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

NCT ID: NCT03193086

Last Updated: 2017-06-20

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 35 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2017-01-01
• Study Completion Date: 2020-03-31

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.

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.

Conditions

Multiple Sclerosis

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

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).

Alemtuzumab

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Other Intervention Names

Lemtrada

Eligibility 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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Genzyme, a Sanofi Company

INDUSTRY

Sponsor Role: collaborator

Glostrup University Hospital, Copenhagen

OTHER

Sponsor Role: lead

Responsible Party

Peter FredSvan

Medical Doctor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Henrik BW Larsson, MD, Prof.

Role: STUDY_DIRECTOR

Functional Imaging Unit, Department of Clinical Physiology, Nuclear medicine and PET, Glostrup Hospital

Locations

Functional Imaging Unit, Department of Clinical Physiology, Nuclear medicine and PET, Glostrup Hospital

Glostrup Municipality, Copenhagen Capital Region, Denmark

Site Status: RECRUITING

Countries

Denmark

Central Contacts

Peter F Svane, MD

Role: CONTACT

peter.frederiksen.svane@regionh.dk

93906653 ext. 45

Stig P Cramer, MD, PhD

Role: CONTACT

stig.praestekjaer.cramer@regionh.dk

38634624 ext. 45

Facility Contacts

Peter F Svane, MD

Role: primary

peter.frederiksen.svane@hotmail.com

93906653 ext. 45

Stig P Cramer, MD, PhD

Role: backup

stig.praestekjaer.cramer@regionh.dk

38634624 ext. 45

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Other Identifiers

GZ-2016-11629

Identifier Type: -

Identifier Source: org_study_id