High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT MS) Study

NCT00288626 | Completed Phase 2 Results DMC

• 2 other identifiers: DAIT ITN033AIDAIT SCMS2
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 4

Brief Summary

The purpose of this study is to determine the effectiveness of a new treatment for multiple sclerosis (MS), a serious disease in which the immune system attacks the brain and spinal cord. MS can be progressive and severe and lead to significant disability. The study treatment involves the use of high-dose chemotherapeutic drugs to suppress the immune system. The participant's own (autologous) blood-forming (hematopoietic, CD34+) stem cells are collected before the chemotherapy is given, and then transplanted back into the body following treatment. Transplantation of autologous hematopoietic stem cells is required to prevent very prolonged periods of low blood cell counts after the high-dose chemotherapy.

Conditions

Relapsing-Remitting Multiple Sclerosis

Keywords

hematopoietic stem cell transplantation; HCT- autologous hematopoietic cell transplant; HDIT-high-dose immunosuppressive therapy; BEAM -Carmustine (BCNU), Etoposide (VP-16), Cytarabine (ara-C), and Melphalan

Outcome Measures

Primary Outcomes (1)

• Event-Free Survival Probability During the 5 Years After Transplant

  Event-free survival (EFS) is survival without death or disease activity from any one of the following criteria: 1) loss of neurological function, defined as a change in pretransplant Extended Disability Status Scale (EDSS) of \> 0.5. 2) Relapse, defined as the development of a new neurological sign and corresponding symptom, or worsening of an existing neurological sign and symptom, localized to central nervous system white matter, resulting in neurological deficit/disability, and lasting over 48 hours. 3) New lesions on magnetic resonance imaging (MRI), defined as presence of 2 or more independent multiple sclerosis brain lesions detected on MRI 1 year or more after stem cell transplant. Kaplan-Meier estimates of survival probability, with 90% confidence interval based on Greenwood's formula for standard error.

  5 years

Secondary Outcomes (19)

• Event-Free Survival Probability During the 3 Years After Transplant

  3 years

• Survival From Treatment-Related Mortality

  From study entry to death, loss to follow-up, or the end of the study, whichever came first, up to 6 years

• Overall Survival

  From study entry to death, loss to follow-up, or the end of the study, whichever came first, up to 6 years

• Survival From MS-Related Mortality

  From study entry to death, loss to follow-up, or the end of the study, whichever came first, up to 6 years

• Percent of Participants Who Experienced All-Cause Morbidity

  From the time of enrollment until completion of the 5-year follow-up, an average of 6 years.

Study Arms (1)

MS Treatment

EXPERIMENTAL

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.

Drug: Granulocyte-colony stimulating factor (G-CSF) and prednisone; Drug: Carmustine, etoposide, cytarabine, and melphalan (BEAM); Procedure: Autologous hematopoietic stem cell transplant

Interventions

Granulocyte-colony stimulating factor (G-CSF) and prednisone DRUG

Growth factor regimen; occurs at study entry

MS Treatment

Carmustine, etoposide, cytarabine, and melphalan (BEAM) DRUG

High-dose chemotherapy; occurs seven or more days following collection of autologous graft

MS Treatment

Autologous hematopoietic stem cell transplant PROCEDURE

Occurs after growth factor regimen and collection of autologous graft

MS Treatment

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Diagnosis of relapsing-remitting or progressive-relapsing multiple sclerosis for less than 15 years using McDonald Criteria. More information on this criterion can be found in the protocol
• 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.
• 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.

You may not qualify if:

• Primary progressive MS
• 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

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Immune Tolerance Network (ITN): collaborator

Study Sites (4)

Ohio State University School of Medicine

Columbus, Ohio, 43210, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

M.D. Anderson Cancer Center; Transplant site, please contact Baylor College of Medicine

Houston, Texas, 77230-1402, United States

Location

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109-1024, United States

Location

Related Publications (11)

• 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.

  PMID: 15302338 BACKGROUND

• 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.

  PMID: 16406806 BACKGROUND

• 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.

  PMID: 15738052 BACKGROUND

• 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.

  PMID: 15546956 BACKGROUND

• 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.

  PMID: 15958063 BACKGROUND

• 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.

  PMID: 18565456 BACKGROUND

• 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.

  PMID: 25546364 RESULT

• 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.

  PMID: 24531550 RESULT

• 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.

  PMID: 28148635 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

• 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.

  PMID: 29456529 DERIVED

Related Links

• National Institute of Allergy and Infectious Diseases (NIAID) website
• Immune Tolerance Network (ITN) website

MeSH Terms

Conditions

Multiple Sclerosis, Relapsing-Remitting

Interventions

Granulocyte Colony-Stimulating Factor; Prednisone; Carmustine; Etoposide; Cytarabine; Melphalan

Condition Hierarchy (Ancestors)

Multiple Sclerosis; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Nitrosourea Compounds; Urea; Amides; Organic Chemicals; Nitroso Compounds; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Glucosides; Glycosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids

Limitations and Caveats

24 of the 25 planned transplants occurred. One of the enrolled participants developed adverse events that caused withdrawal from the study before the planned transplant.

Results Point of Contact

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

DAITClinicalTrialsGov@niaid.nih.gov

301-594-7669

Study Officials

• Richard A. Nash, MD

  Blood and Marrow Transplant Program, Colorado Blood Cancer Institute, Presbyterian/St. Luke's Medical Center, Denver

  STUDY CHAIR

• James D. Bowen, MD

  Multiple Sclerosis Center, Swedish Neuroscience Institute, Seattle, Washington

  STUDY CHAIR

• George H. Kraft, MD

  Departments of Neurology and Rehabilitation Medicine, University of Washington

  STUDY CHAIR

• George J. Hutton, MD

  The Maxine Messinger Multiple Sclerosis Clinic, The Methodist Hospital, Baylor College of Medicine

  STUDY CHAIR

• Uday Popat, MD

  Department of Blood and Marrow Transplantation, University of Texas, M.D. Anderson Cancer Center

  STUDY CHAIR

• Michael K. Racke, MD

  Department of Neurology, Ohio State University Medical Center

  STUDY CHAIR

• Steven M. Devine, MD

  Department of Hematology and Oncology, Ohio State University Medical Center

  STUDY CHAIR

• Annette Wundes, MD

  Department of Neurology, University of Washington

  STUDY CHAIR

• George E. Georges, MD

  Fred Hutchinson Cancer Research Center, Clinical Research Division, University of Washington

  STUDY CHAIR

Publication Agreements

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

Study Design

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

Study Record Dates

• First Submitted: February 7, 2006
• First Posted: February 8, 2006
• Study Start: July 1, 2006
• Primary Completion: November 1, 2015
• Study Completion: November 1, 2015
• Last Updated: September 19, 2017
• Results First Posted: April 4, 2017

Record last verified: 2017-08

Data Sharing

• IPD Sharing: Will share

Locations

US (4)