Scleroderma: Cyclophosphamide or Transplantation

NCT00114530 | Completed Phase 2 Results DMC

• 2 other identifiers: DAIT SCSSc-01NIAID CRMS ID#: 20133
• Study Type: interventional
• Target: 75
• Locations: 2 countries
• Sites: 17

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.

Conditions

Scleroderma, Systemic; Sclerosis; Autoimmune Disease

Keywords

systemic sclerosis; hematopoietic stem cell transplant; clinical trial; global rank composite score

Outcome Measures

Primary Outcomes (1)

• Global Rank Composite Score (GRCS) (Month 54, ITT)

  The GRCS is an analytic tool that accounts for multiple disease manifestations simultaneously. It does not measure clinical disease activity or severity but reflects how participants compared to one another based on a hierarchy of ordered outcomes: death, event-free survival (EFS), forced vital capacity (FVC), Health Assessment Questionnaire - Disability Index (HAQ-DI), and Modified Rodnan Skin Score (mRSS). Participants alive ranked higher than those who died; those who survived event-free ranked higher than EFS failures. EFS failure included death, respiratory failure (decrease from baseline of \>30% in DLCO % predicted or \>20% in FVC % predicted ), renal failure (chronic dialysis \> 6 month or renal transplant), or cardiac failure (clinical congestive heart failure or left ventricular ejection fraction \<30%). The lowest 3 GRCS components are ordinal; improvement, stability, or worsening from baseline (±10% change in FVC % predicted, ±0.4 change in HAQ-DI, ±25% change in mRSS).

  54 Months Post-Randomization

Secondary Outcomes (40)

• Global Rank Composite Score (GRCS) (Month 54, PP)

  54 Months Post-Randomization

• Global Rank Composite Score (GRCS) (Month 48, ITT)

  48 Months Post-Randomization

• Global Rank Composite Score (GRCS) (Month 48, PP)

  48 Months Post-Randomization

• Event-Free Survival (EFS) (Month 54, ITT)

  54 Months Post-Randomization

• Event-Free Survival (EFS) (Month 54, PP)

  54 Months Post-Randomization

Study Arms (2)

mHSCT

EXPERIMENTAL

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.

Biological: mHSCT

cyclophosphamide

EXPERIMENTAL

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).

Drug: cyclophosphamide

Interventions

mHSCT 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).

Also known as: Myeloablative Hematopoietic Stem Cell Transplant

mHSCT

cyclophosphamide 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.

Also known as: cytoxan, CY

cyclophosphamide

Eligibility Criteria

• Age: 18 Years - 69 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Rho Federal Systems Division, Inc.: collaborator

Study Sites (17)

City of Hope National Medical Center

Duarte, California, 91010-3000, United States

Location

UCLA Medical School

Los Angeles, California, 90095-1670, United States

Location

University of Kentucky

Lexington, Kentucky, 40536-0284, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Boston University School of Medicine

Boston, Massachusetts, 02118, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Duke University Medical Center

Durham, North Carolina, 27709, United States

Location

University of Toledo Health Science Campus

Toledo, Ohio, 43606, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15261, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

University of Texas-Houston Medical School

Houston, Texas, 77030, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77230, United States

Location

Fred Hutchinson Cancer Research Center (FHCRC)

Seattle, Washington, 98109, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

University of Calgary

Calgary, Alberta, Canada

Location

Dr. Markland Medical Professional Corporation

Saskatoon, Saskatchewan, S7K OH6, Canada

Location

Related Publications (11)

• 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.

  PMID: 17452515 BACKGROUND

• 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.

  PMID: 27213276 BACKGROUND

• 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.

  PMID: 20800376 RESULT

• 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.

  PMID: 20708086 RESULT

• 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.

  PMID: 23418384 RESULT

• 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.

  PMID: 28602891 RESULT

• 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.

  PMID: 29298160 RESULT

• 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.

  PMID: 33131208 RESULT

• 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.

  PMID: 34533286 RESULT

• 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.

  PMID: 35904231 DERIVED

• 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.

  PMID: 35108379 DERIVED

Related Links

• National Institute of Allergy and Infectious Diseases (NIAID)
• Division of Allergy, Immunology, and Transplantation (DAIT)
• Scleroderma: Cyclophosphamide or Transplantation (SCOT) Study

MeSH Terms

Conditions

Scleroderma, Systemic; Sclerosis; Autoimmune Diseases

Interventions

Cyclophosphamide

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Skin Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Limitations and Caveats

Results are applicable for SSc with severe internal organ disease and may not be generalizable to all those with dcSSc. The hierarchical components of the GRCS are specific to this SSc population and may not be generalizable to other SSc populations.

Results Point of Contact

• Title: Director, Clinical Research Operations Program
• Organization: DAIT/NIAID

DAITClinicalTrialsGov@niaid.nih.gov

301-594-7669

Study Officials

• Keith M. Sullivan, MD

  Duke University

  STUDY CHAIR

• Daniel E. Furst, MD

  University of California, Los Angeles Rheumatology

  STUDY CHAIR

• Peter A. McSweeney, MD

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

  STUDY CHAIR

• Leslie J. Crofford, MD

  University of Kentucky, Women's Health Program: Rheumatology

  PRINCIPAL INVESTIGATOR

• Maureen D. Mayes, MD, MPH

  University of Texas - Houston Health Science Center

  PRINCIPAL INVESTIGATOR

• Richard A. Nash, MD

  Fred Hutchinson Cancer Research

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 15, 2005
• First Posted: June 16, 2005
• Study Start: June 1, 2005
• Primary Completion: April 1, 2016
• Study Completion: April 1, 2016
• Last Updated: April 12, 2023
• Results First Posted: July 14, 2017

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will share

Locations

CA (2); US (15)