A Phase 2 Trial Assessing Ifenprodil as a ReMyelinating repurpOsed Drug in Multiple Sclerosis
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 60
- 试验地点
- 2
- 主要终点
- Change in P100 latency according to visual evoked potential.
研究概览
简要总结
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Signed informed consent form at pre-inclusion visit
- •Age between 18 years and 55 years, inclusive, at time of pre-inclusion visit.
- •Patient with a RR form of MS according McDonald criteria 2017 at pre-inclusion visit
- •Able to comply with the study protocol and to understand the purpose and risks of the study, in the investigator's judgment
- •Social security registration (AME excluded) at time of pre-inclusion visit
- •At least one eye with a P100 latency > 118ms on visual evoked potential at baseline (defining the qualifying eye) at time of pre-inclusion visit
- •Retinal nerve fibre layer thickness on spectral-domain optical coherence tomography [OCT] > 70 μm in the VEP qualifying eye (to increase the likelihood that the number of surviving axons is sufficient to provide the substrate for remyelination to occur) at time of pre-inclusion visit
- •Patient under disease modifying therapy (first or second line approved immune active therapy) or patient without any DMT at time of pre-inclusion visit
- •EDSS score ≤ 6 at time of pre-inclusion visit
- •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
- •Age between 18 years and 55 years, inclusive
- •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%)
- •Able to comply with the study protocol, in the investigator's judgment
- •Social security registration (AME excluded)
排除标准
- •Patient with an acute NORB in the last 6 months prior to pre-inclusion visit
- •Patient with a clinical relapse other than NORB in the last 6 months prior to pre-inclusion visit
- •Patients having received methylprednisolone infusion in the last 4 weeks prior to pre-inclusion visit
- •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
- •Known long QT syndrome or long QT syndrome (the limit is defined at 450 ms on corrected QT) highlighted during the pre-inclusion visit
- •Any uncontrolled general (cancer, infectious, hematologic, hepatic, immunologic, endocrinologic, neurologic, dermatologic, psychiatric, allergic, renal, or cardiovascular) disease.
- •Creatinine clearance < 60 ml/min at pre-inclusion visit
- •ASAT, ALAT of alkaline phosphatase > 3-fold the upper limit normal at pre-inclusion visit
- •Know Galactosemia, glucose malabsorption or lactase deficiency
- •Known of lack of peripheral venous access or lack of peripheral venous access highlighted during the pre-inclusion visit
- •Thrombocytopenia with platelets < 100 000/mm3
- •Pregnancy and/or lactating women
- •Legal protection (curatorship or tutorship)
- •Deprive of freedom or under security measure
- •Participation in another interventional trial evaluating a health product or any randomized trial or being in the exclusion period at the end of a previous study
- •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
- •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, etc).
- •Impossibility to complete a PET scan: pregnancy, nuclear medicine irradiation for clinical research in the year preceding baseline visit.
- •Contraindication to auxiliary medicinal products ([18F]-florbetaben)
- •Known presence of any neurological disorders
- •Pregnancy and/or lactation
- •Lack of peripheral venous access
- •Terminal renal insufficiency (Creatinin clearance < 60 ml/min)
- •Legal protection (curatorship or tutorship)
- •Deprive of freedom or under security measure
- •Participation in another interventional trial evaluating a health product or any randomized trial or being in the exclusion period at the end of a previous study
- •Refusal to be informed in case of clinically significant incidental discovery after MRI
研究组 & 干预措施
Ifenprodil
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.
干预措施: Ifenprodil (Drug)
Placebo
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.
干预措施: Placebo (Drug)
结局指标
主要结局
Change in P100 latency according to visual evoked potential.
时间窗: Between months 6 and months 12
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.
次要结局
- 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 retinal nerve fibre layer (RNFL) and ganglion cell complex (GCC) thickness on OCT(Between 6 months and 12 months)
- The comparison of the proportion of remyelinating voxels extracted in white matter lesions from [18F]florbetaben PET 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 the brain atrophy rate(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(Between 6 months and 12 months and the pre-treatment individual remyelination profiles as determined during the Run-in period)
- 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)
- Incidence of adverse drug reactions(Between inclusion and 12 months)