Ifenprodil as a ReMyelinating repurpOsed Drug in Multiple Sclerosis

NCT06330077 | Not Yet Recruiting Phase 2

• 2 other identifiers: APHP2000272021-003584-99
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 2

Brief Summary

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).

Conditions

Multiple Sclerosis; Remitting Relapsing Multiple Sclerosis

Keywords

Multiple Sclerosis; Ifenprofil; Combination of magnetic resonance imaging (MRI) and positron emission tomography (PET); 18f-Florbetaben; Remyelination

Outcome Measures

Primary Outcomes (1)

• 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.

  Between months 6 and months 12

Secondary Outcomes (9)

• Proportion of voxels within white matter lesions classified as remyelinating

  Between 6 months and 12 months

• Proportion of remyelinating voxels extracted in cortical regions from magnetization transfer imaging (MTR) acquisitions

  Between 6 months and 12 months

• Change in amplitude of P100 on to visual evoked potential

  Between 6 months and 12 months

• Change in retinal nerve fibre layer (RNFL) and ganglion cell complex (GCC) thickness on OCT

  Between 6 months and 12 months

• Change in blood concentration of NfL fragments

  From Pre-inclusion visit to 6 months and from 6 months to 9 months and 6 months to 12 months

Study Arms (2)

Ifenprodil

EXPERIMENTAL

Ifenprodil : 20mg three time a day (60mg/day). Patients will have an escalation of dose over 48 hours (from Day 1) in order to achieve at the end of the 144 hours (6 days, Day 6) a dose of 60mg/day.

Drug: Ifenprodil

Placebo

PLACEBO COMPARATOR

Placebo of ifenprodil : 20mg three time a day (60mg/day). Patients will have an escalation of dose over 48 hours (from Day 1) in order to achieve at the end of the 144 hours (6 days, Day 6) a dose of 60mg/day.

Drug: Placebo

Interventions

Ifenprodil DRUG

Treatment administration

Ifenprodil

Placebo DRUG

Treatment administration

Placebo

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Patients:
• Able to comply with the study protocol and to understand the purpose and risks of the study, in the investigator's judgment
• For women of childbearing potential : Efficient contraception include oral contraception, intrauterine devices hormonal device, intrauterine hormone-releasing system, sterilization method and other forms of contraception with failure rate \<1%)
• Healthy Volunteers
• \. Signed informed consent form 2. Age between 18 years and 55 years, inclusive 3. All female subjects of childbearing potential must practice effective contraception include oral contraception, intrauterine devices hormonal device, intrauterine hormone-releasing system, sterilization method and other forms of contraception with failure rate \<1%) 4. Able to comply with the study protocol, in the investigator's judgment 5. Social security registration (AME excluded)

You may not qualify if:

• Patients
• Contraindications to investigational medicinal products (ifenprodil/placebo) and to auxiliary medicinal products (gadolinium, \[18F\]-florbetaben)
• Inability to complete an MRI (contraindications for MRI include but are not restricted to weight ≥ 140 kg, pacemaker, cochlear implants, presence of foreign substances in the eye, intracranial vascular clips, surgery within 6 weeks of entry into the study, coronary stent implanted within 8 weeks prior to the time of the intended MRI, contraindication to gadoteric acid etc.).
• PET imaging performed in the past 12 months as part of clinical research
• History or incidental discovery of significant cardiac conduction block
• Orthostatic hypotension Syndrome define as a drop of \> 20 mmHg in systolic, and/or \> 10 mmHg in diastolic between lying down and immediate standing
• Any uncontrolled general (cancer, infectious, hematologic, hepatic, immunologic, endocrinologic, neurologic, dermatologic, psychiatric, allergic, renal, or cardiovascular) disease.
• Know Galactosemia, glucose malabsorption or lactase deficiency
• Thrombocytopenia with platelets \< 100 000/mm3
• Pregnancy and/or lactating women
• Legal protection (curatorship or tutorship)
• Deprive of freedom or under security measure
• Refusal to be informed in case of clinically significant incidental discovery after MRI
• Patient treated for hypertension with the following drugs blocking the alpha-adrenergic system either in periphery (prazosine, urapidil, moxisylyte, labetalol) or centrally (clonidine, monoxidine, methyldopa)
• Healthy Volunteers

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (2)

Hôpital Neurologique Pierre WERTHEIMER - HCL

Bron, 69677, France

Location

Groupe Hospitalier Pitié Salpêtrière - APHP

Paris, 75013, France

Location

MeSH Terms

Conditions

Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting

Interventions

ifenprodil

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Central Study Contacts

Bruno STANKOFF, MD

CONTACT

0171970659; bruno.stankoff@aphp.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 12, 2024
• First Posted: March 26, 2024
• Study Start: March 1, 2024
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): June 1, 2027
• Last Updated: March 26, 2024

Record last verified: 2023-09

Locations

FR (2)