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).
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.
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.
Onset of acute MS relapse, or
Parallel
Autologous Hematopoietic Stem Cell Transplantation
Procedure/Surgery1. 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.
Best Available Therapy (BAT)
Biological/VaccineDisease-modifying therapy (DMT) selected by the Site Investigator from the below: * cladribine * natalizumab * alemtuzumab * ocrelizumab, * rituximab, * ofatumumab, or * ublituximab
Multiple Sclerosis (MS) Relapse-Free Survival
MS relapse-free survival, analyzed as time from treatment randomization until MS relapse or death from any cause.
Number of Multiple Sclerosis (MS) Relapses Per Year
Annual Relapse Rate (ARR) time calculated as number of confirmed relapses divided by time in study per year.
The Occurrence of Any Evidence of Multiple Sclerosis (MS) Disease Activity or Death From Any Cause
The occurrence of any evidence of MS disease activity or death from any cause, analyzed as time-to-event.
The Occurence of Confirmed Disability Worsening by the Kurtz Expanded Disability Status Scale (EDSS)
Measured by the Kurtzke Expanded Disability Status Scale performed by the masked (blinded) rater. EDSS, defined by: * A decrease in EDSS of ≥ 1.0 step(s) compared to the EDSS at randomization (Day 0) and * Confirmation of disability improvement ≥ 6 months later. The time of confirmed disability worsening measured by EDSS will be the time of first increase in EDSS ≥ 1.0 step(s).
The Occurrence of Confirmed Disability Improvement by the Kurtz Expanded Disability Status Scale (EDSS)
Measured by the Kurtzke Expanded Disability Status Scale performed by the masked (blinded) rater. Confirmed disability improvement defined by: * A decrease in EDSS of ≥ 1.0 step(s) compared to the EDSS at randomization (Day 0) and * Confirmation of disability improvement ≥ 6 months later. The time of confirmed disability improvement measured by EDSS will be the time of first decrease in EDSS ≥ 1.0 step(s).
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National Institute of Allergy and Infectious Diseases (NIAID)
Lead sponsor
Immune Tolerance Network (ITN)
Collaborator
Blood and Marrow Transplant Clinical Trials Network
Collaborator
PPD Development, LP
Collaborator
Rho Federal Systems Division, Inc.
Collaborator
