Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

The Effect of Alemtuzumab on the Blood-brain-barrier and the Brain's Metabolism in Multiple Sclerosis Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03193086
Recruitment Status : Recruiting
First Posted : June 20, 2017
Last Update Posted : June 20, 2017
Sponsor:
Collaborator:
Genzyme, a Sanofi Company
Information provided by (Responsible Party):
Peter FredSvan, Glostrup University Hospital, Copenhagen

Brief Summary:
The development and progression of multiple sclerosis seem to be driven by concomitant inflammation and, to a less well-defined degree, disturbances in metabolism of individual cells of the human central nervous system as well as changes in the dynamical supply of blood to the brain. These alterations in normal physiology can be quantified by investigating the change in specific parameters over the time course of multiple sclerosis evolution. Amongst these specific parameters, the ability of the so-called blood-brain-barrier to selectively filter nutrients from the blood stream prior to passage into the nervous tissue, is disrupted in multiple sclerosis, and the severity of this deficiency seem to be related to the underlying disease burden. The present study utilises a novel imaging technology in order to monitor changes in the integrity of the blood-brain-barrier over the course of treatment with a biological disease modifying agent known as alemtuzumab. Alemtuzumab is a potent immunosuppressant drug. It is hypothesised that alemtuzumab reverts the deficiency in blood-brain-barrier integrity and, conversely, the severity of blood-brain-barrier disruption at several time points during alemtuzumab treatment can be utilised as prognostic marker for the requirement of additional administration of alemtuzumab beyond the regular treatment regimen. In addition, several other factors are investigated by advanced imaging techniques in combination with blood and urine samples in order to elucidate the possible underlying mechanism of alemtuzumab efficacy. It is hypothesized that alemtuzumab normalises metabolic alterations and changes in the blood supply through resolution of inflammation in the brains of multiple sclerosis patients.

Condition or disease Intervention/treatment
Multiple Sclerosis Drug: Alemtuzumab

Detailed Description:

Traditional paraclinical measures of disease severity in multiple sclerosis (MS), such as T2 lesion load as measured by magnetic resonance imaging (MRI), are poorly correlated with long-term disability accumulation. Other surrogate markers of the current and future disease burden are therefore needed. The permeability of the blood-brain-barrier (BBB) seems to better reflect the substantial, subclinical disease activity underlying MS progression. Its useful role as a prognostic marker in MS has been clearly established by the recent observation that BBB permeability increase in optic neuritis patients is associated with conversion to definite MS. BBB permeability can be quantified, in a convenient manner to the patient, using Dynamic-Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) by modelling the change in intrinsic MRI parameters of the human brain in response to the administration of a bolus contrast agent. Alemtuzumab is a disease modifying drug that depletes T- and B-cells. It is administered in two series separated by 12 months, as explained in the section "Groups and Interventions." The number of relapses are significantly reduced as compared to other efficacious treatments in MS, as demonstrated recently (study referred to by its ClinicalTrials.gov identifier NCT00050778). The efficacy of alemtuzumab in resolving the inflammatory burden underlying relapses is, thus, well-established. Its influence on subclinical inflammation, however, remains unknown. It is the aim of the present study to investigate whether or not the latter influence is of importance, and, consequently, can be used to evaluate the need for an intensified treatment, in the form of an additional series of alemtuzumab administration.

BBB permeability changes, as surrogate markers of subclinical inflammation, are measured every 6 months just prior to and during the course of alemtuzumab treatment. In order to elucidate other potential mechanisms involved in disability accumulation, biomarkers and MRI-derived parameters are evaluated concomitantly. Specifically, the role of metabolic changes are investigated using MRI methods that measures blood perfusion and oxygen consumption. Secondarily, the BBB permeability and metabolic changes are correlated to novel biomarkers of inflammation and neurodegeneration in serum and urine, as well as conventional measures of MS severity: annual relapse rate, Expanded Disability Severity Score, MRI-derived estimates of disease activity and brain atrophy.

35 patients are included in the study in order to achieve enough statistical power and accommodate drop-outs. Patients are MRI scanned at baseline, 6 months after alemtuzumab treatment, and, finally, prior to administration of the second series of alemtuzumab 12 months after the baseline MRI scanning. At each time point, the patient's disease status is evaluated by an experienced neurologist, and urine and serum samples are obtained. Repeated Measures Analysis Of Variance (ANOVA) will be used to evaluate changes of permeability of the BBB and metabolic parameters at different time points, and baseline characteristics, such as prednisolone treatment will be implemented as between-subjects covariates. Logistic regression will be applied to estimate the ability of BBB permeability changes to predict the need for additional series of alemtuzumab administration.


Layout table for study information
Study Type : Observational
Estimated Enrollment : 35 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: The Effect of Alemtuzumab on the Blood-brain-barrier and Cerebral Metabolism in Multiple Sclerosis Patients; a New MRI Method for Treatment Response Evaluation in Multiple Sclerosis
Actual Study Start Date : January 1, 2017
Estimated Primary Completion Date : March 31, 2020
Estimated Study Completion Date : March 31, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Alemtuzumab

Group/Cohort Intervention/treatment
Alemtuzumab treated MS patients
Those with Multiple Sclerosis that have commenced therapy with alemtuzumab (60 mg infusion over the course of 5 days) and completed treatment with alemtuzumab (additional 36 mg infusion during the course of 3 days, 12 months later).
Drug: Alemtuzumab
Alemtuzumab is administered to eligible patients in accordance with established treatment regimes. Initially 60 mg of alemtuzumab is injected intravenously over the course of 5 days. The first treatment series is followed by the injection of 36 mg of alemtuzumab over the course of 3 days 12 months later. During both drug interventions, the transient exacerbation in disease severity is alleviated by concomitant steroid therapy.
Other Name: Lemtrada




Primary Outcome Measures :
  1. Blood-Brain-Barrier Permeability [ Time Frame: 1 year ]
    Blood-Brain-Barrier Permeability as measured by Dynamic-Contrast-Enhanced MRI (DCE-MRI)


Secondary Outcome Measures :
  1. Oxygen Consumption [ Time Frame: 1 year ]
    The Cerebral Metabolic Rate of Oxygen Consumption as measured by a novel MRI technique

  2. Cerebral perfusion [ Time Frame: 1 year ]
    Quantification of cerebral perfusion using DCE-MRI and Arterial-Spin-Labelling MRI

  3. Diffusion Tensor MRI parameters and MR spectroscopy metabolite concentrations [ Time Frame: 1 year ]
    Measurement of changes in microstructural organization as measured by Diffusion Tensor MRI

  4. Brain atrophy [ Time Frame: 2 years ]
    Voxel-Based-Morphometry of grey and white matter utilizing high-resolution MRI

  5. Clinical Severity of Disease [ Time Frame: 1 year ]
    Estimation of disease severity by the Expanded Disability Severity Scale (EDSS)

  6. Relapse frequency [ Time Frame: 1 year ]
    Number of relapses during follow-up and past history

  7. Plasma markers of Blood-Brain-Barrier breakdown [ Time Frame: 1 year ]
    Detection of markers associated with Blood-Brain-Barrier breakdown nervous system

  8. Plasma markers of neuronal damage [ Time Frame: 1 year ]
    Detection of markers associated with neuronal damage

  9. Urinary markers of inflammation [ Time Frame: 1 year ]
    Detection of markers associated with inflammatory activity specific to macrophages/microglia in the human central nervous system


Biospecimen Retention:   Samples Without DNA
plasma, urine


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients are recruited from the two dedicated MS clinics in the secondary health care sector of the danish capital region.
Criteria

Inclusion Criteria:

  • A diagnosis of Relapsing-Remitting Multiple Sclerosis
  • Eligible for alemtuzumab treatment at Glostrup Hospital or The Danish Kingdom Hospital
  • Subjects must be deemed physically and mentally able to participate in the study

Exclusion Criteria:

  • Contraindications to MRI scanning (pregnancy, pacemakers, claustrophobia, extreme obesity)
  • Contraindications to the use of MRI contrast agents (kidney disease, previous allergic reactions)
  • Conflicting disorders (e.g. disorders with a systemic, inflammatory component)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03193086


Contacts
Layout table for location contacts
Contact: Peter F Svane, MD 93906653 ext 45 peter.frederiksen.svane@regionh.dk
Contact: Stig P Cramer, MD, PhD 38634624 ext 45 stig.praestekjaer.cramer@regionh.dk

Locations
Layout table for location information
Denmark
Functional Imaging Unit, Department of Clinical Physiology, Nuclear medicine and PET, Glostrup Hospital Recruiting
Glostrup, Copenhagen Capital Region, Denmark, 2600
Contact: Peter F Svane, MD    93906653 ext 45    peter.frederiksen.svane@hotmail.com   
Contact: Stig P Cramer, MD, PhD    38634624 ext 45    stig.praestekjaer.cramer@regionh.dk   
Sponsors and Collaborators
Glostrup University Hospital, Copenhagen
Genzyme, a Sanofi Company
Investigators
Layout table for investigator information
Study Director: Henrik BW Larsson, MD, Prof. Functional Imaging Unit, Department of Clinical Physiology, Nuclear medicine and PET, Glostrup Hospital

Publications:

Layout table for additonal information
Responsible Party: Peter FredSvan, Medical Doctor, Glostrup University Hospital, Copenhagen
ClinicalTrials.gov Identifier: NCT03193086     History of Changes
Other Study ID Numbers: GZ-2016-11629
First Posted: June 20, 2017    Key Record Dates
Last Update Posted: June 20, 2017
Last Verified: June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Peter FredSvan, Glostrup University Hospital, Copenhagen:
Multiple Sclerosis
Blood-Brain-Barrier
Treatment response
Metabolism
Alemtuzumab
Perfusion
Oxygen consumption

Additional relevant MeSH terms:
Layout table for MeSH terms
Multiple Sclerosis
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Alemtuzumab
Antineoplastic Agents, Immunological
Antineoplastic Agents