Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for Multiple Sclerosis (BEAT-MS)

NCT04047628 | Recruiting Phase 3 DMC FDA Drug

• 4 other identifiers: DAIT ITN077AIUM1AI109565NIAID CRMS ID#: 38573BMT CTN 1905
• Study Type: interventional
• Target: 156
• Locations: 1 country
• Sites: 22

Brief Summary

This is a multi-center prospective rater-masked (blinded) randomized controlled trial of 156 participants, comparing the treatment strategy of Autologous Hematopoietic Stem Cell Transplantation (AHSCT) to the treatment strategy of Best Available Therapy (BAT) for treatment-resistant relapsing multiple sclerosis (MS). Participants will be randomized at a 1 to 1 (1:1) ratio. All participants will be followed for 72 months after randomization (Day 0, Visit 0).

Conditions

Relapsing Multiple Sclerosis; Relapsing Remitting Multiple Sclerosis; Secondary Progressive Multiple Sclerosis

Keywords

Treatment-Resistant Relapsing Multiple Sclerosis (MS); Autologous Hematopoietic Stem Cell Transplantation (AHSCT); Autologous Peripheral Blood Stem Cells (PBMCs) Graft; Best Available Therapy (BAT); Disease-Modifying Therapy (DMT); BAT DMT

Outcome Measures

Primary Outcomes (1)

• Multiple Sclerosis (MS) Relapse-Free Survival

  MS relapse-free survival, analyzed as time from treatment randomization until MS relapse or death from any cause.

  From Day 0 (Randomization to Treatment) Up to 36 Months (3 Years)

Secondary Outcomes (12)

• Number of Multiple Sclerosis (MS) Relapses Per Year

  From Day 0 (Randomization to Treatment) Up to 72 Months (6 Years)

• The Occurrence of Any Evidence of Multiple Sclerosis (MS) Disease Activity or Death From Any Cause

  From Day 0 (Randomization to Treatment) Up to 72 Months (6 Years)

• The Occurence of Confirmed Disability Worsening by the Kurtz Expanded Disability Status Scale (EDSS)

  From Day 0 (Randomization to Treatment) Up to 72 Months (6 Years)

• The Occurrence of Confirmed Disability Improvement by the Kurtz Expanded Disability Status Scale (EDSS)

  Day 0 (Randomization to Treatment) Up to Month 72 (6 Years)

• Whole Brain Volume Change from Pre-Randomization Visit to the follow-up evaluations

  From Visit Pre-R Up to 72 Months (6 Years)

Study Arms (2)

AHSCT

EXPERIMENTAL

AHSCT: Myeloablative and Immunoablative therapy followed by Autologous Hematopoietic Stem Cell Transplantation Participants will undergo: 1. Mobilization and graft collection: mobilization of peripheral blood stem cells (PBSC) with cyclophosphamide, filgrastim, and dexamethasone. The autologous graft will be collected by leukapheresis and cryopreserved. 2. Conditioning: high dose myeloablative and immunoablative conditioning with a six-day BEAM chemotherapy and rabbit anti-thymocyte globulin regimen will be initiated ≥30 days after cyclophosphamide mobilization. 3. Autologous cryopreserved graft infusion: the cryopreserved peripheral blood stem cells (PBSC) graft will be thawed and infused the day following completion of the conditioning regimen. Each bag will be thawed and infused according to institutional standards consistent with the Foundation for the Accreditation of Cellular Therapy (FACT) guidelines. Participants will receive prednisone following graft infusion.

Procedure: Autologous Hematopoietic Stem Cell Transplantation

Best Available Therapy (BAT)

ACTIVE COMPARATOR

Participants randomized to BAT: Best available therapy will be selected by the Site Investigator from: Cladribine (Mavenclad®), natalizumab (Tysabri®), alemtuzumab (Campath®, Lemtrada®), ocrelizumab (Ocrevus®), ublituximab (BRIUMVI™), rituximab (Rituxan®), or ofatumumab (Arzerra®) (after approval by the FDA for relapsing MS).

Biological: Best Available Therapy (BAT)

Interventions

Best Available Therapy (BAT) BIOLOGICAL

Disease-modifying therapy (DMT) selected by the Site Investigator from the below: * cladribine * natalizumab * alemtuzumab * ocrelizumab, * rituximab, * ofatumumab, or * ublituximab

Also known as: natalizumab (Tysabri®), alemtuzumab (Campath®, Lemtrada®), ocrelizumab (Ocrevus®), rituximab (Rituxan®), cladribine (Mavenclad®), ofatumumab (Kesimpta®), ublituximab (BRIUMVI™)

Best Available Therapy (BAT)

Autologous Hematopoietic Stem Cell Transplantation PROCEDURE

1. PBSC mobilization \& collection regimen per protocol/ institutional standards includes: intravenous cyclophosphamide (Cytoxan®), 4 grams/m\^2); intravenous mesna (Mesnex®),a total delivery of 4 grams/m\^2); oral dexamethasone, 10 mg dose, four times daily); subcutaneous filgrastim,10 mcg/kg/day until leukapheresis goal is completed; and CD34+ peripheral blood stem cells collection by leukapheresis. 2. Conditioning per protocol\& institutional standards: * 6-day BEAM (e.g. Carmustine (BCNU), Etoposide (VP-16), Cytarbine (Ara-C), and Melphalan) chemotherapy protocol and, * rabbit anti-thymocyte globulin (rATG) 2.5 mg/kg/day x2 3. Autologous cryopreserved graft infusion: The target Cluster of Differentiation (CD)34+ cell dose for infusion is 5 x 10\^6 CD34+ cells/kg (minimum 4 x 10\^6 CD34+ cells/kg; maximum 7.5 x 10\^6 CD34+ cells/kg). For 1\&2 above: Ideal body weight (IBW) versus Actual Body Weight (ABW) are applicable.

Also known as: AHSCT

AHSCT

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Age 18 to 55 years, inclusive, at the time of the screening Visit -2.
• Diagnosis of MS according to the 2017 McDonald Criteria139.
• EDSS ≤ 6.0 at the time of randomization (Day 0).
• T2 abnormalities on brain MRI that fulfill the 2017 McDonald MRI criteria for dissemination in space139. A detailed MRI report or MRI images must be available for review by the site neurology investigator.
• Highly active treatment-resistant relapsing MS, defined as ≥ 2 episodes of disease activity in the 36 months prior to the screening visit (Visit -2). The two disease activity episodes will be a clinical MS relapse or MRI evidence of MS disease activity and must meet all the criteria described below:
• At least one episode of disease activity must occur following ≥ 1 month of treatment with one of the following: (i) an oral DMT approved by the FDA for the treatment of relapsing MS, or (ii) a monoclonal antibody approved by the FDA for the treatment of relapsing MS, or (iii) rituximab. Qualifying DMTs include: dimethyl fumarate, diroximel fumarate, monomethyl fumarate, teriflunomide, cladribine, daclizumab, ponesimod, siponimod, ozanimod, fingolimod, rituximab, ocrelizumab, natalizumab, alemtuzumab, ublituximab, and ofatumumab, and
• At least one episode of disease activity must have occurred within the 12 months prior to the screening visit (Visit -2), and
• At least one episode of disease activity must be a clinical MS relapse (see item c.i. below). The other episode(s) must occur at least one month before or after the onset of the clinical MS relapse, and must be either another clinical MS relapse or MRI evidence of disease activity (see item c.ii. below):
• i. Clinical MS relapse must be confirmed by a neurologist's assessment and documented contemporaneously in the medical record. If the clinical MS relapse is not documented in the medical record, it must be approved by the study adjudication committee (see Section 3.5), and ii. MRI evidence of disease activity must include ≥ 1 unique active lesion on one or more brain or spinal cord MRIs. Detailed MRI reports or MRI images must be available for review by the site neurology investigator. A unique active lesion is defined as either of the following:
• \. A gadolinium-enhancing lesion, or 2. A new non-enhancing T2 lesion compared to a reference scan obtained not more than 36 months prior to the screening visit (Visit -2).
• \. Candidacy for treatment with at least one of the following high efficacy BAT DMTs: cladribine, natalizumab, alemtuzumab, ocrelizumab, ofatumumab, ublituximab and rituximab. Candidacy for treatment for each BAT DMT is defined as meeting all of the following:
• No contraindication to the candidate BAT DMT, and
• No treatment with the candidate BAT DMT in the 12 months prior to screening.
• \. Completion of COVID-19 vaccination series, according to the current Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) recommendations, ≥ 14 days prior to randomization (Day 0).
• \. Positive for VZV antibodies, or completion of at least one dose of the varicella zoster glycoprotein E (gE) Shingrix vaccine at least 4 weeks prior to randomization (Day 0).

You may not qualify if:

• Diagnosis of primary progressive MS according to the 2017 McDonald criteria.
• History of neuromyelitis optica spectrum disorder or MOG antibody disease.
• Prior treatment with an investigational agent within 3 months or 5 half-lives, whichever is longer. Agents authorized by the FDA for prevention or treatment of COVID-19 are not considered investigational.
• Either of the following within one month prior to randomization (Day 0):
• Onset of acute MS relapse, or
• Treatment with intravenous methylprednisolone 1000 mg/day for 3 days or equivalent.
• Initiation of any BAT DMT (see Section 5.2.1) between Visit -2 and randomization (Day 0).
• Brain MRI or cerebrospinal fluid (CSF) examination indicating a diagnosis of progressive multifocal leukoencephalopathy (PML).
• History of cytopenia consistent with the diagnosis of myelodysplastic syndrome (MDS).
• Presence of unexplained cytopenia, polycythemia, thrombocythemia or leukocytosis.
• History of sickle cell anemia or other hemoglobinopathy.
• Evidence of past or current hepatitis B or hepatitis C infection, including treated hepatitis B or hepatitis C. Hepatitis B surface antibody following hepatitis B immunization is not considered to be evidence of past infection.
• Presence or history of mild to severe cirrhosis.
• Hepatic disease with the presence of either of the following:
• Total bilirubin ≥ 1.5 times the upper limit of normal (ULN) or total bilirubin ≥ 3.0 times the ULN in the presence of Gilbert's syndrome, or

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Immune Tolerance Network (ITN): collaborator
• Blood and Marrow Transplant Clinical Trials Network: collaborator
• PPD Development, LP: collaborator
• Rho Federal Systems Division, Inc.: collaborator

Study Sites (22)

Stanford Multiple Sclerosis Center

Palo Alto, California, 94304, United States

RECRUITING

Rocky Mountain Multiple Sclerosis Center, University of Colorado School of Medicine

Aurora, Colorado, 80045, United States

RECRUITING

Northwestern University

Evanston, Illinois, 60208, United States

RECRUITING

University of Massachusetts Memorial Medical Center

Worcester, Massachusetts, 01655, United States

RECRUITING

University of Minnesota Multiple Sclerosis Center

Minneapolis, Minnesota, 55455, United States

ACTIVE NOT RECRUITING

Mayo Clinic

Rochester, Minnesota, 55905, United States

RECRUITING

John L. Trotter Multiple Sclerosis Center, Washington University School of Medicine in St. Louis

St Louis, Missouri, 63110, United States

RECRUITING

Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Siinai

New York, New York, 10029, United States

RECRUITING

Rochester Multiple Sclerosis Center, University of Rochester

Rochester, New York, 14620, United States

NOT YET RECRUITING

Duke University Medical Center

Durham, North Carolina, 27710, United States

ACTIVE NOT RECRUITING

University of Cincinnati (UC) Waddell Center for Multiple Sclerosis

Cincinnati, Ohio, 45219, United States

RECRUITING

Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic

Cleveland, Ohio, 44195, United States

RECRUITING

Multiple Sclerosis Center, Oregon Health & Science University

Portland, Oregon, 97239, United States

RECRUITING

Penn Comprehensive MS Center, Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

University of Texas Southwestern Medical Center: Division of Multiple Sclerosis and Neuroimmunology

Dallas, Texas, 75390, United States

RECRUITING

Maxine Mesigner Multiple Sclerosis Comprehensive Care Center, Baylor College of Medicine Medical Center

Houston, Texas, 77030, United States

RECRUITING

University of Virginia

Charlottesville, Virginia, 22903, United States

RECRUITING

Virginia Commonwealth University Multiple Sclerosis Treatment and Research Center

Richmond, Virginia, 23219, United States

RECRUITING

Clinical Research Division, Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109, United States

RECRUITING

Multiple Sclerosis Center, Swedish Neuroscience Institute

Seattle, Washington, 98122, United States

RECRUITING

Multiple Sclerosis Center at Northwest Hospital

Seattle, Washington, 98133, United States

RECRUITING

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

RECRUITING

Related Publications (3)

• 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 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 BACKGROUND

• Cohen JA, Baldassari LE, Atkins HL, Bowen JD, Bredeson C, Carpenter PA, Corboy JR, Freedman MS, Griffith LM, Lowsky R, Majhail NS, Muraro PA, Nash RA, Pasquini MC, Sarantopoulos S, Savani BN, Storek J, Sullivan KM, Georges GE. Autologous Hematopoietic Cell Transplantation for Treatment-Refractory Relapsing Multiple Sclerosis: Position Statement from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2019 May;25(5):845-854. doi: 10.1016/j.bbmt.2019.02.014. Epub 2019 Feb 19.

  PMID: 30794930 BACKGROUND

Related Links

• National Institute of Allergy and Infectious Diseases (NIAID)
• Division of Allergy, Immunology, and Transplantation (DAIT)
• Immune Tolerance Network (ITN)
• Visit this ITN Study website for more information

MeSH Terms

Conditions

Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis, Chronic Progressive

Interventions

Natalizumab; Alemtuzumab; ocrelizumab; Rituximab; Cladribine; ofatumumab; ublituximab

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; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Antibodies, Monoclonal, Murine-Derived; 2-Chloroadenosine; Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxyadenosines; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Jeffrey A. Cohen, MD

  Mellen Center for MS Treatment and Research, Cleveland Clinic

  STUDY CHAIR

• George E. Georges, MD

  Northwestern University

  STUDY CHAIR

• Paolo A. Muraro, MD, PhD

  Department of Medicine, Imperial College London

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 5, 2019
• First Posted: August 7, 2019
• Study Start: December 19, 2019
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2029
• Last Updated: January 6, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, ANALYTIC CODE
• Time Frame: After completion of the trial, within 24 months status post database lock.
• Access Criteria: Registration is available for the Immunology Database and Analysis Portal (ImmPort) at: https://www.immport.org/registration and submit a rationale for the purpose of requesting study data access. ImmPort is a long-term archive of clinical and mechanistic data, a National Institute of Allergy and Infectious Diseases Division of Allergy, Immunology and Transplantation (NIAID DAIT)-funded data repository. This archive is in support of the NIH mission to share data with the public. Data shared through ImmPort is provided by NIH-funded programs, other research organizations and individual scientists, ensuring these discoveries will be the foundation of future research.

Locations

US (22)