- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03193086
The Effect of Alemtuzumab on the Blood-brain-barrier and the Brain's Metabolism in Multiple Sclerosis Patients
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
Study Overview
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.
Study Type
Enrollment (Anticipated)
Contacts and Locations
Study Contact
- Name: Peter F Svane, MD
- Phone Number: 45 93906653
- Email: peter.frederiksen.svane@regionh.dk
Study Contact Backup
- Name: Stig P Cramer, MD, PhD
- Phone Number: 45 38634624
- Email: stig.praestekjaer.cramer@regionh.dk
Study Locations
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Copenhagen Capital Region
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Glostrup, Copenhagen Capital Region, Denmark, 2600
- Recruiting
- Functional Imaging Unit, Department of Clinical Physiology, Nuclear medicine and PET, Glostrup Hospital
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Contact:
- Stig P Cramer, MD, PhD
- Phone Number: 45 38634624
- Email: stig.praestekjaer.cramer@regionh.dk
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Contact:
- Peter F Svane, MD
- Phone Number: 45 93906653
- Email: peter.frederiksen.svane@hotmail.com
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Sampling Method
Study Population
Description
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)
Study Plan
How is the study designed?
Design Details
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
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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).
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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 Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Blood-Brain-Barrier Permeability
Time Frame: 1 year
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Blood-Brain-Barrier Permeability as measured by Dynamic-Contrast-Enhanced MRI (DCE-MRI)
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1 year
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Oxygen Consumption
Time Frame: 1 year
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The Cerebral Metabolic Rate of Oxygen Consumption as measured by a novel MRI technique
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1 year
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Cerebral perfusion
Time Frame: 1 year
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Quantification of cerebral perfusion using DCE-MRI and Arterial-Spin-Labelling MRI
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1 year
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Diffusion Tensor MRI parameters and MR spectroscopy metabolite concentrations
Time Frame: 1 year
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Measurement of changes in microstructural organization as measured by Diffusion Tensor MRI
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1 year
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Brain atrophy
Time Frame: 2 years
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Voxel-Based-Morphometry of grey and white matter utilizing high-resolution MRI
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2 years
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Clinical Severity of Disease
Time Frame: 1 year
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Estimation of disease severity by the Expanded Disability Severity Scale (EDSS)
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1 year
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Relapse frequency
Time Frame: 1 year
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Number of relapses during follow-up and past history
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1 year
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Plasma markers of Blood-Brain-Barrier breakdown
Time Frame: 1 year
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Detection of markers associated with Blood-Brain-Barrier breakdown nervous system
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1 year
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Plasma markers of neuronal damage
Time Frame: 1 year
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Detection of markers associated with neuronal damage
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1 year
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Urinary markers of inflammation
Time Frame: 1 year
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Detection of markers associated with inflammatory activity specific to macrophages/microglia in the human central nervous system
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1 year
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Collaborators and Investigators
Collaborators
Investigators
- Study Director: Henrik BW Larsson, MD, Prof., Functional Imaging Unit, Department of Clinical Physiology, Nuclear medicine and PET, Glostrup Hospital
Publications and helpful links
General Publications
- De Keyser J, Steen C, Mostert JP, Koch MW. Hypoperfusion of the cerebral white matter in multiple sclerosis: possible mechanisms and pathophysiological significance. J Cereb Blood Flow Metab. 2008 Oct;28(10):1645-51. doi: 10.1038/jcbfm.2008.72. Epub 2008 Jul 2.
- Law M, Saindane AM, Ge Y, Babb JS, Johnson G, Mannon LJ, Herbert J, Grossman RI. Microvascular abnormality in relapsing-remitting multiple sclerosis: perfusion MR imaging findings in normal-appearing white matter. Radiology. 2004 Jun;231(3):645-52. doi: 10.1148/radiol.2313030996.
- Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, Skoromets A, Stolyarov I, Bass A, Sullivan H, Margolin DH, Lake SL, Moran S, Palmer J, Smith MS, Compston DA. Alemtuzumab more effective than interferon beta-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology. 2012 Apr 3;78(14):1069-78. doi: 10.1212/WNL.0b013e31824e8ee7. Epub 2012 Mar 21.
- Cramer SP, Modvig S, Simonsen HJ, Frederiksen JL, Larsson HB. Permeability of the blood-brain barrier predicts conversion from optic neuritis to multiple sclerosis. Brain. 2015 Sep;138(Pt 9):2571-83. doi: 10.1093/brain/awv203. Epub 2015 Jul 17.
- Barkhof F. The clinico-radiological paradox in multiple sclerosis revisited. Curr Opin Neurol. 2002 Jun;15(3):239-45. doi: 10.1097/00019052-200206000-00003.
- Cramer SP, Larsson HB. Accurate determination of blood-brain barrier permeability using dynamic contrast-enhanced T1-weighted MRI: a simulation and in vivo study on healthy subjects and multiple sclerosis patients. J Cereb Blood Flow Metab. 2014 Oct;34(10):1655-65. doi: 10.1038/jcbfm.2014.126. Epub 2014 Jul 30.
- Broholm H, Andersen B, Wanscher B, Frederiksen JL, Rubin I, Pakkenberg B, Larsson HB, Lauritzen M. Nitric oxide synthase expression and enzymatic activity in multiple sclerosis. Acta Neurol Scand. 2004 Apr;109(4):261-9. doi: 10.1111/j.1600-0404.2004.00207.x.
- D'haeseleer M, Cambron M, Vanopdenbosch L, De Keyser J. Vascular aspects of multiple sclerosis. Lancet Neurol. 2011 Jul;10(7):657-66. doi: 10.1016/S1474-4422(11)70105-3.
- Gauthier SA, Berger AM, Liptak Z, Duan Y, Egorova S, Buckle GJ, Glanz BI, Khoury SJ, Bakshi R, Weiner HL, Guttmann CR. Rate of brain atrophy in benign vs early multiple sclerosis. Arch Neurol. 2009 Feb;66(2):234-7. doi: 10.1001/archneurol.2008.567.
- Ge Y, Zhang Z, Lu H, Tang L, Jaggi H, Herbert J, Babb JS, Rusinek H, Grossman RI. Characterizing brain oxygen metabolism in patients with multiple sclerosis with T2-relaxation-under-spin-tagging MRI. J Cereb Blood Flow Metab. 2012 Mar;32(3):403-12. doi: 10.1038/jcbfm.2011.191. Epub 2012 Jan 18.
- Larsson HB, Stubgaard M, Frederiksen JL, Jensen M, Henriksen O, Paulson OB. Quantitation of blood-brain barrier defect by magnetic resonance imaging and gadolinium-DTPA in patients with multiple sclerosis and brain tumors. Magn Reson Med. 1990 Oct;16(1):117-31. doi: 10.1002/mrm.1910160111.
- Larsson HB, Courivaud F, Rostrup E, Hansen AE. Measurement of brain perfusion, blood volume, and blood-brain barrier permeability, using dynamic contrast-enhanced T(1)-weighted MRI at 3 tesla. Magn Reson Med. 2009 Nov;62(5):1270-81. doi: 10.1002/mrm.22136.
- Naismith RT, Cross AH. Enhancing our understanding of white matter changes in early multiple sclerosis. Brain. 2015 Sep;138(Pt 9):2465-6. doi: 10.1093/brain/awv196. No abstract available.
- Scalfari A, Neuhaus A, Degenhardt A, Rice GP, Muraro PA, Daumer M, Ebers GC. The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability. Brain. 2010 Jul;133(Pt 7):1914-29. doi: 10.1093/brain/awq118. Epub 2010 Jun 9.
- Steen C, D'haeseleer M, Hoogduin JM, Fierens Y, Cambron M, Mostert JP, Heersema DJ, Koch MW, De Keyser J. Cerebral white matter blood flow and energy metabolism in multiple sclerosis. Mult Scler. 2013 Sep;19(10):1282-9. doi: 10.1177/1352458513477228. Epub 2013 Feb 21.
- Sun X, Tanaka M, Kondo S, Okamoto K, Hirai S. Clinical significance of reduced cerebral metabolism in multiple sclerosis: a combined PET and MRI study. Ann Nucl Med. 1998 Apr;12(2):89-94. doi: 10.1007/BF03164835.
- Tuohy O, Costelloe L, Hill-Cawthorne G, Bjornson I, Harding K, Robertson N, May K, Button T, Azzopardi L, Kousin-Ezewu O, Fahey MT, Jones J, Compston DA, Coles A. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. J Neurol Neurosurg Psychiatry. 2015 Feb;86(2):208-15. doi: 10.1136/jnnp-2014-307721. Epub 2014 May 21.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- GZ-2016-11629
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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