Multiple sclerosis (MS) is the most frequently acquired demyelinating disease and the first cause of non-traumatic chronic disability in young adults. Major progress has been achieved in the treatment of MS through the development of therapies targeting the adaptative immune system, which drastically reduce the relapse rate, with various efficiency and safety profiles (Ontaneda, 2015). However, these drugs generally fail to prevent disability worsening along the disease course, and we are now assisting to a shift in therapeutic objectives from the development of new immune drugs towards the identification of therapeutic strategies that could prevent neurodegeneration by promoting myelin regeneration (Stangel, 2017; Stankoff, 2016), in order to prevent neurological disability in MS (Irvine and Blakemore, 2008; Patrikios, 2006; Duncan I, 2017, Bodini, 2016). Among the first candidate compounds developed to promote remyelination was the anti Lingo1 antibody, which enhance remyelination (Mi, 2009). Medium and large throughput screening of drug libraries subsequently identified several chemical classes of compounds with strong promyelinating properties, such as the antifongic drug miconazole (Najm, 2015) or the muscarinic antagonist clemastine (Wei, 2014). A recent innovative trial has investigated the effect of clemastine, compared to placebo, in a small sample of subjects (25 patients per group) and showed that clemastine could significantly improve the optic nerve conduction speed which reflecting myelin integrity and functionality (Green, 2017). Our preclinical research has allowed us to identify ifenprodil as a powerful drug to promote myelin repair in vitro and in vivo across species. In parallel our team recently pioneered and optimized a PET imaging approach for quantifying remyelination in the whole brain, that allowed to enhance the sensitivity to detect the myelin repair process, and showed that patients are characterized by heterogeneous profiles of spontaneous remyelination profiles that are closely linked to disability accrual (Bodini, 2016).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
60
Treatment administration
Treatment administration
Hôpital Neurologique Pierre WERTHEIMER - HCL
Bron, France
Groupe Hospitalier Pitié Salpêtrière - APHP
Paris, France
Change in P100 latency according to visual evoked potential.
Assess the efficacy of ifenprodil on the remyelination of the optic nerve measured as the improvement of P100 latency, assessed using full field visual evoked potentials.
Time frame: Between months 6 and months 12
Proportion of voxels within white matter lesions classified as remyelinating
Change in remyelination potential measured by PET-MR Between M6 (end of run-in, calculation of pre-treatment remyelination potential, randomization) and M12 (end of follow-up, calculation of post-treatment remyelination potential) in each group.
Time frame: Between 6 months and 12 months
Proportion of remyelinating voxels extracted in cortical regions from magnetization transfer imaging (MTR) acquisitions
Change in the proportion of remyelinating voxels extracted in cortical regions from MTR acquisitions (as cortical myelin in not assessed by PET) between M6 and M12 in each group
Time frame: Between 6 months and 12 months
Change in amplitude of P100 on to visual evoked potential
o determine whether the treatment by ifenprodil could influence axonal damage in the visual pathway assessed by the amplitude of P100
Time frame: Between 6 months and 12 months
Change in retinal nerve fibre layer (RNFL) and ganglion cell complex (GCC) thickness on OCT
To determine whether the treatment by ifenprodil could influence neurodegeneration measured by optical coherence tomography (OCT) parameters in each group
Time frame: Between 6 months and 12 months
Change in blood concentration of NfL fragments
To determine whether the treatment by ifenprodil could influence axonal damage assessed by the blood concentration of neurofilament light chain (NfL) in each group
Time frame: From Pre-inclusion visit to 6 months and from 6 months to 9 months and 6 months to 12 months
Change in the brain atrophy rate
To determine whether the treatment by ifenprodil could influence white matter lesions load or brain atrophy rate in each group
Time frame: From baseline to 6 months and 6 months to 12 months
The correlation between the change in the proportion of remyelinating voxels extracted in white matter lesions from [18F]florbetaben PET acquisitions
To determine whether the efficacy of ifenprodil is influenced by endogenous remyelination profiles assessed in the run-in period, and to describe the profile of optimal responders
Time frame: Between 6 months and 12 months and the pre-treatment individual remyelination profiles as determined during the Run-in period
The comparison of the proportion of remyelinating voxels extracted in white matter lesions from [18F]florbetaben PET acquisitions
To assess whether the disease modifying therapies received during the study influence the remyelination level and/or the ifenprodil effect on remyelination
Time frame: Between 6 months and 12 months
Incidence of adverse drug reactions
Time frame: Between inclusion and 12 months
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