Safety and Efficacy of Cladribine Therapy After Anti CD20 Therapy

Study Overview
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Brief Summary
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Prolonged anti CD20 therapy for the treatment of active multiple sclerosis leading to continuous B cell depletion is associated with hypogammaglobulinemia predisposing to a potentially increased risk of serious infections, particularly in the more disabled and aged patients. No data have been published on the sequential use of anti CD20 therapies and cladribine, that is thought to act as an immune reconstitution agent. his study aims at investigating IgG and IgM serum concentration changes at 6 and 12 months after switching to cladribine in patients previously treated with anti CD20 therapies (ie, ocrelizumab ≥1.8 gr or rituximab 3.0 gr) for ≥18 months, as compared to continued anti CD20 therapies.

Detailed Description
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The study population will include patients with remitting relapsing multiple sclerosis consulting the Multiple Sclerosis Center of Neurocenter of Southern Switzerland. Enrolled patients will have 5 Study Visits, one every 3 months according to clinical practice. At visits at 3 and 6 months only adverse events will be collected for study purposes. Clinical assessments will be performed at baseline, Month 6 and Month 12. Clinical assessments correspond to medical exams performed routinely in MS patients treated with anti CD20 or cladribine therapy: clinical assessments, monitoring haemoglobin parameters, serum immunoglobulins, liver and renal function.(6, 12 months), radiological disability progression and biomarker of ongoing neurodegeneration (12 months).

Official Title
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Safety and Efficacy of a Therapy With Cladribine Following a Treatment With Anti CD20 Compounds in Relapsing Multiple Sclerosis Patients: a Pilot Study

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Cladribine Oral Tablet
* Drug: Rituximab
* Drug: Ocrelizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Relapsing MS according to Lublin; Treatment with ocrelizumab or rituximab for ≥18 months and having received 1.8 / 3.0 gr, respectively; CLAD_GROUP: Planning to switch to cladribine because of concerns about increased risks of infections related to hypogammaglobulinemia developing during long term anti CD20 therapies or a documented decrease of ≥10% IgG and/or IgM compared to pre- anti CD20 therapy; or CD20_GROUP: no need to stop CD20 therapy due decrease of ≥10% IgG and/or IgM, or increased risk of infections related to hypogammaglobulinemia or other reasons, continued anti CD20 therapies clinically indicated; EDSS ≤7.0; Age >18 years. Exclusion Criteria: Non relapsing MS; Pregnancy - breastfeeding; Contraindications to perform MRI; Contraindication to receive cladribine or to continue anti CD therapies

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| CLAD-GROUP<br>Patients with cladribine therapy | Drug: Cladribine Oral Tablet<br>* Treatment according to the label and medical prescription<br>* Other names: Mavenclade;|
| CD20-GROUP<br>Patients with anti CD20 therapy (ocrelizumab or rituximab) | Drug: Rituximab<br>* Treatment according to the label and medical prescription<br>* Other names: Mabthera, Rixathon;Drug: Ocrelizumab<br>* Treatment according to the label and medical prescription<br>* Other names: Ocrevus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in IgG serum concentrations in Cald-Group | Standard laboratory test | 6 months | 
| Changes in IgM serum concentrations in Cald-Group | Standard laboratory test | 6 months | 
| Changes in IgG serum concentrations in Clad-Group | Standard laboratory test | 12 months | 
| Changes in IgM serum concentrations in Clad-Group | Standard laboratory test | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in IgG serum concentrations after switching to cladribine, as compared to continued anti CD20 therapies | Standard laboratory test | 6 months | 
| Changes in IgM serum concentrations after switching to cladribine, as compared to continued anti CD20 therapies | Standard laboratory test | 6 months | 
| Changes in IgG serum concentrations after switching to cladribine, as compared to continued anti CD20 therapies | Standard laboratory test | 12 months | 
| Changes in IgM serum concentrations after switching to cladribine, as compared to continued anti CD20 therapies | Standard laboratory test | 12 months | 
| Proportion of patients reaching NEDA -3 | NEDA -3: no relapses, no disability progression, no new/enlarging or Gd enhancing brain or spinal MR lesions | 12 months | 
| Annualized relapse rate (ARR) over 12 months after switching to cladribine as compared to patients continuing anti CD20 therapies | ARR will be calculated based on recorded number of relapses | 12 months | 
| Proportion of patients with disability progression | Expanded disability scale 0-6 (6 worst outcome) | 6 months | 
| Proportion of patients with disability progression | Expanded disability scale 0-6 (6 worst outcome) | 12 months | 
| Number/volume of cumulative new T2/ enlarging lesions at brain and spinal MRI over 12 months after switching to cladribine, as compared to patients continuing anti CD20 therapies | Evaluation of MRI | 12 months | 
| Number/volume of cumulative Gd enhancing lesions at brain and spinal MRI over 12 months after switching to cladribine, as compared to patients continuing anti CD20 therapies | Evaluation of MRI | 12 months | 
| Changes in serum neurofilament light chain concentration | single-molecule array (Simoa) assay | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anti CD20 therapy, cladribine