No Evidence Of Disease Activity After Autologous Haematopoietic Stem Cell Transplantation In Aggressive Multiple Sclerosis

Trial details

Who runs it

Fondazione Italiana Sclerosi Multipla Ente Del Terzo Settore/et S

Trial code

EU 2024-515470-26-00

Record updated

2025. november 17.

Original description

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

NO EVIDENCE OF DISEASE ACTIVITY AFTER AUTOLOGOUS HAEMATOPOIETIC STEM CELL TRANSPLANTATION IN AGGRESSIVE MULTIPLE SCLEROSIS: THE NET-MS STUDY

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

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: Receipt of live or live-attenuated vaccines within 6 weeks of randomization; 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; Prior history of solid organ transplantation; Prior history of AHSCT; Prior exposure to mitoxantrone; Prior exposure to cyclophosphamide; 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); Treatment with ocrelizumab, ofatumumab, ublituximab, alemtuzumab and cladribine within the last 3 months; Any active uncontrolled viral, bacterial, fungal, endoparasitic, or opportunistic infection; Serological positivity to HCV or HIV; Presence or history of Child-Pugh score B and C hepatic cirrhosis; 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); Known untreated or unregulated thyroid disease; Failure to willingly accept or comprehend risk of irreversible sterility as a side effect of therapy; 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; 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; 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; 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; Left ventricular ejection fraction (LVEF) < 50%; eGFR < 60 mL/min/1.73m2; 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; Diagnosis of primary and secondary progressive MS according to the 2017 McDonald criteria; Patients who are unwilling to practice pharmacological prophylaxis in case of HBsAg or HBcAb positivity; Forced expiratory volume in one second (FEV1) <70% predicted (no bronchodilator); Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for Hgb) < 70% predicted; 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; Inability to understand the contents of the Informed Consent form; Brain MRI or Cerebrospinal fluid (CSF) examination indicating or suggesting a diagnosis of progressive multifocal leukoencephalopathy (PML).

EU CTIS 2024-515470-26-00