RECRUITING

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

Conditions

Relapsing Multiple Sclerosis Relapsing Remitting Multiple Sclerosis Secondary Progressive Multiple Sclerosis 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

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

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).

Official Title

A Multicenter Randomized Controlled Trial of Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for Treatment-Resistant Relapsing Multiple Sclerosis (ITN077AI)

Quick Facts

Study Start:2019-12-19

Study Completion:2029-10

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT04047628

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:18 Years to 55 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:ADULT

Inclusion Criteria	Exclusion Criteria
1. Age 18 to 55 years, inclusive, at the time of the screening Visit -2. 2. Diagnosis of MS according to the 2017 McDonald Criteria139. 3. EDSS ≤ 6.0 at the time of randomization (Day 0). 4. 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. 5. 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: 1. 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 2. At least one episode of disease activity must have occurred within the 12 months prior to the screening visit (Visit -2), and 3. 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): 1. 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). 6. 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: 1. No prior disease activity episode, as defined in Inclusion Criterion #5, with the candidate BAT DMT, and 2. No contraindication to the candidate BAT DMT, and 3. No treatment with the candidate BAT DMT in the 12 months prior to screening. 7. 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). 8. 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). 9. Insurance approval for MS treatment with at least one candidate BAT DMT (see Inclusion Criterion #6). 10. Ability to comply with study procedures and provide informed consent, in the opinion of the investigator. 11. Females of childbearing potential (defined in Section 5.4.3.1) and males with female partners of childbearing potential are required to adhere to the contraception provisions of Section 5.4.3.1. 12. For participants who use medicinal or recreational marijuana, willingness to substitute MARINOL® if randomized to AHSCT (Section 5.4.2.6).	1. Diagnosis of primary progressive MS according to the 2017 McDonald criteria. 2. History of neuromyelitis optica spectrum disorder or MOG antibody disease. 3. 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. 4. Either of the following within one month prior to randomization (Day 0): 1. Onset of acute MS relapse, or 2. Treatment with intravenous methylprednisolone 1000 mg/day for 3 days or equivalent. 5. Initiation of any BAT DMT (see Section 5.2.1) between Visit -2 and randomization (Day 0). 6. Brain MRI or cerebrospinal fluid (CSF) examination indicating a diagnosis of progressive multifocal leukoencephalopathy (PML). 7. History of cytopenia consistent with the diagnosis of myelodysplastic syndrome (MDS). 8. Presence of unexplained cytopenia, polycythemia, thrombocythemia or leukocytosis. 9. History of sickle cell anemia or other hemoglobinopathy. 10. 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. 11. Presence or history of mild to severe cirrhosis. 12. Hepatic disease with the presence of either of the following: 1. 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 2. Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) ≥ 2.0 times the ULN. 13. Positive COVID-19 PCR test, or alternative nucleic acid amplification test (NAAT) per institutional standards, within 14 days prior to randomization (Day 0). 14. Evidence of HIV infection. 15. Positive QuantiFERON - TB Gold,TB Gold Plus, or T-SPOT®.TB test results. PPD tuberculin test may be substituted for QuantiFERON - TB Gold, TB Gold Plus, or T-SPOT®.TB test. 16. Active viral, bacterial, endoparasitic, or opportunistic infections. 17. Active invasive fungal infection. 18. Hospitalization for treatment of infections or parenteral (IV or IM) antibacterials, antivirals, antifungals, or antiparasitic agents within the 30 days prior to randomization (Day 0) unless clearance is obtained from an Infectious Disease specialist. 19. Receipt of live or live-attenuated vaccines within 6 weeks of randomization (Day 0). 20. Presence or history of clinically significant cardiac disease including: a. Arrhythmia requiring treatment with any antiarrhythmia therapy, with the exception of low dose beta blocker for intermittent premature ventricular contractions. 21. Left ventricular ejection fraction (LVEF) \< 50%. 22. Impaired renal function defined as eGFR \< 60 mL/min/1.73 m2, according to the CKD-EPI formula144. 23. Forced expiratory volume in one second (FEV1) \< 70% predicted (no bronchodilator). 24. Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for Hgb) \< 70% predicted. 25. Poorly controlled diabetes mellitus, defined as HbA1c \> 8%. 26. History of malignancy, except adequately treated localized basal cell or squamous skin cancer, or carcinoma in situ of the cervix. Malignancies for which the participant is judged to be cured will be considered on an individual basis by the study adjudication committee (see Section 3.5). 27. Presence or history of any moderate to severe rheumatologic autoimmune disease requiring treatment, including but not limited to the following: systemic lupus erythematous, systemic sclerosis, rheumatoid arthritis, Sjogren's syndrome, polymyositis, dermatomyositis, mixed connective tissue disease, polymyalgia rheumatica, polychondritis, sarcoidosis, vasculitis syndromes, or unspecified collagen vascular disease. 28. Presence of active peptic ulcer disease, defined as endoscopic or radiologic diagnosis of gastric or duodenal ulcer. 29. Prior history of AHSCT. 30. Prior history of solid organ transplantation. 31. Positive pregnancy test or breastfeeding. 32. Failure to willingly accept or comprehend irreversible sterility as a side effect of therapy. 33. Psychiatric illness, mental deficiency, or cognitive dysfunction severe enough to interfere with compliance or informed consent. 34. History of hypersensitivity to rabbit or Escherichia coli-derived proteins. 35. Any metallic material or electronic device in the body, or other condition that precludes the participant from undergoing MRI with gadolinium administration, as determined by the site radiologist. 36. Presence or history of ischemic cerebrovascular disorders, including but not limited to transient ischemic attack, subarachnoid hemorrhage, cerebral thrombosis, cerebral embolism, or cerebral hemorrhage. 37. Presence or history of other neurological disorders, including but not limited to CNS or spinal cord tumor; metabolic or infectious cause of myelopathy; genetically-inherited progressive CNS disorder; CNS sarcoidosis; or systemic autoimmune disorders potentially causing progressive neurologic disease or affecting ability to perform the study assessments. 38. Presence of any medical comorbidity that the investigator determines will significantly increase the risk of treatment mortality. 39. Presence of any other concomitant medical condition that the investigator deems incompatible with trial participation.

Inclusion Criteria

Exclusion Criteria

1. Age 18 to 55 years, inclusive, at the time of the screening Visit -2.
2. Diagnosis of MS according to the 2017 McDonald Criteria139.
3. EDSS ≤ 6.0 at the time of randomization (Day 0).
4. 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.
5. 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:
1. 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
2. At least one episode of disease activity must have occurred within the 12 months prior to the screening visit (Visit -2), and
3. 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):
1. 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).
6. 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:
1. No prior disease activity episode, as defined in Inclusion Criterion #5, with the candidate BAT DMT, and
2. No contraindication to the candidate BAT DMT, and
3. No treatment with the candidate BAT DMT in the 12 months prior to screening.
7. 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).
8. 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).
9. Insurance approval for MS treatment with at least one candidate BAT DMT (see Inclusion Criterion #6).
10. Ability to comply with study procedures and provide informed consent, in the opinion of the investigator.
11. Females of childbearing potential (defined in Section 5.4.3.1) and males with female partners of childbearing potential are required to adhere to the contraception provisions of Section 5.4.3.1.
12. For participants who use medicinal or recreational marijuana, willingness to substitute MARINOL® if randomized to AHSCT (Section 5.4.2.6).

1. Diagnosis of primary progressive MS according to the 2017 McDonald criteria.
2. History of neuromyelitis optica spectrum disorder or MOG antibody disease.
3. 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.
4. Either of the following within one month prior to randomization (Day 0):
1. Onset of acute MS relapse, or
2. Treatment with intravenous methylprednisolone 1000 mg/day for 3 days or equivalent.
5. Initiation of any BAT DMT (see Section 5.2.1) between Visit -2 and randomization (Day 0).
6. Brain MRI or cerebrospinal fluid (CSF) examination indicating a diagnosis of progressive multifocal leukoencephalopathy (PML).
7. History of cytopenia consistent with the diagnosis of myelodysplastic syndrome (MDS).
8. Presence of unexplained cytopenia, polycythemia, thrombocythemia or leukocytosis.
9. History of sickle cell anemia or other hemoglobinopathy.
10. 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.
11. Presence or history of mild to severe cirrhosis.
12. Hepatic disease with the presence of either of the following:
1. 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
2. Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) ≥ 2.0 times the ULN.
13. Positive COVID-19 PCR test, or alternative nucleic acid amplification test (NAAT) per institutional standards, within 14 days prior to randomization (Day 0).
14. Evidence of HIV infection.
15. Positive QuantiFERON - TB Gold,TB Gold Plus, or T-SPOT®.TB test results. PPD tuberculin test may be substituted for QuantiFERON - TB Gold, TB Gold Plus, or T-SPOT®.TB test.
16. Active viral, bacterial, endoparasitic, or opportunistic infections.
17. Active invasive fungal infection.
18. Hospitalization for treatment of infections or parenteral (IV or IM) antibacterials, antivirals, antifungals, or antiparasitic agents within the 30 days prior to randomization (Day 0) unless clearance is obtained from an Infectious Disease specialist.
19. Receipt of live or live-attenuated vaccines within 6 weeks of randomization (Day 0).
20. Presence or history of clinically significant cardiac disease including: a. Arrhythmia requiring treatment with any antiarrhythmia therapy, with the exception of low dose beta blocker for intermittent premature ventricular contractions.
21. Left ventricular ejection fraction (LVEF) \< 50%.
22. Impaired renal function defined as eGFR \< 60 mL/min/1.73 m2, according to the CKD-EPI formula144.
23. Forced expiratory volume in one second (FEV1) \< 70% predicted (no bronchodilator).
24. Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for Hgb) \< 70% predicted.
25. Poorly controlled diabetes mellitus, defined as HbA1c \> 8%.
26. History of malignancy, except adequately treated localized basal cell or squamous skin cancer, or carcinoma in situ of the cervix. Malignancies for which the participant is judged to be cured will be considered on an individual basis by the study adjudication committee (see Section 3.5).
27. Presence or history of any moderate to severe rheumatologic autoimmune disease requiring treatment, including but not limited to the following: systemic lupus erythematous, systemic sclerosis, rheumatoid arthritis, Sjogren's syndrome, polymyositis, dermatomyositis, mixed connective tissue disease, polymyalgia rheumatica, polychondritis, sarcoidosis, vasculitis syndromes, or unspecified collagen vascular disease.
28. Presence of active peptic ulcer disease, defined as endoscopic or radiologic diagnosis of gastric or duodenal ulcer.
29. Prior history of AHSCT.
30. Prior history of solid organ transplantation.
31. Positive pregnancy test or breastfeeding.
32. Failure to willingly accept or comprehend irreversible sterility as a side effect of therapy.
33. Psychiatric illness, mental deficiency, or cognitive dysfunction severe enough to interfere with compliance or informed consent.
34. History of hypersensitivity to rabbit or Escherichia coli-derived proteins.
35. Any metallic material or electronic device in the body, or other condition that precludes the participant from undergoing MRI with gadolinium administration, as determined by the site radiologist.
36. Presence or history of ischemic cerebrovascular disorders, including but not limited to transient ischemic attack, subarachnoid hemorrhage, cerebral thrombosis, cerebral embolism, or cerebral hemorrhage.
37. Presence or history of other neurological disorders, including but not limited to CNS or spinal cord tumor; metabolic or infectious cause of myelopathy; genetically-inherited progressive CNS disorder; CNS sarcoidosis; or systemic autoimmune disorders potentially causing progressive neurologic disease or affecting ability to perform the study assessments.
38. Presence of any medical comorbidity that the investigator determines will significantly increase the risk of treatment mortality.
39. Presence of any other concomitant medical condition that the investigator deems incompatible with trial participation.

Contacts and Locations

Principal Investigator

Jeffrey A. Cohen, MD

STUDY_CHAIR

Mellen Center for MS Treatment and Research, Cleveland Clinic

George E. Georges, MD

STUDY_CHAIR

Fred Hutchinson Cancer Center

Paolo A. Muraro, MD, PhD

STUDY_CHAIR

Department of Medicine, Imperial College London

Study Locations (Sites)

Stanford Multiple Sclerosis Center

Palo Alto, California, 94304

United States

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

Aurora, Colorado, 80045

United States

University of Massachusetts Memorial Medical Center

Worcester, Massachusetts, 01655

United States

University of Minnesota Multiple Sclerosis Center

Minneapolis, Minnesota, 55455

United States

Mayo Clinic

Rochester, Minnesota, 55905

United States

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

Saint Louis, Missouri, 63110

United States

Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Siinai

New York, New York, 10029

United States

Rochester Multiple Sclerosis Center, University of Rochester

Rochester, New York, 14620

United States

Duke University Medical Center

Durham, North Carolina, 27710

United States

University of Cincinnati (UC) Waddell Center for Multiple Sclerosis

Cincinnati, Ohio, 45219

United States

Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic

Cleveland, Ohio, 44195

United States

Multiple Sclerosis Center, Oregon Health & Science University

Portland, Oregon, 97239

United States

Penn Comprehensive MS Center, Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104

United States

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

Dallas, Texas, 75390

United States

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

Houston, Texas, 77030

United States

Virginia Commonwealth University Multiple Sclerosis Treatment and Research Center

Richmond, Virginia, 23219

United States

Clinical Research Division, Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109

United States

Multiple Sclerosis Center, Swedish Neuroscience Institute

Seattle, Washington, 98122

United States

Multiple Sclerosis Center at Northwest Hospital

Seattle, Washington, 98133

United States

Collaborators and Investigators

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Jeffrey A. Cohen, MD, STUDY_CHAIR, Mellen Center for MS Treatment and Research, Cleveland Clinic
George E. Georges, MD, STUDY_CHAIR, Fred Hutchinson Cancer Center
Paolo A. Muraro, MD, PhD, STUDY_CHAIR, Department of Medicine, Imperial College London

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2019-12-19

Study Completion Date2029-10

Study Record Updates

Study Start Date2019-12-19

Study Completion Date2029-10

Terms related to this study

Keywords Provided by Researchers

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

Additional Relevant MeSH Terms

Relapsing Multiple Sclerosis
Relapsing Remitting Multiple Sclerosis
Secondary Progressive Multiple Sclerosis