NET-MS

Treatment tested

• Filgrastim

  Granulocyte colony stimulating factor receptor agonist

• Carmustine

  DNA inhibitor|Glutathione reductase inhibitor|RNA inhibitor

• Etoposide

  DNA topoisomerase II inhibitor

• Cytarabine

  DNA inhibitor|DNA polymerase (alpha/delta/epsilon) inhibitor|RNA inhibitor

• CICLOFOSFAMIDE MONOIDRATA
• IMMUNOGLOBULINA DI CONIGLIO ANTITIMOCITI UMANI
• MELFALAN CLORIDRATO
• Cyclophosphamide anhydrous
• Melphalan flufenamide
• RABBIT ANTI-HUMAN THYMOCYTE IMMUNOGLOBULIN
• ANTI-HUMAN T-LYMPHOCYTE IMMUNOGLOBULIN FROM RABBITS

Compared with

• Ocrelizumab

  B-lymphocyte antigen CD20 binding agent

• Ofatumumab

  B-lymphocyte antigen CD20 binding agent

• Natalizumab

  Integrin alpha-4/beta-1 inhibitor|Integrin alpha-4/beta-7 inhibitor

• Alemtuzumab

  CAMPATH-1 antigen inhibitor

• Ublituximab

  B-lymphocyte antigen CD20 binding agent

Other measures (36)

Inclusion: - Diagnosis of relapsing remitting MS according to the 2017 Mc Donald’s criteria. - Treatment-resistant MS, defined as the occurrence of disease activity following ≥ 6 months of treatment with an oral agent or a monoclonal antibody in the 12 months prior to the screening visit (≥ 1 relapse AND the occurrence of MRI evidence of disease activity, defined as ≥ 1 gadolinium-enhancing lesion or ≥ 1 new non-enhancing T2 lesion compared to a reference scan obtained not more than 18 months prior to the screening visit). OR aggressive-highly active MS, characterized by the presence of at least one disabling relapse in the 6 months prior to the screening visit AND the evidence at MRI of ≥ 1 gadolinium enhancing lesion or ≥ 1 new non-enhancing T2 lesion compared to a reference scan obtained not more than 6 months prior to the screening visit. For aggressive-highly active MS, the following additional inclusion criteria must be present: high brain lesion load or the presence of spinal cord lesions. - Age ≥ 18 and ≤ 55. - Expanded Disability Status Scale (EDSS) ≥ 2.0 and ≤ 6.0. - Candidacy for treatment with at least one of the following diseases modifying treatments (DMT): natalizumab, alemtuzumab, ocrelizumab and/or ublituximab. Candidacy must include no prior treatment failure with the candidate DMT and no contraindication to the candidate DMT. Exclusion: - Diagnosis of primary and secondary progressive MS according to the 2017 McDonald criteria - Any active uncontrolled viral, bacterial, fungal, endoparasitic, or opportunistic infection. - Serological positivity to HCV or HIV - Patients who are unwilling to practice pharmacological prophylaxis in case of HBsAg or HBcAb positivity - Receipt of live or live-attenuated vaccines within 6 weeks of randomization. - Presence or history of Child-Pugh score B and C hepatic cirrhosis. - Hepatic disease with the presence at two consecutive assessments 15 days apart of either of the following: 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 alanine aminotransferase or aspartate aminotransferase ≥ 3.0 times the ULN. - Presence or history of clinically significant cardiac disease (including coronary artery disease, moderate to severe valve stenosis or insufficiency, symptomatic mitral valve prolapse, presence of prosthetic mitral or aortic valve). - Left ventricular ejection fraction (LVEF) < 50%. - eGFR < 60 mL/min/1.73m2 - Forced expiratory volume in one second (FEV1) <70% predicted (no bronchodilator). - Treatment with natalizumab, fingolimod and dimethyl-fumarate within the last 4 weeks to allow for proper wash-out. For previously natalizumab-treated patients with a positive John Cunningham virus antibody index, a negative CSF JCV-PCR is required. - Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for Hgb) < 70% predicted - Known untreated or unregulated thyroid disease. - Positive pregnancy test or breast-feeding. - Patients who are unwilling to practice adequate contraception during the duration of the study. Female participants of child-bearing potential should use highly effective contraception for 12 months after AHSCT, 4 months after the last infusion of alemtuzumab and for the entire time of natalizumab, ocrelizumab, ofatumumab and ublituximab treatment. Female highly effective contraception methods include: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal); Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable implantable); Intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion; vasectomised partner; sexual abstinence. Male participants with female partners of child-bearing potential must be willing to use highly effective contraception if they are randomized to the AHSCT arm for 12 months after treatment. Male highly effective contraception methods include: vasectomy, sexual abstinence or the use of male condom with or without spermicide plus one highly effective contraception method for the female partner. - Prior history of solid organ transplantation. - Prior history of AHSCT. - Prior exposure to mitoxantrone. - Prior exposure to cyclophosphamide. - Inability to understand the contents of the Informed Consent form. - Failure to willingly accept or comprehend risk of irreversible sterility as a side effect of therapy. - Treatment with teriflunomide within the last 2 years unless cleared from the body (plasma concentration < 0.02 mcg/ml following elimination from the body with cholestyramine or activated powdered charcoal). - Any condition that precludes the participant from undergoing MRI with gadolinium administration. - Presence or history of genetically inherited progressive central nervous system disorder, or central nervous system tumors. - Treatment with ocrelizumab, ofatumumab, ublituximab, alemtuzumab and cladribine within the last 3 months. - Known hypersensitivity or other known serious side effects for any of the study medications, including co-medications such as high-dose steroids and rabbit anti-thymocyte globulin. - Brain MRI or Cerebrospinal fluid (CSF) examination indicating or suggesting a diagnosis of progressive multifocal leukoencephalopathy (PML). - If white blood cells < 1,5 x 109/L and/or lymphocytes CD4+ < 200/mm3 because of a reversible effect of documented ongoing medication, the WBC count must be ≥ 1,5 x 109/L and lymphocytes CD4+ ≥ 200/mm3 before start of study treatment. - In case of unexplained cytopenia, polycythemia, thrombocythemia diagnosis of myelodysplastic syndrome must be ruled out before including patient in the protocol. - History of malignancy, with the exception of adequately treated localized basal cell or squamous skin cancer, or carcinoma in situ of the cervix.

The primary outcome is the occurrence of any evidence of multiple sclerosis disease activity (NEDA-3) over 36 months, analyzed as time-to-event