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

Official 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).

Eligibility Requirements

• Minimum Age: 18 Years
• Maximum Age: 55 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: SINGLE
• Enrollment: 156 participants

Study Arms

• 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 r
• 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).

Interventions

• PROCEDURE: Autologous Hematopoietic Stem Cell Transplantation — 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
• BIOLOGICAL: Best Available Therapy (BAT) — Disease-modifying therapy (DMT) selected by the Site Investigator from the below: * cladribine * natalizumab * alemtuzumab * ocrelizumab, * rituximab, * ofatumumab, or * ublituximab

Primary Outcomes

• Multiple Sclerosis (MS) Relapse-Free Survival (From Day 0 (Randomization to Treatment) Up to 36 Months (3 Years))

Secondary Outcomes

• 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))

Eligibility Criteria

Inclusion 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):

   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:

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).

Exclusion Criteria:

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. Evid

Trial Locations

• Stanford Multiple Sclerosis Center, Palo Alto, California, United States
• Rocky Mountain Multiple Sclerosis Center, University of Colorado School of Medicine, Aurora, Colorado, United States
• Northwestern University, Evanston, Illinois, United States
• University of Massachusetts Memorial Medical Center, Worcester, Massachusetts, United States
• University of Minnesota Multiple Sclerosis Center, Minneapolis, Minnesota, United States
• Mayo Clinic, Rochester, Minnesota, United States
• John L. Trotter Multiple Sclerosis Center, Washington University School of Medicine in St. Louis, St Louis, Missouri, United States
• Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Siinai, New York, New York, United States
• Rochester Multiple Sclerosis Center, University of Rochester, Rochester, New York, United States
• Duke University Medical Center, Durham, North Carolina, United States
• ...and 10 more locations

Study Officials

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

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