Signatures of Immune Reprogramming in Anti-CD52 Therapy of MS: Markers for Risk Stratification and Treatment Response

Study Overview
=================
Brief Summary
-----------------
Alemtuzumab is a highly effective therapy in relapse remitting multiple sclerosis (RRMS). The aim of this study is to elucidate the mechanism of action of the neuroprotective potential of alemtuzumab in RRMS. Therefore, the investigators will semi-annually analyse blood samples of RRMS patients treated with alemtuzumab up to 36 months. Using in vitro/ ex vivo assays the investigators aim to detect and characterize immune cells including their functional activity. Furthermore, the study aims to combine this analysis with clinical data (MRI, EDSS: Expanded Disability Status Scale, MSFC: Multiple Sclerosis Functional Composite) to reveal the underlining mechanism of action of alemtuzumab to further improve its efficacy and safety for present and future patients.

Official Title
-----------------
Signatures of Immune Reprogramming in Anti-CD52 Therapy of MS: Markers for Risk Stratification and Treatment Response

Conditions
-----------------
Multiple Sclerosis

Intervention / Treatment
-----------------
* Drug: Alemtuzumab Injection [Lemtrada]


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of MS according to the McDonald criteria 2010 and cranial MRI scan demonstrating white matter lesions attributable to MS within 5 years before prior to signing the informed consent form (ICF) Age > 18 years Written informed consent to study participation Exclusion Criteria: Medical, psychiatric, cognitive, or other conditions that, in the Investigator's opinion, compromise the patient's ability to understand the patient information, to give informed consent, or to complete the study Any progressive form of MS Any condition that serves as a contraindication for alemtuzumab treatment Any disability acquired from trauma or another illness that could interfere with the evaluation of disability due to MS Major systemic disease or other illness that would, in the opinion of the Investigator, compromise patient safety or interfere with the interpretation of study results, e.g., current peptic ulcer disease or other conditions that may predispose to hemorrhage Significant autoimmune disease including but not limited to immune cytopenias, rheumatoid arthritis, systemic lupus erythematosus, other connective tissue disorders, vasculitis, inflammatory bowel disease, severe psoriasis Inability to undergo MRI with gadolinium administration

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| De novo patients with alemtuzumab<br>De novo patients prior and after alemtuzumab treatment initiation | Drug: Alemtuzumab Injection [Lemtrada]<br>* Administration of 2 courses of alemtuzumab at an interval of 1 year. Course 1: Intravenous infusion of 12 mg alemtuzumab per day on 5 consecutive days. Course 2: Intravenous infusion of 12 mg alemtuzumab per day on 3 consecutive days.<br>|
| Alemtuzumab treatment<br>Patients under alemtuzumab treatment | Drug: Alemtuzumab Injection [Lemtrada]<br>* Administration of 2 courses of alemtuzumab at an interval of 1 year. Course 1: Intravenous infusion of 12 mg alemtuzumab per day on 5 consecutive days. Course 2: Intravenous infusion of 12 mg alemtuzumab per day on 3 consecutive days.<br>|
| Extended alemtuzumab treatment<br>Patients requiring more than two alemtuzumab infusions | Drug: Alemtuzumab Injection [Lemtrada]<br>* Administration of 2 courses of alemtuzumab at an interval of 1 year. Course 1: Intravenous infusion of 12 mg alemtuzumab per day on 5 consecutive days. Course 2: Intravenous infusion of 12 mg alemtuzumab per day on 3 consecutive days.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute and relative change of cell-counts compared to baseline of T cell subsets in the peripheral blood (every 6 months) | • T cell subsets: CD (cluster of differentiation) 4 and CD8 positive T cells: naïve T cells, T effector cells, T memory cells, regulatory T cells T-helper subsets: Th1, Th2, Th17 | 36 month | 
| Absolute and relative change of cell-counts compared to baseline of B-cell subsets in the peripheral blood (every 6 months) | • B cell subsets: Recent bone marrow emigrants, mature naïve, memory B cells Plasma cells | 36 month | 
| Absolute and relative change of cell-counts compared to baseline of natural killer cells in the peripheral blood (every 6 months) | • Natural killer cells: CD56bright, CD56dim Natural killer T cells | 36 month | 
| Absolute and relative change of cell-counts compared to baseline of antigen-presenting cells in the peripheral blood (every 6 months) | • Antigen-presenting cells: Dendritic cells: CD303+ plasmacytoid, CD11c+ and CD141+ myeloid dendritic cells Monocytes and macrophages | 36 month | 
| Absolute and relative change of cell-counts compared to baseline of myeloid-derived suppressor cells in the peripheral blood (every 6 months) | • Myeloid-derived suppressor cells | 36 month | 
| Change from baseline in levels of markers of autoimmunity (ANA, cANCA and pANCA) in the serum (every 6 months): | - IFT (immunoflescence-test) of ANA, cANCA and pANCA | 36 month | 
| Change from baseline in levels of markers of autoimmunity (anti-dsDNA) in the serum (every 6 months): | - RIA (radioimmunoassay) of anti-dsDNA | 36 month | 
| Change from baseline in levels of markers of autoimmunity (anti-TSH-Receptor) in the serum (every 6 months): | - Levels of anti-TSH-Receptor (U/ml) | 36 month | 
| Change from baseline in levels of markers of autoimmunity(anti-TPO) in the serum (every 6 months): | - Levels of anti-TPO (U/ml) | 36 month | 
| Change from baseline in levels of markers of autoimmunity (Rheumatoid factor) in the serum (every 6 months): | - Levels of Rheumatoid factor (U/ml) | 36 month | 
| Change from baseline in levels of markers of autoimmunity (anti-CCP) in the serum (every 6 months): | - Levels of anti-CCP (U/ml) | 36 month | 
| Change from baseline in levels of markers of autoimmunity (anti-GBM) in the serum (every 6 months): | - Levels of anti-GBM (U/ml) | 36 month | 
| Change from baseline in levels of markers of autoimmunity (antiplatelet antibodies) in the serum (every 6 months): | - Levels of antiplatelet antibodies (U/ml) | 36 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional characterization of T-cells and B cells in the peripheral blood (every 6 months) |  | 36 month |