Trial document




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  DRKS00007777

Trial Description

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Title

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

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Trial Acronym

ALAIN01

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URL of the Trial

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Brief Summary in Lay Language

Alemtuzumab is the active agent of a drug called Lemtrada®. In the EU, 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®. This knowledge is expected to allow optimization of the treatment and of the monitoring for side effects. Thus the best possible relation of risk and benefit might be attained.

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. Beyond the examinations recommended for all patients treated with Lemtrada®, additional investigations are planned in this study to attain additional patient safety and for scientific reasons.

Substantial Amendment "Protocol Vers. 2.0, 15.07.2015" was approved by PEI and ethics committee (28.08.2015)

Substantial Amendment "Protocol Vers. 3.0, 13.04.2016" was approved by PEI (06.06.2016) and ethics committee (23.05.2016).

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Brief Summary in Scientific Language

Alemtuzumab is a humanized, monoclonal antibody to CD52. It has been approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS) patients by the European Medicine Agency.

Alemtuzumab leads to a rapid and complete depletion of CD52 expressing cells. Beyond changes in the immune cell repertoire, consecutive repopulation shows qualitative alterations of immune components which enable rebalancing of immune-tolerance networks. This, however, is associated with a considerable risk of secondary autoimmunity creating the need for thorough surveillance programs even several years after treatment.

The present study aims to elucidate the mechanisms of actions underlying the observed clinical effects and adverse events. The understanding of these mechanisms is expected to improve treatment monitoring and drug efficacy aiming at the best possible benefit-risk ratio for the individual patient.

Substantial Amendment "Protocol Vers. 2.0, 15.07.2015" was approved by PEI and ethics committee (28.08.2015).

Substantial Amendment "Protocol Vers. 3.0, 13.04.2016" was approved by PEI (06.06.2016) and ethics committee (23.05.2016).

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Organizational Data

  •   DRKS00007777
  •   2015/03/20
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  •   yes
  •   Approved
  •   2014-545-f-A, Ethik-Kommission der Ärztekammer Westfalen-Lippe und der med. Fakultät der Westfälischen Wilhelms-Universität Münster
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Secondary IDs

  •   U1111-1156-6489 
  •   2014-000709-10 
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Health Condition or Problem studied

  •   G35.10 -  [generalization G35: Multiple sclerosis]
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Interventions/Observational Groups

  •   Active Agent: Alemtuzumab.
    Proprietary name: Lemtrada®
    Dosage: 2 courses at a 1 year interval.
    Course 1: 12 mg as intravenous infusion on 5 consecutive days (total dose 60 mg).
    Course 2: 12 mg as intravenous infusion on 3 consecutive days (total dose 36 mg).
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Characteristics

  •   Interventional
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  •   Single arm study
  •   Open (masking not used)
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  •   Uncontrolled/Single arm
  •   Basic research/physiological study
  •   Single (group)
  •   IV
  •   No
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Primary Outcome

Absolute and relative change from basline 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.

Times of assessment:
12, 24 and 36 months after treatment initiation. If patients provided supplemental consent: additional assessments 6, 18 and 30 months after treatment initiation.

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Secondary Outcome

1. Absolute and relative change from baseline of cell-counts in the cerebrospinal fluid (CSF). The same cell-types as indicated for the primary endpoints are 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:
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)
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).

Times of assessments in blood, assessments by MRI and assessments by optical coherence tomography:
12, 24 and 36 months after treatment initiation. If patients provided supplemental consent: additional assessments 6, 18 and 30 months after treatment initiation.

Times of assessments in CSF:
12, 24 and 36 months after treatment initiation. Conduct of examinations only if patients provided supplemental consent.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Actual
  •   2015/06/11
  •   15
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   55   Years
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Additional 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)

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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, double-barrier contraception (condom and occlusive cap [diaphragm or cervical cap used with spermicide])
Beyond these criteria, patients will be considered screening failures, if treatment with alemtuzumab has not been started within 28 days after signing the informed consent form.

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Addresses

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    • Universitätsklinikum Münster, Dr. Christoph Hoppenheit
    • Albert-Schweitzer-Campus 1, Gebäude D 5
    • 48149  Münster
    • Germany
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    • Universitätsklinikum Münster, Klinik für Allgemeine Neurologie
    • Mr.  Univ.-Prof. Dr. med. Dr. rer. nat.  Sven  Meuth 
    • Albert-Schweitzer-Campus 1, Gebäude A1
    • 48149  Münster
    • Germany
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    • Universitätsklinikum Münster, Klinik für Allgemeine Neurologie
    • Mr.  Dr.  Tobias  Ruck 
    • Albert-Schweitzer-Campus 1
    • 48149  Münster
    • Germany
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Sources of Monetary or Material Support

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    • Genzyme Corporation
    • 500 Kendall Street
    • Cambridge, MA 02142
    • United States
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.