Investigation on how alemtuzumab acts in patients with relapsing remitting multiple sclerosis.

• Register: EUCTR
• Last refreshed on: 5 April 2021
• Main ID: EUCTR2014-000709-10-DE
• Date of registration: 13/10/2014
• Prospective Registration: Yes
• Primary sponsor: Universitätsklinikum Münster
• Public title: Investigation on how alemtuzumab acts in patients with relapsing remitting multiple sclerosis.
• Scientific title: Alemtuzumab in Autoimmune Inflammatory Neurodegeneration: Mechanisms of Action and Neuroprotective Potential - ALAIN01
• Date of first enrolment: 19/12/2014
• Target sample size: 15
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-000709-10
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: Open: Single blind: Double blind: Parallel group: Cross over: Other: If controlled, specify comparator, Other Medicinial Product: Placebo: Other:
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Germany

Contacts

• Name: Klinik für Allgemeine Neurologie
• Affiliation: Universitätsklinikum Münster

• Name: Klinik für Allgemeine Neurologie
• Affiliation: Universitätsklinikum Münster

Key inclusion & exclusion criteria

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 disease-modifying 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 varizella zoster virus (VZV)

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 15
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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 x ULN
26. Vaccinat

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

relapsing-remitting multiple sclerosis
MedDRA version: 20.0 Level: PT Classification code 10063399 Term: Relapsing-remitting multiple sclerosis System Organ Class: 10029205 - Nervous system disorders

Intervention(s)

Trade Name: LEMTRADA 12 mg Konzentrat zur Herstellung einer Infusionslösung
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Alemtuzumab
CAS Number: 216503-57-0
Other descriptive name: ALEMTUZUMAB
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Primary Outcome(s)

Primary end point(s): Absolute and relative change from baseline of the following cell-counts in the peripheral blood:
a. T cell subsets:
- CD4 and CD8 positive T cells: naïve T cells, T effector cells, T memory cells, regulatory T cells;
- T-helper subsets: Th1, Th2, Th17
b. B cell subsets:
- Recent bone marrow emigrants, mature naïve, memory B cells
- Plasma cells
c. Natural killer cells:
- CD56bright, CD56dim
- Natural killer T cells
d. Antigen-Presenting cells:
- Dendritic cells: CD303+ plasmacytoid, CD11c+ and CD141+ myeloid dendritic cells
- Monocytes and macrophages
e. Myeloid-derived suppressor cells.

Timepoint(s) of evaluation of this end point: 12, 24 and 36 months after initiaton of investigational treatment. In addition, on an optional basis: 6, 18 and 30 months after treatment initiation.

Main Objective: Combining clinical data with ex vivo and in vitro data, the study aims to shed more light on the mechanisms of action and the neuroprotective potential of alemtuzumab

Secondary Objective: Not appicable

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Effficacy endpoints:
12, 24 and 36 months after initiation of investigational treatment. In addition, on an optional basis: 6, 18 and 30 months after treatment initiation, evaluation of certain non-invasive investigations even every 3 months. Examinations of CSF every 12 months only using samples collected on an optional basis.

Safety endpoints:
At least monthly monitoring for autoimmune diseases, at least quarterly monitoring for autoimmune thyroid diseases, at least semiannual performance of any other safety assessments.

Secondary end point(s): 1. Absolute and relative change from baseline in cell-counts in the CSF. The same cell-types as indicated for the primary endpoints will be evaluated.

2. Functional characterization of T-cells in the peripheral blood and the CSF:
a. Activation status of cell surface receptors assessed by flow cytometry:
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
b. Expression of co-inhibitory molecules assessed by flow cytometry:
Relative and absolute change from baseline of MFI and of proportion of positive cells regarding PD-1 = CD279, ICOS = CD278, TIM-3, CTLA4 expression
c. Effector functions of CD4 and CD8 positive T cells:
- 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
d. Migrational capacity:
- 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
e. Spectratyping of the T cell repertoire concerning the expansion of distinct clones:
- Relative and absolute change from baseline for complexity scores
- Qualitative comparison of the distribution of CDR3 sequences
f. Regulatory T-cell function:
- 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.

3. Neuroprotective potential of alemtuzumab:
a. Relative and absolute change from baseline concentration in the CSF of following markers:
S100ß, Tau, phospho-Tau, ß-Amyloid, Neurofilament (low weight), Neurofilament (high weight), N-acetylaspartate (NAA), Tubulin, Actin, neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP)
b. 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
c. Relative and absolute change from baseline concentration in the peripheral blood and the CSF of following neurotrophic factors:
Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), ciliary neurotrophic factor (CNTF)
d. 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
e. Relative and absolute change from baseline in retinal nerve fiber layer thickness (assessment by optical coherence tomography).

Safety endpoints: Data on Adverse Events.

Secondary ID(s)

UKM12_0026

Source(s) of Monetary Support

Genzyme Corporation

Ethics review

Status: Approved
Approval date: 19/12/2014
Contact: