Clinical trial NCT00114530: Scleroderma: Cyclophosphamide or Transplantation
Official title: A Randomized, Open-Label, Phase II Multicenter Study of High-Dose Immunosuppressive Therapy Using Total Body Irradiation, Cyclophosphamide, ATGAM, and Autologous Transplantation With Auto-CD34+HPC Versus Intravenous Pulse Cyclophosphamide for the Treatment of Severe Systemic Sclerosis (SCSSc-01)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Scleroderma, Systemic
Sclerosis
Autoimmune Disease
Keywords: systemic sclerosis
hematopoietic stem cell transplant
clinical trial
global rank composite score
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Rho Federal Systems Division, Inc.
First posted: 2005-06-16
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Global Rank Composite Score (GRCS) (Month 54, ITT)
timeFrame: 54 Months Post-Randomization
Secondary outcomes:
measure: Global Rank Composite Score (GRCS) (Month 54, PP)
timeFrame: 54 Months Post-Randomization
measure: Global Rank Composite Score (GRCS) (Month 48, ITT)
timeFrame: 48 Months Post-Randomization
measure: Global Rank Composite Score (GRCS) (Month 48, PP)
timeFrame: 48 Months Post-Randomization
measure: Event-Free Survival (EFS) (Month 54, ITT)
timeFrame: 54 Months Post-Randomization
measure: Event-Free Survival (EFS) (Month 54, PP)
timeFrame: 54 Months Post-Randomization
measure: Event-Free Survival (EFS) (Month 48, ITT)
timeFrame: 48 Months Post-Randomization
measure: Event-Free Survival (EFS) (Month 48, PP)
timeFrame: 48 Months Post-Randomization
measure: Treatment-Related Mortality (Month 54, ITT)
timeFrame: 54 Months Post-Randomization
measure: Treatment-Related Mortality (Month 54, PP)
timeFrame: 54 Months Post-Randomization
measure: Treatment-Related Mortality (Month 48, ITT)
timeFrame: 48 Months Post-Randomization
measure: Treatment-Related Mortality (Month 48, PP)
timeFrame: 48 Months Post-Randomization
measure: All-Cause Mortality (Month 54, ITT)
timeFrame: 54 Months Post-Randomization
measure: All-Cause Mortality (Month 54, PP)
timeFrame: 54 Months Post-Randomization
measure: All-Cause Mortality (Month 48, ITT)
timeFrame: 48 Months Post-Randomization
measure: All-Cause Mortality (Month 48, PP)
timeFrame: 48 Months Post-Randomization
measure: Change From Baseline to Month 54 in Health Assessment Questionnaire - Disability Index (HAQ-DI) (ITT)
timeFrame: 54 Months Post-Randomization
measure: Change From Baseline to Month 54 in Health Assessment Questionnaire - Disability Index (HAQ-DI) (PP)
timeFrame: 54 Months Post-Randomization
measure: Change From Baseline to Month 54 in Short Form 36 Health Survey (SF-36) (ITT)
timeFrame: 54 Months Post-Randomization
measure: Change From Baseline to Month 54 in Short Form 36 Health Survey (SF-36) (PP)
timeFrame: 54 Months Post-Randomization
measure: Change From Baseline to Month 54 in Diffusion in Liters of Carbon Monoxide (DLCO) (ITT)
timeFrame: 54 Months Post-Randomization
measure: Change From Baseline to Month 54 in Diffusion in Liters of Carbon Monoxide (DLCO) (PP)
timeFrame: 54 Months Post-Randomization
measure: Change From Baseline to Month 54 in Forced Vital Capacity (FVC) (ITT)
timeFrame: 54 Months Post-Randomization
measure: Change From Baseline to Month 54 in Forced Vital Capacity (FVC) (PP)
timeFrame: 54 Months Post-Randomization
measure: Change From Baseline to Month 54 in Modified Rodnan Skin Score (mRSS) (ITT)
timeFrame: 54 Months Post-Randomization
measure: Change From Baseline to Month 54 in Modified Rodnan Skin Score (mRSS) (PP)
timeFrame: 54 Months Post-Randomization
measure: New or Worsening Arrhythmias, Congestive Heart Failure, or Pericardial Effusion (ITT)
timeFrame: 54 Months Post-Randomization
measure: New or Worsening Arrhythmias, Congestive Heart Failure, or Pericardial Effusion (PP)
timeFrame: 54 Months Post-Randomization
measure: New or Worsening Pulmonary Hypertension (ITT)
timeFrame: 54 Months Post-Randomization
measure: New or Worsening Pulmonary Hypertension (PP)
timeFrame: 54 Months Post-Randomization
measure: Occurrence of Scleroderma Renal Crisis (ITT)
timeFrame: 54 Months Post-Randomization
measure: Occurrence of Scleroderma Renal Crisis (PP)
timeFrame: 54 Months Post-Randomization
measure: Documented Myositis (ITT)
timeFrame: 54 Months Post-Randomization
measure: Documented Myositis (PP)
timeFrame: 54 Months Post-Randomization
measure: Initiating Use of Disease-Modifying Antirheumatic Drugs (DMARDs) by Month 54 (ITT)
timeFrame: 54 Months Post-Randomization
measure: Initiating Use of Disease-Modifying Antirheumatic Drugs by Month 54 (DMARDs) (PP)
timeFrame: 54 Months Post-Randomization
measure: Regimen-Related Toxicities
timeFrame: Randomization through end of study follow-up (up to Month 72 post-randomization)
measure: Number of Subjects With Regimen-Related Toxicities
timeFrame: Randomization through end of study follow-up (up to Month 72 post-randomization).
measure: Infectious Complications
timeFrame: Randomization through end of study follow-up (up to Month 72 post-randomization).
measure: Number of Subjects With Infectious Complications
timeFrame: Randomization through end of study follow-up (up to Month 72 post-randomization).
measure: Time to Absolute Neutrophil Count Engraftment
timeFrame: 28 days post-transplant
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Los Angeles
country: United States
facility: UCLA Medical School
state: California
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston University School of Medicine
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Toledo
country: United States
facility: University of Toledo Health Science Campus
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Houston
country: United States
facility: University of Texas-Houston Medical School
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center (FHCRC)
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Saskatoon
country: Canada
facility: Dr. Markland Medical Professional Corporation
state: Saskatchewan
Study officials:
affiliation: Duke University
name: Keith M. Sullivan, MD
role: STUDY_CHAIR
affiliation: University of California, Los Angeles Rheumatology
name: Daniel E. Furst, MD
role: STUDY_CHAIR
affiliation: Presbyterian/St. Luke's Medical Center:Rocky Mountain Cancer Center
name: Peter A. McSweeney, MD
role: STUDY_CHAIR
affiliation: University of Kentucky, Women's Health Program: Rheumatology
name: Leslie J. Crofford, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Texas - Houston Health Science Center
name: Maureen D. Mayes, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Fred Hutchinson Cancer Research
name: Richard A. Nash, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
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.
citation: 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.