Clinical trial NCT01567553: The Inflammatory Process and the Medical Imaging in Patients With an Inflammatory Disease of the Central Nervous System.
Official title: Early Neuroinflammatory Changes as a Prognostic Marker in Clinically Isolated Syndromes Patients.
Study type: OBSERVATIONAL
Overall status: TERMINATED
Conditions: Multiple Sclerosis (MS)
Inflammatory Disease
Keywords: inflammatory disease of the central nervous system
early clinical deficit
multiple sclerosis (MS)
Lead sponsor: Rennes University Hospital
Sponsor class: OTHER
Collaborators: name: Bayer
First posted: 2012-03-30
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: CIS at presentation (clinically isolated syndromes) will be recruited with MRI evidence of at least two asymptomatic brain MRI lesions. The group will compromise 50 CIS patients. These CIS patients will be included within three months after first clinical presentation.

Brief summary: While significant progress has been made on medical imagery in recent years in the individualization of different lesions in the nervous system for demyelination, axonal loss, atrophy, little progress has been made in the specific recognition the inflammatory process. Yet this point is essential since the currently available treatments have a partial impact mainly on the inflammatory component and that many uncertainties remain about the links between inflammation and tissue destruction affecting myelin and axons. The recent discovery of a macrophage cell marker in the CNS, more specific (USPIO) of inflammation gives us the opportunity to answer important questions which one can sense that this could have a significant impact on therapeutic drug monitoring of these patients. This study will involve 50 patients recruited in five French centers (Marseille, Paris, Reims, Rennes, Toulouse) from the earliest manifestations of the disease with clinical and MRI scheduled for the first 3 years of their disease.

Detailed description: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system affecting 60.000 persons in France and characterized by widespread inflammation, focal demyelination, and a variable degree of axonal loss. In recent years the concept of MS as an inflammatory neurodegenerative disease has been corroborated by neuropathologic and in vivo MR imaging studies. A number of MR studies show that the principal pathological substrate of permanent disability is axonal loss as detected in MR studies as global atrophy, but also regionally in the white or grey matter, and that atrophy already occurs at early stages of the disease. Though MR imaging is a powerful tool for MS in terms of diagnosis, description of the natural history of the disease and treatment monitoring, the major drawback of MRI in MS is the lack of specificity of the MR findings. Furthermore, with the advent of disease modifying drugs, there is a need for robust and specific MR markers to identify e.g. clinically isolated syndrome (CIS) patients at presentation at high risk to develop MS or a more severe disease course. An increasing body of MRI evidence corroborates that CIS show early and dynamic changes detected by MR imaging, such as global or regional brain atrophy, as a sign of progressive axonal loss, but atrophy is already a late stage sign of the disease, when tissue is lost. Considerable efforts are spent today to identify early and prognostic MR markers for high risk CIS patients.

In the current project we endeavour to study CIS patients with inflammatory disease of the central nervous system or early clinical deficit by using cell labelling MR imaging with ultra small superparamagnetic iron oxide particles (USPIO), which specifically label blood-borne macrophages, a key cell population in MS. We hypothesise that number/volume of USPIO (SH U 555 C) enhancement during the first year is a predictive marker for high risk CIS patients at presentation. This hypothesis is in line with recent findings in the animal model of MS, EAE. Secondary measures of this study will include comparison of the USPIO (SH U 555 C) findings with other highly sensitive, but non-specific MR parameters.

Eligibility criteria: Inclusion Criteria:

* Age between 18 and 45 years
* Patients with a first episode suggestive of MS (monofocal or multifocal)
* Presence of a first neurologic event suggestive of MS that lasted for at least 24 hours
* Patients with a spatial dissemination criteria according to the Mc Donald diagnostic criteria
* With an Expanded Disability Status Scale (EDSS) score at baseline between 0 and 5
* USPIO (SH U 555 C) injection has to be performed within 3 months after start of clinical event
* Patients have to be in-patients for a minimum of 24 hours after the first USPIO (SH U 555 C) injection
* Patients with positive or negative USPIO-MRI during screening are included
* Patients must be compliant with study protocol
* Patients must have given their written consent to participate in this study

Exclusion Criteria:

* Any CIS patients having received steroid treatment before acquisition of the baseline USPIO MR scan
* Patients in whom any disease other than MS could explain their signs and symptoms,
* Patients with complete transverse myelitis or bilateral optic neuritis will be excluded,
* Patients who had received prior immunosuppressive or immunomodulatory treatment will be excluded.
* Patients who had received corticoids 30 days before USPIO-RMI
* Patients which cannot be in-patients for a minimum of 24 hours after the first USPIO (SH U 555 C) injection
* Female patients without efficient contraception (oral or others) Pregnant or lactating patients
* Patients with a known allergy to iron particles and/or dextrans
* Patients having received in the past 5 months iron oxide particles preceding the MRI examination
* Patients with a past history of bronchial asthma or any other allergic disorder
* Patients with a past history for a lower threshold of seizures
* Any patient presenting with a known contra-indication for MR scanning
* Non-compliant or uncooperative patients with regard to study protocol
* Patients not having given their written consent to participate in this study
* Any patient with an accompanying systemic disease, renal disease, cardiac disease or mental disorder

Primary outcomes:
measure: ▪ Change in USPIO enhancing MS lesion
timeFrame: Change from baseline in USPIO enhancing MS lesion at 12 months after the first event of the disease
Secondary outcomes:
measure: Comparison of primary outcome measures with clinical outcomes and role of USPIO
timeFrame: at 12 months after the first event of the disease
measure: Relationship of USPIO (SH U 555 C) enhancing MRI lesions with other MR parameters
timeFrame: at 12 months after the first event of the disease
measure: Change in USPIO and/or Gadolinium enhancing MS lesions (primary outcome measure)
timeFrame: Change from baseline in USPIO and/or Gadolinium enhancing MS lesions at 3 years after the first event of the disease
Other outcomes:
Locations:
city: Marseille
country: France
facility: La Timone University Hospital (APHM)
city: Paris
country: France
facility: La Pitie-Salpaetriere Hospital (APHP)
city: Reims
country: France
facility: Maison Blanche Hospital
city: Rennes
country: France
facility: Rennes University Hospital
city: Toulouse
country: France
facility: Purpan Hospital
Study officials:
affiliation: Rennes University Hospital
name: EDAN Gilles
role: PRINCIPAL_INVESTIGATOR
References:
citation: Crimi A, Commowick O, Maarouf A, Ferre JC, Bannier E, Tourbah A, Berry I, Ranjeva JP, Edan G, Barillot C. Predictive value of imaging markers at multiple sclerosis disease onset based on gadolinium- and USPIO-enhanced MRI and machine learning. PLoS One. 2014 Apr 1;9(4):e93024. doi: 10.1371/journal.pone.0093024. eCollection 2014.