High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT MS) Study
NCT ID: NCT00288626
Last Updated: 2017-09-19
Study Results
Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.
View full resultsBasic Information
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COMPLETED
PHASE2
25 participants
INTERVENTIONAL
2006-07-31
2015-11-30
Brief Summary
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Detailed Description
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In ITN033AI, high-dose chemotherapy with autologous CD34-selected hematopoietic cell transplantation will be given to confirm the results from the pilot study and to offer therapy to patients with early MS and a poor prognosis. Research studies will be performed in addition to clinical assessments to better understand the effect of the treatment on the activity of MS. High-dose chemotherapy will be used to deplete autoreactive immune cells. These regimens also deplete the bone marrow, the source of blood-forming CD34+ stem cells which causes very low blood counts. Therefore, the participant's autologous CD34+ hematopoietic stem cells will be collected before high dose immunosuppressive therapy is given and then returned as a transplant post-chemotherapy. Patients will be followed closely after the autologous transplantation since they will be at risk for infections after treatment.
At the beginning of the study, participants will undergo a number of screening and baseline procedures, including a physical exam, blood collection, MS-confirming neurology exams and questionnaires, and MRI procedures. Participants will be given prednisone and granulocyte-colony stimulating factor (G-CSF) to mobilize CD34+ hematopoietic stem cells from the bone marrow into the peripheral blood. When the peripheral blood CD34+ cell count reaches 20,000 cells/ml or greater, these cells will be collected by leukapheresis. In this process, a catheter is placed into a large blood vessel, peripheral blood is withdrawn, and a high speed sedimentation (leukapheresis) device is used to separate and retain the cells required for autologous transplantation. Other blood cells are then returned to the participant's body. In the laboratory, the CD34+ hematopoietic stem cell graft will be selected and prepared from the leukapheresis collection, and stored until needed for transplant. Seven or more days following the collection of their autologous graft, participants will be hospitalized and receive high-dose chemotherapy consisting of carmustine, etoposide, cytarabine, and melphalan (BEAM) and thymoglobulin. This is followed by transplantation of the autologous hematopoietic cell graft. Participants will remain in the hospital for observation during recovery of their peripheral blood cell counts, as described in the protocol. Participants will receive G-CSF and blood transfusions, if needed, and will be monitored for infections. Following discharge from the hospital, eight study visits will occur over sixty months (five years). During these visits, participants will undergo blood and urine collection, MRI studies, leukapheresis, and MS neurology exams and will complete questionnaires.
Conditions
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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MS Treatment
Autologous peripheral blood stem cell grafts were CD34+ selected; the participants then received high-dose treatment with carmustine, etoposide, cytarabine, and melphalan as well as rabbit antithymocyte globulin before autologous HCT.
Granulocyte-colony stimulating factor (G-CSF) and prednisone
Growth factor regimen; occurs at study entry
Carmustine, etoposide, cytarabine, and melphalan (BEAM)
High-dose chemotherapy; occurs seven or more days following collection of autologous graft
Autologous hematopoietic stem cell transplant
Occurs after growth factor regimen and collection of autologous graft
Interventions
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Granulocyte-colony stimulating factor (G-CSF) and prednisone
Growth factor regimen; occurs at study entry
Carmustine, etoposide, cytarabine, and melphalan (BEAM)
High-dose chemotherapy; occurs seven or more days following collection of autologous graft
Autologous hematopoietic stem cell transplant
Occurs after growth factor regimen and collection of autologous graft
Eligibility Criteria
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Inclusion Criteria
* Score between 3.0 and 5.5 on the Expanded Disability Status Scale (EDSS)
* T2 abnormalities on brain MRI consistent with MS
* Two or more relapses in 18 months time on interferon (IFN), glatiramer acetate (GA), natalizumab or cytotoxic therapy with EDSS increase of 1.0 or greater for participants with EDSS at screening of 3.0 to 3.5 (0.5 or greater for participants with EDSS at screening of 4.0 to 5.5) sustained at least 4 weeks after at least one of these relapses OR one relapse on IFN, GA, natalizumab or cytotoxic therapy with EDSS increase of 1.5 or greater (1.0 for subjects with EDSS at screening of 5.5) sustained at least 4 weeks, together with MRI changes consistent with poor prognosis. More information on this criterion can be found in the protocol.
* On IFN or GA for at least 6 months before the relapses occur that are counted to satisfy previous inclusion criterion OR have received adequate doses of natalizumab or cytotoxic therapy on a treatment schedule before the relapses occur that are counted to satisfy previous inclusion criterion
* Approval by an MS Review Panel to participate in the study. More information on this criterion can be found in the protocol
* In good clinical condition with adequate organ function and without coexisting medical problems that would increase the risk to the participant
* Willing to use acceptable methods of contraception
* Willing and able to comply with all study requirements and
* Willing to accept and comprehend irreversible sterility as side effect of therapy.
Exclusion Criteria
* Secondary progressive MS without relapses (i.e., progression without exacerbations or relapses) for 12 or more months
* Neuromyelitis optica, a disease similar to MS
* Initiation of new immunosuppressant treatment after the participant becomes eligible for the protocol or continuance of immunosuppressant drugs after the participant is screened for the protocol. Treatment with IFN, GA, or corticosteroids is permitted after the participant becomes eligible for the protocol.
* Lapse of greater than 6 months between the time a participant is eligible for the protocol and initiation of protocol treatment except when judged acceptable by the MS Review Panel
* Prior treatment with investigational immunosuppressive agents within 3 months of study eligibility
* Positive baseline plasma and CSF testing for JC virus or a brain MRI that has changes consistent with a diagnosis of progressive multifocal encephalopathy (PML)
* History of cytopenia consistent with the diagnosis of myelodysplastic syndrome (MDS)
* Active hepatitis B or C infection, cirrhosis, or HIV infection
* Uncontrolled diabetes mellitus
* Uncontrolled viral, fungal, or bacterial infection. Patients with asymptomatic bacteriuria are not excluded
* Any illness that would jeopardize the ability to tolerate aggressive chemotherapy
* Prior history of malignancy, except localized basal cell or squamous skin cancer. Other malignancies for which the subject is judged cured by the administered therapy will be considered on an individual basis.
* Hypersensitivity to mouse, rabbit, or Escherichia coli-derived proteins or to iron compounds/medications
* Metallic objects implanted in the body that would affect MRI exams
* Psychiatric illness, mental deficiency, or cognitive dysfunction or
* Pregnancy.
18 Years
60 Years
ALL
No
Sponsors
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Immune Tolerance Network (ITN)
NETWORK
National Institute of Allergy and Infectious Diseases (NIAID)
NIH
Responsible Party
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Principal Investigators
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Richard A. Nash, MD
Role: STUDY_CHAIR
Blood and Marrow Transplant Program, Colorado Blood Cancer Institute, Presbyterian/St. Luke's Medical Center, Denver
James D. Bowen, MD
Role: STUDY_CHAIR
Multiple Sclerosis Center, Swedish Neuroscience Institute, Seattle, Washington
George H. Kraft, MD
Role: STUDY_CHAIR
Departments of Neurology and Rehabilitation Medicine, University of Washington
George J. Hutton, MD
Role: STUDY_CHAIR
The Maxine Messinger Multiple Sclerosis Clinic, The Methodist Hospital, Baylor College of Medicine
Uday Popat, MD
Role: STUDY_CHAIR
Department of Blood and Marrow Transplantation, University of Texas, M.D. Anderson Cancer Center
Michael K. Racke, MD
Role: STUDY_CHAIR
Department of Neurology, Ohio State University Medical Center
Steven M. Devine, MD
Role: STUDY_CHAIR
Department of Hematology and Oncology, Ohio State University Medical Center
Annette Wundes, MD
Role: STUDY_CHAIR
Department of Neurology, University of Washington
George E. Georges, MD
Role: STUDY_CHAIR
Fred Hutchinson Cancer Research Center, Clinical Research Division, University of Washington
Locations
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Ohio State University School of Medicine
Columbus, Ohio, United States
Baylor College of Medicine
Houston, Texas, United States
M.D. Anderson Cancer Center; Transplant site, please contact Baylor College of Medicine
Houston, Texas, United States
Fred Hutchinson Cancer Research Center
Seattle, Washington, United States
Countries
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References
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Fassas A, Nash R. Stem cell transplantation for autoimmune disorders. Multiple sclerosis. Best Pract Res Clin Haematol. 2004 Jun;17(2):247-62. doi: 10.1016/j.beha.2004.04.005.
Muraro PA, Douek DC. Renewing the T cell repertoire to arrest autoimmune aggression. Trends Immunol. 2006 Feb;27(2):61-7. doi: 10.1016/j.it.2005.12.003. Epub 2006 Jan 6.
Muraro PA, Douek DC, Packer A, Chung K, Guenaga FJ, Cassiani-Ingoni R, Campbell C, Memon S, Nagle JW, Hakim FT, Gress RE, McFarland HF, Burt RK, Martin R. Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients. J Exp Med. 2005 Mar 7;201(5):805-16. doi: 10.1084/jem.20041679. Epub 2005 Feb 28.
Saccardi R, Mancardi GL, Solari A, Bosi A, Bruzzi P, Di Bartolomeo P, Donelli A, Filippi M, Guerrasio A, Gualandi F, La Nasa G, Murialdo A, Pagliai F, Papineschi F, Scappini B, Marmont AM. Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact on disease activity and quality of life. Blood. 2005 Mar 15;105(6):2601-7. doi: 10.1182/blood-2004-08-3205. Epub 2004 Nov 16.
Tyndall A, Saccardi R. Haematopoietic stem cell transplantation in the treatment of severe autoimmune disease: results from phase I/II studies, prospective randomized trials and future directions. Clin Exp Immunol. 2005 Jul;141(1):1-9. doi: 10.1111/j.1365-2249.2005.02806.x.
Mancardi G, Saccardi R. Autologous haematopoietic stem-cell transplantation in multiple sclerosis. Lancet Neurol. 2008 Jul;7(7):626-36. doi: 10.1016/S1474-4422(08)70138-8.
Nash RA, Hutton GJ, Racke MK, Popat U, Devine SM, Griffith LM, Muraro PA, Openshaw H, Sayre PH, Stuve O, Arnold DL, Spychala ME, McConville KC, Harris KM, Phippard D, Georges GE, Wundes A, Kraft GH, Bowen JD. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3-year interim report. JAMA Neurol. 2015 Feb;72(2):159-69. doi: 10.1001/jamaneurol.2014.3780.
Muraro PA, Robins H, Malhotra S, Howell M, Phippard D, Desmarais C, de Paula Alves Sousa A, Griffith LM, Lim N, Nash RA, Turka LA. T cell repertoire following autologous stem cell transplantation for multiple sclerosis. J Clin Invest. 2014 Mar;124(3):1168-72. doi: 10.1172/JCI71691. Epub 2014 Feb 17.
Nash RA, Hutton GJ, Racke MK, Popat U, Devine SM, Steinmiller KC, Griffith LM, Muraro PA, Openshaw H, Sayre PH, Stuve O, Arnold DL, Wener MH, Georges GE, Wundes A, Kraft GH, Bowen JD. High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS. Neurology. 2017 Feb 28;88(9):842-852. doi: 10.1212/WNL.0000000000003660. Epub 2017 Feb 1.
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.
Harris KM, Lu T, Lim N, Turka LA. Challenges and Opportunities for Biomarkers of Clinical Response to AHSCT in Autoimmunity. Front Immunol. 2018 Feb 2;9:100. doi: 10.3389/fimmu.2018.00100. eCollection 2018.
Related Links
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National Institute of Allergy and Infectious Diseases (NIAID) website
Immune Tolerance Network (ITN) website
Other Identifiers
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DAIT SCMS2
Identifier Type: -
Identifier Source: secondary_id
DAIT ITN033AI
Identifier Type: -
Identifier Source: org_study_id