Alemtuzumab in Autoimmune Inflammatory Neurodegeneration: Mechanisms of Action and Neuroprotective Potential

Phase 4

Completed

• Conditions: Multiple Sclerosis, Relapsing-Remitting
• Interventions: Drug: Alemtuzumab

• Registration Number: NCT02419378
• Lead Sponsor: University Hospital Muenster

Brief Summary

Alemtuzumab is the active agent of a drug called Lemtrada®. In the European Union, Lemtrada® is approved for the treatment of a particular form of multiple sclerosis (the so called relapsing remitting form). The excellent efficacy of the drug justifies its administration albeit a high risk of considerable side effects. In this context, so called secondary (occurring after the administration of Lemtrada®) autoimmune diseases are of particular importance. In these diseases the immune system acts against structures of the body itself; the reasons are still unknown. Autoimmune diseases may even occur several years after treatment with Lemtrada®. Therefore, patients who once received the drug need to undergo intensive long term health monitoring.

This study aims to elucidate which mechanisms cause to the positive and negative effects of Lemtrada®.

The study includes patients only, who suffer from multiple sclerosis and are indicated to be treated with Lemtrada®. All patients receive the drug according to the official recommendations.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2015-03-31
• Study First Submitted QC: 2015-04-13
• Study First Posted: 2015-04-17
• Study Start: 2015-06
• Primary Completion: 2020-07
• Study Completion: 2020-11
• Status Verified: 2021-10
• Last Update Submitted: 2021-10-25
• Last Update Posted: 2021-10-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 15

Inclusion Criteria

1. Signed informed consent form (ICF)
2. Age 18 to 55 years old (inclusive) as of the date the ICF is signed
3. Diagnosis of MS according to the McDonald criteria 2010 and cranial MRI scan demonstrating white matter lesions attributable to MS within 10 years before Screening
4. Onset of MS symptoms (as determined by a neurologist, either at present or retrospectively) within 10 years of the date the ICF is signed
5. EDSS score 0.0 to 5.0 (inclusive) at Screening
6. Patients with (highly) active RRMS disease course indicated to receive alemtuzumab according to the following conditions (at least 1 out of 3 conditions has to be fulfilled): 1. ≥2 MS relapses within 24 months, 2. clinical (≥1 relapse) or MRI (new gadolinium enhancing lesions) disease activity under therapy with other diseasemodifying therapies, 3. severe relapse with high disease activity (≥9 T2 hyperintense Lesions and ≥1 gadolinium enhancing lesion) on MRI.
7. Completion of all vaccinations required by the applicable immunization guidelines published by "ständige Impfkommission" (STIKO)
8. History of chickenpox or positive test for antibodies against varicella zoster virus (VZV)

Exclusion Criteria

1. Participation in another clinical trial at present or within 4 weeks of study entry. There may be exceptions at the discretion of the Investigator.

2. Has any progressive form of MS

3. Hypersensitivity to the active substance, or to any of the excipients of Lemtrada®

4. 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, to comply with the trial protocol, or to complete the study

5. Any disability acquired from trauma or another illness that could interfere with evaluation of disability due to MS

6. 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

7. Known bleeding disorder (e.g,. dysfibrinogenemia, factor IX deficiency, hemophilia, Von Willebrand's disease, disseminated intravascular coagulation (DIC), fibrinogen deficiency, or clotting factor deficiency)

8. 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

9. History of malignancy, except basal skin cell carcinoma

10. Major psychiatric disorder that is not adequately controlled by treatment

11. Epileptic seizures that are not adequately controlled by Treatment

12. Active infection, e.g., deep-tissue infection, that the Investigator considers sufficiently serious to preclude study participation

13. In the Investigator's opinion, is at high risk for infection (e.g., indwelling catheter, dysphagia with aspiration, decubitus ulcer, history of prior aspiration pneumonia or recurrent urinary tract infection)

14. Seropositivity for human immunodeficiency virus (HIV)

15. Infection with hepatitis C Virus

16. Past or present hepatitis B infection (positive hepatitis B serology)

17. Active infection with human cytomegaly virus (HCMV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV)

18. Latent tuberculosis unless effective anti-tuberculosis therapy has been completed, or active tuberculosis.

19. Invasive fungal infections in history and at present

20. Cervical cytology other than PAP I or PAP II (Papanicolaou) or cervical high risk human papillomavirus (HPV) positivity

21. Any other illness or infection (latent or active) that, in the Investigator's opinion, could be exacerbated by study medication

22. Differential blood count < lower limit of normal (LLN) at Screening

23. Confirmed platelet count < the LLN of the evaluating laboratory at Screening or documented at <100,000/μL within the past year on a sample without platelet clumping

24. Presence (i.e., above the ULN) of anti-thyroid stimulating hormone receptor antibodies (anti-TSHR) and anti-thyroid peroxidase antibody (anti-TPO)

25. Any hepatic or renal function value grade 2 or higher at Screening, with the exception of hyperbilirubinemia due to Gilbert's syndrome. See Table below, drawn from the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events v4.0 (CTCAE), published 28 May 2009.

    Hepatic

    Bilirubin >1.5 × ULN

    SGOT/AST >3.0 × ULN

    SGPT/ALT >3.0 × ULN

    Alkaline phosphatase >2.5 × ULN

    Renal

    Creatinine > 1.5 × ULN

26. Vaccination less than 6 weeks prior to treatment with Lemtrada.

27. Treatment with antineoplastic or immunosuppressive drugs within 8 weeks prior to study inclusion

28. Intolerance of pulsed corticosteroids, especially a history of steroid psychosis

29. Inability to undergo MRI with gadolinium administration

30. Of childbearing potential with a positive serum pregnancy test, pregnant or lactating

31. Female patients of childbearing potential: Unwilling to agree to use a reliable and acceptable contraceptive method (Pearl index <1) throughout the study period. These methods include: hormone releasing intrauterine device (IUD), hormonal-based contraception, surgical sterilization, abstinence, or double-barrier contraception (condom and occlusive cap [diaphragm or cervical cap combined with spermicide]).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
alemtuzumab	Alemtuzumab	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.

Primary Outcome Measures

Name	Time	Method
Relative change from baseline in naïve CD8 positive T cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in naïve CD8 positive T cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in naïve CD4 positive T cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in CD8 positive T effector cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative change from baseline in CD4 positive T memory cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative change from baseline in CD8 positive T memory cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in CD8 positive regulatory T cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in Th1 T-helper cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative change from baseline in naïve CD4 positive T cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in CD4 positive T memory cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in CD4 positive regulatory T cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative change from baseline in CD4 positive regulatory T cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative change from baseline in CD8 positive regulatory T cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in CD4 positive T effector cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative change from baseline in CD4 positive T effector cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in CD8 positive T memory cell counts peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative change from baseline in Th1 T-helper cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in Th2 T-helper cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative change from baseline in Th2 T-helper cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in Th17 T-helper cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative change from baseline in Th17 T-helper cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in recent bone marrow emigrant B cell counts peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative change from baseline in recent bone marrow emigrant B cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in mature naïve B cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative change from baseline in mature naïve B cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in memory B cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative change from baseline in memory B cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in plasma cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative change from baseline in plasma cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in CD56bright natural killer cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative change from baseline in CD56bright natural killer cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in CD56dim natural killer cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative change from baseline in CD56dim natural killer cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in natural killer T cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative change from baseline in natural killer T cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in CD303+ plasmacytoid dendritic cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative change from baseline in CD303+ plasmacytoid dendritic cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in CD11c+ myeloid dendritic cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative change from baseline in CD11c+ myeloid dendritic cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in CD141+ myeloid dendritic cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative change from baseline in CD141+ myeloid dendritic cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in monocyte counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative change from baseline in monocyte counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in macrophage counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative change from baseline in macrophage counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Absolute change from baseline in myeloid-derived suppressor cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative change from baseline in myeloid-derived suppressor cell counts in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.

Secondary Outcome Measures

Name	Time	Method
Absolute change from baseline in naïve CD4 positive T cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative change from baseline in naïve CD4 positive T cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in naïve CD8 positive T cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative change from baseline in naïve CD8 positive T cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in CD4 positive T effector cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in CD4 positive T memory cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in CD8 positive regulatory T cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative change from baseline in CD4 positive T effector cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in CD8 positive T effector cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in Th1 T-helper cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative change from baseline in Th17 T-helper cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative change from baseline in CD8 positive T effector cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in CD8 positive T memory cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in CD4 positive regulatory T cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in Th2 T-helper cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in Th17 T-helper cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative change from baseline in CD4 positive T memory cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative change from baseline in CD8 positive regulatory T cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative change from baseline in CD8 positive T memory cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative change from baseline in CD4 positive regulatory T cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in recent bone marrow emigrant B cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative change from baseline in Th1 T-helper cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative change from baseline in Th2 T-helper cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in mature naïve B cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative change from baseline in mature naïve B cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in memory B cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative change from baseline in memory B cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in plasma cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative change from baseline in recent bone marrow emigrant B cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative change from baseline in plasma cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in CD56bright natural killer cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative change from baseline in CD141+ myeloid dendritic cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative change from baseline in CD56bright natural killer cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in CD56dim natural killer cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative change from baseline in CD56dim natural killer cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in natural killer T cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative change from baseline in natural killer T cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in CD303+ plasmacytoid dendritic cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative change from baseline in CD303+ plasmacytoid dendritic cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in CD11c+ myeloid dendritic cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative change from baseline in CD11c+ myeloid dendritic cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in CD141+ myeloid dendritic cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in monocyte counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in myeloid-derived suppressor cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Activation status of cell surface receptors on T cells from cerebrospinal fluid as assessed by flow cytometry	12, 24 and 36 months after initiation of investigational treatment on an optional basis	Relative and absolute change from baseline of mean fluorescence intensity (MFI) and of proportion of positive cells regarding CD25, HLA-DR, LFA-1, CD29, CD69, CD71 expression
Spectratyping of the T cell repertoire of T cells from cerebrospinal fluid concerning the expansion of distinct clones	12, 24 and 36 months after initiation of investigational treatment on an optional basis	* Relative and absolute change from baseline for complexity scores; * Qualitative comparison of the distribution of CDR3 sequences
Relative change from baseline in macrophage counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Effector functions of CD4 and CD8 positive T cells from cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis	* Relative and absolute change from baseline of the results of cell proliferation assays assessed as percentage of proliferated cells; * Relative and absolute change from baseline of cytokine production measurement assessed as concentration; * Relative and absolute change from baseline of cytolytic activity assessed by flow cytometry measurement of MFI and proportion of positive cells regarding Granzyme B, Perforin and CD107a expression; * Relative and absolute change from baseline of intracellular calcium response assessed as concentration
Migrational capacity of T cells from cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis	* Relative and absolute change from baseline MFI and proportion of positive cells assessed by flow cytometry expression analysis of CD11a, CD31, CD44, CD49d, CCR5, CCR6, CCR7; * Absolute and relative change of cell numbers of migrated cells compared to baseline assessed in an in vitro model by flow cytometry analysis
Spectratyping of the T cell repertoire of T cells from peripheral blood concerning the expansion of distinct clones	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.	* Relative and absolute change from baseline for complexity scores; * Qualitative comparison of the distribution of CDR3 sequences
Regulatory T-cell function in peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.	* Relative and absolute change from baseline in production of TGF-beta and IL-10 of CD4+CD25+FOXP3+ regulatory T cells; * Suppression of T cell proliferation: Relative and absolute change from baseline in responder T cell proliferation assessed by suppression assays
Relative change from baseline in monocyte counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative change from baseline in myeloid-derived suppressor cell counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Absolute change from baseline in macrophage counts in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Expression of co-inhibitory molecules by T cells from cerebrospinal fluid as assessed by flow cytometry	12, 24 and 36 months after initiation of investigational treatment on an optional basis	Relative and absolute change from baseline of MFI and of proportion of positive cells regarding PD-1 = CD279, ICOS = CD278, TIM-3, CTLA4 expression
Migrational capacity of T cells from peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.	* Relative and absolute change from baseline MFI and proportion of positive cells assessed by flow cytometry expression analysis of CD11a, CD31, CD44, CD49d, CCR5, CCR6, CCR7; * Absolute and relative change of cell numbers of migrated cells compared to baseline assessed in an in vitro model by flow cytometry analysis
Activation status of cell surface receptors on T cells fom peripheral blood as assessed by flow cytometry	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.	Relative and absolute change from baseline of mean fluorescence intensity (MFI) and of proportion of positive cells regarding CD25, HLA-DR, LFA-1, CD29, CD69, CD71 expression
Expression of co-inhibitory molecules by T cells from peripheral blood as assessed by flow cytometry	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.	Relative and absolute change from baseline of MFI and of proportion of positive cells regarding PD-1 = CD279, ICOS = CD278, TIM-3, CTLA4 expression
Effector functions of CD4 and CD8 positive T cells from peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.	* Relative and absolute change from baseline of the results of cell proliferation assays assessed as percentage of proliferated cells; * Relative and absolute change from baseline of cytokine production measurement assessed as concentration; * Relative and absolute change from baseline of cytolytic activity assessed by flow cytometry measurement of MFI and proportion of positive cells regarding Granzyme B, Perforin and CD107a expression; * Relative and absolute change from baseline of intracellular calcium response assessed as concentration
Regulatory T-cell function in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis	* Relative and absolute change from baseline in production of TGF-beta and IL-10 of CD4+CD25+FOXP3+ regulatory T cells; * Suppression of T cell proliferation: Relative and absolute change from baseline in responder T cell proliferation assessed by suppression assays
Relative and absolute change from baseline in the concentration of markers in the cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment on an optional basis	* S100β; * Tau; * phospho-Tau; * β-Amyloid; * Neurofilament (low weight); * Neurofilament (high weight); * N-acetylaspartate (NAA); * Tubulin; * Actin; * neuron-specific enolase (NSE); * glial fibrillary acidic protein (GFAP)
Relative and absolute change from baseline in neuronal activity, action potential generation and cellular integrity by obtained human CSF supernatant samples using multi-electrode arrays	12, 24 and 36 months after initiation of investigational treatment on an optional basis
Relative and absolute change from baseline in the concentration of neurotrophic factors in the peripheral blood	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.	* Nerve growth factor (NGF); * brain-derived neurotrophic factor (BDNF); * neurotrophin-3 (NT-3); * and neurotrophin-4 (NT-4); * ciliary neurotrophic factor (CNTF)
Relative and absolute change from baseline in the concentration of neurotrophic factors in cerebrospinal fluid	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.	* Nerve growth factor (NGF); * brain-derived neurotrophic factor (BDNF); * neurotrophin-3 (NT-3); * and neurotrophin-4 (NT-4); * ciliary neurotrophic factor (CNTF)
Percent change from Baseline in the following MRI findings which are defined as markers for neurodegeneration: MRI-T1-measured cerebral volume, MRI-T1-measured number of black holes	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Relative and absolute change from baseline in retinal nerve fiber layer thickness (assessment by optical coherence tomography)	12, 24 and 36 months after initiation of investigational treatment. In addition on an optional basis: 6, 18 and 30 months after treatment initiation.
Data on Adverse Events	Each day when the patient has a consultation with the investigator	Clinically significant deteriorations from baseline in vital signs, results of physical examination and laboratory assessments in blood or CSF will be documented as Adverse Events

Trial Locations

Locations (1)

Universitätsklinikum Münster, Klinik für Allgemeine Neurologie; 🇩🇪 Münster, Germany