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
|Condition or disease||Intervention/treatment|
|Multiple Sclerosis||Drug: Alemtuzumab|
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 :||Observational|
|Estimated Enrollment :||35 participants|
|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|
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 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
- Blood-Brain-Barrier Permeability [ Time Frame: 1 year ]Blood-Brain-Barrier Permeability as measured by Dynamic-Contrast-Enhanced MRI (DCE-MRI)
- Oxygen Consumption [ Time Frame: 1 year ]The Cerebral Metabolic Rate of Oxygen Consumption as measured by a novel MRI technique
- Cerebral perfusion [ Time Frame: 1 year ]Quantification of cerebral perfusion using DCE-MRI and Arterial-Spin-Labelling MRI
- 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
- Brain atrophy [ Time Frame: 2 years ]Voxel-Based-Morphometry of grey and white matter utilizing high-resolution MRI
- Clinical Severity of Disease [ Time Frame: 1 year ]Estimation of disease severity by the Expanded Disability Severity Scale (EDSS)
- Relapse frequency [ Time Frame: 1 year ]Number of relapses during follow-up and past history
- Plasma markers of Blood-Brain-Barrier breakdown [ Time Frame: 1 year ]Detection of markers associated with Blood-Brain-Barrier breakdown nervous system
- Plasma markers of neuronal damage [ Time Frame: 1 year ]Detection of markers associated with neuronal damage
- 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
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03193086
|Contact: Peter F Svane, MD||93906653 ext firstname.lastname@example.org|
|Contact: Stig P Cramer, MD, PhD||38634624 ext email@example.com|
|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 firstname.lastname@example.org|
|Contact: Stig P Cramer, MD, PhD 38634624 ext 45 email@example.com|
|Study Director:||Henrik BW Larsson, MD, Prof.||Functional Imaging Unit, Department of Clinical Physiology, Nuclear medicine and PET, Glostrup Hospital|