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

Multiple Sclerosis Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03193086
• Other study ID #: GZ-2016-11629
• Status: Recruiting
• Phase: N/A
• First received: June 14, 2017
• Last updated: June 16, 2017
• Start date: January 1, 2017
• Est. completion date: March 31, 2020

Study information

• Verified date: June 2017
• Source: Glostrup University Hospital, Copenhagen
• Contact: Peter F Svane, MD
• Phone: 93906653
• Email: peter.frederiksen.svane[@]regionh.dk
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 35
• Est. completion date: March 31, 2020
• Est. primary completion date: March 31, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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)

Related Conditions & MeSH terms

• Multiple Sclerosis
• Sclerosis

Intervention

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.

Locations

Country	Name	City	State
Denmark	Functional Imaging Unit, Department of Clinical Physiology, Nuclear medicine and PET, Glostrup Hospital	Glostrup	Copenhagen Capital Region

Sponsors (2)

Lead Sponsor	Collaborator
Glostrup University Hospital, Copenhagen	Genzyme, a Sanofi Company

Country where clinical trial is conducted

Denmark, 

References & Publications (17)

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* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Blood-Brain-Barrier Permeability	Blood-Brain-Barrier Permeability as measured by Dynamic-Contrast-Enhanced MRI (DCE-MRI)	1 year
Secondary	Oxygen Consumption	The Cerebral Metabolic Rate of Oxygen Consumption as measured by a novel MRI technique	1 year
Secondary	Cerebral perfusion	Quantification of cerebral perfusion using DCE-MRI and Arterial-Spin-Labelling MRI	1 year
Secondary	Diffusion Tensor MRI parameters and MR spectroscopy metabolite concentrations	Measurement of changes in microstructural organization as measured by Diffusion Tensor MRI	1 year
Secondary	Brain atrophy	Voxel-Based-Morphometry of grey and white matter utilizing high-resolution MRI	2 years
Secondary	Clinical Severity of Disease	Estimation of disease severity by the Expanded Disability Severity Scale (EDSS)	1 year
Secondary	Relapse frequency	Number of relapses during follow-up and past history	1 year
Secondary	Plasma markers of Blood-Brain-Barrier breakdown	Detection of markers associated with Blood-Brain-Barrier breakdown nervous system	1 year
Secondary	Plasma markers of neuronal damage	Detection of markers associated with neuronal damage	1 year
Secondary	Urinary markers of inflammation	Detection of markers associated with inflammatory activity specific to macrophages/microglia in the human central nervous system	1 year