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

This is an interventional treatment trial for Relapsing Multiple Sclerosis focused on measuring 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 Read More

Inclusion Criteria:

Participant(s) must meet all of the following criteria to be eligible for this study:

1. Diagnosis of Multiple Sclerosis (MS) according to the 2017 McDonald Criteria
2. (Kurtzke) Expanded Disability Status Scale (EDSS) ≤ 6.0 at the time of randomization (Day 0)

3. T2 abnormalities on brain Magnetic Resonance Imaging (MRI) that fulfill the 2017 McDonald MRI criteria for dissemination in space

   --A detailed MRI report or MRI images must be available for review by the site neurology investigator.

4. 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 as described below:

   1. At least one episode of disease activity must occur following ≥ 1 month of treatment with an oral DMT approved by the FDA or MHRA for the treatment of relapsing MS, or a monoclonal antibody, specifically: dimethyl fumarate (Tecfidera®), diroximel fumarate, teriflunomide (Aubagio®), cladribine (Mavenclad®), daclizumab (Zinbryta®), siponimod (Mayzent®), ozanimod, fingolimod (Gilenya®), rituximab (Rituxan®), ocrelizumab (Ocrevus®), natalizumab (Tysabri®), alemtuzumab (Campath®, Lemtrada®), or ofatumumab (Arzerra®), 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 d.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, and

   ii. MRI evidence of disease activity must include ≥ 2 unique active lesions on a brain or spinal cord MRI. A detailed MRI report 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
   • A new non-enhancing T2 lesion compared to a reference scan obtained not more than 24 months prior to the screening visit (Visit -2).

5. Candidacy for treatment with at least one of the following high efficacy DMTs:

   Cladribine, natalizumab, alemtuzumab, ocrelizumab, rituximab, and ofatumumab (after approval by the FDA for relapsing MS). Candidacy for treatment for each DMT is defined as meeting all of the following:

   • No prior disease activity with the candidate DMT, and
   • No contraindication to the candidate DMT, and
   • No treatment with the candidate DMT in the 12 months prior to screening.
6. Completion of SARS-CoV-2 vaccination series ≥ 14 days prior to randomization (Day 0).
7. 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).
8. Insurance or public funding approval for MS treatment with at least one candidate DMT, and
9. Ability to comply with study procedures and provide informed consent, in the opinion of the investigator.

Exclusion Criteria:

Subject(s) who meet any of the following criteria will not be eligible for this study:

1. Diagnosis of primary progressive Multiple Sclerosis (MS) according to the 2017 McDonald criteria
2. History of neuromyelitis optica or anti-myelin oligodendrocyte glycoprotein (anti-MOG) antibodies associated encephalomyelitis
3. Prior treatment with an investigational agent within 3 months or 5 half-lives, whichever is longer. Agents authorized by the FDA or MHRA for prevention or treatment of SARS-CoV-2 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 natalizumab, alemtuzumab, ocrelizumab, or rituximab between screening visit (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

    -Note: 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 SARS-CoV-2 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 (e.g., blood test results. Purified Protein Derivative (PPD) tuberculin test may be substituted for QuantiFERON - TB Gold, TB Gold Plus, or T-SPOT®.TB test results.
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:

    1. Arrhythmia requiring treatment with any antiarrhythmia therapy, with the exception of low dose beta blocker for intermittent premature ventricular contractions

    2. Coronary artery disease with a documented diagnosis of either:

       • Chronic exertional angina, or
       • Signs or symptoms of congestive heart failure.

    3. Evidence of heart valve disease, including any of the following:

       • Moderate to severe valve stenosis or insufficiency,
       • Symptomatic mitral valve prolapse, or
       • Presence of prosthetic mitral or aortic valve.
21. Left ventricular ejection fraction (LVEF) < 50%
22. Impaired renal function defined as Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m^2 according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula
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, with the exception of adequately treated localized basal cell or squamous skin cancer, or carcinoma in situ of the cervix.

    -Note:Malignancies for which the participant is judged to be cured prior to randomization (Day 0) will be considered on an individual basis by the study adjudication committee.

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
    • Sjögren'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 breast-feeding
32. Inability or unwillingness to use effective means of birth control
33. Failure to willingly accept or comprehend irreversible sterility as a side effect of therapy
34. Psychiatric illness, mental deficiency, or cognitive dysfunction severe enough to interfere with compliance or informed consent
35. History of hypersensitivity to mouse, rabbit, or Escherichia coli-derived proteins
36. Any metallic material or electronic device in the body, or condition that precludes the participant from undergoing MRI with gadolinium administration
37. Presence or history of ischemic cerebrovascular disorders, including but not limited to transient ischemic attack, subarachnoid hemorrhage, cerebral thrombosis, cerebral embolism, or cerebral hemorrhage

38. Presence or history of other neurological disorders, including but not limited to:

    • central nervous system (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.
39. Presence of any medical comorbidity that the investigator determines will significantly increase the risk of treatment mortality, or
40. Presence of any other concomitant medical condition that the investigator deems incompatible with trial participation.