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

NCT02419378 | Completed Phase 4

• 2 other identifiers: UKM12_0026U1111-1156-6489
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

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.

Conditions

Multiple Sclerosis, Relapsing-Remitting

Outcome Measures

Primary Outcomes (47)

• 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.

• 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.

• 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 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 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 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 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 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 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 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.

• 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.

• 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 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 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 Outcomes (67)

• 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

Other Outcomes (19)

• Number of patients who experienced sustained accumulation of disability (SAD) during the study period

  Date of last patient out anticipated about 4 years after study initiation

• Time to SAD

  At the end of each patient's study participation, i.e. 36 months after treatment initiation

• Time to sustained reduction in disability (SRD) based on EDSS scores

  At the end of each patient's study participation, i.e. 36 months after treatment initiation

Study Arms (1)

alemtuzumab

EXPERIMENTAL

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.

Drug: Alemtuzumab

Interventions

Alemtuzumab DRUG

alemtuzumab

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Signed informed consent form (ICF)
• Age 18 to 55 years old (inclusive) as of the date the ICF is signed
• 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
• Onset of MS symptoms (as determined by a neurologist, either at present or retrospectively) within 10 years of the date the ICF is signed
• EDSS score 0.0 to 5.0 (inclusive) at Screening
• 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.
• Completion of all vaccinations required by the applicable immunization guidelines published by "ständige Impfkommission" (STIKO)
• History of chickenpox or positive test for antibodies against varicella zoster virus (VZV)

You may not qualify if:

• Participation in another clinical trial at present or within 4 weeks of study entry. There may be exceptions at the discretion of the Investigator.
• Has any progressive form of MS
• Hypersensitivity to the active substance, or to any of the excipients of Lemtrada®
• 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
• Any disability acquired from trauma or another illness that could interfere with 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
• Known bleeding disorder (e.g,. dysfibrinogenemia, factor IX deficiency, hemophilia, Von Willebrand's disease, disseminated intravascular coagulation (DIC), fibrinogen deficiency, or clotting factor deficiency)
• 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
• History of malignancy, except basal skin cell carcinoma
• Major psychiatric disorder that is not adequately controlled by treatment
• Epileptic seizures that are not adequately controlled by Treatment
• Active infection, e.g., deep-tissue infection, that the Investigator considers sufficiently serious to preclude study participation
• 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)
• Seropositivity for human immunodeficiency virus (HIV)
• Infection with hepatitis C Virus

Sponsors & Collaborators

• University Hospital Muenster: lead
• Genzyme, a Sanofi Company: collaborator

Study Sites (1)

Universitätsklinikum Münster, Klinik für Allgemeine Neurologie

Münster, 48149, Germany

Location

Related Publications (1)

• Ruck T, Afzali AM, Lukat KF, Eveslage M, Gross CC, Pfeuffer S, Bittner S, Klotz L, Melzer N, Wiendl H, Meuth SG. ALAIN01--Alemtuzumab in autoimmune inflammatory neurodegeneration: mechanisms of action and neuroprotective potential. BMC Neurol. 2016 Mar 10;16:34. doi: 10.1186/s12883-016-0556-9.

  PMID: 26966029 DERIVED

MeSH Terms

Conditions

Multiple Sclerosis, Relapsing-Remitting

Interventions

Alemtuzumab

Condition Hierarchy (Ancestors)

Multiple Sclerosis; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Sven Meuth, Prof. Dr. Dr.

  University Hospital Muenster

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 31, 2015
• First Posted: April 17, 2015
• Study Start: June 1, 2015
• Primary Completion: July 1, 2020
• Study Completion: November 1, 2020
• Last Updated: October 26, 2021

Record last verified: 2021-10

Locations

DE (1)