CYTARABINE for Relapsing-remitting multiple sclerosis

Stratification factors

• V2 EDSS score grouped as 2 ≤ EDSS ≤ 4 and 4.5 ≤ EDSS ≤ 6

Inclusion criteria

• {"criterion_text":"- Diagnosis of relapsing remitting MS according to the 2017 Mc Donald’s criteria."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Age ≥ 18 and ≤ 55."}
• {"criterion_text":"- Expanded Disability Status Scale (EDSS) ≥ 2.0 and ≤ 6.0."}
• {"criterion_text":"- 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 criteria

• {"criterion_text":"- Diagnosis of primary and secondary progressive MS according to the 2017 McDonald criteria"}
• {"criterion_text":"- Any active uncontrolled viral, bacterial, fungal, endoparasitic, or opportunistic infection."}
• {"criterion_text":"- Serological positivity to HCV or HIV"}
• {"criterion_text":"- Patients who are unwilling to practice pharmacological prophylaxis in case of HBsAg or HBcAb positivity"}
• {"criterion_text":"- Receipt of live or live-attenuated vaccines within 6 weeks of randomization."}
• {"criterion_text":"- Presence or history of Child-Pugh score B and C hepatic cirrhosis."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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)."}
• {"criterion_text":"- Left ventricular ejection fraction (LVEF) < 50%."}
• {"criterion_text":"- eGFR < 60 mL/min/1.73m2"}
• {"criterion_text":"- Forced expiratory volume in one second (FEV1) <70% predicted (no bronchodilator)."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for Hgb) < 70% predicted"}
• {"criterion_text":"- Known untreated or unregulated thyroid disease."}
• {"criterion_text":"- Positive pregnancy test or breast-feeding."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Prior history of solid organ transplantation."}
• {"criterion_text":"- Prior history of AHSCT."}
• {"criterion_text":"- Prior exposure to mitoxantrone."}
• {"criterion_text":"- Prior exposure to cyclophosphamide."}
• {"criterion_text":"- Inability to understand the contents of the Informed Consent form."}
• {"criterion_text":"- Failure to willingly accept or comprehend risk of irreversible sterility as a side effect of therapy."}
• {"criterion_text":"- 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)."}
• {"criterion_text":"- Any condition that precludes the participant from undergoing MRI with gadolinium administration."}
• {"criterion_text":"- Presence or history of genetically inherited progressive central nervous system disorder, or central nervous system tumors."}
• {"criterion_text":"- Treatment with ocrelizumab, ofatumumab, ublituximab, alemtuzumab and cladribine within the last 3 months."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Brain MRI or Cerebrospinal fluid (CSF) examination indicating or suggesting a diagnosis of progressive multifocal leukoencephalopathy (PML)."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- In case of unexplained cytopenia, polycythemia, thrombocythemia diagnosis of myelodysplastic syndrome must be ruled out before including patient in the protocol."}
• {"criterion_text":"- History of malignancy, with the exception of adequately treated localized basal cell or squamous skin cancer, or carcinoma in situ of the cervix."}

Primary endpoints

• {"endpoint_text":"- The primary outcome is the occurrence of any evidence of multiple sclerosis disease activity (NEDA-3) over 36 months, analyzed as time-to-event [Time frame: from randomization up to 36 months post randomization]","definition_or_measurement_approach":"Occurrence of any evidence of multiple sclerosis disease activity (NEDA-3) over 36 months; analyzed as a time-to-event outcome from randomization up to 36 months post randomization."}

Secondary endpoints

• {"endpoint_text":"- The proportion of participants who experience a serious adverse event [Time frame: from randomization up to 36 months post randomization]","definition_or_measurement_approach":"Proportion of participants with a serious adverse event assessed from randomization up to 36 months post randomization."}
• {"endpoint_text":"- The proportion of participants who experience a serious late adverse event [Time frame: from day 100 post AHSCT up to 36 months post randomization].","definition_or_measurement_approach":"Proportion experiencing serious late adverse events assessed from day 100 post-AHSCT up to 36 months post randomization."}
• {"endpoint_text":"- The annual relapse rate at 12, 24 and 36 months","definition_or_measurement_approach":"Annualized relapse rate measured at 12, 24 and 36 months."}
• {"endpoint_text":"- The incidence of 6 months confirmed disability improvement as measured by the EDSS over 36 months","definition_or_measurement_approach":"Incidence of confirmed disability improvement (6 months) measured by EDSS during 36 months."}
• {"endpoint_text":"- The prevalence of disability improvement over 36 months","definition_or_measurement_approach":"Prevalence of disability improvement assessed over 36 months."}
• {"endpoint_text":"- The proportion of patients who have confirmed disability improvement, confirmed stable EDSS or confirmed disability progression at 12, 24 and 36 months","definition_or_measurement_approach":"Proportion with confirmed disability improvement, stable EDSS or progression at 12, 24 and 36 months."}
• {"endpoint_text":"- The incidence of 6 months confirmed progression on hand/arm function as measured by the 9HPT over 36 months","definition_or_measurement_approach":"Incidence of 6-month confirmed progression on hand/arm function measured by 9HPT over 36 months."}
• {"endpoint_text":"- The incidence of 6 months confirmed progression on ambulation as measured by the T25FW test over 36 months","definition_or_measurement_approach":"Incidence of 6-month confirmed progression on ambulation measured by T25FW over 36 months."}
• {"endpoint_text":"- Number of new brain lesions at 12, 24 and 36 months","definition_or_measurement_approach":"Count of new brain lesions measured at 12, 24 and 36 months by MRI."}
• {"endpoint_text":"- Number of gadolinium-enhancing brain lesions at 12, 24 and 36 months","definition_or_measurement_approach":"Count of gadolinium-enhancing brain lesions on MRI at 12, 24 and 36 months."}
• {"endpoint_text":"- Changes in whole brain volume at 12, 24 and 36 months","definition_or_measurement_approach":"Change in whole brain volume measured by MRI at 12, 24 and 36 months."}
• {"endpoint_text":"- The proportion of patients with no evidence of disease activity including atrophy (NEDA-4) at 12, 24 and 36 months","definition_or_measurement_approach":"Proportion meeting NEDA-4 (including atrophy) at 12, 24 and 36 months."}
• {"endpoint_text":"- Changes in MRI T2-weighted hyperintense lesion volume over 36 months","definition_or_measurement_approach":"Change in T2-weighted hyperintense lesion volume on MRI over 36 months."}
• {"endpoint_text":"- Changes in MRI T1-weighted hypointense lesion volume over 36 months","definition_or_measurement_approach":"Change in T1-weighted hypointense lesion volume on MRI over 36 months."}
• {"endpoint_text":"- Changes in BICAMS z-scores at 12, 24 and 36 months","definition_or_measurement_approach":"Change in BICAMS z-scores measured at 12, 24 and 36 months."}
• {"endpoint_text":"- Changes in MSFC z-scores at 12, 24 and 36 months","definition_or_measurement_approach":"Change in MSFC z-scores at 12, 24 and 36 months."}
• {"endpoint_text":"- Changes in serum neurofilament light chain concentration at 12, 24 and 36 months","definition_or_measurement_approach":"Change in serum neurofilament light chain concentrations measured at 12, 24 and 36 months."}
• {"endpoint_text":"- Changes in the IgG/IgM index in the cerebrospinal fluid at 36 months","definition_or_measurement_approach":"Change in CSF IgG/IgM index measured at 36 months."}
• {"endpoint_text":"- Presence of oligoclonal bands in the cerebrospinal fluid at 36 months","definition_or_measurement_approach":"Presence/absence of oligoclonal bands in CSF at 36 months."}
• {"endpoint_text":"- Changes in the 2.5 low contrast visual acuity at 12, 24 and 36 months","definition_or_measurement_approach":"Change in 2.5 low contrast visual acuity at 12, 24 and 36 months."}
• {"endpoint_text":"- Changes in the peripheral retinal nerve fiber layer thickness assessed by optical coherence tomography at 12, 24 and 36 months","definition_or_measurement_approach":"Change in peripheral retinal nerve fiber layer thickness by OCT at 12, 24 and 36 months."}
• {"endpoint_text":"- Changes in the retinal inner nuclear layer thickness assessed by optical coherence tomography at 12, 24 and 36 months","definition_or_measurement_approach":"Change in retinal inner nuclear layer thickness by OCT at 12, 24 and 36 months."}
• {"endpoint_text":"- Changes in the Multiple Sclerosis Impact Scale at 12, 24 and 36 months","definition_or_measurement_approach":"Change in MS Impact Scale at 12, 24 and 36 months."}
• {"endpoint_text":"- Changes in Multiple Sclerosis Walking Scale over at 12, 24 and 36 months","definition_or_measurement_approach":"Change in MS Walking Scale at 12, 24 and 36 months."}
• {"endpoint_text":"- Changes in the Modified Fatigue Impact Scale at 12, 24 and 36 months","definition_or_measurement_approach":"Change in Modified Fatigue Impact Scale at 12, 24 and 36 months."}
• {"endpoint_text":"- Changes in the WHO-QOL-Bref and the EuroQoL EQ-5D at 12, 24 and 36 months","definition_or_measurement_approach":"Change in WHO-QOL-Bref and EQ-5D measures at 12, 24 and 36 months."}
• {"endpoint_text":"- All-cause mortality over 36 months","definition_or_measurement_approach":"All-cause mortality assessed over 36 months."}
• {"endpoint_text":"- Proportion of participants who develop secondary autoimmune diseases over 36 months","definition_or_measurement_approach":"Proportion developing secondary autoimmune diseases during 36 months."}
• {"endpoint_text":"- Time to neutrophil engraftment among AHSCT recipients","definition_or_measurement_approach":"Time (days) to neutrophil engraftment after AHSCT among recipients."}
• {"endpoint_text":"- Proportion of AHSCT recipients who experience primary or secondary graft failure","definition_or_measurement_approach":"Proportion of AHSCT recipients with primary or secondary graft failure."}
• {"endpoint_text":"- Percentage of female patients who experiences amenorrhoea during the study period","definition_or_measurement_approach":"Percentage of female participants experiencing amenorrhoea during study period."}
• {"endpoint_text":"- Percentage of female patients of child-bearing potential who maintains or resumes regular menstruation","definition_or_measurement_approach":"Percentage of female participants of child-bearing potential who maintain or resume regular menstruation."}
• {"endpoint_text":"- Time to resumption of spontaneous menses after AHSCT and/or interruption of hormonal contraception","definition_or_measurement_approach":"Time to resumption of spontaneous menses after AHSCT and/or after stopping hormonal contraception."}
• {"endpoint_text":"- Variation in ovarian reserve parameters (anti-mullerian hormone levels and antral follicular count) over 36 months","definition_or_measurement_approach":"Variation in AMH levels and antral follicular count measured over 36 months."}
• {"endpoint_text":"- Variation in sperm count, motility and morphology over 36 months","definition_or_measurement_approach":"Variation in sperm count, motility and morphology measured over 36 months."}
• {"endpoint_text":"- Percentage of pregnancy within 12 months of attempts among patients that will try to conceive after AHSCT [Time frame: from day 365 post AHSCT up to 36 months post randomization].","definition_or_measurement_approach":"Percentage of pregnancies within 12 months of attempts among patients attempting conception after AHSCT; measured from day 365 post-AHSCT up to 36 months post randomization."}
• {"endpoint_text":"- Number of new cervical spinal cord T2 lesions and of T1 gadolinium-enhancing lesions at 36 months.","definition_or_measurement_approach":"Number of new cervical spinal cord T2 lesions and T1 gadolinium-enhancing lesions measured at 36 months by MRI."}

Italy

Earliest CTIS Part Ii Submission Date

09-10-2024

Latest Decision Or Authorization Date

17-11-2025

Processing Time Days

404

Number Of Sites

8

Number Of Participants

90

Primary sponsor

Full Name

Fondazione Italiana Sclerosi Multipla Ente Del Terzo Settore/et S

Organisation Type

Patient organisation/association

Country Of Registered Address

Italy