD, Crofford L, Csuka ME, Phillips K, Khanna D, Simms R, Ballen K, LeClercq S, Clair WS, Nixon AB, Nash R, Wener M, Brasington R, Silver R, Griffith LM, Furst DE, Goldmuntz E, Sullivan KM. Lymphocyte subset abnormalities in early severe scleroderma favor a Th2 phenotype and are not altered by prior immunosuppressive therapy. Rheumatology (Oxford). 2022 Oct 6;61(10):4155-4162. doi: 10.1093/rheumatology/keac015.

Reference Type: DERIVED

PMID: 35108379 (View on PubMed)

Related Links

https://www.niaid.nih.gov/

National Institute of Allergy and Infectious Diseases (NIAID)

https://www.niaid.nih.gov/about/dait

Division of Allergy, Immunology, and Transplantation (DAIT)

http://www.sclerodermatrial.org/

Scleroderma: Cyclophosphamide or Transplantation (SCOT) Study

Other Identifiers

NIAID CRMS ID#: 20133

Identifier Type: OTHER

Identifier Source: secondary_id

DAIT SCSSc-01

Identifier Type: -

Identifier Source: org_study_id

NCT00472277

Identifier Type: -

Identifier Source: nct_alias

NCT00545038

Identifier Type: -

Identifier Source: nct_alias

NCT00848614

Identifier Type: -

Identifier Source: nct_alias

NCT00871221

Identifier Type: -

Identifier Source: nct_alias

NCT00872508

Identifier Type: -

Identifier Source: nct_alias