Relapsing Remitting Multiple Sclerosis MedDRA version: 21.1 Level: PT Classification code 10063399 Term: Relapsing-remitting multiple sclerosis System Organ Class: 10029205 - Nervous system disorders MedDRA version: 20.1 Level: PT Classification code 10028245 Term: Multiple sclerosis System Organ Class: 10029205 - Nervous system disorders
Conditions
Interventions
Pharmaceutical Form: Solution for injection
INN or Proposed INN: FILGRASTIM
Current Sponsor code: Non disponibile
Concentration unit: U/ml unit(s)/millilitre
Concentration type: equal
Concentration nu
Sponsors
FONDAZIONE ITALIANA SCLEROSI MULTIPLA ONLUS
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Diagnosis of relapsing remitting MS according to the 2017 Mc Donald’s criteria(1). 2. 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. Disease activity is defined as: i. the occurrence of = 1 relapse AND ii. the occurrence of MRI evidence of disease activity, defined as one or more gadolinium-enhancing lesion(s) or one or more new non-enhancing T2 lesion(s) compared to a reference scan obtained not more than 18 months prior to the screening visit. 3. Age = 18 and = 55. 4. Expanded Disability Status Scale (EDSS) = 2.0 and = 6.0. 5. Candidacy for treatment with at least one of the following diseases modifying treatments (DMT): natalizumab, alemtuzumab, ocrelizumab and/or ofatumumab. Candidacy must include no prior treatment failure with the candidate DMT and no contraindication to the candidate DMT. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 90 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Diagnosis of primary and secondary progressive MS according to the 2017 McDonald criteria. 2. 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. 3. 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). 4. Treatment with ocrelizumab, ofatumumab, alemtuzumab and cladribine within the last 3 months. 5. 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. 6. Brain MRI or Cerebrospinal fluid (CSF) examination indicating or suggesting a diagnosis of progressive multifocal leukoencephalopathy (PML). 7. 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. 8. In case of unexplained cytopenia, polycythemia, thrombocythemia diagnosis of myelodysplastic syndrome must be ruled out before including patient in the protocol. 9. History of malignancy, with the exception of adequately treated localized basal cell or squamous skin cancer, or carcinoma in situ of the cervix. 10. Any active uncontrolled viral, bacterial, fungal, endoparasitic, or opportunistic infection. 11. Serological positivity to HCV or HIV 12. No adequate pharmacological prophylaxis in case of HBsAg or HBcAb positivity and allocation to AHSCT, alemtuzumab, ocrelizumab or ofatumumab. 13. Receipt of live or live-attenuated vaccines within 6 weeks of randomization. 14. Presence or history of Child-Pugh score B and C hepatic cirrhosis. 15. 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. 16. 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). 17. Left ventricular ejection fraction (LVEF) < 50% (if randomized to AHSCT). 18. eGFR < 60 mL/min/1.73m2. 19. Forced expiratory volume in one second (FEV1) <70% predicted (no bronchodilator) (if randomized to AHSCT). 20. Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for Hgb) < 70% predicted (if randomized to AHSCT) 21. Known untreated or unregulated thyroid disease. 22. Positive pregnancy test or breast-feeding. 23. Patients who are unwilling to practice adequate contraception during the duration of the study. For female participants of child-bearing potential, adequate contraception includes the use of active contraception for 12 months after AHSCT, 4 months after the last infusion of alemtuzumab and for the entire time of natalizumab, ocrelizumab and ofatumumab treatment. Male participants with female partners of child-bearing potential must be willing to use adequate contraception if they are randomized to the AHSCT arm
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Secondary Objective: Secondary outcomes at 36 months: ¿Incidence of serious adverse events and all-cause mortality ¿Annual relapse rate ¿Number of newT2/gadolinium enhancing T1lesions ¿Incidence of confirmed disability improvement and confirmed disability progression ¿Changes in brain volume ¿Changes in serum neurofilament light chain concentration ¿Changes in BICAMS scores ¿Changes in MSFC scores ¿Changes in the IgG/IgM index in the cerebrospinal fluid ¿Changes in the peripheral retinal nerve fiber layer and inner nuclear layer thickness ¿Changes in patient’s reported outcomes ¿Percentage of patients of child-bearing potential who maintains or resumes menstruation ¿Variation in anti-Mullerian hormone levels and antral follicular count ¿Variation in sperm count motility and morphology ¿Changes in advanced MRI metrics of tissue integrity inflammation and functional plasticity ¿Immunological changes associated with immune tolerance ¿Changes in the gut microbiota;Main Objective: The primary outcome is the occurrence of any evidence of multiple sclerosis disease activity (NEDA-3) over 36 months, analyzed as time-to-event;Primary end point(s): The primary outcome is the occurrence of any evidence of multiple sclerosis disease activity (NEDA-3) over 36 months, analyzed as time-to-event. NEDA-3 is the absence of any disease activity event, consisting of: - MRI evidence of disease activity (which includes one or more T1 gadolinium-enhanced lesion(s) on MRI, with the exclusion of the reference scan obtained at Month 3, and/or one or more new or unequivocally enlarged T2 hyperintense lesion(s) on MRI compared with the MRI reference scan obtained at Month 3) - A multiple sclerosis relapse - 6 months confirmed disability progression based on increases in Expanded Disability Status Scale (EDSS);Timepoint(s) of evaluation of this end point: From day 0 (treatment day) up to 36 months | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. The proportion of participants who experience a serious adverse event [Time frame: from day 0 up to 36 months] 2. The proportion of participants who experience a serious late adverse event [Time frame: from day 100 up to 36 months]. 3. The annual relapse rate at 12, 24 and 36 months 4. The incidence of 6 months confirmed disability improvement as measured by the EDSS over 36 months 5. The prevalence of disability improvement over 36 months 6. The proportion of patients who have confirmed disability improvement, confirmed stable EDSS or confirmed disability progression at 12, 24 and 36 months 7. The incidence of 6 months confirmed progression on hand/arm function as measured by the 9HPT over 36 months 8. The incidence of 6 months confirmed progression on ambulation as measured by the T25FW test over 36 months 9. Number of new brain lesions at 12, 24 and 36 months 10. Number of gadolinium-enhancing brain lesions at 12, 24 and 36 months 11. Changes in whole brain volume at 12, 24 and 36 months 12. The proportion of patients with no evidence of disease activity including atrophy (NEDA-4) at 12, 24 and 36 months 13. Changes in MRI T2-weighted hyperintense lesion volume over 36 months 14. Changes in MRI T1-weighted hypointense lesion volume over 36 months 15. Changes in BICAMS z-scores at 12, 24 and 36 months 16. Changes in MSFC z-scores at 12, 24 and 36 months 17. Changes in serum neurofilament light chain concentration at 12, 24 and 36 months 18. Changes in the IgG/IgM index in the cerebrospinal fluid at 36 months 19. Presence of oligoclonal bands in the cerebrospinal fluid at 36 months 20. Changes in the 2.5 low contrast visual acuity at 12, 24 and 36 months 21. Changes in the peripheral retinal nerve fiber layer thickness assessed by optical coherence tomography at 12, 24 and 36 months 22. Changes in the retinal inner nuclear layer thickness assessed by optical coherence tomography at 12, 24 and 36 months 23. Changes in the Multiple Scleros | — |
Countries
Italy
Contacts
Public ContactDINOGMI
Università di Genova
Outcome results
None listed