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


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).


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) ≥ 2.0 and ≤ 5.5 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 treatment
failure in the 24 months prior to the screening visit (Visit -2). as described below:

1. Each episode of treatment failure must occur following ≥ 3 months of treatment
with an FDA-approved Disease-modifying Therapy (DMT) for relapsing forms of MS,
or with rituximab, and

2. At least one episode of treatment failure must occur with an oral agent or a
monoclonal antibody, specifically: dimethyl fumarate (Tecfidera®), teriflunomide
(Aubagio®), cladribine (Mavenclad®), daclizumab (Zinbryta®), siponimod
(Mayzent®), fingolimod (Gilenya®), rituximab (Rituxan®), ocrelizumab (Ocrevus®),
natalizumab (Tysabri®), or alemtuzumab (Campath®, Lemtrada®), and

3. At least one episode of treatment failure must have occurred within the 12 months
prior to the screening visit (Visit -2), and

4. At least one episode of treatment failure must be a clinical MS relapse (see item
d.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

– 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:
natalizumab, alemtuzumab, ocrelizumab, and/or rituximab.

–Note: Rituximab and ocrelizumab are considered equivalent for candidacy.Candidacy
for treatment for each DMT is defined as meeting all of the following:

– No prior treatment failure 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. Insurance or public funding approval for MS treatment with at least one candidate DMT,

7. 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

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

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. Evidence of HIV infection

14. Positive QuantiFERON – TB Gold or TB Gold Plus test results (e.g., blood test results
that detect infection with Mycobacterium tuberculosis) Note: A Purified Protein
Derivative (PPD) tuberculin test may be substituted for QuantiFERON – TB Gold or TB
Gold Plus test.

15. Active viral, bacterial, endoparasitic, or opportunistic infections

16. Active invasive fungal infection

17. 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

18. Receipt of live or live-attenuated vaccines within 6 weeks of randomization (Day 0)

19. 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

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.

20. Left ventricular ejection fraction (LVEF) < 50% 21. 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 22. Forced expiratory volume in one second (FEV1) <70% predicted (no bronchodilator) 23. Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for Hgb) < 70% predicted 24. Poorly controlled diabetes mellitus, defined as HbA1c >8%

25. 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 by therapy
completed at least 5 years prior to randomization (Day 0) will be considered on an
individual basis by the study adjudication committee.

26. 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.

27. Presence of active peptic ulcer disease, defined as endoscopic or radiologic diagnosis
of gastric or duodenal ulcer

28. Prior history of AHSCT

29. Prior history of solid organ transplantation

30. Positive pregnancy test or breast-feeding

31. Inability or unwillingness to use effective means of birth control

32. Failure to willingly accept or comprehend irreversible sterility as a side effect of

33. Psychiatric illness, mental deficiency, or cognitive dysfunction severe enough to
interfere with compliance or informed consent

34. History of hypersensitivity to mouse, rabbit, or Escherichia coli-derived proteins

35. Any metallic material or electronic device in the body, or condition that precludes
the participant from undergoing MRI with gadolinium administration

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:

– 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.

38. Presence of any medical comorbidity that the investigator determines will
significantly increase the risk of treatment mortality, or

39. Presence of any other concomitant medical condition that the investigator deems
incompatible with trial participation.


  • Stanford Multiple Sclerosis Center, Palo Alto, California, United States, 94304
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